US 20190247050A1

( 19) United States

(12 )Goldsmith
Patent Application Publication ( 10) Pub . No.: US 2019 /0247050 A1
(43) Pub. Date : Aug. 15 , 2019
(54 ) INTEGRATED SYSTEM FOR THE INFIXION A61B 2017 /00876 (2013 .01); A61B 18 /18
AND RETRIEVAL OF IMPLANTS (2013.01); A61B 2017/00411 (2013.01 ); A61B
2017/ 0065 (2013. 01 ); A61B 2017/1205
(71 ) Applicant: David S . Goldsmith , Atlanta, GA (US) ( 2013 .01); A61B 17 /0057 ( 2013 .01)
(72) Inventor: David S . Goldsmith, Atlanta ,GA (US) (57 ) ABSTRACT
(21 ) Appl . No.: 15 /932,172 Described are coordinated apparatus and methods for drug
targeting, clearing the lumen , placing implants within the
(22 ) Filed : Feb . 14 , 2018 wall of, and stenting, as necessary , any tubular anatomical
structure with single luminal entry . Miniature balls , or
Publication Classification miniballs, are introduced into the wall aeroballistically from
within the lumen , or small arcuate bands called stays
(51) Int. Cl. inserted through the outer tunic by means of a hand tool.
A61B 17/ 12 ( 2006 .01 ) When miniballs must be placed too closely together to be
A61F 2 /82 ( 2006 .01 ) controlled by hand , a positional control system assists in
A61B 1734 ( 2006 .01) discharge . Implantation within or proximal to diseased tis
A61B 17 /00 ( 2006 .01) sue targeting , and thus concentrating the medication in that
A61B 18 / 18 (2006 . 01) tissue , miniballs and stays can be used to deliver and
(52 ) U .S . CI. controllably release multiple drugs , a radionuclide , or an
CPC .. A61B 17 / 12118 ( 2013 .01); A61B 17 / 12181 open or closed loop smart-pill , for example. A glossary of
(2013 .01 ) ; A61F 2 / 82 ( 2013 .01) ; A61B terms follows the specification . Balance of abstract
17/3468 (2013 .01 ); A61B 17/00491 ( 2013.01); appended to the section entitled Summary of the Invention .

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Patent Application Publication Aug. 15 , 2019 Sheet 16 of 29 US 2019 /0247050 A1

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Patent Application Publication Aug. 15 , 2019 Sheet 19 of 29 US 2019/0247050 A1

ANGIOPLASTY CONTROL PANEL

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Patent Application Publication Aug. 15 , 2019 Sheet 20 of 29 US 2019 /0247050 A1

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Patent Application Publication Aug. 15 , 2019 Sheet 21 of 29 US 2019/0247050 A1

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Patent Application Publication Aug. 15 , 2019 Sheet 22 of 29 US 2019 /0247050 A1

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Patent Application Publication Aug. 15 , 2019 Sheet 23 of 29 US 2019/0247050 A1

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Patent Application Publication Aug. 15 , 2019 Sheet 24 of 29 US 2019/0247050 A1

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Patent Application Publication Aug. 15 , 2019 Sheet 25 of 29 US 2019/0247050 A1

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Patent Application Publication Aug. 15 , 2019 Sheet 26 of 29 US 2019/0247050 A1

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US 2019 /0247050 A1 Aug. 15 , 2019

INTEGRATED SYSTEM FOR THE INFIXION published on 12 Jun. 2014 as 2014 /0163664 under the title
AND RETRIEVAL OF IMPLANTS Integrated System for the Ballistic and Nonballistic Infixion
and Retrieval of Implants with or without Drug Targeting .
CROSS REFERENCE TO RELATED Parent application Ser. No. 11/ 986 , 021 succeeded and
APPLICATION claimed the benefit of Disclosure Document 565662, filed
on 21 Nov . 2004, and Provisional Patent Application 60 / 860 ,
[0001] This application is a continuation - in -part of parent 392, filed on 21 Nov . 2006 under 35 U .S .C . 119 (e ), the
application Ser. No. 11 / 986 , 021, filed on 19 Nov . 2007 and content of these earlier disclosures incorporated by refer
published on 11 Nov. 2010 as 20100286791 under the title ence. This continuation -in - part application supersedes par
Integrated System for the Ballistic and Nonballistic Infixion ent application Ser. No. 11/ 986 ,021 and continuation - in -part
and Retrieval of Implants and also continuation - in -part application Ser. No . 13 /694 , 835 , these earlier applications
application Ser. No. 13 /694 ,835 , filed on 9 Jan . 2013 and herewith abandoned .
TABLE OF CONTENTS
CROSS REFERENCE TO RELATED APPLICATION
TABLE OF CONTENTS
BACKGROUND OF THE INVENTION
1. Field of the invention
2 . Preliminary description of the invention
3 . Terminology
4 . Concept of the ductus-intramural implant
4a. Tissue acceptance of ductus- intramural implant
4a ( 1). Significance of sterile antixenic immune tissue reaction
4a ( 2 ). Duration , extent, and outcome of sterile tissue reaction
4a( 3 ). Tissue reaction ameliorative measures
4b . Medicinal and medicated miniballs and stays
4b ( 1 ). Drug-releasing and irradiating miniballs , stays, and ferrofluids
4b (2 ). Local release of drugs by miniballs and stays
4b (3). Use of drug-releasing ductus-intramural implants to locally counteract or reinforce angiogenic or
other systemic medication
46 (4 ). System implant magnetic drug and radiation targeting
4b (5 ). Circulating drug -blocking and drug interaction avoidance
46 (6 ). Drug-targeting miniballs and stays
4c . Implants that radiate heat on demand
4d. Chemical adjuvants and precautionary measures
4d (1). Administration of target and target-adjacent implantation -preparatory substances
4d ( 2 ). Ductus wall tumefacients
4d (3 ). Nontumefacient enabled attainment of implantable ductus-intramural thickness
4e . Stabilization of the implant insertion site
4e ( 1). Gross positional stabilization immobilizaton ) of the implant insertion site
4e ( 2 ). Tissue stabilization at the treatment site
4e ( 2) (a ). Temperature stabilization
4e (2 ) (b ). Removal of vulnerable plaque or accreted material at the implant insertion site
4f. Abrupt closure with thrombus and vasospasm
4f( 1) . Risk of abrupt closure with thrombus and vasospasm
4f(2 ) . Prevention of abrupt closure with thrombus and vasospasm
4g . Emergency recovery of miniballs and stays
5 . Means for the placement of ductus-intramural implants
6 . Endoluminal prehension ofminiballs and ferrofluids
7 . Comparison with prior art angioplasty
8 . Concept of the extraluminal stent
8a. Basic strengths and weaknesses of prior art stenting in vascular, tracheobronchial, gastrointestinal,
and urological interventions
8b . The extraluminal stent
8b ( 1 ). The intraductal component of the extraluminal stent and the means for its insertion
86 (1 ) (a ). Types of ductus-intramural implants used for stenting
86 (1 )(b ). Use of ductus-intramural implants for stenting
8b (2 ). The extraductal component of the extraluminal stent and the means for its insertion
8b (2 )(a ). Types of stent- jacket
8b (2 )(a )(i). Extrinsically magnetized stent-jackets
8b (2 ) (a ) ( ii ). Intrinsically magnetized stent-jackets
8b (2 )(a )(iii ). Hybrid extrinsically and intrinsically magnetized stent-jackets
8b (2 ) (a ) ( iv ). Quasi -intrinsically magnetized stent-jackets
8b (2 ) (a ) (v ). Laminated stent-jackets
8b (2 )(a )(vi). Spine and ribs-type stent-jackets
8 (2 ) (a )( vii ). Absorbable stent - jackets
8b ( 2) (a ) (viii ). Radiation shield -jackets and radiation shielded stent- jackets absorbable and
nonabsorbable
8c . Placement of the extraluminal stent
8c ( 1). Considerations as to access
8c ( 2 ). Means for the placement of the stent- jacket
8d . Closer comparison of extraluminal to endoluminal, or conventional, stenting
8e . Accommodation of the adventitial vasculature , innervation , and perivascular fat
8f. Necrosis and atherogenesis -noninducing conformation of stent-jackets
US 2019 /0247050 A1 Aug. 15 , 2019

-continued
TABLE OF CONTENTS
CROSS REFERENCE TO RELATED APPLICATION
TABLE OF CONTENTS
BACKGROUND OF THE INVENTION
8g. Means for accommodating the vasa and nervi vasora with special reference to the end -arterial form
and neovascularization of the corronary arteries
8h. Requirement for moisture barrier- coated viscoelastic polyurethane foam linings
8i. Positional stabilization of implants
8i( 1 ). Use of solid protein solders
8i(2 ). Means for inducing the formation of a strong implant-tissue bond
9 . Minimizing the risk of rebound
10 . Concept of ballistic insertion
11. Use of a positional control system
12. Concept of the impasse -jacket
13. Concept of the magnet-wrap
14 . Concept of the nonjacketing side-entry connector
15 . System requirements
16 . System features

10002 ] OBJECTS OF THE INVENTION [0031] 110c. Absorbable and nonabsorbable periductal
100031 SUMMARY OF THE INVENTION jackets with medicated linings
10004 ] BRIEF DESCRIPTION OF THE DRAWINGS [0032 ] 111 . STENT- JACKET EXPANSION INSERTS
[0005 ] DESCRIPTION OF THE PREFERRED [0033 ] Illa. Expansion inserts absorbable , meltable, and
EMBODIMENTS comminutable for time- discrete decremental contraction of
[0006 ] I. STENT-JACKETS AND STENT- JACKET SUP stent-jackets
PORTING ELEMENTS [0034 ] 111b . Intracavitary infusion of fluid for lithotriptor
[ 00071 11 . General considerations to include insertion dissolution of long - term controlled destruction - time expan
[ 0008 ] 12 . Structural and functional considerations sion inserts or a final stone base -tube bonded layer in
[0009] 13 . Order of stent- jacket placement multilayered expansion inserts
[0010 ] 13a . Circumstances recommending the use of a [0035 ] I11c . Absorbable stent-jacket expansion insert
shield - jacket or preplacement of the stent- jacket materials with relatively short breakdown times
[ 0011 ] 13b . Sequence of stent- jacket placement and 100361 111d . Lithotriptor- destructible stone stent- jacket
implantation expansion inserts and differentially destructible expansion
[0012] 13c . Sequence of stent-jacket placement and insert layers
implantation in relation to trap - extractor (recovery ) electro [0037 ] Ille . Expansion insert bonding agents (adhesives )
magnet susceptibility and field intensity [0038 ] Ille ( 1 ). Intrinsic shorter-term insert-to -base -tube
[0013 ] 14 . Internal environment-resistant base -tube poly and segment- to - segment bonding agents
mers , metals , and combinations thereof [0039] 111e (2 ). Longer-term expansion insert -to -base
[ 0014] 15 . Protective encapsulation of the stent- jacket tube and layer-to -layer bonding agents
[0015 ] 16 . Stent- jackets with sling string pull opener [0040) Ille ( 3 ) . Extrinsic shorter-term (absorbable ) to lon
[0016 ] 17 . Stent and shield - jacket protective linings ger - term ( stone ) layer bonding agents
[0017 ] 17a . Double -wedge stent- and shield -jacket [0041 ] 112 . Retardation in the dissolution of absorbable
rebound -directing linings stent-jackets , stent- jacket expansion inserts , and stays
[ 0018 ] 17a ( 1 ). Conformation of double -wedge linings [0042] 113 . Alternative procedure to the use of expansion
[0019] 17a ( 2 ). Functional background to double -wedge inserts
linings [0043 ] 114 . SECTIONAL , OR CHAIN -STENTS , SEG
[0020 ] 17a ( 3). Materials suitable for rebound -directing MENTED AND ARTICULATED
double -wedge linings 00441 114a . Purposes and types of chain -stent
[0021] 17a (4 ). Nonmagnetized base - tube and double 0045 ] 114b . Procedure for placement of a chain -stent
wedge shield - jackets [0046 ] 115 . MINIBALL AND FERROFLUID - IMPASS
[ 0022 ] 17b . Stent - and shield -jacket moisture barrier ABLE JACKETS , OR IMPASSE - JACKETS
coated viscoelastic polyurethane foam linings [0047 ] 115a . Uses of impasse -jackets
[0023] 17c. Stent- and shield - jacket anti -migration linings [0048 ] 115b . Structure of impasse-jackets
100241 18 . Radiation shielded stent- jackets [0049 ] 115c . Braced , compound , and chain impasse - jack
[0025 ] 19 . Jacket end -ties and side- straps ets
10026 ] 19a . Form of end -ties [0050] 115d . Cooperative use of impasse- jackets in pairs
[0027] 19b . Use of end - ties and gradient arrays
[0028 ] 110 . Absorbable extraluminal magnetic stent- jack [0051 ] 115e . Direct lines from the body surface to and
ets and materials from impasse - and other type jackets
[0029 ] I10a . Absorbable base-tube and stent- jacket, mini [0052 ] 115f. Single and plural circuit pumping through
ball, stay, and clasp -magnet matrix materials direct lines to jackets
( 0030 ) I10b . Noninvasive dissolution on demand of 10053 ]. 116 . STENT-JACKET INSERTION TOOLS
absorbable stent- jackets, base -tubes , radiation shields, and [0054 ] 116a. Insertion tool structure
miniballs 10055 ] 116b . Use of the stent-jacket insertion tool
US 2019 /0247050 A1 Aug. 15 , 2019

100561. II. CLASP -MAGNETS [0092] VII2b (2 ). Trap and extraction recovery tractive
[0057 ] II1 . Subcutaneous, suprapleural, and other organ electromagnets for the recovery of loose and extraction of
attachable clasp - or patch -magnets mispositioned miniballs
[0058 ] 112 . Chemical isolation of patch -magnet and other [0093] VII2c . Application of simple pipe -type barrel-as
implanted components sembly to the magnetic correction of tracheal and bronchial
[0059 ] III. MAGNET- WRAPS collapse ( veterinary )
[ 0060 ] III1. Use of a magnet -wrap [0094 ] VII2c ( 1). Treatment of tracheal collapse in the
10061] III2 . Magnet-wrap structure cervical segments , i.e ., cephalad or anterior to the thoracic
10062] IV . CLASP -PATCHES AND CLASP -WRAPS inlet
[0063 ] [V1. Creation of a magnetically retractable surface [0095 ] VII2c( 1) (a ). Use of a magnet-wrap about the
layer esophagus to treat tracheal collapse in a small dog, for
[ 0064 ] [V2. Use of a clasp -wrap example
[0065 ] IV3. Clasp -wrap -alternative methods for achieving [0096 ] VII2c ( 1)(b ). Use of a simple pipe barrel -assembly
adhesion to the outer surface of the ductus to treat tracheal collapse in a small dog , for example
[ 0066 ] IV3a . Stays configured and/ or coated to promote [0097 ] VII2c(2 ). Treatment of tracheal collapse in the
tissue infiltration and adhesion thoracic segments , i.e ., caudad , or posterior , to the thoracic
[0067] IV3b . Injectable magnetic fluids inlet
10068 ]. V . MINIBALLS [0098 ] VII2d . Ablation and angioplasty -incapable radial
[0069 ] V1. Miniature ball implants discharge barrel- assemblies
[0070 ] V2. Miniball types, radiation -emitting,medication , [0099 ] VII2d ( 1 ). Limited purpose single barrel (monobar
drug - eluting magnetized , and magnetized
rel) radial discharge barrel-assembly
[ 0071] V3 . Medication (nonstent) implants and medica [0100] VII2d (2 ). Multiple radial discharge barrel-assem
tion - coated miniballs, implants , and prongs blies with one- to four- or more -way radial discharge
[0072 ] V4 . Medication - coated miniballs, stays, and muzzle -heads
prongs with a heat- activated (-melted , -denatured ) tissue [0101] VII2d ( 3 ). Ablation and angioplasty -incapable
adhesive-hardener or binder -fixative radial discharge barrel-assembly muzzle-heads
[0073 ] V5. Heating control over implants and coated [0102 ] VII2d ( 3 )(a ). Monobarrel radial discharge barrel
implants , to include miniballs , stays, and prongs assembly muzzle -head
[0074 ] V5a. Heating of implants and coated implants, to [0103] VII2d ( 3 )(a )(i). Structure of monobarrel radial dis
include miniballs , stays, and prongs using implant- passive charge barrel-assemblies
ductus -external or extrinsic means [0104 ] VII2d ( 3 )(a )( ii ). Materials of radial discharge bar
[0075 ] V5b . Extracorporeal energization of intrinsic rel - assemblies
means for radiating heat from within medication implants [0105] VII2d (3 )(b ). Muzzle- head turret-motor (turret -ser
and medication and /or the tissue bonding -coatings of vomotor )
implants
[0076 ] V6 . Chemical control over implants and coated [0106 ] VII2d (3 )(c ). Muzzle -head servomotor ( turret-mo
implants , to include miniballs , stays , and prongs tor ) desiderata
10077] V7. Radiation - emitting (brachytherapeutic , endo [0107] VII2d (3 )( d ). Turret-motor operational modes
curietherapeutic , sealed source radiotherapeutic , internal 10108 ] VII2d ( 3 )( d ) (i). Turret -motor rotational mode
radiation therapy) miniballs [0109] VII2d ( 3 )( d ) ( ii ). Turret-motor oscillatory mode
[0078 ] V8 . Temporary (absorbable ) ferromagnetic mini [0110] VII2d (3 )( d )(iii). Turret-motor heating mode
balls and other implants [0111 ] VII2d (3 ) (e ). Radial discharge barrel-assembly
[0079 ] VI. ROTARY MAGAZINE CLIPS working arc
[0080 ] VII. BARREL -ASSEMBLIES [0112 ] VII2d (3 )(f). Rotation of working arc
[ 0081] VII1 . Types and capabilities of barrel- assemblies [0113] VII2d (3 )( g). Control of muzzle-head turret -motor
[0082 ] VIIla . Types of barrel-assemblies angle within working arc
[ 0083] VIIlb . Capabilities of different type barrel-assem 10114 ] VII2d ( 3 )(h ). Factors that affect muzzle - head nos
blies ing length or reach , steerability , and trackability
[0084 ] VII2 . Ablation and angioplasty -incapable barrel [0115 ] VII2d ( 3 ) (i). Trap and extraction recovery tractive
assemblies electromagnets in radial discharge barrel- assemblies for the
[0085 ] VII2a . Simple pipe barrel-assemblies recovery of loose and extraction of mispositioned miniballs
[0086 ] VII2b . Simple pipe ablation and angioplasty - inca [0116 ] VII2d ( 3 ) ( ). Blood - grooves on muzzle -heads for
pable barrel-assembly muzzle -heads use in blood vessels
[ 0087] VII2b ( 1 ). Simple pipe barrel-assembly with [0117] VII2d (4 ). Forward drive and sag leveling and sta
bounce- plate bilizing device
[0088 ] VII26 (1)(a). Intracorporeally nondeployable nor [0118 ] VII2d(4 )( a ). Use of a forward drive stabilizer
adjustable bounce -plate attachment [0119 ] VII2d(4 ) (b ). Structure of forward drive stabilizing
[ 0089 ] VII26 ( 1 )(b ). Intracorporeally controllable bounce and leveling extension linkage
plates [0120 ] VII2d (5 ). Direction of radial discharge barrel-as
[0090 ] VII26 (1 ) (b ) (i). Intracorporeally controllable sembly muzzle-head on discharge as antegrade (advancing,
bounce- plate with limited adjustability in elevation forward , distad ) or retrograde (withdrawing, backward ,
[0091] VII26 ( 1 )(b )(ii). Intracorporeally controllable proximad )
bounce -plate with precision adjustment in rebound elevation [0121] VII2e . Simple pipe and radial discharge barrel
and rotation assembly common elements
US 2019 /0247050 A1 Aug . 15 , 2019

[0122 ] VII2e( 1 ). Barrel -catheters, barrel-tubes, and barrel- [0152 ] VII2g ( 3 )( e)(i). Types and functions of radial pro
assemblies jection unit tool- inserts, electrical and fluidic or Piped
[ 0123] VII2e (2 ). Connectors (couplings ) for quick release [0153] VII2g (3 )( e) ( ii ). Self -contained electrical/ fluid sys
and reconnection of the barrel-assembly to the airgun with tem -neutral tool- inserts, to include injection and ejection
proper alignment syringes
[ 0124 ] VII2e (3 ). Twist- to - stop and lock connector ( twist [0154 ] VII2g ( 3) (e)( iii). Self -contained electrical / fluid sys
lock connector, keyed spring lock connector ) tem -neutral tool- insert internal stopping membranes and
[ 0125 ] VII2e( 4 ). Engagement of the barrel-assembly in lifting springs
the airgun [0155] VII2g ( 3 )( e )(iv ). Electrical and electrochemical
[ 0126 ] VII2e ( 5 ). Barrel- assembly end - plate tool- inserts, to include gas discharged injection and ejection
[0127 ] V1I2e (6 ). Electrical connection of the barrel- as syringes
sembly to the airgun [0156 ] VII2g(3 )(e) (v ). Temperature control in electrical
[0128] VII2f. Radial discharge barrel- assembly elements tool- inserts
[ 01291 VII2f( 1 ). Tube polymer nonintrinsic barrel- cath [0157 ] VII2g ( 3 )(e )( vi). Fluid -operated tool-inserts , to
eter flexibility (bendability, trackability ) setting and altering include ejector- irrigator -aspirators and injectors
elements [0158 ] VII2g( 3 ) ( e ) ( vii ). Use of flow - reversible tool-in
[0130 ] VII2f( 1 )(a ). Tubing materials for barrel-catheters serts for microaspiration
and radial discharge barrel-tubes [0159 ] VII2g( 3) (e)(viii ). Temperature control in fluid
[0131 ] VII2f( 1)(b ). Centering devices ( centering disks ) (piped ) tool-inserts
[0132] VII2f( 2 ). Embolic trap filter in radial discharge [0160 ] VII2g( 3) ( e)(ix ). Doublet irrigator-aspirator tool
muzzle -heads for use in the vascular tree inserts , or point-washers
[ 0133] VII2f(2 ) (a ). Trap filter deployment and retrieval [0161] VII2g (3 )(e )(x ). Elimination of gases from fluid
mechanism radial projection unit lines
[0134 ] VII2f(2 )(b ). Automatic disabling of implant-dis [0162] VII2g (3 )(f). Radial projection unit control and con
charge, radial projection units , and turret-motor trol panels, elecrical and fluidic or piped
[0135 ] V1I2f(3 ). Blood - tunnels [0163] VII2g ( 3 )( g ). Coordinated use of aspiration and
[0136 ] VII2f( 4 ). Incorporation of a bounce -plate into piped radial projection units to remove diseased tissue or
radial discharge barrel-assemblies obtain tissue samples for analysis
[0137] VII2f(5 ). Use of minimally and fully angioplasty [0164 ] VII2g (4 ). Minimally ablation and ablation and
capable radial discharge barrel -assemblies angioplasty -capable barrel-assembly control panels
[0138 ] VII2f(6 ). Ablation and angioplasty - incapable bar 10165 ] VII2h . ABLATION AND ABLATION AND
rel-assembly controls on the airgun ANGIOPLASTY -CAPABLE BARREL - ASSEMBLIES
[ 0139] VII2g . Minimally ablation or ablation and angio [0166 ] VII2h ( 1 ). Distinction in ablation or ablation and
plasty -capable barrel-assemblies angioplasty -capable barrel- assemblies as unitary or bipartite
[0140 ] VII2g ( 1). Minimally thermal ablation or angio [0167) VII2h ( 2 ). Specific advantages in the elimination or
plasty -capable barrel-assemblies minimization of connection to the airgun ( tethering )
[0141] VII2g (2 ). Minimally ablation or ablation and [0168 ] VII2h ( 3 ). The radial discharge barrel- assembly as a
angioplasty -capable barrel- assembly side- socket separate and independent angioplasty device
[0142 ] VII2g ( 3 ). Minimally and fully (airgun -indepen [0169] VII2h (4 ). Componentry required for airgun - inde
dent) ablation or ablation and angioplasty -capable radial pendent use
discharge muzzle -heads [0170 ] VII2h (5 ). Thermal ablation and angioplasty -( lu
[ 0143] VII2g (3 )(a ). Rapid cooling catheter and cooling men wall priming searing - or cautery - ) capable barrel
capillary catheter for cooling heated turret-motor, electri assemblies
cally operated radial projection unit lifting thermal expan 10171] VII2h (6 ). Ablation and ablation and angioplasty
sion wires and heaters , and recovery magnets capable barrel-assembly end - sockets
[ 0144 ] VII2g ( 3 ) (b ) . Turret -motor and recovery electro [0172 ] VII2h ( 7). Ablation and ablation and angioplasty
magnet insulation , leads, and control of winding tempera capable barrel -assembly side - socket s
tures when used as a heating elements in ablation or ablation [0173 ] VII2h (8 ). BARREL -ASSEMBLY POWER AND
and angioplasty - capable barrel - assemblies CONTROL HOUSING
0145 ] VII2g ( 3 ) ( C ). Thermal conduction windows (heat [0174 ] VII2h (8 )(a ). Connection of the power and control
windows) and insulation of the muzzle -head body in mini housing to the airgun
mally or fully thermal ablation and thermal ablation and [0175 ] VII2h (8 ) (b ). Slidable ablation or ablation and
angioplasty -capable ( independently usable ) barrel -assem angioplasty - capable barrel -assembly power and control
blies housing
[0146 ] VII2g (3)(d ). RADIAL PROJECTION UNITS [0176 ] VII2h ( 8 )(c ). Universal barrel-assembly power and
[ 01471. VII2g ( 3 ) ( d )(i). Structure of radial projection units control housing
[ 0148 ] VII2g (3 )(d )(i)( 1). Structure of electrically operated [0177 ] VII2h ( 8 ) (d ). Rechargeable battery pack local to the
radial projection units electrical terminals
[0149] VII2g (3 )(d )(i)( 2 ). Structure of fluidically and [0178 ] VII2h ( 9) (e). Ablation and ablation and angio
microfluidically operated radial projection units plasty -capable onboard barrel-assembly control
[0150 ] VII2g ( 3) (d )(i)(3 ). Extended projection scissors lift 01791 VII2h ( 9 )( f). Ablation and ablation and angioplasty
platform mechanism capable barrel-assembly onboard control Panel
[0151] VII2g (3 )(e ). RADIAL PROJECTION UNIT [0180 ] VII2h ( 10 ). Control of transluminal rate of transla
TOOL - INSERTS tion
US 2019 /0247050 A1 Aug. 15 , 2019

[0181 ] VII2i . Procedure for the extraluminal stenting of a [0216 ] XII. SERVICE -CATHETERS
smaller vas using the apparatus described herein [0217 ] XII1 . Service -catheters, service -channels, and use
101821 VII2j. THROUGH - BORE , OR COMBINATION of the barrel-assembly as a guide-catheter
FORM , BARREL -ASSEMBLIES [0218 ] X112 . Muzzle-head access through a service -chan
[0183] VII2j( 1). Incorporation of adscititious capabilities nel without the aid of and by means of inserting a service
into barrel-assemblies catheter
[0184 ] VII2j(2 ). Accommodation of rotational ablating [0219] XI13 . Cyanoacrylate cement injection service -cath
and atherectomizing side- cutting devices in combination eter
forms [0220] XII4 . Service - channel adhesive delivery line
[ 0185 ] VII2j (3 ). Types of combination - form barrel-assem [0221 ] XII5 . Cooling catheters ( temperature -changing ser
blies vice -catheters )
[0186 ] VII2j(4 ). Forward -directed clearing ( ablation and 0222 ]. XII6 . Preparation of service -catheters for use as
angioplasty ) means for integration into the muzzle-Head transbarrel-assembly hypotubes
[ 0187 ] VII2j(5 ). Barrel-assembly with built in excimer (0223) X117 . Use of the barrel-assembly as an aspirator or
laser transluminal extraction catheter for the removal of soft
[0188 ] VII2j(6 ). Barrel-assembly with exchangeable or plaque or mispositioned miniballs
built in rotational atherectomy burr 0224 XII8 . Use of the barrel -assembly as an aspirator or
[0189 ] VII2j(7 ). Flow -through barrel-assembly for use in transluminal extraction catheter to retrieve biopsy samples
blood vessels [0225 ] X119 . Rotation of muzzle -heads with unused bar
0190 VII2i( 8 ). Widely applicable barrel -assembly rel-tubes for use as a guide -catheters
[0191 ] VIII . RADIAL PROJECTION CATHETERS [0226 ] XII10 . Delivery of a measured quantity of a liquid
[0192 ] VIII1. Types of radial projection catheters through a service -channel
[ 0193] VIII2 . Simple , or noncombination -form , radial [0227 ] XII11. Delivery of a measured quantity of a gas
projection catheters through a service - channel
10194 ] VIII3 . THROUGH -BORE , OR COMBINATION [0228 ] XII12. Delivery of a measured quantity of a pow
FORM , RADIAL PROJECTION CATHETERS der through a service - channel
[0195 ] V1114 . Slidable projection catheter power and con [0229 ] XII13 . Midprocedural delivery of lubricant to the
trol housing muzzle -head
[0196 ] VI115 . Fabrication of radial projection catheters [0230] XIII . AIRGUNS
101971. IX . SIDE - PORTS [0231] XIII1. Operational requirements
[0198 ] IX1. Proximal side -ports in angioplasty -capable [0232] XIII2 . Modification of commercial airguns
barrel - assemblies [0233 ] XIII2a . Simple airgun modified to allow limited
[ 0199 ] IX2 . Proximal side-ports in combination - form bar application
rel-assemblies and combination - form radial projection cath [0234 ] XIII2b . Simple airgun modified to allow wider
eters application
[ 02000 IX3. Distal side - ports in combination - form barrel [02351 XIII2c . Control of propulsive force (exit velocity )
assemblies and combination - form radial projection catheters by means of a calibrated slide cover over a slit cut into the
0201) X . Steering and emergency recovery of implants valve body
with the aid of an external ( extracorporeal) Electromagnet (0236 ) XIII2d . Docking stations for modified commercial
[0202 ] X1. Use of an external electromagnet to assist in airguns
steering or in freeing the muzzle -head [0237 ] XIII2e. Positioning modes of operation
[0203] X2. Use of an external electromagnet to assist in [0238 ] XIII2e (1 ). Positioning with a simple pipe
mishap recovery [0239 ] XIII2e(2 ). Automated positioning with a radial
[0204 ] X2a . Interception and recovery of a miniball enter discharge barrel-assembly
ing the circulation [0240) XIII3 . DEDICATED INTERVENTIONAL AIR
[0205 ] X2a ( 1). Midprocedural interception and recovery GUNS
of a miniball entering the circulation [0241] XIII3a . Operational requirements
[ 0206 ] X2a (2 ). Postprocedural recovery of a miniball in [0242 ] XIII3b . Interventional airgun with liquid vaporiza
the vascular tree tion -upon - release cartridge or compressed gas cylinder con
[0207 ] X2b . Stereotactic resituation of a mispositioned nected directly to the valve body inlet suitable for use over
miniball a range of exit velocities (forces of penetration ) in quick
[0208 ] X2c . Stereotactic arrest and extraction of a circu succession with moderate redundancy as to points of control
lating, dangerously mispositioned, or embolizing miniball over discharge
[ 0209 ] X2d . Downstream disintegration of a circulating [0243] XIII3c . Interventional airgun suitable for proce
miniball dures involving the treatmentof different tissues to different
[0210 ] X3. Perforations along the gastrointestinal tract depths in quick succession with redundant points of control
[0211 ] XI. HYPDXIA AND ISCHEMIA -AVERTING to adjust the exit velocity
ELEMENTS [0244 ] XIII3d . Interventional airgun with multiple exit
[ 0212] XI1. Blood - grooves velocity control points for quick midprocedural adjustment,
[0213] XI2 . Blood -tunnels using rotary magazine clips, and with an automatic posi
[0214 ] XI3 . Flow -through bore in combination -form bar tional control system suitable for implanting the wall of a
rel -assemblies and combination -form radial projection cath blood vessel
eters used in blood vessels [0245 ] XIII3e . Linear positioning stage or table airgun
[ 0215 ] X14. Push -arm radial projection unit tool- inserts mount
US 2019 /0247050 A1 Aug . 15 , 2019

[0246 ] XIII3f. Positioning of the barrel-assembly with the [0287 ] XVI9 . Powered stay insertion tool holder for the
linear positioning table and turret-motor attachment of medication or tissue sealant syringes whether
[ 0247 ] XIII3f( 1). Type and efficiency of control single , dual, or multi - chambered as supplied , for tool slave
[0248 ] XIII3f( 2 ). Airgun control panel follower or independent use
[0249 ] XIII3f( 3 ). Relation of control panels to the turret [0288 ] XVI9a . Use of commercial syringes and extension
motor and airgun linear positioning table axes, to discharge , tubes
and to one another [0289] XVI9b . Avoidance of remote syringe placement
[0250 ] XIII3f (4 ). Automatic close - formation pattern and long adhesive delivery lines
implantation 0290] XVI9c. STAY INSERTION TOOL AUXILIARY
[ 0251 ] XIII4 . Pairing of barrel -assembly and airgun SYRINGES
[0252] XII15 . Remote controls [0291 ] XVI9c( 1). Control of auxiliary syringes
[0253 ] XIV . MODES OF FAILURE [0292 ] XVI9c( 2). Tissue sealant syringe holder (holding
[0254 ] XIV1. Failure to properly discharge frame) and attachment
[ 0255 ] XIV2. Shallow termination into the lumen wall or f0293 ] XVI9c ( 3 ). Structure of tissue sealant syringe
other tissue of the trajectory holder
[ 0256 ] XIV3. Perforations [0294 ] XVI9c(4 ). Stay insertion tool auxiliary syringe
[0257 ] XIV4. Jamming holding frame attachment
[0258 ] XIV5. Premature follow -on discharge [0295 ] XVI9c (5 ) . Connection of the holding frame to the
[ 0259 ] XIV6 . Endothelial cling and seizure stay insertion tool
[0260 ] XIV7. Radial projection unit lift -platform malfunc [0296 ] XVI9c (6 ). Supporting arm and connecting cable
tion [0297 ] XVI9c(7 ). Control of auxiliary syringe eject-ahead
[0261] XIV8. Entry of a miniball into the bloodstream or eject- after with determinate timing
[0262] XV. ARCUATE STAYS [0298 ] XVI9c(8 ). Independent and subordinated control
[ 0263] XV1. Medication or radiation (nonstent), and of a stay insertion tool auxiliary syringe holding Frame
medication -coated stays 02991 XVI10 . BINDING OF LINES AND CABLES
[ 0264 ] XV2. Arcuate stent-stays ( stent-ribs ) for use with ALONGSIDE THE STAY INSERTION TOOL
magnetic stent-jackets [0300 ] XVI10a . Uses of stay insertion tool mounting clips
[0265 ] XV3 . Structure of stays and bands
[0266 ] XV4. Partially and completely absorbed stays [0301] XVI10b . Use of stay insertion tool side mounting
[0267] XV5. Circumstances dissuading or recommending clips to juxtaposition (fasten alongside ) an endoscope
the use of stays [0302 ] XVI10c . Use of stay insertion tool side mounting
[ 0268 ] XV6 . Stays coated with a heat- activated (-melted , clips to juxtaposition ( fasten alongside) a vacuum (aspira
-denatured ) tissue adhesive -hardener, or binder- fixative tion , suction ) line
[ 0269 ] XV7. Stays coated with a solid protein solder [0303 ] XVI10d . Use of stay insertion tool side mounting
coating and cyanoacrylate cement clips to juxtaposition ( fasten alongside) a CO2 cylinder or
0270 XV8. Use of cement and solder coated stays cold air gun line
[ 0271] XV9. Specification of cyanoacrylate tissue sealants [0304 ] XVI11. USE OF STAY INSERTION TOOL
and bonding agents [0305 ) XVII. TESTING AND TESTS
[0272 ] XV10 . Practitioner preference for cyanoacrylate [0306 ] XVIII. Need of a means for testing the resistance
tissue sealant to puncture , perforation , and delamination of tissue requir
[0273 ] XVI. STAY INSERTION TOOLS ing treatment
[0274 ] XVI1 . Stay insertion tool structure [0307] XVII2 . Midprocedural preinsertion testing
[0275 ] XVI2. Stay insertion tool inmate stay recall (retrac [0308 ] XVI13 . Confirmation of terminus
tion ) and recovery electromagnet [0309 ] XVII4 . In situ test on endoluminal approach for
[ 0276 ) XVI3 . Stay insertion tool inmate tissue sealant susceptibility of the ductus wall to puncture , penetration ,
and / or medication delivery line and perforation
[0277 ] XVI4 . Sealing of stay insertion incisions [0310 ] XVII5 . In situ test on endoluminal approach for
[ 0278 ] XV14a . Cement-before insertion (cement-ahead intra - or inter - laminar separation (delamination , laminar
operation ) avulsion )
[0279 ] XV14b . Sealant cartridges and sealants (adhesives ) [0311 ] XVII6 . Endoluminal approach test for intra - or
[0280] XVI4c.Mechanism for adjustment in stay insertion inter- laminar separation following the insertion of a test
tool ejection cycle inmate cement delivery Interval miniball
[ 0281 ] XVI4d . Control over the quantity of fluid dis [0312 ] XVII7 . In situ test on extraluminal approach for
charged intra - or inter -laminar separation (delamination , avulsion )
[0282 ] XVI4e . Mechanism for switching from cement [0313 ] XVII8 . In situ test on endoluminal approach for
ahead to cement- follower operation intra - or inter -laminar separation following the insertion of
[0283 ] XVI5 . Stay insertion tool with pivoting base a test miniball
[ 0284 ] XVI6 . Butt -pad with retractable slitting edge [0314 ] XV119 . In situ test on extraluminal approach for
[0285 ] XVII. Stay insertion tool- inserts and extension resistance to centrifugal pull - through
devices [0315] XVII10 . Interconvertibility of results among tests
[ 0286 ] XVI8 . Use of multiple component adhesives with [0316 ] XVII11. In situ muzzle -head adhesion test
a stay insertion tool [0317 ] XVIII. Followup examination
US 2019 /0247050 A1 Aug. 15 , 2019

10318 ] XIX . STERILIZATION stent-jacket, or if to be extracted to the perivascular space,

[0319 ] XX . EXEMPLARY CHANNEL OF CONTROL an impasse - jacket, so that the drug or drugs are drawn
IN A FULLY IMPLANTED AMBULATORY ADAPTIVE against or into the lesioned wall of the lumen , or if contained
HIERARCHICAL CONTROL SYSTEM FOR AUTO within a miniball or microsphere shell but not inseparably
MATIC RESPONSE TO A COMORBID CONDITION bound to the magnetically susceptible particles, or ferro
10320 ) XXI. FULLY IMPLANTED AMBULATORY co -bound , the drug or drugs are released into the lumen .
ADAPTIVE HIERARCHICAL CONTROL SYSTEMS More specifically , as will be described , when a drug is to be
FOR AUTOMATIC RESPONSE TO A COMORBID CON directly delivered to the target organ , tissue, or segment
DITION along a tubular anatomical structure through the circulation ,
10321] XXII. GLOSSARY OF TERMS uptake from an infused or injected drug dispersed in a
[0322] CLAIMS ferrofluid is through a port at the body surface , thence
[0323 ] ABSTRACT OF THE DISCLOSURE through a fluid line leading to the tissue with uptake by
BACKGROUND OF THE INVENTION detention at the target segment and and absorption through
the endothelium or urothelium , for example , by means of an
1. Field of the invention impasse - jacket . An electromagnetized jacket allows the drug
[0324 ] The apparatus and methods to be described are to be drawn into the intima or suburothelium , for example.
intended for use by veterinary specialists , pulmonologists, When the drug is to be delivered to an organ , for example,
interventional radiologists and cardiologists , cardiovascular, delivery is into the lumen of the organ blood supply through
thoracic , and neurological surgeons, gastroenterologists , and a ductus side -entry jacket or if into the parenchyma, a
urologists to : nonjacketing side -entry connector as described in copending
[03251 1 . Targetmedication and /or therapeutic substances applications specified below .
into the wall surrounding a lumen by radially directed or [0331] 7. Where the substance, usually a drug must be
side - looking injection from within the lumen , with retention prevented from further circulation , position a final impasse
by radially outward attraction by a magnetized jacket, or by jacket downstream or at the outflow , such as venous, of the
embedding tiny implants within this or any other diseased target organ to suspend within the lumen a reversal agent
tissue . Few drugs released into the circulation have a natural ( counteractant, antidote , neutralizing agent ) to the drug
affinity for the organ or tissue intended as iodine has for the released by the upstream implant or by positioning increas
thyroid gland. Instead , the drug is delivered to all the tissues ingly magnetized implants about the lumen to truncate its
of the body at the dose required to treat the intended organ continued flow to nontargeted tissue.
or tissue, even though exposure to the drug of other tissue
may be harmful. This is usually the cause of adverse side [0332] Presented here will be a form of magnetic stenting
effects , drug - drug, and drug - food interactions. Moreover , which is fundamentally superior to any endoluminal or
when not targeted , efficacy necessitates that the dose intravascular magnetic stent, or any endoluminal stent
required be much larger and therefore more costly . Accord intended to be attracted to a magnetic field generated from
ingly , one object here is to provide means that allow outside the stented conduit, or ductus. More specifically, the
squarely targeting a specific organ , segment along a tubular type stent described is superior to any endouminal stent
anatomical structure , or tissue. magnetic or not. That is , whether the lumen of a blood
[ 0326 ] 2 . Ablate diseased and /or obstructive tissue from or vessel, the airway , the digestive tract , urogenital (or urino
angioplasty the walls surrounding a bodily conduit, that is, genital), tract, or an endocrine duct, magnetically suscep
the passageway or lumen through a tubular anatomical tible endoluminal stents and coiled stents positioned inside
structure , whether that of a blood vessel, a duct, ureter, vas the lumen to achieve the pushing outward of the wall
deferens , fallopian tube , the gut, trachea , or a bronchus, for surrounding an inflamed , constricted , or obstructed lumen
example , any ofwhich may be properly referred to as a vas , when attracted to an extraluminalmagnet are fundamentally
vessel, ductus , duct, canal, or channel inferior to the intramural, or infixed within the lumen wall ,
[0327 ] 3 . Position increasingly magnetized spherules, means described herein . The reasons for this superiority are
stays , impasse -, or stent-jackets along a ductus in the ante sufficiently pertinent from a medical standpoint as to warrant
grade (anterograde ) direction to draw and concentrate fer preliminary comment.
romagnetic carrier-bound drugs from the passing circulation [0333 ] First , where intramurally positioned implants, ordi
into the lumen wall. narily distributed uniformly about the lumen wall for attrac
[ 0328 ] 4 . Position these minute implants so as to target a tion to a magnetized jacket surrounding the ductus or
specific segment of a ductus or an organ , and if necessary . conduit, uniformly expand the lumen radially outward in all
[0329 ] 5 . Embed implants containing sufficient ferromag directions , endoluminal magnetic stents only pull at the
netic material to serve as the intraductal component of an substrate conduit or ductus in the direction of attraction . The
extraluminal stent, where any or all of the foregoing func tiny magnetically susceptible intramural implants used to
tions can be accomplished in any combination or sequence impart patency to a constricted lumen , which can incorpo
with single entry . Small implants consisting almost entirely rate or be coated with medication of any kind , are positioned
of medication can be implanted in any tissue, to include the entirely about the lumen wall , and rather than drawn to an
wall surrounding a lumen , or can be positionally stabilized extracorporeal magnet, are surrounded by an implanted
inside the lumen alongside a diseased segment. foam -lined jacket ( collar, mantle ) in immediate contact with
[0330 ] 6 . Target drugs within supply conduits, such as the substrate ductus . When spherical, these implants are
arteries , by suspending these as magnetically susceptible referred to as miniballs; when band (strip , tang )-shaped , the
carrier superparamagnetic nanoparticles or microparticles term used is stays. In comparison, endoluminal magnetic
within a magnetic jacket encircling the conduit , either a stents are incapable of treating the radial asymmetries or
US 2019 /0247050 A1 Aug . 15 , 2019

eccentricities characteristic of angiosclerotic lesions or body such as an endoluminal stent or an intraluminal

plaques discriminately, instead covering over unaffected implant in a vascular and collagenous fibrous capsule , the
radii about the arterial wall . process known as the foreign body response or foreign body
[0334 ] The jacket is magnetized perpendicularly to the granuloma.
long axis of the conduit or ductus and may be rolled from [0339] However, formation of this isolating layer is typi
magnetized stainless steel sheet, or as shown in FIGS. 2 thru cally 50 -200 micrometers in thickness enough to isolate an
6 , comprise a polymeric base - tube having small permanent implant chemically, but even with the high level ofmotion
magnets or electromagnets affixed thereto . When drawn to about a stent to stimulate an increase in this thickness , not
an outside magnet, an endoluminal magnetic stent is drawn enough to afford sufficient protection against themechanical
up against the ipsilateral luminal wall , imposing a significant forces imposed upon the tissue in contact with the stent (see ,
indenting force thereupon in excess of the outward force an for example , de la Oliva , N ., Navarro , X ., and Del Valle , J.
endoluminal stentmust exert to prevent migration under any 2018 . “ Time Course Study of Long-term Biocompatibility
circumstances. This is a potential source of serious compli and Foreign Body Reaction to Intraneural Polyimide -based
cations that a stent having no part within the lumen can Implants,” Journal of BiomedicalMaterials Research . Part
never present. Recovery of an endoluminal stent is by A 106 (3 ):746 - 757 ; Klopfleisch , R . and Jung, F . 2017 . “ The
reentry and surgical cut-down, which is why once placed , an Pathology of the Foreign Body Reaction Against Biomate
endoluminal stent is removed only when removal cannot be rials,” Journal of Biomedical Materials Research . Part A
avoided . 105 (3 ) :927 - 940 ; Wang , Y ., Vaddiraju , S ., Gu, B ., Papadimi
[0335 ] An endoluminal stent has one means for avoiding trakopoulos, F ., and Burgess, D . J. 2015 . “ Foreign Body
migration protrusion into the surrounding lumen lining . Reaction to Implantable Biosensors : Effects of Tissue
The struts of a scaffold type stent or the wire of a coiled stent Trauma and Implant Size ,” Journal of Diabetes Science and
must be made thinner to further protrude into the lining Technology 9 (5 ):966 -977 ; Wazen , R . M ., Currey, J. A .,Guo ,
Properly placed , an intraluminal stent cannot migrate . The H ., Brunski, J. B ., Helms, J. A ., and Nanci, A . 2013 .
intraluminal component is embedded within the lumen wall , “Micromotion -induced Strain Fields Influence Early Stages
and located outside the substrate ductus or vessel, the of repair at Bone -implant Interfaces,” Acta Biomaterialia
magnetized stent-jacket can be fixed in position in several 9 (5 ):6663 -6674 ; Morais, J. M ., Papadimitrakopoulos, F .,
ways . Small optional suture loops or eyelets integral with the and Burgess, D . J. 2010 . “ Biomaterials/ Tissue Interactions :
jacket allow suture to be passed through for fixation to Possible Solutions to Overcome Foreign Body Response ,”
neighboring tissue. American Association of Pharmaceutical Scientists Journal
[0336 ] When suture is riveted or already connected by 12 ( 2 ): 188- 196 ).
suture loops to the ends of the jacket (referred to as end -ties ) [0340 ] It is during the granulation and maturation phase
as manufactured , the suture can be used as indicated , leading up to formation of the capsule — variable in duration
wrapped about the substrate ductus beyond the jacket mar depending upon the material used , but generally taking
gins, or both . Where vasotonic is pronounced or the activity about 2 to 4 weeks— that the tissue in contact with the stent
of the patient is conducive to displacement, one or two is especially vulnerable . “ Biomaterial surface properties
outrigger or dummy collars, shown as parts of an impasse play an important role in modulating the foreign body
jacket described below in sections 12 entitled Concept of the reaction in the first two to four weeks following implantation
Impasse -jacket and 115 entitled Miniball and Ferrofluid of a medical device, even though the foreign body reaction
impassable Jackets , or Impasse - jackets can be provided , and at the tissue/material interface is present for the in vivo
both the stent-jacket proper and the outriggers can be lifetime of the medical device.” ( Anderson , J. M ., Rodri
fastened as stated with suture . guez , A ., and Chang, D . T . 2008 . “ Foreign Body Reaction to
[0337 ] Magnetically susceptible endoluminal stents are Biomaterials,” Seminars in Immunology 20 ( 2 ): 86 - 100 ).
usually widely open pitched (space wound, open wound) [0341 ] However, the fibrous tissue with an endoluminal
non - overwound coils , that is , single turn or single wrap coils stent will be continuous over the length of the stent, inter
having wide gaps between the consecutive turns (winds, fering with endothelial or urothelial function , and only the
wraps), precluding drug elution as a partially remediating endoluminal stent will remain within the lumen to pose the
measure for the chronic irritation caused . A distinct irritant, risk of migration and present a distinct obstruction to any
endoluminal stents in the vascular tree of all kinds, but later transluminal procedure . Before fibrous encapsulation
especially those susceptible to a magnetic field have the forms, a stent placed within any native lumen presents the
potential not only to stimulate intimal hyperplasia leading to potential for ischemia -inducing intramedial protrusion ,
restenosis, but accelerate atherosclerosis , better endoluminal which can lead to an erosion , incision , and fistulation
stents ameliorating the problem with drugs such as everoli ( fistulization ) responsive to continuous irritation of physi
mus . ologically active tissue. That this is virtually certain with a
[ 0338 ] Rapamycin - derived drugs such as everolimus are direct blow and impossible when no stent is in the lumen is
used primarily as immunosuppressants , of special benefit clear.
with an endoluminal stent, which to preventmigration , must [0342 ] Endoluminal stents are potentially more injurious
maintain firm contact with the surrounding luminal wall , than medicinal treatment without stenting ; local adaptation
thereby provoking a foreign body adverse tissue reaction or notwithstanding, continued force of indentation , aggravated
immune response . Even in a nonallergic patient, such reac by the normal intrinsic vasotonic and pulsatile or peristaltic
tions are unavoidable ; however, the contact area with the motility of the conduit increases the risk of infection,
surrounding tissue of miniballs and stays is much less than interferes with , impairs the function of, and injures the
that of an endoluminal stent, and these too can be coated endothelium , urothelium , or other lining, thereby interfering
with drugs such as everolimus. In most cases , the immune with normal endothelial, urothelial, or digestive enzymatic
system will encapsulate the protrusive surfaces of a foreign function , and creating the risks of fistulation and perforation .
US 2019 /0247050 A1 Aug . 15 , 2019

In the arterial tree , such risk includes incisions , aneurysm , where any of numerous animals in whom tracheal collapse
pseudoaneurysm , and migration . The guide wire used to is progressive and the conventional remedy is surgical, an
deliver an endoluminal stent to the target level is itself a endoluminal stent that must be placed in lieu of surgery
source of numerous complications to include perforations, because the animal is too debilitated to tolerate the proce
fracture , and migration , to which the blunt or bull -nosed dure must remain in place indefinitely as an increasingly
leading tip of the delivery means described here — a barrel injurious obtrusion .
assembly — is not. To recover an errant endoluminal stent or [0347 ] That a magnetic intraluminal stent avoids both the
guidewire can involve greater surgical risk than the risk the problems of an endotracheal stent and the need for critically
stent was placed to ameliorate. more traumatic surgery is clear. Unless springy with restor
[0343] Endothelial dysfunction is central in causing coro ative force such that the contralateral side of the stent
nary artery disease and other expressions of chronic arterial remains in contact with the contralateral wall , the contral
inflammation . In any situation where the force of the mag ateral side of the stent is drawn away from the contralateral
netic field would adversely extract spherical implants, wide wall and further into the lumen . This adaxial shifting only
band - or tongue - shaped implants are used , the means for the increases interference with free luminal flow -through of any
insertion thereof- stay insertion tools - described herein . endoluminal stent. Even when remaining in flush contact
Where an endoluminal stent is in contact with the surround with the contralateral wall, numerous problems arise from
ing lumen wall, it blocks not only endothelial effusion into the presence in a native lumen of a foreign object, interfer
the lumen of prostacyclin , endothelin , and locally control ence if not prevention of subsequent transluminal treatment
ling angiotensin - II, but the vasodilator nitric oxide . Also not the least of these . For this reason , the advantage in an
denied over the contact area is access to the passing luminal extraluminal stent increases in proportion to the probability
contents , those native , blood , urine , endocrine secretion , that the patient will require a followup transluminal inter
gametes, or food , enzymes , hormones , other proteins, and vention .
therewith , nonendogenous agents, meaning medication . [0348 ] The incorporation of magnetically susceptible mat
[0344 ] Whether coiled or scaffold in type, when attracted ter in an implant allows the implant not only to attracted to
by an externalmagnet, an endoluminal stent is pulled further a magnet, but when placed in a radiofrequency alternated
into the lumen wall. In marked contrast to such endoluminal magnetic field , allows the implant to be heated . Thermo
stents, intramural stents lie outside the lumen ; the magneti plastic ablation by impregnating a neoplasm with suscep
cally susceptible component comprises a uniformly spaced tible implants and placing the patient in such a field has long
grouping of tiny implants infixed within the lumen wall been standard practice. The application of heat of value in
where the nonliving connective tissue elastic laminae protect numerous other contexts — site specifically controlling drugs
the other laminae (tissue layers , tunics ) consisting of living or surgical adhesives , for examplescaffold or coiled
cells which comprise the lumen wall from injury . Migration endoluminal stents heat the lumen wall not uniformly , but
or dislodgement a serious risk with any endoluminal stent, disproportionately where the struts or turns are in direct
such is not possible when no stent is inside the lumen . That contact with the lumen wall. Moreover, even though the
the tiny intramurally positioned susceptible implants are lesion to be heated is eccentric , such stents are limited to the
uniformly distributed over the area stented is of fundamental application of heat in this disjointed way without deviation
significance . from radial or rotational symmetry , thus heating sectors of
[ 0345 ] Disposed thus, attraction by an external magnet, the ductus not beneficially and perhaps adversely affected
rather than concentrating the attractive force over a small thus. By contrast, intramural stenting allows discretionary
contact area between the stent and the lumen wall, uniformly eccentric or radially asymmetrical heating .
lifts the wall abaxially or outward as a continuous sheet over [0349] The miniballs , or tiny spherules , and bands, or
the completely surrounding area of the stent rather than stays, referred to herein can consist of magnetically suscep
concentrating a force of indentation in excess of that tible matter, usually encapsulated , medication , radiation
imposed by an endoluminal stent under any circumstances emitting ‘ seeds,' or any of these in combination . To impart
over a restricted area , increasing the risks of injury and targetability to medication spherules, for example, a mag
incision . Such a stent can , however , accommodate eccentric netized ductus side- entry jacket or nonjacketing connector is
or asymmetrical lesions according to the distribution of the positioned at the target site , and magnetically susceptible
implants . In most cases , however, the jacket entirely sur matter, usually magnetite , maghemite , or iron powder, added
rounding the substrate native conduit or ductus, the mag to the spherules. Ferrofluids conveying magnetically carried
netic attraction is uniformly exerted entirely about the drugs ratioactive or not can thus be steered to the treatment
conduit or ductus. Accordingly, rather than for the stent to be site without the need for intrinsic affinity , such as that of
forcibly attracted into the lumen wall, intramurally posi iodine for the thyroid gland . All drugs harbor adverse side
tioned implants lift the lumen wall uniformly round and effects and have toxic dose limits . Two types of drugs in
about toward the surrounding magnetized jacket. particular are , however, more injurious when admitted into
[0346 ] In the trachea, where an intramural magnetically the general circulation .
susceptible stent as described herein is superior to the [0350 ] These are immunosuppressives , which expose the
considerably traumatic conventional surgical procedure for patient to infection , and anticancer drugs, which are toxic to
correction , an endoluminal stent obstructs mucociliary clear normal as well as malignant tissue . Minimally invasive and
ance , facilitating the accumulation of debris, increasing the minor surgical procedures make possible the implantation of
risk of infection . In a neonate , in whom tracheomalacia magnetically susceptible drug - carrier releasing and attract
infrequently appears as a condition encountered when the ing implants that allow treatments intermediate between
tracheal cartilages remain premature at birth , the short- term medical management and open surgery . More specifically ,
placement of an endoluminal stent when there is a risk of by allowing the circumscription of target tissue for the
suffocation then prudent. However, in veterinary practice , delivery of drugs or other therapeutic substances, minor
US 2019 /0247050 A1 Aug. 15 , 2019

surgery to place such implants can be used to significantly overgrowth is likely to lead to gastric infection, the inter
expand the reach of medical management. The methods ference with iron absorption to iron deficiency anemia ,
described herein represent a level of treatment intermediate possibly pica , the interference with vitamin B2 ( niacin )
between medical management and surgery, that of medical absorption to pellagra, and the metaplasia to additional
surgery, or surgery to enable or facilitate medical manage malabsorption such as the loss of parietal cells, hence ,
ment. gastric intrinsic factor needed to absorb vitamin B . ( coba
[ 0351] The presupposition that surgery should always be lamin ).
considered the last resort so that the administration of drugs , [0354 ] This then can lead to pernicious anemia , megalo
all potentially harmful, to temporarily alleviate the symp blastic anemia, and gastric adenocarcinoma, as well as open
toms of chronic disorders on a long -term if not life - long the way for numerous additional gastrointestinal, neuropsy
basis is superior therapy compared to performing a one - time chiatric , and systemic disorders . Untreated , this degenera
relatively safe surgical procedure is often micsonceived . tive cascade results in death . However, the administration of
Examples are many and apply to almost if not all drugs used antibiotics to compensate for infectious consequences of the
thus, the most common being: reduction in stomach acidity also destroys beneficial intes
[0352 ] a. Antacids in lieu of endoscopic repair of an hiatus tinal microbiota ( dysbiosis , dysbacteriosis ), risking leaky
hernia , and/ or highly selective vagotomy, or the placement gut syndrome. This also allows pathogenic microbiota unaf
of a special esophagogastric collar about the lower esopha fected by the antibiotic to survive, reproduce, and become
geal sphincter, or transoral incisionless endoscopic fundopli more resistant to the antibiotic , a misapplication of antibi
cation (see , for example , Fass , R . 2017 . “ An Overview of otics that contributes to the growing problem of drug resis
Transoral Incisionless Fundoplication and Magnetic Sphinc tant pathogens, and may prompt the administration of pro
ter Augmentation for GERD ,” Gastroenterology and Hepa biotics to repopulate the gut with beneficial microbiota .
tology (New York , N . Y .) 13 ( 1):50 -52 ; Trad , K . S ., Fox, M . [0355 ] Especially in patients with health problems, probi
A ., Simoni, G ., Shughoury , A . B ., Mavrelis, P . G ., and 3 otics occasionally cause adverse sequelae , to include unde
others 2017 . “ Transoral Fundoplication Offers Durable sirable gene transfer, digestive problems, systemic infec
Symptom Control for Chronic GERD : 3 -year Report from tions, equivocally, endocarditis, bloating, flatulence, in
the TEMPO [ Transoral incisionless fundoplication ] Eso larger doses, diarrhea , an increase in gastroesophageal
phyX vs Medical Proton Pump Inhibitor Open Label Trial] reflux, and/ or other problems ( see , for example , Aaron , J. G .,
Randomized Trial with a Crossover Arm ,” Surgical Endos Sobieszczyk , M . E ., Weiner, S . D ., Whittier , S ., and Lowy,
copy 31(6 ): 2498 - 2508 ; Huang, X ., Chen , S ., Zhao , H ., Zeng, F . D . 2017 . “ Lactobacillus rhamnosus Endocarditis after
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with a Review of the Literature ,” American Journal of Pustulosis Resembling Toxic Epidermal Necrolysis Caused
Gastroenterology 93 ( 5 ):822 - 826 ; García Rodríguez, L . A ., by Famotidine,” Acta Dermato - venereologica 83 ( 1 ):76 -77 ;
Wallander, M . A ., and Stricker, B . H . 1997 . “ The Risk of Marcus , E . L ., Clarfield , A . M ., Kleinman , Y., Bits, H .,
Acute Liver Injury Associated with Cimetidine and Other Darmon , D ., Da’ as , N . 2002 . “ Agranulocytosis Associated
Acid -suppressing Anti -ulcer Drugs,” British Journal of with Initiation of Famotidine Therapy,” Annals of Pharma
Clinical Pharmacology 43 (2 ):183 - 188 ; Kallal , S . M . and cotherapy 36 ( 2 ):267-271 ; von Einsiedel, R . W ., Roesch - Ely ,
Lee, M . 1996 . “ Thrombotic Thrombo -cytopenic Purpura D ., Diebold , K ., Sartor, K ., Mundt, C ., and Bergemann , N .
Associated with Histamine H2 -receptor Antagonist 2002 . “ H ( 2 )-histamine Antagonist (Famotidine ) Induced
Therapy ,” Western Journal of Medicine 164 (5 ):446 -448 ; Adverse CNS Reactions with Long -standing Secondary
US 2019 /0247050 A1 Aug. 15 , 2019

Mania and Epileptic Seizures,” Pharmacopsychiatry 35 ( 4 ): Juto , J. E . 1995 . “ Four-week Use of Oxymetazoline Nasal
152 - 154 ; Yuan , R . Y ., Kao, C . R ., Sheu , J. J., Chen , C . H ., Spray (Nezeril) Once Daily at Night Induces Rebound
and Ho, C . S . 2001. “ Delirium Following a Switch from Swelling and Nasal Hyperreactivity ,” Acta Otolaryngo
Cimetidine to Famotidine,” Annals of Pharmacotherapy logica 115 ( 1 ):71 - 75 ) .
35 (9 ): 1045- 1048 ; Rodgers, P . T . and Brengel, G . R . 1998 . [0363] Most nasal decongestants provoke rebound vaso
" Famotidine-associated Mental Status Changes,” Pharma dilative congestive swelling of the mucosa , or rhinitis medi
cotherapy 18 (2 ): 404 -407 ; Odeh , M . and Oliven , A . 1998 . camentosa . Other side effects of al adrenergic receptor
“ Central Nervous System Reactions Associated with Famo agonists and a2 adrenergic receptor partial agonists such as
tidine : Report of Five Cases ,” Journal of Clinical Gastro oxymetazoline, xylometazoline, naphazoline, and phe
enterology 27 (3 ): 253 - 254; Brunner, M ., Vardarman , E ., nylephrine are drowsiness , epistaxis (nosebleed ), rebound
Goldermann , R ., Goerz , G ., Niederau , D ., Merk , H . F ., and inflammation , nasal dryness , and some effect on hearing
Scharffetter -Kochanek , K . 1995. “ Toxic EpidermalNecroly (Teixeira , M . S ., Alper, C . M ., Martin , B . S ., Helal, N .,
sis (Lyell Syndrome) Following Famotidine Administra Doyle , B . M ., and Doyle , W . J. 2016 . " Oxymetazoline
tion ,” British Journal of Dermatology 133 (5 ) :814 -815 ; Applied Topically to the Nasal Mucosa Decreases Trans
Ament, P. W ., Roth , J. D ., and Fox , C . J. 1994 . “ Famotidine mucosal Nitrous Oxide Exchange for the Middle Ear,"
induced Mixed Hepatocellular Jaundice ,” Annals of Phar Annals of Otology, Rhinology, and Laryngology 125 ( 5 ):400
macotherapy 28 ( 1 ):40 -42 ; Ahmad , S . 1991. “ Famotidine 407 ). Phenylephrine hydrochloride can cause bradycardia .
and Cardiac Arrhythmia ,” Drug Intelligence and Clinical (Farkas, A ., Dempster, J., and Coker, S . J. 2008 . “ Importance
Pharmacy : The Annals of Pharmacotherapy 25 (3 ):315 ; Nor of Vagally Mediated Bradycardia for the Induction of Tor
wood , J., Smith , T . M ., and Stein , D . S . 1990 . “ Famotidine sade de Pointes in an In Vivo Model,” British Journal of
and Hyperpyrexia ,” Annals of Internal Medicine 112 ( 8 ): Pharmacology 154 (5 ): 958 - 970 ).
632 ; Henann , N . E ., Carpenter, D . U ., and Janda , S . M . 1988. [0364 ] Steroid nasal sprays can cause burning , itching , and
" Famotidine -associated Mental Confusion in Elderly dryness of the nasal and pharyngeal mucosae , cephalalgia ,
Patients,” Drug Intelligence and Clinical Pharmacy 22 ( 12 ) : or headache , epistaxis, or nosebleed , running nose , sneezing ,
976 - 978 ). Famotidine induces urticaria in those allergic but immunosuppression leading to infection, serious effects on
has value in the treatment of urticaria (Fedorowicz , Z ., van vision such as glaucoma, hives , angioedema, anaphylaxis ,
Zuuren , E . J., and Hu , N . 2012 . “ Histamine H2-receptor dysmenorrhea , and endocrine problems such as weight gain
Antagonists for Urticaria ,” Cochrane Database of System (Mangan , T. 2017 . “ Side Effects ofNasal Steroid Spray,” at
atic Reviews (3 ):CD008596 ; Watson , N . T ., Weiss, E . L ., and https://www . livestrong .com /article/ 234291-types -of-pre
Harter, P. M . 2000. “ Famotidine in the Treatment of Acute scription - nasal- sprays/). Discrete organs can be targeted
Urticaria ,” Clinical and Experimental Dermatology 25 ( 3 ): with any drug that can be prepared for delivery to and
186 -189 ). release by an impasse - jacket placed at an inlet to the organ
[ 0361] Famotidine may be of greater value for off-label such as the renal artery to target a kidney or other inlet such
than conventional use ( Joe , S ., Kim , E ., Park , J., Lee , D ., as a ureter to target the bladder. If take -up of the drug by the
Son , J., and Kim , H . 2017 . “ Famotidine - induced Reversal of target organ would leave a potentially harmful residue pass
Meperidine -related Serotonin Syndrome: A Case Report” into the outflow , then an impasse -jacket at the outlet is used
Korean Journal of Anesthesiology 70 (2 ):221 -223; Mes to release a reversal agent, thus circumscribing a delimited
kanen , K ., Ekelund, H ., Laitinen , J., Neuvonen , P. J., portion ofthe circulation and its territory for exposure to the
Haukka , J., Panula , P ., and Ekelund , J. 2013 . “ A Random drug .
ized Clinical Trial of Histamine 2 Receptor Antagonism in 103651. These examples are cited to make the general point
Treatment-resistant Schizophrenia ,” Journal of Clinical that minor surgery should not perfunctorily be relegated to
Psychopharmacology 33 (4 ): 472 -478 ; Rosenberg , P. B ., the course of last resort, without regard to remedies for these
Rosse , R . B ., John , S . K ., Kendrick , K ., Fay -McCarthy, M ., conditions specifically using means described herein , con
and 4 others 1996 . “ Smooth Pursuit Eye Movements in the ventional measures for alleviating hyperacidity and nasal
Evaluation of Famotidine Adjunctive Therapy of Schizo congestion without the use of drugs specified above . Endog
phrenia : A Preliminary Report,” Clinical Neuropharmacol enous histamine type H , is a causative agent for hyperchlo
ogy 19 (3 ):276 - 281 ). rhydria (hyperacidity, ' heatburn ') (see, for example , Mejia ,
[0362 ] b . Nasal decongestants in lieu of balloon rhino A . and Kraft , W . K . 2009 . “ Acid Peptic Diseases: Pharma
plasty or outfracture of the swollen lower turbinates with cological Approach to Treatment,” Expert Review of Clini
widening of the nasal passages through cautery . Oxymeta cal Pharmacology 2 (3 ): 295 -314 ; Scarpignato , C ., Pelosini,
zoline hydrochloride, for example , is associated with numer I., and Di Mario , F . 2006 . “ Acid Suppression Therapy :
ous systemic side effects (see , for example, Dokuyucu, R ., Where Do We Go From Here ? ,” Digestive Diseases (Basel ,
Gokce , H ., Sahan , M ., Sefil , F ., Tas , Z . A ., and 4 others 2015 . Switzerland ) 24 ( 1- 2 ):11-46 ; Beales, I. L . 2002. “ Easy as 1 ,
“ Systemic Side Effects of Locally Used Oxymetazoline,” 2 , 3 ? Histamine Receptors and Gastric Acid ,” Gut 50 (6 ):
International Journal of Clinical and Experimental Medi 747 -748 ).
cine 8 (2 ): 2674 - 2678 ; Ramey , J. T., Bailen , E ., and Lockey, [0366 ] Histamine Types H and Hz are the causative
R . F . 2006 . “ Rhinitis Medicamentosa ,” Journal of Investi agents for swollen nasal membranes ( see , for example ,
gational Allergology and Clinical Immunology 16 (3 ): 148 Bosma, R ., Witt, G ., Vaas, L . A . I., Josimovic , I., Gribbon ,
155; Graf, P. 1997 . “ Rhinitis Medicamentosa : Aspects of P ., and 3 others 2017 . “ The Target Residence Time of
Pathophysiology and Treatment,” Allergy 52 (40 Supple Antihistamines Determines Their Antagonism of the G
ment): 28 - 34 ; Graf, P. and Hallén , H . 1996 . “ Effect on the Protein - Coupled Histamine H1 Receptor," Frontiers in
Nasal Mucosa of Long- term Treatment with Oxymetazoline , Pharmacology 8 :667 ; Procopiou , P. A ., Ford , A . J., Gore, P .
Benzalkonium Chloride , and Placebo Nasal Sprays ,” Lar M ., Looker, B . E ., Hodgson , S . T., and 7 others 2017 .
yngoscope 106 (5 Part 1 ):605 -609 ; Graf, P ., Hallén , H ., and “ Design of Phthalazinone Amide Histamine Hi Receptor
US 2019 /0247050 A1 Aug. 15 , 2019

Antagonists for Use in Rhinitis,” American Chemical Soci develop resilience so that no surgical remedy should be
ety Medicinal Chemistry Letters 8 (5 ):577 -581 ; Khanfar, M . attempted . In this instance , the short- term placement of a
A ., Affini, A ., Lutsenko , K ., Nikolic , K ., Butini, S ., and stent with close monitoring of the condition is justified to
Stark , H . 2016 . “ Multiple Targeting Approaches on Hista eliminate the risk of suffocation .
mine H3 Receptor Antagonists,” Frontiers in Neuroscience [0370 ] d . Another example of the eventual harm which can
10 : 201 ; Slack , R . J., Russell, L . J., Hall , D . A ., Luttmann, M . accrue if effective measures are not taken at the outset is the
A ., Ford , A . J ., and 5 others 2011 . “ Pharmacological Char placement of a conventional stent or stent- graft to correct a
acterization of GSK1004723 , a Novel, Long -acting Antago more severe coarctation of the aorta where surgical recon
nist at Histamine H ( 1 ) and H ( 3 ) Receptors,” British Journal struction ab initio , while itself subject to adverse sequelae ,
of Pharmacology 164 (6 ): 1627 - 1641; Lieberman , P . 2009. is currently still the more reliable approach for long term
“ The Role of Antihistamines in the Treatment of Vasomotor repair , especially in the young if not too ill to tolerate the
Rhinitis,” World Allergy Organization Journal 2 (8 ): 156 surgery, then justifying the placement of a covered stent or
161; Taylor-Clark , T ., Sodha , R ., Warner, B ., and Foreman , stent-graft (see, for example , Promphan , W . and Qureshi, S .
J. 2005 . “ Histamine Receptors that Influence Blockage of A . 2016 . “ What Interventional Cardiologists are Still Leav
the Normal Human Nasal Airway,” British Journal of Phar ing to the Surgeons ? ,” Frontiers in Pediatrics 4 :59 ; Torok ,
macology 144 (6 ):867- 874). R . D ., Campbell, M . J., Fleming, G . A ., and Hill, K . D . 2015 .
[0367] For most conditions, the means described herein “ Coarctation of the Aorta : Management from Infancy to
provide alternatives to the administration of potentially Adulthood ,” World Journal of Cardiology 7 ( 11 ):765 -775 ;
harmful drugs on a long -term if not lifelong basis . Less Bruckheimer, E . and Pedra , C . A . C . 2013 . “ Stenting Options
serious conditions, where surgical access to the nidal site or for Coarctation of the Aorta ,” Interventional Cardiology
sites is relatively direct, are treated by connecting a jacket Clinics 2 ( 1 ): 115 - 129 ; Luijendijk , P., Bouma, B . J.,
for the directly targeted release of drugs, for example , into Groenink , M ., Boekholdt, M ., Hazekamp, M . G ., and 4
one or more supply arteries proximate to the affected organ others 2012 . “ Surgical Versus Percutaneous Treatment of
or tissue. Alternatively, a tissue surface connector is affixed Aortic Coarctation : New Standards in An Era of Transcath
to the surface of the affected organ or tissue so that the eter Repair," Expert Review of Cardiovascular Therapy
styloid device it mounts , such as a hollow needle , angio 10 ( 12 ): 1517 - 1531; Kische , S ., Schneider, H ., Akin , I.,
scope , charge coupled device camera (charge coupled device Ortak , J., Rehders , T . C ., Chatterjee , T., Nienaber, C . A ., and
camera , or fluorescence lifetime imaging microscopy ( see Ince, H . 2010 . “ Technique of Interventional Repair in Adult
below in section 4 ( 3 ), entitled Nontumefacient Enabled Aortic Coarctation ,” Journal of Vascular Surgery 51 (6 ):
Attainment of Implantable Ductus -intramural Thickness ), 1550- 1559 ; Egan , M . and Holzer, R . J. 2009. " Comparing
intravascular ultrasound probe ,high intensity forcused ultra Balloon Angioplasty, Stenting and Surgery in the Treatment
sound probe , or excimer laser, is stably oriented , or aimed , of Aortic Coarctation ,” Expert Review of Cardiovascular
within the substrate organ or tissue. Therapeutic and diag Therapy 7 (11): 1401- 1412 ), would prove more sufficient and
nostic apparatus using a nonimplanable conrol console are durable.
attached to the implant system through a socket in the body [0371] Often effective for avoiding a more radical coarc
surface port. toplasty or coarterectomy in an adult, in a neonate or infant,
[0368] The placement of these involves relatively minor conventional covered self - expanding stents or stent grafts
surgery performed under local anesthesia . More serious may not hold fast and migrate as the aorta grows, migration
conditions warrant more intricate surgery under general occasionally occuring in an adult as well ( see , for example ,
anesthesia ; however, in all cases, the fact that drugs and Rad , E . M .,Mortezaeian , H ., Pouraliakbar, H . R ., and Hijazi,
other treatment modalities are directly targeted means that Z . M . 2017 . “ Pitfalls of Stenting Coarctation of an Angu
adverse side effects are minimized if not eliminated . This lated Right Circumflex Aortic Arch in Goldenhar Syn
may make possible the problem -free use of long available drome,” Annals ofPediatric Cardiology 10 (2 ): 194 - 196 ; Jha ,
drugs to which many patients have an adverse reaction over N . K ., Tofeig , M ., Kumar, R . A ., ElTahir , A ., Athar , S . M .,
time and for which certain patients have little if any toler AlHakami, A ., Khan , A ., and Khan , M . D . 2016 . “ Stent
ance when the drugs are systemically circulated . Similar to Dilatation of Atretic Aortic Coarctation in an Adult - Case
opting for the use of nontargeted , systemically circulated report and Literature Review ,” Journal of Cardiothoracic
drugs is the use of appliances that pose the risk of compli Surgery 11 : 10 ; Forbes , T . J. and Gowda , S . T. 2014 . “ Intra
cations. vascular Stent Therapy for Coarctation of the Aorta ,” Meth
[0369] c . In veterinary practice , for example , the postpon odist Debakey Cardiovascular Journal 10 (2 ): 82 - 87 ; Ang, H .
ing of surgery , instead opting for the use of a tracheal stent L ., Lim , C . W ., Hia , C ., Yip , J., and Quek , S . C . 2014 .
to suppress the symptoms associated with tracheal collapse " Coarctation of the Aorta : Nonsurgical Treatment Using
(the progressive loss in resilience of the tracheal cartilage Stent Implantation,” Singapore Medical Journal 55 (6 ): 302
rings ) interferes with mucociliary clearance , promoting the 304 ; Ringel, R . E ., Vincent, J ., Jenkins, K . J. , Gauvreau , K .,
accumulation of mucus and the inviting of infection . In this Moses, H ., Lofgren , K ., and Usmani, K . 2013 . “ Acute
case , however , the conventional surgical remedy calls for Outcome of Stent Therapy for Coarctation of the Aorta :
extensive incision , dissection , and stitching. While requiring Results of the Coarctation of the Aorta Stent Trial," Cath
general anesthesia , the alternative remedy set forth herein , eterization and Cardiovascular Interventions 82 ( 4 ):503
delineated below in sections VII2c ( 1 )( a ) and VII2c ( 1 )( b ), 510 ; Yaylali, Y . T., Evrengul, H ., and Uludag, B . 2013 .
for the alleviation of tracheal collapse involves minimal “ Successful Management of a Proximally Migrated Stent in
surgery . This condition , which presents in animals, is not the a Middle -aged Woman with Unnoticed Native Aortic Coarc
same as the trachemalacia occasionally seen in an infant The tation ,” International Journal of Cardiology 168 ( 1 ): e19 -21;
latter spontaneously resolves of its own accord as the Kannan , B . R . and Srinivasan , M . 2012 . “ Stent Migration
tracheal rings, premature and lacking in resilience at birth , During Transcatheter Management of Coarctation of Aorta,"
US 2019 /0247050 A1 Aug . 15 , 2019
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Catheterization and Cardiovascular Interventions 79 ( 3 ): V ., Khelif, K ., Moulin , D ., Vliers, A ., Jaumin , P., and
408 -413; Nikolov, D ., Grigorova , V ., Petrov , I., and Ivanov, Chalant, C . H . 1992. “ Surgical Repair of Coarctation of the
V . 2011 . “ Emergency Surgical Intervention After Unsuc Aorta in Infants Under One Year of Age . Long-term Results
cessful Percutaneous Transluminal Angioplasty and Stenting in 146 Patients Comparing Subclavian Flap Angioplasty and
of Aortic Coarctation ,” Interactive Cardiovascular and Tho Modified End -to -end Anastomosis,” Journal of Cardiovas
racic Surgery 13 ( 1 ): 98 - 100 ; Forbes, T . J.,Garekar, S ., Amin , cular Surgery ( Turin , Italy ) 33 (2):216 -222), this in addition
Z ., Zahn , E . M ., Nykanen , D ., and 19 others 2007. “ Proce to the risks besides abnormal blood pressure following
dural Results and Acute Complications in Stenting Native surgery for adults ( see , for example , Bruckheimer, E . and
and Recurrent Coarctation of the Aorta in Patients over 4 Pedra , C . A . C . 2013 , Op cit .).
Years of Age : A Multi- institutional Study," Catheterization 103741 e . Yet another example of the eventual harm which
and Cardiovascular Interventions 70 (2 ):276 - 285 ; Karl, T. R . accrues if effective measures are not taken at the outset is
2007 . “ Surgery is the Best Treatment for Primary Coarcta reconstruction of a severely malformed neonate or infant
tion in the Majority of Cases,” Journal of Cardiovascular heart when a replacement is available . No repair of more
Medicine (Hagerstown, Md.) 8 ( 1):50 - 56 ). Coarctation is complex congenital heart defects however skilled achieves
further addressed below . normal circulatory function , surgical remediation often
[0372 ] While in an adult , growth is not a risk for dislodge properly relegated to a bridging procedure until a replace
ment so that stenting is more dependable than in an infant , mentheart can be found. So long as development continues
in the young , stenting may be chosen as a bridging (holding , with a badly defective heart, the lack of normal circulation
salvaging) strategy until the patient, usually very ill, is ready is propagated throughout the body as a chronic hypoxia that
to undergo reconstructive surgery ( see , for example , Bugeja , results in progressive multiple , indeed global, organ dam
J., Cutajar, D ., Zahra , C ., Parascandalo , R ., Grech , V ., and age, severely affecting the brain , liver, and kidneys, and a
DeGiovanni, J. V . 2016 . “ Aortic Stenting for Neonatal life limited by a continuous and inexorable increase in left
Coarctation of the Aorta — When Should this be Consid ventricular load that comes with growth to add to the
ered ?," Images in Paediatric Cardiology 18 ( 3 ): 1 -4 ; Hapo intrinsic antecedent dysfunction until left ventricular over
niuk , I., Chojnicki, M ., Steffens, M ., Jaworski, R ., Szofer load can no longer be withstood .
Sendrowska , A ., and 5 others 2013 . “ Miniinvasive [0375] That following replacement, using the means
Interventional Bridge to Major Surgical Repair of Critical described herein , immunosuppressive , antimicrobial, and
Aortic Coarctation in a Newborn with Severe Multiorgan anti-inflammatory drugs can be automatically and directly
Failure ” Wideochirurgia Inne TechnikiMaloinwazyjne [Vid targeted to the transplant substantially diminishes the quality
eosurgery and Other Miniinvasive Techniques ] 8 (3 ):244 of life -degrading need for the patient to self- administer these
248; Sreeram , I., Sreeram , N ., and Bennink, G . 2012 . for life , and the fact that drug delivery is directly pipe
“ Palliative Stent Implantation for Coarctation in Neonates targeted to the transplant with or without a background
and Young Infants ,” Annals of Pediatric Cardiology 5 (2 ): systemic dose means that the severe side effects of immu
145 - 150 ). nosuppressives with increased exposure to infection is mini
[0373 ] Other growth -related problems threaten the young mized if not eliminated .
patient following surgical repair: especially when ductal 0376 ] Prompt replacement of a univentricular or other
(ductus arteriosus ) tissue is not completely resected , surgery wise severely malformed and not adequately repairable heart
is not necessarily free of numerous growth - related adverse in the younghas inadequate durability . Although less so with
sequelae ( Torok , R . D ., Campbell, M . J., Fleming , G . A ., and increasing pharmaceutical experience , remedial procedures
Hill, K . D . 2015 . “ Coarctation of the Aorta : Management only alter, but do not dispel, the pulmonary vascular resis
from Infancy to Adulthood ," World Journal of Cardiology tance and hypertension that makes the condition harmful and
7 (11):765-775 ; Vergales, J. E ., Gangemi, J. J., Rhueban , K . precarious. By instantly and precisely responding to altera
S ., and Lim , D . S . 2013 . “ Coarctation of the Aorta — The tions in adverse pulmonary arterial indicia with new and
Current State of Surgical and transcatheter Therapies ,” Cur improved drugs , an automatic prosthetic disorder response
rent Cardiology Reviews 9 ( 3 ):211 -219 ; Rosenthal, E . 2005 . system should significantly lessen hypertension at every
“ Coarctation of the Aorta from Fetus to Adult: Curable stage in treatment , extend the periods between successive
Condition or Life Long Disease Process ?,” Heart (journal of stages in surgical correction , and if not accomplished at the
the British Cardiac Society ) 91 (11): 1495 - 1502 ; Head , C . E ., outset, transplantation and if still necessary, retransplanta
Jowett, V . C ., Sharland, G . K ., and Simpson , J. M . 2005. tion . The overall result is an extended and less oppressive
“ Timing of Presentation and Postnatal Outcome of Infants life .
Suspected of Having Coarctation of the Aorta During Fetal [0377 ) A completed Fontan repair ameliorates but does not
Life ," Heart (journal of the British Cardiac Society ) 91 (8 ): alleviate the key problem of pulmonary vascular resistance ,
1070 - 1074 ; Backer, C . L ., Mavroudis, C ., Zias, E . A ., Amin , and its reinstatement following transplantation combined
Z ., and Weigel, T. J. 1998 . “ Repair of Coarctation with with growth will eventually necessitate retransplantation
Resection and Extended End-to - end Anastomosis,” Annals ( see, for example , Hauck , A ., Porta , N ., Lestrud , S ., and
of Thoracic Surgery 66 ( 4 ): 1365 - 1371; Van Son , J . A ., Falk , Berger , S . 2017 . “ The Pulmonary Circulation in the Single
V ., Schneider, P., Smedts , F ., and Mohr, F . W . 1997 . “ Repair Ventricle Patient,” Children (Basel, Switzerland ) 4 ( 8 ). pii:
of Coarctation of the Aorta in Neonates and Young Infants ,” E71; Egbe, A . C ., Connolly . H . M ., Miranda, W . R .,
Journal of Cardiac Surgery 12 ( 3 ): 139 - 146 ; Rajasinghe, H . Ammash , N . M ., Hagler, D . J., Veldtman , G . R ., and
A ., Reddy, V . M ., van Son , J. A ., Black , M . D .,McElhinney , Borlaug , B . A . 2017 . “ Hemodynamics of Fontan Failure :
D . B ., Brook , M . M ., and Hanley, F . L . 1996 . “ Coarctation The Role of Pulmonary Vascular Disease," Circulation .
Repair Using End -to - side Anastomosis ofDescending Aorta Heart Failure 10 ( 12 ). pii: e004515 ; Kindel, S . J . and Everitt,
to Proximal Aortic Arch ,” Annals of Thoracic Surgery M . D . 2016 . “ A Contemporary Review of Paediatric Heart
61 ( 3 ):840- 844 ; Rubay, J. E ., Sluysmans, T., Alexandrescu , Transplantation and Mechanical Circulatory Support,” Car
US 2019 /0247050 A1 Aug. 15 , 2019
15

diology in the Young 26 (5 ):851 -859; Fredenburg , T. B ., Sadeghpour, A ., Jalali , A . H ., and 3 others 2017, Op cit.), or
Johnson , T . R ., and Cohen , M . D . 2011. “ The Fontan septation procedure to divide the one functional ventricle
Procedure : Anatomy, Complications, and Manifestations of (Bove, E . L . 1986 , Op cit.), or a transplant, an automatic
Failure,” Radiographics 31 (2 ):453 -463 ; Maxwell, B . G ., adaptive disorder response system as delineated in sections
Sheikh , A . Y ., Ajuba- Iwuji, C . C ., Heitmiller, E . S ., and XX and XX below will provide better support before or with
Vricella, L . A . 2015 . “ Pulmonary Vascular Resistance Index any resolution .
and Mortality after Paediatric Heart Transplant,” Cardiology [0380 ] More specifically, the controlling program adap
in the Young 25(6 ): 1141- 1147 ; Snarr, B . S ., Paridon , S . M ., tive , once placed in a prenate or neonate , the system will
Rychik , J., and Goldberg , D . J. 2015. “ Pulmonary Vasodi continuously optimize medicinal therapy at every succeed
lator Therapy in the Failing Fontan Circulation : Rationale ing stage in the disease and its treatment, to include that
and Efficacy,” Cardiology in the Young 25 (8 ): 1489 - 1492 ; preceding any treatment, that following preliminary proce
Michielon , G ., Carotti, A ., Pongiglione , G ., Cogo , P., anf dures such as banding and cavopulmonary connection , and
Parisi, F . 2011. " Orthotopic Heart Transplantation in any measures applied thereafter to include Fontan - prepara
Patients with Univentricular Physiology ,” Current Cardiol tory (Norwood , Hemi- Fontan , or Glenn ) ( see , for example ,
ogy Reviews 7 (2 ):85 - 91 ;Gazit , A . Z . and Canter, C . E . 2011. Liang, F., Senzaki, H ., Yin , Z ., Fan , Y., Sughimoto , K ., and
“ Impact of Pulmonary Vascular Resistances in Heart Trans Liu , H . 2013 . “ Transient Hemodynamic Changes upon
plantation for Congenital Heart Disease,” Current Cardiol Changing a BCPA [bidirectional cavopulmonary (Glenn )
ogy Reviews 7 (2 ):59 -66 ). anastomosis ) into a TCPC [total cavopulmonary connection ]
[ 0378 ] Even with banding of the pulmonary artery to in Staged Fontan Operation : A Computational Model
suppress hypertension and a superior cavopulmonary con Study ,” Scientific World Journal 2013 :486815 ; Podzolkov,
nection operation , leaving otherwise untreated a univen V . P., Zelenikin , M . M ., Yurlov, I. A ., Kovalev, D . V.,
tricular heart results in the progressive degradation and Mchedlishvili, K . A ., Putiato , N . A ., and Zaets, S . B . 2011 .
maldevelopment of all organ systems from the moment of " Immediate Results of Bidirectional Cavopulmonary Anas
birth (Al-Dairy , A ., Dehaki, M . G ., Omrani, G ., Sadeghpour, tomosis and Fontan Operations in Adults ,” Interactive Car
A ., Jalali, A . H ., and 3 others 2017 . “ The Outcomes of diovascular and Thoracic Surgery 12 (2 ): 141 - 145 ; Giglia , T.
Superior Cavopulmonary Connection Operation : A Single M . and Humpl, T . 2010 . “ Preoperative Pulmonary Hemo
Center Experience,” Brazilian Journal of Cardiovascular dynamics and Assessment of Operability: Is There a Pul
Surgery 32 (6 ):503 -507 ; Kalantre, A ., Sunil, G . S., and monary Vascular Resistance that Precludes Cardiac Opera
Kumar, R . K . 2016 . “ Pulmonary Venous Hypertension May tion ?,” Pediatric Critical Care Medicine 11 ( 2 Supplement) :
Allow Delayed Palliation of Single Ventricle Physiology S57 - 569 ), then a Fontan , and with the means described
with Pulmonary Hypertension ,” Annals of Pediatric Cardi herein , best followed by a transplant.
ology 9 ( 2 ): 147 - 152 ; Alsoufi, B ., McCracken , C ., Schlosser, [0381] That is, the will adaptively dispense medication to
B ., Sachdeva , R ., Well , A ., and 3 others 2016 . “ Outcomes of optimize circulation before repair or replacement. Quick to
Multistage Palliation of Infants with Functional Single Ven adapt, it therefore better sustains the pre - and post - Fontan or
tricle and Heterotaxy Syndrome,” Journal of Thoracic and other repair in preparation for a transplant, and then better
Cardiovascular Surgery 151(5 ):1369 - 1377 .e2 ; Alsoufi, B ., sustains the transplant, extending the time until — at the
Manlhiot, C ., Ehrlich , A ., Oster, M ., Kogon , B ., and 4 others present state in development of transplant support the
2015 .“ Results of Palliation with an Initial Pulmonary Artery effects of residual pulmonary hypertension necessitate
Band in Patients with Single Ventricle Associated with retransplantation . In favorable circumstances and with opti
Unrestricted Pulmonary Blood Flow ," Journal of Thoracic mized pharmacy , the need for a retransplantation might be
and Cardiovascular Surgery 149 (1 ) :213 - 220; Schwartz, M . avoided .
C ., Sullivan , L ., Cohen , M . S ., Russo , P ., John , A . S ., Guo , [0382] Deferral of transplantation following a Fontan
R ., Guttenberg, M ., and Rand, E . B . 2012 . “ Hepatic Pathol repair can actually preclude transplantation ( see , for
ogy May Develop Before the Fontan Operation in Children example , Dijkstra , H ., Wolff , D ., van Melle , J. P ., Bartelds ,
with Functional Single Ventricle: An Autopsy Study,” Jour B ., Willems, T. P., and 6 others 2017 . “ Diminished Liver
nal of Thoracic and Cardiovascular Surgery 143( 4 ): 904 Microperfusion in Fontan Patients : A Biexponential DWI
909 ; Alsoufi , B ., Manlhiot, C ., Awan , A ., Alfadley, F., [iffusion -weighted imaging ] Study," Public Library of Sci
Al-Ahmadi, M ., and 3 others 2012 . " Current Outcomes of ence One 12 ( 3 ):e0173149; Greenway, S . C ., Crossland , D .
the Glenn Bidirectional Cavopulmonary Connection for S ., Hudson , M ., Martin , S . R ., Myers , R . P ., and 3 others
Single Ventricle Palliation ,” European Journal of Cardio 2016 . “ Fontan - associated Liver Disease : Implications for
thoracic Surgery 42 (1 ):42 -49; Bove, E . L . 1986 . “ Cardiac Heart Transplantation,” Journal of Heart and Lung Trans
Surgery for the Adolescent with Univentricular Heart ," plantation 35 ( 1 ): 26 -33 ; Michielon , G ., Carotti, A ., Pongigli
Pediatrician 13 ( 4 ): 171- 179 ), essentially forcing either a one , G ., Cogo , P., and Parisi , F. 2011, Op cit . — “ It is
Fontan procedure to ameliorate but not eliminate the pro erroneous to assume that because a Fontan patient is alive ,
gressive degradation , or if a replacement heart is available , the pulmonary vascular resistance is low enough to tolerate
a heart transplantation , which conventionally supported , an OHT ( orthotopic heart transplantation ];" see also Giglia ,
substantially discontinues most organ system breakdown T . M . and Humpl, T . 2010 , Op cit.). Moreover, the combi
and provided the baby is closely monitored and the drug nation of nontargeted immunosuppressive and pulmonary
regimen adhered to , reduces but does not eliminate pulmo impairment promotes infection (Michielon , G ., Carotti, A .,
nary vascular resistance . Pongiglione, G ., Cogo , P., anf Parisi, F . 2011 , Op cit.
[0379 ] Because it responds instantly and precisely at any “ Intolerance to Fontan physiology with prolonged pleural
time in any place with repair , usually a Fontan , modified , or effusions, ascites , lymphopenia and protein dispersion can
hybrid , superior cavopulmonary connection operation ( see , predispose to life -threatening infections that are triggered by
for example, Al-Dairy, A ., Dehaki, M . G ., Omrani, G ., post-OHT immunosuppression" ).
US 2019 /0247050 A1 Aug. 15 , 2019

[0383 ] While it is possible to support a Fontan procedure also beneficiates transplantation otherwise jeopardized by
with such an implanted automatic adaptive response system two other key deterrents drug regimen noncompliance and
to deliver respiration and circulation supportive drugs (see , imunosuppresive side effects.
for example , Dasse, K . A ., Petit, P. C ., Fine, D . H ., and [0386 ] This is because the system directly pipe -targets the
Vasquez, G . 2017 . Method and Apparatus for Administering drugs to the treatment site , sparing other organs and tissue
Nitric Oxide with Supplemental Drugs , World Intellectual and regimen noncompliance the second most significant
Property Organization Patent Application 2017 / 116 ,776 ; cause of failure because it dispenses the drugs the moment
Oldenburger, N . J.,Mank , A ., Etnel, J., Takkenberg , J. J., and the need therefor is reported by the implanted sensors to the
Helbing, W . A . 2016 . " Drug Therapy in the Prevention of implanted microprocessor — anywhere, anytime in the
Failure of the Fontan Circulation : A Systematic Review ," middle of the nightwhile the baby is asleep , before the baby
Cardiology in the Young 26 (5 ):842 -850 ; Mori, H ., Park , I. senses any experiential correlate , before there is any real
S ., Yamagishi, H . 1, Nakamura , M ., Ishikawa, S ., and 5 ization of such need , and without a clinician present. Equally
others 2016 . “ Sildenafil Reduces Pulmonary Vascular Resis important, the system adaptively dispenses the drugs on the
tance in Single Ventricular Physiology,” International Jour basis of the previous diagnostic -to -medication relationship
nal of Cardiology 221 : 122 - 127 ; Butts, R . J., Chowdhury , S . data it has accumulated , thus assuring not only immediate
M ., Baker, G . H ., Bandisode, V ., Savage , A . J., and Atz, A . but theranostic drug delivery under any circumstances .
M . 2016 . " Effect of Sildenafil on Pressure - volume Loop [0387 ] More specifically, since the system is adaptive , this
Measures of Ventricular Function in Fontan Patients,” Pedi applies with the system placed in the neonate or infant prior
atric Cardiology 37 ( 1 ): 184 - 191 ; Bosc , L . V . G ., Maston, L . to and following surgical repair, then following heart trans
D ., and Rest, T. 2016 . Compositions and Methods for plantation if applicable , and in some cases, liver transplan
Treatment of Pulmonary Hypertension , World Intellectual tation , the system designed to remain in place with the
Property Organization Patent Application 2016 /176 ,399 ; ability to accommodate growth for years. Some babies will
Coyle , K ., Coyle , D ., Blouin , J., Lee, K ., Jabr, M . F ., and 4 require a replacement heart, liver, and lungs, which should
others 2016 . “ Cost Effectiveness of First -line Oral Therapies be staged over intervals sufficient for full recovery . The sites
for Pulmonary Arterial Hypertension : A Modelling Study," of flexibility that allow for growth are summarized below
PharmacoEconomics 34 (5 ):509 - 520 ; Hebert, A ., Mik toward the end of section XXI, for example , entitled Fully
kelsen , U . R ., Thilen , U ., Idorn , L ., Jensen , A . S ., and 4 Implanted Ambulatory Adaptive Hierarchical Control Sys
others 2014 . “ Bosentan Improves Exercise Capacity in tems for Automatic Response to a Comorbid Condition .
Adolescents and Adults after Fontan Operation : The [0388 ] However, in contrast to attempts at surgical repair,
TEMPO ( Treatment with Endothelin Receptor Antagonist in prompt transplantation with proper pharmaceutical manage
Fontan Patients , a Randomized , Placebo -controlled , ment of pulmonary vascular resistance better supports early
Double - blind Study Measuring Peak Oxygen Consumption ) development where a nominally repaired and still defective
Study,” Circulation 130 ( 23 ):2021 - 2030 ; Chen , Y . F., Jowett, heart does not, and later transplantation of an inadequately
S ., Barton , P., Malottki, K ., Hyde, C ., and 5 others 2009 . repaired congenital heart can never return to normal all other
“ Clinical and Cost- effectiveness of Epoprostenol, Iloprost, organ systems that had been left to develop abnormally (see ,
Bosentan , Sitaxentan and Sildenafil for Pulmonary Arterial for example , Kelly , C . J.,Makropoulos , A ., Cordero -Grande ,
Hypertension within Their Licensed Indications : A System L ., Hutter, J., Price , A ., and 15 others 2017 . “ Impaired
atic Review and Economic Evaluation ," Health Technology Development of the Cerebral Cortex in Infants with Con
Assessment (Winchester, England ) 13 (49) : 1 - 320 ; Sim genital Heart Disease is Correlated to Reduced Cerebral
monds, J., Burch , M ., Dawkins , H ., and Tsang, V . 2008 . Oxygen Delivery,” Scientific Reports 7 ( 1): 15088 ; Puelz , C .,
“ Heart Transplantation after Congenital Heart Surgery : Acosta , S ., Rivière, B ., Penny , D . J., Brady , K . M ., and
Improving Results and Future Goals, ” European Journal of Rusin , C . G . 2017 . “ A Computational Study of the Fontan
Cardiothoracic Surgery 34 ( 2 ):313 - 317 ), when a replace Circulation with Fenestration or Hepatic Vein Exclusion ,”
ment heart is available, it is preferable to replace the Computers in Biology and Medicine 89 : 405 -418 ; Goldberg ,
defective heart ab initio . D . J., Surrey , L . F ., Glatz, A . C ., Dodds , K ., O 'Byrne, M . L .,
[0384 ] However , if a replacement is unavailable , since it is and 6 others 2017 . “Hepatic Fibrosis is Universal Following
likely that the speed and accuracy of response will better Fontan Operation , and Severity is Associated with Time
sustain a Fontan until a replacement heart becomes avail from Surgery : A Liver Biopsy and Hemodynamic Study ,"
able , the system is best implanted to support the Fontan and Journal of the American Heart Association 6 ( 5 ) ; Dijkstra H .,
then reprogrammed to support the new heart. Such repro Wolff, D ., van Melle, J. P., Bartelds, B ., Willems, T . P ., and
gramming does not include the drug response to the pulmo 6 others 2017 , Op cit .; Ohuchi, H . 2017 . “ Where is the
nary hypertension induced by the pretransplantation pulmo “ Optimal” Fontan Hemodynamics ? ,” Korean Circulation
nary vascular resistance , to which the adaptive system will Journal 47 (6 ):842 - 857; Morton , P . D ., Korotcova, L .,
spontaneously adjust, but rather the addition of immunosup Lewis, B . K ., Bhuvanendran , S ., Ramachandra , S . D ., and 7
pressives and anti -inflammatories , for example , as pertinent. others 2017 . " Abnormal Neurogenesis and Cortical Growth
in Congenital Heart Disease ,” Science Translational Medi
[0385 ] An automatic prosthetic disorder response system cine 9 (374 ) . pii: eaah7029; Fidai, A ., Dallaire , F ., Alvarez ,
as delineated below in sections XX entitled Exemplary N ., Balon , Y., Clegg , R ., and 11 others 2017 . “ Non - invasive
Channel of Control in a Fully Implanted Ambulatory Adap Investigations for the Diagnosis of Fontan - associated Liver
tive Hierarchical Control System for Automatic Response to Disease in Pediatric and Adult Fontan Patients ,” Frontiers in
a Comorbid Condition and XXI entitled Fully Implanted Cardiovascular Medicine 4 : 15 ; Hilscher, M . B ., Johnson, J.
Ambulatory Adaptive Hierarchical Control Systems for N ., Cetta , F., Driscoll , D . J. 3 , Poterucha , J. J., and 3 others
Automatic Response to a Comorbid Condition in combina 2017 . “ Surveillance for Liver Complications after the Fon
tion with new and improved drugs for immunosuppression tan Procedure ,” Congenital Heart Disease 12 (2 ):124 - 132 ;
US 2019 /0247050 A1 Aug . 15 , 2019
17

Oh , C ., Youn , J. K ., Han , J. W ., Kim , G . B ., Kim , H . Y ., and McCrindle , B . W ., and Kanter, K . 2016 . “ Outcomes ofHeart
Jung , S . E . 2016 . “ Hepatocellular Carcinoma after the Transplantation in Children with Hypoplastic Left Heart
Fontan Procedure in a 16 -year-old Girl: A Case Report," Syndrome Previously Palliated with the Norwood Proce
Medicine (Baltimore , Md.) 95 (41): e4823 ; Josephus Jitta , D ., dure,” Journal of Thoracic and Cardiovascular Surgery
Wagenaar, L . J., Mulder , B . J., Guichelaar, M ., Bouman , D ., 151( 1) :167- 175 .el-e2 ; Schumacher, K . R . and Goldberg , D .
and van Melle , J. P. 2016 . “ Three Cases of Hepatocellular J. 2016 . “ Biomarkers and the Fontan Circulation ,” Journal
Carcinoma in Fontan Patients : Review of the Literature and of the American Heart Association 5 ( 1 ). pii: e002926 ; Lang ,
Suggestions for Hepatic Screening,” International Journal S . M ., Frazier, E . A ., and Collins, R . T . 2nd 2016 . “ Aortic
of Cardiology 206 : 21 - 26 ; Takuma, Y ., Fukada , Y ., Iwadou , Complications following Pediatric Heart Transplantation : A
S ., Miyatake , H ., Uematsu , S ., and 7 others 2016 . “ Surgical Case Series and Review ,” Annals of Pediatric Cardiology
Resection for Hepatocellular Carcinoma with Cardiac Cir 9 ( 1): 42 - 45 ; Alsoufi, B ., Deshpande, S ., McCracken , C .,
rhosis after the Fontan Procedure , " Internal Medicine ( To Kogon, B ., Vincent, R ., Mahle , W ., and Kanter, K . 2015 .
kyo, Japan ) 55 (22 ):3265- 3272 ; Chen , B ., Schreiber, R . A ., “ Results ofHeart Ttransplantation Following Failed Staged
Human , D . G ., Potts , J. E ., and Guttman , O . R . 2016 . Palliation ofHypoplastic Left Heart Syndrome and Related
“ Assessment of Liver Stiffness in Pediatric Fontan Patients Single Ventricle Anomalies ,” European Journal of Cardio
Using Transient Elastography,” Canadian Journal of Gas thoracic Surgery 48 (5 ):792 -799 , also cited below ; Kanter,
troenterology and Hepatology 2016 :7125193; Wolff, D ., van K . R ., Mahle , W . T., Vincent, R . N ., and Berg , A . M . 2011 .
Melle , J. P ., Dijkstra , H ., Bartelds , B ., Willems, T. P ., and 5 “ Aortic Complications after Pediatric Cardiac Transplanta
others 2016 . " The Fontan Circulation and the Liver: A tion in Patients with a Previous Norwood Reconstruction ,"
Magnetic Resonance Diffusion -weighted Imaging Study," Seminars in Thoracic and Cardiovascular Surgery. Pediat
International Journal of Cardiology 202:595 -600 ; Kwon , ric Cardiac Surgery Annual 14 ( 1) :24 - 28 ; Simmonds, J.,
S ., Scovel, L ., Yeh , M ., Dorsey, D ., Dembo , G ., and 6 others Burch , M ., Dawkins, H ., and Tsang, V . 2008, Op cit.).
2015 . “ Surgical Management of Hepatocellular Carcinoma [0390 ] To the foregoing can be added the preference in
after Fontan Procedure ,” JournalofGastrointestinal Oncol every instance for endoluminal over extraluminal stents, the
ogy 6 ( 3 ):E55- E60; Wu, F. M ., Jonas, M . M ., Opotowsky, A . deterrent consisting of the need for a small incision and
R ., Harmon , A ., Raza , R ., and 6 others 2015 . “ Portal and some relatively minor dissection to proceed directly to the
Centrilobular Hepatic Fibrosis in Fontan Circulation and level along the ductus to be treated . The added trauma to
Clinical Outcomes,” Journal of Heart and Lung Transplan gain access is compensated for by an outcomemore reliable
tation 2015 34 (7 ): 883 - 891; Assenza , G . E ., Graham , D . A ., over the long term . When the lumen contains no stent,
Landzberg , M . J ., Valente , A . M ., Singh , M . N ., and 6 others in -stent restenosis , for example , is impossible , this but one
2013. “ MELD -XI [Model for End -stage Liver Disease of numerous risks associated with the use of guidewires and
eXcluding International Normalization Ratio score ) Score allowing a foreign object to remain in the lumen , as will be
and Cardiac Mortality or Transplantation in Patients after delineated herein . For example , the presence of a stent in the
Fontan Surgery ," Heart (British Cardiac Society ) 99 ( 7 ) :491 lumen jeopardizes the subsequent use of an atherectomy
496 ; Rychik , J., Veldtman , G ., Rand , E ., Russo , P ., Rome, J . rotablator which can jam and deform the stent so that it no
J., and 4 others 2012 . “ The Precarious State of the Liver after longer serves its purpose . Rotablator jamming is addressed
a Fontan Operation : Summary of a Multidisciplinary Sym below in section VII2j( 1) entitled Incorporation of Adsciti
posium ,” Pediatric Cardiology 33( 7 ): 1001- 1012 ; Goldberg , tious Capabilities into Barrel-assemblies.
C . S ., Mussatto , K ., Licht, D ., and Wernovsky, G . 2011 . [0391] Blocked by the sternum , direct access to the right
" Neurodevelopment and Quality of Life for Children with coronary artery or branch thereof for placement of an
Hypoplastic Left Heart Syndrome: Current Knowns and extraluminal stent is not through a more traumatic median
Unknowns,” Cardiology in the Young 21 Supplement 2 : 88 sternotomy (midsternal thoracotomy, " zipper” incision ), but
92 ; Ghaferi, A . A . and Hutchins, G . M . 2005. “ Progression rather through a trephine sternotomy with a low speed , high
of Liver Pathology in Patients Undergoing the Fontan Pro torque trephine drill under saline irrigation , the plug
cedure : Chronic Passive Congestion , Cardiac Cirrhosis, returned to the opening upon withdrawal and closing .Means
Hepatic Adenoma, and Hepatocellular Carcinoma,” Journal for minimizing the risk of adverse events sequelary to
of Thoracic and Cardiovascular Surgery 129 (6 ): 1348 penetration of the sternum are available (see, for example,
1352 ). Asakura, Y., Kinoshita , M ., Kasuya, Y ., Sakuma, S ., and
[0389 ] Nevertheless, the promptreplacement of a severely Ozaki, M . 2017 . “ Ultrasound - guided Sternal Bone Marrow
defective heart in utero or shortly postpartum averts opera Aspiration ,” Blood Research 52 (2 ):148 - 150 ; Friedlis , M . F.
tive and postoperative complications which can result from and Centeno , C . J. 2016 . “ Performing a Better Bone Marrow
preceding attempts at reconstruction , to include the adverse Aspiration ,” Physical Medicine and Rehabilitation Clinics
respiratory effects of Fontan circulation , obscuring scarring , of North America 27 (4 ):919 -939 ) .
adhesions (Lamour , J. M ., Kanter, K . R ., Naftel, D . C ., 10392 ] Broadly , poor outcomes often eventuate with trans
Chrisant, M . R ., Morrow , W . R ., Clemson , B . S ., and luminal procedures opted for purely on the basis ofminimal
Kirklin , J. K . 2009 . “ The Effect of Age, Diagnosis, and invasiveness . For a debilitated patient less able or unable to
Previous Surgery in Children and Adults Undergoing Heart tolerate an open procedure , less traumatic procedures are
Transplantation for Congenital Heart Disease ,” Journal of approariate. However, when this is not the case, an open
the American College of Cardiology 54 ( 2): 160 - 165 ), aswell procedure more likely to finally end the problem is to be
as delay a proper correction as damage caused by faulty preferred , someadded trauma notwithstanding . This applies
circulation continues to accumulate , significantly increasing to small arterial stents and aortic sent grafts as addressed
the need while decreasing the prospects for successful below . The misguided approach is clearly seen when failure
transplantation at a later time ( see , for example , Alsoufi, B ., of the transluminal repair necessitates open repair later
Mahle, W . T., Manlhiot , C ., Deshpande, S ., Kogon , B ., anyway — when the patient has further deteriorated .
US 2019 /0247050 A1 Aug . 15 , 2019

[0393 ] Adverse sequelae to surgicalbreech of the sternum , Nephropathy ] Study ): A Randomised Trial,” Lancet 384
such as pericardial tamponade, are rare and have established ( 9955): 1684 - 1690 ; Vazquez , J. A ., Miceli, M . H ., and Alan
remedies (see , for example, Golota , J. J., Orlowski, T ., gaden , G . 2013 . “ Invasive Fungal Infections in Transplant
Iwanowicz, K ., Snarska, J. 2016 . “ Air Tamponade of the Recipients ,” Therapeutic Advances in Infectious Disease
Heart,” Kardiochirurgia i Torakochirurgia Polska [Polish 1 ( 3 ) :85 - 105 ; Hanaway, M . J., Woodle , E . S ., Mulgaonkar,
Journal of Cardiothoracic Surgery ] 13 ( 2 ): 150 - 153; Santavy, S ., Peddi, V . R ., Kaufman , D . B ., First, M . R ., Croy, R ., and
P ., Troubil, M ., and Lonsky, V . 2013 . “ Pericardial Tampon Holman , J. 2011 . “ Alemtuzumab Induction in Renal Trans
ade: A Rare Complication of SternalBone Marrow Biopsy,” plantation ,” New England Journal of Medicine 364( 20 ):
Hematology Reports 5 (3 ):e13 ; Inoue, H ., Nakasato , T., 1909 - 1919 ; Safdar, N ., Smith , J., Knasinski, V, Sherkow , C .,
Yamauchi, K .,Nakamura , Y., Oshida , S ., and Ehara , S . 2010 . Herrforth , C ., Knechtle, S ., and Andes, D . 2010 . “ Infections
“ Risk Factors Concerning Sternal Bone Marrow Aspiration After the Use of Alemtuzumab in Solid Organ Transplant
and Patient Safety in Japan ,” Internal Medicine ( Tokyo , Recipients : A Comparative Study," Diagnostic Microbiol
Japan ) 49( 12 ):1089 - 1095 ; Jarry, J., Lang -Lazdunski, L ., ogy and Infectious Disease 66 ( 1 ) :7 - 15 ) with an antibiotic or
Perez , J. P., Barthelemy, R ., Berets , O ., and Jancovici , R . antiviral when indicated , such as when the donor is cyto
2004. “ A Serious Complication of Sternal Puncture : Ppen megalovirus -seropositive and the recipient cytomegalovi
etrating Injury of the Ascending Thoracic Aorta ,” in French rus- seronegative , azathioprine, basiliximab , cyclosphosph
with Engish abstract at Pubmed , Presse Medicale 33 ( 1 ):22 amide , cyclosporine, tacrolimus, everolimus , sirolimus ,
24 ) . steroids, and so on , or radionuclides with or without an
[ 03941 Relative efficacy as between minimally invasive inherent affinity for the organ , to only the transplanted organ
transluminal procedures and surgical intervention is not without suppression of the immune system for other disease ,
static but subject to new developments , is gradually shifting eliminates the need for separate incisional access.
in favor ofmore conservative transluminal approaches over [0396 ] Generally, even though the directly targeted dose
time. For example, carotid endarterectomy, which may be can be more highly concentrated than if dispersed through
untenably risky with severely impaired patients posing a the general circulation , any fraction not taken up within the
significant surgical risk , has been found to result in better treatment site or nidus will quickly become so diluted within
outcomes than does carotid artery stenting, which is better the bloodstream as not to pose the prospect of injury to
tolerated , and coronary artery bypass grafting has histori upsteam tissue. If this is not so , as when the drug is
cally provided better outcomes than does balloon angio radioactive, the drug is delivered in magnetically susceptible
plasty. This is , however, gradually changing with the advent form so that the residue is stopped from furher travel
of improved medical management and apparatus such as downstream by forcible detention , either against the
drug eluting stents and cerebral embolic protective devices, endothelium or urothelium . If the passing blood is not
addressed below in several sections but especially in section significantly irradiated , the downstream ductus side - entry
4d (2 ) entitled Ductus Wall Tumefacients, and flow reversal, impasse -jacket includes a permanent magnet sub - shell layer
addressed below in section X2b entitled Stereotactic Res magnetized perpendicular to the bloodstream to hold the
ituation of a Mispositioned Miniball . drug against the endothelium .
[0395 ] The prepositioning of impasse - jackets described [0397] When drug delivery is directly pipe or feedline
herein and ductus side - entry jackets as described in copend targeted to the nidus or lesion , medication that is radioactive
ing application Ser. No . 14 / 121, 365 published as or otherwise potentially harmful introduced through the pipe
20160051806 , on pedicles or stumps in organ transplanta or feedline in a ferrofluid bypasses the upstream circulation
tion allows the targeted delivery of graft sustaining antig and the tissue it supplies . If radioactive, the feedline , as
enotherapy and if necessary , immunosuppressive drugs, and shown in copending applications Ser . No. 14 / 121, 365 , FIGS .
thus significant reduction if not elimination in the systemic 5 , 6 , and Ser . No. 14 /998 ,495 FIGS . 10A and 10B is
dose of potentially harmful immunosuppressive drugs such shielded . If administration of the drug is to continue over a
as aclizumab , basiliximab , eculizumab , daclizumab , inflix long term , a small port at the body surface is used as the drug
imab , alemtuzumab , and other immunosuppressives which entry point. If uptake at the lesion is not complete and a
reduce patient resisance to infectious disease (see , for radioactive residue is not to continue past the drug delivery
example , Shao , M ., Tian , T., Zhu , X ., Ming, Y ., Iwakiri, Y ., target, the residue is curtailed from continuation through the
Ye , S ., and Ye , Q . 2017 . “ Comparative Efficacy and Safety bloodstream by a sub- shell electromagnet layer in the side
of Antibody Induction Therapy for the Treatment of Kidney : entry jacket, piped impasse -jacket, or nonjacketing side
A Network Meta -analysis ,” Oncotarget 8 ( 39):66426 -66437 ; entry connector to project an attractive field perpendicular or
Zheng, J. and Song, W . 2017 . “ Alemtuzumab Versus Anti
thymocyte Globulin Induction Therapies in Kidney Trans normal to the long central axis of the substrate vessel.
plantation Patients: A Systematic Review and Meta -analysis [0398 ] The field strength of the electromagnet layer is set
of Randomized Controlled Trials,” Medicine ( Baltimore , to no greater than is necessary to draw the drug into the
Md.) 96 ( 28 ):e7151 ; Hill, P., Cross, N . B ., Barnett , A . N ., intima or equivalent layer. If the drug is not harmful to
Palmer , S . C ., and Webster , A . C . 2017 . " Polyclonal and normal tissue and is to be drawn against rather than through
Monoclonal Antibodies for Induction Therapy in Kidney the endothelium or urothelium , for example , an impasse
Transplant Recipients,” Cochrane Database of Systematic jacket with permanent magnet layer as shown in FIGS. 16A ,
Reviews 1 :CD004759; Haynes , R ., Harden , P., Judge, P., 16B , and 16C and described below in sections 12 and 115 is
Blackwell, L ., Emberson , J., Landray, M . J., Baigent, C ., used . If harmful to normal tissue aside from the target lesion ,
Friend , P. J., and 154 collaborators 2014 . “ Alemtuzumab the magnetically carried residue can be extracted through the
based Induction Treatment Versus Basiliximab -based Induc grid of the impasse - jacket into the perivascular far or
tion Treatment in Kidney Transplantation (the 3C [Campath , equivalent tissue with the aid of a powerful external ( extra
Calcineurin Inhibitor Reduction and Chronic Allograft corporeal) tractive electromagnet .
US 2019 /0247050 A1 Aug . 15 , 2019
19

[0399 ] Anonradioactive but potentially harmful residue is in a Fully Implanted Ambulatory Adaptive Hierarchical
neutralized through the release through a downstream ductus Control System for Automatic Response to a Comorbid
side -entry jacket of a reversal agent. If delivery is automatic Condition .
by a microprocessor as addressed below in sections XX and [0404] Ductus side-entry jackets and nonjacketing side
XXI, then the delivery of both the drug and the reversal entry connectors are adaptations of the jackets or collars
agent or antidote is automated . If not, then the residue is described herein , to allow the direct piping of drugs,
manuially introduced immediately after the drug. If no metabolites , enzymes, hormones , temperature sensor/heat
reversal agent is available , further passage through the ing or cooling devices, and miniature cabled devices, such as
bloodstream is prevented by introducing the drug as mag lasers , electrostimulatory, or neuromodulatory, electrodes ,
netically carried for recovery by a downstream impasse intravascular ultrasound viewing, or high - intensity focused
jacket. Nanoparticulate drugs can be indissolubly or dissolu ultrasound , or ultrasonic histotripsy , ablation , probes to be
bly encapsulated to prevent or detain dissolution . fully implanted and stably positioned over an indefinitely
[ 0400 ] Because drugs are directly pipe-targeted to the long period . Piping is addressed below in section 115e
treatment site , were the the donor cytomegalovirus -seroposi entitled Direct Lines from the Body Surface to and from
tive and the recipient cytomegalovirus - seronegative, for Impasse - and Other Type Jackets . An exemplary automatic
example , then provided the efficacy of such treatment had disorder response system is addressed in section XX below
been established , antivirals and immunosuppressive drugs and FIG . 107 , with the control of such an implanted arrange
such as azathioprine, basiliximab , cyclosphosphamide , ment addressed in section XXI and FIG . 108 .
cyclosporine, everolimus, tacrolimus , sirolimus, methotrex [0405 ] Using magnetic force to restrict delivery of graft
ate , steroids , and/or radionuclides with or without an inher antigens , counteractive antibodies and immunosuppressive
ent affinity for the organ , can be targeted to the graft without medication to and concentrate these in a targeted segment or
injury to other tissue or impairment to the immune system as organ , for example , leaves the rest of the body substantially
would expose the patient to pathogens. immunocompetent, reducing the risk of transplant infection
[ 0401] Means for the automatic delivery of antimicrobial with an immunosuppression -opportunistic cytomegalovirus,
and rejection - counteractive substances to sustain a trans Epstein -Barr virus, which poses the threat of post transplan
plant on a continuous basis and alleviate dependency upon tation lymphoproliferative disease that can lead to non
potentially toxic systemic doses of immunosuppressive Hodgkin 's lymphoma and death ( see , for example , Marti
drugs are described in copending application Ser. No. nez , O . M . and Krams, S . M . 2017 . “ The Immune Response
14 / 121 , 365 published as 20160051806 , entitled Ductus to Epstein Barr Virus and Implications for Posttransplant
Side- entry Jackets and Prosthetic Disorder Response Sys Lymphoproliferative Disorder," Transplantation 101(9 ):
tems, which describes a belt- supported power , control, and 2009 - 2016 ; Bishnoi, R ., Bajwa, R ., Franke, A . J., Skelton ,
pump /reservoir pack that delivers drugs through a small port W . P . 4th , Wang , Y ., and 4 others 2017 . “ Post -transplant
at the body surface , and application Ser. No . 14 / 998 ,495 Lymphoproliferative Disorder (PTLD ): Single Institutional
published as 20170197028 entitled Nonjacketing Side -entry Experience of 141 Patients,” Experimental Hematology and
Connectors and Prosthetic Disorder Response Systems, Oncology 6 :26 ; Das , B ., Morrow , R ., Huang , R ., and Fixler,
which describes the implantation of these components with D . 2016 . “ Persistent Epstein -Barr Viral Load in Epstein -Barr
transdermal energy transfer for closed body ambulatory Viral Naïve Pediatric Heart Transplant Recipients: Risk of
operation and telemetric data transfer to the clinic . Late -onset Post-transplant Lymphoproliferative Disease ,”
[0402 ] Such communication can transmit both command World Journal of Transplantation 6 (4 ): 729 -735 ; “ Dharnid
and diagnostic signals ( see , for example , Mirbozorgi, S . A ., harka , V . R ., Webster , A . C ., Martinez, O . M ., Preiksaitis, J.
K ., Leblond , V . 5 ., and Choquet, S . 2016 . “ Post-transplant
Bahrami, H ., Sawan , M ., Rusch , L . A ., and Gosselin , B . Lymphoproliferative Disorders, ” Nature Reviews. Disease
2016 . “ A Single - Chip Full-duplex High Speed Transceiver Primers 2 : 15088 ; Jha, H . C ., Pei, Y., and Robertson , E . S .
for Multi- site Stimulating and Recording Neural Implants," 2016 . “ Epstein -Barr Virus : Diseases Linked to Infection and
Institute of Electrical and Electronics Engineers Transac Transformation ,” Frontiers in Microbiology 7 :1602; Lynch ,
tions on Biomedical Circuits and Systems 10 ( 3 ) :643- 653; J. P . 3rd , Sayah , D . M ., Belperio , J. A ., and Weigt, S . S . 2015
Hannan ,MA., Abbas , S . M ., Samad , S . A ., and Hussain , A . “ Lung Transplantation for Cystic Fibrosis : Results , Indica
2012 . “Modulation Techniques for Biomedical Implanted tions, Complications , and Controversies ,” Seminars in
Devices and Their Challenges," Sensors (Basel , Switzer Respiratory and Critical Care Medicine 36 ( 2 ): 299 - 320 ;
land ) 12 ( 1):297 -319 ). While a centralized computer to San - Juan , R ., Manuel, O ., Hirsch , H . H ., Fernández -Ruiz,
administer patient- specific prescription programs would M ., López -Medrano , F ., and 4 others with 105 collaborators
eliminate the need for a microcontroller implant in each 2015 . " Current Preventive Strategies and Management of
patient or included in a carried power and control pack , Epstein - Barr Virus-related Post-transplant Lymphoprolif
current telemetric communication between the centralized erative Disease in Solid Organ Transplantation in Europe .
controller and each patient falls far short of the dependabil Results of the ESGICH [European Study Group of Infec
ity required in such an arrangement. tions in Compromised Hosts ] Questionnaire -based Cross
[0403] The same may be said for transdermal or transcu sectional Survey," Clinical Microbiology and Infection
taneous charging of the implanted or carried battery , dis 21 (6 ):604 .el -9 ; San - Juan , R ., Comoli, P., Caillard , S .,
tance considerations for the transmission of power thus Moulin , B ., Hirsch , H . H ., and Meylan , P . 2014 . “ Epstein
currently limiting charging to an at-home or clinic function . Barr Virus- related Post -transplant Lymphoproliferative Dis
Eventually, large regions may be administered by central order in Solid Organ Transplant Recipients ," ClinicalMicro
ized computers . The current state of the medical data tele biology and Infection 20 Supplement 7: 109 - 118 ; Green , M .
metric and transcutaneous charging capabilities is addressed and Michaels , M . G . 2013 . “ Epstein -Barr Virus Infection
below in the section entitled Exemplary Channel of Control and Posttransplant Lymphoproliferative Disorder,” Ameri
US 2019 /0247050 A1 Aug. 15 , 2019
20
can Journal of Transplantation 13 Supplement 3 :41 11 .-54
54 ; New York , N . Y.:McGraw -Hill, pages 781- 789; Koukoulaki,
Allen , U . D ., Farkas, G ., Hébert, D ., Weitzman , S ., Stephens, M ., Grispou, E ., Pistolas, D ., Balaska , K ., Apostolou , T., and
D ., and 6 others 2005. “ Risk Factors for Post- transplant 7 others 2009 . “ Prospective Monitoring of BK Virus Rep
Lymphoproliferative Disorder in Pediatric Patients : A Case lication in Renal Transplant Recipients ," Transplant Infec
control Study ," Pediatric Transplantation 9 (4 ): 450 - 455 ; tious Disease 11( 1): 1- 10 ), resulting in irremediable graft
Allen , U ., Alfieri , C ., Preiksaitis , J., Humar, A ., Moore , D ., sloughing.
and 8 others 2002. “ Epstein -Barr Virus Infection in Trans [0407] The Merck Manual of Diagnosis and Therapy,
plant Recipients: Summary of a Workshop on Surveillance , Edition 18, Chapter 166 , “ Transplantation ,” page 1369 enu
Prevention , and Treatment,” Canadian Journal of Infectious merates viral, bacterial, fungal, and parasitic organisms
Diseases 13 ( 2 ):89- 99 ; Aris, R . M ., Maia , D . M ., Neuringer, found to infect immunocompromised recipients. If neces
I. P ., Gott , K ., Kiley , S ., Gertis , K ., and Handy , J. 1996 . sary, the same or another impasse -jacket at the arterial inlet
“ Post -transplantation Lymphoproliferative Disorder in the is used to release a viricide. Regardless of the projected time
Epstein - Ban Virus - naïve Lung Transplant Recipient, ” or times for release , the impasse - jacket or jackets are fixed
American Journal of Respiratory and Critical Care Medi in position just after the organ is removed and before
cine 154 (6 Part 1): 1712 - 1717 ). completing the graft. Thereafter, release using any of several
[0406 ] Polyoma papovavirus, usually BK virus [ from the mechanisms addressed in sections herein on impasse - jackets
initials of a renal transplant patient ]), or Polyomavirus can be preemptive, prophylactic , or both .
hominis type 1 infection is another significant threat ( see , for [0408 ] Transplant harvesting preserves sufficient connec
example , Ambalathingal, G . R ., Francis, R . S ., Smyth , M . J. tions or pedicles including major arteries and veins to allow
2 , Smith , C ., and Khanna, R . 2017 . “ BK Polyomavirus : the placement of entry inlet , inflow ) and exit (outlet,
Clinical Aspects, Immune Regulation , and Emerging Thera outflow ) impasse - jackets, so that these are introduced hav
pies," Clinical Microbiology Reviews 30 ( 2 ):503 -528 ; ing already been applied to the target organ . A kidney, for
Abend, J. R ., Changala , M ., Sathe , A ., Casey, F ., Kistler, A ., example , is harvested with its renal artery, renal vein , and
Chandran , S ., Howard , A ., and Wojciechowski, D . 2017 . ureter remaining attached . Perigraft infection should it ensue
“ Correlation of BK Virus Neutralizing Serostatus with the can be treated using the same impasse - jacket or jackets .
Incidence of BK Viremia in Kidney Transplant Recipients ," When graft antigens, counteractive antibodies, immunosup
Transplantation 101 (6 ): 1495 - 1505; Kable , K ., Davies , C . pressive , and antibiotic drugs , for example , must be deliv
D ., O 'connell, P. J., Chapman , J. R ., and Nankivell , B . J. ered to different ductus, Ommaya -type reservoirs , subcuta
2017 . “ Clearance of BK Virus Nephropathy by Combination neous infusion set cannulae with catheters leading to the
Antiviral Therapy with Intravenous Immunoglobulin ," respective jackets , or similar access portals at the body
Transplantation Direct 3 ( 4 ):e142; Sharma, R ., Tzetzo , S ., surface are spaced apart to reduce the chance for human
Patel, S., Zachariah , M ., Sharma, S ., and Melendy, T . 2016 . error in administering the medication .
“ BK Virus in Kidney Transplant: Current Concepts, Recent [0409 ] Direct piping from the body surface , addressed
Advances, and Future Directions," Experimental and Clini below in the sections entitled Direct Lines from the Body
cal Transplantation 14 (4 ): 377 -384 ; Jamboti , J. S . 2016 . Surface to and from Impasse - and Other Type Jackets and
“ BK Virus Nephropathy in Renal Transplant Recipients ," Single and Plural Circuit Pumping through Direct Lines to
Nephrology (Carlton , Victoria , Austrailia ) 21(8 ):647 - 654 ; Jackets makes it possible to selectively target each impasse
Vigil , D ., Konstantinov , N . K ., Barry , M ., Harford , A . M ., jacket with the substance intended by direct piping. Syringe
Servilla , K . S ., and 4 others 2016 . “ BK Nephropathy in the refill cartridges or portable miniature metering pumps con
Native Kidneys of Patients with Organ Transplants: Clinical nected to the access portals or infusion cannulae at the body
Spectrum of BK Infection ,” World Journal of Transplanta surface selectively supply the drug for each target impasse
tion 6 (3 ):472 -504; Umbro , I., Tinti, F., Muiesan , P ., and jacket. Access to intermittent segments along a ductus, such
Mitterhofer, A . P. 2016 . “ Different Behaviour of BK - virus as unresected skip lesions of Crohn ' s disease , or regional
Infection in Liver Transplant Recipients,” World Journal of enteritis, or with atherosclerotic plaques where remodeling
Gastroenterology 22 (4 ):1532-1540 ; Huang, G ., Wang , C . discourages transluminal treatment , the chronic condition
X ., Zhang, L ., Fei, J. G ., Deng, S . X ., and 5 others 2015. warrants the implantation of fluid feedlines with a small port
“ Monitoring of Polyomavirus BK Replication and Impact of at the body surface .
Preemptive Immunosuppression Reduction in Renal -trans [0410 ] Branching the feedline distal to the port opening
plant Rrecipients in China: A 5 - year Single - center Analy allows the use of a single opening in the port at the body
sis,” Diagnostic Microbiology and Infectious Disease 81 ( 1 ): surface . If medication is to be administered automatically ,
21 - 26 ; Pham , P . T ., Schaenman , J., and Pham , P . C . 2014 . then a controlling microprocessor and associated compo
“ BK Virus Infection Following Kidney Transplantation : An nents as appropriate and delineated in sections XX and XXI
Overview of Risk Factors, Screening Strategies , and Thera below are implanted . When the delivery line is branched ,the
peutic Interventions," Current Opinion in Organ Transplan microprocessor actuates the one small flat drug reservoir
tation 19 ( 4 ):401-412 ; Huang , G ., Zhang, L ., Liang, X ., Qiu , pump to medicate the lesions at once . Likewise to reserve
J., Deng , R ., and 4 others 2014 . “ Risk Factors for BK Virus port openings for other drugs in comorbidity, when a given
Infection and BK Virus- associated Nephropathy Under the drug or other therapeutic substance would best be delivered
Impact of Intensive Monitoring and Pre - emptive Immuno to separate points in a particular order, successive side
suppression Reduction ,” Transplantation Proceedings branches from a common line may be used , whether the
46 ( 10 ):3448 - 3454 ; Hirsch , H . H . and Snydman , D . R . 2005 . takeoffs follow in anterograde or retrograde order .
“ BK Virus: Opportunity Makes a Pathogen ,” Clinical Infec [0411] An unmagnetized inlet jacket directly piped to from
tious Diseases 41 (3 ):354 - 360 ; Finberg , R . and Fingeroth , J. a portal at the body surface can deliver a drug and when
2005 . “ Infections in Transplant Recipients,” Chapter 117 in necessary , an outlet jacket similarly piped can deliver a
Harrison 's Principles of Internal Medicine , 16th Edition , reversal agent. Where dosing would best respond quickly to
US 2019 /0247050 A1 Aug. 15 , 2019
21

changing physiological criteria such as pulse rate or blood sections entitled Concept of the Impasse -jacket, Miniball
pressure , sensors placed to transmit the pertinent data to the and Ferrofluid -borne Particle - impassable Jackets , or
pump can be used to administer the medication automati Impasse -jackets, and Cooperative Use of Impasse-jackets in
cally . Direct line feed to impasse - jackets and /or their out- Pairs and Gradient Arrays, or stent -jackets , addressed below
riggers or dummy collars from the body surface is addressed in the section entitled Stent -jackets and Stent- jacket Sup
below in the section of like title. Either or both impasse - portng Elements , a collar side-slot accommodates a running
jackets and dummy collars can be directly supplied or lumen attachment of connective tissue, for example .
contents drawn by a portable pump connected to an infusion [0416 ] When it is realized that many ailments can be
set cannula with catheter leading to the jacket or an Ommaya treated through the differential delivery of drugs to ductus
reservoir type connector implanted at the body surface . such as blood vessels as these enter and depart a target
[0412] Single, dual, and multipump circuits are delineated organ , a lesioned segment, or different segments of a lumen ,
below in the section entitled Single and Plural Circuit the potential significance of such means becomes clear.
Pumping through Direct Lines to jackets . The jackets and /or When the medication is encapsulated in the form of micro
other implants described herein , to include patch -magnets , spheres or miniballs, it is also possible with the aid of an
and magnet -wraps, and bonding of the drug to the magnetic external electromagnet to extract these should some mishap
drug carrier then serve to steer the medication into the lumen occur or some unforeseen eventuality arise . The term 'bar
wall, the anastomosis, or parenchyma. Broadly, impasse rel- assembly used to denote a catheteric extension to the
jackets for later use are easily prepositioned as a part of any barrel of a specially adapted , or interventional, airgun and
open procedure where an eventual need for drug targeting is ‘muzzle -head' or ‘muzzle - probe,' its distal terminus, when
probable essentially, always . When the initialmedication the medication is in the form of a ferrofluid , recovery is by
requires only an entry jacket but the prospective need for means of an endoscope with a magnetized tip or the recovery
another drug that would generate a residue requiring reversal tractive electromagnets in the muzzle -head of a barrel
or neutralization is present, an exit jacket is prepositioned assembly, as will be described .
without being charged , or loaded with the reversal agent. [0417 ] Although treatment is targeted at a certain organ or
[0413] Magnetic drug -targeting implants applied to the segment, associated symptoms, however remote , induced by
ileum and colon , for example , make it possible to direct the primary pathology, that is , secondary or sequelary ,
corticosteroids, immunomodulators , antiinfectives, gene derived from those primary , rather than parallel or pleiotro
therapy vehicles , vaccines, antineoplastic drugs , enzymes , pic , are inhibited from spreading as well. With respect to the
cytokines, whether as “smart pills,' for example , to only Crohn 's example , the disease appears to involve an abnor
those segments affected by regional enteritis most often seen mal immune response ofmultifactorial genetic basis to the
as ileocolitis or Crohn 's disease , in high concentration with normal flora occupying the gut, so that associated symp
minimal delivery to the rest of the body. When tight control toms, to include those concomitant or antecedent, however
over distribution is not critical, passive apportionment remote , would appear to be co -original.
among a number of jackets is sometimes possible at less risk [0418 ] Bowel disorders briefly addressed below , extraint
and expense ; however, when it is essential, more extended estinal symptoms, more frequent with perianal Crohn ' s
coverage is achieved by direct line delivery to any or all of disease (see, for example , Mahmoud , N . N ., Halwani, Y.,
a plurality of impasse - jackets. The strength ofmagnetization Montbrun, S ., Shah , P. M ., Hedrick , T. L . and 8 others 2017 .
or degree of tractive force from collar to collar is increased " Current Management of Perianal Crohn ' s Disease ,” Cur
in the Proximodistal , or antegrade, direction . rent Problems in Surgery 54 ( 5 ): 262 -298 ; Klag , T., Goetz ,
[0414 ] Particles with a greater mass of ferromagnetic or M ., Stange, E . F ., and Wehkamp, J. 2015 . “Medical Therapy
susceptible content will generally decrease from jacket to of Perianal Crohn ' s Disease ," Viszeralmedizin (Visceral
jacket. When the particles are equally susceptible , the dis Medicine ) 31(4 ):265-272 ; Freidman , S . and Blumberg , R . S .
tribution results from chance proximity to each pole tra 2005 . “ Inflammatory Bowel Disease ,” “ in Harrison 's Prin
versed . Provided care is given to avoiding interactions ciples of InternalMedicine, 16th Edition , New York , N . Y.:
between different ductus treated thus and recurving of the McGraw -Hill, page 1783; Galandiuk , S ., Kimberling , J.,
same ductus , this allows a range of tractive force over the Al-Mishlab, T. G ., and Stromberg , A . J. 2005 . “ Perianal
distance covered by the array or arrays at different levels Crohn Disease : Predictors of Need for Permanent Diver
along the ductus . While the contingency of drug -carrier sion ,” Annals of Surgery 241(5 ): 796 -802 ), include those
particle proximity to each collar along the gut requires that ocular, arthritic, hepatic, hematologic , and cobalamin ( vita
the apportionment of the drug among the collars deviate min B .) deficiency (Babior, B . M . and Bunn , H . F . 2005 .
from the ideally uniform or aliquot, the statistical appor “ Megaloblastic Anemias,” in Harrison 's op cit ., Page 604 ),
tionment among collars of the array gradient is sufficient to posing a risk for atrophic gastritis, and if not corrected ,
treat each segment affected . Once placed , the jackets are gastric adenocarcinoma, magaloblastic anemia, achlorhy
prepositioned for followup dosage at any later time. dria predisposing to salmonellosis, and neurologic dysfunc
[0415 ] Ending the array with a jacket, an exit -jacket, that tion , among others (see , for example , Del Valle , J. 2005 .
releases a reversal agent allows drugs so highly toxic that “ Peptic Ulcer Disease and Related Disorders,” in Harrison 's
even a residue in the bloodstream can prove problematic , op cit., Page 1761; The Merck Manual of Diagnosis and
notably those chemotherapeutic , to be restricted to the target Therapy , 18th Edition, 2006 , Section 2 , Gastrointestinal
segment with an exit impasse -jacket or exit jacket to release Disorders, Subsection 18, “ Inflammatory Bowel Disease ,"
a reversal agent to eliminate any residue when a recom page 149 and Section 14 , Infectious Diseases, Subsection
mended precaution . Similarly , placing a drug trapping and 167 , “ Biology of Infectious Diseases,” page 1387).
releasing impasse -jacket at the inlet to an organ and an exit (0419 ] Extraintestinal symptoms appearing before frank
jacket at the outlet allows the selective targeting of that ileocolitis should prompt consideration of placing collars to
organ . Whether impasse - jackets , addressed below in the preemptively inhibit spread of the disease to the mesentery ,
US 2019 /0247050 A1 Aug. 15 , 2019

for example. Such implants also allow the controlled and manner to release chemicals that combine to form a thera
targeted release and suppression of released drugs or other peutic compound or mixture or which act synergistically .
substances from outside the body . Different layers or con Such capability is expected to prompt the development of
centric shells of drugs in miniball or microsphere implants magnetically susceptible nanoparticle bound drugs specially
as well as those applied as coatings to other type implants formulated for such delivery . Situating magnetized mini
such as absorbable stent-jackets and magnet -wraps, to be balls , stays, arrays thereof, or jackets along a section of a
described herein can be released by : ductus allows targeting a drug or drugs to that segment for
[0420 ] 1. Spontaneous dissolution at body temperature , controlled uptake from outside the body with or without
accelerated by the blood washing over the implant when such timed and coordinated release .
suspended in the bloodstream . [0427 ] Once the blood - borne overload passing through the
[0421] 2 . Exposing the layer to another agent whether liver reaches a threshold , the significance of iron as a
released from a second such implant whether by the same or carcinogen is established ; however, here thr blood concen
differentmeans, such as infused , injected , or ingested , that tration of iron cannot rise to the level of toxicity, even when
induces the dissolution of the layer. the tiny miniballs or stays are not encapsulated within a
[0422] 3. With the use of an alternating magnetic or polymeric outer jacket or shell ; using the methods described
electromagnetic field , induction heating each successive herein should not release an absolute amountof iron into the
magnetically susceptible nanoparticle -bound drug or radio bloodstream as would even rise to the level of medical
isotope carrier- incorporating layer to its respective tempera significance .Much pertinent research is open to question in
ture of dissolution any event (see , for example , Deugnier, Y . and Loréal, O .
[0423] 4 . When the implant is sufficiently stable in posi 2000 . " Iron as a Carcinogen ," Chapter 22 , pages 239 -249 in
tion , using a constantmagnetic field to break up each layer. Barton , J. C . and Edwards, C . Q . (eds.), Hemochromatosis :
5 . Providing each layer or shell with a proportionally distinct Genetics, Pathophysiology, Diagnosis and Treatment, Cam
mass of magnetically susceptible matter to allow that layer bridge, England : Cambridge University Press. When con
to be disintegrated through a combination of heating, trac taining radioisotopes , an absorbable radiation shield -jacket
tion , and / or exposure to another chemical in any combina with dissolution timekeyed to the half- life of the radioiso
tion . tope is used , as addressed below in the section entitled
0424 ] Stent- and impasse - jackets provide such a constant Radiation Shield - jackets and Radiation Shielded Stent- jack
magnetic field and allow endoluminally implanted drugs to ets Absorbable and Nonabsorbable .
be aligned to lesions. If placed near to the body surface, [0428 ] Due to dilution , any conventional drug that is
noninjurious heating can be accomplished by means of an highly concentrated for the lesioned segment that may
aquathermia pad , hot air gun, or hand held blow dryer. In continue in the circulation will be innocuous. Reciprocally,
addition to thermoelectric heat induction by placement in a dependency upon circulation of the drug eliminated , first
radiofrequency alternating magnetic field , the dissolution of pass or presystemic metabolic reduction is avoided so that
more deeply placed biodegradable (absorbable ) implants its concentration or dose can be keyed to that optimal for
with or without the release of therapeutic substances, such as direct delivery to the lesion without a need to reduce the
those encapsulated or entrapped within a polyanhydride , can level to avoid adverse side effects risked when it is circu
be effected with conventional electromagnetic eddy current lated . When available , unconventional drugs that despite
induction heating ( see, for example , Hartshorn , L . 1949 . dilution would be toxic are neutralized by the release from
Radio -frequency Heating , London , England : Allen and a segment exit or outlet jacket of a reversal or neutralizing
Unwin ). agent, as addressed below in the section entitled Cooperative
[ 0425 ] Since ductus -intramural implants incorporate suf Use of Impasse -jackets in Pairs and Higher Combinations,
ficient ferrous content to allow their magnetic relocation or among others allows a concentraton of the drug in the lesion .
extraction at any moment if necessary, the ferrous content is 10429 ]. For toxic antineoplastic drugs, release is initiated at
usually sufficient for heat induction as well . The potential the start of the segment or inlet of the organ to be treated .
applications for the heating of implants are numerous and Provided a counteractant is available , any residue can be
will be specified . Where arrestability and recoverability of a neutralized by a counteractant released from an exit jacket at
miniball that enters the circulation are satisfied by the the end of the segment or outlet of the organ . Targeted
incorporation of sufficient superparamagnetic magnetite or chemotherapy through the application of magnetic force ,
maghemite nanoparticles or finely grained powder, induc with or without surgery or radiation to treat localized ( non
tion more effective with larger grains . Powder and grains disseminated , nonmetastazized , nonmetastatic ) as opposed
both present sufficient surface area for quick absorption at a to a systemic disease thus averts the need to moderate the
subtoxic level. The formulation of ductus - intramural dose , instead allowing the drug to be administered at the
implants and miniballs in particular, is addressed below in optimal concentration for the lesion in virtually any patient
the section entitled Noninvasive Dissolution on Demand of regardless of performance status . Whether given as neoad
Absorbable Stent-jackets , Base -tubes , Radiation Shields, juvant, or before surgery to enhance resectability and /or
and Miniballs . preserve local organ function (Merck Manual of Diagnosis
[0426 ] With release controllable from outside the body, and Therapy, 18th edition , page 1167 ), or additionally
the layers can represent doses of the same drug , or a drug, administered as a precaution , only the backup or adjuvant
chemical, or enzyme, for example , released to supplement or chemotherapeutic level of the drug circulated requires the
counteract one released earlier. Sequential release from the application of toxicity -averting dose - interval strategy that
same implant, such as a ductus- intramurally implanted stay currently dominates the use of such drugs.
or miniball or a lumen suspended miniball can then be [0430 ] Equally important, the elimination or substantial
coordinated between and among any such implants . Differ - elimination of a drug from the bloodstream also avoids the
ent implants can be controlled in a coordinated and timed liver and eliminates drug -drug interactions, not only allow
US 2019 /0247050 A1 Aug . 15 , 2019

ing concomitant treatment of a systemic comorbidity with a and Tests (see also Kolossváry , M ., Szilveszter, B .,Merkely ,
drug that must be circulated , but keeping the bloodstream DB .., and Maurovich -Horvat, P . 2017 . “ Plaque Imaging with
free of a drug that would later become a deterrent to the use CT — A Comprehensive Review on Coronary CT Angiogra
of another drug to treat an unforeseeable intercurrent sys phy Based Risk Assessment,” Cardiovascular Diagnosis
temic disease . Drug -drug interactions are then limited to the and Therapy 7 (5 ):489 - 506 ; Obaid , D . R ., Calvert, P . A .,
targeted lesion . The use of drug miniballs, stays , and Gopalan , D ., Parker, R . A ., Hoole , S . P ., and 4 others 2013.
impasse - jackets to treat a local area by direct breakdown , “ Atherosclerotic Plaque Composition and Cclassification
elution , or attracting a magnetized carrier-bound drug from Identified by Coronary Computed Tomography : Assessment
the passing blood , and impasse -jackets in pairs, for example , of Computed Tomography - generated Plaque Maps Com
to mark off a segment of a ductus or an entire organ is not pared with Virtual Histology Intravascular Ultrasound and
intended to affect liver metabolism or the systemic serum Histology," Circulation . Cardiovascular Imaging 6 (5 ):655
level of a constituent or constituents known harmful for the 664 ; Matsuo , Y., Takumi, T., Mathew , V., Chung , W . Y .,
diseased area defined thus , but rather to block the transport Barsness , G . W ., and 8 others 2012 . “ Plaque Characteristics
of these harmful substances across cell membranes at the and Arterial Remodeling in Coronary and Peripheral Arterial
locus, segment, or organ . Systems," Atherosclerosis 223( 2 ):365-371) . If necessary ,
[ 0431] The apparatuses described herein are determined in some thickness of the tissue surrounding the ductus can be
size by the diameter of the lumen to be treated and ultimately hardened , or sclerosed , and made strongly adherent to the
limited in this regard by the degree of miniaturization that adventitia by microinjection with a tissue adhesive -hardener
can be achieved . While implantation within the walls of or binder- fixative effectively increasing the thickness and
lumina is specifically addressed , limitation to such use and strengthening the wall . The least effective magnetic force
not to other organs is not to be imputed . Embodiments for used , this will often allow the lumen wall to accommodate
use in the trachea , bronchi, or gastrointestinal tract, which and retain magnetically retracted ductus-intramural implants
are relatively large , can incorporate components which for without delamination , or the separation or avulsion of the
use in smaller blood vessels and ureters , for example , will tunics or tissue layers of the ductus, here veins .
demand greater miniaturization over time. Such components [0435 ] Tissue which surrounds and participates in the
include plural implant discharge channels, or barrel-tubes , to physiology of the ductus as to support normal function as
allow the delivery ofmultiple implants per discharge , and a addressed below in the section entitled Accommodation of
central passageway to accommodate a commercial cabled the Adventitial Vasculature , Innervation , and Perivascular
device , such as an endoscope, laser, or rotational tool. Where Fat, is usually not to be treated thus ; however, perivascular
possible , control electronics that can compensate for com fat that is responsible for endothelial dysfunction is best
ponents too large to fit inside the endoluminal portion of the
apparatus are relegated to an extracorporeal power and included in the hardened tissue thus adding thickness and
control housing. reducing the adverse effect at the same time ( see , for
[0432 ] An example is the use of an embedded mixed
example , Kennedy, S. and Salt , I. P . 2017 . “ Molecular
signalmicrocontroller to regulate the temperature of heating Mechanisms Regulating Perivascular Adipose Tissue - Po
tential Pharmacological Targets ?,” British Journal of Phar
elements using the equivalent direct electrical current, thus macology 174 (20 ): 3385- 3387 ; Zaborska, K . E ., Wareing,
eliminating the need to position temperature feedback sen M ., and Austin , C . 2017 . “ Comparisons Between Perivas
sors inside the catheteric member. Suitable microcontrollers cular Adipose Tissue and the Endothelium in Their Modu
are produced by Microchip Technology, Atmel, Freescale lation of Vascular Tone ,” British Journal of Pharmacology
Semiconductor, and Texas Instruments corporations, for 174 ( 20 ): 3388 - 3397 ; Akoumianakis, I., Tarun , A ., and Anto
example . Remote control by a centralized computer and niades, C . 2017 . “ Perivascular Adipose Tissue as a Regula
charging of the implanted battery by distributed charging tor of Vascular Disease Pathogenesis : Identifying Novel
stations is briefly addressed above in this section and below Therapeutic Targets ,” British Journal of Pharmacology 174
in the section entitled Exemplary Channel of Control in a ( 20 ): 3411 - 3424 ; Ayala -Lopez , N . and Watts , S . W . 2017 .
Fully Implanted Ambulatory Adaptive Hierarchical Control “ New Actions of An Old Friend : Perivascular Adipose
System for Automatic Response to a Comorbid Condition . Tissue 's Adrenergic Mechanisms,” British Journal of Phar
[0433] The applicability of the system described herein to macology 174 ( 20 ):3454 - 3465 ; Nosalski, R . and Guzik , T. J.
ductus with weak , disease -weakened or malacotic walls , 2017 . “ Perivascular Adipose Tissue Inflammation in Vascu
such as of veins and atheromatous arteries , wherewith lar Disease ,” British Journal of Pharmacology 174 ( 20 ) :
remodeling has atrophied the media ( see , for example , 3496 - 3513 ; Srikakulapu, P ., Upadhye , A ., Rosenfeld , S . M .,
Glagov , S ., Weisenberg , E ., Zarins , C . K ., Stankunacius, R ., Marshall, M . A ., McSkimming , C ., and 6 others 2017 .
and Kolettis , G . J. 1987. “ Compensatory Enlargement of “ Perivascular Adipose Tissue Harbors Atheroprotective
Human Atherosclerotic Coronary Arteries,” New England IgM -Producing B Cells,” Frontiers in Physiology 8 :719 ;
Journal of Medicine 316 ( 22 ): 1371 -1375), and the tunica Horimatsu , T., Kim , H . W ., and Weintraub , N . L . 2017 . “ The
adventitia ( tunica externa ) appears too weak to compensate Role of Perivascular Adipose Tissue in Non -atherosclerotic
(Haurani, M . J. and Pagano , P. J. 2007. “ Adventitial Fibro Vascular Disease .” Frontiers in Physiology 8 : 969 ; Ramirez ,
blast Reactive Oxygen Species as Autacrine and Paracrine J. G ., O 'Malley , E . J., and Ho, W . S . V . 2017 . “ Pro
Mediators of Remodeling: Bellwether for Vascular Dis contractile Effects of Perivascular Fat in Health and Dis
ease ?," Cardiovascular Research 75 ( 4 ):679 -689 ), for ease,” British Journal of Pharmacology 174 (20 ):3482 - 3495 ;
example , is extended by the capability to include a suitable Li, C ., Wang , Z ., Wang , C ., Ma, Q ., and Zhao , Y. 2015 .
thickness of tissue surrounding the ductus. “ Perivascular Adipose Tissue - derived Adiponectin inhibits
[0434] Calcification introduces a factor of unpredictability Collar -induced Carotid Atherosclerosis by Promoting Mac
that requires testing of the vessel or other ductus wall rophage Autophagy,” Public Library of Science One 10 ( 5 ) :
strength as addressed below in section XVII entiled Testing e0124031 ; Villacorta , L . and Chang , L . 2015 . “ The Role of
US 2019 /0247050 A1 Aug. 15 , 2019
24

Perivascular Adipose Tissue in Vasoconstriction , Arterial sufficient outward force to prevent migration . If to comple
Stiffness , and Aneurysm ,” Hormone Molecular Biology and ment the lumen , the endswere made unequal in diameter ,the
Clinical Investigation 21 ( 2 ): 137 - 147 ; Manka , D ., Chatter sides would incline between the two diameters ; by contrast ,
jee , T . K ., Stoll, L . L ., Basford , J. E ., Konaniah , ES , and extraluminal stent -jackets can adjust for variation in the
6 others 2014 . “ Transplanted Perivascular Adipose Tissue diameter of the substrate ductus the jacket encircles by
Accelerates Injury - induced Neointimal Hyperplasia : Role of altering the strength of ,mgnetization along the length of the
Monocyte Chemoattractant Protein - 1,” Arteriosclerosis, jacket, which is uniform in diameter from end to end .
Thrombosis, and Vascular Biology 34 (8 ): 1723 - 1730 ; Payne ,
G . A . 2010 . Contribution of Perivascular Adipose Tissue to [0439] That is , while ordinarily made to standard dimen
Coronary Vascular Dysfunction, Dissertation , Indiana Uni sions and field strengths rather than customized , extralumi
versity ; Payne , G . A ., Bohlen , H . G ., Dincer, U . D ., Bor nal stent- jackets conform to all but the most pronounced
bouse , L ., and Tune , J. D . 2009. “ Periadventitial Adipose changes in diameter of the substrate ductus due to the
Tissue Impairs Coronary Endothelial Function via PKC compliance of the foam lining, and past that degree of
beta -dependent Phosphorylation of Nitric Oxide Synthase ,” change in diameter, itself unlikely , the jacket can be differ
American Journal of Physiology . Heart and Circulatory entially magnetized from one segment to another along the
Physiology 297 ( 1 ):H460-H465 ; Payne , G . A ., Borbouse , L ., jacket length without affecting stent diameter . An extralu
Bratz , I. N ., Roell, W . C ., Bohlen , H . G ., Dick , G . M ., and minal stent does not have margins unlike or less flexible than
Tune , J. D . 2008 . “ Endogenous Adipose - derived Factors intervening segments and can be adjusted in strength of
Diminish Coronary Endothelial Function via Inhibition of magnetization in any segment. The ductus - intramural
Nitric Oxide Synthase ,” Microcirculation 15 (5 ):417 -426 ; implants for insertion in the arterial tree contain sufficient
Dick , G . M ., Katz , P. S ., Farias , M . 3rd , Morris, M ., James , ferrous content to assure retrieval by prepositioned means.
J., Knudson , J. D ., and Tune , J. D . 2006 . “ Resistin Impairs Such implants can incorporate medication , non -drug thera
Endothelium -dependent Dilation to Bradykinin , but Not
Acetylcholine , in the Coronary Circulation ,” American peutic substances, a radiation emitting seed , or protein
Journal of Physiology . Heart and Circulatory Physiology solder, for example , in any combination .
291 (6 ):H2997 -H3002). [0440 ] When not specifically encapsulated to prevent dis
[0436 ] A small or miniature spine and ribs type stent solution , iron -containing absorbable implants described
jacket , described below in the section entitled Spine and herein will leave an iron residue too small to produce iron
Ribs-type Stent-jacket, is used to avoid any blood vessels or overload . When the sum quantity of iron would exceed the
nerves . The fast initial setting and curing times of long chain 5 or so grams that induce exogenous or secondary acquired
cyanoacrylate cements allows the incorporation into stay iron overload with tissue damage (hemochromatosis ), the
insertion tools of an applicator to coat each stay with cement ferromagnetic material is chemically isolated by encapsula
on ejection . Testing methods to assist in determining tion metallic or polymeric . The source of iron overload
whether preparatory remedial measures are necessary to known , limited , and temporary rather than diagnostic for
stent an artery weakened by disease , for example, are chronic defective hematopoesis, anemia , ( The Merck
delineated below in the section entitled Testing and Tests. Manual of Diagnosis and Therapy, 18th edition , pages
[ 04371 In instances where arterial shrinkage and enlarge 1131- 1133 ) or infection , so long as deposition remains at a
ment produce irregularity in the luminal diameter or radial concentration too small to do tissue damage (hemosidero
symmetry of the luminal wall (see , for example , de Groot, sis ), treatment is not necessary .
P . and Veldhuizen , R . W . 2006 . “ Human Coronary Artery [0441 ] Laser welding surgical tissue solder polymers (see ,
Remodeling, Beginning and End of the Atherosclerotic for example , ACS [American Chemical Society ] News Ser
Process," Public Library of Science One 1 :e91 ; Smits, P . C ., vice Weekly PressPac 2013 . " Improved Material for 'Laser
Bos, L . Quarles van Ufford , M . A ., Eefting , F . D ., Pas Welding ' of Tissue in Intestinal Surgery ," ACS News Service
terkamp, G ., and Borsta , C . 1998 . “ Shrinkage of Human Weekly PressPac Wed May 8 , at https://www .acs .org /con
Coronary Arteries is an Important Determinant of de Novo tent/ acs / en /pressroom / presspacs /2013 / acs - presspac -may - 8
Atherosclerotic Luminal Stenosis : An in Vivo Intraductal 2013 /improved -mater - ial- for - laser -welding - of - tissue -in -in
Ultrasound Study,” Heart 79 (2 ): 143 - 147 ; Prati , F., Mallus, testinal-surgery.html) can release therapeutic drugs not
M . T., Parma, A ., Lioy, E ., Pagano , A ., and Boccanelli , altered by the heat used to flow the solder ( see , for example ,
A .1998. “ Incidence of Compensatory Enlargement and Prosperi, D ., Colombo, M ., Zanoni, I., and Granucci, F .
Paradoxical Shrinkage of Coronary Arteries in Presence of 2017 . “ Drug Nanocarriers to Treat Autoimmunity and
Atherosclerotic Lesions : An Intracoronary Ultrasound Study Chronic Inflammatory Diseases ," Seminars in Immunology
Based on Multiple Cross -section Analysis Per Artery,” Gior 34 :61 -67; Mundargi, R . C ., Babu , V . R ., Rangaswamy, V .,
nale Italiano di Cardiologia 28 ( 10 ) : 1063 - 1071; Birnbaum , Patel, P., d Aminabhavi, T . M . 2008 “ Nano/Micro Technolo
Y., Fishbein , M . C ., Luo , H ., Nishioka , T., and Siegel, R . J. gies for Delivering Macromolecular Therapeutics Using
1997 . “ Regional Remodeling of Atherosclerotic Arteries: A Poly (D , L - lactide -co - glycolide ) and Its Derivatives,” Jour
Major Determinant of Clinical Manifestations of Disease, ” nal of Controlled Release 125 ( 3 ): 193 - 209 ; Perugini, P.,
Journal of the American College of Cardiology 30 (5 ) :1149 Genta, I., Conti, B ., Modena , T., and Pavanetto , F . 2001.
1164 ), an extraluminal stent with foam lining and spring “ Long - term Release of Clodronate from Biodegradable
hinge enabled expandability can maintain patency with less Microspheres,” Pharm Sci Tech 2 (3 ):E10 ). Small miniballs
trauma and disruption to normal physiology than can an and stays can include or consist of long -term drug release
endoluminal stent. microspheres (see , for example, Varde, N . K . and Pack , D .
[0438 ] To accommodate a tapered segment along a ductus W . 2004 . “ Microspheres for Controlled Release Drug Deliv
and its lumen , an endoluminal or intravascular stent may flex ery , Expert Opinion on Biological Therapy 4 ( 1 ):35 -51) or
to some extent, but the margins and body must exert nano or microparticles (see , for example , RaviKumar, M . N .
US 2019 /0247050 A1 Aug . 15 , 2019
25

2000 . “ Nano and Microparticles as Controlled Drug Deliv Response to ROS [reactive oxygen species ],” Proceedings
ery Devices,” Journal of Pharmacy and Pharmaceutical of the National Academy of Sciences of the United States of
Sciences 3 (2 ): 234 -58 ). America ; Sordet, O ., Redon, C . E ., Guirouilh -Barbat, J.,
Smith , S ., Solier, S ., and 8 others 2009. “ Ataxia Telangiec
[0442 ] Asused here, the term medication includes those tasia Mutated Activation by Transcription - and Topoi
all of which pose the risk of adverse side effects that if somerase l- induced DNA Double - strand Breaks,” European
directly targeted through use of the means described Molecular Biology Organization Reports 10 ( 8 ):887 - 893 ;
herein — would be significantly lessened , antiangiogenic Morio , T . and Kim , H . 2008 . “ Ku, Artemis, and Ataxia
( antivasofactive ), proangiogenic , proneurogenic , chemo telangiectasia -mutated : Signalling Networks in DNA Dam
therapeutic , oncolytic viral, antibiotic , precursory (prodrug , age ,” International Journal of Biochemistry and Cell Biol
proenzyme, prohormone ), nanomedical, gene therapeutic to
include ataxia- telangiectasia mutated protein activating (see, ogy 40 ( 4 ) :598 -603 ; Juang, S . H ., Lung, C . C ., Hsu , P . C .,
for example, Comunanza , V . and Bussolino, F . 2017. Hsu , K . S ., Li, Y . C ., and 16 others 2007 . “ D -501036 , a
“ Therapy for Cancer: Strategy of Combining Anti -angio Novel Selenophene -based Triheterocycle Derivative , Exhib
genic and Target Therapies ," Frontiers in Cell and Devel its Potent in Vitro and in Vivo Antitumoral Activity which
opmental Biology 5 : 101 ; Kachaamy, T., Gupta , D ., Edwin , Involves DNA Damage and Ataxia Telangiectasia -mutated
P ., and Vashi, P . 2017 . " Safety of Endoscopy in Cancer Nuclear Protein Kinase Activation,” Molecular Cancer
Patients on Antiangiogenic Agents: A retrospective Multi Therapeutics 6 ( 1 ):193 - 202 ; Ismail , I. H ., Nyström , S .,
center Outcomes Study,” Public Library of Science One Nygren , J., and Hammarsten , O . 2005 . “ Activation of Ataxia
Telangiectasia Mutated by DNA Strand Bbreak - inducing
12 ( 5 ): e0176899 ; Tanabe, K ., Maeshima, Y ., Sato , Y ., and Agents Correlates Closely with the number of DNA Double
Wada, J. 2017 . “ Antiangiogenic Therapy for Diabetic Neph Strand Breaks,” Journal of Biological Chemistry 280 (6 ):
ropathy,” BioMed Research International 2017 :5724069; 4649-4655 ).
Rajabi, M . and Mousa , S . A . 2017. “ The Role of Angiogen
esis in Cancer Treatment,” Biomedicines 5 (2 ). pii: E34 ; Cao , [0443 ] Also included is in vivo magnetic assisted trans
Y . 2016 . “ Future Options of Anti- angiogenic Cancer fection of small interfering (short interfering, silencing,
Therapy ,” Chinese Journal of Cancer 35 :21 ; Zhang, Q ., knockdown ) ribonucleic acid (see , for example , Covarru
Cao, J., Xue, K ., Liu , X ., Ji, D .,Guo , Y., and Hong, X . 2016 . bias, S ., Robinson , E . K ., Shapleigh , B ., Vollmers , A .,
“ Recombinant Human Endostatin in Combination with Katzman , S ., and 4 others 2017 . “ CRISPR /Cas [ clustered
CHOP [ cyclophosphamide, doxorubicin , vincristine and regularly -interspaced short palindromic repeats/CRISPR
prednisone ] Regimen for Peripheral T cell Lymphoma," associated ]-based Screening of Long Non -coding RNAS
Onco Targets and Therapy 10 : 145 - 151; Vecchio , D . and (lncRNAs) in Macrophages with an NF -kB [ nuclear factor
Frosina , G . 2016 . “ Targeting the Ataxia Telangiectasia kappa - light-chain -enhancer of activated B cells ] Reporter,”
Mutated Protein in Cancer Therapy,” Current Drug Targets Journal of Biological Chemistry 292 (51) :20911 - 20920 ;
17 ( 2 ): 139 - 153 ; Kumar, A ., Purohit, S ., and Sharma, N . K . Unniyampurath , U ., Pilankatta , R ., and Krishnan , M . N .
2016 . “ Aberrant DNA Double - strand Break Repair Threads 2016 . “ RNA Interference in the Age of CRISPR : Will
in Breast Carcinoma: Orchestrating Genomic Insult Sur CRISPR Interfere with RNAi?,” International Journal of
vival,” Journal of Cancer Prevention 21 (4 ):227- 234 ; Ye , B ., Molecular Sciences 17 ( 3 ):291; Mykhaylyk , O ., Sanchez
Hou , N ., Xiao , L ., Xu , Y ., Xu, H ., and Li, F . 2016 . “ Dynamic Antequera , Y., Vlaskou, D ., Cerda , M . B ., Bokharaei, M .,
Monitoring of Oxidative DNA Double -strand Break and and 3 others 2015 . “ Magnetic Nanoparticle and Magnetic
Repair in Cardiomyocytes ," Cardiovascular Pathology Field Assisted siRNA [small interfering or interference ]
25 (2 ): 93 - 100 ; Farooqi, A . A ., Attar, R ., Arslan , B . A ., Delivery in Vitro ,” Methods in Molecular Biology ( Clifton ,
Romero , M . A ., ul Haq , M . F., and Qadir , M . I. 2014. N . J.) 1218 :53 - 106 ; Boettcher , M . and McManus , M . T .
“ Recently Emerging Signaling Landscape of Ataxia -telangi 2015 . “ Choosing the Right Tool for the Job : RNAi [RNA
ectasia Mutated (ATM ) Kinase ," Asian Pacific Journal of interference ], TALEN [transcription activator- like effector
Cancer Prevention 15 ( 16 ):6485 -6488 ; Andrs , M ., Kora nucleases ], or CRISPR [clustered regularly - interspaced
becny, J., Nepovimova , E ., Jun , D ., Hodny, Z ., and 3 others short palindromic repeats ],” Molecular Cell 58 (4 ) :575 -585 ;
2014 . “ The Development of Ataxia Telangiectasia Mutated Laurentt, N ., Sapet, C ., Le Gourrierec , L ., Bertosio , E ., and
Kinase Inhibitors ," Mini Reviews in Medicinal Chemistry Zelphati , O . 2011 . “ Nucleic Acid Delivery Using Magnetic
14 ( 10 ):805- 811; Vasudev , N . S . and Reynolds , A . R . 2014 . Nanoparticles : The Magnetofection Technology,” Therapeu
" Anti-angiogenic Therapy for Cancer : Current Progress, tic Delivery 2 (4 ):471-482 ; Plank , C ., Zelphati, O ., and
Unresolved Questions , and Future Directions,” Angiogen Mykhaylyk , O . 2011 . “Magnetically Enhanced Nucleic Acid
esis 17 ( 3 ):471 -494 ; Elice , F . and Rodeghiero , F . 2012 . “ Side Delivery . Ten Years of Magnetofection -progress and Pros
Effects of Anti-angiogenic Drugs," Thrombosis Research pects,” Advanced Drug Delivery Reviews 63( 14 - 15 ): 1300
129 Supplement 1: S50 -S53 ; Elice , F . and Rodeghiero , F . 1331 ; Mykhaylyk , O ., Zelphati , O ., Hammerschmid , E .,
2010 . Bleeding Complications of Antiangiogenic Therapy : Anton , M ., Rosenecker, J., and Plank , C . 2009. “ Recent
Pathogenetic Mechanismsand Clinical Impact,” Thrombosis Advances in Magnetofection and Its Potential to Deliver
Research 125 Suppl 2 :S55 -S57 ; Abdollahi, A . and Folkman , siRNAs siRNA [ small interfering or interference ) in Vitro ,"
J . 2010 . “ Evading Tumor Evasion : Current Concepts and Methods in Molecular Biology (Clifton , N . J.) 487 : 111 - 146 ;
Perspectives of Anti-angiogenic Cancer Therapy ,” Drug Mykhaylyk , O ., Zelphati , O ., Rosenecker , J., and Plank , C .
Resistance Updates 13 ( 1 - 2 ): 16 - 28 ; Alexander, A ., Cai, S . L ., 2008. “ siRNA Delivery by Magnetofection ,” Current Opin
Kim , J., Nanez , A ., Sahin , M ., and 9 others 2010 . “ ATM ion in Molecular Therapeutics 10 (5 ):493 -505; Kawakami,
[ataxia -telangiectasia mutated ] Signals to TSC2 [tuberin , S . and Hashida , M . 2007. “ Targeted Delivery Systems of
tuberous sclerosis complex 2 protein encoded by the TSC2 Small Interfering RNA by Systemic Administration ,” Drug
gene ] in the Cytoplasm to Regulate mTORC1 [mammalian , Metabolism and Pharmacokinetics 22 ( 3 ) : 142- 151) , mutant
or mechanistic , target of rapamycin complex 1 protein ) in human tumor necrosis factor (Liu , X ., Zhang, X . F ., Zheng ,
US 2019 /0247050 A1 Aug. 15 , 2019

Z . W ., Lu , H ., Wu, X ., Huang , C ., Wang, C ., and Guang , G . prevented from continued movement with the aid of a
prevo
2004 . “ The Effect ofChemotherapy Combined with Recom magnet. Where barrel assemblies are transluminal devices
bination Mutant Human Tumor Necrosis Factor on that introduce spherical implants into the wall surrounding
Advanced Cancer," Journal of TranslationalMedicine 2 ( 1 ): the lumen radially outward and forward at an acute angle by
33 ), glutamate antagonistic , and /or irradiating . aeroballistic ejection from within the lumen , stay insertion
[0444 ] Whether containing an irradiating seed , the surface devices insert tiny band shaped implants into the luminal
of stay and miniball implants , metallic , absorbable , or hav wall from outside the ductus . As addressed in section XV5
ing an outer absorbable layer or layers can be prepared to below entitled Circumstances Dissuading or Recommending
emit radiation (see , for example, Cardoso , R . M ., de Souza , the Use of Stays , this ability of the integrated system set
C . D ., Rostelato , M . E ., and Araki, K . 2017 . “ Highly forth herein to accomplish implantation either from within
Efficient Method for Production of Radioactive Silver Seed or without the ductus makes possible the secure and well
Cores for Brachytherapy,” Applied Radiation and Isotopes placed positioning of the implants in any anatomical con
120 : 76 -81; Li, Z . Y ., Langhans, L ., Klausen , T . L ., Tved text.
skov, T . F ., Talman , M . L ., Oturai, P . S ., Vejborg, I., Kroman , [0448 ] Since the stent- jacket must be placed from outside
N ., and Hesse , B . 2016 . “ Preparation and Administration of the ductus in any event, the use of stays eliminates the need
1 - 125 Labeled Seeds for Localization of Nonpalpable Breast for double , or transluminal approach , as well. In some
Lesions,” Current Radiopharmaceuticals 9 (2 ): 143 - 149; anatomical and pathological situations, one and the same
Gao , H . B ., Deng, X . S ., Zhou , L ., Zhang , W . H ., Han , L . G ., ductus might best be treated in partby either type device . As
Jin , X . H ., and Cui, H . P. 2015 . “ Preparation of (103)Pd explicated herein , provided it is warranted by the severity of
Brachytherapy Seeds by Electroless Plating of (103 ) Pd onto the condition , the advantages of a periductal stent-jacket
Carbon Bars,” Applied Radiation and Isotopes 103: 128 - 130 ; over a conventional endoluminal stent justify the dissection
Lee , J. H ., Choi, K . H ., and Yu , K . H . 2014 . “ Surface required to place the jacket. By the same token , the endolu
Treatments of Silver Rods with Enhanced Iodide Adsorption minal/extraluminal double approach provided by the system
for I- 125 Brachytherapy Seeds,” Applied Radiation and described means that often , extensive perivascular dissec
Isotopes 85 : 96 - 100 ; Otani, Y ., Yamada, T., Kato , S ., tion to place magnetically susceptible implants can be
Shikama, N ., Funakoshi, K ., and 5 others 2013 . “ Source avoided . This double approach capability also means that
Strength Assay of Iodine - 125 Seeds Sealed within Sterile implantation can span the length of the defect and avoid
Packaging ,” Journal of Applied Clinical Medical Physics problems of conventional stenting, such as migration .
2013 14 ( 2 ):4082 ; Fischell, T . A . and Hehrlein , C . 1998 . “ The [0449 ] Endoluminal stent migration is no less a risk in the
Radioisotope Stent for the Prevention of Restenosis ,” Herz aortic arch ( see , for example , Rad , E . M ., Mortezaeian , H .,
23 (6 ): 373 -379 ; Sekina , T., Watanabe, S ., Osa , A ., Ishioka , Pouraliakbar, H . R ., and Hijazi, Z . M . 2017 , Op cit.; van den
N ., Koizumi, M . and 8 others 2001. “ Xenon 133 Radioactive Hoven , A . T ., Duijnhouwer , A . L ., Eicken , A ., Aboulhosn , J .,
Stent for Preventing Restenosis of Blood Vessels and a de Bruin , C ., and 9 others 2017 . “ Adverse Outcome of
Process for Producing the Same,” U . S . Pat. No. 6 , 192 ,095 ). Coarctation Stenting in Patients with Turner Syndrome,”
Apparatus according to the invention allow the targeted Catheterization and Cardiovascular Interventions 89 ( 2 ) :
delivery of medication into luminal lesions endoluminally . 280 -287 ; Yaylali , Y. T., Evrengul, H ., and Uludag, B . 2013 .
[0445 ] One type, barrel-assemblies, are catheteric exten " SuccessfulManagement of a Proximally Migrated Stent in
sions to the barrel of a modified or special purpose inter a Middle - aged Woman with Unnoticed Native Aortic Coarc
ventional airgun . This introduces the medication in the form tation ,” International Journal of Cardiology 168 ( 1 ):e19 -21;
of tiny spherules or miniballs . Another type , radial projec Kannan , B . R . and Srinivasan , M . 2012 . “ Stent Migration
tion assemblies or catheters deliver medication endolumi During Transcatheter Management of Coarctation of Aorta ,"
nally using side- looking , or luminal wall -directed , injection Catheterization and Cardiovascular Interventions 79 ( 3 ) :
microsyringes or hypotubers . Yet another apparatus is a stay 408 -413 ; Forbes, T. J., Garekar, S ., Amin , Z ., Zahn , E . M .,
insertion hand tool that allows injection extraluminally . The Nykanen , D ., and 19 others 2007 , Op cit.).
endoluminal types include barrel assemblies such as shown [0450 ] Whether additionally coated with medication or
in FIGS. 31 thru 35 , and 38 thru 49 and 716 , and radial radioactive, for example , miniballs, stays, magnet - jackets ,
projection catheters such as shown in FIG . 71a . stent - jackets , and impasse -jackets can all be used to con
[0446 ] As shown in FIG . 71, which shows how these need centrate a drug carrier nanoparticle or ferrofluid -bound drug
not be mutually exclusive , the radial projection catheter in or other therapeutic substance such as small interfering
FIG . 71a , for example , devised to slide over , thereby to ribonucleic acid passing in the circulation and draw the drug
ensheath the barrel-assembly of complementary conforma abaxially away from the long axis , lateral, peripheral,
tion shown in FIG . 71b to constitute a composite , duplex , or outward ) through the lumen wall into the lesion . Permanent
bipartite combination radial projection catheter /barrel- as encirclement of the ductus by an expandable collar, or
sembly shown in FIG . 710 such the the two can be used stent-jacket, having a lining to protect the fine vessels and
separately or as unitized . In numerous alternative configu nerves that surround the ductus and tiny magnets mounted
rations where these are independent, either can include about its outer surface allows the implants to serve as the
features of the other. Such multifeatured transluminal cath intraductal component of an extraluminal stent. A structure
eters are always ablation and angioplasty capable . The requiring stenting may have collapsed , become constricted
implants can consist purely ofmedication or of ferrous cores ( stenosed , stenotic , stegnotic , strictured , coarctated , nar
or radiation -emitting seeds enveloped within layers ofmedi rowed ), or have been alleviated of constriction or occlusion
cation , for example . (blockage ) where the patency achieved must now be sus
[0447 ] By including ferromagnetic material, implants that tained.
are mispositioned , dropped , or due for removal because the 0451] Validation of stenting as efficacious in the treat
period for treatment has ended are made retrievable or ment of coarctation of the aorta extends the application of
US 2019 /0247050 A1 Aug. 15 , 2019
27

stents to this congenital or ‘ native ' form of narrowing Implantation and Long -term Follow - up Results ,” Catheter
( stenosis , stricture , constriction ) (Bassiri, H . A ., Abdi, S ., ization and Cardiovascular Interventions 71(6 ): 831 - 841;
Shafe, O ., and Sarpooshi, J. 2017 . “ Early and Midterm Moodie, D . 2008 . “ Stent Implantation as Effective Treat
Results Following Interventional Coarctoplasty : Evaluation ment of Vascular Stenosis in Young Infants with Congenital
of Variables that Can Affect the Results ,” Korean Circula Heart Disease : Acute Implantation and Follow - up ,” Cath
tion Journal 47 (1 ):97 - 106 ; Georgescu , A ., Onorato , E ., eterization and Cardiovascular Interventions 71 (6 ):842 ;).
Nicolae, S ., and Balnescu , S . 2015 . “ Aortic Coarctation With an extraluminal stent of the kind to be described ,
Treated by PTA and Stenting: A Case Presentation and ferromagnetic implants positioned beneath or subjacent to
Literature Review ," Maedica (Bucharest, Romania ) 10 ( 4 ): the outer fibrous coat or tunic if not within deeper, that is ,
342- 347; Forbes, T. J. and Gowda , S . T. 2014 , Op cit.; more adluminal or medial, tissue of a tubular anatomical
Forbes TJ, Kim DW , Du W , Turner DR , Holzer R . J., Amin structure can be placed under the sustained retractive force
Z , Hijazi Z , and 18 others 2011 . “ Comparison of Surgical, ofminute surrounding magnets to maintain the patency and
Stent, and Balloon Angioplasty Treatment of Native Coarc thus sustain themovement of contents through the structure .
tation of the Aorta : An Observational Study by the CCISC [0454 ] The subject of stent migration addressed below ,
(Congenital Cardiovascular Interventional Study Consor extraluminal stents are easily provided with suture loops or
tium ),” Journal of the American College of Cardiology suture eyelets and end - ties for use as necessary to reinforce
58 ( 25 ): 2664 - 2674; Holzer, R . J., Qureshi, S ., Ghasemi, A ., the positional stability afforded by the spring hinges joining
Vincent, J., Sievert, H ., Gruenstein , D ., Weber, H ., and 6 the half -cylinders and the resistance to sliding afforded by
others 2010. “ Stenting of Aortic Coarctation : Acute , Inter the foam jacket lining. Except in large gastrointestinal
mediate , and Long- term Results of a Prospective Multi stents, such collateral tethering is not possible when the stent
institutional Registry - Congenital Cardiovascular Interven is endoluminal, conventional stents sometimes migrating to
tional Study Consortium (CCISC )," Catheterization and pose significant danger (see , for example, Orellana -Barrios ,
Cardiovascular Interventions 76 ( 4 ):553 -563 ). M ., Patel, N ., Arvandi, A ., Paone , R ., and Santana, D . 2017 .
[0452] If not conclusively successful, such application " Venous Stent Migration into Right Ventricle ," Cureus 9 ( 8 ) :
pertains not only to neonates but to critically ill premature e1583 ; Hayashi, T ., Akhtar, S ., and Alwi, M . 2017 . “ Stent
infants as a bridging measure pending surgical reconstruc Migration After Right Ventricular Outflow Tract Stenting in
tion or recorrection thereof where an earlier coarctectomy or the Severe Cyanotic Tetralogy of Fallot Case ,” Annals of
repair of the interrupted aortic arch had failed . Imperiling the Pediatric Cardiology 10 (2 ):206 - 208; Garbey , M ., Salmon ,
left ventricle, which in an effort of compensation to pass R ., Fikfak , V ., and Clerc , C . 0 . 2016 . “ Esophageal Stent
sufficient blood into the systemic circulation , progressively Migration : Testing Few Hypothesis with a Simplified Math
weakens and hypertrophies , prominently presenting as syn ematical Model,” Computers in Biology and Medicine
cope, dyspnea , epistaxis , vertigo , hypertension of the arms 79: 259- 265 ; Moltzer , E ., Ouhlous, M ., Roos -Hesselink , J.
and hypotension of the legs, as well as other indications of W ., Bogers, A . J., and Witsenburg , M . 2013 . “ Proximal
weakness (van den Hoven , A . T ., Duijnhouwer, A . L ., Aortic Stent Migration ,” Netherlands Heart Journal 21( 11 ) :
Eicken , A ., Aboulhosn , J ., de Bruin , C ., and 9 others 2017 . 517 -519 ; Kobayashi, D ., Singh , H . R ., Turner, D . R ., Forbes,
“ Adverse Outcome of Coarctation Stenting in Patients with T . J., and Gowda , S . T . 2012 . " Transcatheter Retrieval and
Turner Syndrome," Catheterization and Cardiovascular Repositioning of Embolized Stent from the Right Ventricle
Interventions 89( 2 ):280- 287 ; Gorenflo , M ., Boshoff , D . E ., in an Infant,” Texas Heart Institute Journal 39(5 ):639 -643 ).
Forbes , T . J. and Gowda , S . T . 2014 . “ Intravascular Stent [0455 ] For ductus that require clearing prior to stenting
therapy for Coarctation of the Aorta,” Methodist Debakey implantation , the endoluminal apparatus incorporates radi
Cardiovascular Journal 10 (2 ):82 -87 ; Heying, R ., Eyskens , ally protrusible tools that can prepare the wall for treatment
B ., Rega , F., Meyns , B ., and Gewillig , M . 2010 . “ Bailout by injection or wetting, for example , then shave , abrade, or
Stenting for Critical Coarctation in Premature/ Critical/Com scrape ( curet, evide ) away adhesions or plaque along the
plex /Early Recoarcted Neonates," Catheterization and Car lumen wall . The extraluminal stents described herein elimi
diovascular Interventions 75 ( 4 ):553 -561; Bentham , J., Shet nate the need to situate a foreign object within the lumen and
tihalli , N ., Orchard , E ., Westaby , S ., and Wilson , N . 2010 . are intended to be usable in any vas or ductus of any
“ Endovascular Stent Placement is an Acceptable Alternative vertebrate that is wide enough in diameter to admit the
to Reoperation in Selected Infants with Residual or Recur apparatus used to place the implants and provides a wall
rent Aortic Arch Obstruction ," Catheterization and Cardio thickness sufficient to accommodate these . That an endolu
vascular Interventions 76 (6 ): 852 -859 ) minal stentmust clog in the airway, especially when used for
[0453 ] Pediatric application has also been successfully a chronic congestive condition such as bonchiectasis , is
extended to coronary and venous stenoses ( see, for example , indisputable. Any endoluminal stent, regardless of the type
Aldoss, O ., Arain , N ., Menk, J., Kochilas , L ., and Gruen ductus in which it is placed, is susceptible to accretions,
stein , D . 2014 . “ Endovascular Stent Provides More Effective irritation , occlusion , and migration (dislocation , displace
Early Relief of SVC [superior vena caval Obstruction Com ment ), and any of these , much less its fracture, can result in
pared to Balloon Angioplasty ," Catheterization and Cardio serious consequences .
vascular Interventions 83 ( 7 ) :E272 -E276 ; Bratincsák , A ., [0456 ] In the digestive tract, an endoluminal stent is often
Salkini, A ., El-Said , H . G ., and Moore, J. W . 2012 . “ Percu pushed along by the passing contents as well as peristalsis ,
taneous Stent Implantation into Coronary Arteries in making migration common unless the stent is fixed in
Infants," Catheterization and Cardiovascular Interventions position by stapling or the use of more than one stent. Just
79 ( 2 ): 303 -311; Stanfill , R ., Nykanen , D . G ., Osorio , S ., as endoluminal stents , extraluminal stents can be used to
Whalen , R ., Burke , R . P ., and Zahn , E . M . 2008 . “ Stent alleviate the symptoms of tracheal or bronchial stenosis or
Implantation is Effective Treatment of Vascular Stenosis in collapse , obturate fistulas , preserve the patency of blood
Young Infants with Congenital Heart Disease : Acute vessels, and maintain the patency of ureters and gamete
US 2019 /0247050 A1 Aug. 15 , 2019

transporting ducts, for example. Stenotic conditions ame tion and endoluminal stenting reinforces (see , for example,
nable to treatment with a stent exclude noncompliant con Cui, Y ., Liu , Y ., Zhao , F., Shi, D ., and Chen , K . 2016 .
strictions of the lumen due to a congenital malformation . " Neoatherosclerosis after Drug -Eluting Stent Implantation :
Elimination from the lumen eliminates contact with the Roles and Mechanisms,” Oxidative Medicine and Cellular
healing endothelium as well as the risks assocated with Longevity 2016 :5924234 ; Veerasamy, M ., Bagnall , A .,
migration , fracture , or fragmentation , and allows the stent to Neely, D ., Allen , J., Sinclair, H ., and Kunadian , V . 2015 .
expand and contract without stressing or deforming the “ Endothelial Dysfunction and Coronary Artery Disease: A
ductus . State of the Art review ," Cardiology in Review 23 ( 3 ):119
[0457 ] Intrinsically and quasi-intrinsically magnetized 129 ; Komiyama, H ., Takano , M ., Hata , N ., Seino , Y.,
stent-jackets , addressed below in the section entitled Types Shimizu , W ., and Mizuno, K . 2015 . “ Neoatherosclerosis:
of Stent-jacket, eliminate permanent magnets mounted Coronary Stents Seal Atherosclerotic Lesions but Result in
about the outer surface of a stent-jacket. The thinner stent Making a New Problem of Atherosclerosis ,” World Journal
jacket with no outward projections can be fitted to arteries of Cardiology 7 (11):776 - 783 ; Rudolph , A ., Teske, M ., Illner,
ensheathed within muscle , notably , to treatperipheral artery S ., Kiefel, V ., Sternberg , K ., and 3 others 2015 . “ Surface
disease. Prepositioned impasse -jackets allow continued drug Modification of Biodegradable Polymers Towards Better
targeting at any level along any ductus to include such Biocompatibility and Lower Thrombogenicity,” Public
locations , as well as protect against embolism by a miniball Library of Science One 10 ( 12 ):e0142075 ; Wang, X ., Zach
whether mid - or postprocedurally , and whether the result of man , A , L ., Chun , Y. W ., Shen , F . W ., Hwang, Y. S ., and
human error or a direct blow . Medicated and irradiated Sung, H . J. 2014 . “ Polymeric Stent Materials Dysregulate
stent-jackets are less and less limited to the palliative and Macrophage and Endothelial Cell Functions: Implications
more and more able to effect an actual cure . for Coronary Artery Stent," International Journal of Car
diology 174 (3 ):688 -695 ; “Murase , S ., Suzuki, Y ., Yamagu
2 . Preliminary Description of the Invention chi, T., Matsuda, O ., Murata , A ., and Ito , T. 2014 . “ The
[ 0458 ] Brief summaries are provided above in the abstract Relationship Between Re-endothelialization and Endothe
and below in the section entitled Summary of the Invention . lial Function After DES [drug -eluting stent] Implantation :
The invention pertains to means for ablation or angioplasty Comparison Between Paclitaxcel -eluting Stent and Zotaroli
as appropriate , the targeting of drugs, and the infixion of tiny mus-eluting Stent," Catheterization and Cardiovascular
implants within organs and in particular, into the walls of Interventions 83 (3 ):412 -417 ; Minami, Y., Kaneda , H .,
tubular anatomical structures , to treat lesions or pathological Inoue, M ., Ikutomi, M ., Morita , T., and Nakajima, T. 2013 .
conditions thereof, such as stenosis or collapse . Whether the “ Endothelial Dysfunction Following Drug-eluting Stent
contents are medicinal, irradiating, and /or ferromagnetic, the Implantation : A Systematic Review of the Literature , ” Inter
implants meant for infixion within tissue such as ductus national Journal of Cardiology 165 (2 ):222 - 228 ; Gutiérrez ,
intramural are distinguished by type based upon conforma E ., Flammer, A . J., Lerman , L . O ., Elizaga , J., Lerman , A .,
tion as either miniature balls, or miniballs , which are spher and Fernández - Avilés, F . 2013 . “ Endothelial Dysfunction
ules introduced from within the lumen , or as small arcuate Over the Course of Coronary Artery Disease,” European
bands, or stays , which are introduced from outside the outer Heart Journal 34 ( 41 ):3175 - 3181; Nakazawa, G ., Otsuka , F.,
fibrous jacket or tunic , the tunica fibrosa or adventitia , of the Nakano, M ., Vorpahl, M ., Yazdani, S . K ., and 4 others 2011 .
organ , vessel, or duct. Such implants can be used for drug “ The Pathology of Neoatherosclerosis in Human Coronary
delivery , drug targeting, and/ or to stent . Implants Bare -metal and Drug - eluting Stents,” Journal of
10459 ) Other implants to be described are collars or jack the American College of Cardiology 57 ( 11 ): 1314 -1322;
ets for placement about ductus which are used with these Kim, J. W ., Suh , S . Y., Choi, C . U ., Na, J. O ., Kim, E . J., and
infixed implants to retract the implants and thus act as a stent 4 others 2008 . “ Six -month Comparison of Coronary
and /or to attract drug delivery nanoparticles, microspheres , Endothelial Dysfunction Associated with Sirolimus- eluting
orminiballs via the lumen .Miniballs and stays are alike only Stent Versus Paclitaxel- eluting Stent,” Journal of thd Ameri
in positioning and general functions. Miniballs are quickly can College of Cardiology Cardiovascular Interventions
placed from within the lumen without the need for local 1 ( 1 ):65 -71; Caramori, P. R . A .; Lima, V . C .; Seidelin , P . H .;
access through a small or laparoscopic incision . Placement Newton , G . E ; Parker, J. D ; Adelman , A . G . 1999. “ Long
thereof is prompted when an antecedent procedure such as term Endothelial Dysfunction after Coronary Artery Stent
an angioplasty necessitates transluminal ( transcatheter ) ing,” Journal of the American College of Cardiology 34 ( 6 ) :
treatment in any event. Spheroidal for ballistic delivery but 1675 - 1679 ; van Beusekom , H . M ., Whelan , D . M ., Hofma,
poor for magnetic susceptibility , miniballs are placed in S . H ., Krabbendam , S . C ., van Hinsbergh , V . W ., Verdouw ,
relatively tight formation to uniformly distribute the tractive P . D ., and van der Giessen , W . J . 1998 . “ Long -term Endothe
lial Dysfunction is More Pronounced after Stenting than
force and avoid pull -through or delamination . after Balloon Angioplasty in Porcine Coronary Arteries,”
10460 ] An extraluminal stent in the vascular tree leaves no Journal of the American College of Cardiology 32 ( 4 ):
foreign object in the lumen , which is the central source of 1109- 1117).
adverse sequelae with endoluminal stents, to include reoc
clusion . Unless placed in a surgical field opened for another 10461] Some endothelial dysfunction is to be expected
reason , stays are less quickly placed through an incision at from intervention of any kind ( see , for example , Borovac , J.
the body surface than are miniballs. Stenting with stays or A ., D ' Amario , D ., and Niccoli , G . 2017 . " Neoatherosclero
miniballs not only avoids the need to situate a foreign object sis and Late Thrombosis After Percutaneous Coronary Inter
in the lumen , but avoids the lumen entirely . The result is a vention : Translational Cardiology and Comparative Medi
stent which is less likely to perpetuate the chronic endothe cine from Bench to Bedside," Yale Journal of Biology and
lial dysfunction that led to inflammation and atheroma, Medicine 90 ( 3 ):463 - 470 ; Rudolph , A ., Teske, M ., Illner, S .,
fibroatheroma, ormore complicated lesion , which interven Kiefel , V ., Sternberg, K ., and 3 others 2015 , Op cit .);
US 2019 /0247050 A1 Aug. 15 , 2019

however, this should be significantly less with extraluminal ductal Component of the Extraluminal Stent and the Means
means, and remedial meaures are becoming apparent (see , for Its Insertion among others , rib - jackets addressed in the
for example, Liu , H ., Ba, P., Li, L ., Wang , Y., Xu, C ., Deng, section below entitled Spine and Ribs -type Stent- jackets ,
M ., Zhang, J., and Zhao , X . 2017 . “ Pitavastatin Nanopar and magnet -jackets, or magnet-wraps, addressed below in
ticle -engineered Endothelial Progenitor Cells Repair Injured the section entitled Concept of the Magnet-wrap represent a
Vessels,” Scientific Reports 7 ( 1): 18067; Lu, Q ., Ye, F ., Yang , graduated series of type jackets based upon firmness or
X ., Gu, Q ., Wang , P ., Zhu , J., Shen , L ., and Gong, F. 2015 . backing firmness. Stent-jackets must possess the longitudi
“ Accelerated Recovery of Endothelium Function After Stent nal and circumferential firmness to stent, that is , to not flex
Implantation with the Use of a Novel Systemic Nanoparticle inward under the magnetic attractive force needed to draw
Curcumin ,” Biomed Research International 2015 :291871; the encircled or substrate ductus- intramural implants radi
Cerrato , E ., Echavarria -Pinto , M ., Tandjung , K .,Macaya , C ., ally outward . Stent- jackets need not, however, be more firm
and Escaned , J. 2014 . “ Optimizing Vessel Healing Follow than is necessary to accomplish this as is based upon the
ing Drug Eluting Stent Implantation with Biodegradable retractive force needed to keep the ductus patent .
Polymer DES [drug - eluting stent )," Minerva Cardioangio [0465 ] Rib jackets are firm or firmly backed circumferen
logica 62 (5 ) :407 -420 ; Hu, C . H ., Ke, X ., Chen , K ., Yang, D . tially but not longitudinally as complies with peristalsis
Y ., Du, Z . M ., and Wu, G . F. 2013 . “ Transplantation of along the gastrointestinal tract, or in miniature form , ureters
Human Umbilical Cord - derived Endothelial Progenitor and fallopian tubes . Magnet jackets are stretchable in all
Cells Promotes Re- endothelialization of the Injured Carotid directions as allows complete compliance with the intrinsic
Artery After Balloon Injury in New Zealand White Rabbits," movement within the substrate ductus where the attractive
Chinese Medical Journal ( in English ) 126 (8 ): 1480 - 1485 ; force is applied at a distance to affect magnetically suscep
van den Heuvel, M ., Sorop , O ., van Beusekom , H . M ., and tible implants fastened to or infixed within distant tissue or
van der Giessen , W . J. 2009. “ Endothelial Dysfunction After draw susceptible matter such as miniballs or nanoparticles
Drug Eluting Stent Implantation ,” Minerva Cardioangio from the substrate lumen contents where that ductus is not
logica 57 (5 ):629 -643). collapsed , malacotic , or constricted . In magnetic stenting or
[0462 ] Extended circumferentially and parallel to the sub tissue retraction applications, the ductus- intramural or intra
strate ductus, stays provide more continuous expansive ductal implants include nonmagnetized magnetically sus
lifting and have greater retentive ability , especially when ceptible ( ferrous ) material, and are attracted or drawn rather
coated with a cement that prevents ductus wall failure . than attracting or drawing . That this relationship might be
Nonabsorbable miniballs and stays to be integrated into the reversed so that the implants were magnetized is considered
surrounding tissue are provided with an undercut textured obvious . Miniballs and stays are not limited to magnetic
surface . Stays are automatically coated with a cement when stenting or the retraction of tissue using magnetic force .
ejected from the insertion tool that incorporates tissue stimu [0466 ] Either can incorporate ferromagnetic material for
lating substances to encourage the gradual infiltration and use with a magnetic stent- jacket, medication , concentric
supplantation of the cement by tissue. To deliver the cement layers of different medication , a radionuclide, or a protein
with miniballs without fouling the airgun requires followup solder, for example , in any combination , as well as include
injection with the aid of side-looking radial projection unit magnetically attracting or attracted material for retrievabil
injection tool- inserts, as addressed below in the section ity if dropped or mispositioned . Implants to be fully
entitled Self -contained Electrical/Fluid System -neutral absorbed omit magnetized content, which a toxic lanthanoid
Tool- inserts , to Include Injection and Ejection Syringes or a ( see, for example, Donohue , V . E .,McDonald , F ., and Evans ,
service catheter hypotube injector, as mentioned below in R . 1995 . “ In Vitro Cytotoxicity Testing of Neodymium -Iron
the section entitled Risk of Abrupt Closure with Thrombus Boron Magnets ,” Journal of Applied Biomaterials 6 ( 1 ):69
and Vasospasm . 74 ) , is encapsulated for chemical isolation , usually with gold
[0463] This depiction of a stent-jacket in FIG . 5 with small plate , which is further treated to eliminate any voids or
permanent magnets mounted about its outer surface is surface residue, as addressed below in the section entitled
presented for clarity of the underlying concept; most stent Stent -jackets and Stent- jacket Supportng Elements and is
jacket achieve uniformity of the magnetic tractive force preferred to the poly (p -xylylene® ) AF - 4 polymer ( Paralyne )
without outward protrusion of discrete magnets by embed passivation thin film commonly used to coat stents or
ding the magnetized material within the jacket, as explained polytetrafluoroethylene ( see , for example , Oje , A . M . and
below in the section entitled Types of Stent-jacket. Any of Ogwu, A . A . 2017 . “ Chromium Oxide Coatings with the
the implants to be described can be magnetized for drug Potential for Eliminating the Risk of Chromium Ion Felease
targeting. If accidently dropped or mispositioned ,medicinal in Orthopaedic Implants,” Royal Society Open Science 4 ( 7 ) :
and/ or irradiating miniballs and stays include sufficient 170218 ; Aramesh , M ., Tong , W ., Fox , K ., Turnley, A ., Seo ,
superparamagnetic magnetite or maghemite nanoparticles or D . H ., Prawer, S ., and Ostrikov, K . K . 2015 . “ Nanocarbon
finely grained powder to allow instant arrest and retrieval coated Porous Anodic Alumina for Bionic Devices,” Mate
using the recovery electromagnets of the recovery and rials (Basel, Switzerland ) 8 (8 ):4992 -5006 ; Liao , W . H ., Lin ,
extraction miniball electromagnet assembly built into the C . R ., Wei, D . H ., Shen , Y . R ., Li, Y . C ., Lee , J. A ., and
insertion apparatus, a separate caheteric probe with magne Liang, C . Y . 2012. “ Concurrent Improvement in Biocom
tized tip , impasse - jackets prepositioned downstream pre patibility and Bioinertness of Diamond-like Carbon Films
cisely to truncate further migration , or if necessary such as with Nitrogen Doping,” Journal of Biomedical Materials
if embolizing, a powerful external electromagnet positioned Research . Part A 100 ( 11 ):3151- 3156 ; Wang , G . and Zreiqat ,
to suddently pull the implant outside of the ductus or other H . 2010 . “ Functional Coatings or Films for Hard -tissue
structure . Applications ,” Materials (Basel, Switzerland ) 3 (7 ):3994
[ 0464 ] Stent- jackets, addressed in the sections below 4050 ; Hinüber, C ., Kleemann , C ., Friederichs , R . J.,
entitled Concept of the Extraluminal Stent and The Extra - Haubold , L ., Scheibe , H . J., and 3 others 2010 . “ Biocom
US 2019 /0247050 A1 Aug. 15 , 2019
30

patibility and Mechanical Properties ofDiamond -like Coat Therapeutics Using Poly ( D ,L - lactide -co - glycolide) and Its
ings on Cobalt -chromium -molybdenum Steel and Titanium Derivatives,” Journal of Controlled Release 125 (3 ): 193
aluminum - vanadium Biomedical Alloys ,” Journal of 209 ). The entire implant or its outer layer can release a
BiomedicalMaterials Research . Part A 95 (2 ):388 -400 ; Roy , chemotherapeutic drug that also radiosensitizes the targeted
R . K . and Lee , K . R . 2007. “ Biomedical Applications of tissue, such as cisplatin , nimorazole , or cetuximab . Just as
Diamond - like Carbon Coatings : A Review ,” Journal of with prior art seeds, radiation stays can incorporate metals to
Biomedical Materials Research . Part B , Applied Biomate aid in targeting intensity -modulated radiation therapy
rials 83 ( 1 ):72 -84 ; Ahmad , K . A ., Drummond, J. L ., Graber, ( IMRT) , for example .
T., and BeGole, E . 2006 . “Magnetic Strength and Corrosion [0470 ] Stays containing a radioactive seed also contain
of Rare Earth Magnets ,” American Journal of Orthodontics ferromagnetic material, which if sufficient allows these to be
and Dentofacial Orthopedics 130 (3 ) :275 . el1-5 ; Noar, J. H ., used as the intraductal component of a magnetic stent. Such
Wahab , A ., Evans, R . D ., and Wojcik, A . G . 1999 . “ The stays can likewise be coated with concentric layers each
Durability of Parylene Coatings on Neodymium - iron -boron containing a drug or drugs and/ or other therapeutic sub
Magnets ,” European Journal of Orthodontics 21 (6 ):685 stances. In the trachea and bronchi, gastrointestinal tract, and
693 ) . many muscular arteries , ferrous content allows any number
[ 0467 ] Not limited to the walls of ductus, miniballs and of irradiating seed stays of higher dose - rate than could be
stays can be implanted anywhere in the body. The major used if irretrievable to be recovered at any time. Moreover ,
categories of miniballs and stays are absorbable ( temporary , seed stays are implantable in ductus wallsmore quickly than
usually medicinal), combination absorbable -nonabsorbable , could be accomplished using conventional means when
which have a permanent or intravascular ferromagnetic core, these are even capable of placement thus . Furthermore ,
and nonabsorbable or permanent used to secure a magnetic unlike conventional seed implant devices, regardless of its
extraluminal stent of the kind to be described . Temporary content, only the miniball or stay enters the tissue to be
( absorbed ) miniballs contain medication , adhesives , or both . treated , so that the penetration path or trajectory is no larger
Temporary (absorbed ) staysmade of the samematerials that in cross - section than is the implant itself .
are used to make absorbable suture and tissue engineering [0471 ] By entering suddenly at high velocity , miniballs
scaffolds can be used as buttress supports to sustain the preempt the evasive receding of flaccid tissue to effect
patency of a collapsed or stenosed lumen over the dissolu infixion with minimal tearing or stretching injury through a
tion period. trajectory no wider than the miniball itself. The sudden
[0468 ] Any kind of stay can incorporate or be coated with extraction or evulsion of a miniball as addressed in section
medication , foreign body tissue reaction suppressive sub X2c below entitled Stereotactic Arrest and Extraction of a
stances, such as dexamethasone , or an adhesive , or any Circulating, Dangerously Mispositioned , or Embolizing
combination of these . Including sufficient ferromagnetic Miniball is similarly intended to reverse the action of
material such as magnetite or maghemite nanoparticles or aeroballistic infixion by preempting any ability of interven
finely grained powder in an absorbable stay or miniball ing tissue to resist perforation . Loaded with sharp stays, a
assures retractability with a magnet. Ductus -intramural quick action of the hand on the insertion tool produces the
implants (stays and miniballs ) used as the intraductal com same result. Properly applied , perforations of the ductus wall
ponent of a magnetic stent contain a ferromagnetic material, should seldom occur. Stent- jacket and stay insertion tools
usually in the form of a core encapsulated within a biocom generally incorporate clips not included in the drawing
patible chemical isolation layer. The core can be overlain figures for attaching alongside a fine gauge endocscope with
with additional layers ofmedication , a tumefacient, sclero illumination , aspiration , cautery , cryogenic , or heating line ,
sant, adhesive , or any combination of these . or laser, for example, as necessary .
[0469 ] Such constituents can be dispersed or noncontinu [0472 ] Regardless of content, wider stays with a nonab
ous and intermingled , so that rather than homogeneous, each sorbable exterior and/or nonmagnetic can be used to main
layer might include particles , microspheres, or nanorods of tain the patency of a collapsed ductus by acting as mechani
various therapeutic substances ( see, for example , Nabar, G . cal supporting buttresses without the need for a circumductal
M ., Mahajan , K . D ., Calhoun , M . A ., Duong, A . D ., Souva , or extravascular collar type stent component. In a magnetic
M . S ., and 6 others 2018 . “ Micelle -templated , Poly (lactic stent, the ferromagnetic material in the implant is attracted
co - glycolic Acid ) Nanoparticles for Hydrophobic Drug to small chemically isolated neodymium iron boron lantha
Delivery," International Journal of Nanomedicine 13 :351 noid magnets mounted :
366 ; Zhu , X ., Liu , C ., Duan , J., Liang , X ., Li, X ., Sun , H ., [0473 ] 1 . About an encircling (periductal, perivascular,
Kong , D ., and Yang, J. 2016 .“ Synthesis of Three-arm Block circumductal, circumvascular) stent-jacket, or
Copolymer Poly (lactic- co - glycolic Acid )-poly ( ethylene [0474 ] 2 . To small platform base plates with prongs
Glycol) with Oxalyl Chloride and Its Application in Hydro described below in the section entitled Subcutaneous , Supra
phobic Drug Delivery ,” International Journal of Nanomedi pleural , and Other Organ - attachable Clasp - or Patch -mag
cine 11:6065-6077 ; Cho, H .,Gao , J., and Kwon , G . S . 2016 . nets , or
“ PEG -b -PLA Micelles and PLGA -b -PEG -b -PLGA Sol-gels [0475 ] 3 . To magnet-wraps, described below in the section
for Drug Delivery,” Journal of Controlled Release 240 : 191 of like title . As addressed below in the section entitled
201; McKenzie , M ., Betts, D ., Suh , A ., Bui, K ., Tang, R ., Significance of SterileAntixenic Immune Tissue Reaction , to
and 4 others 2016 . “ Proof- of- concept of Polymeric Sol-Gels delay if not prevent a foreign body reaction, implants and
in Multi -Drug Delivery and Intraoperative Image - guided prongs that penetrate tissue to secure implant backings in
Surgery for Peritoneal Ovarian Cancer,” Pharmaceutical place are coated with reaction - suppressive substances, such
Research 33 (9 ):2298 -2306 ; Mundargi, R . C ., Babu , V . R ., as phosphorylcholine , dexamethasone, and /or curcumin .
Rangaswamy, V ., Patel, P ., and Aminabhavi, T . M . 2008 . [0476 ] The various components used may be classified as
“ Nano /Micro Technologies for Delivering Macromolecular 1. Transluminal , to include special catheters used as airgun
US 2019 /0247050 A1 Aug . 15 , 2019
31

barrels (some also made angioplasty capable ); 2 . Intraductal, wald , E ., Fauci, A . S ., Hauser, S . L ., Longo , D . L ., and
to include miniballs and stays ; or 3 . Extraductal, to include Jameson , J. L ., Harrison 's Principles of Internal Medicine ,
stent-jackets , clasp -wraps, and magnet -wraps. Completely 16th Edition , New York , N . Y .: McGraw - Hill, page 477 ) , to
extracorporeal are modified commercial and dedicated inter - be used efficiently, kept away from nontargeted tissue , and
ventional airguns and stay insertion tools, to be described . applied to lesions surrounding lumina not previously tar
Stent-jackets may be made adaptive to the reduction in getable . Dose minimization by targeting also results in a
caliber of vasa with subsidence (detumescence, regression ) reduction in side effects .
in an initially enlarged condition thereof, while stays may be 0481 ] The use of an impasse - jacket as a holding jacket, as
adaptive in partial or complete dissolution over a control addressed below in the section entitled Endoluminal Pre
lable period . Stays and miniballs can additionally be made hension of Miniballs and Ferrofluids , to retain or draw a
to release medication or radiation . FIG . 1 shows the inter drug such as paclitaxel administered in the form of a drug
relations among the different type implants described herein . carrier nanoparticle containing ferrofluid or in encapsulated
[ 0477 ] Pursuant to 37 CFR 1.475 , the apparatus and microspheres from the bloodstream for local infusion into an
methods go to a group of interrelated devices and procedures atheromatous plaque or carcinoma is addressed in the sec
that respond to a single generative inventive concept and so tions below entitled Concept of the Impasse -jacket and
conform to the requirement for unity of invention . Accord Interception and Recovery of a Miniball Entering the Cir
ing to the medical necessity , each and every element of the culation . Implants containing ferromagnetic material can be
invention can have an immediate and compulsory relation of retrieved if dropped or if used to fully or paritally encircle
combination with any of the others, and none is used with a ductus so that its wall can be retracted by means of a
devices not included in the system . Self-contained and mantling (periductal, perivascular, circumductal, circumvas
independent from the prior art , the system provides all of the cular ) pliant jacket with a slit along one side having tiny
means essential to accomplish the type of implantation it permanent magnets mounted about its outer surface .
makes possible , to include site preparation , implant infixion , [0482] The implants then constitute the intraductal or
and the implants themselves. Site preparation includes the ductus - intramural component of an extraluminal stent, the
delivery of medication , atherectomy (atherotomy), angio extraductal component consisting of the immediately peri
plasty , and ablation . ductal stent-jacket having the small permanent magnets
10478 ) Other means described herein are ancillary but mounted about it or of small but slightly more powerful
essential to support these type implants , whether as insertion magnets implanted at a greater distance by means of patch
tools, adjuvantmedication , or as means for pretesting patient magnets or magnet- jackets to be described . To freely expand
tissue in situ in order to ascertain as best one might the with the pulse and not interfere with the contractive waves
prospective safety in using these means , for example . Con of peristalsis passing through , stent- jackets are sized for the
sistent with this unity in conception , the various instruments quiescent outer diameter of the ductus to be treated , and for
and supplies described herein can be combined in different minimal mass and intracorporeal obstrusiveness as might
ways , the medical circumstances determining such use . That encroach upon or abrade neighboring structures , the bar
the attracting and attracted elements described herein , spe magnets mounted about the outer surface of the resilient
cifically , magnets and nonmagnetized ferromagnetic mini segment of tubing , or the base -tube , part number 5 in the
balls and stays respectively , could be reversed to obtain the drawing figues , are of high energy product neodymium iron
same result is considered obvious. boron , which allows these to be small and unobtrusive .
[0479 ] Implantation ofminiballs by means of a specially [0483] When properly matched to the collapsed or stenotic
adapted , or interventional, airgun not only overcomes tissue ductus, the stent- jacket retracts the implanted wall outwards
flaccidity but affords an implant loading point that proximate to the proper quiescent diameter. Elastic , the jacket expands
to the operator or an assistant, allows immediate adaptation up to the maximum diameter of the ductus ( such as on the
to the conditions actually encountered following entry with systoles ). Because veins are substantialliy inert, stent- jack
out the need to withdraw . The implants tiny, such work is ets , clasp -wraps, and magnet -jackets placed on veins, unlike
generally accomplished under magnification , any accidental arteries and peristaltic ductus, can be coated on the inner
perforations quickly sealed interventionally if not spontane surface with a surgical adhesive when placed . A stent- jacket
ously . In most instances , the implants will consist entirely of used as a circumvascular or circumtracheal stent can be
medication or of radiation - emitting seeds with surrounding inserted through one or two incisions that are smaller than
coats of medication for localized placement within a cir the incisions required by conventional open procedures and
cumscribed area , usually within the wall of a tubular ana secured by means of end - ties ( addressed below ). Because
tomical structure . The dose is thus concentrated in or adja repair tends to be deferred until the patient is older and
cent to the targeted tissue and minimized for nontargeted impaired , the lesser trauma is significant.
tissue, whether by diffusion or through the circulation . [0484 ] The nontransluminally delivered extraductal com
Reducing systemic dispersion before take - up allows consid ponents to be described herein — stent - jackets , stays, clasp
erable reduction in the overall dose . wraps, and so on - allow passage through an entry wound
[0480 ] Delivery in this manner allows medication cur smaller in size than does conventional open repair, typically
rently high in cost, such as time-released trastuzumab with a small ( stab , “ keyhole ," " bandaid ," or laparoscopic ) inci
paclitaxel, for example , conventionally administered by sion , or microincision . Applied to a procedure of like
intravenous infusion with a cremophore -containing vehicle objective as a surgical atherectomy, an atherectomy accom
that can cause hypersensitivity reactions injection , or by plished transluminally avoids the need for an incision , and
release from an endoluminal drug -eluting stent to treat an also allows extraluminal stenting through such a small
atheromatous lesion (Sauseville , E . A . and Longo , D . L . incision . When for any reason ballistic implantation is
2005 . “ Principles of Cancer Treatment: Surgery , Chemo contraindicated , a plurality of arcuate stent- stays containing
therapy, and “ Biologic Therapy,” in Kaspar, D . L , Braun ferrous metal or a clasp -wrap , likewise used with a stent
US 2019 /0247050 A1 Aug. 15 , 2019
32

jacket, can be manually inserted into the wall of the ductus polyurethane, or viscoelastic polyurethane foam , for
through a local incision , stays by meansof special hand tools example , averts perivascular or periductal compression of
to be described. the microvasculature and small nerves about the periphery
[0485 ] Endoluminal and extraluminal tests are provided in of the ductus , and providing cutouts ( perforations, portals ),
the sections below entitled In Situ Test upon Endoluminal allows some nonenclosure of the outer surface of the ductus,
Approach for Intra - or Inter- laminar Separation (Delamina allowing gas exchange and evaporation from the outer
tion , Laminar Avulsion ) and in Situ Test upon Extraluminal surface of the ductus , or adventia .
Approach for Intra - or Inter - laminar Separation (Delamina
tion , Avulsion ) for separation within a tunic ( intralaminar or [04901 While shape memory is not synonymous with fine
intratunical separation ) or between tunics (interlaminar or shape accommodation or compliance , alternative shape
intertunical separation , dilaceration , or avulsion , decolle memory materials are under development which do or
ment; delamination ), such as between the adventitia and the should eventually satisfy this requirement ( see , for example,
media . The test is intended to determine whether spherules , Zhang , K ., Feng , X ., Ye , C ., Hempenius , M . A ., and Vancso ,
stays , or a clasp -wrap , can be used at all, if so , at what depth G . J. 2017 . “ Hydrogels with a Memory : Dual-Responsive,
into the ductus wall the type that is most suitable should be Organometallic Poly (ionic Liquid )s with Hysteretic Vol
implanted , with or without the aid of a surgical adhesive . ume- Phase Transition ,” Journal of the American Chemical
The result may determine , for example , that no type of Society 139 (29 ): 10029 - 10035 ; Lowenberg , C ., Balk , M .,
implant can be placed subadventitially, so that the implant Wischke , C ., Behl, M ., and Lendlein , A . 2017. “ Shape
must be implanted within the media . memory Hydrogels : Evolution of Structural Principles to
[0486 ] When transluminal access is best avoided, stays , Enable Shape Switching of Hydrophilic Polymer Net
which are placed inside the ductus wall, or a clasp -wrap , works,” Accounts of Chemical Research 50 ( 4 ):723 - 732 ;
which that encircles and engages the ductus from without, Landsman , T. L ., Touchet, T., Hasan , S . M ., Smith , C .,
each ofwhich is inserted through the same local incision as Russell , B ., and 3 others 2017 . " A Shape Memory Foam
the stent-jacket, are used . A clasp -wrap , as addressed below Composite with Enhanced Fluid Uptake and Bactericidal
in the section of like title , is an alternative means for Properties as a Hemostatic Agent,” Acta Biomaterialia
introducing ferromagnetic implants into the wall of a ductus 47 :91- 99 ; Walker, R . M ., Gillespie , B . M ., Thalib , L .,
when the adventitia is too weakened ( softened , malacotic , Higgins , N . S ., and Whitty , J. A . 2017 . “ Foam Dressings for
malacic ) for ballistic implantation . Clasp -wraps are similar Treating Pressure Ulcers,” Cochrane Database of System
to stays in being applied from outside the ductus, which atic Reviews 10 :CD011332; Chan , B . Q ., Low , Z . W ., Heng,
eliminates the need for transluminal access. However, these S . J., Chan , S . Y., Owh, C ., and Loh , X . J. 2016 . “ Recent
differ in attaching the ferromagnetic implants to an elastic Advances in Shape Memory Soft Materials for Biomedical
backing that aids retention by a weakened adventitia , and in Applications ,” American Chemical Society Applied Materi
applicability only to ductus which can be fully encircled . als and Interfaces 8 ( 16 ): 10070 -10087 ; Hardy, J. G ., Palma,
[0487] In most situations , especially when to serve as the M ., Wind, S . J., and Biggs, M . J. 2016 . “ Responsive Bio
intraductal component of a magnetic stent, either miniballs materials : Advances in Materials Based on Shape-memory
or stays will be better suited to the condition presented , the Polymers,” Advanced Materials (Deerfield Beach , Fla.)
use of both exceptional, and in the same ductus , seldom to 28 ( 27 ) :5717 - 5724 ; Ebara , M . 2015 . “ Shape -memory Sur
be expected ; however, individual implants of the kind cho faces for Cell Mechanobiology,” Science and Technology of
sen can differ in medication or other therapeutic substances Advanced Materials 16 (1 ):014804 ).
contained . When an open surgical field has not already been
cleared , to implant stays requires access to the target ductus [0491 ] Absorbable materials of this kind are also under
through a small incision from outside the body . Approach development (see , for example, Balk , M ., Behl, M ., Wis
thus avoids the lumen entirely both during placement and as chke, C ., Zotzmann , J., and Lendlein , A . 2016 . “ Recent
infixed . This means that no foreign object is inserted into the Advances in Degradable Lactide- based Shape -memory
lumen , and that in a blood vessel, the compresence of an Polymers,” Advanced Drug Delivery Reviews 107: 136 - 152 ).
infectious pathogen bacterial, mycotic , or viral, will not Absorbable stent and impasse - jackets use biodegradable
provide a pathway into the ductus wall. shape memory foam (Peterson , G . I., Dobrynin , A . V ., and
[ 0488 ] For the placement of medication implants which Becker, M . L . 2017 . “ Biodegradable Shape Memory Poly
are fully absorbed , access through an external incision is mers in Medicine ,” Advanced Healthcare Materials 6 ( 21) ;
generally less attractive than is the endoluminal delivery of Singhal, P., Small , W ., Cosgriff -Hernandez , E .,Maitland , D .
miniballs. For stenting ,however, especially where an angio J., and Wilson , T. S . 2014 . “ Low Density Biodegradable
plasty is unnecessary, the intraductal component is usually Shape Memory Polyurethane Foams for Embolic Biomedi
permanent, and to place the stent- jacket requires an incision cal Applications,” Acta Biomaterialia 10 ( 1 ):67 -76 ).
from the outside anyway, making the use of stays overall [0492] The moisture barrier prevents the breakdown prod
less intrusive . Unless the miniball or stay subadventital or ucts of the viscoelastic polyurethane foam from being
subfibrosal implants are drawn outwards towards the inner released into the surrounding tissue and bloodstream where
surface of the stent- jacket noncompressively with little it is toxic , as was the problem with earlier breat implants .
damage to vasa and nervi vasorum , the adverse sequelae of Any polymerization process residue or plasticizer must be
endothelial dysfunction , atheromatous lesioning, and a loss thoroughly removed . The presence of toxic residues from
in wall strength will ensue. Damage to the vasa vasorum in polymerization ofmoisture barrier-coated viscoelastic poly
third stage syphilis , for example , results in aortic aneurysm . urethane foam linings can be averted with suitable prelimi
[0489 ] Lining the side - slitted and perforated jacket with nary cleaning of the material (see Maxwell , G . P. and
moisture barrier -coated nonbiodegradable or bioresistant Gabriel, A . 2017 . “ Breast Implant Design ,” Gland Surgery
moisture barrier moisture protection -coated visco - elastic 6 ( 2 ): 148 - 153 ; Daka, J. N . and Chawla , A . S . 1993 . “ Release
US 2019 /0247050 A1 Aug . 15 , 2019
33

of Chemicals from Polyurethane Foam in the Même Breast urethane foam (see , for example , Puskas, J. E . and Luebbers ,
Implant,” Biomaterials, Artificial Cells , and Immobilization M . T. 2012 . “ Breast Implants: The Good , the Bad and the
Biotechnology; 21(1):23 -46 ). Ugly. Can Nanotechnology Improve Implants ?,” Wiley
Interdisciplinary Reviews. Nanomedicine and Nanobiotech
[0493] The polyurethane foam used in stent- and impasse
jackets is enveloped within a shape compliant moisture nology 4 (2 ):153 - 168 , bottom left page 155 ; Handel, N .
barrier that affords additional protection from any break 2006 . “ Long - term Safety and Efficacy of Polyurethane
down products of the primary component . Even were the Foam -covered Breast Implants ,” Aesthetic Surgery Journal
same polyurethane foam used as that in the breast implants 26 (3 ): 265- 274 ).
withdrawn from the market in 1991, the release of 2 , 4 [0495 ] As used here , tissue reaction and infiltration into
toluenediamine ( TDA ) from the foam lining of a stent the closed cell material should not be problems as require
jacket, impasse - jacket, or outrigger, which is minute in surface treatment to lessen if not prevent; the foam is not
amount compared to that in a breast implant, would be too embedded within butmerely makes contact with the tissue ,
little to act as a carcinogen . That is , the absolute volume of and the tissue contacted is intact , not injured , or granulated ,
the material in any of the jackets described herein is minute and rapidly proliferating to heal at the interface with the
compared to that in a breast implant, making it improbable foam . The same nonembedded condition that tends to retard
that its degredation would release an amount of the material the spontaneous absorption of absorbable materials also
that would accede to a toxic burden (see , for example , alleviates degradation of the urethane.
Pompei, S ., Evangelidou , D ., and Ferrante , G . 2017 . “ Com - (0496 ] Furthermore , the junction between adventitia and
ments on “ Commentary On : The Modern Polyurethane foam is not compressive as with ‘negative pressure wound
coated Implant in Breast Augmentation : Long- term Clinical therapy ' where bandage lining ingrowth discourages the use
Experience,” Aesthetic Surgery Journal 37 (5 ):NP56 -NP57 ; of urethane . Whether to use miniballs or stays is determined
Frame, J. 2016 . “ Commentary On: The Modern Polyure on the basis of the overall medical considerations to include
thane - coated Implant in Breast Augmentation : Long- term site accessibility . When not practically accessible from with
Clinical Experience ,” Aesthetic Surgery Journal 36 ( 10 ): out (extracorporeally), implantation is of miniballs translu
1130 - 1132 ; Pompei, S ., Evangelidou , D ., Arelli , F., and minally by means of a special catheter devised to serve as an
Ferrante , G . 2016 . “ The Modern Polyurethane - coated extension to the barrel of a specially adapted semiautomatic
Implant in Breast Augmentation : Long -term Clinical Expe gas -operated implant insertion airgun .
rience,” Aesthetic Surgery Journal 36 ( 10 ): 1124 - 1129 ; [0497 ] Such a specialized catheter, consisting of a unitized
Vazquez , G . and Pellón , A . 2007 . “ Polyurethane-coated barrel-catheter and distal muzzle-head , is referred to as a
Silicone Gel Breast Implants Used for 18 Years,” Aesthetic barrel-assembly . Practical barrel-assemblies encompass
Plastic Surgery 31 (4 ):330 -336 ; Kulig , K . 1998 . “ Lifetime multiple endoluminal capabilities. The airgun projects the
Risk from Polyurethane Covered Breast Implants,” Envi spherules through the barrel- assembly and out the muzzle
ronmentalHealth Perspectives 106 ( 11 ):A526 - A527 ; Hester, head at its distal end at an acute forward angle , preferably to
T. R . Jr., Ford , N . F ., Gale, P . J., Hammett , J. L ., Raymond , a point subjacent to (underlying) the outer fibrous sheath of
R ., Turnbull , D ., Frankos, V. H ., and Cohen , M . B . 1997 . the ductus, the tunica adventitia or tunica fibrosa in the
“ Measurement of 2 ,4 -toluenediamine in Urine and Serum trachea , or the tunica adventitia or tunica externa in blood
Samples from Women with Même or Replicon Breast vessels , for example . When the discharge velocity is set
Implants,” Plastic and Reconstructive Surgery 100 (5 ): 1291 within the allowable range, which is tested beforehand , the
1298 ). Signifiantly, as addressed below in the sections elastic layers in the wall of the ductus prevent puncture . The
entitled Absorbable Base - tube and Stent- jacket ; Miniball, miniballs are so small that unless the patient has been
Stay, and Clasp -magnet Matrix Materials ; Significance of heavily anticoagulated , spontaneous sealing is prompt . Also ,
Sterile Antixenic Immune Tissue Reaction ; and Materials the risk of injury to neighboring tissue is negligible. Excep
Suitable for Rebound -directing Double -wedge Linings , tionally, the implants are placed more deeply ( adluminally,
among others, means for encouraging or forestalling attack medially ).
by the immune system allow the rate of breakdown and [0498 ] Viscoelastic polyurethane foam linings are
persistence of implanted polyurethane to be widely adjusted . addressed below in the sections entitled Requirement for
[0494) Furthermore, a rate of chemical breakdown of 0 . 8 Moisture Barrier -coated Viscoelastic Polyurethane Foam
percent per year (Benoit, F . M . 1993. “ Degradation of Linings and Stent- and Shield -jacket Moisture Barrier
Polyurethane Foams Used in the Même Breast Implant,” coated Viscoelastic Polyurethane Foam Linings. When
Journal of Biomedical Materials Research 27 ( 10 ): 1341 placed in a wet location , such linings have a typically
1348) or alteration in cushioning properties exhibited by vapor-deposited or sputtered moisture barrier. Not intro
existing materials allows many years of use, and the pres duced into the bloodstream , stays reduce if not eliminate the
ence of TDA or any other toxic product of foam degradation need for systemic medication to suppress clotting , and are
is readily detectable through urinalysis ( Shanmugam , K ., therefore to be preferred when the prospect of surgery is
Subrahmanyam , S ., Tarakad, S . V ., Kodandapani, N ., and pronounced . When such is not the case , the length of the
Stanly, D . F. 2001. “ 2 ,4 - Toluene Diamines — Their Carcino segment to be implanted is extensive, and procedural time
genicity , Biodegradation , Analytical Techniques and an with general anesthesia would best be minimized , miniballs
Approach towards Development of Biosensors,” Analytical are preferable to stays .
Sciences 17 (12 ): 1369- 1374 ; Santerre , J . P ., Woodhouse , K ., 104991. In that case , combinations of a systemically circu
Laroche, G ., and Labow , R . S. 2005. “ Understanding the lated anticoagulant where each implant has been coated with
Biodegradation of Polyurethanes : From Classical Implants a reversal agent for hemostasis in the event of an accidental
to Tissue Engineering Materials," Biomaterials 26 ( 35 ): perforation such as warfarin - vitamin K as phytonadione ,
7457 -7470 ). Soy based foam is rejected as allergenic . Con anti- inhibitor coagulant complexes , or systemic heparin with
tinued work should further improve the longevity of poly protamine sulfate will be too slow -acting . Provided it is
US 2019 /0247050 A1 Aug . 15 , 2019
34

sufficiently pliant to comply in investing the small vessels of dissection is much the same whether stays orminiballs are
and nerves about the ductus, the hermetic , such as chemical used . Accidental perforation through the ductus wall by a
vapor deposited highly plasticized (Parylene® Cor N ), miniball discharged at too high a velocity or normal (per
coating , which completely biocompatible , is used to coat pendicular ) to the axis of the ductus ordinarily seals spon
numerous implants such as stents ( see , for example , taneously as to pose no threat. If, however, a vulnerable
Schwarz , J. A ., Contescu , C . I., and Putyera , K . 2004. neighboring structure such as a ganglion might be struck or
Dekker Encyclopédia of Nanoscience and Nanotechnology , septic contents allowed to spill out of the lumen , a shield
Volume 1 , page 263 , Boca Raton, Fla .: Chemical Rubber jacket is used . Radiation shield - jackets can be used with
Company Press), protects the foam from moisture break seed stays as well as miniballs.
down . [0503 ] Broadly, the apparatus used to place the implants of
[0500 ] The same treatment when applied to the outside of the ductus - intramural component of the extraluminal mag
the jackets described herein will inhibit the deposition of netic stents to be described and the applications most suited
clot, and prevent the catching onto or abrasion of neighbor to various embodiments of these fall into three categories:
ing tissue , as well as prevents fluid infiltration . In the [0504 ] 1. The air pistol as modified for interventional use ,
mainlines , this prevents extravasation , and in the sidelines, addressed below in the section entitled Modification of
fluid infiltration or leakage , assuring that dosing is accurate . Commercial Airguns , with a simple pipe -type barrel -assem
Such a physical vapor deposited coating can be provided by bly, addressed below in the section entitled Simple Pipe
several companies to include Acree Technologies Incorpo Type Barrel-assemblies, suitable, for example , for use in the
rated , Concord , Calif., Para -Coat Technologies, Johnstown , airway where a . The anatomy is differentiated or structured ,
Pa ., and KDF Electronic and Vacuum Services Incorporated , b . The implantsmust be accurately placed in relation thereto
Rockleigh , N .J. Where the ductus is sufficiently exposed to with the exit port easily viewed , c . The larger size of the
serous fluid , for example, as to be quite wet, a hand dryer is lumen allows the apparatus to be positioned without injury
used to remove most of the moisture before placing the to the lumen wall , and d . Sufficient speed with precision
side- entry jacket or nonjacketing side - entry connector. does not require multiple discharge. To make possible the
[0501 ] Instead , a systemic antiplatelet blocker is admin accuracy required , a simple pipe will usually have a fiberop
istered and the miniballs coated with a fast-acting reversal tic endoscope , or angioscope , permanently attached , or
agent or hemostat, such as kaolin (A12Si205 (OH ) 4 ) ( Trab where the viewing device is costly and wanted for use with
attoni, D ., Gatto , P ., and Bartorelli, A . L . 2012 . " A New more than one barrel- assembly , lashed alongside. As with
Kaolin -based Hemostatic Bandage Use after Coronary the wires for the recovery electromagnet and any bounce
Diagnostic and Interventional Procedures ,” International plate device as shown in FIGS. 35 , 36 , and 37 , these cannot
Journal of Cardiology 156 ( 1 ):53 -54 ; Kheirabadi, B . S ., continue into the airgun barrel. The electrical connection for
Scherer, M . R ., Estep , J. S ., Dubick , M . A ., and Holcomb , J. the electromagnet is of the form shown in FIG . 75 .
B . 2009. “ Determination of Efficacy of New Hemostatic [0505 ] 2. The dedicated interventional airgun with a radial
Dressings in a Model of Extremity Arterial Hemorrhage in discharge barrel-assembly, generally for use in a lumen that
Swine,” Journal of Trauma 67 (3 ): 450 -460 ; Politi, L ., Aprile, unlike the trachea , for example , is relatively undifferentiated
A ., Paganelli, C ., Amato , A ., Zoccai, G . B ., and 5 others or uniform in structure , wherein the need for speed is
2011. “ Randomized Clinical Trial on Short-time Compres greatest in blood vessels, the carotid and coronary arteries in
sion with Kaolin - filled Pad : A New Strategy to Avoid Early particular. Ablation and ablation and angioplasty -capable
Bleeding and Subacute Radial Artery Occlusion after Per barrel-assembly muzzle -heads enclose the barrel- tubes
cutaneous Coronary Intervention ,” Journal of Interventional within a torpedo - shaped outer shell and discharge radially,
Cardiology 24 ( 1):65 -72; Griffin , J. H . 1978 . “Role of Sur or more accurately , frontoradially . To be usable in blood
face in Surface - dependent Activation of Hageman Factor vessels , barrel -assemblies must include gas pressure diver
(Blood Coagulation Factor XII ;" Proceedings of the sion channels . Thus, a barrel -assembly capable of perform
National Academy of Sciences of the United States of ing an angioplasty will always be capable of performing an
America 75 (4 ): 1998 - 2002; Walsh , P. N . 1972 . “ The Effects ablation in a ductus of arterial diameter. Ablation and
of Collagen and Kaolin on the Intrinsic Coagulant Activity ablation and angioplasty -capable barrel -assemblies are also
of Platelets. Evidence for an Alternative Pathway in Intrinsic classified according to whether these are for use during and
Coagulation Not Requiring Factor XII,” British Journal of solely as an adjunct to discharge while engaged in and
Haematology 22 (4 ):393 - 405 ) or methyl prednisolone dependent upon the airgun for power and control, or whether
( Qureshi, A . I. and Suri, M . F . 2008 . “ Acute Reversal of these can be used as standalone means for ablation or
Clopidogrel-related Platelet Inhibition Using Methyl Pred angioplasty .
nisolone in a Patient with Intracranial Hemorrhage ,” Ameri [0506 ] 3. The manual insertion of stays, which inserted
can Journal of Neuroradiology 29 (10 ):e97 ). from outside the ductus, avoids not only the numerous
[ 0502 ] More specifically , the coating includes adenosine disadvantages of placement of a foreign body within the
diphosphate, fibrin , and a kaolinite- derived aluminosilicate lumen but also any complications that might arise from the
nanoparticlate . The insoluble kaolin coagulant is chemically ballistic placement of miniballs in a lumen carrying infec
inert and becomes embedded within the surrounding tissue . tious or septic contents . Placed with less speed , stays avoid
In an extraction from an impasse - jacket using a powerful the lumen entirely, can often be placed laparoscopically
external electromagnet , the extraction is stereotactically under a local anesthetic , and therefore mitigate the need for
oriented to avoid any vulnerable structures . In blood vessels speed .
no anticoagulant is administered , and sealing occurs quickly. [0507 ] A more detailed breakdown of barrel-assemblies
In other type ductus, problematic leakage can be averted by by type is provided below in the section entitled Types of
placing an absorbable shield -jacket. If the application Barrel -assemblies . An ablation or ablation and angioplasty
involves the placementof a circumvascular jacket, the extent capable barrel-assembly is equipped to perform an endolu
US 2019 /0247050 A1 Aug. 15 , 2019
35

minal ablation or an angioplasty or atherectomy indepen combination - form type, it must be withdrawn to allow a
dently of and without connection to an airgun . Another barrel-assembly to be introduced for initiating stenting dis
device , a radial projection catheter, addressed below in the charge .
section entitled Radial projection catheters , when matched [0512 ] By contrast, whether an ablation or an ablation and
in size to the barrel-assembly , can be slid over to ensheath , angioplasty - capable barrel- assembly achieves this capabil
or ensleeve , the barrel-assembly , thereby supplementing the ity with radial projection units built into its muzzle -head or
number of side -looking (lumen wall-radially directed ) abla by acquiring these through the addition of a radial projection
tion or angioplasty tool lift - shafts integral to the barrel catheter, it need not be withdrawn from the ductus and
assembly muzzle-head . reinserted through the introducer sheath before the muzzle
[0508 ] To allow discharge at a greater distance down a head at its distal end is passed transluminally to the segment
narrowing lumen , the portion of the muzzle -head distal to or to be treated to initiate stenting implantation . Radial pro
forward of the miniball discharge exit -port or ports is kept jection catheters are addressed below in the section of like
short. Keeping the muzzle -head small in diameter allows title . Following treatment with the ablation or ablation and
access to lumina of smaller caliber and allows the pulse to angioplasty -capable barrel-assembly while unconnected to
force blood past a muzzle -head that completely occludes the the airgun , the free (proximal, extracorporeal) end of an
lumen of a nonarteriosclerosed elastic artery. Bipartite or barrel -assembly is inserted into the barrel of the airgun .
duplex radial projection catheters can be slid over the [0513] Such a barrel-assembly to which is added a
barrel- catheter of a barrel- assembly to add radial projection through - and-through passageway or central channel along
units or be used separately to perform an angioplasty. In the central axis and an extracorporeal end - or side -socket
nonelastic arteries, occlusive diameter must be compensated through which to pass a cable from a control console is
for with blood - grooves that run the length of the muzzle referred to as a through -bore or combination - form barrel
head , for example. Radial projection unit push - arm tool assembly . Such a barrel-assembly allows the insertion
inserts can nudge the muzzle - head to a side to let blood pass . through the central bore of a fiberoptic or video endoscope ,
rotational atherectomy burr, or excimer laser, for example .
[0509] Combination -forms with side -ports can pass blood Even though a negligible accumulation of debris generally
through the bore , and provided the lumen wall stength test exerts little practical effect on miniball exit velocity , the
addressed below under the section entitled In Situ Test on barrel - assembly must be configured to minimize the entry of
Endoluminal Approach for Susceptibility of the Ductus Wall debris through the exit ports during transluminal advance
to Puncture , Penetration , and Perforation indicates that the ment.
ductus is unlikely to incur stretching or dissection injury, a (05141. To minimize the risk of hypoxia , gas embolism ,
hand -held external electromagnet as specified below in the traumatizing parectasia (overdistention , overstretching), and
section entitled Use of an External Electromagnet to Assist dissections, a barrel -assembly for use in the vascular tree
in Steering or in Freeing the Muzzle -head can be used as must further incorporate internal gas pressure relief and
addressed below in this section to increase or create a gap for other features to be described , platelet blockade used to
lumen contents to pass. Multiple push -arm type radial pro prevent the formation of microthrombi at the sites of mini
jection unit tool- inserts , addressed below in the sections ball entry . Venting the column of air in the barrel -tube or
entitled Push -arm Radial Projection Unit Tool-inserts and tubes also reduces resistance to miniball travel, especially
Ablation and Angioplasty -incapable Radial Discharge Bar when the barrel-assembly is inserted against the flow and
rel -assembly Muzzle -heads, among others can be used to discharged during the pulse , thereby allowing the use of an
like effect . airgun that generates expulsive force less than would be
[ 0510 ) Such a combination constitutes a bipartite or necessary otherwise .
duplex ablation or ablation and angioplasty -capable barrel [05151. Transluminal movement to another site for implan
assembly, in which the apportionment of side -looking tool tation is usually by means of a stepper or 3 -phase brushless
lift- shafts, or radial projection units , as between the muzzle synchronous iron core linear motor - driven precision
head and radial projection catheter vary inversely within the machining linear positioning stage ( linear stage , translation
sum total for the two as a unit . Thus, at one extreme, the stage, linear table ). Positional control also makes it possible
muzzle -head might include so large a number of radial to lay down tight formations of miniballs for the more
projection units as never to require supplementation by uniform distribution ofmagnetic pull, and if the miniballs
ensheathment within a radial projection catheter, while at the are coated , then a more even distribution and accurate
opposite extreme, the muzzle -head includes no radial pro targeting of the coating substances . Conventional vascular
jection units, so that any must be obtained through ensheath cryoplasty and thermoplasty consist of running chilled or
ment. A radial projection catheter at this level of sufficiency heated fluid through an angioplasty balloon with the primary
can perform an ablation or an angioplasty as an independent object of structurally degrading the plaque so that dissec
device ; however, it is not a barrel- assembly and cannot tions are minimized and the dilatation forces exerted by the
implant miniballs . balloon meet with less resistance to produce a more uniform
[0511 ] To minimize hindrance in steering , and tracking, distention .
the unsheathed component of a bipartite or duplex barrel [0516 ] If sufficiently hot, the balloon probably does
assembly is usually first positioned at the treatment site , after destroy some potentially embolizing debris that would have
which the matching radial projection cathetetic component been discharged were a vulnerable or unstable plaque ( see
is slid over the barrel- catheter using it as a guide wire to abut Maseri, A . and Fuster, V. 2003 . “ Is There a Vulnerable
against the rear of the muzzle -head . The radial projection Plaque ? ,” Circulation 107 ( 16 ): 2068 - 2071) to rupture ; how
catheter can then be withdrawn and replaced with the same ever, the plaque is mostly just crushed against the lumen
or another sheath without moving the muzzle -head . Unless wall (see, for example , Algowhary , M ., Matsumura , A .,
the radial projection catheter is of the through -bore or Hashimoto , Y ., and Isobe , M . 2006 . " Poststenting Axial
US 2019 /0247050 A1 Aug. 15 , 2019
36

Redistribution of Atherosclerotic Plaque into the Reference eter, under automatic machine control desirable . Vasodila
Segments and Lumen Reduction at the Stent Edge : A tors can be used to reduce the limitation on gauge of the
Volumetric Intravascular Ultrasound Study,” International muzzle -head and minimize if not eliminate the need for
Heart Journal 47 ( 2 ): 159 - 171; American Journal of Cardi extracorporeal oxygenation . The concurrent use of nonva
ology 89( 4 ): 368 -371 ; Hong , M . K ., Park , S . W ., Lee , C . W ., sodilating (nonantgiotensive , nonvasotensive ) inotropic
Kim , Y . H ., Song J. M ., and 4 others 2002. “ Relation medication to increase the force of the heart contraction
Between Residual Plaque Burden after Stenting and Six without interfering with the vasodilation is additionally
month Angiographic Restenosis,” Honda, Y., Yock , P . G ., helpful. When the degree of dilation sought is greater, more
and Fitzgerald , P . J. 1999 . “ Impact of Residual Plaque extended in length , and more demanding in terms of speed ,
Burden on Clinical Outcomes of Coronary Interventions," the medication is administered by infusion .
Catheterization and Cardiovascular Interventions 46 (3 ) : 10521 ] Otherwise , the muzzle - head can itself be used to
265 -276 ; Alfonso , F ., García , P., Pimentel, G ., Hernández , deliver medication as it approaches, the rate of advancement
R ., Sabaté , M ., Escaned , J., Bañuelos, C ., Fernández , C ., and adjusted to accommodate the medication response time.
Macaya , C . 2003 . “ Predictors and Implications of Residual Vasospasm reflexive to the presence of the muzzle -head , for
Plaque Burden after Coronary Stenting : An Intravascular example , should it arise , is prevented through the site
Ultrasound Study,” American Heart Journal 145 ( 2 ): 254 specific release of antispasmodic or spasmolytic drugs.
261) . Ordinarily through an open -ended service catheter to pre
[0517 ] The failure to actually remove plaque not only serve use of the barrel-tube for miniball discharge or ballistic
impairs healing, exacerbates the disease , and promotes rest implantation , the muzzle -head could be used to deliver liver
enosis, but can result in the prolapse of residual tissue metabolism nondependent vasodilators highly localized to
through the stent struts, as addressed below in the section the treatment site , such as adenosine , nitrates (nitroglycerin ,
entitled Basic Strengths and Weaknesses of Prior Art Stent nitroprusside , isosorbide mono or dinitrate ), mannitol,
ing in Vascular, Tracheobronchial, Gastrointestinal, and hydralazine hydrochloride, nicardipine , nesiritide , nimo
Urological Interventions, among others. When the plaque dipine, verapamil, milrinone , trimethaphan , fasudil , and
and subjacent tissue are too hard to be smashed or reduced , colforsin daropate, as well as platelet blockade or heparin ,
the balloon accomplishes luminal dilation by tearing cir for example.
cumferential fibers. This is often the basis for the stretching [0522 ] Application thus can be accomplished in any of
injury which results in endothelial dysfunction and induces several ways , to include ejection by ejection tool- inserts ,
the intimal (endangial) and medial hypoplasia that ensue. injection by injection tool- inserts, and ejection by open or
[0518 ] Themeans to be described removes plaque through injection by hypotube - ended service catheter syringes, all to
cutting, abrasion , thermoplasty, cryoplasty , or any combi be addressed . Prepositioned impasse - jackets whether used to
nation of these . Theremoplasty, for example , is routinely prepare a segment of a ductus for discharge implantation in
used to destroy potentially embolizing debris that might be advance in the manner addressed in the sections below
discharged by the rupture of erodable fibrous , vulnerable , or entitled Concept of the Impasse - jacket and Miniball and
unstable plaque by the passing muzzle - head. In Barrel Ferrojluid -borne Particle - impassable jackets , or Impasse
assemblies which incorporate fluidically operated radial jackets , do not interfere with the use of a barrel- assembly .
projection units , addressed below in the section entitled With the availability in the form of impasse -jacket held
Radial Projection Units , cryoplasty , believed to retard inti miniballs of a counteractant or reversal, that is , neutralizing
mal (internal lining , Bichat’s tunic ) hyperplasia , is also or scavenging agent, such as mannitol dehydrogenase or
available . Where disease is extensive , thermoplasty is used mannitol 2 -dehydrogenase , the localized (nonsystemic , tar
as a precaution over the entire length of the artery, usually geted ) application of mannitol, for example , can be deliv
not as a preliminary procedure but just in advance of implant ered at a high dose as localized that is systemically minute .
discharge . [0523] Delivered peripherally or otherwise distant from
[0519] When the application of any of these ablative or the coronary arteries, mannitol, for example , can be admin
angioplasty means to include heat, cold , abrasion , and istered to patients with advanced coronary disease , if distant
cutting or shaving is continuous over a significant length of from theheart, to those with heart failure, if distant from the
the lumen , the speed of travel , or rate of transluminal kidneys, to those with renal insufficiency , and if distant from
advancement of the muzzle -head over the internal surface of the lungs, to those with pulmonary vascular congestion ,
the ductus, is set for the prescribed time of exposure for the (see , for example, The Merck Manual of Diagnosis and
diagnosis. Cryoplasty, for example , is performed atminus 10 Therapy , 18th Edition , 2006 , page 2578 ), while avoiding
degrees centigrade for 20 seconds. Executing a tightly unwanted side-effects such as diarrhea (Merck Manual,
controlled rate of travel, hence , time of exposure is usually pages 78 and 84 ), gastric upset (nausea , vomiting ), diuresis ,
entrusted to a variable speed linear positioning stage . Off for which the dose of mannitol as a dehydrating agent and
pump use in the coronaries and use in the carotids especially osmotic diuretic must be larger, headache, confusion, hyper
demands a muzzle - head that least interferes with perfusion . glycemia , and allergic reactions , among others . Unlike a
Despite the features incorporated into the muzzle -head to radially symmetrical balloon , the muzzle -head , which is
minimize obstruction summarized below in the section contrast marked to assist in its orientation , can be used to
entitled Hypoxia and Ischemia -averting Elements, a muzzle treat radially asymmetrical, or eccentric , lesions in a discre
head of a diameter suitable for use in a peripheral artery of tionary manner provided these can be clearly seen .
the same diameter would be too large . [0524 ] Impasse -jackets can suspend drug carrier nanopar
10520 ) At the same time, minimizing procedural duration ticles in a ferrofluid or medication miniballs , to include those
and achieving uniformity of implant placement are all the comprising ‘ smart pills ,' in the lumen that will release
more important in these arteries, making the use of multi medication only when signaled or stimulated to do so from
barrel-tube barrel- assemblies, which must be larger in diam outside the body . The jacket is then reloaded as necessary .
US 2019 /0247050 A1 Aug . 15 , 2019
37

Self-reloading of the impasse-jacket , magnetized miniballs , [0528 ] Veterinary drugs are regulated by the Department
stays , arrays thereof, patch -magnet , or magnet- jacket of a of Agriculture Center for Veterinary Biologics , or the Food
drug carrier nanoparticulate or miniballs outside the clinic to and Drug Administration Center for Veterinary Medicine ,
reach a level along the gastrointestinal tract is by ingestion , and may not undergo multiple extensive clinical trials ; as is
with a followup triggering substance administered likewise applied to drugs for use in man , drug testing results obtained
as needed . Magnetically susceptible nanoparticle -bound with animals is tentative . While the propulsive force speci
drugs that can be ingested to pass through the gut and liver fied herein is supplied as in most airguns by pressurized gas,
and into the bloodstream are under development. Secondary such as compressed air or carbon dioxide (CO ) delivered
triggering as needed or prescribed makes it possible for the from a cylinder (which may be referred to as a tank , canister ,
patient to initiate the release of a prepositioned drug outside powerlet , pistolet, capsule, or cartridge ), alternative propul
the clinic preferably by ingesting or otherwise injecting a sive means, such as a spring -piston or an internal air column
triggering substance or solvent and /or by applying heat at that is pressurized by a hand pump as in pneumatic airguns
the treatment site for example . could be similarly applied . Some stents can release medi
cation as they disintegrate . Whether this effects a cure
[0525 ) Delivery to the trachea and bronchi is by inhalation depends upon the lesion and the patient. With the exception
of the nanoparticulate -bound drug as a metered dose inhaler that stents which release medication and /or radiation have
delivered aerosol. Charging and triggering along the vascu the potential to effect a cure , to the extent they are mechani
lar tree are preferably by ingestion , or if necessary , by cal scaffolds, stents are nosotropic or symptomatically cor
injection or subcutaneously implanted access portals (ports,
portacaths ) or peripherally entered central catheters ( The rective through mechanicalmeans, not etiotropic or curative .
Merck Manual of Diagnosis and Therapy, page 1161), these 105291 No claim beyond this is made for any of the means
latter also suited to allow direct access to urinogenital to be described . However, patency is always essential to
( urogenital, genitourinary ) ductus. Recharging and trigger sustain function and life , making the capability to do so with
ing are addressed below in the sections entitled System fewer sequelae over a long period important. Stenting does
Implant Magnetic Drug and Radiation Targeting and Coop not supplant but complements concurrent medical manage
erative Use of Impasse - jackets in Pairs and Gradient Arrays , ment ; the decision to insert a stent to maintain luminal
among others . patency in cases of bronchiectasis, for example, will depend
upon the variable symptoms of specific patients . Moreover,
[0526 ] Unlike the implantation of spherules (miniature noninvasive management cannot duplicate the remedial
balls , miniballs ), stays , or implants in the form of tiny effect of a stent, is seldom any more able to effect a cure , and
arcuate bands, are nonballistically inserted into the wall of always carries the risk of side effects . The apparatus to be
the ductus from the outside by means of a special hand tool described targets medication at or into the lesion , minimiz
to be described . When the ductus to receive the implants is ing the dose and promoting local uptake thus avoiding the
already exposed or can be accessed with trauma justified circulation , and is able to apply various therapeutic trea
within the medical context, a hand tool is used to implant the ments as well as introduce the intraductal component of an
stay or stays through an incision little more than microscopic extraluminal stent.
in length . Existing means for delivering drugs ballistically
are not endoluminal (see, for example, Kendall, M . A . 2010 . [0530] While never used in extraluminal stents , magnets
have been used intracorporeally to induce compression
" Needle - free Vaccine Injection ,” Handbook of Experimental necrosis , anastomosis , and other purposes for decades and
Pharmacology ( 197 ): 193 - 219 ; Liu , Y . 2007 . “ Impact Studies
of High -speed Micro -particles Following Biolistic Deliv continues in use (see , for example , Jansen , A ., Keeman , J.
ery ,” Institute of Electrical and Electronics Engineers Trans N ., Davies, G . A ., and Klopper, P . J. 1980 . “ Early Experi
actions on Biomedical Engineering. 54 ( 8 ): 1507 - 1513 ; Ken ences with Magnetic Rings in Resection of the Distal
dall, M ., Mitchell, T ., and Wrighton - Smith , P. 2004 . Colon ,” Netherlands Journal of Surgery 32 (1 ):20 -27 ; Cope,
“ Intradermal Ballistic Delivery of Micro - particles into C . 1995 . “ Creation of Compression Gastroenterostomy by
Excised Human Skin for Pharmaceutical Applications," Means of the Oral, Percutaneous, or Surgical Introduction of
Journal of Biomechanics 37 (11) :1733 - 1741 ), which distinc Magnets : Feasibility Study in Swine,” Journal of Vascular
tion is critical for the treatment of disease affecting any and Interventional Radiology 6 ( 4 ) :539 - 545 ; Yamanouchi,
tubular structure (see , for example, Kendall, M ., Mitchell , E ., Kawaguchi, H ., Endo , I., and Arakawa, H ., Yamaguchi,
T ., and Wrighton - Smith , P . 2004 , Op cit.). T., Sakuyama, K , et al. 1998 . “ A New Interventional
Method : Magnetic Compression Anastomosis with Rare
[0527 ] The terms ballistic or biolistic in relation to gene earth Magnets,” Cardiovascular and Interventional Radiol
alteration and treatments with gene guns and the delivery of ogy 21 (Supplement1 ):S155 ; Okajima, H ., Okajima, H .,
drugs through the skin are thus unrelated to the content Kotera , A ., Takeichi, T., Ueno , M ., Ishiko , T., and 4 others
herein . An extraluminal stent leaves the lumen free and clear 2005 . “Magnet Compression Anastomosis for Bile Duct
of any foreign object and is substantially compliant with the Stenosis after Duct- to - duct Biliary Reconstruction in Living
functional changes in gauge of the ductus . It therefore less Donor Liver Transplantation ,” Liver Transplantation 11 (4 ) :
alters flow -through , does not contact,much less chronically 473 -475 ; Kaidar -Person , O ., Rosenthal, R . J ., W?xner, S . D .,
irritate the lumen lining , and less interferes with subsidence Szomstein , S ., and Person , B . 2008 . “ Compression Anasto
in inflammation and healing . Avoiding the implantation of a mosis: History and Clinical Considerations,” American
foreign object within the lumen and interference with the Journal of Surgery 195 (6 ):818 -826 ; Jamshidi, R ., Stephen
expansion , contraction , and flexion of the ductus is critical son , J. T., Clay, J. G ., Pichakron , K . O ., and Harrison , M . R .
for accommodating normal physiology while maintaining 2009. “Magnamosis: Magnetic Compression Anastomosis
patency . The citation of drugs herein is for the purpose of with Comparison to Suture and Staple Techniques,” Journal
suggesting applications related to the apparatus described of Pediatric Surgery 44 ( 1 ):222 -228 ; Jang , S . I., Kim , J. H .,
and not an endorsement or recommendation . Won , J. Y ., Lee, K . H ., and 4 others 2011. “Magnetic
US 2019 /0247050 A1 Aug. 15 , 2019
38

Compression Anastomosis is Useful in Biliary Anastomotic introduced and/or positioned using means set forth herein .
Strictures after Living Donor Liver Transplantation ,” Gas Such placement is either within the wall surrounding a
trointestinal Endoscopy 74 ( 5 ): 1040 - 1048 ). lumen or other tissue , or is in surrounding , or periductal,
relation to the native tubular anatomical structure or condit,
3 . Terminology as is the case with stent- and impasse-jackets .Unless absorb
[0531 ] ‘ Proximal' and 'distal are used in relation to the able , implants are to remain inside the body following
operator, not the treatment site . “Vessel ,” ‘ vas,' ' ductus,' and placement. Nonperiductal, or intralmural, implants consist
' conduit ' all denote tubular anatomical structures, but ‘ ves of medication and /or magnetically susceptible matter in the
sel' is generally understood and is used here to refer to blood relative proportion optimal for the site of treatment. In this
vessels rather than to other kinds of vessels . Terms derived context, optimization comprises structural correction ,medi
from ' vessel,' such as “intravascular,' extravascular,’ ‘ intra cal remediation , and the inclusion of only so much mag
netically susceptible content as is necessary to assure
vasated ,' and ' extravasated ' pertain to blood vessels . “Duc implant retractability or recoverability should the need arise .
tus ' is used to refer to any kind of tubular structure and not
just a duct leading away from a gland, for example , and the [0536 ] Not referred to as “ implants ’ are tools used to place
terms ' intraductal' and ' extraductal ' are used with respect to implants, to include stay insertion devices, barrel-assem
any type ductus . ‘Miniball ' as used herein refers to milli blies , and combination form barrel- assemblies. The lack of
metric range spherules for implantation to treat disease with prior art formethods and means of treatment directed toward
no relation to ammunition . the placement of implants within the walls of ductus is
[ 0532 ] The term “ base - tube' denotes a platform for mag reflected in an inadequacy of established terms. 'Endolumi
nets; nonplatform jackets such as intrinsically susceptible to nal,' indicates that the referent (usually a stent) is not simply
magnetic tractive force are not base - tubes but stent-jackets intraductal but within the lumen ; when dealing with extralu
in themselves . Where greater tractive force is required to minal stents , which include a collective or distributed intra
draw the susceptible matter into the wall of the ductus, either ductal component which is extraluminal as situated within
type jacket can be used . The context will make it plain the lumen wall but otherwise external to the ductus as
whether use of the term ' flow reversal' pertains to a . Carotid consisting of a circumvascular component, the term ' endolu
angioplasty and stenting , addressed below in section VII2j minal' serves to distinguish prior art stents from the extralu
( 1) entitled Incorporation of Adscititious Capabilities into minal stents described herein .
Barrel -assemblies , b . Aortic regurgitation on the diastoles [0537] Except in using the standard term “ intraductal
due to aortic valve impairment, or c . Switching from out brachytherapy, ' intraductar is used to mean within the wall
flow , ejection, or irrigation to inflow or aspiration in the use of the ductus , not passed through its lumen . Because the
tool- inserts , addressed below in section VII2g ( 3 ) ( e )( vi ), recognized terms “ intraductal,’ ‘intratubal,' “ intraluminal, ' or
entitled Fluid - operated Tool-inserts , to Include Ejector -irri applying the term more generally than to the subarachnoid
gator -aspirators and Injectors . or subdural spaces , ‘ intrathecal,' do not distinguish 'within
[ 0533] Terms pertaining to detailed parts of components a ductus from ‘within the lumen of the ductus, here the more
are presented in the respective section describing the com recently recognized (included in medical dictionaries ) but
ponent and not anticipated. The superior thoracic aperture is long commonly used and immediately understood terms
the thoracic inlet of the anatomist and thoracic outlet of the ‘ endoluminal and extraluminal' are used . The term
clinician . Reference herein to the thoracic inlet is to desig ‘ intraluminal' had already been accepted , but its comple
nate this axial level in a dog or other quadruped with tracheal ment, ' extraluminal,' had not.
collapse . The term “propulsive force ' applies to the momen [0538 ] The term ' endoluminal' is not widely recognized as
tum imparted to a miniball by the gas pressure that drives it combining a Greek prefix with a Latin stem word or root, but
forward through the barrel- assembly and to the force the term ' endovascular (endoluminal vascular ),' of like
imparted to a bolus advanced through the digestive tract, the composition , has more recently been accepted through com
contextmaking which meaning pertains clear. “ Thermoplas mon use as necessary and obvious in meaning. Suture loops,
tic ' and 'thermoplasty ' pertain to thermal angioplasty , not or suture eyelets, are small optional handles integral with the
viscosity , hardness , or cosmetic surgery . Consistent there stent -jacket for passing through suture in order to stabilize
with , while any tubular anatomical structure may be referred the stent -jacket in position by attachment to neighboring
to as a vas or ductus , the term ' endovascular,’ for example , tissue in locations where pronounced vasotonic , peristaltic,
because it is derived from ‘ vascular, ’ implies limitation to an or bodily movement might otherwise cause the stent- jacket
arterial or a venous stent and is therefore avoided . to become displaced , or migrate . End-ties are suture , usually
10534 ] When used as an anatomical term , the plural for prefastened to the stent-jacket, either with rivets or through
ductus is ductus (pronounced ducktoose , not " ducti ).” An suture loops or suture eyelets for wrapping about the ends of
implant placed within the wall of a ductus is in the ductus but a stent- jacket to the substrate ductus beyond the end margins
not within the lumen of the ductus, which distinction is here to fix the stent-jacket in position .
significant. “Wider ' is short for larger in diameter, and [0539 ] ‘ Endomural' and ‘ endoparietal' likewise combine a
‘ narrower ' for smaller in diameter, gauge, or caliber. Greek prefix with Latin suffixes , and are not conventionally
‘ Hypoxia ’ is used to denote an insufficiency of oxygen due applied to ductus , so that an implant within the wall of a
to obstruction whether caused by intrinsic endoluminal ductus is left to be “ intramural' or ' intraparietal,' the con
deformation or by apparatus in the airway or the blood ventional pertinence to a wall surrounding a cavity forgone.
stream , whereas ‘ ischemia ' refers only to obstruction of the The recognized term “ endoprosthesis ' and unrecognized
blood supply . term “ endostent' as a contraction for endovascular or endolu
[0535] As used herein , the term “implant denotes solid minal, stent to denote a conventional or intraluminal stent ,
objects or pre - solid infusions or injections that aggregate can be used for brevity ; however, since an extraluminal stent
together and cure to become solid or semisolid objects of the kind to be described herein is not entirely extraductal,
US 2019 /0247050 A1 Aug . 15 , 2019
39

the contractions ' extrastent' and 'exostent are rejected as remotely controlled electrical motor to rotate the distal
misleading in addition to lacking acceptance . muzzle - head of the barrel-assembly . “ Injectant' is used to
[0540 ] An “extraluminal stent consists of subadventitial refer to any substance to be injected — not just an allergen .
(perimedial ) or medial, hence , intraductal but extraluminal The term ' orthosis ' suggestive of artificial limbs, the term
spherule implants, and an extraductal, specifically circum “prosthesis ' is used to denote a device that does not neces
ductal or periductal, a fortiori, extraluminal, stent-jacket, sarily replace , but rather augments or supports a part that
magnet - jacket (magnet -wrap ), or otherwise , subcutaneous failed due to disease , such use conventional. “ Thermal
or suprapleural clasp -magnets . The term " external stent” as window ' and 'heat-window ' denote a temperature changing
previously used applies to various cuffs and sheaths that in window whether used for heating or chilling.
application, structure , and function are fundamentally dif [0545 ] Most often the term 'heat-window will refer to a
ferent from the extraluminal stents to be described herein . A heat conduction plate overlying an electrical winding used
ductus is effectively “stented ' whether the extraluminal intra as the heat source . The term “ablation ' as conventionally
ductal component consists of ferromagnetic miniballs, stays , used is not limited to the removal of tissue by means of
a clasp -jacket, or a combination of these , and whether the cutting, and here , consistent therewith , denotes the destruc
extraductal component consists of a periductal (circumduc tion of tissue protrusive into a lumen whether by means of
tal) stent-jacket,more remotely placed patch -magnets , mag thermal (thermocautery ) or cryogenic cautery ( cryocautery )
net-wraps, or a combination of these. or by cutting ( shaving) or abrasive action . The term “ barrel”
(0541) “ Abluminar 'means “more distant from the ductus as denoting a cylindrical form or cylindrically formed part of
or its central axis . Inside the lumen , “ abluminal' means a larger structure is in standard use relative to guns, eyelets ,
farther from the longitudinal central axis, hence , closer to rivets , syringes, springs , and plating equipment, all directly
the lumen wall, whereas outside the ductus, Sabluminal' involved herein , the context making it clear which of these
means farther from the lumen wall . ‘ Adluminal ’ ‘means the meanings is intended .
opposite closer to the ductus or to its central axis ; outside
the ductus, “ adluminal' means closer to the lumen wall or [0546 ] Most often the term “barrel ' will pertain to that of
outer tunic , and within the lumen , away from the lumen wall a commericial airgun or the primary vertical member in a
or inner tunic and toward the lumen axis . “Luminal 'means control syringe -type stay insertion tool. Exceptionally , the
of or about the lumen ; ‘ adluminal,' never “ luminal” used 'barrel in an ejection or injection tool-insert refers to
herein to denote closer to the central axis of the lumen . function as a piston or plunger receiving component , regard
These terms are purely directional, hence , nonspecific as to less of cross section , which can be other than circular. The
the layer, depth , or distance . term 'barrel- catheter ' as used herein , if not unique , is
[0542 ] The terms “circumluminal' and 'periluminal' are believed to have little prior use , but the term ' barrel
neither recognized nor clear in distinguishing whether the assembly ' is commonly used with respect to firearms,
surrounding is of or along the internal surface of the lumen , extruders, hydraulic pistons, microscopes , syringes, door
within the wall about the lumen , or about the ductus as a curtain supports, and many other devices not related to the
whole . The term “ subadventitial ' as used herein denotes the apparatus to be described .
depth into the lumen wall at which the material of the wall [0547] Depending upon the context, 'clip ' denotes a maga
becomes the peripheral connective tissue comprised of the zine clip used to load spherule implants in an interventional
external elastic lamina (lamina elastica externa ) just outside airgun for discharge , strips of stays for loading into and
of the smooth muscle and inside the tunica adventitia or sequential ejection from a stay insertion tool in a manner
outer fibrous jacket . “ Ferromagnetic ' denotes drawn to a analogous to office staples, or spring clips for fastening
magnet, or magnetizable . The term “magnetized ' denotes attachments alongside a stay insertion tool, all to be
intrinsic magnetization or provided with magnets. described . Even though clasp -magnets and clasp -wraps
10543] A barrel- assembly uses a narrow pliant catheter to attach to tissue with clasps or prongs, these are not referred
extend the muzzle of an airgun forward or distad allowing to as ' clips .' The term ‘magazine' used alone likewise refers
transluminal passage and endoluminal discharge . Since the to a container for a load of projectible implants queued for
effective muzzle is no longer that of the airgun , the term discharge from an airgun or a stay insertion tool. The term
‘muzzle - head' is used to denote the displaced or effective ' eccentric ' with respect to vascular lesions denotes radially
muzzle, “ exit port' or 'exit - hole ' to denote the aperture of asymmetrical, and with respect to the axle in a miniature
projectile release , and exit velocity ' used in lieu of muzzle fluid damper-valve to be described , off -center.
velocity . The term 'bore ' is not literally applicable to the [0548 ] “Impasse- jacket denotes an impasse-jacket with
internal diameter of a barrel -tube, which is an extrusion , but any associated dummy collars or outriggers. An ‘ airgun ' or
is nevertheless useful to denote the lumen or diameter ‘ air gun ' discharges implants as projectiles ; a vortex tube
(gauge , caliber ) thereof ' Port' and ' portal' refer to the entry based cooling and heating device is referred to by the
incision or wound , not a sleeve inserted to expedite passage standard industrial term " cold air gun .' ' Applicator ' herein
therethrough . While no guidewire is used , the terms “ steer refers to a syringe , such as one used to dispense a surgical
ability ' and ' trackability are used to denote the same attri cement or tissue sealant as a whole and not just the nozzle ,
butes in relation to a barrel -assembly or radial projection outlet tube , or ' tip ' thereof, nor a separate spatula or brush
catheter. for spreading a cement, or to a tool- insert type syringe , as
10544 ) “ Torqueability ' denotes the resistance of a catheter will be described . The traditional meaning of 'percutaneous
to twisting or helical deformation when rotated at the as passing through without breaking the skin (transcutane
manipulated or proximal end . Parenthetically , in the present ous; transdermic ; diadermic ) is no longer restricted in mean
context, when the need for steerability outweighs the need ing thus, the very term 'percutaneous transluminal coronary
for torqueability, the pliancy required results in a loss of angioplasty for procedures that require entry by incision
torqueability, necessitating the incorporation of a hard -wire and arteriotomy making the point.
US 2019 /0247050 A1 Aug . 15 , 2019
40

[ 0549 ] The unrecognized terms ' permural' and 'perparial point, zero point ) input device , or control, such as a digital
are commonly used to refer to the walls of body cavities and encoder or an analogue (resolver or synchro ), a programmed
organs but not the walls of ductus . “Parietal' as it pertains , motion instruction director or controller, a differential ( com
for example , to cells of the stomach lining, (parietal cells, parator ), servomotor (actuator), machine table , shaft, or
acid cells, oxyntic cells) is used to refer to the lining of a other driven member , and output or positional difference
ductus when an outpocketing of a cavity , such as the inside (displacement ) measuring device , usually of the same kind
of the stomach , but not the vascular endothelium or intima. as the command input device, that provides the signal fed
The term 'ductus- intramural' is used herein to denote a back to the differential.
position within the wall about a lumen . Until changed by (0554 ] This combination and integration has resulted in
adjustment of the controller ( indexer ) or changing the step much confused terminology , such as use of the term ' ampli
mode at the driver (amplifier ), a stepper motor rotates by a fier,' normally synonymous with ' driver,' to denote an
consistent angle as would move or 'increment' a linear apparatus that actually includes the control or controller .
positioning table ( linear positioning stage ) by the equivalent Herein , the terms 'controller ' or ' servocontroller ' denote the
constant linear distance , here along the lumen of a ductus. set point positional director or controller, and the other terms
[0550 ) To distinguish between these ' increments as are specific , so that “ amplifier ' or 'servoamplifier ' denotes
elementary rotatory steps set by the step -angle from the the amplifier , “ differential' the differential, and so on . The
overall segment or distance along the lumen traversed as the simplest barrel-assemblies consist of only a ballistic com
sum of these elementary steps, the term 'step ' is limited to ponent. More advanced barrel-assemblies add components
the action of the stepper motor, and the term ' increment inside of, that is , centrally or medially to , and /or outside of,
applied to the transluminal segment traversed as the sum of that is, peripherally to , the ballistic component . The ballistic
these steps. The term ' torquer ’ is used to describe both a kind component consists of the barrel- tube or tubes, one or more
of electrical motor and knobs used to rotate catheters , the recovery tractive electromagnets , and in barrel - assemblies
term ' cure ' used for the setting time of an adhesive and the for use in the bloodstream , gas pressure relief or diversion
time to heal, the context making it clear which of these channels .
meanings is intended . The specification of a stepper motor as [0555 ] In a radial projection catheter , which specifically
linear stage driver is based upon the prevalence of such lacks a ballistic component, there are only inner and outer
application and not to be taken in a limiting sense . “ Atherec components. When more than one barrel-tube is present, the
tomy' denotes a form of angioplasty that unlike the com gas pressure diversion channel is usually shared by and
pression of plaque by a balloon , cuts the plaque away. positioned between or amid the barrel -tubes. While central
[0551] Thermal and laser catheters actually remove (ab and referred to as the central canal , it is not a central
late, atherectomize ) rather than merely crush plaque or effect component but rather part of the ballistic component. To
luminal distention by tearing circumferential fibers , but allow for the incorporation of a central component, the gas
cutting as suggested by the suffix -' ectomy' is uninvolved , so pressure diversion channel is divided as to be respective of
that these methods are usually referred to as forms of each barrel-tube , displacing these ballistic components
angioplasty . The angioplasty - capable barrel-assemblies and peripherally, as seen in an edge - discharge barrel -assembly .
radial projection catheters to be described can eliminate When displaced peripherally thus, a single central gas pres
plaque by different means , to include cutting action with sure diversion channel, or central canal, is no longer present.
radial projection unit tool-inserts, which constitutes a form [0556 ] A central component is a commercial device , such
of atherectomy literally understood , but also by thermal, as a laser or atherectomy cutting tool, to which is applied the
cryogenic , or laser action , for example , which are more least modification that will allow it to be incorporated into
accurately referred to as types of angioplasty . Since the term the ballistic catheter, or barrel-assembly . A barrel - asembly
“ angioplasty ' is applied to atherectomy but the reverse is not that includes a central channel for a permanent central
true, the one term that covers both actions of a barrel component or interchageable central components is a com
assembly used as an independent plaque -removal device is bination - form barrel - assembly , the central component occu
'angioplasty , prompting the term 'angioplasty -capable bar pying the central channel, passage, or passageway . Combi
rel -assembly ' or ' angioplasty barrel- assembly.' nation- form barrel-assemblies include central and ballistic
[0552] The term “ cavitation in engineering denotes the components , and unless omitted to allow additional cross
generation of bubbles in a fluid medium , whereas in medical sectional area for these , a peripheral component. Thus, only
use , the same term denotes the formation of vacuities , a combination - form barrel -assembly can include a central,
vacuoles , or cavities whether normal or pathological. The and therewith , all three components . A peripheral compo
term ' sweep , ' as in “ side - sweeper,' is used to mean to pass nent consists of radial projection units , which belong to one
over , to sweep past or across, whether with a hot gas, fluid or more circuits electrical and / or fluidic .
medication, a shaving or an abrading head , only the last of [0557] The term ' fluidic ' herein is applied not only to a
these applying a brushing action and not necessarily using fluid circuit but to components that are inserted into a fluid
bristles . The term ' recovery ' applied to electromagnets line . When the ballistic component is omitted , the apparatus
denotes applicability to retrieve dropped ( intravasated , is not a barrel-assembly but a specialized radial projection
escaped ) or extractmispositioned miniballs or stays, sparing catheter and the terms central, ballistic , and peripheral do
all of “ recovery and extraction miniball electromagnet not apply . Structurally isolated from other components , such
assembly. is no longer a component or peripheral. However, if a central
[ 0553] Whereas the electronic components in positional component in the form of a laser , thrombectomizer, or
control systems were once separate and distinct, miniatur - atherectomizer, for example is incorporated into a radial
ization has led to miniaturized combinations of these that projection catheter, central and peripheral components are
obscure the functional distinctness of each component. included in a catheteric device which is not a barrel
These include a manually operated positional command (set assembly. 'Stereotactic ' or ' stereotaxic ' denotes the precise
US 2019 /0247050 A1 Aug. 15 , 2019

positioning of a removal path for a miniball to be relocated the entry of a miniball into the circulation are addressed in
or removed through the use of three -dimensional coordi several sections . Provided the protective measures indicated
nates , suitable imaging machine , contrast dye , and a pow are employed , these potential deterrents will be kept to a
erful extracorporeal electromagnet. minimum if not eliminated and should pose no greater
[ 0558 ) Such extended use to parts of the body other than hazard than do existing standard of care measures.
the brain appears in use of the term “ stereotactic mammog [0563] Miniballs and stays can be placed in a preliminary
raphy,' for example . A ballistic catheter includes only the procedure and allowed to become integrated into , that is ,
ballistic component, making terms pertaining to relative infiltrated or ingrown by and adherent to the surrounding
position among components inapplicable . A ballistic cath tissue; over an interval, the use of tissue binding agents and
eter can be a simple pipe or a radial discharge barrel cellular proliferation -accelerating substances applied when
assembly , which consists of a barrel -tube or tubes jacketed the need for stenting is urgent. Since stays used to stent are
about to avoid injury to narrow ductus . Simple pipes and introduced through the same small access portal (keyhole
radial discharge barrel-assemblies with a single barrel- tube incision , laparascopic entry wound ) as is the stent- jacket, to
are monobarrels. Radial discharge monobarrels and multi place both during a single procedure is preferred . When
barrels for use in the bloodstream include one or more gas necessary, however, the incision is left to heal by tertiary
pressure diversion channels . Since the jacket and gas diver intention or delayed primary closure , thus preserving access
sion channels are parts of the ballistic component, a basic without the need for reincision to introduce the stent -jacket
radial discharge barrel -assembly , even when a multibarrel, at a later date .
includes only a ballistic component. [05641. Local subcutaneous injection of methylpredniso
[0559] "Gas -operated in the present context denotes only lone acetate (Depo -Medrol® Pfizer) synthetic glucocorti
that pressurized gas rather than a spring mechanism , for costeoid can be used to further retard union , oral retinoids
example, is used to propel the miniball implants, and not that (Wicke, C ., Halliday, B ., Allen , D ., Roche, N . S ., Scheuen
the exhaust gas of the preceding discharge is used to stuhl, H ., Spencer, M . M ., Roberts, A . B ., and Hunt, T . K .
chamber the next miniball as in the blowback operation of 2000 . " Effects of Steroids and Retinoids on Wound Heal
a firearm . Use of the term ' discharge to denote actions so ing,” Archives of Surgery 135 (11): 1265 - 1270 ) and / or pos
different as the sudden expulsion of miniballs and the sibly the infusion of IGF - I into the wound chamber (Suh , D .
relatively quiescent release of substances from syringes Y., Hunt, T . K ., and Spencer, E . M . 1992 . “ Insulin -like
accords with convention . The terms ‘aspiration and Growth Factor-I Reverses the Impairment ofWound Healing
‘microaspiration ' as used herein denote and are consistent Induced by Corticosteroids in Rats,” Endocrinology 131 (5 ) :
with the processes used to study embryos, for example, and 2399 - 2403 ) used to reverse the effect if necessary . Properly
not factors in pulmonary or airway disease . used and disinfected , the risk of infection is slight even if
[ 0560 ] Miniball -impassable jackets, or magnetized months pass until the stent-jacket is inserted .
impasse -jackets , are singular or simple ; simple -extended or 10565 ] 4a . Tissue Acceptance of Ductus -Intramural
braced when effectively elongated for positional stability Implants
through the addition of unmagnetized dummy-collars fas [0566 ] 4a( 1 ). Significance of Sterile Antixenic Immune
tened by rigid bridging arms at either or both ends; com Tissue Reaction
pound when two magnetized jackets are included , or
chained when including more than two, such latter triple , [0567] An adverse or allergic tissue reaction that is not
quadruple , and so on . Since the addition of dummy - collars temporary will result in implantation failure , making mate
imparts both stabilizing elongation and multipartedness , rials testing critical. Ductus- intramural implants include
braced jackets are technically compound and compound miniballs and stays . The immune response to sterile implants
jackets ‘ braced ;" however, it being superfluous , compound is not confined to individual hypersensitivity or allergic
impasse -jackets are not referred to as braced nor braced reactions to certain proteins but can occur upon introduction
jackets as compound . of any implant into the body as foreign (see, for example ,
[0561 ] " Chain ' jackets refers to impasse - jackets that Malik, A . F ., Hogue, R ., Ouyang , X ., Ghani, A ., Hong, E .,
include more than two dummy-collars and compound and 8 others 2011 . “ Inflammasome Components Asc and
jackets that include two or more constituent jackets. 'Com Caspase - 1 Mediate Biomaterial-induced Inflammation and
posite ' or 'mixed ' refers to compound or chain jackets in Foreign Body Response,” Proceeding of the National Acad
emy of Sciences of the United States of America 108 (50 ) :
which one or more of the constituent jackets is used to trap 20095 - 20100 ; Anderson , J. M ., Rodriguez , A ., and Chang ,
any passing miniball, that is, as a “ trap -jacket,' while one or D . T. 2008 . “ Foreign Body Reaction to Biomaterials,"
more is used to retain a radiation or drug -releasing miniball Seminars in Immunology 20 (2 ):86 - 100 ; Wilson , C . J., Clegg ,
or miniballs at a certain level in the lumen as a 'holding R . E ., Leavesley, D . I., and Pearcy , M . J. 2005. “Mediation
jacket.' 'Gastrointestinal' as used herein refers to the entire of Biomaterial-cell Interactions by Adsorbed Proteins : A
digestive tract inferior to the cricoid cartilage , and not just Review ,” Tissue Engineering 11 ( 1- 2 ):1 - 18 ; Hu, W -J., Eaton ,
the stomach and intestines as the literal meaning would J. W ., Ugarova, T. P., and Tang , L . 2001. “Molecular Basis
suggest. of Biomaterial-mediated Foreign Body Reactions ,” Blood
4 . Concept of the Ductus-Intramural Implant 98 (4 ): 1231 - 1238 ; Kao, W . J., Lee , D ., Schense , J. C ., and
Hubbell, J. A . 2001. Fibronectin Modulates Macrophage
[0562] The four methods for placing magnetically suscep Adhesion and FBGC Formation : The Role of RGD ,
tible implants within the wall surrounding the lumen of a PHSRN , and PRRARV Domains,” Journal of Biomedical
tubular anatomical structure (conduit, ductus, vas, vessel) Materials Research 55 (1 ):79 -88 ; Jenney, C . R . and Ander
are specified below in section XXII, entitled Glossary of son , J. M . 2000 . “ Adsorbed Serum Proteins Responsible for
Terms. Clotting, problem bleeding following the adminis - Surface Dependent Human Macrophage Behavior,” Journal
tration of anticlotting drugs, and accidental intraysation or of BiomedicalMaterials Research 49 (4 ):435 -447 ; van der
US 2019 /0247050 A1 Aug . 15 , 2019

Giessen , W . J., Lincoff , A . M ., Schwartz, R . S ., van microspheres of time-released dexamethasone, for example ,
Beusekom , H . M ., Serruys , P . W ., Holmes, D . R . Jr., Ellis , S . to defer a foreign body reaction is valuable in allowing an
G ., and Topol, E . J. 1996 . “Marked Inflammatory Sequelae interval for recovery from the immediate trauma associated
to Implantation of Biodegradable and Nonbiodegradable with insertion ; however , a coating of implant fibrinogin
Polymers in Porcine Coronary Arteries,” Circulation 94 ( 7 ): adsorption - averting serum , albumin , or hypofibrinogenemic
1690 - 1697 ; Tang, L . and Eaton , J. W . 1995 . “ Inflammatory plasma can ameliorate if not eliminate such a reaction (Hu,
Responses to Biomaterials,” American Journal of Clinical W -J., Eaton , J. W ., Ugarova, T. P ., and Tang, L . 2001.
Pathology 103 ( 4 ): 466 -471) . “ Molecular Basis of Biomaterial-mediated Foreign Body
[0568] Immune system macrophage attack of implanted Reactions,” Blood 98 ( 4 ): 1231 - 1238 ).
polyurethanes in nonductus -intramural implants such as [0572 ] An additional measure for deterring if not elimi
base -tubes and the linings thereof is inhibited by means nating a detrimental reaction , surface modification , is appli
addressed below in the sections below entitled Internal cable to the permanent outer surface of miniballs to serve as
Environment- resistant Base -tube Polymers, Metals , and the intravascular component of a magnetic stent even when
Combinations Thereof and Materials Suitable for Rebound overlain by an absorbable layer or layers (Nair, A ., Zou, L .,
directing Double -wedge Linings . For medication implants Bhattacharyya , D ., Timmons , R . B ., Tang , L . 2008. “ Species
that will be dissipated or assmilated through dissolution , and Density of Implant Surface Chemistry Affect the Extent
enzymatic action , and sometimes hydrolysis and not subject of Foreign Body Reactions ," Langmuir 24 ( 5 ): 2015 - 2024 ;
to tractive force except when any must be recovered , tissue Anderson , J. M . and Jones, J. A . 2007. “ Phenotypic Dichoto
reactions are usually temporary and of negligible conse mies in the Foreign Body Reaction ,” Biomaterials 28 (34) :
quence . For stenting stays , which will be subjected to mild 5114 - 5120 ), perhaps the simplest being polishing (De
tractive force , where a treatment unrelated weakening con Scheerder , I., Verbeken , E ., and Van Humbeeck , J . 1998 .
dition following insertion is anticipated , the stays are coated “Metallic SurfaceModification ,” Seminars in Interventional
with a tissue hardening and bonding agent, wetted with an Cardiology 3 (3 - 4 ):139 - 144 ).
adverse tissue reaction counteractant, and time time allowed 10573 ]. The need to further defer the onset of a foreign
for tissue integration until placement of the stent-jacket in a body reaction with systemic medication will depend upon
second procedure . the risk of stent failure due to such a reaction ; integration of
10569 ) Counteractants are addressed below in the section the sterile intraductal implants should allow a gradual tough
entitled Tissue Reaction Ameliorative Measures. Various ening of the tissue between the implant and the magnet
means for warming the site to accelerate the release of stay ( references at the section entitled Stent-jacket Expansion
contents and uptake are addressed herein , and keeping the Inserts ), whereas an application of excessive tractive force
site warm should accelerate healing and tissue acceptance . while the tissue remains unaccepting of the implant
The interval between placement of the stays and placement increases the risk of pull-through or delamination .
of the stent - jacket must be sufficient to allow tissue integra [0574 ] 4a ( 2 ). Duration , Extent, and Outcome of Sterile
tion and not just acceptance and healing. Unless deterred , a Tissue Reaction
foreign body reaction to a nonabsorbable implant can be [0575 ] The duration , extent, and outcome of tissue reac
acute and chronic , resulting in implant failure and harm to tion must be considered over the range of variability for
the patient. Stenting is but one application for miniballs , different individuals, tissues, and pathology for implants
which have multiple drug, radiation , and other therapeutic with a surface of bare metal, a protein solder doped onto a
agent-delivery applications that may or may not include polymer scaffold , the same impregnated with any of many
stenting . different types ofmedication in any of a number of different
[0570 ] All ductus -intramural implants contain sufficient particulate conformations or combinations thereof, and any
ferromagnetic content to allow retrieval should any be of the foregoing with an outer coating of a given surgical
dropped , mispositioned , or reauire emergency recovery . cement. Depending upon the specific application , the impact
Miniballs used for magnetic drug-targeting and/or to stent upon the implants and any coatings of the tissue response
generally require more magnetically susceptible content. and internal environment over the long term must be con
While it should seldom prove necessary , if the mass of sidered (see , for example , Kirkpatrick , C . J., Krump -Kon
lanthanoid needed to achieve the magnetic susceptibility valinkova , V ., Unger, R . E ., Bittinger, F., Otto , M ., and
required were to demand miniballs too large for the appli Peters, K . 2002 . “ Tissue Response and Biomaterial Integra
cation , then any other space -taking agent coatings to be tion : The Efficacy of in Vitro Methods,” Biomolecular
delivered in other miniballs or would be introduced not as Engineering 19( 2 -6 ):211 - 217 ).
outer layers but rather through endoluminal injection by [0576 ] Miniballs and stays that emit radiation can also be
tool - inserts , as addressed below in the section entitled prepared , for example , by ion surface engineering (see, for
Radial Projection Unit Tool-inserts , a coating of protein example , Fortin , M . A ., Paynter, R . W ., Sarkissian , A ., and
solder being an exception . Not subsumed by stenting , Stansfield , B . L . 2006 . “ Radioactive Sputter Cathodes for
implantation and miniballs should be considered as capable 32P Plasma-based Ion Implantation ,” Applied Radiation and
of supporting stenting as but one application therefor. Isotopes 64 (5 ):556 -562 ). Implants that emit radiation super
f0571] Prepositioning of the stent -jacket, addressed below impose upon the foregong additional variables consisting of
in the section entitled Circumstances Recommending the the numerous differences among individuals in the reaction
Use of a Shield -jacket or Preplacement of the Stent -jacket, of different tissues to radiation (see , for example , Li, X . A .,
usually restricted to the use of wide stays with greater O 'Neill, M ., and Suntharalingam , M . 2005 . “ Improving
adherent surface than miniballs in any event, will be limited Patient-specific Dosimetry for Intravascular Brachy
to wide stays where healing time is extended and it is sought therapy,” Brachytherapy 4 (4 ):291-297 ; Bentzen , S . M . and
to avoid the long term systemic administration of resolvent Overgaard , J. 1994 . “ Patient-to - Patient Variability in the
(anti-inflammatory ) medication . A coating containing Expression of Radiation -Induced Normal Tissue Injury.”
US 2019 /0247050 A1 Aug. 15 , 2019
43

Seminars in Radiation Oncology 4 ( 2 ):68 -80 ). Variables arise Angiogenesis ,” Journal of Controlled Release 117 ( 1 ):68 -79 ;
when the radiation responds to carcinoma (see , for example, Patil, S . D ., Papadimitrakopoulos, F., and Burgess , D . J.
Andreassen , C . N . and Alsner , J. 2009. "Genetic Variants 2004 . “ Dexamethasone- loaded Poly (lactic - co - glycolic )
and Normal Tissue Toxicity after Radiotherapy : A System Acid Microspheres/Poly (vinyl alcohol) Hydrogel Compos
atic Review ,” Radiotherapy and Oncology 92 ( 3 ):299 - 309 ). ite Coatings for Inflammation Control,” Diabetes Technol
[0577] Predictive capability for individual reaction differ ogy and Therpeutics 6 (6 ): 887 -897 ).
ences not sufficiently developed (see , for example , Bentzen , [0581 ] However, the implant itself or nearby magnetized
S . M ., Parliament, M ., Deasy , J. O ., Dicker, A ., Curran , W . miniballs , stays , impasse -jackets , magnet -wraps, and patch
J., Williams, J. P ., and Rosenstein , B . S . 2010 . “ Biomarkers magnets , for example , can attract a magnetically susceptible
and Surrogate Endpoints for Normal- Tissue Effects of drug carrier bound nanoparticlate , for example , that incor
Radiation Therapy : The Importance of Dose -volume porates any of numerous adverse tissue response counter
Effects,” International Journal of Radiation Oncology, Biol actants from the passing blood or other luminal contents for
ogy, and Physics 76 ( 3 Supplement ): S145 - 150 ; Popanda, O ., concentration at the area required , as addressed below in the
Marquardt, J. U ., Chang - Claude, J., and Schmezer, P. 2009. sections entitled Concept of the Impasse -jacket and Coop
" Genetic Variation in Normal Tissue Toxicity Induced by erative Use of Impasse -jackets in Pairs and Gradient Arrays,
Ionizing Radiation ,” Mutation Research 667 ( 1 - 2 ): 58 -69; among others. More specifically, strongly magnetized
Williams, J. R ., Zhang , Y ., Zhou, H ., Russell, J., Gridley, D . implants , such as magnet -wraps generally and miniballs ,
S ., Koch , C . J., and Little J. B . 2008 . “ Genotype -dependent stays , and impasse -jackets positioned to attract drug carrier
Radiosensitivity : Clonogenic Survival, Apoptosis and Cell binding nanoparticles will attract such a counteractant
cycle Redistribution ,” International Journal of Radiation whether administered separately from or as cobound with a
Oncology, Biology, and Physics 84 ( 2 ): 151- 164; Williams, J. primary agent, whereas stent -jackets, which must be less
R ., Zhang, Y., Zhou , H ., Gridley, D . S ., Koch , C . J., Slater, strongly magnetized to avoid delamination and pull -through
J. M ., and Little J. B . 2008 . “ Overview of Radiosensitivity are initially coated with the agent and supplemented at the
of Human Tumor Cells to Low - dose -rate Irradiation .,” Inter sides with more strongly magnetized miniballs or stays for
national Journal of Radiation Oncology, Biology, and Phys this purpose .
ics 72 ( 3 ): 909- 917 ) , whenever possible , preliminary testing [0582 ] When the ductus - intramural or intravascular com
should be done using long established methods. ponent of the extraluminal stent consists of miniballs, the
[0578 ] In empirical pretesting , a miniball of the kind outriggers are most easily placed at the start and end of
contemplated for use can also be implanted in superficial implantation discharge ; when stays, the more strongly mag
skeletal muscle or in the submandibular salivary gland , netized stays are placed at the distal and proximal sides of
which relatively superficial, includes much smooth muscle the other stays . When a preparatory angioplasty or ablation
tissue. The internal anal spincter provides superficial smooth can be avoided , the use of stays exclusively allows avoiding
muscle of sufficient thickness and continuity for testing but the lumen entirely ; however, if miniball implantation fol
is adversely located from the standpoint of risking infection . lows a transluminal step, then stays are just as easily placed
The inclusion of superparamagnetic magnetite or to either side of the stent -jacket when it is introduced . Broad
maghemite nanoparticles or finely grained powder allows stays afford a volume that allows these to be coated with
quick retrieval of the test miniball. For testing, miniballs of other reaction countering and other biological and /or non
identical composition as the stays actually proposed are used biological pharmaceuticals. The outer surface of the
( Sigler, M ., Paul, T ., and Grabitz , R . G . 2005 . “ Biocompat implants will often require a coating that incorporates mul
ibility Screening in Cardiovascular Implants,” Zeitschrift für tiple substances , typically, one to avert inter or intratunical
Kardiologie 94 (6 ):383 -391). delamination , another infection , and yet another to moderate
[0579 ] 4a( 3 ). Tissue Reaction Ameliorative Measures any adverse tissue reaction .
[ 0580 ] Substances incorporated into implants or the coat [0583] One solution is to incorporate substances that pure
ings thereof may be distinguished as either therapeutic or as or admixed , will not break down when one constituent, such
intended to counteract an adverse tissue response evoked by as an outer coating of a solid protein solder formulated to
the implant itself. Since the outer surface of each implant flow or denature at a low temperature , still has a relatively
can consist of bare metal or layers and an outer coating of high melting point (see Bogni, S ., Stumpp , O ., Reinert, M .,
substances that are different and numerous , the duration for and Frenz , M . 2010 . " Thermal Model for Optimization of
tissue subsidence and accommodation or acceptance and Vascular Laser Tissue Soldering ,” Journal of Biophotonics
integration will be variable . While controlled release from 3 (5 -6 ):284- 295). Current solders into which other sub
the implants can extend the term over which dexametha stances have been blended may still impose the risk of injury
sone , for example, can continue to be delivered , eventual when used to bond arteries (Bregy, A ., Bogni, S ., Bernau,
exhaustion may require systemic administration (see, for Vajtai , I., and 6 others 2008 . “ Solder Doped Polycaprolac
example , Vacanti, N . M ., Cheng, H ., Hill, P . S ., Guerreiro , J . tone Scaffold Enables Reproducible Laser Tissue Solder
D ., Dang, T. T., and 5 others 2012. “ Localized Delivery of ing,” Lasers in Surgery and Medicine 40 ( 10 ):716 -725 ) .
Dexamethasone from Electrospun Fibers Reduces the For Protein solders usually consist of bovine serum albumin
eign Body Response,” Biomacromolecules 13 ( 10 ):3031 containing a dye to enhance laser absorption at the wave
3038 ; Bhardwaj, U ., Sura , R ., Papadimitrakopoulos , F., and length employed (see Maitz , P. K . M ., Trickett, R . I. Tos, P .
Burgess , D . J. 2010 . “ PLGA / PVA Hydrogel Composites for Lanzetta , M . Owen , E . R ., Dekker, P. Dawes , J. M ., and
Long- term Inflammation Control Following S . C . [Subcu Pipet, J. A . 2000 . “ Tissue Repairs Using a Biodegradeable
taneous) implantation ,” International Journal of Pharma Laser-activated Solid Protein Solder,” IEEE Lasers and
ceutics 384 ( 1 - 2 ):78- 86 ; Patil , S . D ., Papadmitrakopoulos, F ., Electro -Optics Conference Proceedings, pages 446 -447;
and Burgess , D . J. 2007 . “ Concurrent Delivery of Dexam Maitz, P. K ., Trickett, R . I., Dekker, P ., Tos, P., Dawes, J. M .,
ethasone and VEGF for Localized Inflammation Control and Piper, J. A ., Lanzetta , M ., and Owen , E . R . 1999 . “ Sutureless
US 2019 /0247050 A1 Aug . 15 , 2019
44
Microvascular Anastomoses by a Biodegradable Laser - ac Otherwise , the retardant is prepared in the form of implant
tivated Solid Protein Solder," Plastic and Reconstructive coated or embedded particles, microspheres , or nanorods
Surgery 104 (6 ):1726 - 1731). ( see, for example , Mercanzini, A ., Reddy, S . T., Velluto , D .,
[0584 ] Any proteinaceous material that thermally dena Colin , P ., Maillard , A ., Bensadoun, J. C ., Hubbell , J. A ., and
tures upon heating can be used as a soldering agent, to Renaud , P . 2010 . “ Controlled Release Nanoparticle - embed
include any serum protein , such as albumin , fibronectin , Von ded Coatings Reduce the Tissue Reaction to Neuroprosthe
Willebrand factor, vitronectin , or any mixture of proteins or ses,” Journal of Controlled Release 145 ( 3 ): 196 - 202 ; Bhard
peptides (Gregory, K . W . 1998 . “Method of Producing waj, U ., Papadimitrakopoulos, F., and Burgess, D . J. 2008 .
Biomaterials,” Patent W0 /1998 /036707 ). Any or all of these " A Review of the Development of a Vehicle for Localized
materials can evoke an adverse tissue reaction . For cohesion and Controlled Drug Delivery for Implantable Biosensors,”
and pliability, the proteinaceousmaterial is applied or doped Journal of Diabetes Science and Technology 2 (6 ): 1016
onto a synthetic polymer such as glycolic (alpha -hydroxy 1029 ; Bhardwaj, U ., Sura , R ., Papadimitrakopoulos, F ., and
acetic ) acid as a scaffold (backing , basement layer ). Such Burgess D . J. 2007. “ Controlling Acute Inflammation with
scaffolding will usually contain alpha-hydroxy polyesters Fast Releasing Dexamethasone -PLGA Microsphere/PVA
(see , for example , Andrade, M . G . S ., Weissman , R ., and Hydrogel Composites for Implantable Devices,” Journal of
Reis , S . R . A . 2006 . “ Tissue Reaction and Surface Morphol Diabetes Science and Technology 1 (1 ):8 - 17 ; Patil, S . D .,
ogy of Absorbable Sutures after in Vivo Exposure,” Journal Papadimitrakopoulos, F ., and Burgess , D . J. 2004 . “ Dexam
of Materials Science : Materials in Medicine 17 ( 10 ): 949 - 961 ethasone -loaded Poly (lactic -co -glycolic ) Acid Micro
Bostman , O ., Partio E ., Hirvensalo , E ., and Rokkanen , P . spheres/ Poly ( vinyl alcohol) Hydrogel Composite Coatings
1992 . “ Foreign -body Reactions to Polyglycolide Screws: for Inflammation Control,” Diabetes Technology and Thera
Observations in 24 /216 Malleolar Fracture Cases,” Acta peutics 6 (6 ):887 -897 ; Hickey, T., Kreutzer, D ., Burgess, D .
Orthopaedica 63 (2 ): 173 - 176 ). Solders that heat by photo J., and Moussy, F . 2002. “ In Vivo Evaluation of a Dexam
sensitizing absorption of light at a certain frequency recom ethasone /PLGA Microsphere System Designed to Suppress
mend the use of combination - form barrel- assembly or radial the Inflammatory Tissue Response to Implantable Medical
projection catheter with a fiber optic catheter or fiberoptic Devices,” Journal of BiomedicalMaterials Research 61 ( 2 ) :
endoscope , or angioscope , can be used to activate a photo 180 - 187 ). See also the section below entitled Medication
sensitive ingredient. The same action at the same or a Implants and Medicated Implants and Prongs.
different frequency can be used to release medication . [0588 ] For miniballs and stays, which actually penetrate
10585 ) Curcumin has been demonstrated to reduce the through the substrate tissue, surface treatment to moderate
inflammatory response associated with poly ( L -lactic acid the reaction that ensues following the initial adsorption of
(Dende, C ., Meena, J., Nagarajan , P ., Nagaraj, V . A ., Panda , endogenous proteins is difficult to avoid but is likely to
A . K ., and Padmanaban , G . 2017 . “ Nanocurcumin is Supe prove critical for tissue acceptance ( see , for example , Nils
rior to Native Curcumin in Preventing Degenerative son , B ., Korsgren , O ., Lambris, J. D ., and Ekdahl, K . N .
Changes in Experimental Cerebral Malaria ,” Scientific 2010 . “ Can Cells and Biomaterials in Therapeutic Medicine
Reports 7 ( 1): 10062; Flora , G ., Gupta , D ., and Tiwari, A . be Shielded from Innate Immune Recognition ?," Trends in
2013 . “ Nanocurcumin : A Promising Therapeutic Advance Immunology 31( 1):32 - 38 ; Jones , K . S . 2008 . “Effects of
ment Over Native Curcumin ,” Critical Reviews in Thera Biomaterial - induced Inflammation on Fibrosis and Rejec
peutic Drug Carrier Systems 30 ( 4 ):331- 368 ; Jurenka , J. S . tion ,” Seminars in Immunology 20 ( 2 ): 130 - 136 ; Tang, Land
2009 . “ Anti- inflammatory Properties of Curcumin , a Major Hu, W -J. 2005 . “Molecular Determinants of Biocompatibil
Constituent of Curcuma Longa : A Review of Preclinical and ity ,” Expert Review of Medical Devices. 2 ( 4 ):493 -500 ; Hu,
Clinical Research ” Alternative Medicine Review 14 (2 ): 141 W - J., Eaton , J. W ., Ugarova , T. P ., and Tang, L . 2001.
53 ; erratum at 14 ( 3 ) :277 ; Su , S . H ., Nguyen , K . T ., Satasiya , “Molecular Basis of Biomaterial-mediated Foreign Body
P ., Greilich , P. E ., Tang , L ., and Eberhart, R . C . 2005. Reactions ,” Blood 98( 4 ): 1231 - 1238 ; Tang, L . and Eaton , J.
“ Curcumin Impregnation Improves the Mechanical Proper W . 1995 . “ Inflammatory Responses to Biomaterials ,”
ties and Reduces the Inflammatory Response Associated American Journal of Clinical Pathology 103 (4 ):466 -471 ).
with Poly ( L -lactic Acid ) Fiber ,” Journal of Biomaterials [0589 ] Protein adhesion a given , the surface chemistry and
Science . Polymer Edition 16 ( 3 ): 353 -370 ; Chainani-Wu, N . topography of miniballs and stays is devised to maximize
2003. “ Safety and Anti-inflammatory Activity ofCurcumin : tissue acceptance (see , for example , Morais , J. M .,
A Component of Tumeric (Curcuma Longa ),” Journal of Papadimitrakopoulos, F ., and Burgess, D . J. 2010 . “ Bioma
Alternative and Complementary Medicine 9 ( 1): 161- 168 ). terials/ Tissue Interactions: Possible Solutions to Overcome
[0586 ] As with any substance to be implanted , to mini Foreign Body Response,” American Association of Phar
mize if not avert an adverse tissue response to the solder, its maceutical Scientists Journal 12 ( 2 ): 188 -196 ; Zaveri, T . D .,
coatings, or inclusions, the patient is pretested for sensitivity Dolgova , N . V ., Chu, B . H ., Lee , J., Wong , J., Lele, T. P.,
to various formulations of these materials . Adverse tissue Ren , F ., and Keselowsky, B . G . 2010 . “ Contributions of
reactions can be forestalled and possibly moderated if not Surface Topography and Cytotoxicity to the Macrophage
eliminated to afford an implant to dissolve, become Response to Zinc Oxide Nanorods ,” Biomaterials 31 ( 11 ):
absorbed , or intentionally extracted through an impasse 2999- 3007 Kalasin , S . and Santore , M . M . 2009. “ Non
jacket, for example, or to permit an initial interval for tissue specific Adhesion on Biomaterial Surfaces Driven by Small
integration , by jacketing the implants within a coating of Amounts of Protein Adsorption , " Colloids and Surfaces. B .
scaffold material containing or itself coated with substances Biointerfaces 73 ( 2 ): 229 -236 ; Lee , J., Kang, B . S ., Hicks, B .,
such as phosphorylcholine , and /or dexamethasone, or cur Chancellor, T . F Jr., Chu, B . H ., Wang , H . T., Keselowsky ,
cumin . B . G ., Ren , F ., and Lele, T. P . 2008. “ The Control of Cell
[ 0587] When fluid , these are used to wet implants such as Adhesion and Viability by Zinc Oxide Nanorods,” Bioma
miniballs, stays, and stent-, impasse -, and magnet- jackets . terials 29(27):3743 - 3749 ; Thevenot, P ., Hu, W ., and Tang, L .
US 2019 /0247050 A1 Aug. 15 , 2019
45

2008 . “ Surface Chemistry Influences Implant Biocompat [0595 ] Noncombinatory implants are readily producible in
ibility ,” Current Topics in Medicinal Chemistry 8 (4 ):270 large numbers at relatively little cost, allow a larger dose to
280 ; Tang , L . and Hu, W . 2005 . “ Molecular Determinants of mass ratio , and can be arranged in pattern , making these
Biocompatibility ,” Expert Review of Medical Devices 2 ( 4 ) : more versatile than specially formulated implants. All of the
493 - 500 ; Kao , W . J., Liu , Y ., Gundloori, R ., Li, J ., Lee , D ., drug targeting means and procedures described herein have
Einerson , N ., Burmania, J., and Stevens, K . 2002. “ Engi the object ofmedical management where minor surgery is
neering Endogenous Inflammatory Cells as Delivery essential to gain access to the treatment site . The interven
Vehicles,” Journal of Controlled Release 78 ( 1 -3 ) :219 - 233 ; tional means for administering medication to be described
Jenney, C . R . and Anderson , J. M . 1999. “ Alkylsilane extend to new pharmacological agents, to include gene
modified Surfaces : Inhibition of Human Macrophage Adhe therapeutic and nanotechnological, for example , thus
sion and Foreign Body Giant Cell Formation ,” Journal of extending for the foreseeable future the continuation of
Biomedical Materials Research 46 ( 1 ): 11 -21; Kao , W . J., interventional methods. Ballistic implantation not only
Hubbell, J. A ., and Anderson , J. M . 1999 . “ Protein -mediated allows temporary or permanent seed - containing miniballs to
Macrophage Adhesion and Activation on Biomaterials: A be placed where conventional seeds can only with difficulty
Model for Modulating Cell Behavior,” Journal of Materials if at all, but reduces the cross sectional area of the penetra
Science. Materials in Medicine 10 (10 / 11 ):601 -605 ). tion path to that of the miniball.
[0590 ] 46 .Medicinal and Medicated Miniballs and Stays [0596 ] Drug delivering implants can be used indepen
[ 0591] 4b ( 1). Drug -Releasing and Irradiating Miniballs, dently of or in conjunction with a magnetic stent-jacket (see ,
Stays, and Ferrofluids for example , Faxon, D . P . ( ed .) 2001. Restenosis: A Guide to
10592] The means described herein allow the placement of Therapy , London , England : Martin Dunitz/ Informa Health
implants in the form ofminiballs or stays in locations, such Care . ISBN : 1 - 85317 -897 - 7 ; Gruberg , L ., Waksman, R .,
as within the walls of muscular arteries and the ureters , Satler , L . F ., Pichard , A . D ., and Kent, K . M . 2000. “ Novel
inaccessible to any means of the prior art such as endo Approaches for the Prevention of Restenosis ,” Expert Opin
scopic . Placed thus, these implants can be used to release ion on Investigational Drugs 9 ( 11 ):2555 - 2578 ) or drug
any therapeutic substance which can be prepared for release eluting (drug coated ,medicated ) (see , for example, Moses ,
thus, or to stent, or both . Depending upon the specific J. W ., Kipshidze , N ., and Leon , M . B . 2002. “ Perspectives of
application , long - or short -term (absorbed ), miniballs and Drug -eluting Stents: The Next Revolution ,” American Jour
stays may be made capable of spontaneously adaptive nal of Cardiovascular Drugs 2 (3 ):163 - 172 ; Nowak , B .,
(“ smart,' closed -loop , self- adjusted ) drug release in response Meyer, J. M ., Goergen , T., Fluehs, D ., Block , S ., Guenther,
to the instant milieu , or, based upon the results of follow -up R . W , Hoecker, H ., and Buell U . 2001. “ Dosimetry of a
examinations, controlled from outside the body. Implants 188rhenium -labeled Self-expanding Stent for Endovascular
within atheromas and tumors , for example , can be used to Brachytherapy in Peripheral Arteries,” Cardiovascular
release antiangiogenic medication or nanoprobes from suc Radiation Medicine 2 (4 ): 246 -253 ). Miniballs and stays can
cessive or interleaved layers or shells , for example . be open or closed - loop ‘ smart pills ,' for permanent or
10593 ) Control using direct or induced heat is addressed temporary placement (Bawa, P ., Pillay, V ., Choonara , Y . E .,
below in the sections entitled Implants that Radiate Heat on and du Toit, L . C . 2009. “ Stimuli-responsive Polymers and
Demand ; Medication -coated Miniballs , Stays, and Prongs Their Applications in Drug Delivery,” BiomedicalMaterials
with a Heat-activated (-melted , -denatured ) Tissue Adhe 4 (2 ):022001; Alvarez -Lorenzo , C . and Concheiro , A . 2008.
sive - hardener or Binder - fixative ; Heating Control over “ Intelligent Drug Delivery Systems: Polymeric Micelles and
Implants and Coated Implants, to Include Miniballs , Stays , Hydrogels," Mini Reviews in Medicinal Chemistry 8 (11):
and Prongs ; Heating of Implants and Coated Implants , to 1065 - 1074 ); Traitel, T ., Goldbart, R ., and Kost, J. 2008 .
Include Miniballs, Stays , and Prongs Using Implant- passive “ Smart Polymers for Responsive Drug -delivery Systems,"
Ductus-external or Extrinsic Means; Extracorporeal Energi Journal of Biomaterials Science . Polymer Edition 19 (6 ):
zation of Intrinsic Means for Radiating Heat from Within 755 -767; Moschou, E . A ., Madou , M . J ., Prescott, J. H .,
Medication Implants and Medication and/ or the Tissue Lipka , S., Baldwin , S ., Sheppard , N . F . Jr , and 5 others 2006 .
Bonding - coatings of Implants ; and Chemical Control over “ Chronic , Programmed Polypeptide Delivery from an
Implants and Coated Implants , to Include Miniballs, Stays , Implanted , Multireservoir Microchip Device ,” Nature Bio
and Prongs ; among others. technology 24 (4 ): 437 -438; Bachas, L . G ., and Daunert, S .
[0594 ] The stent- unrelated, or drug delivery applications 2006 . “ Voltage -switchable Artificial Muscles Actuating at
of the miniballs and stays , or ductus - intramural implants to Near Neutral pH ," Sensors and Actuators B : Chemical
be described , for example , will allow medication to be 115 (1 ): 379 -383 ; Xu , H ., Wang , C ., Wang , C ., Zoval, J., and
released from within or adjacent to a lesion in the wall of an Madou , M . 2006 . “ Polymer Actuator Valves Toward Con
anatomical structure. The implants to be described herein trolled Drug Delivery Application ,” Biosensors and Bioelec
can incorporate irradiating seeds and /or medication , whether tronics 21 (11):2094 -2099).
time released (prolonged release ), for insertion within a [0597] In addition to drugs already mentioned , numerous
ductus wall . By contrast, long -term or sustained delivery of other substances have been implemented or proposed for
a drug would require an invasive procedure for each dose , so inhibiting intimal (endarterial) thickening , to include growth
that for this purpose , the implants are magnetized and placed factor blockers (see , for example, Asada, Y ., Tsuneyoshi, A .,
once to attract the magnetically susceptible nonoparticle Marutsuka , K , and Sumiyoshi, A . 1994 . “ Suramin Inhibits
bound or cobound drug or drugs , as will be addressed . While Intimal Thickening Following Intimal Injury in the Rabbit
individual miniballs and stays can serve more than one Aorta in Vivo ," Cardiovascular Research 28 (8 ): 1166 - 1169),
purpose , such as to stent, release , and attract medication policosanol (Noa , M ., Más, R ., and Mesa , R . 1998 . “ Effect
and/ or radiation , these functions are more economically of Policosanol on Intimal Thickening in Rabbit Cuffed
assigned to neighboring, less specialized implants . Carotid Artery,” International Journal of Cardiology 67 (2 ):
US 2019 /0247050 A1 Aug . 15 , 2019
46

125 - 132 ; Noa , M ., Más, R ., and Lariot, C . 2007 . “ Protective absorbable implants, usually medicinal, are smooth and
Effect of Policosanol on Endothelium and Intimal Thickness include ferrous material only to allow magnetic recovery if
Induced by Forceps in Rabbits ,” Journal of Medicinal Food necessary.
10 ( 3 ):452 -459 ), glycoprotein IIb /IIIa receptor antagonists , (0601] In absorbable implants such as medication mini
nitric oxide (nitrogen monoxide , an endothelium -derived balls and stays , the polymer of the matrix or polymers of the
relaxing factor) donors ( see Lefkovits , J. and Topol, E . J. layers thereof, or the medication or layers thereof whether
1997 . “ Pharmacological Approaches for the Prevention of time- released , or any combination of the foregoing , set the
Restenosis after Percutaneous Coronary Intervention ," period or successive intervals for dissolution . The depth of
Progress in Cardiovascular Diseases 40 ( 2 ): 141- 158 ), and the layer that incorporates superparamagnetic magnetite or
vascular neutral endopeptidase (Barber , M . N ., Kanaga maghemite nanoparticles or finely grained powder, for
example , depends upon the potential need to retrieve what
sundaram , M ., Anderson , C . R ., Burrell, L . M ., and Woods, remains of the implant were it to become mispositioned .
R . L . 2006 . “ Vascular Neutral Endopeptidase Inhibition That is, retrievability is lost upon dissolution of the deepest
Improves Endothelial Function and Reduces IntimalHyper layer containing ferromagnetic material. Implants intended
plasia ,” Cardiovascular Research 71 (1 ): 179 - 188 ). Vascular for use as the intraductal component of an extraluminal
endothelial growth factor receptor 2 has been found to retard magnetic stent require a higher proportion of ferrous mate
atherogenesis in mice (Hauer, A . D ., van Puijvelde , G . H ., rial, generally not dispersed superparamagnetic magnetite or
Peterse , N ., de Vos, P., and eight other authors, 2007. maghemite nanoparticles or finely grained powder, but
“ Vaccination Against VEGFR2 Attenuates Initiation and rather conformed for optimal susceptibility to magnetic
Progression of Atherosclerosis,” Arteriosclerosis, Thrombo tractive force and chemically isolated as a core for perma
sis, and Vascular Biology 27 (9 ): 2050 - 2057 ). nence .
[ 0598 ] Exceptwhen accidently released , dropped , or mis [0602 ] A stent, or stenting, miniball can be given outer
positioned , implants other than temporary irradiating seeds, layers of therapeutic substances, of course . Such substances
which are exceptional, are not intended for recovery. If when present directly support implantation , and typically
necessary , any miniball or stay can include ferrous matter include antiseptics, antibiotics, lubricants , tissue cements ,
and be recovered using the recovery electromagnet built into protein solders , and numerous others singly or severally .
same barrel - assembly or that of the same stay insertion tool Permanent implants include the intravascular components of
that was used to place the implant, whether immediately as magnetic stents and /or nontemporary ( low dose - rate ) irra
when mispositioned , or at a later date , such as with a diating seeds, which can also be enclosed within layers of
temporary seed on the basis of results at an interval follow therapeutic agents . The permanent or nonabsorbable surface
ing placement. Provided sufficient continuous ferromagnetic of a permanent implant is given a deeply textured surface
material is incorporated into a medication miniball, for and otherwise treated to encourage tissue adhesion , infiltra
example , the miniball can be remotely , noninvasively, tion , and integration . To the extent that a dense and deep
heated by placing the patient in a radiofrequency alternating surface texture allows propulsive gas to escape about the
magnetic or electromagnetic field . Induction heating further miniball periphery during discharge , the loss in expulsive
allows the noninvasive detection of implant temperature by force must be compensated for by increasing the exit veloc
means of an equivalent temperature calibrated eddy current ity (*muzzle velocity '). To offset losses in exit velocity due
detector. to leakage or adjust for differences in tissue hardness , an
interventional airgun must allow regulation of the expulsive
[0599] In extraluminal stent-jackets , this allows the post force .
procedural thermoplasty of reobstructive hyperplasia by [0603 ] This capability also allows reducing the velocity to
noninvasive heating of the jacket with the temperature control the depth of miniball penetration and avoid perfo
noninvasively read by means of an equivalent temperature rations . Where the length of the ductus to be implanted with
calibrated eddy current detector. Moreover, because the medication or radiation seeds , for example, is large, but
intensity of induction can be increased as necessary , stent focused drug targeting or irradiation is wanted , nonstenting
jackets intended to be noninvasively heatable need not medication or radiation seed miniballs, which do not require
coordinate the number of breathing perforations seen as local percutaneous entry either to gain access as do stays nor
119 in FIGS . 6 , 13 , 14 , and 15 with resistance to eddy current to place a jacket, are used . This eliminates any extensive
circuits . Dipolar polymers such as acetates, polyvinyl chr percutaneous access . Whereas to place any number , size , or
loride, and polyamides , notably nylon , which are likewise type ofminiballs necessitates single percutaneous entry and
heated when placed in a radio frequency alternating mag withdrawal and can be accomplished with accuracy in a
netic or electromagnetic field are avoided when their resil relatively short time, the prior art alternative of placing
ience , springiness, or shape - restorative property is used . multiple endoluminal stents requires but single femoral,
[0600 ] When heated in the internal environment, some cubital, or brachial (radial) entry , but repeated withdrawal
plastics may additionally release harmful degradation prod and reentry to separately place each stent.
ucts. Stretched segments anticipated to reocclude can thus [06041 Repeated withdrawal and entry increases the risk of
be preemptively jacketed to counter this eventuality even entry wound hematoma and infection and increases proce
where no ductus - intramural implants have been placed . The dural time. If the miniballs are to be used for stenting, then
noninvasive heating of nonabosrbable and absorbable depending upon how closely together extraluminal stents are
implants has many applications, to include on - demand dis to be placed , a separate access incision at the body surface
solution , release ofmedication , accelerated drug uptake and allows placement of from 1 to 3 extraluminal stents without
healing, pain reduction , and reducing the setting and curing repeated irritation of a single entry wound . With a barrel
times of a surgical cement, and . Unless rippled to increase assembly equipped with a built- in wide angle fiberoptic
the surface area for quicker dissolution , nonpermanent or endoscope or angioscope or a combination - form barrel
US 2019 /0247050 A1 Aug. 15 , 2019
47

assembly with such a device inserted through its central therapy as well as radiation and/or surgery and for neoad
channel to afford a clear view , miniballs can be accurately juvant chemotherapy preparatory to surgical resection of a
placed . If the ductus is malacotic , determined by the means tumor. The spherical seed miniballs are magnetically
described in the section below entitled Testing and Tests , extracted through penetration paths no greater in cross
implantation by ballistic means may be discounted and sectional area than the seeds. If the coating of platelet
stays , which involve no transluminal component to place , blockade about the seed -miniballs is not sufficient to sup
are used . press thrombosis on insertion , then systemic medication is
[ 0605] If the number of ductus- intramural implants is required as when the miniballs are eventually recovered .
relatively few , a malacotic ductus may be implanted if first [0609 ] Higher dose -rates have also been shown more
treated to strengthen or bind it , as addressed below in the effectively palliative for the treatment of advanced carci
section entitied Medication - coated Miniballs, Stays , and noma ( see, for example, Skowronek , J., Piotrowski, T., and
Prongs with a Heat-activated (-melted , -denatured ) Tissue Zwierzchowski, G . 2004 . “ Palliative Treatment by High
Adhesive -hardener or Binder - fixative. If only slightly mala dose -rate Intraluminal Brachytherapy in Patients with
cotic , a tissue hardener and prepositioned double -wedge Advanced Esophageal Cancer,” Brachytherapy 3 ( 2 ):87 -94 ;
stent-jacket rebound -directing lining insert, as addressed Skowronek , J., Piotrowski, T., Mlynarczyk , W ., and Ramlau ,
below in the section of like title may be used to prevent R . 2004. “ Advanced Tracheal Carcinoma — Therapeutic Sig
perforations . The terms ' tissue hardener ' and ' sclerosant in nificance of HDR Brachytherapy in Palliative Treatment,”
this context refer to stiffening agents that indurate malacotic Neoplasma 51 ( 4 ): 313 - 318; Churn , M ., Jones , B ., and Myint,
tissue, not to agents used to embolize a varicosity or a polyp , A . S . 2002 . “ Radical Radiotherapy Incorporating a Brachy
for example . The means to be described provide additional therapy Boost for the Treatment of Carcinoma of the Tho
methods of treatment using radiation (brachytherapy endo racic Oesophagus: Results from a Cohort of Patients and
curietherapy , sealed source radiotherapy). Review of the Literature ,” Clinical Oncology (Royal Col
[ 0606 ] Currently, high dose -rate treatment is applied with lege of Radiology ) . 14 ( 2 ): 117 - 122 ; Sur, R . K ., Donde, B .,
a remote afterloader, which has limited organ applicability , Levin , V . C ., and Mannell, A . 1998 . “ Fractionated High
and must be withdrawn leaving no radioactive substance in Dose Rate Intraluminal Brachytherapy in Palliation of
the patient. This denies the ability to terminate the treatment Advanced Esophageal Cancer," International Journal of
based upon reexaminations at intervals without the need to Radiation Oncology, Biology, and Physics 40 (2 ):447 -453 ) .
repeat the procedure. The embedding and suturing of mul Used in arteries , radioactive stents have been found to cause
tiple interstitial high dose - rate catheter sleeves or trocars and narrowing at the margins and substantially eliminated from
the passing therethrough of source guides, for example , is use (Waksman , R . 2006 . “ Catheter-Based Radiation," in
sufficiently intricate as to discourage repeated treatments Ellis, S . G . and Holmes , D . R . Jr. Strategic Approaches in
thus. Aside from the relative difficulty , longer procedural Coronary Intervention, Philadelphia , Pa .: Lippincott Wil
time, and greater trauma of introducing conventional seeds, liams and Wilkins, page 161).
especially into the walls of lumina , low dose -rate conven 0610 ] Intermediate dose - rate implants are not introduced
tional seeds, as well as stents , are implanted with no expec with the expectaton of retrieval based upon followup diag
tation of recovery following treatment, limiting the dose nostics at intervals following implantation . Additionally ,
rate whereas an irremovable dose - rate limited irradiating stent is
[0607] Affording comparable results at greater conve endoluminal and interferes with vasomotility and the pass
nience to the patient, the use of a higher dose - rate has been ing through of contents, a radiation emitting seed - stay is
recommended over lower dose - rate brachytherpy in the extraluminal ( ductus - intramural) . Irradiating miniballs ,
treatment of cervical cancer, for example (see , for example, whether containing a seed -core or a radiactive coating , can
Wang, X ., Liu , R ., Ma, B ., Yang , K ., Tian , J., and 7 others be implanted in the walls of the gastrointestinal tract, for
2010 . “ High Dose Rate Versus Low Dose Rate Intracavity example, then recovered with slight trauma based upon the
Brachytherapy for Locally Advanced Uterine Cervix Can results of followup examinations. By contrast, once
cer,” Cochrane Database of Systematic Reviews (online ) decayed , conventional seeds are left implanted .
7 :CD007563 ; Viani, G . A ., Manta , G . B ., Stefano , E . J ., and 10611 ] The Cordis CheckmateTM System P990036 uses
de Fendi, L . I. 2009 . “ Brachytherapy for Cervix Cancer: seeds to treat in - stent restenosis ( see , for example , Waks
Low -dose Rate or High -dose Rate Brachytherapy - A Meta man , op cit , page 162 ). Unlike radiation seeds ,which left in
analysis of Clinical Trials,” Journal of Experimental and place , are limited to low dose -rates or radionuclides ( radio
Clinical Cancer Research 5 ; 28:47 ) . In addition to directly isotopes ) of short half- life such as Xenon - 133 (see , for
targeted treatment, malignant tumors that shed ‘ daughter example , Sekine , T., Watanabe , S ., Osa , A ., Ishioka, N ., and
cells which travel through the bloodstream to induce metas nine other inventors , 2001. " Xenon - 133 Radioactive Stent
tases elsewhere in the body, and persist after the primary for Preventing Restenosis of Blood Vessels and a Process for
tumor has been eliminated , require systemic chemotherapy. Producing the Same,” U . S . Pat. No. 6 ,192 , 095 ), ductus
[ 0608 ] However, because nontargeted tissue is little intramurally placed stays and miniballs are practicably
exposed , the less so when a counteractant is available , a recoverable and thus usable for delivering medication or
directly targeted tumor can be treated with more concen radiation in higher doses for a limited period .
trated and if appropriate , radioactive medication As [0612 ] In more advanced disease, external beam radiation
addressed above in the section entitled Field of the Invention may be essential to supplement the radiation provided by
and in the sections below in order entitled Drug -releasing seeds. In the irradiaton intervening tissue, this negates the
and Irradiating Miniballs , Stays , and Ferrofluids, Drug key benefit in the use of seeds over external irradiaton or
targeting Miniballs and Stays , 80 and Cooperative Use of delivery through the systemic circulation by infusion or
Impasse -jackets in Pairs and Gradient Arrays, among others, ingestion . Themeans to be described assume the recoverable
isolated lesions can be magnetically targeted for chemo implantation of variable dose-rate miniballs or stays,making
US 2019 /0247050 A1 Aug . 15 , 2019

extended exposure to radiation possible without the need to of Cancer ) 87 (7 -8 ):547 -550 ; al-Robaish , A ., Lien , D . C .,
introduce additional irrecoverable seeds or stents, and with Slatnik , J., and Nguyen , G . K . 1995 . “ Sarcoma of the
out the need for any foreign object in the lumen where it Pulmonary Artery Trunk : Report of a Case Complicated
interferes with the pulse or peristalsis and can result in with Hemopericardium and Cardiac Tamponade," Canadian
numerous complications . Journal of Cardiology 11(8 ):707-709; Thijs , L . G ., Kroon , T.
[0613] Existing nominally permanent seeds implanted in A ., and van Leeuwen , T. M . 1974 . “ Leiomyosarcoma of the
patients previously treated for a malignancy can , if infre Pulmonary Trunk Associated with Pericardial Effusion ,”
quently , demand periodic reexamination or surgical excision Thorax 29 (4 ):490 -494 ).
( see , for example , Sachdeva , S ., Udechukwu , N . S ., Elbelasi, [0616 ] Within an artery, the traveling radial excursion and
H ., Landwehr, K . P., St Clair, W . H ., and Winkler, M . A . return of the wall by the pulse is not large enough to result
2016 . “ Prostate Brachytherapy Seed Migration to the Heart in significant implantmispositionings .Moreover, in a coro
Seen on Cardiovascular Computed Tomographic Angiogra nary artery , the muzzle -head moves closely enough with the
phy,” Radiology Case Reports 12 ( 1):31- 33 ; Calvert, A . D ., beating heart that wobble does not affect implant positioning
Dyer, A . W ., and Montgomery , V . A . 2016 . “ Embolization of to any significant extent. Thus , as with conventional inter
Prostatic Brachytherapy Seeds to Pulmonary Arteries : A ventional apparatus, substantially conjoint movement with
Case Study,” Radiology Case Reports 12 (1 ) :34- 38 ; Nguyen , the containing coronary artery allows procedures to be
B . D ., Schild , S . E ., Wong, W . W ., and Vora , S . A . 2009. performed off-pump. The movement of blood past the
“ Prostate Brachytherapy Seed Embolization to the Right muzzle -head by the pulse is dependent upon the diameter
Renal Artery,” Brachytherapy 8 ( 3 ):309 -312 ; Stewart, A . J., and length of the muzzle -head , whether the muzzle -head
O ' Farrell , D . A ., Mutyala , S ., Bueno , R ., Sugarbaker, D . J., incorporates a bypass groove or grooves, is of the combi
Cormack , R . A ., and Devlin , P. M . 2007 . “ Severe Toxicity nation - form type with an unoccupied bore to allow blood to
after Permanent Radioactive Seed Implantation for Medi pass through , the elasticity of the artery , and the blood
astinal Carcinoid Tumors,” Brachytherapy 6 ( 1 ): 58 -61; pressure .
Ankem , M . K ., DeCarvalho , V . S ., Harangozo, A . M ., [0617 . By contrast, the insertion of stays in a coronary
Hartanto , V . H ., Perrotti , M ., and 8 others 2002 . “ Implica artery must be performed on -pump . Except in the trachea
tions of Radioactive Seed Migration to the Lungs after and gastrointestentstinal tract, to which access does not
Prostate Brachytherapy," Urology 59 ( 4 ):555 -559 ). require incision, the administration of medication in the
[0614 ] The miniballs or stays can contain a seed -core , form of miniballs or stays is normally undertaken as sec
carry a radioactive coating, or have a surface that has been ondary to and supportive of an antecedent or primary reason
ion impregnated . Stay insertion tools as shown in FIGS. 87 , for entry , usually to ablate and /or stent; generally, only a
88 thru 91, with a detailed view provided in FIG . 95 and localized and exigent condition such as a tumor justifies
described in section below entitled XVI. Stay Insertion administration thus. Unlike parenteral administration
Tools, incorporate a surgical cyanoacrylate cement stay whether oral, by injection , or infusion ,medicinal implants of
coater to positionally stabilize each stay, extending the time the kind to be described impart the ability to target diseased
for fibrous encapsulation . Almost all miniballs and stays tissue within the wall of a ductus, for example , at too
incorporate sufficient ferromagnetic material to allow recov awkward an angle and in too small as size as would allow
ery . The use of these in high motility ductus such as the injection endoscopically . This allows the use of a small but
gastrointestinal tract makes possible , for example , the place concentrated dose with less systemic dispersion . Existing
ment of higher dose-rate seeds on a temporary basis. methods do not allow injection much less quick shot
Another advantage of implants other than irretrievable delivery into the walls of small lumina .
endoluminal stents are adaptability to normal growth , [0618 ] The ability to target medication poses benefits in
changes in the pathology, or both . terms of efficacy and reducing side effects , as well as in
[ 0615 ] Existing radioactive seeds and stents are not readily economy and efficiency , and should continue to be of benefit
adapted for use in the luminal walls of most structures , such long past the age ofmechanical intervention for most other
as the great vessels and heart (see , for example , Talukder, M . purposes when nanotechnological and gene therapeutic
Q ., Deo , S . V .,Maleszewski, J. J., and Park , S . J. 2010 . “ Late modalities will be prevalent. The simplest and least expen
Isolated Metastasis of Renal Cell Carcinoma in the Left sive barrel-assemblies provide this capability . Whether a
Ventricular Myocardium ," Interactive Cardiovascular and miniball introduced from within the lumen or a stay intro
Thoracic Surgery 11 (6 ):814 - 816 ; Omura , A ., Tobe , S ., duced through the outer tunic, the lesion or tissue targeted
Yoshida, K ., and Yamaguchi, M . 2008 . “ Surgical Treatment implant is formulated using methods already known in the
for Recurrent Pulmonary Artery Sarcoma," General Tho pharmaceutical field to release different contents at the same
racic and Cardiovascular Surgery 56 ( 1):28 - 31 Rastan , A . J., or different intervals and rates . Following placement, the
Walther, T., Mohr, F . W ., and Kostelka, M . 2004 . “ Leiomyo implant can be acted upon extracorporeally such as through
sarcoma - An Unusual Cause of Right Ventricular Outflow the application of heat , to effect its dissolution or the release
Tract Obstruction ,” Thoracic and Cardiovascular Surgeon of constituents in a temperature selective manner, for
52 (6 ): 376 -377 ; Sánchez -Muñoz, A ., Hitt , R ., Artiles , V ., example . The concentric layering ofmedication for differ
López, A ., Hernández , R ., Cortés -Funes, H ., and Colomer, ential release after infixion when desired by magnetic force ,
R . 2003 . “ Primary Aortic Sarcoma with Widespread Vascu heat, or chemical exposure, for example , are all possible .
lar Embolic Metastases,” European Journal of Internal [0619] The selective breakdown of microspheres or nano
Medicine 14 (4 ): 258 -261 ; Ceccaldi, B ., Dourthe , L . M ., tubes within layers or of continuous layers one or more at a
Garcin , J. M ., Vergeau , B ., Chanudet, X ., and Larroque, P. time at later dates allows medication to be prepositioned for
2000 . “ Léiomyosarcome cardiaque du ventricule droit dispersal as periodic followup reevaluations indicate . The
[Leiomyosarcoma of the Right Ventricle ]," ( in French with combination ofmedication miniballs , and magnetically sus
abstract in English at Pubmed ) Bulletin du Cancer (Bulletin ceptible drug carrier bound nanoparticles introduced in a
US 2019 /0247050 A1 Aug . 15 , 2019
49
ferrofluid , for example , with impasse - jackets expands the Lawrence, J. B ., Prevosti, L . G ., Kramer, W . S ., Lu, D . Y .,
scope of drug delivery. Different forms of drug targeting are and Leon , M . B . 1989 . “ Platelet Adherence and Thrombus
described . Miniballs and stays can deliver a drug or other Formation with Flowing Human Blood on Atherosclerotic
therapeutic substance from a point by simple or time Plaque : Reduced Thrombogenicity of Watanabe -heritable
prolonged (time-released ) dissolution or by elution . Mini Hyperlipidemic Rabbit Aortic Subendothelium ,” Thrombo
balls and stays include sufficient superparamagnetic mag sis Research 54( 2 ): 99 - 114 ).
netite or maghemite nanoparticles or finely grained powder [0624 ] Targeted statin delivery , for which impasse-jackets ,
or magnetically susceptible content for retrieval if mis for example, can be pre -positioned , allows a considerably
placed , and increasing this content allows initiating and/ or reduced serum or systemic background level of a statin to be
accelerating drug delivery by direct or induction heating . administered , minimizing adverse side effects, while seg
[0620] Since an invasive procedure is required and the site ments which are already or can be predicted to become
of release cannot be replenished at will as can an impasse severely atheromatous can be given a concentrated dose .
jacket, this form of drug targeting is almost always limited The background or systemically circulated statin enhances
to incidental or adjunct application during a primary inva the catabolism of low density lipoprotein by the liver,
sive procedure catheteric or through open exposure that is whereas that targeted at the atheromatous lesion delivers
essential. Miniballs that consist of a drug or drugs can be other beneficial effects of the statin .
interspersed among stenting miniballs , for example . 0625 ] In atherosclerosis , endothelial activation and dys
Whereas implanted miniballs and stays are embedded within function lead to chronic intimal inflammation and atheroma
the diseased tissue , limiting followup access to these by tous lesioning ( Alom -Ruiz , S . P ., Anilkumar, N ., and Shah ,
absorption through the lumen wall or injection with the aid A . M . 2008 . “ Reactive Oxygen Species and Endothelial
of radial projection unit (side- looking) injection tool-inserts, Activation ,” Antioxidants and Redox Signaling 10 (6 ): 1089
a miniball , for example , suspended in the lumen by an 1100 ) . Atheromatous lesions and transluminal interventions
impasse - jacket remains accessible to substances adminis are both associated with endothelial dysfunction (Padfield ,
tered at a later time whether orally or by injection to end or G . J., Newby, D . E ., and Mills, N . L . 2010 . Understanding
modify its action . the Role of Endothelial Progenitor Cells in Percutaneous
10621] That is , an impasse -jacket allows follow - up access Coronary Intervention ,” Journal of the American College of
to the suspendant and is rechargeable ( replenishable ) to Cardiology 55 ( 15 ): 1553- 1565; Caramori, P. R . A .; Lima, V .
allow continued or adjusted administration of a drug or C .; Seidelin , P . H .; Newton , G . E ; Parker, J. D ; Adelman , A .
drugs as necessary . Injected miniballs, microspherules, and G . 1999. “ Long- term Endothelial Dysfunction after Coro
prospectively , ingested drug carrier nanoparticles can be nary Artery Stenting,” Journal of the American College of
trapped and suspended in the lumen by an impasse - jacket to Cardiology 34 (6 ): 1675- 1679 ).
deliver a drug through any of the foregoing processes [0626 ] However, if reinstatable to normal endothelial
repeatedly at any time. Lumen side - looking injectors, radial function , sites of vulnerable plaque may take a long time to
discharge barrel-assemblies, and impasse -jackets able to do so , and in themeantimepose an immediate risk of rupture
deliver mediation into the wall surrounding a delimited with dangerous consequences , as to demand active inter
segment of even a small ductus where no means could do so vention . Whether intimal tissue in a state of chronic inflam
before, the facility of treatment may be critically augmented . mation or frankly atheromatous has the potential to recover
With certain conditions , this can justify the invasive proce to a state of normal endothelial function with treatment
dure to place the jacket. would appear to depend upon how severe are the disease and
10622 ] Atherosclerosis consists of a systemic inflamma how traumatizing the treatment. Statins having been shown
tion throughout the arterial tree but most prominent and to exert a considerable healing effect on diseased intima,
vulnerable at discrete sites where the forces generated by searing and /or targeting ofatheromatous lesions with a statin
lumen conformation and flow produces lesions the location at a concentration higher than should be circulated with a
of which are predictable at bifurcations. The object in background of circulated statin to treat chronically inflamed
treatment should be to reinstate normal endothelial function intima is an approach that the inventive system makes
and the healing of frank lesions. This is accomplished with possible .
a statin (3 -hydroxy -3 -methylglutaryl- coenzyme A (or HMG [0627 ] A statin applied directly to an atheromatous seg
COA ) reductase inhibitor ) in the systemic circulation and the ment without passing through or being limited to the liver
singling out lesions for special treatment. While mildly provides direct benefits for the consequences of protracted
inflamed intima treated only medically should re -endothe elevated serum cholesterol and not just a reduction in serum
lialize and recover without scarring or the formation of cholesterol production as such , as well as exercises a demon
neointima, severely diseased tissue warrants elimination to strable healing function in vascular tissue (see , for example ,
avert an acute event despite the probability that the condition Mitsuhashi, T., Uemoto , R ., Ishikawa, K ., Yoshida , S ., Ikeda ,
itself and the treatment will detain if not preclude eventual Y ., and 4 others 2018 . “ Endothelial Nitric Oxide Synthase
healing of which the lesion was probably incapable in any independent Pleiotropic Effects of Pitavastatin against
event. Atherogenesis and Limb Ischemia in Mice ,” Journal of
10623 ] One means for the spot treatment of lesions that Atherosclerosis and Thrombosis 25 ( 1 ):65 - 80 ; Gavazzoni,
reduces the risk for thrombogenesis is thermoplasty (see , for M ., Gorga, E ., Derosa , G ., Maffioli, P ., Metra , M ., and
example , Lawrence , J . B ., Prevosti, L . G ., Kramer, W . S ., Raddino , R . 2017 . “ High - dose Atorvastatin VersusModerate
Smith , P . D ., Bonner, R . F ., Lu , D . Y ., and Leon , M . B . 1992 . Dose on Early Vascular Protection after ST-elevation Myo
“ Pulsed Laser and Thermal Ablation of Atherosclerotic cardial Infarction ,” Drug Design , Development, and
Plaque : Morphometrically Defined Surface Thrombogenic Therapy 11 : 3425 - 3434 ; Balan , A ., Szaingurten -Solodkin , I.,
ity in Studies Using an Annular Perfusion Chamber,” Jour Swissa , S . S ., Feinshtein , V., Huleihel, M ., and 3 others
nal of the American College of Cardiology 19 (5 ):1091 -1100 ; 2017. “ The Efects of Pravastatin on the Normal Human
US 2019 /0247050 A1 Aug . 15 , 2019
50
placenta : Lessons from ex - vivo models ,” Public Library of “ PCSK9 Targets Important for Lipid Metabolism ," Clinical
Science One 12 (2 ): e0172174 ; Akarsu , M ., Saygun , O ., Research in Cardiology Supplements 12 (Supplement 1 ):2
Aydinuraz , K ., Aydin , O ., Daphan , C . E ., and 3 others 2017 . 11 ; Glerup , S ., Schulz, R ., Laufs, U ., and Schlüter, K . D .
“ The Effects of Simvastatin on Ischemia Reperfusion Injury 2017 . “ Physiological and Therapeutic Regulation of PCSK9
in an Experimental Colon Anastomosis Model," Indian Activity in Cardiovascular Disease ,” Basic Research in
Journal of Surgery 79 ( 5 ):390 - 395 ; Owens, A . P . 3rd , Pas Cardiology 112 (3 ):32; Seidah , N . G . 2016 . “ New Develop
sam , F . H ., Antoniak , S ., Marshall, S . M ., McDaniel, A . L ., ments in Proprotein Convertase Subtilisin - Kexin 9 's Biol
Rudel , L ., Williams J. C ., and 15 others 2012 . “ Monocyte ogy and Clinical Implications,” Current Opinion in Lipidol
Tissue Factor - dependent Activation of Coagulation in ogy 27 ( 3 ): 274 - 281 ; Gupta , S . 2016 . “ Development of
Hypercholesterolemic Mice and Monkeys is Inhibited by Proprotein Convertase Subtilisin /Kexin Type 9 Inhibitors
Simvastatin ,” Journal of Clinical Investigation 122 ( 2 ): 558 and the Clinical Potential of Monoclonal Antibodies in the
568 ; Silverstein , R . L . 2012 . “ Teaching an Old Dog New Management of Lipid Disorders,” Vascular Health and Risk
Tricks: Potential Antiatherothrombotic Use for Statins," Management 12 : 421-433 ; McDonagh , M ., Peterson , K .,
Journal of Clinical Investigation 122 (2 ): 478 -481 ; Marzilli , Holzhammer, B ., and Fazio , S . 2016 . " A Systematic Review
M . 2010 . “ Pleiotropic Effects of Statins: Evidence for Ben of PCSK9 Inhibitors Alirocumab and Evolocumab ,” Journal
efits Beyond LDL - cholesterol Lowering.,” American Jour ofManaged Care and Specialty Pharmacy 22 (6 ):641-653q;
nal of Cardiovascular Drugs 10 Supplement 1 : 3 - 9 ; Peder Zhang , L ., Song, K ., Zhu , M ., Shi, J., Zhang , H ., Xu, L ., and
sen , T. R . 2010 . “ Pleiotropic Effects of Statins: Evidence Chen , Y . 2016 . “ Proprotein Convertase Subtilisin /Kexin
Against Benefits Beyond LDL -cholesterol Lowering, " Type 9 (PCSK9) in Lipid Metabolism , Atherosclerosis , and
American Journal of Cardiovascular Drugs 10 Supplement Ischemic Stroke," International Journal of Neuroscience
1 : 10 - 17 ; Smaldone, C ., Brugaletta , S ., Pazzano, V ., and 126 ( 8 ):675 -680 ; Urban , D ., Pöss, J., Böhm , M ., and Laufs,
Liuzzo , G . 2009. “ Immunomodulator Activity of 3-hydroxy - U . 2013. “ Targeting the Proprotein Convertase Subtilisin/
3 -methilglutaryl-CoA Inhibitors ,” Cardiovascular and Kexin Type 9 for the Treatment of Dyslipidemia and Ath
Hematological Agents in Medicinal Chemistry 7 (4 ): 279 - 94 ; erosclerosis,” Journal of the American College of Cardiol
li, M . and Losordo, D . W . 2007 . “ Statins and the Endothe ogy 62( 16 ): 1401 - 1408 ; Steinberg , D . and Witztum , J. L .
lium ," Vascular Pharmacology 46 ( 1 ) : 1 - 9 ; Dilaveris , P ., 2009. “ Inhibition of PCSK9: A Powerful Weapon for
Giannopoulos , G ., Riga , M ., Synetos, A ., and Stefanadis , C . Achieving Ideal LDL Cholesterol Levels ,” Proceedings of
2007. “ Beneficial Effects of Statins on Endothelial Dysfunc the National Academy of Sciences of the United States of
tion and Vascular Stiffness ," Current Vascular Pharmacol America 106 (24 ): 9546 - 9547 ), cholesterylester transfer pro
ogy 5 (3 ):227 - 237 ; Calabrò , P. and Yeh , E . T. 2005 . “ The tein (CETP ) inhibitors ( see , for example , Han , S ., Levoci,
Pleiotropic Effects of Statins," Current Opinion in Cardiol L ., Fisher , P., Wang , S . P., and 7 others 2012. “ Inhibition of
ogy 20 (6 ):541-546 ). Cholesteryl Ester Transfer Protein by Anacetrapib Does Not
Impair the Anti-inflammatory Properties of High Density
[ 0628 ] The pleiotropic or liver metabolism - independent/ Lipoprotein ," Biochimica et Biophysica Acta December 23
local application potential of relatively new drugs, such as pii: S1388 -1981( 12 )00262 -00264 ; Nicholls , S . J., Brewer,
proprotein convertase subtilisin /kexin type 9 (PCSK9) H . B ., Kastelein , J. J ., Krueger, K . A ., Wang, M . D ., and 4
inhibitors and investigatory or experimental small interfer others 2011 . “ Effects of the CETP Inhibitor Evacetrapib
ence RNA PCSK9 messenger RNA inhibitor (inclisiran ) Administered as Monotherapy or in Combination with Sta
( see, for example , Fitzgerald , K ., White , S ., Borodovsky , A .,
Bettencourt, B . R ., Strahs, A ., and 10 others 2017 . “ A Highly tins on HDL and LDL Cholesterol: A Randomized Con
Durable RNAi Therapeutic Inhibitor of PCSK9," New Eng trolled Trial," Journal of the American Medical Association
land Journal of Medicine 376 ( 1 ):41- 51 ; Ray, K . K ., 306 ( 19 ): 2099 -2109), such as anacetrepib (Merck ), evace
Landmesser, U ., Leiter, L . A ., Kallend , D ., Dufour, R ., and trapib (Lilly ), currently under clinical trials, or isolated ethyl
eicosapentaenoic acid (Vascepa ( Amarin ), Epadel
8 others 2017 . “ Inclisiran in Patients at High Cardiovascular (Mochida ) to function locally or pleiotropically as do statins
Risk with Elevated LDL Cholesterol," New England Journal appears not as yet to have been investigated .
of Medicine 376 (15 ): 1430 - 1440 ; Hadjiphilippou , S . and
Ray , K . K . 2017 . “ PCSK9 Inhibition and Atherosclerotic [0629 ] In addition to raising high density lipoprotein , this
Cardiovascular Disease Prevention : Does Reality Match the class of drugs appears to decrease low density lipoprotein
Hype?," Heart (British Cardiac Society ) 103 (21): 1670 more than the reduction obtained with a statin alone, and
1679 ; Shah , P., Glueck , C . J., Goldenberg , N ., Min , S ., may prove valuable on that basis. However, the drug
Mahida , C ., and 4 others 2017 . " Efficacy , Safety , Low induced high density lipoprotein produced appears dissimi
Density Lipoprotein Cholesterol Lowering, and Calculated lar from that originated in the gut and liver (see , for
10 - year Cardiovascular Risk Reduction of Alirocumab and examples, Rader, D . J. and Hobbs , H . H ., 2005 . “ Disorders
Evolocumab in Addition to Maximal Tolerated Cholesterol of Lipoprotein Metabolism ," Chapter 335 , page 2288 , in
Lowering Therapy: A Post-commercialization Study,” Lip Harrison 's Principles of Internal Medicine, New York ,
ids in Health and Disease 16 ( 1): 19 ; Choi, J., Khan , A . M ., N . Y .: McGraw -Hill) and relatively ineffective at recovering
Jarmin , M ., Goldenberg , N ., Glueck , C . J., anf Wang, P . cholesterol and other lipids , to include that within atheroma
2017 . “ Efficacy and Safety of Proprotein Convertase Sub tous tissue, and transporting it to the liver for reformulation
tilisin -Kexin Yype 9 (PCSK9) Inhibitors , Alirocumab and or breakdown and disposal, which subject is under study
Evolocumab , a Post- commercialization Study,” Lipids in ( see, for example , Nicholls , S . J.,Gordon , A ., Johannson , J.,
Health and Disease 16 ( 1): 141; Wicinski, M ., Zak , J., Ballantyne, C . M ., Barter, P . J., Brewer, H . B ., Kastelein , J.
Malinowski, B ., Popek , G ., and Grze?k , G . 2017 . “ PCSK9 J., Wong, N . C ., Borgman , M . R ., and Nissen , S . E . 2012 .
Signaling Pathways and Their Potential Importance in Clini “ ApoA -I Induction as a Potential Cardioprotective Strategy:
cal Practice ,” European Predictive Medicine Association Rationale for the SUSTAIN and ASSURE Studies,” Car
Journal 8 (4 ):391 -402; Schulz , R . and Schlüter, K . D . 2017 . diovascular Drugs and Therapy 26 (2 ): 181- 187 ).
US 2019 /0247050 A1 Aug. 15 , 2019
51

[ 0630 ] Rather than to force the natural production of bospondin Accelerates Reendothelialization and Reduces
defective high density lipoprotein ,one approach would be to Neointima Formation in Balloon - injured Rat Carotid
directly synthesize a molecule identical to natural high Artery,” Circulation 100( 8 ): 849-854 ), estrogen receptor
density lipoprotein and directly pipe it to the circulatory alpha (see Brouchet, L ., Krust, A ., Dupont, S ., Chambon , P .,
system through a nonmagnetized or magnetized jacket from Bayard , F ., and Arnal, J. F . 2001 . “ Estradiol Accelerates
a portal implanted at t he body surface as described herein . Reendothelialization in Mouse Carotid Artery through
Awareness of the pleiotropic effects of statins has existed for Estrogen Receptor-alpha but Not Estrogen Receptor-beta,"
years (Lahera , V ., Goicoechea , M ., de Vinuesa, S . G .,Miana , Circulation 103 (3 ):423 -428 ), estrogen receptor modulators
M ., de las Heras, N ., Cachofeiro , V., and Luño , J. 2007. ( see, for example , Christodoulakos , G . E ., Lambrinoudaki, I.
“ Endothelial Dysfunction , Oxidative Stress and Inflamma V ., and Botsis , D . C . 2006 . “ The Cardiovascular Effects of
tion in Atherosclerosis : Beneficial Effects of Statins,” Cur Selective Estrogen Receptor Modulators ,” Annals of the
rent Medicinal Chemistry 14 (2 ):243- 248 ; Sipahi, I., Nich New York Academy of Sciences 1092 :374 -384 ; Savolainen
olls, S . J., Tuzcu , E . M ., and Nissen , S . E . 2006 . “ Coronary
Atherosclerosis Can Regress with Very Intensive Statin Peltonen , H ., Luoto , N . M ., Kangas, L ., and Häyry , P . 2004 .
Therapy,” Cleveland Clinic Journal of Medicine 73 ( 10 ): “ Selective Estrogen Receptor Modulators Prevent
937 - 944 ; Nissen , S . E ., Nicholls , S . J., Sipahi, I., Libby, P., Neointima Formation after Vascular Injury,” Molecular and
Raichlen J. S , Ballantyne C M , Davignon J, and 9 other Cellular Endocrinology 227 ( 1 -2 ):9 - 20 ; Yue, T. L ., Vickery
ASTEROID Trial Investigators 2006 . “ Effect of Very High Clark , L ., Louden , C . S ., Gu , J. L ., Ma, X . L ., Narayanan , P .
intensity Statin Therapy on Regression of Coronary Athero K ., and 6 others “ Selective Estrogen Receptor Modulator
sclerosis : The ASTEROID Trial,” Journal of the American Idoxifene Inhibits Smooth Muscle Cell Proliferation ,
Medical Association 295 ( 13 ) : 1556 - 1565 ; Arnaud, C ., Veil Enhances Reendothelialization, and Inhibits Neointimal
lard , N . R .,Mach , F . 2005 . “ Cholesterol- independent Effects Formation in Vivo after Vascular Injury ," Circulation 2000
of Statins in Inflammation , Immunomodulation and Athero 102 ( 19 Supplement 3 ): 111281 -111288 ) and endothelial pro
sclerosis,” Current Drug Targets. Cardiovascular and Hae genitor cells ( see Chen L , Wu F , Xia W H , Zhang Y Y , Xu
matological Disorders 5 ( 2 ): 127 -134 ; Sorrentino , S . and S Y , and 5 others 2010 . “ CXCR4 Gene Transfer Contributes
Landmesser, U . 2005 . “ Nonlipid -lowering Effects of Sta to in Vivo Reendothelialization Capacity of Endothelial
tins,” Current Treatment Options in Cardiovascular Medi Progenitor Cells ,” Cardiovascular Research 88 ( 3 ) :462 -470 )
cine 7 (6 ): 459 - 466 ; Calabrò , P . and Yeh , E . T . 2005. “ The as well as other substances have been found to expedite
Pleiotropic Effects of Statins," Current Opinion in Cardiol healing in lower mammals.
ogy 20 (6 ):541- 546 ; Davignon , J. 2004 . “ Atherosclerosis : [0633 ] The capability for impasse - jackets , medication
Evolving Vascular Biology and Clinical Implications. Ben ductus - intramural implants , patch -magnets, and magnet
eficial cardiovascular pleiotropic effects of statins,” Circu jackets to implement the local delivery of medication is a
lation 109( 23 Supplement 1 ):11139- 11143; Walter, D . H ., primary object of the inventive system as delineated in the
Zeiher, A . M ., and Dimmeler, S . 2004 . “ Effects of Statins on sections respective of each type implant. Analogously, local
Endothelium and Their Contribution to Neovascularization and regional cancer is treated with radiation and surgery ,
by Mobilization of Endothelial Progenitor Cells," Coronary whereas systemic cancer is treated by chemotherapy. The
Artery Disease 15 (5 ):235 - 242 ; Walter, D . H ., Rittig , K ., benefits of statins have been noted as pleiotropic for the
Bahlmann , F . H ., Kirchmair , R ., Silver, M ., and 5 others treatment of cancer as well as atheromatous disease ( see , for
2002. " Statin Therapy Accelerates Reendothelialization : A example , Gazzerro P , Proto MC, Gangemi G , Malfitano A
Novel Effect Involving Mobilization and Incorporation of M , Ciaglia E , and 4 others . 2012. “ Pharmacological Actions
Bone marrow - derived Endothelial Progenitor Cells,” Circu of Statins: A Critical Appraisal in the Management of
lation 105 ( 25 ):3017 - 3024 ). Cancer,” Pharmacological Reviews 64 ( 1 ) : 102- 146 ; Zeich
[0631] That the non - LDL - Cholesterol-lowering or pleio ner, S ., Mihos, C . G ., and Santana , O . 2012 . “ The Pleiotropic
tropic effects of statins, to include anti- inflammatory , immu Effects and Therapeutic Potential of the Hydroxy -methyl
nomodulatory , and antithrombotic , may not reduce the inci glutaryl-COA Reductase Inhibitors in Malignancies : A Com
dence of acute events (see , for example , Robinson , J. G ., prehensive Review ," Journal of Cancer Research and
Smith , B ., Maheshwari, N ., and Schrott, H . 2005 . “ Pleio Therapeutics 8 (2 ): 176 - 183 ). The toxicity and adverse side
tropic Effects of Statins: Benefit Beyond Cholesterol Reduc effects of chemotherapy are serious and can begin with
tion ? A Meta -Regression Analysis,” Journal of the American extravasation during infusion of a vesicant drug that leads to
College ofCardiology 46 ( 10 ):1855- 1862) may not equate to tissue necrosis (see, for example , Ener, R . A .,Meglathery, S .
a lack of benefit for reducing inflammation leading to B ., and Styler, M . 2004 . “ Extravasation of Systemic
healing in less severely diseased and iatrogenically affected Hemato - oncological Therapies,” Annals of Oncology 15 (6 ):
tissue . The benefits of statins by direct application are also 858 - 862) .
addressed below in the section entitled Cooperative Use of [0634 ] However, magnetized miniballs, stays , impasse
Impasse - jackets in Pairs and Gradient Arrays . jackets , and patch -magnets make it possible to isolate a
[ 0632 ] Vascular endothelial growth factor (see, for tumor in a context of systemic disease for receiving a high
example , Asahara , T ., Bauters , C ., Pastore , C ., Kearney, M ., concentration of the anticancer drug, thus allowing the
Rossow , S ., Bunting , S ., Ferrara , N ., Symes , J. F ., and Isner, systemic dose to be reduced , while local and regional tumors
J. M .1995 . “ Local Delivery of Vascular Endothelial Growth can be treated by targeted chemotherapy by means of
Factor Accelerates Reendothelialization and Attenuates Inti magnetic force that allows the systemic dose to be elimi
mal Hyperplasia in Balloon - injured Rat Carotid Artery ," nated . Magnetically targeted chemotherapy may seek to kill
Circulation 91( 11 ): 2793 - 2801) , thrombospondin blockade tumor cells directly — through mitotoxity , cytotoxicity , anti
(see Chen , D ., Asahara, T., Krasinski, K ., Witzenbichler, B ., angionicity, metabolic mechanism , and so on by antine
Yang, J., and 5 others 1999. “ Antibody Blockade of Throm oplastic drugs otherwise delivered systemically — or indi
US 2019 /0247050 A1 Aug. 15 , 2019

rectly, by enhancing susceptibility of tumor cells to layer of medication . This makes it possible to release
radiation , or both , again using known systemic drugs for the selectable medication from a prepositioned locus in response
purpose . to diagnostic testing according to a prescribed timetable as
[0635 ] Implanting medication miniballs and stays to dictated by the course of the condition .
deliver a statin or an antineoplastic drug , for example ,makes [0639] The overall dose of each constituent at a given
it possible to concentrate the drug or drugs within the wall interval is determined by the number of implants placed at
surrounding a susceptible segment, allowing a background the site and the concentration and rates of release of the
serum level of the drug if any, and therewith , unwanted side different constituents, the selective release of each limited
effects, to be reduced accordingly , the overall reduction in only by the kinds and intensities of energy used to release it .
the amount of the drug used considerable . For drugs needed If noncritical and simply accomplished , the patient can be
over a brief period to treat a temporary condition , the sum contacted to perform the necessary action at home. Releas
dose that can be delivered within the lumen wall of a more ing a selectable number of layers allows controlling the dose
acutely affected segment by medication miniballs or stays, or the specific medication or medications according to the
whether at once or time- released , can often be made sufti results of periodic diagnostic testing . Combining separate
cient to allow effective treatment. However, the administra hemispheres to make the miniballs or separate halves to
tion of a statin and other drugs to treat a condition that results make stays doubles the absolute number of substances that
from a metabolic disorder, even when concentrated at the might be released from each implant and allows different
lesion and formulated for release at a slow rate or only when substances to be released together and simultaneously or
heated , will not provide a beneficial effect unless sustained sequentially .
indefinitely, as is the disorder. [ 0640 ] Extracorporeal control over the dissolution of
[ 0636 ] To deliver drugs on a sustained basis , the implants medication -containing implants or side-looking syringe
are not used to release the drugs but rather to attract the injector tool- insert injectants previously introduced into a
drugs from the passing lumen contents . The magnetized tumor or plaque, for example , can be used to generate heat
implants are placed in a one -time invasive procedure that within and thereby release an antitumor agent within or
will allow the effective targeting of a certain segment ablate a tumor (see , for example , Thomas , C . R ., Ferris , D .
indefinitely , whenever the drug is taken , preferably by P., Lee , J. H ., Choi, E ., Cho , M . H ., and 5 others 2010 .
mouth . The magnetically susceptible carrier -bound drugs “ Noninvasive Remote -controlled Release of Drug Mol
may be added to food for treating an esophageal neoplasm ecules in Vitro Using Magnetic Actuation of Mechanized
or formulated into capsules that will release a ferrofluid Nanoparticles ,” Journal of the American Chemical Society
which will pass into the bloodstream to be trapped along a 132 ( 31 ): 10623 - 10625 ; Hayashi, K ., Ono, K ., Suzuki, H .,
more severely diseased segment of an artery. Once in the Sawada , M .,Moriya, M ., Sakamoto , W ., and Yogo , T. 2010 .
bloodstream , the nanoparticle carrier ferrobound drug “ High -frequency, Magnetic - field -Responsive Drug Release
moves until it reaches the segment that has the magnetized from Magnetic Nanoparticle /Organic Hybrid Based on
miniballs, stays, impasse -jackets, stent- jackets , or magnet Hyperthermic Effect,” American Chemical Society Applied
wrap . To define a segment, the implants are arranged along Materials and Interfaces 2 (7 ): 1903 - 1911; Richter, H ., Ket
that segment or if the lesion is eccentric , then according to tering, M ., Wiekhorst, F ., Steinhoff, U ., Hilger, I., and
the eccentricity , in order of increased strength of magneti Trahms, L . 2010 . “Magnetorelaxometry for Localization
zation in the antegrade direction . and Quantification of Magnetic Nanoparticles for Thermal
[0637] A more even distribution of the drug is also Ablation Studies,” Physics in Medicine and Biology 55 (3 ) :
obtained when the drug carrier is likewise graduated in 623 -633 ; Hilger, I., Hiergeist, R ., Hergt, R ., Winnefeld , K .,
magnetic susceptibility . The carrier -bound drug is then Schubert, H ., and Kaiser, W . A . 2002 . “ Thermal Ablation of
drawn from the passing blood into the wall surrounding the Tumors Using Magnetic Nanoparticles : an in Vivo Feasi
segment defined for treatment. Any residue, indeed , the bility Study,” Investigative Radiology 37 ( 10 ):580- 586 ;
entire dose , of any conventional drug that continues past the Babincová , M ., Cicmanec, P Altanerová , V ., Altaner, C ., and
target segment, even though concentrated for the segment, Babinec , P. 2002 . “ AC -magnetic Field Controlled Drug
will be so diluted as rarely if ever pose a risk of unwanted Release from Magnetoliposomes: Design of a Method for
side effects . The addition of a terminal or exit impasse - jacket Site- specific Chemotherapy,” Bioelectrochemistry 55 ( 1- 2 ):
(exit - jacket) allows the release of a reversal agent to coun 17 - 19 ).
teract a drug so toxic or radioactive that even the diluted [0641] Any of the implants and means for implanting
residue might do harm . Such a drug will usually be an these described herein can be used for magnetic hyperther
anticancer chemotherapeutic, but might also be a drug mia apart from the flowing of any outer layers. Several
needed to treat a localized nematodiasistic , protozoan , methods for the release on command of drugs previously
mycotic , or other infection that is resistant to conventional implanted exist. Where the inclusion within the implants of
therapy , for example . An exit jacket is placed and charged or ferromagnetic material precludes the use of magnetic force
loaded with the reversal agent or counteractant first. with distinctions in field strength as would allow either
[ 0638 ] Since any local point of release or reversal can be retrieval of the intact implant or the release of a drug from
initially or subsequently affected through the application of within it , externally applied heating such as with ultrasound
heat, irreversible electroporation , or by administering other can be used to effect the release of therapeutic agents on a
substances , the possibilities comprehended are too numer selective basis ( see , for example , Frenkel, V . 2008 . “ Ultra
ous to enumerate in any detail. For example, different sound Mediated Delivery of Drugs and Genes to Solid
melting points or fracture resistances to a magnetic field of Tumors,” Advanced Drug Delivery Reviews 60 ( 10 ):1193
the superparamagnetic magnetite or maghemite nanopar 1208 ; Dromi, S ., Frenkel, V ., Luk, A ., Traughber, B ., Ang
ticles or finely grained powder-including encapsulating layer stadt, M ., and 6 others 2007 . “ Pulsed -high Intensity Focused
can be used to cause a prepositioned implant to release a Ultrasound and Low Temperature - Sensitive Liposomes for
US 2019 /0247050 A1 Aug . 15 , 2019
53

Enhanced Targeted Drug Delivery and Antitumor Effect,” reducing the cost of treatment. Whether due to disease or
Clinical Cancer Research 13 (9 ):2722- 2727 ; Iga , K ., Ogawa, normal function, where the luminal contents are infectious
Y ., and Toguchi, H . 1992 . “ Heat- induced Drug Release Rate or septic , stays , described below , which are inserted from
and Maximal Targeting Index of Thermosensitive Liposome outside the ductus , are used .
in Tumor-bearing Mice,” Pharmaceutical Research 9 (5 ) : [0646 ] Proangioangenic , neurogenic , and antineuropathic
658-662 ). drugs with wide application for promoting healing willmore
[0642 ] Release triggering also includes activation follow often be associated with absorbable implants that consist
ing placement using ultrasound ( see , for example , solely of medication . Growth trajectory -determining pro
Tachibana, K ., Feril, L . B . Jr., and Ikeda -Dantsuji, Y . 2008. teins have both mitogenic and mitoinhibitory potential (see ,
" Sonodynamic Therapy," Ultrasonics 48 (4 ):253 -259 ; for example, Wilson , B . D ., M ., Park , K . W ., Suli , A .,
Staples, M ., Daniel, K ., Cima, M . J., and Langer, R . 2006 . Sorensen , L . K ., and 11 other authors , 2006 . " Netrins
“ Application of Micro - and Nano -electromechanical Promote Developmental and Therapeutic Angiogenesis ,"
Devices to Drug Delivery,” Pharmaceutical Research 23 ( 5 ): Science 313 (5787 ):640 -644 ; Park , K . W ., Crouse , D ., Lee ,
847 - 863; Liu , Y ., Miyoshi, H ., and Nakamura , M . 2006 . M ., Karnik , S . K ., Sorensen , L . K ., Murphy, K . J., Kuo , C .
“ Encapsulated Ultrasound Microbubbles : Therapeutic J., and Li, D . Y. 2004 . “ The Axonal Attractant Netrin - 1 is an
Application in Drug /Gene Delivery,” Journal of Controlled Angiogenic Factor,” Proceedings of the National Academy
Release 114 ( 1):89- 99 , Tachibana , K . 2004 .“ Emerging Tech of Sciences of the United States of America 101( 46 ): 16210
nologies in Therapeutic Ultrasound : Thermal Ablation to 16215 ). Local or short path targeting, that is, placement of
Gene Delivery ,” Human Cell 17 ( 1 ):7 -15 ; Unger, E . C ., the implant within or adjacent to the lesion , of oncolytic
Hersh , E ., Vannan , M ., Matsunaga , T. O ., and McCreery , T. viruses (see, for example, Kinoh , H . and Inoue, M . 2008 .
2001 . “ Local Drug and Gene Delivery through “New Cancer Therapy Using Genetically - engineered Onco
Microbubbles,” Progress in Cardiovascular Diseases 44 ( 1 ): lytic Sendai Virus Vector,” Frontiers in Bioscience 13 : 2327
45 - 54 ; Tachibana , K . and Tachibana , S . 1998 . “ Application 2334 ; Davydova , J., Le, L . P ., Gavrikova , T ., Wang, M .,
of Ultrasound Energy as a New Drug Delivery System ,” ( in Krasnykh , V ., and Yamamoto , M . 2004 . " Infectivity - en
Japanese with abstract in English at Pubmed ), Nippon hanced Cyclooxygenase -2 -based Conditionally Replicative
Rinsho [ Japanese Journal of Clinical Medicine ] 56 (3 ):584 Adenoviruses for Esophageal Adenocarcinoma Treatment,"
588). Cancer Research 64 ( 12 ): 4319 - 4327 ) avoids systemic dis
[0643] As with photosensitizer inclusive protein solder, persion , concentrates a small dose in the target tissue,
where adequate absorption can be achieved , a combination minimizes the action onset interval, or delay before the agent
form barrel-assembly or radial projection catheter with a takes effect, reduces systemic dispersal, and therefore the
fiberoptic endoscope, angioscope , or laser can be used to likelihood of unwanted side -effects .
activate a photosensitive ingredient (see , for example , [0647 ] The number of implants used is one factor in
Cheng, F . Y., Su , C . H ., Wu, P . C ., and Yeh , C . S . 2010 . determining the local dosage . Once expended , drug -contain
“Multifunctional Polymeric Nanoparticles for Combined ing miniballs and stays are fully absorbed and left in place ,
Chemotherapeutic and Near-infrared Photothermal Cancer superparamagnetic magnetite or maghemite nanoparticles or
Therapy in Vitro and in Vivo ," Chemical Communications finely grained powder included to allow recovery if neces
46 ( 18 ):3167-3169) . sary likewise dissipated . Targeted administration should
[0644 ] 46 (2 ). Local Release of Drugs by Miniballs and reduce the neovascularization already undergone as an
Stays inherent result of the disease process and any interventional
[ 0645 ] Antiangiogenic drugs such as interferon alpha , measures, and where applicable, to counteract the effect of
antiangiogenic antithrombin , angiostatin , endostatin , vascu more widely dispersed angiogenic medication . The other
lostatin , and so on , have two distinct applications in con application of antiangiogenic drugs is as a coating on
nection with the implants to be described herein . The first is ferromagnetic miniballs and stays for reducing any neovas
for incorporation into or the coating ofminiballs and stays cularization following placement of a stent- jacket. The cita
for subadventitial implantation at the site of an atheromatous tion of statins herein as affording benefits when locally
plaque or tumor for the purpose of inhibiting neovascular targeted to avoid the liver and systemic circulation is exem
ization of the vasa vasorum . The systemic administration of plary of innumerable other drugs administered to smaller
such drugs typically covers a period of months , its timing a populations. Due to the size of the population prescribed
central consideration ( see, for example , Duda, D . G . 2007 . statins, the incidence of side effects in absolute numbers is
" American Association for Cancer Research 98th Annual considerable despite relatively infrequent occurrence by
Meeting. Angiogenesis and Anti- angiogenesis in Cancer," percent.
IDrugs 10 (6 ):366 - 369; Goh , P. P., Sze , D . M ., and Roufo [0648 ] Drugs cited as specifically antiatherogenic in col
galis, B . D . 2007. “ Molecular and Cellular Regulators of lared hypercholesterolemic rabbits include isradipine and
Cancer Angiogenesis,” Current Cancer Drug Targets 7 (8 ): lacidipine (Donetti, E ., Fumagalli , R ., Paoletti , R ., and
743- 758 ; van Kempen , L . C . and Leenders , W . P. 2006 . Soma, M . R . 1997 . “ Direct Antiatherogenic Activity of
“ Tumours Can Adapt to Anti-angiogenic Therapy Depend Isradipine and Lacidipine on Neointimal Lesions Induced by
ing on the Stromal Context: Lessons from Endothelial Cell Perivascular Manipulation in Rabbits,” Pharmacological
Biology,” European Journal of Cell Biology 85 (2 ):61-68 ; Research 35 (5 ) :417 -422 ), bosentan (Marano , G ., Palazzesi,
Novak , K . 2002 . “ Angiogenesis Inhibitors Revised and S ., Bernucci, P ., Grigioni, M ., Formigari , R ., and Ballerini,
Revived at the AACR ” [American Association for Cancer L . 1998 . “ ET (A )/ET(B ) Receptor Antagonist Bosentan
Research ], Nature Medicine 8 (5 ):427). The controlled Inhibits Neointimal Development in Collared Carotid Arter
release ofsuch agents close to or at the site of the lesion with ies of Rabbits,” Life Sciences 63 ( 18 ):PL259- 266 , TAK - 044 ;
focal concentration should allow the use of much less of the Reel, B ., Ozkal, S ., Islekel, H ., Ozer, E ., Oktay G , and five
agent relative to body mass ,minimizing any side effects and other authors, 2005 . “ The Role of Endothelin Receptor
US 2019 /0247050 A1 Aug. 15 , 2019
54

Antagonism in Collar- induced Intimal Thickening and Vas Atherosclerosis Reports 11(1 ) :58 -63 ; Puranik , R ., Bao , S .,
cular Reactivity Changes in Rabbits,” Journal of Pharmacy Nobecourt, E ., Nicholls , S . J., Dusting, G . J., Barter, P. J.,
and Pharmacology 57 ( 12 ): 1599 - 1608 ), the selective estro Celermajer, D . S ., and Rye , K . A . 2008 . “ Low Dose Apo
gen receptor modulator raloxifene (Bellosta , S ., Baetta , R ., lipoprotein A -I Rescues Carotid Arteries from Inflammation
Canavesi, M ., Comparato , C ., and 6 others, 2007. “Ralox in Vivo ," Atherosclerosis 196 ( 1 ):240 - 247; Nicholls, S . J.,
ifene Inhibits Matrix Metalloproteinases Expression and Dusting, G . J., Cutri, B ., Bao , S ., Drummond , G . R ., Rye , K .
Activity in Macrophages and Smooth Muscle Cells,” Phar A ., Barter, P . J. 2005. “ Reconstituted High - density Lipopro
macological Research 56 ( 2 ): 160 - 167 ) , and lercanidipine teins Inhibit the Acute Pro -oxidant and Proinflammatory
(Soma, M . R ., Natali , M ., Donetti, E ., Baetta, R ., and five Vascular Changes Induced by a Periarterial Collar in Nor
other authors, 1998 . “ Effect of Lercanidipine and Its ( R ) mocholesterolemic Rabbits,” Circulation 111 ( 12 ): 1543
enantiomer on Atherosclerotic Lesions Induced in Hyperc 1550 ).
holesterolemic Rabbits ,” British Journal of Pharmacology [0651] The efficacy of lipoprotein A - 1 for reversing ath
1998 125 (7 ): 1471- 1476 ). erosclerosis in man has not been established . As an alterna
[0649 ] Drugs that have been cited as inhibiting atherogen tive to transluminal approach , whereby miniballs are
esis include, among others, bevacizumab ( Stefanadis, C ., implanted ballistically from within the lumen producing
Toutouzas, K ., Stefanadi, E ., Tsiamis , E ., Vavuranakis, M ., minute puncture and trajectory wounds impelling the use of
and Kipshidze , N . 2008 . “ Avastin - eluting Stent: Long -term antiplatelet medication, when the lumen would best be
Angiographic and Clinical Follow -up ,” Hellenic Journal of avoided entirely, speed is not critical, and the anatomy and
Cardiology 49( 3 ): 188 - 90 ), statins (Moulton , K . S ., Heller, apparatus permit, stays are implanted by extraductal
E ., Konerding, M . A ., Flynn , E ., Palinski, W ., and Folkman , approach . Miniballs can , however, include antithrombo
J. 1999. Angiogenesis Inhibitors Endostatin or TNP -470 genic medication , usually as an outer coating .
Reduce Intimal Neovascularization and Plaque Growth in [0652 ] Other substances proposed for the prevention and
Apolipoprotein E - deficientMice,” Circulation 99 ( 13 ): 1726 possible treatment of atherosclerosis as can be mediated by
1732 ; Wilson, S . H ., Herrmann , J., Lerman , L . O ., Holmes, segment or organ delivery by impasse -jackets in concen
D . R . Jr., Napoli , C ., Ritman , E . L ., and Lerman , A . 2002. trated and replenishable dosage within circumscribed sites
“ Simvastatin Preserves the Structure of Coronary Adventi averting side effects include , among others, lacidipene
tial Vasa Vasorum in Experimental Hypercholesterolemia (Soma, M . R ., Donetti, E ., Seregni, R ., Barberi, L ., Fuma
Independent of Lipid Lowering,” Circulation 105 ( 4 ):415 galli , R ., Paoletti, R ., and Catapano , A . L . 1996 . “ Effect of
418 ; Baetta , R ., Camera , M ., Comparato , C ., Altana , C ., Lacidipine on Fatty and Proliferative Lesions Induced in
Ezekowitz , M . D ., and Tremoli, E . 2002 . “ Fluvastatin Hypercholesterolaemic Rabbits ," British Journal of Phar
Reduces Tissue Factor Expression and Macrophage Accu macology 118 ( 2 ):215 - 219 ) isradipine (Donetti, E . et al. op
mulation in Carotid Lesions of Cholesterol-Fed Rabbits in cit. 1997 ) , lercanidipine (Soma, M . R ., et al. op cit. 1998 ),
the Absence of Lipid Lowering,” Arteriosclerosis, Throm carvedilol (Wu, T. C ., Chen , Y . H ., Leu, H . B ., Chen , Y . L .,
bosis , and Vascular Biology 1 ;22( 4 ):692 -698 ) the anti- in - Lin , F . Y ., Lin , S . J., and Chen , J. W . 2007. “ Carvedilol, A
flammatory dexamethazone (Hagihara et al. 1991 , cited Pharmacological Antioxidant, Inhibits Neointimal Matrix
above ) , antioxidants (see , for example , Wu, T . C ., Chen , Y . Metalloproteinase - 2 and - 9 in Experimental Atherosclero
H ., Leu , H . B ., Chen , Y. L ., Lin , F . Y ., Lin , S . J., and Chen , sis ," Free Radical Biology and Medicine 43 ( 11 ): 1508
J. W . 2007 . “ Carvedilol, a Pharmacological Antioxidant, 1522), probucol (Donetti , E ., Soma, M . R ., Barberi, L .,
Inhibits Neointimal Matrix Metalloproteinase - 2 and -9 in Paoletti, R ., Fumagalli , R ., Roma, P., and Catapano, A . L .
Experimental Atherosclerosis ," Free Radical Biology and 1998 . “ Dual Effects of the Antioxidant Agents Probucol and
Medicine 43 ( 11): 1508 - 1522 ), and /or estrogen (see Akishita, Carvedilol on Proliferative and Fatty Lesions in Hypercho
M ., Ouchi, Y ., Miyoshi, H ., Kozaki, K ., Inoue , S ., Ishikawa, lesterolemic Rabbits,” Atherosclerosis 141( 1 ):45 -51;
M ., Eto , M ., Toba, K ., and Orimo, H . 1997 . " Estrogen Kuzuya , M . and Kuzuya , F. 1993 . “ Probucol as An Anti
Inhibits Cuff- induced Intimal Thickening of Rat Femoral oxidant and Antiatherogenic Drug ," Free Radical Biology
Artery : Effects on Migration and Proliferation of Vascular and Medicine 14 ( 1 ):67- 77 ), BO -653 (2 ,3 - dihydro -5 -hy
Smooth Muscle Cells," Atherosclerosis 130 ( 1 -2 ):1 - 10 ). droxy -2 ,2 -dipentyl-4 ,6 -di-tert -butylbenzofuran ) (Cynshi O ,
Drug miniballs and stays can release drugs in situ and Kawabe Y , Suzuki T , Takashima Y , Kaise H , Nakamura M ,
magnetized ones and impasse - jackets can be used to draw and 12 others 1998 . “ Antiatherogenic Effects of the Anti
magnetized carrier -bound drugs from the passing blood . oxidant BO -653 in Three Different Animal Models ,” Pro
[ 0650 ] Selective Inhibitors of Protein Kinase C may be ceedings of the National Academy of Sciences of the United
used to inhibit the proliferation of smooth muscle cells (see , States of America 95 ( 17 ):10123 - 10128 ), and gene transfer
for example, Tardif, J. C . 2010 . “ Emerging High -density administered interleukin 10 ( von der Thüsen , J. H ., Kuiper,
Lipoprotein Infusion Therapies : Fulfilling the Promise of J., Fekkes , M . L ., de Vos, P ., van Berkel, T. J., and Biessen ,
Epidemiology ?,” Journal of Clinical Lipidology 4 (5 ):399 E . A . 2001. “ Attenuation of Atherogenesis by Systemic and
404 ; Newby, A . C ., Lim , K ., Evans, M . A ., Brindle, N . P. J., Local Adenovirus -mediated Gene Transfer of Interleukin - 10
and Booth , R . F . G . 1995 . “ Inhibition of Rabbit Aortic in LDLr- /- Mice,” Federation of American Societies for
Smooth Muscle Cell Proliferation by Selective Inhibitors of Experimental Biology Journal 15 ( 14 ):2730 - 2732).
Protein Kinase C ,” British Journal of Pharmacology 114 [0653] 46 (3 ). Use of Drug-Releasing Ductus-Intramural
( 8 ): 1652 - 1656 ). More recently , apolipoprotein A - 1 in a Implants to Locally Counteract or Reinforce Angiogenic or
single low dose has been cited as inhibiting acute common Other Systemic Medication
carotid artery inflammation in normocholesterolemic Dow [0654] The reciprocal use of drugs that are released from
Corning Silastic® collared rabbits (see , for example , Tardif, tiny miniball or stay conformed implants at fixed sites to
J . C ., Heinonen , T ., and Noble , S . 2009. “ High - density locally inhibit or counteract the action of an injected or
Lpoprotein / Apolipoprotein A -I Infusion Therapy,” Current intravenously infused drug that diffuses through the region
US 2019 /0247050 A1 Aug. 15 , 2019
55

has no less potential. As with any medication or combination 2002. “ Clinical Trials of Gene Therapy for Atherosclerotic
thereof, the miniballs or stays can be open or closed -loop Cardiovascular Disease ,” Current Opinion in Lipidology
sources . The focused use of counteractants or inhibitors to 13 (6 ): 653 -661).
blank out or exclude a delimited site has numerous potential 10658 ] Generally, the ability to block out a circumscribed
applications. For example , atherogenesis involves the elabo segment of a vessel wall from uptake of a regionally diffused
ration of the vasa vasorum with the proliferation ofmicrove drug has numerous potential applications in the gastrointes
ssels into the plaque for commensurate perfusion and drain tinal tract and airway as well as in the vascular tree. In
age as a plaque continues to develop. bypass graft vessels, for example, placing angiogenic agent
[ 0655 ] Any substance in liquid or semiliquid form can also time- releasing implants at the anastomoses can encourage
be introduced at a preferred temperature into the lumen by revascularization of the graft or grafts while other implants
side-looking ejection syringes , or ejectors, or into the lumen that release antiangiogenic agents prevent neovasculariza
wall by side - looking injection syringes , or radial projection tion of the vasa vasorum of nonoperated arteries (see , for
unit tool -insert injectors , whether electrical/ fluid system example , George , S . J., Channon , K . M ., and Baker, A . H .
neutral or operated fluidically , as addressed below in the 2006 . “ Gene Therapy and Coronary Artery Bypass Grafting :
section entitled Radial Projection Units. These disease pro Current Perspectives,” Current Opinion in Molecular
cess generated microvessels tend to be weak and probably Therapeutics 8 ( 4 ): 288 - 294 ). Similarly , in hybrid revascular
render the plaque more readily susceptible to rupture or ization combining bypass surgery with angioplasty ( see , for
erosion . The rupture or erosion of such a vulnerable or example, Byrne, J. G ., Leacche , M ., Vaughan , D . E ., and
unstable plaque produces a breach in the intima that prompts Zhao , D . X . 2008 . “ Hybrid Cardiovascular Procedures,”
the formation of a thrombus , which if not the direct cause, Journal of the American College of Cardiology Cardiovas
can nevertheless precipitate an acute cardiac event, most cular Interventions 1 (5 ):459 - 468 ) where the use of endothe
often through the release of embolizing debris ( see , for lial growth factor is favorable for the bypass but not for the
example, Frink , R . J., Trowbridge , J. O ., and Rooney, P. A . balloon dilation - stressed or stretched artery , the ability to
Jr. 1978 . “Nonobstructive Coronary Thrombosis in Sudden differentially suppress neovascularization of the vessel
Cardiac Death ,” American Journal of Cardiology 42 ( 1):48 plaque vasa vasora is advantageous .
51). [0659 ] Implanted perpendicularly to the longitudinal axis
of the ductus , stays do not interfere with smooth muscle
[ 0656 ] Thus, in direct intramyocardial injection of an function , and nonabsorbed drug -releasing stays with a
angiogenic agent such as vascular endothelial growth factor deeply textured surface become integrated so as never to
or its genetic precursor (see , for example, Kleiman , N . S ., require recovery once the medication has been expended .
Patel , N . C ., Allen , K . B ., Simons, M ., Ylä -Herttuala, S ., Miniballs of like function could also remain . Unlike radia
Griffin , E ., and Dzau , V. J. 2003 . “ Evolving Revasculariza tion seeds, which left in place , are limited to low dose - rates
tion Approaches for Myocardial Ischemia,” American Jour or radionuclides (radioisotopes ) of short half-life such as
nal of Cardiology 92( 9B ) :9N - 17N ) to encourage the devel Xenon - 133 (see , for example, Sekine , T., Watanabe, S ., Osa ,
opment of collateral circulation , the ability to place implants A ., Ishioka , N ., and nine other inventors , 2001. “ Xenon - 133
that release antiangiogenic medication ductus -intramurally, Radioactive Stent for Preventing Restenosis of Blood Ves
that is, within the wall of an atherosclerosed coronary artery sels and a Process for Producing the Same," U . S . Pat. No .
situated at the vulnerable or unstable plaque , makes it 6 , 192,095 ), ductus - intramurally placed stays and miniballs
possible to suppress the concomitant neovascularization of are practicably recoverable and thus usable for delivering
the vasa vasorum . The coexpression of a counteractant to medication or radiation in higher doses for a limited period .
exclude certain targets from reaction is exhibited by malig In more advanced disease , external beam radiation may be
nant tumors , which release antiangiogenic factors that sup essential to supplement the radiation provided by seeds. In
press the growth of metastases while releasing vascular the irradiaton intervening tissue, this negates the key benefit
endothelial growth factor to stimulate the proximate forma in the use of seeds over external irradiaton or delivery
tion of vessels essential for the primary tumor to expand . through the systemic circulation by infusion or ingestion .
[ 0657 ] The ability to differentially eliminate a response of [0660] In transmyocardial laser revascularization (see , for
plaque vasa vasora to angiogenetic agents administered to example , Bhimji, S . 2006 . “ Transmyocardial Laser Revas
treat vascular disease by blocking out local areas has poten cularization ," eMedicine ) performed in conjunction with
tial value even where surgery is uninvolved ( see , for coronary artery bypass surgery (see , for example , Allen , K .
example , Ylä -Herttuala , S . and Baker, A . H . 2017. “ Cardio B ., Kelly , J., Borkon , A . M ., Stuart , R . S ., Daon , E ., Pak , A .
vascular Gene Therapy : Past, Present, and Future ,” Molecu - F ., Zorn , G . L ., and Haines, M . 2008. “ Transmyocardial
lar Therapy 25 (5 ):1095 - 1106 ; Stewart, D . J., Hilton , J. D ., Laser Revascularization : From Randomized Trials to Clini
Arnold , J. M ., Gregoire , J., and sixteen other authors 2006 . cal Practice . A Review of Techniques, Evidence -based Out
“ Angiogenic Gene Therapy in Patients with Nonrevascular comes , and Future Directions," Anesthesiology Clinics
izable Ischemic Heart Disease : A Phase 2 Randomized , 26 ( 3 ):501-519 ; Atluri, P ., Panlilio , C . M ., Liao , G . P ., Suarez
Controlled Trial of AdVEGF (121) (AdVEGF121 ) [ vascular E E , and seven other authors, 2008 . “ Transmyocardial
endothelial growth factor delivered in adenovirus ] Versus Revascularization to Enhance Myocardial Vasculogenesis
Maximum Medical Treatment,” Gene Therapy 13 (21): 1503 and Hemodynamic Function ,” Journal of Thoracic and
1511; Penny , W . F . and Hammond , H . K . 2004 . “ Clinical Cardiovascular Surgery 135 (2 ):283 -291 ; Horvath , K . A .
Use of Intracoronary Gene Transfer of Fibroblast Growth 2008 . “ Transmyocardial Laser Revascularization ,” Journal
Factor for Coronary Artery Disease ," Current Gene Therapy of Cardiac Surgery 23 ( 3 ): 266 - 276 ; Spiegelstein , D ., Kim ,
4 ( 2 ): 225 -230 ; Mukherjee , D . 2004 . " Current Clinical Per C ., Zhang , Y ., Li, G ., Weisel, R . D ., Li, R . K ., and Yau , T .
spectives on Myocardial Angiogenesis ,” Molecular and M . 2007. “ Combined Transmyocardial Revascularization
Cellular Biochemistry 264( 1 -2 ): 157 - 167 ; Freedman , S . B . and Cell-based Angiogenic Gene Therapy Increases Trans
US 2019 /0247050 A1 Aug. 15 , 2019
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planted Cell Survival,” American Journal of Physiology. or urine, for example, and draw the drug abaxially through
Heart and Circulatory Physiology 293 (6 ):H3311 -H3316 ); the lumen wall into the lesion (see, for example , Alexiou , C .,
Horvath , K . A ., Lu, C . Y ., Robert, E ., Pierce , G . F ., Greene , Jurgons, R ., Schmid , R . J., Bergemann , C ., Henke, J., and 3
R ., Sosnowski, B . A ., and Doukas , J . 2005 . " Improvement of others, 2003 . “ Magnetic Drug Targeting - Biodistribution of
Myocardial Contractility in a Porcine Model of Chronic the Magnetic Carrier and the Chemotherapeutic Agent
Ischemia Using a Combined Transmyocardial Revascular Mitoxantrone after Locoregional Cancer Treatment,” Jour
ization and Gene Therapy Approach ,” Journal of Thoracic nal of Drug Targeting 11 (3 ):139- 149; Alexiou, C ., Schmid ,
and Cardiovascular Surgery 129( 5 ): 1071- 1077 ; Heilmann , R . J., Jurgons, R ., Bergemann , C ., Arnold , W ., and Parak , F .
C . A ., Attmann, T., von Samson , P ., Göbel, H .,Marmé, D ., G . 2003. “ Targeted Tumor Therapy with ‘Magnetic Drug
Beyersdorf, F ., and Lutter, G . 2003 . “ Transmyocardial Laser Targeting:' Therapeutic Efficacy of Ferrofluid Bound Mitox
Revascularization Combined with Vascular Endothelial antrone,” in Odenbach , S . ( ed .), Ferrofluids: Magnetically
Growth Factor 121 (VEGF121) Gene Therapy for Chronic Controllable Fluids and their Applications, Lecture Notes in
Myocardial Ischemia — Do the Effects Really Add Up ?,” Physics 594 :233 - 251; Lübbe, A . S ., Alexiou , C ., and Berge
European Journal of Cardiothoracic Surgery 23 ( 1 ):74 -80 ), mann , C . 2001. " Clinical Applications of Magnetic Drug
for example , the direct, nondiffuse , fully contained or cir Targeting ,” Journal of Surgical Research 95 (2 ):200 -206 ;
cumscribed if not time- released introduction of an angio Alexiou , C ., Arnold , W ., Klein , R . J., Parak , F . G ., Hulin , P.,
genic agent such as matrix metalloproteinase- 9 ( Johnson , C ., and 4 others , 2000 . “ Locoregional Cancer Treatment with
Sung, H . J., Lessner, S . M ., Fini, M . E ., and Galis , Z . S . Magnetic Drug Targeting,” Cancer Research 60 (23 ) :6641
2004. “Matrix Metalloproteinase - 9 is Required for Adequate 6648 ; Deleporte , A ., Flamen , P., and Hendlisz , A . 2010 .
Angiogenic Revascularization of Ischemic Tissues: Poten “ State of the Art: Radiolabeled Microspheres Treatment for
tial Role in Capillary Branching,” Circulation Research Liver Malignancies,” Expert Opinion on Pharmacotherapy
94 ( 2 ): 262 - 268 ) into the myocardium overlooking the left 11 ( 4 ):579 -586 ; Vente , M . A ., Hobbelink, M . G ., van Het
ventricle would further encourage the formation of capillar Schip , A . D ., Zonnenberg , B . A ., and Nijsen , J. F . 2007 .
ies about the lased channels and at the ends of the anasto “ Radionuclide Liver Cancer Therapies: From Concept to
moses . Current Clinical Status,” Anticancer Agents in Medicinal
[0661] Then diffusion to the vasa vasorum of the left Chemistry 7 (4 ) :441 -459).
anterior descending coronary artery, for example (whether [ 0665 ] Medication miniballs and stays can thus release
untreated, angioplastied , or stented ), would be avoided ; medication within the implanted tissue or when suspended
however , continued administration of angiogenic agents within an impasse -jacket, as addressed below in the section
could be systemic , and if so , likely to encourage further entitled Concept of the Impasse - jacket, or within a magnet
harmful expansion of the vasa vasorum supplying the wrap , addressed below in the section entitled Concept of the
plaques of the ungrafted , unaffected , or angioplastied arter magnet -wrap , or a stent - jacket, and highly magnetized mini
ies . The graft itself will most likely be an internal thoracic balls and stays can be used to attact drugs bound to or with
artery , which little dependent upon a vasa vasorum , should magnetically susceptible carriers . The use of magnetized
not require antiangiogenic implants . In this situation , the ductus -intramural implants to define a segment of a ductus
ability to inhibit an angiogenic response locally within the for delivery of a drug or drugs is the same as described
walls of the coronary arteries by prepositioning artery below for impasse - jackets in the section entitled Coopera
intramural implants releasing angiogenic agent inhibitor at tive Use of Impasse -jackets in Pairs and Gradient Arrays and
the sites of the vasa vasora would assist to truncate contin same for magnet-wraps, which are limited to large ductus.
ued atheromatous lesioning . [0666 ] The drawing from the circulation of magnetically
[ 0662] If the nongrafted arteries had been angioplastied , susceptible drug carrier nanoparticles by a stent- or impasse
then this procedure may itself have promoted vasal neovas jacket , for example , can be used to deliver a drug into the
cularization . Were a means found for causing the channels to adluminal lesion or simply to prevent the drug from con
remain patent (see , for example , Krabatsch , T., Schäper, F ., tinued travel through the circulation . Interception of a drug
Leder, C ., Tülsner, J., Thalmann , U ., and Hetzer, R . 1996 . before reaching the liver or another structure or organ is one
“ Histological Findings after Transmyocardial Laser Revas approach to minimizing adverse drug interactions . As
cularization ,” Journal of Cardiac Surgery 11 (5 ):326 - 331) if addressed below in the section entitled Cooperative Use of
not expand into sinuses as earlier postulated , then the Impasse - jackets in Pairs and Gradient Arrays , whether
epithelialization of the sinuses would likely serve more through miniball or stay insertion , lumen segment specifi
functional perfusion . Then artery - intramural antiangiogenic cation , or magnetic , drug -targeting allows the focused deliv
implants at the sites or potential sites of plaques would serve ery of medication into a lesion that if circulated would
to counteract the angiogenic agent or agents while angio indiscrimately disperse the drug throughout the entire body,
genic agent releasing implants at the anastomoses of the allow it to interact with other drugs and food , in all cases
graft or grafts would allow local zones of reinforcement to increasing the risks for producing adverse side -effects.
the angiogenic agent or agents injected or infused to pro [0667] With a systemic condition such as atherosclerosis
mote revascularization . where certain segments are accutely affected , a statin is both
[ 0663] 46 (4 ). System Implant Magnetic Drug and Radia circulated and concentrated in the lesions by binding only a
tion Targeting fraction of the dose to magnetic dose carrier nanoparticles .
[0664 ] Whether additionally coated with medication or Situating progressively more strongly magnetized jackets
radioactive, for example,magnetized miniballs, stays, clasp proximadistad , or in order of increasing strength along the
jackets , and all stent-jackets , impasse -jackets , and magnet- bloodstream , some of the drug is delivered to each jacket . In
jackets can be used to concentrate a drug carrier particle or this way, the magnetic field strength of any jacket is kept
nanoparticle - bound drug and/or radionuclide passing beneath the value that would cause the lumen to become
through the circulation , food or chyme bolus, gland exudate , clogged . Equally contributing to differential delivery when
US 2019 /0247050 A1 Aug. 15 , 2019
57

necessary, the drug carrier particles consist of a mixture of J. A . 2007. “ In Vitro Study of Ferromagnetic Stents for
separately preprared portions or fractions, each differing in Implant Assisted -magnetic Drug - targeting,” Journal of
its magnetically susceptible content. Magnetism and Magnetic Materials 311 (1):306 -311 , Pro
[0668 ] Magnetic marker monitoring (see , for example , ceedings of the Sixth International Conference on the Sci
Laulicht, B .,Gidmark , N . J., Tripathi, A ., and Mathiowitz , E . entific and Clinical Applications of Magnetic Carriers ).
2011 . “ Localization of Magnetic Pills,” Proceedings of the [ 0671 ] While entailing a minor surgical procedure, an
National Academy of Sciences of the United States of extraluminal magnetic stent or impasse-jacket as described
America 108(6 ):2252 -2257 Weitschies W , Blume H , Mön herein leaves the lumen clear, the stent not within the lumen
nikes H . 2010 . “ Magnetic Marker Monitoring: High Reso so that it attracts the drug carrier nanoparticle - bound drug to
lution Real- time Tracking of Oral Solid Dosage Forms in the itself but rather draws the drug into the lesion or neoplasm ,
Gastrointestinal Tract,” European Journal of Pharmaceutics and can usually occupy the spatial volume needed to bring
and Biopharmaceutics 74 ( 1 ): 93 - 101; Bergstrand, M ., Söder far greater local field intensity than the endoluminal space
lind , E ., Weitschies, W ., and Karlsson , M . O . 2009 . “ Mecha would allow (see , for example , Polyak , B . and Friedman , G .
nistic Modeling of a Magnetic Marker Monitoring Study 2009 . " Magnetic Targeting for Site -specific Drug Delivery :
Linking Gastrointestinal Tablet Transit, in Vivo Drug Applications and Clinical Potential,” Expert Opinion on
Release , and Pharmacokinetics," Clinical Pharmacology Drug Delivery 6 ( 1 ):53 -70, also cited above in the section
and Therapeutics 86 ( 1 ) :77 - 83 ; Corá , L . A ., Romeiro , F . G ., entitled Concept of the Impasse -jacket and that below
Américo , M . F., Oliveira , R . B ., Baffa , O ., Stelzer, M ., and entitled Interception and Recovery of a Miniball Entering
Miranda, J. R . 2006 . “ Gastrointestinal Transit and Disinte the Circulation ).
gration of Enteric Coated Magnetic Tablets Assessed by AC [0672] By comparison , an endoluminal paclitaxel eluting
Biosusceptometry ,” European Journal of Pharmaceutical stent allows the blood to wash away some of the drug. With
Sciences 27 ( 1 ): 1 - 8 ) makes it possible to identify the level or a magnetized implant such as an impasse - jacket, magnet
levels along the gastrointestinal tract for optimal absorption wrap , patch -magnet, or magnetized miniball, stay or array
ofmagnetic drug - targeting ferrofluid -bonded drugs (see , for thereof positioned to target the treatment site , ingestible
example , Saravanan , M ., Bhaskar, K ., Maharajan , G ., and drugs formulated for such use in the vascular tree will free
Pillai, K . S . 2011 . “Development of Gelatin Microspheres magnetic drug-targeting from the need for an external mag
Loaded with Diclofenac Sodium for Intra - articular Admin net or magnets and therewith , the clinic . Other routes for
istration ” Journal of Drug - targeting 19 (2 ):96 - 103 ). vascular or other system ductus delivery amenable to self
[0669 ] Optimization of these agents for absorption will admnistration are subcutaneously implanted direct and cen
make oral administration possible ( see , for example , Cai, Z ., tral catheter access injection and / or infusion portals . Then ,
Wang, Y ., Zhu, L . J., and Liu , Z . Q . 2010 . “Nanocarriers : A while to emplace a patch -magnet, stent-jacket, or impasse
General Strategy for Enhancement ofOral Bioavailability of jacket, for example , will involve a minor surgical procedure ,
Poorly Absorbed or Pre -systemically Metabolized Drugs ," once accomplished , it will be possible to administer a
Current Drug Metabolism 11 (2 ): 197 - 207 ; Yamanaka, Y . J . magnetically targetable drug by mouth that on circulating ,
and Leong, K . W . 2008. “ Engineering Strategies to Enhance will be drawn from the bloodstream to the lesion or neo
Nanoparticle -mediated Oral Delivery ,” Journal of Biomate plasm targeted .
rials Science. Polymer Edition 19 ( 12 ): 1549 - 1570 ; Florence , [0673 ] In single stage magnetic drug -targeting, a magne
A . T. 2004 . “ Issues in Oral Nanoparticle Drug Carrier tized collar such as a stent- or impasse -jacket is placed in
Uptake and Targeting,” Journal of Drug- targeting 12( 2 ):65 encircling relation to the segment of an artery to be treated ,
70 ; Florence , A . T. and Hussain , N . 2001. “ Transcytosis of for example . Since the jacket is placed circumadventitially,
Nanoparticle and Dendrimer Delivery Systems: Evolving it draws the ferromagnetic or superparamagnetic drug carrier
Vistas,” Advanced Drug Delivery Reviews 50 (Supplement nanoparticules , for example , into the lesion in the wall of the
1 ): 569-889; Florence , A . T. 1997. “ The Oral Absorption of artery , not to an in the way endoluminal stent. The latter
Micro - and Nanoparticulates : Neither Exceptional nor blocks the further passage of the drug into the lesion and is
Unusual,” Pharmaceutical Research 14 ( 3 ):259 - 266 ; too limited in available space to generate a high gradient
Thomas, N . W ., Jenkins, P. G ., Howard , K . A ., Smith , M . W ., local field .
Lavelle , E . C ., Holland, J., and Davis , S . S . 1996 . “ Particle [0674 ] In dual or 2 -stage magnetic drug -targeting as an
Uptake and Translocation across Epithelial Membranes ,” example of multistage magnetic drug-targeting, a first
Journal of Anatomy 189 (Part 3 ):487-490 ). extraluminal intrinsic motion compliant stent or impasse
[0670 ] Insertion of a magnetized endoluminal stent for the jacket assists to draw the orally administered drug with
purpose of targeting drug carrier particles into a lesion or carrier nanoparticles toward the villi of an optimal segment
neoplasm appears in the literature no later than 2004 (see , of the gastrointestinal tract for passage into the bloodstream
for example, Chen , H ., Ebner, A . D ., Rosengart, A . J., (see , for example , Cherry, E . M ., Maxim , P. G ., and Eaton ,
Kaminski M . D ., and Ritter, J. A . 2004 . " Analysis of J. K . 2010 . “ Particle Size , Magnetic Field , and Blood
Magnetic Drug Carrier Particle Capture by a Magnetizable Velocity Effects on Particle Retention in Magnetic Drug
Intravascular Stent: 1 . Parametric Study with Single Wire targeting,” Medical Physics 37( 1 ): 175 - 182 ; Shaw , S . and
Correlation ,” Journal of Magnetism and Magnetic Materials Murthy , P . V . S . N . 2010 . “Magnetic Drug -targeting in the
284: 181- 194 ; Chen , H ., Ebner, A . D ., Kaminski M . D ., Permeable Blood Vessel — The Effect of Blood Rheology,”
Rosengart, A . J., and Ritter, J. A . 2005. “ Analysis of Journal of Nanotechnology in Engineering and Medicine
Magnetic Drug Carrier Particle Capture by a Magnetizable 1 (2 ):021001-021012 ; Cheng, J., Teply , B . A ., Yoon Jeong,
Intravascular Stent: 2 : Parametric Study with Multi-wire S ., Yim , C . H ., Ho , D ., Sherifi, I., and 4 others, 2006 .
Two -dimensional Model,” Journal of Magnetism and Mag “Magnetically Responsive Polymeric Microparticles for
netic Materials 293 ( 1) : 616 -632 ; Avilés , M . O ., Chen , H ., Oral Delivery of Protein Drugs,” Pharmaceutical Research
Ebner, A . D ., Rosengart, A . J., Kaminski, M . D ., and Ritter, 23 (3 ):557 -564; des Rieux , A ., Fievez , V., Garinot, M .,
US 2019 /0247050 A1 Aug. 15 , 2019
58

Schneider, Y. J., and Préat, V . 2006 “Nanoparticles as bevacizumab to target endoglin , thereby to suppress angio
Potential Oral Delivery Systems of Proteins and Vaccines : A genesis in colon and lung cancer (Wood , L . M ., Pan , Z . K .,
Mechanistic Approach ,” Journal of Controlled Release 116 Guirnalda , P ., Tsai, P., Seavey , M ., and Paterson , Y . 2011.
( 1 ): 1 - 27 ; Ito , R ., Machida , Y ., Sannan , T., and Nagai, T . “ Targeting Tumor Vasculature with Novel Listeria -based
1990 . “ Magnetic Granules : A Novel System for Specific Vaccines Directed against CD105 ,” Cancer Immunolology
Drug Delivery to Esophageal Mucosa in Oral Administra and Immunotherapy 60 ( 7 ):931 - 942 ), and the use of Listeria
tion ,” International Journal of Pharmaceutics 61( 1- 2 ): 109 based vaccines to target breast cancer (Kim , S . H ., Castro , F .,
117 ) , and a second such implant placed about the target Paterson , Y ., and Gravekamp, C . 2009 . “ High Efficacy of a
segment along the ductus draws the nanoparticles into the Listeria -based Vaccine against Metastatic Breast Cancer
lesion or neoplasm . Reveals a Dual Mode of Action ,” Cancer Research 69( 14 )
[ 0675 ] The first implant does not allow passage through :5860 -5866 ).
the villi that the chemistry and shape of the nanoparticles [0679] That an impasse-jacket will stop any magnetically
would disallow or disfavor but rather accelerates the con susceptible matter regardless of its chemistry or physiologi
gregation over the villi surfaces of the particles and prevents cal association means that drugs and /or others pharmaceu
the loss of particles by continued passage through the ticals or therapeutic substances can be delivered to it in any
gastrointestinal tract . Similarly , a duct, artery, or vein of a combination in any sequence . Varying the susceptible con
gland or organ can be collared with an extraluminal mag tent of the miniball and/ or the strength of magnetization of
netic stent- jacket, impasse -jacket, or magnet-wrap (magnet successive impasse - jackets allows some measure of direc
jacket ) to target a hormone, enzyme, or the section associ tion to one of several impasse -jackets when present ; how
ated with that structure . The avoidance of clogging or ever , multiple jackets are reliably addressed by direct injec
embolization is achieved by administration in sub -embolic tion . Untilmeans for the oral administration of the substance
doses . Nonmetallic stent- jackets and impasse - jackets are or load intended for delivery to a given jacket are available ,
nonabsorbable ; limited -term administration of such medica Impasse - jackets used at the inlet and outlet of a luminal
tion may use an absorbable jacket as addressed below in the segment, organ , or gland that necessitate frequent dosing
sections on stent and impasse -jackets . will require a lead - in catheter with injection portal at the
[0676 ] Significantly, stent-jacket, impasse - jackets, and body surface . Application to the thyroid gland is briefly
magnet-jackets can all be used to draw and concentrate mentioned in the sections below entitled Stent- jackets and
magnetic drug carrier particles , which most often will be Stent-jacket Supportng Elements : Structural and Functional
moving through the blood vessel these encircle even though Considerations and Subcutaneous, Suprapleural, and Other
havng been implanted with no forethought as to such use . Organ -attachable Clasp - or Patch -magnets.
The multimodal potential offered by nanotubules, nanopar [0680 ] Radionuclide carrier nanoparticles or micro
ticles, and microspheres containing iron oxide or magneti spheres, for example , can be introduced by infusion or
cally susceptible metals (cobalt, iron , or cobalt- iron ) for injection upstream from a stent -, impasse -, magnet -jacket, or
concurrent nanoimaging , magnetic drug -targeting , and patch -magnet , for example, to be drawn from the passing
extracorporeal or remote heat induction applies to miniballs, blood up against and into the lesion . Clasp - or patch
stays, and the other implants described herein . Extracorpo magnets applied to the surface of an organ can be used to
real heatability in turn enables the release or accelerated draw drug carrier nanoparticles from the blood. This brute
release of a drug from a drug eluting or drug coated implant, force approach can be used to deliver antineoplastic drugs to
or accelerated uptake of a drug or increased rate of chemical the affected organ with or withoutmatter for concurrent or
action of a therapeutic substance in the tissue treated . subsequent radiofrequency hyperthermia or thermablation .
[ 0677] Heating a miniball or stay, for example , can be used This differs from the metabolic targeting of an organ to
to accelerate the denaturing of a proteinaceous coating such deliver radiofrequency heatable particles in necessitating a
as a tissue solder or the initial setting or curing of a surgical preliminary invasive procedure to place the magnetic
adhesive , for example . Miniballs can implant and radial implants , which can , however, be made to disintegrate
projection unit side - looking injection tool- inserts can inject without necessitating a second procedure to remove it .
medication ductus-intramurally independently of magnetic [ 0681 ] By comparison ,metabolic targeting is completely
force , and as addressed below in the section entitled Coop noninvasive , but dependent upon the development of sub
erative Use of Impasse - jackets in Pairs and Gradient Arrays , stances naturally drawn to the target organ (see , for example ,
impasse - jackets can be paired as entry and exit jackets to Kennedy , L . C ., Bickford , L . R ., Lewinski , N . A ., Coughlin ,
stipulate the starting and stopping points ( levels ) for expo A . J., Hu, Y ., Day, E . S., West, J. L ., and Drezek , R . A . 2011 .
sure of the lumen to a drug. These techniques allow the local " A New Era for Cancer Treatment: Gold -nanoparticle -me
release or the extraction and accumulation from the circu diated Thermal Therapies ," Small 7 ( 2 ): 169- 183 ; Cherukuri,
lation of a drug or drugs that if circulated would be toxic. P. and Curley, S . A . 2010 . “ Use of Nanoparticles for Tar
Statins are used as exemplary of closely targeted drug geted , Noninvasive Thermal Destruction of Malignant
delivery , because of the prevalence of arterial disease ; Cells,” Methods in Molecular Biology 624 : 359 - 373 ; Cheru
virtually every therapeutic substance poses a risk of kuri, P ., Glazer, E . S ., and Curley, S . A . 2010 . “ Targeted
unwanted side effects if allowed access to the tissue sus Hyperthermia Using Metal Nanoparticles,” Advanced Drug
ceptible thus. Delivery Reviews 62( 3 ): 339 - 345 ; Cardinal, J., Klune, J. R .,
[0678 ] Magnetic drug and/or radioisotope ( radionuclide ) Chory , E ., Jeyabalan , G ., Kanzius , J. S ., Nalesnik , M ., and
targeting can compensate for or eliminate the requirement Geller, D . A . 2008 . “ Non - invasive Radiofrequency Ablation
for the intrinsic affinity or normal uptake of the drug or of Cancer Targeted by Gold Nanoparticles ,” Surgery 144
therapeutic substance by the target organ or tissue such as (2 ): 125 - 132 ; Curley , S . A ., Cherukuri, P ., Briggs, K ., Patra ,
radiolabeled iodine by the thyroid gland. Other examples C . R ., Upton , M ., Dolson , E ., and Mukherjee , P . 2008 .
that might be cited are the systemic administration of “ Noninvasive Radiofrequency Field - induced Hyperthermic
US 2019 /0247050 A1 Aug. 15 , 2019
59
Cytotoxicity in Human Cancer Cells Using Cetuximab external ( extracorporeal) electromagnet to extract a trapped
targeted Gold Nanoparticles,” Journal of Experimental miniball or any magnetically susceptible residue . Where
Therapeutics and Oncology 7 (4 ):313 - 326 ; Gannon , C . J., circumductal space is inadequate, the fine gauge and round
Cherukuri, P ., Yakobson , B . I., Cognet, L ., Kanzius, J. S ., contour of the wires of the extraction grid , both of which
Kittrell, C ., Weisman , B ., Pasquali , M ., Schmidt, H . K ., factors may militate against achieving the required field
Smalley , R . E ., and Curley, S . A . 2007 . “ Carbon Nanotube strength to stop a passing microsphere or nanoparticle
enhanced Thermal Destruction of Cancer Cells in a Nonin containing magnetically susceptible matter when intrinsi
vasive Radiofrequency Field ,” Cancer 110 ( 12 ): 2654 -2665 ; cally magnetized , even with a magnetized coating, a chemi
Klune, J. R ., Jeyabalan , G ., Chory, E ., Kanzius, J. S ., and cal isolation- encapsulated neodymium bar magnetized nor
Geller, D . A . 2007. “ Pilot Investigation of a New Instrument mal to the lumen axis is fused or bonded to the exterior
for Non - invasive Radiowave Ablation of Cancer,” Journal surface of the grid in long coaxial relation and aside from the
of Surgical Research 137: 263 ). potential extraction path .
[0682] Seed and irradiated stays or miniballs implanted [0686 ] If necessary ,more distant butmore powerfulpatch
within or close to the lesion ab initio can emit radiation as magnets can also be placed with magnetic field oriented
well. Except for those with a punched (perforated ) base perpendicularly to the jacket. Like stent - jackets , impasse
tube , a stent- jacket can provide not only the magnetic field and magnet -jackets can also include some tissue surround
for use with an implant or an injected or infused drug and/or ing the ductus. For stenting , this allows the use of a tissue
radioisotope -bound nanoparticle -containing ferrofluid , for hardener to allow placing the intravascular component of the
example , but can be coated with tissue- isolating radiation extraluminal stent or ductus - intramural implants (miniballs
shielding . The shielding, to which body tissues will be or stays ) when the wall of the ductus is too thin to be
exposed if incorporated into the absorbable matrix of an implanted or too weak to withstand the tractive force applied
absorbable stent-jacket, for example , once dissipated , can to the ductus - intramural implants to open the lumen . Unless
consist of an overlapping gold or platinum particulate . Other a stent-jacket is absorbable so that an underlying extraction
shielding materials , tungsten , iridium , and osmium , are toxic grid will be exposed upon its dissolution , it cannot, as does
and require nonabsorbable encapsulation for chemical iso an impasse -jacket, allow a suspended miniball to be nonin
lation such as with gold . vasively extracted , but can incorporate radiation shielding .
[ 0683 ] Bioabsorbable polymers are numerous and [0687 ] High dose -rate stays, or seed - stays, and the shield
addressed below in the section entitled Absorbable Base jacket or shielded stent- jacket are placed and removed
tube and Stent-jacket, Miniball, Stay , and Clasp -magnet through the same local percutaneous incision , so that even
Matrix Materials. To allow addition to any preexisting though the stays must be inserted first, the time other tissue
stent-jacket, the shielding is glued to the outer surface of the is exposed to the radiation is slight. Since the radiation
stent- jacket as an elastic polymeric matrix layer containing shield - jacket or shielded stent-jacket encloses the stays ,
one or a combination of the foregoing materials embedded removal of the stays would ordinarily require that the jacket
as an overlapping particulate . If the stent -jacket is absorb - be removed first;. However, the need for recovery is avoided
able , then the matrix of the shield layer is absorbable as well . by using an absorbable shield and absorbable stays, ofwhich
Unlike gold compounds administered orally in the form of the toxic shielding particles , usually tungsten , are encapsu
a powder, residual elemental gold or platinum are not lated in gold . Radiation shielded stent-jackets can be incor
absorbed and not toxic . If an absolute amount of a poten porated into a chain with any other type stent or impasse
tially toxic particulate is used in an absorbable implant such jackets where each jacket is selected to treat the segment it
as a stent- jacket, then it is chemically isolated by nonab encircles .
sorbable encapsulation , metallic or polymeric . [0688 ] When miniballs , placement requires triple access ,
[0684] If the use of large or multiple absorbable shielded transluminal for the miniballs, through a local incision for
stents pose the risk of toxicity and the particulate is not to the local shielding stent -jacket, and another incision to place
remain as a residue but be absorbed at a rate subtoxic for the a second shielded stent - jacket or impasse - jacket with
specific substance , then different thicknesses of a shield absorbable shield downstream to trap any miniball that
particle - encapsulating coating polymer and /or polymers accidentally enters the bloodstream . The latter is placed first,
with different rates of absorption are used to stage dissolu - the local shielding jacket second , and the miniballs last.
tion in fractions. The same measures pertain to the dissipa Reasons for placing the jacket first, primarily to serve as a
tion of ferromagnetic particulate embedded in an absorbable barrier to protect against a perforation or radiation on
stent -jacket, which if iron must be controlled in rate and if discharge , are addressed below in the section entitled
sintered lanthanoid must be permanently encapsulate, as Sequence of Stent-jacket Placement and Implantation . A
addressed below in the section entitled Absorbable Base nonabsorbable local stent-jacket with a radiation shield can
tube and Stent -jacket, Miniball , Stay , and Clasp -magnet be left in place after nonabsorbable seed miniballs have
Matrix Materials . Within the size constraints imposed , plas recovered with the tractive electromagnets in the muzzle
tic radiation barriers do not afford adequate shielding. Radia head .
tion shielding for higher dose - rate emissive material is also [0689] When not supported by a downstream external
addressed below in the section entitled Stent-jackets and electromagnet to arrest and extract a miniball and / or impasse
Stent- jacket Supportng Elements. trap - jacket that accidently enters the circulation , radiation
[0685 ] The thickness of the shielding layer applied to the shield - jackets and seed miniballs contain sufficient ferrous
base -tube is varied in proportion to the level of radiation to matter to assure that the miniballs will remain fixed in place
be shielded up to the point where pliancy sufficient to without exerting deflective force on the muzzle -head . Thus,
comply with the intrinsic action in the substrate ductus is while radiation or seed miniballs that are encapsulated in
significantly degraded . An impasse - jacket encircles the duc gold need never be removed , local and usually downstream
tus in a magnetized grid that allows the use of a powerful jackets are still placed for shielding and for positional
US 2019 /0247050 A1 Aug. 15 , 2019
60

security . Nonabsorble radiation shield -jackets and shielded netic field for the purpose of heating implants containing
stent- jackets can likewise be left in place , or alternatively, ferrous and / or cobalt-chromium alloy matter, for example ,
these jackets can be made to be absorbed . encircled within the shielded stent- jacket to accelerate the
[ 0690 ] Inasmuch as noninvasive extraction necessitates an release and / or uptake of a drug applied as a coating to
uninterrupted path from the adventitia to the extraction miniballs , for example, as addressed below in the section
end -point outside the ductus or to the exterior , an impasse entitled Extracorporeal Energization of Intrinsic Means for
jacket provides an extraction grid of fine wire strongly Radiating Heat from within Medication Implants and Medi
magnetized at a strength normal to the longitudinal axis that cation and/ or the Tissue bonding -Coatings of Implants .
drops off moving away to either side from the center. In an Unless exceptionally the stent- jacket has been placed solely
impasse - jacket to serve as a trap - jacket, the strength of to attract and shield against radiation emitting matter for a
magnetization about the circumference may be uniform , or limited time after which it is intended to be removed , the
to favor attraction to the arc closer to the body surface incorporation of a shielding layer or layers in the base -tube
through which a prospective extraction would be performed , is practicably incompatible with direct extraction .
eccentric . Similarly, in impasse - jackets to draw medication [0695 ] Instead , the recovery electromagnets in a barrel
from the passing luminal contents , the strength of magne assembly would have to extract the implants endoluminally,
tization is eccentric according to the arcuate distribution of requiring reentry. An impasse -jacket is configured to allow
the lesion targeted . A radiation shield , however , must be radially outward extraction of a miniball from within the
continuous, so that when the shield is nonabsorbable , the lumen to the exterior with the aid of an extracorporeal
requirements for radiation shielding and extractability electromagnet and cannot be continuously shielded over any
directly conflict. portion of the circumference essential for extraction .
[0691] For this reason , the radiation shield is usually made Because it still presents obstructive areas at the surface, even
to break up after the radiation has become depleted or is a stent-jacket without a continuous layer of shielding and
made noninvasively destructible on demand through the having a punched base-tube is unsuited to the direct extrac
inclusion of continuous ferrous matter to allow magnetic or tion of miniballs or carrier nanoparticles.
electromagnetic heat induction , as addressed above in the [ 0696 ] 4b (5 ). Circulating Drug - Blocking and Drug Inter
sections entitled Field of the Invention and Implants that action Avoidance
Radiate Heat On Demand , among others Destruction thus 106971. Drug -targeting through local release and uptake
requires that the shield layer incorporate sufficient continu not only focuses drug delivery in the diseased tissue , but by
ous ferrous matter to allow noninvasive dissolution by substantially withholding the drug from the circulation ,
magnetic or electromagnetic heat induction . An absorbable minimizes the potential for adverse interactions with any
stent- jacket can incorporate an extraction grid , but practical other drug or nutrient in the circulation . Reciprocally , an
extraction grids must usually be made of magnetizable unpaired impasse - jacket, for example , can be positioned to
stainless steel, which unlike magnesium , for example , is not remove a drug from the circulation thereby preventing a
absorbable . lesion or structure from exposure to that drug . Provided the
[0692] To avoid tunical delamination or pull- through or substances essential are available , a segment of an artery , the
the extraction of the ductus - intramural implants through the liver, or a kidney, for example, can be targeted for receiving
adventitia , stent- jackets should exert the least magnetic or for not receiving a drug, for example .
tractive force , whereas impasse - jackets must provide suffi 10698 ] Removal can be through the release of a second
cient force to extract relatively low susceptibility particles, substance such as by the infusion , injection , or injection of
for example . Neodymium magnets should not demagnetize a third substance and /or heat that reverrses , counteracts , or
over time as to necessitate compensatory overmagnetization neutralizes the first or by extracting the first substance by the
for use in the very young . If after decades this becomes a magnetic field of the magnetized miniball, stay , array
concern , the stent- jacket should be recovered and replaced . thereof, impasse -, stent-, or magnet- jacket, or patch -magnet.
Thus , stent -jackets but not impasse -jackets, which are The avoidance of adverse side effects and drug-drug inter
devised to allow extraction out the sides , can be shielded . To actions is addressed above in the section entitled Field of the
strengthen the tractive force , the gauge of the grid wire in an Invention and below in the section entitled Cooperative Use
impasse -jacket must be increased . of Impasse - jackets in Pairs and Gradient arrays , among
[0693] An impasse -jacket of this kind can also serve as a others .
stent- jacket only so long as this increase does not signifi [0699 ] Magnetic drug carrier nanoparticles used to treat
cantly affect its compliance with the action in the ductus. lesions in the lumen wall are ferrobound so that upon release
That requires dispensing with an intrinsically flexible base from a miniball suspended in the lumen by an impasse
tube and instead using spring hinges as used in impasse jacket, for example , upon dissolution by the passing blood ,
jackets generally. Where injury to the surrounding tissue is infusion of another substance , and/ or the application of heat,
not a concern , such as when the segment treated extends past the drug is drawn by the magnetically susceptible compo
the jacket margins and the lesion is thick enough to absorb nent against the lumen wall and into the lesion . By contrast,
the radiation , an impasse - jacket can be used with high particles used to treat organs can be ferro co -bound so that
dose -rate miniballs to expedite extraction following short only the susceptible component of or enclosed with the
term exposure. However, it is not able to provide shielding . particles are drawn to the impasse - jacket, while the drug or
Depending upon the surrounding anatomy, retrieval can be radionuclide is carried forward in the bloodstream , for
conventional through the grid with the use of a high power example, into the target organ .
external electromagnet or transluminal using the recovery 10700 ) A second impasse - jacket at the end of the treatment
electromagnets in the barrel- assembly muzzle -head . segment or target organ can release a reversal or neutralizing
0694 ] Shielding is , however, compatible with the appli- substance , whether released by the first substance or another
cation of a high intensity radiofrequency alternating mag chemical or an enzyme. The ability to selectively pass and
US 2019 /0247050 A1 Aug . 15 , 2019

prevent certain drugs from continued passage to or from the among others. Unlike a radio frequency alternating magnetic
liver in particular has profound drug interaction implica field , high intensity focused ultrasound directly heats tissue
tions . If the dose is large enough to risk clogging an impasse rather than a target containing ferrous or titanium matter
or stent-jacket, for example, then successive jackets along implanted within the tissue .
the artery, for example , are positioned in order of increasing [0704 ] 46 (6 ). Drug - Targeting Miniballs and Stays
field strength for the expected range in blood pressure . [0705) Miniballs and stays that generate a magnetic field
[0701] The field strength produced by the jackets must of the required strength can be used to attractmagnetic drug
also take the blood pressure , velocity , and posture into and / or radionuclide carrier nanopaticles, microspheres, or
account (see , for example , Cherry, E . M ., Maxim , P. G ., and miniballs containing such particles from the passing luminal
Eaton , J. K . 2010 , op cit; Haverkort, J. W ., Kenjeres , S ., and contents. This is especially valuable along the bloodstream ,
Kleijn , C . R . 2009. “ Computational Simulations of Mag but also along a peristaltic ductus such as the digestive tract,
netic Particle Capture in Arterial Flows,” Annals of Bio where an endoluminal stent fails to comply with if not resists
medical Engineering 37 ( 12 ): 2436 -2448 ). Magnetic drug peristalsis , and usually causes significant chronic irritation at
targeting , for example , is addressed above in the section the margins . An endoluminal stent is also likely to have too
entitled Drug- targeting Miniballs and Stays and below in the little space to include sufficientmagnetic material and draws
sections entitled Concept of the Impasse -jacket and Miniball the drug carrier particles to itself , obstructing and thus
and Ferrofluid -borne Particle- impassable Jackets, or minimizing if not preventing delivery to the target tissue
Impasse - jackets, among others . behind (outside, beyond , surrounding) it.
[ 0702 ] That drugs posing a risk to a certain organ or lesion [0706 ] A holding impasse - jacket can be used , for example ,
can be prevented from reaching that part where drug inter to preposition a smart pill by suspension within the circu
action is uninvolved is obvious. The blocking of a particular lation for response to a programmed condition of blood
organ or luminal lesion from exposure to a drug in the chemistry should such arise, without the need for monitor
circulation by removing the drug before it reaches that ing. Unlike those suspended in the bloodstream by means of
structure pertains to larger lumina and structures so that impasse -jackets , addressed below in the section entitled
where the drug is not re -released past the structure , collateral Concept of the Impasse - jacket, miniballs and stays used
circulation should still deliver the drug past that blocked out. without a holding jacket must be implanted ductus -intramu
Adverse interaction avoidance is pertinentwhether the drugs rally . Magnetized stays and miniballs can be used in mul
are to treat the same condition , the condition is ductus tistage drug targeting where the other components placed at
situated , to treat independent and unrelated (trans-nosologi intervals along the lumen are impasse- jackets or patch
cal), or interactive (trans- syndromal) comorbidity ( see, for magnets, for example .
example , McCarthy , C ., Clyne , B ., Corrigan , D ., Boland , F ., [0707 ] Other sections herein pertaining to this include, in
Wallace , E ., and 5 others 2017 . " Supporting Prescribing in order, System Implant Magnetic Drug and Radiation Tar
Older People with Multimorbidity and Significant Polyp geting, Circulating Drug Blocking and Drug Interaction
harmacy in Primary Care (SPPIRE ): A Cluster Randomised Avoidance, Endoluminal Prehension of Miniballs and Fer
Controlled Trial Protocol and Pilot,” Implementation Sci rofluids, Concept of the Impasse - jacket, Uses of Impasse
ence 12 ( 1): 99; Stokes, J., Kristensen , S . R ., Checkland, K ., jackets , Cooperative Use of Impasse -jackets in Pairs and
Cheraghi-Sohi, S ., and Bower, P . 2017 . “ Does the ImpactL0L of Gradient Arrays, and Chemical Control over Implants and
Case Management Vary in Different Subgroups of Multi Coated Implants , to Include Miniballs , Stays , and Prongs . To
morbidity ? Secondary Analysis of a Quasi-experiment,” achieve the least weight and size that will be fully depend
BioMed Central Health Services Research 17 ( 1 ):521 ; able ; neodyimium iron boron , thatmaterial currently known
Smith , S . M ., Wallace, E ., O 'Dowd, T., and Fortin , M . 2016 . with the highest energy product, or magnetic field strength
“ Interventions for Improving Outcomes in Patients with per unitmass , is incorporated , usually as a continuous core.
Multimorbidity in Primary Care and Community Settings ,” [0708 ] This material toxic and an outer layer aiding to
Cochrane Database of Systatic Reviews 3:CD006560; Val produce a deeply textured surface, magnetized miniballs and
deras, J. M ., Starfield , B ., Sibbald , B ., Salisbury, C ., and stays are biocompatibly coated by plating, Microfusion® , as
Roland , M . 2009. “ Defining Comorbidity : Implications for addressed below in the section entitled Stent-jackets and
Understanding Health and Health Services,” Annals of Fam Stent- jacket Supporting Elements, or polymeric encapsula
ily Medicine 7 ( 4 ): 357 - 363) . Care in comorbidity may differ tion . Except for a coating of surgical cement, the space
in a system of socialized medicine (see , for example , Mera constraints will usually disallow any significant outer lay
nius, M . S . and Josefsson , K . 2017 . “ Health and Social Care ering with medication . All miniballs and stays for retentive
Management for Older Adults with Multimorbidity : A Mul infiltration by the surrounding tisssue are given a deeply
tiperspective Approach ,” Scandinavian Journal of Caring textured surface which also helps to retain any cement used
Sciences 31( 1 ): 96 - 103 ). and gradually replaced by the tissue . Once a miniball with
[0703] The risk of rhabdomyolysis when both statins and deep surface texture becomes infiltrated with tissue, an
fibrates and/or niacin are administered , for example, is impasse - jacket allows its extraction with the aid of an
addressed below in the section entitled Cooperative Use of external electromagnet; otherwise , such miniballs should be
Impasse -jackets in Pairs and Gradient Arrays . Numerous left in place . If a need for resonance imaging arises , the
methods are provided herein for accelerating uptake, to miniball is extracted by means of a sudden pulse from a
include drug carrier nanoparticles that allow not only draw powerful external electromagnet.
ing the drug toward an impasse - jacket surrounding the [0709] Magnetized miniballs are oriented to be attracted
lesioned segment, for example , but also allow the medica - by, that is , for opposite polarity to , an external electromagnet
tion to be heated with the aid of a high intensity alternating as might later be needed to extract these . Immediately after
magnetic field , as addressed in in the section below entitled placement, an external magnet is used to orient the miniball
System Implant Magnetic Drug and Radiation Targeting, or miniballs before the surrounding cellular exudate has the
US 2019 /0247050 A1 Aug . 15 , 2019

time to congeal , or coagulate . All but the largest stays are or stay insertion tool as described below in the section of like
magnetized along their average or implied long axis, so that title. Miniballs and stays have no significant longitudinal
attractants are drawn to their tips. Such stays can also extension , so that used in a peristaltic ductus , whether the
incorporate separate magnets toward the tips. Longitudinally gut, a ureter, or gamete tube , both comply with the passing
extended and allowing some clearance from the outer sur wave while drawing magnetically susceptible matter from
face of the ductus, a magnetized collar or extraluminal stent, the passing lumen contents , but except as indicated above ,
whether an impasse - jacket or a stent- jacket with tiny mag no farther radially than their own position . Miniballs and
nets mounted about its outer surface , does not have the stays that are dropped are readily recovered with the imme
flexibility to conform to the passing constrictive wave as the diately present tool that is used to place these , that is , the
outer surface of the gut, for example , is drawn inward recovery electromagnets in the barrel -assembly muzzle
( centrally ) away from the collar. head or the stay insertion tool, or a magnet-tipped catheter,
[ 0710 ] Although the stent- jacket base-tube or the impasse or probe.
jacket wire mesh does not conform to the inward or central [0714 ] Magnetized miniballs and stays coated with an
excursion of peristalsis , it does comply with any outward initial dose to treat the abluminal portions of the ductus or
excursion and is therefore nonconstrictive. The increase in achieve good concentration at the treatment site immediately
field strength required to keep the susceptible matter within can be left in place and thereafter used to attract subsequent
range due to wall recession as the wave passes is insignifi doses whenever administered , whether by infusion , injec
cant even for the treatment of Crohn ' s disease , much less tion , or ingestion . A multiple radial discharge barrel -assem
esophageal cancer. For nonadvanced regional enteritis, it can bly with the recovery electromagnets momentarily switched
be significant. In critical contrast to an extraluminal stent, an off driven by a linear positioning stage can place miniballs
endoluminal stent draws drug /or radionuclide carrier par in a close or high density formation to concentrate the
ticles entirely through the lumen wall; however , the ablu substance or substances drawn into a lesion having longi
minal tractive reach limited by the force exerts , a magne tudinal extension . Using miniballs, an external electromag
tized miniball or stay does not draw carrier particles beyond net is used to align the field of each before the landing point
(radially outward from its own position as would an of each has had the opportunity to coagulate or congeal.
impasse -jacket that encircled the ductus. Asymmetrical, the fields of stays spontaneously align .
[0711 ] For intramural delivery , the drug carrier particles or [0715 ] 4c . Implants that Radiate Heat on Demand
microspheres are formulated for quick dissolution and [0716 ] Implants, to include those ductus-intramural, or
release, whereas for delivery beyond the stent requires a miniballs and stays , containing continuous ferromagnetic
fraction or a separate dose formulated for delayed release . If material such as in the form of encapsulated plates can be
disease would spread from the outer surface of the gut to the heated by placing the patient in a radiofrequency alternating
mesentery ( The Merck Manual of Diagnosis and Therapy , magnetic or electromagnetic field , the temperature noninva
18th Edition , 2006 , Section 2 , Gastrointestinal Disorders, sively monitored by means of an equivalent temperature
Section 18 , “ Inflammatory Bowel Disease ," page 152 ), for calibrated eddy current detector. While more pertinent to
example , an extraluminal chain - stent, because it substan stent-jackets , ductus - intramural implants that radiate heat on
tially surrounds the lesion , reduces access of the disease to demand from outside the body can also be used for hyper
healthy tissue outside the stent. With respect to the Crohn ' s thermic therapy , to apply followup thermoplasty to nonin
example mentioned in the section above entitled Field of the vasively debulk postprocedural hyperplasia , accelerate the
Invention , extraintestinal symptoms resulting from the dissolution and /or uptake of drugs at the implant site , initiate
spread of disease from the gut are restrained , but not or accelerate the dissolution of an absorbable implant,
symptoms that appear separately . and / or to release or accelerate the setting time of an adhesive
[ 0712 ] The systemic medication necessary to suppress the or protein solder, for example .
separate symptoms should be less . As any magnetic drug 107171 Stent-jackets for noninvasive heating incorporate
carrier particle attractor, intravascular, miniballs and stays as many gas exchange perforations as necessary , resistance
draw carrier particles up to the radial distance at which these posed to the eddy currents compensated for by increasing
are infixed but then obstruct the drug and /or radionuclide the intensity of induction . Implants encompass both those
from being drawn beyond itself to the exterior surface of the circumductal, such as stent-jackets, impasse - jackets, and
ductus, much less beyond . So long as disease is confined to clasp -magnets, as well as those ductus- intramural, consist
portions of the ductus adluminal to the miniballs or stays , ing of miniballs and stays. Shallow implants are usually
drug -targeting magnetic miniballs or stays should suffice for warmed ( or chilled ) directly with the aid of a vortex tube
medical management. Here too , either an initial nonmag based , nominally “ cold ,' air gun , which is equally usable for
netic coating or delayed dissolution and release of the heating , or an electrical hand dryer, for example, while
magnetic carrier bound drug allows the delivery of the drug remote heating of more deeply placed implants is usually by
or drugs radially outward from the stay or miniball as the means of induction in a ferromagnetic particulate embedded
target. Disease that is transmural, that is , which has pro within the material of the implant by placing the patient in
gressed to involve the ductus wall through and through a radiofrequency alternating magnetic field , the means for
justifies the addition of an extraluminal stent through a small accomplishing this magnetically addressed below in the
laparoscopic entry portal local to the lesion . section entitled Heating of Implants and Coated Implants, to
[0713] Miniballs should be marked to indicate the north Include Miniballs, Stays , and Prongs Using Implant -passive
pole , and the magnetic orientation of intraluminal and Ductus -external or Extrinsic Means.
extralumal implants should be coordinated . In the gut, the [0718 ] This property in a temporary or absorbable implant
barrel -assembly is introduced rectally as is an endoscope can be used to direct dissolution of the implant on demand .
with no incision involved . Individual drug -targeting stays While most often pertinent to stent- jackets, remote warming
are placed laparoscopically with a suitable pliars -configured and dissolution apply to every type implant described
US 2019 /0247050 A1 Aug. 15 , 2019
62

herein . The eventual object of oral administration will allow alternated at a radiofrequency , the implants described herein ,
selfmedication by the patient away from the clinic, without to include miniballs , stays, and holding jackets , for example ,
the need for infusion or injection through a subcutaneously can be made to radiate heat through oscillation and eddy
implanted portal, as addressed above in the section above current induction . In such use, the impasse-jacket is given an
entitled System Implant Magnetic Drug and Radiation Tar absorbable polymeric coating that incorporates the nanopar
geting and in the section below entitled Cooperative use of ticles . When this matrix can be raised in temperature to a
impasse -jackets in pairs and gradient arrays. When the sufficiently molten or fluid state , physical alternation of the
implant collars about the ductus, drug carrier nanoparticles, nanoparticles also contributes to heating .
for example , injected upstream will be drawn up against the 107231 Remote heating by such means has been widely
lumen wall within the collared segment. studied ( see , for example , Purushotham , S ., Chang, P . E .,
[ 0719 ] Absorbable implants that are made to radiate heat Rumpel, H ., Kee , I. H ., Ng, R . T., Chow , P . K ., Tan , C . K .,
on demand can also be dissipated on demand , with drugs or and Ramanujan , R . V . 2009. “ Thermoresponsive Core -shell
other therapeutic substances incorporated into the absorbed Magnetic Nanoparticles for Combined Modalities of Cancer
matrix released as well. To do this , heating is not to the tissue Therapy,” Nanotechnology 20 ( 30 ): 305101. Luo, Y . L ., Fan ,
injuring melting point but to only the temperature needed to L . H ., Gao , G . L ., Chen , Y . S ., and Shao , X . H . 2009.
release bound water with or without dissolution enzymes “ Fe3O4 /PANI/P (MAA -CO -NVP) Multilayer Composite
from a hydrogel likewise embedded in the matrix . Implants Microspheres with Electric and Magnetic Features : Assem
remotely energized to radiate heat in situ are addressed bly and Characterization ,” Journal of Nanoscience and
below in the section entitled Extracorporeal Energization of Nanotechnology 9 ( 11 ):6439-6452 ; Dennis , C . L ., Jackson ,
Intrinsic Means for Radiating Heat from within Medication A . J., Borchers, J. A ., Hoopes, P. J., Strawbridge, R . and 4
Implants and Medication and/ or the Tissue Bonding - coat others 2009. “ Nearly Complete Regression of Tumors via
ings of Implants. Collective Behavior of Magnetic Nanoparticles in Hyper
[0720 ] The same nanoparticles that allow heating in an thermia,” Nanotechnology 20 ( 39 ): 395103 ; Li, F . R ., Yan , W .
alternating magnetic field produced with a magnetic reso H ., Guo, Y . H ., Qi, H ., and Zhou , H . X . 2009. “ Preparation
nance machine or high amplitude alternating magnetic field of Carboplatin - Fe @ C -loaded Chitosan Nanoparticles and
generator make possible magnetic drug - targeting in a non Study on Hyperthermia Combined with Pharmacotherapy
alternating magnetic field . With an extraluminal stent encir for Liver Cancer,” International Journal of Hyperthermia
cling the ductus (usually a blood vessel) without, rather than 25 (5 ):383- 391 ; Maier -Hauff , K ., Rothe , R ., Scholz , R .,
an endoluminal stent, which inside the lumen draws drug Gneveckow , U ., Wust, P ., and 6 others 2007 . “ Intracranial
carrier nanoparticles, for example , to itself rather than into Thermotherapy Using Magnetic Nanoparticles Combined
the tissue adluminal to it, the drug is drawn into the diseased with External Beam Radiotherapy : Results of a Feasibility
tissue. The distinction between heating implants by radiation Study on Patients with GlioblastomaMultiforme,” Journal
or conduction from an extrinsic heat source and including of Neuro -oncology 81 ( 1) :53-60 ; Baker, I., Zeng, Q ., Wei
means within the implants that allow intrinsic heat genera dong, L ., and Sullivan , C . R . 2006 . “ Heat Deposition in Iron
tion is addressed below in the section entitled Extracorporeal Oxide and Iron Nanoparticles for Localized Hyperthermia ,”
Energization of Intrinsic Means for Radiating Heat from Journal of Applied Physics 99 ( 8 ) 08H106 -08H109; Zhao , D .
within Medication Implants and Medication and / or the Tis L ., Zhang , H . L ., Zeng, X . W ., Xia, Q . S ., and Tang, J. T.
sue Bonding Coatings of Implants . 2006 . “ Inductive Heat Property ofFe304 /Polymer Compos
[0721 ] Thus, miniballs and drug carrier nanoparticles are ite Nanoparticles in an AC Magnetic Field for Localized
first drawn to the stent- jacket , holding jacket, or magnet Hyperthermia ,” Biomedical Materials 1 (4 ): 198 - 201;
jacket collaring about a blood vessel, for example , where Kawashita , M ., Tanaka, M ., Kokubo , T., Inoue, Y ., Yao , T.,
upon heating the jacket and apposed drug delivery agent or Hamada, S ., and Shinjo , T. 2005 . “ Preparation of Ferrimag
agents implants accelerates the dissolution and uptake of the netic Magnetite Microspheres for in Situ Hyperthermic
medication by the lesion . When the core of a miniball with Treatment of Cancer,” Biomaterials 26 ( 15 ): 2231- 2238 ;
multiple layers of medication or other therapeutic substance Ramachandran , N . and Mazuruk , K . 2004 . “ Magnetic
such as a surgical cement, for example , is made to radiate Microspheres and Tissue Model Studies for Therapeutic
heat, the layer having the lowest breakdown or melting point Applications,” Annals of the New York Academy of Sciences
will liquify or melt first, allowing drugs or other therapeutic 1027 :99 - 109 ; R ., DeNardo, S . J., Daum , W ., Foreman , A . R .,
substances with different breakdown points to be sequenced Goldstein , R . C ., Nemkov, V . S ., and DeNardo, G . L . 2005 .
for delivery . Applying the medication or other therapeutic " Application of High Amplitude Alternating Magnetic
substance with the lowest melting point as the outermost Fields for Heat Induction of Nanoparticles Localized in
layer results in the release of that substance first. By shutting Cancer,” Clinical Cancer Research 11 ( 19 Part 2 ): 7093s
off and restarting the alternating magnetic field , each suc 7103s; Muraoka, A ., Takeda, S ., Matsui, M ., Shimizu , T.,
cessive layer can be heat -released at any interval desired . Tohnai, I., Akiyama, S ., and Nakao , A . 2004 . “ Experimental
Alternatively, each layer can be formulated to dissolve at Study of a Novel Thermotherapy for Hepatocellular Carci
successive intervals postoperatively . noma Using a Magnesium Ferrite Complex Powder that
[0722] The use of a magnetic resonance machine or a high Produces Heat under a Magnetic Field ,” Hepatogastroen
amplitude alternating magnetic field applicator to heat the terology 51(60 ): 1662- 1666 ; Kobayashi, T., Tanaka, T ., Kida ,
implants described herein is also addressed below in the Y., Matsui, M ., and Ikeda , T. 1989 . “ Interstitial Hyperther
section entitled Extracorporeal Energization of Intrinsic mia of Experimental Brain Tumor Using Implant Heating
Means for Radiating Heat from within Medication Implants System ,” Journal of Neuro - oncology 7 (2 ):201-208 ).
and Medication and/or the Tissue bonding-Coatings of [0724] Ordinarily , ferromagnetic implants disallow the
Implants . Made of or coated to include materials that can be use of magnetic resonance equipment . This is because the
excited when placed in an extracorporeal magnetic field axial field places tractive force on the implants risking
US 2019 /0247050 A1 Aug. 15 , 2019
64

injury, while the radiofrequency alternating field induces (dipyridamole ), and those for veins with an anticoagulant or
heat that results in burns. However, use of an alternating ' blood thinner,' such as the vitamin K antagonists or cou
magnetic field only can also serve as a means for intention marins (warfarin and / or heparin ) and non vitamin K antago
ally heating an implant directly or by exciting a resonant nists ( see , for example , De Caterina, R ., Husted , S ., Wal
circuit embedded within the implant (Niwa, T ., Takemura , lentin , L ., Andreotti, F., Arnesen , H ., and 11 others 2012.
Y., Inoue, T., Aida , N ., Kurihara , H ., and Hisa , T . 2008. “ New Oral Anticoagulants in Atrial Fibrillation and Acute
“ Implant Hyperthermia Resonant Circuit Produces Heat in Coronary Syndromes : ESC [European Society of Cardiol
Response to MRI Unit Radiofrequency Pulses,” British ogy ] Working Group on Thrombosis - Task Force on Antico
Journal of Radiology 81( 961 ):69 - 72 , available at http ://bjr. agulants in Heart Disease Position Paper,” Journal of the
birjournals.org /cgi/ content/full /81/ 961/69 ; Morita , M ., American College of Cardiology 2012 59 (16 ): 1413- 1425 ;
Inoue, T., Yamada, T., Takemura , Y ., and Niwa, T. 2005. Weitz , J. I. 2012 . “ New Oral Anticoagulants: A View from
“ Resonant Circuits for Hyperthermia Excited by RF Mag the Laboratory," American Journal of Hematology 87
netic Field of MRI,” INTERMAG Asia Magnetics Confer Supplement 1 :S133-S136 ; Bauer, K . A . 2011 . “ Recent Prog
ence 953 -954 ). Digests of the IEEE International). ress in Anticoagulant Therapy : Oral Direct Inhibitors of
[0725 ] The resonant circuit is interposed or sandwiched Thrombin and Factor Xa ,” Journal of Thrombosis and
between a double layered mesh in the half-cylinder to be Haemostasis 9 Supplement 1: 12 - 9 ; Weitz , J. I., Hirsh , J., and
placed more deeply or on the side that will lie more distant Samama, M . M . 2004 . “ New Anticoagulant Drugs," Chest
from the external extraction electromagnet, for example . 126 ( 3 ) :Supplement 265S - 286S ) , thus allowing the systemic
Unlike stent-jackets , which use multiple miniballs implanted dose to be reduced relative to that conventional, and reduc
relatively close to the outer tunic of the ductus where each ing the risk for prolematic bleeding. On healing an extralu
is drawn by a magnetic force which is close and normal to minal, with no presence within the lumen , ceases to pose a
it , a holding jacket will often secure but a single miniball threat of thrombosis .
within the lumen through which contents flow over the [0731 ] Ductus prone to swell if struck from within neces
additional distance that separates the perimedial from an sitate the use of miniballs that also contain anti-inflamma
endoluminal position when the magnetized segment of the tory medication , the NSAIDs diclofenac, indometacin , ibu
jacket is central and less extended . profen and sulindac , for example , having been found to
10726 ). For use in the gastrointestinal tract, ureters , and additionally exert an antiproliferative effect on the smooth
gamete -tranporting ductus, the magnetic strength must be muscle cells of the media (Muñoz, E ., Valero , R . A .,
additionally strong enough to overcome the adaxial (toward Quintana, A ., Hoth , M ., Núñez , L ., and Villalobos , C . 2011 .
the long axis , medial, central , inward ) increase in distance “ Nonsteroidal Anti- inflammatory Drugs Inhibit Vascular
due to retraction by the passing contractive waves . In the Smooth Muscle Cell Proliferation by Enabling the Ca2 +
esophagus and gut, the immediately preceding passage of dependent Inactivation of Calcium Release -activated Cal
the bolus poses yet an additional force promoting dislodge cium /Orai Channels Normally Prevented by Mitochondria ,”
ment. However, the impasse - jacket strength of magnetiza Journal of Biological Chemistry 286 ( 18 ): 16186 - 16196 ;
tion must not be so great as to interfere with ductus - intrinsic Brooks, G ., Yu , X . M ., Wang, Y ., Crabbe, M . J., Shattock , M .
muscular action to a degree that would induce dyspagia , for J., and Harper , J. V. 2003 . “ Non -steroidal Anti- inflammatory
example . Whether a radially symmetrical arrangement of Drugs (NSAIDs) Inhibit Vascular Smooth Muscle Cell Pro
miniballs suspended within the lumen would less likely liferation via Differential Effects on the Cell Cycle ,” Journal
produce disabling consequences warrants study . of Pharmacy and Pharmacology 55 (4 ) :519 -526 ). To reduce
[0727 ] 4d . Chemical Adjuvants and Precautionary Mea the risk of infection -mediated pull -through , the implants are
sures additionally coated with an antibiotic , a dose adjusted sys
[0728 ] 4d (1 ). Administration of Target and Target-Adja temic antibiotic administered as well.
cent Implantation -Preparatory Substances [0732 ] Other measures for reducing the risk of pull
[0729 ] Radial projection unit injection tool - inserts allow through include use of the minimal retractive magnetic field
the local injection of therapeutic substances such as drugs , strength , implants having a textured surface to encourage
hormones, enzymes, or a surgical cement into the target and tissue adhesion and infiltration , or ingrowth , the application
nearby tissue to prepare the ductus for ballistic implantation of phosphorylcholine and/or dexamethasone or curcumin
Avoidance of the lumen a key object in the use of stays , the (referencees provided below in the section entitled Tissue
extraluminal application of medication is preferred with Reaction Ameliorative Measures), and various bonding
stays . Therapeutic substances can also be administered sys agents , such as protein solder or tissue cement, dependent
temically or released onto the endothelium through a non upon the response to be expected for the type and depth of
injecting ejection tool-inserts or through a barrel-tube or tissue based upon the results of pretesting as addressed
tubes used as service channels . In addition to conventional below in the section entitled Testing and Tests. Due to the
types ofmedication such as antibiotics and antithrombogen constant replenishment of tissue, adhesives are chosen that
ics , to better resist migration , delamination , or pull- through , will allow infiltration during dissolution so that the implant
tissue hardening agents that induce the formation of strong will become securely anchored and integrated in position .
tissue about the implants and strong adhesion of the tissue to [0733] In the form of smaller miniballs or stays , these
the implants is used . substances are solid and can consist of a single or multiple
0730 ] Due to the thrombogenicity (thromboplasticity ) of drugs. The heating of solder coated implants following
introducing multiple punctures through the intima and insertion can be used both to release drugs and bind tissue .
media , miniballs for implantation into the walls of arteries To minimize the exposure of surrounding tissue to this heat,
are given an outer coating of an antiplatelet agent, such as electrically or fluidically heated heat -windows, as addressed
a glycoprotein IIB / IIA inhibitor ( abciximab , eptifibatide , below in the section entitled Thermal Conduction Windows
tirofiban , lamifiban ), or adenosine uptake inhibitor (Heat -windows ) and Insulation of the Muzzle -head Body , or
US 2019 /0247050 A1 Aug. 15 , 2019
65
syringe solder injectors , as addressed below under the head magnetic stent. Otherwise , numerous vessels , especially
ing Radial Projection Units are used . Alternatively , external veins and elastic arteries having a thin wall and media , even
ultrasound can be used for heating. Other preparatory agents a carotid , may prove difficult or impossible to implant thus .
allow the intentional swelling of the ductus wall, as next In some instances , implantation is made possible by pro
addressed , to make thin -walled ductus easier if not possible ducing a short -lived or reversible increase in medial thick
to implant. ness . Provided the tenuity is not so extreme or intrinsic
[0734 ] The moisture barrier protected viscoelastic poly strength so lacking that upon subsidence , the implants, even
urethane (memory ) foam lining of the stent-, impasse , and with a fill - coat of protein solder, would perforate through the
magnet-jackets described facilitate the inclusion of adherent adventitia , into the lumen , or both , some walls can be
tissue surrounding the outer ductus when thin -walled due to brought up to an implantable thickness if tumefied ( swol
normal anatomy or disease . The treatment of short segments len ).
will often recommend the use of stays, as addressed below [0740] Long- term fillers as opposed to short term
in the section entitled Circumstances Dissuading or Recom swellants are addressed below in the section entitled The
mending the Use of Stays . When the same means for Extraductal Component of the Extraluminal Stent and the
inserting ferromagnetic implants to draw a magnetic stent- Means for its Insertion . Administration of a tumefacient
jacket can be used to introduce the preparatory medication , specified in this section and drugs specified in the section
the treatment site can often be targeted with negligible that follows is begun sufficiently in advance of the procedure
systemic dispersion . When the drug action response time that requires it . In muscular arteries , tumefacients, or swell
allows, use of the same barrel -assembly allows single entry ing agents , which increase lumen wall thickness by con
and withdrawal. tracting the smooth muscle cells, are vasoconstictors that
[0735 ] When a pretest reveals that the wall of the ductus will reduce the diameter of the lumen . This can be a
is susceptible to inter or intralaminal separation, small consideration in selecting a barrel- assembly or radial pro
implants consisting of an absorbable and tissue infiltatable jection catheter of given caliber but will rarely if ever affect
solid protein solder can be implanted adjacent to the site to the use of stays . Tumefacients not only increase the thick
be implanted with the solder melted (denatured ) and made to ness of the luminal wall allowing it to be implanted but
flow by muzzle -head or piped radial projection unit heat affect other properties of the ductus.
windows, by feeding heated gas down a barrel-tube , or 10741] Tumefacients that work by inducing the contrac
through use of external ultrasound. Following any step tion of medial smooth muscle , for example , increase resis
involving heating , a cooling catheter, as addressed below in tance of the wall to perforation and reduce the luminal
the section entitled Cooling Catheters ( Temperature - chang diameter. Tumefacients that work in other ways may not
ing Service - catheters ), can be used to hasten the return of affect luminal diameter but will affect the mechanical prop
heated tissue to body temperature . When the cooling cath erties of the luminal wall. In some instances , the primary
eter is prepared by having been stored filled with water in a object in using a tumefacient may be unrelated to wall
freezer and the same barrel -tube is to be used for discharge, thickness . This interaction of key determinants as to the
the cooling catheter should be capped to prevent melt water barrel- assembly and exit velocity to be used means that the
from entering the barrel- tube. tests described below in the section entitled Testing and
[ 0736 ] Deeply textured implants can deliver surface Tests should be performed both before and after any tume
depression adherent liquid or semiliquid substances forward facient contemplated is applied . Tumefacients that affect the
into the ductus wall. Using a barrel -assembly, a service ductus over a longer interval that wanted must have an
catheter, as addressed below in the section of like title , and associated counteractant. This can be done to thicken a wall
using a stay insertion tool, auxiliary syringes , as addressed that is or is not too thin to implant but not too weak to retain
below in the section entitled Stay Insertion Tool Auxiliary an implant once inserted .
Syringes, make it possible to supplement or coat implants . [0742 ] Tumefaction does not involve the permanent
Outside the bloodstream , a service -catheter also allows the implantation of autologous tissue or a polymer between the
delivery of a gas or an aerosol (mist ) whether irradiated or intima and adventitia but swelling that is temporary to allow
having a fine powder dispersed in it . With the latter, cohe or expedite insertion . Otherwise, liposuctioned fat, for
siveness among particles or adhesion to the barrel- tube as example , can be injected through a service - catheter ( qv .)
service channel without a service - catheter will result in with a hypotube , or with an injection tool- insert ( qv.) before
clogging, limiting continued use of any one barrel-tube . implantation . Depending upon lumen caliber, the tumefa
[0737) Barrel-tubes as service channels and service - cath cient can be released along the lumen wall through the
eters can deliver compatible substances jointly , but unless working channel of a fiberoptic endoscope , a barrel -tube
more than one service - channel - as addressed below in the used as a service - channel, a service catheter routed through
sections entitled Muzzle -head Access through a Service a barrel -tube, or an ejection tool- insert . If not extremely
channel without the Aid of and by Means of Inserting a thin -walled , the use of an injection tool- insert or service
Service -catheter and Thermal Ablation or angioplasty - (Lu catheter with a hypotube at the distal end is possible .
men Wall Priming Searing - or Cautery - ) capable Barrel 10743 ) Following the procedure , the wall reverts to its
assemblies — is available, to deliver substances to be kept preprocedural condition , the implant or implants retained for
separated during delivery requires separation through the a time if necessary with the aid of a surgical cement or
use of separate service-channels or service -catheters in
sequence.
protein solder outer layer pending tissue integration . Low
melting point solder on miniballs or stays and cyanoacrylate
[0738 ] 40 (2 ). Ductus Wall Tumefacients cement on stays can be heated endoluminally by muzzle
[0739 ] Whether the result of disease, an angioplasty , or an head heat -windows or hot- plate tool-inserts . Heating thus is
atherectomy, excessive thinness of the luminal wall can focused or aimed and relatively circumscribed . Heating
prohibit implantation to introduce medication or to apply a from outside the body using ultrasound , for example , is
US 2019 /0247050 A1 Aug. 15 , 2019

unfocused and contraindicated for any site close to a devel- need for a target tissue binder or hardener, implants with a
opmental ossification or nervous center, for example . When layer of protein solder or tissue cement, for example, then
stays are to be used or the ductus is to be stented so that used .
extraluminal access will be required in any event, the [0747] 4d (3 ). Nontumefacient Enabled Attainment of
tumefacient can be applied to or through the adventitia. Implantable Ductus-Intramural Thickness
[0744 ] Various approaches to thickening the media [0748 ] Infrequently, a disease condition, such as inflam
include inducing: a . A buildup of osmotic pressure that mation as swelling , a lesion , or inflammation that follows
treatment of the lesion will result in a wall thickness
causes the smooth muscle of the media to contract ( see , for sufficient for implantation , although this will usually be at
example , Ding, Y., Schwartz , D ., Posner, P., and Zhong, J. the expense of strength . A malacotic condition can be
2004. “ Hypotonic Swelling Stimulates L -type Ca2 + Chan overcome by using a radial projection catheter to inject an
nel Activity in Vascular Smooth Muscle Cells Through PKC absorbable tissue hardener or fixative , or filler of the kind
[Protein Kinase ],” American Journal of Physiology. Cell used in facial cosmetic surgery. An intravascular ultrasound
Physiology 2004 287 (2 ): C413 - C421 ); b . A short- lived or probe , charge coupled device camera, or fluorescence life
reversible swelling reaction to a drug or combination of time imaging microscopy, or angioscope either as a sepa
drugs; c. Sterile inflammation as an immune response ; d . rate device or incorporated into a combination form barrel
Reaction to a change in temperature , e . Reaction to a flow of assembly — can be used to examine the reaction of the lumen
current at the target site , f . Mechanical irritation through wall to the procedure just completed ( see , for example ,
brief oscillation of the target site , and injection of a nonir Savastano , L . E . and Seibel, E . J . 2017 . “ Scanning Fiber
ritating absorbable filler such as used in facial cosmetic Angioscopy: A Multimodal Intravascular Imaging Platform
surgery. for Carotid Atherosclerosis,” Neurosurgery 64 (CN Supple
[ 0745 ] In an atheromatous artery to receive miniballs , ment 1 ): 188 -198 ; Savastano , L . E ., Chaudhary , N ., Murga
embolic protective devices such as proximal and distal Zamalloa, C ., Wang, M ., Wang , T., and Thompson , B . G .
balloon occluders and embolic filters (see , for example ,
2017. “ Diagnostic and Interventional Optical Angioscopy in
section 4d ( 2 ) entitled Ductus Wall Tumefacients and
Ex Vivo Carotid Arteries,” Operative Neurosurgery (Hag
Kobayashi, T . anf Giri, J. 2017 . “ The Role of Embolic erstown , Md.) 13 ( 1 ): 36 -46 ; Savastano , L . E ., Zhou , Q .,
Protection in Carotid Stenting Progress in Cardiovascular Smith , A ., Vega, K ., Murga - Zamalloa , C ., and 11 others
Diseases (PCVD )," Progress in Cardiovascular Diseases 2017 . “ Multimodal Laser-based Angioscopy for Structural,
Chemical and Biological Imaging of Atherosclerosis,”
59 (6 ):612 -618 ; Velasco , A . and Mosimann , P. J. 2013 . Nature Biomedical Engineering 1. pii : 0023; Savastano , L .
“ Distal Cerebral Protection Device Filled with Calcified E ., Smith , A ., Vega, K ., Murga -Zamalloa , C ., Gordon , D .,
Plaque Debris after Carotid Stenting ,” Journal of the Ameri and 4 others 2016 . “ Multimodal Endovascular Endoscopy in
can College of Cardiology. Cardiovascular Interventions Carotid Atherosclerotic Disease ," Neurosurgery 63 Supple
6 (4 ):e22 -e23 ; Macdonald , S . 2011. “ New Embolic Protec ment 1: 146; Packard , R . R ., Zhang, X ., Luo , Y ., Ma, T ., Jen ,
tion Devices : A Review ," Journal of Cardiovascular Sur N ., and 7 others 2016 . " Two -point Stretchable Electrode
gery ( Turin , Italy ) 52 (6 ):821 -827 ; Eskandari , M . K . 2005 . Array for Endoluminal Electrochemical Impedance Spec
“ Cerebral Embolic Protection ," Seminars in Vascular Sur troscopy Measurements of Lipid -laden Atherosclerotic
gery 18 (2 ) :95 - 100; Sangiorgi, G . and Colombo , A . 2003 . Plaques ,” Annals of Biomedical Engineering 44 (9 ): 2695
“ Embolic Protection Devices ," Heart (London , England ) 2706 ; Ma, T., Yu , M ., Li, J., Munding , C . E ., Chen , Z ., Fei ,
89 (9 ): 990 - 992 ) that is, a potentially embolizing atheroma C ., Shung, K . K ., and Zhou , Q . 2015 . “Multi- frequency
tous debris - intercepting trap - filter or balloon deployed from Intravascular Ultrasound (IVUS ) Imaging," Institute of
the nose of the muzzle-head can be prepositioned proximal Electrical and Electronics Engineers Transactions on Ultra
or distal to or downstream from the site to be treated . sonics, Ferroelectrics, and Fregency Control62( 1 ): 97 - 107;
[ 0746 ] No embolization device completely eliminates the McVeigh , P . Z ., Sacho , R ., Weersink , R . A ., Pereira, V . M .,
passage ofmicroemboli ; however, the number which pass is Kucharczyk , W ., Seibel, E . J., Wilson, B . C ., and Krings , T.
much reduced (Vos, J. A . 2017. “ Evidence Overview : Ben 2014 . “ High -resolution Angioscopic Imaging During Endo
efit of Cerebral Protection Devices During Carotid Artery vascular Neurosurgery," Neurosurgery 75( 2 ): 171 - 180 ;
Stenting,” Journal of Cardiovascular Surgery ( Turin , Italy ) Suter, M . J., Nadkarni, S . K ., Weisz , G ., Tanaka, A ., Jaffer,
58 ( 2 ): 170 - 177 ; Kassavin , D . S . and Clair, D . G . 2017 . “ An F . A ., Bouma, B . E ., and Tearney, G . J. 2011. “ Intravascular
Update on the Role of Proximal Occlusion Devices in Optical Imaging Technology for Investigating the Coronary
Carotid Artery Stenting,” Journal of Vascular Surgery 65( 1 ): Artery ,” Journal of the American College of Cardiology.
271- 275 ; Knur, R . 2014 . “ Technique and Clinical Evidence Cardiovascular Imaging 4 ( 9 ): 1022- 1039 ; Chou , T . M .,
of Neuroprotection in Carotid Artery Stenting,” VASA . Fitzgerald , P . J ., and Yock , P . G . 2000 . “ Intravascular Ultra
Zeitschrift für Gefässkrankheiten [ Journal for Vascular Dis sound," Chapter 19 in Baim , D . S . and Grossman , W .,
eases] 43( 2 ): 100 - 112 ; Atkins, M . D . and Bush , R . L . 2007. Grossman 's Cardiac Caherterization , Angiography, and
“ Embolic Protection Xevices for Carotid Artery Stenting: Intervention , Philadelphia , Pa .: Lippincott Williams and
Have They Made a Significant Difference in Outcomes ? ," Wilkins ). With a combination - form radial projection cath
Seminars in Vascular Surgery 20 (4 ):244 -251 ). Walls too thin eter, a small intravascular ultrasound probe passed down the
to implant must first be made thicker. Since injection of the bore pre or midprocedurally can be used to observe the effect
ductus wall with a tumefacient or fill - tissue will affect its on wall thickness of the atherectomy just completed using
mechanical properties, the applicable pretest or pretests are the projection catheter, an angioscope useful to examine the
performed at the site following injection to thicken , for lumen interior.
example . Testing is addressed below in the section entitled f0749 ] The administration of a nominally nontumefacient
Testing and Tests. The results of testing will determine the drug specified in this section is begun sufficiently in advance
US 2019 /0247050 A1 Aug. 15 , 2019

to obtain the desired effect by the time of the procedure. If the arterial wall so that it can be implanted and not to
additional thickness is necessary, projection catheter radial strengthen the wall postprocedurally . The short- term and
projection unit injection tool- inserts, for example , can be localized hypertension subsides following the procedure and
used to deliver a tumefacient and the intravascular ultra does not represent the postprocedural strength of the vessel
sound or angioscope used to confirm the result . The ultra wall , which is measured using procedures described below
sound cable is then withdrawn and the barrel- assembly in the section entitled Testing and Tests.
passed down through the bore to initiate miniball discharge . [0754 ] Testing is performed in preparation for implanta
In this process , the radial projection catheter is not with tion following angioplasty or atherectomy, if applicable , and
drawn but remains as both atherectomy device and guide before and after administering the drug. The postprocedural
catheter. If the pretest prescribed below in the section administration of a systemic vasoconstrictor is unacceptable
entitled Testing and Tests indicates a lack of strength that with most vascular disease . An alternative approach for
will subside on healing , consideration may be given to using sustaining strength long enough to allow tissue recovery
a quick -acting tissue binder-hardener rather than aborting without delamination or pull-through is to surround the
implantation . implant with a surgical cement or protein solder that bonds
[0750 ] The use of a bipartite combination -form angio the implant to and hardens the surrounding tissue . Any
plasty -capable barrel -assembly represents a reciprocal stiffening in the ductus wall is tightly focused with little
arrangement, whereby the barrel -assembly is used to per effect on the intrinsic motility of the smooth muscle .
form the atherectomy or other treament with a viewing [0755 ] Drugs distinct in pharmacological action , response
probe in its bore . However , in this case , the probe need not time, and persistence with the individual or combined poten
be withdrawn ; if additional radial projection units are need , tial to cause the ductus wall to increase in thickness more
a matching combination - form radial projection catheter is quickly when applied topically (through a service -catheter
slid over the barrel -catheter as guide wire. Vasodilators relax or auxiliary syringe to be described ) include zymosan ;
the walls of vessels , which temporarily reduces the intimal carrageenan , dextran , uric acid , adrenalin , tumor necrosis
medial thickness , while vasoconstictors (vasopressors ) factor- alpha , sterile lipopolysaccharide and lipo -oligo -sac
effectively toughen the media , due both to increased medial charide endotoxins (see , for example , Kitazawa , M ., Oddo ,
thickness and vasotension . S ., Yamasaki, T. R ., Green , K . N ., and LaFerla , F . M . 2005.
[ 0751] Here the application ofmedication is targeted , the “ Lipopolysaccharide -induced Inflammation Exacerbates
tumefacient , as can any other fluid or semifluid therapeutic Tau Pathology by a Cyclin - dependent Kinase 5 -mediated
substance , injected into the site along the lumen wall to be Pathway in a Transgenic Model of Alzheimer ' s Disease ."
treated by an injection syringe tool- insert, as addressed Journal of Neuroscience 25 ( 39 ):8843 - 8853 ). If necessary,
below in the section entitled Radial Projection Unit Tool once the thickness will admit implants , the implants can
Inserts , so that the hypertensive effect is substantially con carry a coating of these.
fined to the treatment site , making the use of potent hyper [0756 ] Endotoxins should be kept away from the blood
tensives applicable to patients in whom the systemic use of stream . Antidotes are discussed in the literature (see , for
the same drugs would be ill- advised and avoiding vasocon example, Jiang, Z ., Hong, Z .,Guo , W ., Xiaoyun , G .,Gengfa ,
striction that reducing the luminal diameter, would hinder L ., Yongning, L ., and Guangxia , X . 2004 . " A Synthetic
intervention . Where apposite , preparatory systemic medica Peptide Derived from Bactericidal/Permeability -increasing
tion may be prescribed to increase vascular tonus and wall Protein Neutralizes Endotoxin in Vitro and in Vivo ,” Inter
thickness . national Immunopharmacology 4 ( 4 ):527 -537 ; Bhor, V . M .,
10752 ] Over time, some vasoconstrictors , such as uro Thomas, C . J., Surolia , N ., and Surolia , A . 2005 . “ Poly
tensin II, directly stimulate cell proliferation rather than myxin B : An Ode to an Old Antidote for Endotoxic Shock ,"
produce this result only indirectly as a consequence of Molecular BioSystems 1 (3 ):213 - 222 ; Ren , J. D ., Gu , J. S .,
having increased the blood pressure (see , for example , Gao , H . F ., Xia , P. Y., and Xiao , G . X . 2008 . “ A Synthetic
Zhang , Y. G ., Li, J., Li, Y. G ., and Wei , R . H . 2008 . Cyclic Peptide Derived from Limulus Anti-lipopolysaccha
“ Urotensin II Induces Phenotypic Differentiation , Migra ride Factor Neutralizes Endotoxin in Vitro and in Vivo ,"
tion , and Collagen Synthesis ofAdventitial Fibroblasts from International Immunopharmacology 8 (6 ): 775 -781).
Rat Aorta ,” Journal of Hypertension 26 (6 ): 1119 - 1126 ; [0757] Other drugs with the potential to cause an increase
Tamura , K ., Okazaki, M ., Tamura , M ., Isozumi, K ., Tasaki, in intimal-medial thickness as ligands that bind to Toll -like
H ., and Nakashima, Y . 2003 . “ Urotensin II-induced Activa receptors and thus activate immune cell responses include
tion of Extracellular Signal - regulated Kinase in Cultured midazoquinoline , loxoribine , bropirimine , sterile profilin ,
Vascular Smooth Muscle Cells: Involvement of Cell Adhe sterile flagellin (see, for example , Neish , A . S . 2006 . " TLRS
sion -mediated Integrin Signaling,” Life Sciences 72(9 ): [ Toll - like Receptors ] in the Gut. II. Flagellin -induced
1049 - 1060 ). Inflammation and Antiapoptosis,” American Journal of
[ 0753] Where its systemic use is not contraindicated , Physiology. Gastrointestinal and Liver Physiology 292 ( 2 ):
urotensin II may effectively contribute needed strength in G462-G466 ), and polyglycolic acid (see , for example,
the airway , for example , (see , for example , Chen , Y . H ., Ceonzo , K ., Gaynor, A ., Shaffer, L ., Kojima, K ., Vacanti, C .
Zhao , M . W ., Yao , W . Z ., Pang , Y . Z ., and Tang, C . S . 2004. A ., and Stahl, G . L . 2006 . “ Polyglycolic Acid -induced
“ The Signal Transduction Pathway in the Proliferation of Inflammation : Role of Hydrolysis and Resulting Comple
Airway Smooth Muscle Cells Induced by Urotensin II ,” ?in ment Activation ,” Tissue Engineering 12 ( 2 ): 301 -308 ) .
English ] Chinese Medical Journal 117 (1 ):37 -41). Systemic [0758 ] Yet other drugs with the potential to cause an
hypertensives are not used where hypertension and stenosis increase in intimal-medial thickness are oxysterols (oxidized
are primary complaints ; however the one -time and highly cholesterol) ( see , for example, Lemaire -Ewing, S ., Prunet,
localized use of a quick - acting tonus -increasing drug poses C ., Montange , T ., Vejux , A ., and six other authors 2005.
little risk . The object is to thicken and effectively strengthen “ Comparison of the Cytotoxic, Pro -oxidant and Pro -inflam
US 2019 /0247050 A1 Aug . 15 , 2019

matory Characteristics of Different Oxysterols ,” Cell Biol ral blockade or a drug such as glucagon or Valeant Phar
ogy and Toxicology 2005 21(2 ): 97 - 114 ; Joffre, C ., Leclère , maceuticals International Motofen® is accepted practice .
L ., Buteau, B ., Martine, L ., and seven other authors 2007 . [0765 ] The coronary arteries not only pulsate but move
“ Oxysterols Induced Inflammation and Oxidation in Pri with the heart, except in the most practiced hands, preclud
mary Porcine Retinal Pigment Epithelial Cells,” Current Eye ing the off -pump use of stays . On the systoles, the highly
Research 32 (3 ):271- 280 ), thromboxane B2, aldosterone elastic pulmonary artery expands 20 - 25 percent in diameter
( see, for example , Sun , Y., Zhang, J., Lu, L ., Chen , S . S ., ( see, for example, Lin , K . and Can , J. C . 2015 . “MR Imaging
Quinn , M . T., and Weber, K . T . 2002 . “ Aldosterone- induced of the Coronary Vasculature : Imaging the Lumen , Wall, and
Inflammation in the Rat Heart: Role of Oxidative Stress," Beyond,” Radiologic Clinics of North America 53 ( 2 ) :345
American Journal of Pathology 161 (5 ):1773 - 1781), and 353 ; Ishida , M . and Sakuma, H . 2014 . “ Magnetic Resonance
prostaglandin Ez (see , for example, Lees, P., McKellar, Q . of Coronary Arteries : Assessment of Luminal Narrowing
A ., Foot, R ., and Gettinby , G . 1998 . “ Pharmacodynamics and Blood Flow in the Coronary Arteries,” Journal of
and Pharmacokinetics of Tolfenamic Acid in Ruminating Thoracic Imaging 29 ( 3 ) : 155 - 162; Lin , K ., Lloyd - Jones, D .
Calves : Evaluation in Models of Acute Inflammation ,” Vet M ., Liu , Y., Bi, X ., Li, D ., and Carr, J. C . 2011. “ Noninvasive
erinary Journal 155 ( 3 ): 275 -288 ; Sidhu , P . K ., Landoni, M . Evaluation of Coronary Distensibility in Older Adults : A
F ., and Lees , P . 2006 . “ Pharmacokinetic and Pharmacody Feasibility Study with MR Angiography," Radiology 261
namic Interactions of Tolfenamic Acid and Marbofloxacin in (3 ):771 -778 ; Weissman , N . J., Palacios, I. F., and Weyman ,
Goats,” Research in Veterinary Science 80 ( 1):79 - 90 ). A . E . 1995 . “ Dynamic Expansion of the Coronary Arteries :
[0759 ] Both miniballs and stays can consist of a single Implications for Intravascular Ultrasound Measurements,"
drug or aggregations or concentric layers of drugs and can American Heart Journal 130 ( 1): 46 -51; Shelton , D . K . Jr.
be implanted adjacent or proximal to the site for implanta and Olson , R . M . 1972 . “ A Nondestructive Technique to
tion making it possible to deliver a concentrated dose to a Measure Pulmonary Artery Diameter and Its Pulsatile Varia
targeted location . Still other drugs with the potential to cause tions,” Journal of Applied Physiology 33 (4 ):542- 544.). A
an increase in intimal-medial thickness are fibrinogen , ster muscular artery more amenable of stenting as the treatment
ile lipoproteins , glycolipids , lipteichoic acid , heparan sul by the means described herein expands to a lesser degree ,
phate fragments, hyaluronic acid fragments, and imiquimod. and less still when sclerosed (see , for example, Numao , T .,
[0760] 4e. Stabilization of the Implant Insertion Site Ogawa, K ., Fujinuma, H ., and Furuya , N . 1997. “ Pulsatile
Diameter Change of Coronary Artery Lumen Estimated by
[0761] 4e( 1). Gross Positional Stabilization (Immobiliza Intraductal Ultrasound.” Journal of Cardiology (Amster
ton ) of the Implant Insertion Site dam , Holland ) 30 (1 ): 1 -8 (in Japanese with abstract in Eng
[0762 ] Peristalsis and the pulse change the radial distance lish at Pubmed ).
between the target and the longitudinal axis of the lumen , [0766 ] The difference in miniball impact force required to
changing the miniball aiming point or the stay insertion site . perforate rather than to penetrate the luminal wall ofmost
This must be considered for both arteries and contactile ductus is sufficiently large that perforations should seldom
ducti from within the lumen for miniballs and from outside occur. Except in the gastrointestinal tract, where to prevent
the ductus for stays. Generally , the pulse is frequent but can infection , a perforation demands immediate intervention ,
seldom result in misplacements of any significance , even such tiny perforations self seal quickly . Because the targeted
when implantation is under unpaced automatic positional application of anti- clotting medication allows the systemic
and discharge control. A reduction in motility can be brought dose to be minimized if not eliminated , bleeding should not
about by numerous drugs , mechanical interventions , and be a problem . If stent -jacketed , over or under- shots beyond
changes in temperature , which latter can be used to reduce the intended margins can be recovered or made functionalby
motility at the gross, histologic , and metabolic levels . extending the stent- jacket. The discharge control described
[0763] The use of temperature is addressed below in the herein is usually accomplished as an auxiliary function of
section entitled Temperature Stabilization. Where the pulse the automatic positioning system and not synchronized to
interferes , a primary method for slowing the heart is chilling ; the phase of the pulse at the aiming point.
where local anesthesia cannot be used in any event, this [0767 ] To provide an automatic ballistic triggering system
method should be considered . Even when treating a coro to actively adapt the timing ofdischarge to the instantaneous
nary artery or vein graft, on - pump operation should seldom position of the aiming point can be achieved by controlling
prove necessary . Gastrointestinal tract, ureteric, bile, and both the heart rate and discharge by pacing circuitry . This
gamete conduit duct ( vasa deferentia , fallopian tubes ) peri may become necessary with a pulse too irregular for the
stalsis , however, generate displacements that can result in operator to negotiate manually . Disease may further com
the longitudinal misplacement of miniballs and the mis plicate the variability in frequency , amplitude , and tonicity
placement in depth of stays. of smooth muscle action . More significantly , such a system
[0764 ] However, peristalsis , while different in form in is adaptable to the discharge of the airgun , with which it is
different type ductus (see, for example, Woodburne, R . T . not essential, but not a stay insertion tool, which is manually
and Lapides , J. 1972 . “ The Ureteral Lumen during Peristal triggered based upon touch . Stabilization of an insertion site
sis," American Journal of Anatomy 133 ( 3 ):255 -258 ), is may involve retarding the rate of intracellular chemical
intermittent and if necessary , readily suppressed . With stays, activity as well as gross immobilization . If needed , current
peristalsis is less problematic , because it is usually quelled cardiopulmonary bypass machines filter out the microem
as an inherent consequence of manipulating the ductus. bolisms responsible for postperfusion syndrome.
When access to the outside of the ductus has not been [0768 ] If not to synchronize the action of the smooth
created to insert a stent-jacket,medication is used . In the gut, muscle itself, automatic means for effecting discharge would
the contractive waves are slow enough to avoid , and if have to synchronize to that action , which is achievable but
necessary , temporary suppression or immobilization by neu should seldom prove essential. In an artery, absolute radial
US 2019 /0247050 A1 Aug. 15 , 2019
69
displacement of the wall by a pulse of reasonably normal posing no need to move the insertion tool or to suppress the
amplitude will be too slight to cause the target lesion to be pulse , clamping is immediately released following ejection
missed , so that unsynchronized or mistimed discharges are of the stay. Ballistic insertion is normally guided visually ,
seldom likely to result in mispositioning in such degree as to adjustment for the delay of airgun chamber to treatment site
necessitate recovery of the implant. While a hampering transit time spontaneous and the practical effect of inaccu
pulse is ordinarily dealt with using, automatic means for racies insignificant.
controlling both the pulse and discharge ofminiballs based [0773] Arteries are implanted on the pulse and the gastro
upon pacemaking circuitry avoids the need for sensing and intestinal tract aside from any contractive wave . Unless
synchronizing discharge to the intrinsic motility as an adap tissue to the sides is permitted to interfere with the passive
tive function . The use a bypass machine is avoided when resting of the tool on the ductus, the stays enter to the correct
possible but may be necessary to avert hypoxia by luminal depth without lifting or downward force by the operator.
obstruction of the barrel-assembly as well as to achieve Stay insertion tools are made in different sizes and weighted
stabilization . for the median bearing force ordinarily required to implant
[0769] Such circuitry can achieve a speed of discharge that ductus of given types to subadventital or subfibrosal depth .
compensates for the loss in time had discharge to be limited Certain positions, pathology , and the use of attachments
to the diastoles as with manual triggering . Thus, in most such as auxiliary syringes necessitate adjustment in the
situations, whether because the action is slow enough that weight or bearing force, which is applied by the operator
the operator can adapt , or, as is usual, the level (position spontaneously or with the aid of a tonometer or pressure
along the ductus ) of placement is not so critical that the gauge .
phase angle at the instant of discharge must be taken into [0774 ) Greater precision in the size of adjustment to the
account, or because the intensity and / or frequency can be passive weight required can be achieved with the aid of a
suppressed with drugs or mechanical means, the need for tonometer or pressure gauge as described below in the
either an automatic sensing and triggering system for adapt section entitled In situ test on extraluminal approach for
ing to peristalsis can be avoided whether stays or miniballs proper stay insertion bearing force . Since removing weights
are used . When miniballs must be positioned precisely , will not adjust for the weight of attachments , the adjustment
mistiming the discharge in relation to the pulse phase will is applied with the aid of the same force gauge used to
result in mispositioning ; however, the end positions of the conduct the test. To minimize inadvertent changes in bearing
miniballs will not be affected by the infolding or pleating of force during tool actuation, the tool presents the least
the intima during diastoles . resistance possible , and to allow the range of adjustment
[0770 ] The difference in the mechanical properties of necessary to treat ductus of given size and type regardless of
ductus in the elderly , especially in the arterial tree (see , for condition , control by test and touch , or if necessary , with the
example , Fonck , E ., Prod ’hom , G ., Roy , S ., Augsburger, L ., aid of a pressure measuring device, is preferred to remote
Rüfenacht, D . A ., and Stergiopulos, N . 2007. “ Effect of triggering .
Elastin Degradation on Carotid Wall Mechanics as Assessed [0775 ]. The difference in downward force to infix the stay
by a Constituent-based Biomechanical Model,” American to a significantly greater depth is sufficiently large that the
Journal of Physiology. Heart and Circulatory Physiology variance in downward force resulting from the attachment of
292 (6 ):H2754 - 763 ; Samila , Z . J. and Carter, S . A . 1981. auxiliary syringes and , unless excessive, that applied by the
“ The Effect of Age on the Unfolding of Elastin Lamellae and operator, should rarely result in excessively adluminal inser
Collagen Fibers with Stretch in Human Carotid Arteries," tion much less penetration into the lumen . Remote actuation
Canadian Journal of Physiology and Pharmacology 59 ( 10 ): in order to avoid excessive weight from being brought to
1050 - 1057) are inherently adjusted forby the preliminary, in bear down on the tool is therefore unnecessary . If necessary ,
situ testing prescribed below in the section entitled Testing verification of depth can be obtained with the aid of intra
and Tests . vascular ultrasound ; however, this negates an advantage in
[ 0771] The avoidance of instrumentation affords consid the use of stays, which is complete avoidance of the lumen .
erable simplification . The stay insertion tool is weighted and [0776 ) Similarly, a catheteric device is not introduced into
made with a base (working end , distal end ) configured to the lumen to support the arterial wall from within . This is
effect subadventitial insertion when passively resting upon done , however, in the gastrointestinal tract where entry is
the ductus and elevated by the pulse . Even when the nonincisional. In blood vessels, increased resistance to com
surrounding tissue encroaches upon or clings to the tool pression can often be accomplished merely by pinching the
alterring its effective weight (which can be eliminated ductus without the trauma of entry . Since stay insertion is
through use of a lubricant), the pulse, transmitted as tactual best timed to the distention maxima or outward force exerted
feedback , is clearly superimposed upon the restraint, adjust by the smooth muscle, smooth muscle suppressive mea
ment accomplished if not spontaneously , then with the aid of sures, whether relaxants, cuffing, or clamping , are best
a tonometric or pressure sensing device . Extension or retrac avoided in arteries butmay be advantageous in the ureters or
tion of the entry wound should not be necessary . gastrointestinal tract.
[0772] The pulse is felt over an interval sufficient to [0777] Unless otherwise inadvisable , when the pulse is
anticipate successive peaks despite any extrasystoles, ecto weak or the artery sclerosed , as addressed below in the
pic beats , or other arrhythmial (arrhythmical) concomitant. section entitled Blood - grooves on Muzzle -heads for Use in
Should a rapid or erratic pulse not have responded to Blood Vessels , medication to raise the blood pressure is
medication given in preparation for the procedure and make beneficial ( see, for example, McEniery, C . M ., Yasmin , K .,
it necessary , a hemostat (hemostatic clamp, arterial forceps ) Maki-Petaja , M ., McDonnell , B . J., Munnery, M ., and 4
introduced through a second laparoscopic incision is used to others 2010 . “ The Impact of Cardiovascular Risk Factors on
clamp off the segment to be treated no longer than it takes Aortic Stiffness and Wave Reflections Depends on Age: The
to insert one stay; the recovery of a mispositioned stay Anglo - Cardiff Collaborative Trial (ACCT III),” Hyperten
US 2019 /0247050 A1 Aug. 15 , 2019

sion 2010 56 (4 ):591-597 ; Vyssoulis, G . P ., Pietri, P . G ., various drugs , such as esmolol allow slowing the pulse ,
Karpanou , E . A ., Vlachopoulos, C . V ., and 4 others 2010 . others slow peristalsis, and opioids can stop peristalsis
“ Differential Impact of Metabolic Syndrome on Arterial outright. Such a drug can be introduced into the lumen wall
Stiffness and Wave Reflections: Focus on Distinct Defini as a stay , radial projection unit injection tool-insert injectant ,
tions,” International Journal of Cardiology 138 (2 ): 119 - 125 ; or fully absorbable medication miniball preceding stenting
Haynes, F . W ., Ellis , L . B ., and Weiss , S . 1936 . “ Pulse Wave implantation proper. In a bypass -angioplasty mixed proce
Velocity and Arterial Elasticity in Arterial Hypertension , dure where the chest is open , the use of a stabilizer apparatus
Arteriosclerosis , and Related Conditions,” American Heart is standard , and a coronary artery can usually be further
Journal 11 (4 ):385 -401; Bramwell , J. C .McDowall, R . J. S ., stabilized by lifting it away from the surface of the heart and
and McSwiney, B . A . 1923 . “ The Variation of Arterial securing it in position with tape or stitches.
Elasticity with Blood Pressure in Man (Part I),” Proceedings [0782] When the pulse is erratic , one way to avoid the use
of the Royal Society of London . Series B , 94 (656 ):1-vi). of circuitry to automatically synchronize discharge to the
[0778 ] Ballistic insertion, from within the ductus, is timed pulse during automatic (machine - controlled ) discharge in an
reciprocally for the maximum resistance looking radially artery is to make the incision for inserting the stent- jacket
outward . Peristaltic action is usually slow enough to allow prior to discharge , then using a mosquito (Halsted , Kelly,
insertion with stays or miniballs without drugs ( spasmolyt Rochester ) forceps or hemostat, for example , to compress or
ics , antispasmodics , antispasmogenics — loperamide , salbu clamp the artery only so much and briefly enough to
tamol, co -phenotrope , dicyclomine, hyoscyamine , propan suppress the pulse. This is not recommended when a barrel
theline bromide , atropine sulfate , and opioids). When the assembly is used to implantmedication and /or other thera
onset time of the drug allows, the procedure may commence peutic substance - containing miniballs , which does not
with the implanting of stays or miniballs that consist of or necessitate outside access or incision at any time to place
include this medication . If necessary , the rate and force of implants which are completely absorbed .
peristalsis can be adjusted . Adjustment in the rate and force [0783 ] The use of stays necessitates access by means of a
of peristalsis may be necessary to achieve precise placement local incision in any event. Initiating a ß , - or cardioselective
during ductus-intramural implantation or to propel drug beta -blocker (beta adrenergic blocker ), such as atenolol
carrier nanoparticles, for example , past less to more strongly ( Tenormin® ); a calcium channel blocker , such as diltiazam
magnetized impasse -jackets placed at intervals along the (Cardizem® , Dilacor® ) or verapamil (Calan® , Isoptin® );
tract. or digoxin (Lanoxin® ) over the period preparatory to the
[0779 ] Adjustment takes the form of medication , which procedure serves to moderate a problematically fast or
can be locally introduced in a targetd manner by injection erratic heart rate or high blood pressure ( see , for example ,
syringe tool-inserts or as medication miniballs, for example , Landauer, A . A ., Pocock , D . A ., and Prott , F . W . 1979 .
or the introduction of contents into the lumen . In the “ Effects of Atenolol and Propranolol on Human Perfor
digestive tract, the latter will usually involve simply ingest mance and Subjective Feelings ,” Psychopharmacology
ing ordinary food supplemented to include agents that 60 (2 ): 211- 215) .
support the procedure . Whether in the gastrointestinal tract, [0784 ] 4e( 2 ). Tissue Stabilization at the Treatment Site
ureters , or gamete transport conduits, peristalsis is rarely so [0785 ] 4e( 2 )(a ). Temperature Stabilization
fast as to interfere with miniball discharge when adequate [0786 ] Thermal and cryogenic methods to include ther
viewing means are present, or stay insertion using touch . moplasty and cryoplasty have long been used to remove
When the ductus is manipulable , merely handling it will diseased tissue . However, subinjurious chilling of targeted
often suppress peristalsis . Arresting movement in any ductus tissue can also be used to increase its mechanical and
through upsteam clamping should not be necessary . Ateries chemical, or metabolic , stability, that is, reduce :
can usually be clamped long enough for each stay to be [0787] 1. The mobility (plasticity , deformability , nonfix
inserted . ation ) of soft tissue such as mucosal as a hindrance to
[0780 ] Applied from within the lumen , ballistic implanta shaving or abrasive removal (Chick , H . and Lubrzynska, E .
tion preparatory to the placement of a magnetic stent allows 1914 . “ The Viscosity of Some Protein Solutions,” Biochemi
prepositioning of the stent- jacket , which can then serve as a cal Journal 8 ( 1 ): 59 -69 ) , and the rate of chemical activity
motility restraining mantle or cuff ; the stent-jacket side within the tissue (see , for example, Yang , W . J. and Mochi
straps, or belt-straps, are tightened only so long as it is zuki, S . 2003. “ Low Temperature and Cryogenic Applica
necessary to prevent the slide-slit or side-slot from opening tions in Medicine and Surgery ,” in Kakaç , S ., Avelino , M . R .
in response to the pulse . Once implantation has been com and Smirnov, H . F . Low Temperature and Cryogenic Refrig
pleted , the barrel-assembly is withdrawn and the fabric eration , Dordrecht Holland : Kluwer Academic Publishers ).
backed hook and loop (such as Velcro® , made by the firm [0788] 2 . Themagazine clip to slightly reduce miniballs in
of the samename) belt - straps loosened or cut off to allow the diameter.
side - slit or side -slot to comply with the pulse. For ballistic [0789] 3 . The muzzle -head , or
implantation , cuffing in this manner is better than clamping , [0790 ] 4 . The entire barrel -assembly can be used to pro
because it eliminates movement of the lumen wall without mote luminal contraction about the muzzle -head as wll as
completely cutting off circulation past the cuff as well as reduce the rate ofmetabolic activity in the cells.
protects against the possibility of a perforation if the exit [0791 ] Change in temperature, whether an increase or
velocity has been set too high . decrease , stimulates smooth muscle to contract (see , for
[0781 ] The use of a cuff to suppress a problematic pulse example , Tsai, C . S . and Ochillo , R . F . 1989. “ Low Tem
requires that the muzzle - head be small enough in diameter perature and Muscarinic Receptor Activities," Cryobiology
to allow some blood to move past it through the stent 26 (5 ):485 - 95 ; Holzer, P. and Lembeck , F. 1979 . “ Longitu
jacketed segment containing the muzzle -head while tight- dinal Contraction of Isolated Guinea -pig Ileum Induced by
ened without injury to the lumen wall. Adenosine and Rapid Cooling,” Naunyn - Schmiedeberg 's Archives of Phar