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com

Br J Ophthalmol 1999;83:1235–1240 1235

PERSPECTIVE

Closer to nature: new biomaterials and tissue engineering in

ophthalmology
Bruce Allan

Ophthalmology has a long history of successful conven- The pattern of protein adsorption varies between mate-
tional biomaterial applications including viscoelastics, rials, and influences subsequent biological interactions.3
drug delivery vehicles, contact lenses, and a variety of Soluble proteins compete for material surface bonding
implants. A myriad of further possibilities exists as the sites after implantation in a “race for the surface”.4 DiVer-
margins between conventional material concepts and ential adsorption is determined by factors including
natural tissues continue to blur, and biomaterials move implant surface chemistry, concentration in the fluid
closer to nature. Genetically engineered materials (for surround, and intrinsic surface reactivity for each protein
example, hyaluronic acid and fibrin tissue glues) harness- constituent of the adsorbed film. Adsorption is suYciently
ing the power and accuracy of biological systems in rapid that cells may never encounter an unconditioned
molecular synthesis are becoming commonplace. New material surface.5–7
synthetic surfaces capable of upregulating or downregulat- Changes in tertiary structure (molecular folding) occur
ing biological responses at the tissue/material interface are after adsorption. Proteins are probably partially denatured
starting to reach clinical application; and an emerging but retain modified biological activity.3 7
understanding of matrix/cell interactions may soon allow
engineered replacement for a range of tissues in the eye. Foreign body inflammation
Inflammatory cell interactions with protein conditioned
Synthetic materials in ophthalmology surfaces are incompletely understood.7 The classic foreign
A basic classification divides materials according to their body response involves adhesion of, firstly, neutrophils
primary bonding structure into ceramics (ionic bonding), then macrophages to the material surface. Cytokine elabo-
metals (metallic bonding), and polymers (covalent bond- ration activates fibroblasts, and implants are walled oV by
ing). Modern ophthalmic implants are almost all fabri- a variable thickness of new collagen. Macrophages persist
cated from synthetic polymers. at the material surface in the long term, and commonly
Polymeric materials are composed of long chain aggregate to form multinucleate giant cells. The extent to
molecules (polymers) synthesised from repeat units
(monomers) whose chemical character and reactivity
determine many bulk properties. Most polymer chains
have a covalently bonded backbone of carbon atoms joined
to a variety of pendant groups. For siloxanes (“silicone”),
an important group of synthetic biomaterials, this
backbone consists of alternating atoms of silicone and oxy-
gen. Molecular chains vary in length and are irregularly
intertwined, although areas of regular arrangement (crys-
tallinity) may exist. Cross linkage density and the density of
secondary bonding further determine bulk properties for a
given polymeric material.1

Biological conditioning after implantation

Secondary bonding mechanisms (for example, hydrogen
bonds, van der Waals forces) are particularly relevant to
biological systems, and are thought to have an important
role in modulating protein conditioning—the process by
which relatively inert polymeric material surfaces are
rendered biologically active by contact with the tissues or
body fluids.2
Protein conditioning is partly determined by surface
reactivity, which varies between materials. Surface mol-
ecules tend to have more unoccupied bonding sites than
molecules buried within a material, and are at a relatively Figure 1 A simple two dimensional lattice illustrating surface reactivity.
higher energy state (Fig 1). Interfacial free energy for a Molecules within the lattice are at a lower energy state (darker shade)
than molecules at the surface which have more unoccupied bonding sites
material surface is a measure of the number of free bond- (arrows). Interfacial free energy is a measure of the number and reactivity
ing sites per unit area and their reactivity. Soluble proteins of unoccupied bonding sites at the interface between a material surface and
can often achieve a lower energy state by occupying these its surroundings. Polymers such as poly(tetrafluoroethylene) (PTFE,
Teflon) have a have a relatively unreactive surface and are less prone to
free sites, and synthetic materials are quickly coated after biological spoilation in aqueous systems than hydrophobic materials (for
exposure to a biological environment.3 example, silicone, PMMA) with a higher interfacial free energy.
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1236 Allan

Figure 2 3T3 fibroblasts cultured for 24 hours with bromodeoxyuridine (BRDU) to label new DNA shows cell adhesion and division is greatly reduced
for phosphoryl choline copolymer coated (left) versus uncoated (right) poly(methylmethacrylate) (PMMA). (Courtesy of Dr Andrew Lloyd, University of
Brighton.)

which macrophages remain active in elaborating pro- bacterial colonisation, and would promote normal diVer-
inflammatory cytokines is unknown.8 Some continued entiation in the surrounding tissues.13 Specific require-
inflammatory activity can be inferred from progressive ments for biocompatibility vary with the application and
encapsulation responses, as with glaucoma filtration site of implantation, and may conflict. For stable tissue
implants for example; and may be influenced by chemical integration, surface modification to promote cell adhesion
(for example, material degradation) or mechanical factors is desirable. For fluid contacting applications, the reverse is
(for example, implant stability and micromotion).7 8 true: biocompatibility may be significantly impaired by cell
An insight into the influence of protein conditioning in adhesion.
the initiation of inflammatory responses at material
surfaces is available from animal studies examining
neutrophil and macrophage accumulation on intraperito- Bioinert materials
neal implants in mice.9 10 Pretreating with albumin Bioinert materials non-specifically downregulate biological
(occupying surface binding domains with a relatively inert responses. These materials were developed originally as
protein) reduces inflammatory cell recruitment. Comple- non-thrombogenic surfaces for vascular surgery, and are
ment can be activated by adherent immunoglobulins or often referred to as haemocompatible; but have a number
directly via the alternate pathway to initiate neutrophil of possible applications in the eye and other biological fluid
recruitment. Both complement depleted and hypogamma- contacting environments. In addition to reducing fibrin
globulinaemic mice are capable of mounting a normal deposition and platelet activation, bioinert materials resist
inflammatory response, however, indicating that neither biological spoilation generally. Protein deposition, bacte-
immunoglobulins nor complement are actually required to rial and inflammatory cell adhesion are all reduced. Poten-
initiate inflammation. In contrast, fibrinogen depleted tial ocular applications include contact lenses, intraocular
mice do not mount a normal inflammatory response unless lenses, glaucoma drainage devices, keratoprosthesis optics,
the implant is precoated with fibrinogen. Fibrinogen adhe- and vitreous substitutes.
sion would therefore appear to have a pivotal role in initi- Successful development of synthetic bioinert materials
ating inflammatory cell recruitment.9 has been derived from mimicking natural surfaces. A new
Cells do not behave as simple charged spheres during group of materials has been polymerised from monomers
adhesion and spreading. Although some correlation based on phosphoryl choline, the hydrophilic head group
between hydrophilicity (an index of interfacial free energy) of phospholipids (lecithin and sphingomyelin) which
and biological reactivity has been observed for material predominate in the outer envelope of mammalian cell
surfaces, independent variables including surface texture membranes.14 15 In vitro assays for a range of phosphoryl
and receptor specific binding are also important.11 choline (PC) copolymer coated surfaces demonstrate a
Fibrinogen is thought to undergo conformational changes generalised reduction in protein and cell adhesion (Fig 2)
after surface binding to reveal receptor specific domains, in comparison with uncoated controls.16–18 Clinical trials in
which encourage inflammatory cell adhesion.7 10 contact lens wearers show reduced protein and lipid
spoilation,19 and increased comfort20 for patients wearing a
Bacterial colonisation PC based hydrogel lens in one eye and a conventional
Another aspect of the “race for the surface” after material hydrogel lens in the other.
implantation is competition between bacteria and tissue The mechanism by which PC polymers resist protein
cells for reactive domains at a conditioned surface. If bac- and cellular adhesion is the subject of continuing debate.
terial colonisation is established on a synthetic surface, it is The natural cell wall phospholipid bilayer is self assem-
diYcult to eliminate because of enhanced bacterial bling. Stability is achieved by sequestering hydrophobic
resistance to both antibiotics and host defence mecha- lipid moieties to the interior in an aqueous environment.
nisms for organisms encased in biofilm.4 Tissue integration PC polymers may mimic natural cell surfaces by preferen-
is prevented by continued inflammation, and infection is a tially adsorbing a self assembling phospholipid monolayer
common cause of implant extrusion. Conversely, good tis- in the correct configuration.21 Alternatively, resistance to
sue integration and pre-existing colonisation with eukaryo- protein and cell adhesion may be mediated by properties
tic cells tend to protect from bacterial adhesion.4 12 intrinsic to the PC molecule.14 15 PC is zwitterionic,
possessing both positive and negative charges in overall
Biocompatibility electrical neutrality. This juxtaposition attracts a large and
Biocompatibility is a multidimensional concept, which stable hydration shell, which eVectively lowers interfacial
escapes easy definition. In general, an ideal biomaterial free energy and the access to bonding sites for adsorption
would not induce an inflammatory response, would resist (Fig 3).
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New biomaterials and tissue engineering in ophthalmology 1237

Figure 3 Hydrogels reduce their interfacial free energy in aqueous systems

by trapping a shell of water molecules (open circles) which tend to shield
their reactive domains (arrows). Bioinert polymers and natural cell
surfaces may resist non-specific adsorption through this micromolecular
exclusion zone.

The ability to trap water and exclude non-specific mac-

romolecular adsorption may be of fundamental
importance to natural tissue surfaces. Conventional
synthetic hydrogels (weakly cross linked, hydrophilic, soft
polymers) are generally more biologically inert than might
be expected in comparison with non-hydrated polymeric Figure 4 Adsorption of soluble adhesion molecules (thick lines) to a
materials with similar surface energy characteristics. Poly- hydroxyapatite surface may induce a conformational change resulting in
the exposure of previously sequestered integrin binding domains (jagged
(hydroxyethylmethacrylate) (HEMA), for example, depos- lines), promoting cell adhesion. The eVect of incorporating
its cells less readily than poly(methylmethacrylate) integrin-ligand-peptide sequences on cell behaviour in synthetic matrices
(PMMA) when used as an intraocular lens material.22 and artificial surfaces is currently being explored.
Again, this may be explained by a reduction in available
bonding sites caused by water trapping at the material sur- Cytoskeletal microfilaments (for example, actin, myosin,
face. actinin, and tropomyosin) controlling cell shape and
Polyethylene oxide polymers (PEO) are another poten- migration are coupled through specialised cell membrane
tially useful group of bioinert materials, which loosely proteins (integrins) to extracellular adhesion molecules
reflect some of the properties of natural mucous mem- (for example, fibronectin, laminin, vitronectin, throm-
brane surfaces. PEO polymers are highly hydrophilic, bospondin) present in basement membranes and tissue
mobile, long chain molecules, which trap a large hydration matrices.31 32 An interfacial layer of hydroxyapatite may
shell. They enhance resistance to protein and cell adsorb adhesion molecules in a favourable configuration
spoilation when grafted onto a variety of material (Fig 4), exposing a high density of integrin ligand
surfaces.23 24 PEO polymers are also amenable to end domains.33 34 This promotes the formation of focal
group coupling for surface immobilisation of biologically adhesions (Fig 5). Without these anchoring points, cells
active molecules (for example, heparin) to add specific are unable to express a normal phenotype or respond to
functionality.24 trophic cytokines during surface or matrix colonisation.35 36
No synthetic biomaterial surface is truly bioinert, but Growth factors may also be adsorbed to hydroxyapatite
materials such as PC and PEO polymers would appear to surfaces in a favourable configuration, further promoting
oVer considerable promise in downregulating some of the tissue integration.25 37
deleterious biological reactions associated with conven- Current eVorts are being directed towards distilling the
tional polymeric materials in ophthalmology. essence of cell adhesion requirements in new biomaterials
incorporating minimal peptide sequences from the adhe-
sion molecules responsible for integrin binding. The best
Bioactive materials characterised of these integrin ligand domains is the RGD
Zero reaction is often an inappropriate biological reaction sequence (arginine-glycine-aspartate) present in fibro-
to implanted materials. This is particularly true in nectin, vitronectin, collagen, and laminin.31 Polymer matri-
situations where good tissue integration or tissue regenera- ces incorporating RGD sequences enhance cell
tion is paramount. integration.38 A variety of integrins bind to the RGD
Success in creating materials which encourage cell adhe- sequence. Enhanced cell adhesion is relatively non-
sion, tissue integration, and tissue regeneration has been specific, and inflammatory cell binding may compete with
derived from mimicking the natural interface between hard regenerative cell populations for the available binding
and soft tissues. Bioactive materials upregulate specific ele- domains. With the incorporation of more selective integrin
ments of the biological response at the tissue/material binding sequences, it may be possible to further encourage
interface.13 An important group of bioactive materials regenerative responses at the expense of inflammation and
encourages bonding with the soft tissues through an inter- wound healing.39
facial layer of hydroxyapatite,25 the predominant mineral
constituent of bone. Porous hydroxyapatite coral implants
are already widely used in ophthalmology as post enuclea- Tissue engineering
tion ball implants.26 A keratoprosthesis with a coral skirt Beyond simply improving tissue integration for synthetic
element has also been described.27 Synthetic bioactive implants, functional tissue regeneration within artificial
materials, including a range of hydroxyapatites and glass matrices or on artificial surfaces is now possible. This is
ceramics, have been developed for hard tissue replace- where the new science of tissue engineering diverges from
ment. They are available as coatings, resorbable gels, and conventional biomaterials research. Tissue engineering
ceramic-polymer composites.25 Existing applications in- combines elements of engineering and materials science
clude ossicular replacement in degenerative middle ear with genetics, molecular, cell, and developmental biology
disease,28 periodontal bone regeneration,29 and orbital floor in organ replacement and organ regeneration.40 41 Engi-
repair.30 neered replacement tissue constructs are already in devel-
Hydroxyapatite based bioactive implants are thought to opment for a variety of tissues including skin, cartilage,
promote normal diVerentiation in surrounding tissues by nerve, liver, kidney, muscle, heart valves, and blood
providing an enhanced environment for cell adhesion.25 vessels.42–50
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1238 Allan

Figure 5 A scanning electron micrograph showing a human osteoblast reaching pseudopodia out to hydroxyapatite particles (lighter areas) dispersed
within a bioactive ceramic-polymer composite (HAPEX) (scale bar = 10 µm). (Courtesy of Dr Lucy Di Silvio, The IRC in Biomedical Materials,
University of London.)

Many organs have regenerative capacity and will regen- adhesion molecules, and growth factors when the matrix is
erate rather than scar in the absence of matrix destruction. enriched before use. Clinical trials of these skin constructs
Good examples include liver, lung, and epithelial surfaces in conditions of retarded healing (diabetic foot ulcers)
throughout the body including skin and the ocular surface. appear to indicate that cell viability within the engineered
One strategy in tissue engineering with possible relevance replacement dermis is an important determinant of
to ophthalmology is the replacement of damaged tissue successful regeneration.53
with engineered matrices to restore a normal cell adhesion Resorbable matrices for ocular surface regeneration
environment. Good regenerative responses have been analogous to current artificial skin constructs may have
observed clinically after extensive burns using artificial skin applications in external disease, refractive surgery, oculo-
constructs based on collagen/proteoglycan coprecipitates.51 plastics, and glaucoma.
Enhanced axonal regeneration has also been demonstrated Progressing from essentially two dimensional constructs
in a rat model,45 in which a portion of the sciatic nerve is (for example, skin or conjunctival replacement) to solid
replaced by a similar collagen/proteoglycan coprecipitate
organ replacement requires careful consideration of the
within a collagen tube. These matrices are degraded and
nutrient environment. Most cells are unable to survive in a
replaced by autologous matrix from regenerating cells.
matrix at greater than approximately 500 µm from a diVus-
Collagen cross linkage density is varied to match the rate of
matrix degradation with the rate of healing for the tissue to ible nutrient source (blood, aqueous, synovial or cerebro-
be regenerated. Pore size and directionality are also spinal fluid).54 This limitation for non-vascular tissues
controlled to optimise results in the target tissue.52 immediately suggests the cornea as a realistic target for tis-
In some circumstances it may be desirable to preseed the sue engineered replacement. Perfusion culture systems, or
matrix with donor cells in order to normalise the initial cell “bioreactors”, developed for seeding artificial cartilage
signalling environment, rather than waiting for autologous matrices could be modified and applied to the develop-
cells to populate an engineered matrix. For epithelial ment of a true replacement cornea. Early studies have
surfaces, the key to regeneration appears to be a already demonstrated normal morphology and expression
normalised substrate. In skin, for example, dermal replace- of phenotypic markers for engineered corneal constructs
ment promotes epidermal regeneration. Allogeneic dermal (Fig 6) with an epithelial and endothelial layer.55 56 Signifi-
fibroblasts are only weakly antigenic. Neonatal foreskins, cant problems relating to source materials and the optimi-
discarded at circumcision are used as a source of sation of matrix clarity remain; but at the current rate of
fibroblasts for cell seeded artificial skin constructs. These progress, conventional corneal transplantation may be
young cells have immense replicative potential. Incredibly, obsolete within quarter of a century. Theoretical advan-
an area of artificial skin construct the size of a football tages of tissue engineered corneal replacement could
pitch can be seeded from a single donor foreskin.53 Cells include no tissue supply problems, no rejection, and no
seeded within a collagen matrix produce proteoglycans, iatrogenic disease transmission.
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New biomaterials and tissue engineering in ophthalmology 1239

tained intraocular delivery of a variety of cytokines could

potentially be achieved using immunoisolation technology.
Biomaterials research spans the full spectrum of
possibilities for restoring tissue function from entirely syn-
thetic, non-degradable implants and prostheses, through
hybrid cell/matrix constructs, to fully resorbable matrix
templates for organ regeneration. Developments through-
out this exciting spectrum will change the landscape of
medical practice in the coming century. The immediate
challenge for ophthalmology is to translate existing
bioinert, bioactive, and tissue engineering biomaterial con-
cepts into applications relevant to the prevention of visual
loss.
BRUCE ALLAN
Moorfields Eye Hospital, City Road, London EC1V 2PD

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Closer to nature: new biomaterials and tissue

engineering in ophthalmology
BRUCE ALLAN

Br J Ophthalmol 1999 83: 1235-1240

doi: 10.1136/bjo.83.11.1235

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