Contents

2-Commercial non-invasive products: 2

3- Noninvasive continuous glucose monitoring: 5
3-2 Optic 9
3-2-1 Dia Mon Tech company 10
3-2-2 challenge of optical method 10
3-3 Multisensory 11
3-3-1Challenge 12
3-4 Electromagnet 12
3-4-1 Beneficial 13
3-4-2 Challenge 13
3-5 Reverse Iontophoresis 15
3-5-1 Challenge 15
3-5-2 Saliva sample for RI 16
3-5-2-1 saliva glucose based on patch for electrochemical reaction 16
3-5-2-2 Challenge of Saliva sampling based RI 17
3-5-3 Nemaura Med Company (SugarBeat patch system) 17
3-6 enzyme-less based sensor for glucose monitoring 18
3-6-1 Beneficial 19
3-6-2 Challenge 19
3-7 Contact Lens 21
3-7-1-1 Challenge 21
4- Commercial minimally invasive products: 22
5- Minimally invasive continuous glucose monitoring: 24
5-1 Introduction: 24
5-2 Single needles 24
5-2-1 Dexcom Company 24
5-2-1-1 Challenge: 25
5-2-2 Abbott Company 28
5-2-2-1 Challenge 28
5-3 Multi-needles 28
 5-3-1 Multi-functional Microneedle 29
5-3-2 Single-functional Microneedle 29
5-3-2-1 K’Watch Glucose 29
6-Discussion 30
6-1 Non-invasive Discussion & Author’s Idea for Non-invasive Discussion 30
6-2 Minimal invasive discussion 32
6-2-1 Author’s Idea for Minimal Invasive Discussion 32
References: 34

1-Commercial non-invasive products:

Table 1 A few commercial product information for continuous blood glucose monitoring:
# Device Technology advantages Disadvantages/ Image
Challenges

1 GlucoWatch Reverse iontophoresis-ISF Easy to Effect of

manufacture of penetration and
electrode, non- holes of skin,
invasive, checking short time in the
every 10minute, market,
It was removed in
user friendly susceptible to
the market owing to
sweating, not
low accuracy.
able to detect
rapid change in
glucose level, low
accuracy, should
be placed on
intact and healthy
skin, temporary
irritation

2 Pendra Impedance spectroscopy, Non-invasive, Poor accuracy,

it uses electromagnetic detecting every costly, short time
waves. minute but the available in
average of data is marketing,
shown, continuous
detection.

3 C8 Medisensors Raman spectroscopy Noninvasive, Not user friendly

sensing how light everywhere,
scatters upon maybe other
Not available in the glucose in the skin, radars interfere
market. a reading is on this
measured every performance
10 minutes and
transmitted to a
cell phone.

4 GlucoTrack Combination of: (radio Noninvasive, Too complex

waves) device, costly
• Ultrasound
Available in the
market in future.
 • Thermal
• Electromagnetic sensing

5 DermalAbyss Chemical fluorescence, Noninvasive, N/A

continuous, color
It is not qualified
changes in
precise, costly
Not available in proportional to
market (just glucose level
research)

6 Nemaura Med By passing a mild, non- 1-Completely non- Challenge:

Company perceptible electric invasive, 2-
1-shelf-life of
current across the skin, detecting every
battery isn’t yet
the company’s new BEAT 5minute, there is
clear. But Sensor
SugarBEAT system technology draws select no needle.3- It is
lifespan is
patch molecules, such as able to stick onto
18month since it
glucose, into the the skin for 1 day
was bought.
disposable skin-patch. or 14days. 4- It
Website is opened uses a “gentile, 2-SugarBEAT’s
Reverse iontophoresis
by VPN: silicon-based” MARD (Mean
hypo-allergenic Absolute Relative
https://
adhesive that will Deviation —
nemauramedical.co Device:
supposedly measure of CGM
m/
daily disposable adhesive eliminate / cut accuracy) was Package
https:// skin-patch connected to a down skin 19.28% in the 61-
sugarbeat.com/ rechargeable transmitter. irritation or 80 mg/dL range,
insertion problems and 26.92% in the
**According to
experienced with 40-60 mg/dL
the mentioned
It is available in most CGM use, 5- the range. But its
website
European’s countries. transmitter is not performance in https://sugarbe
disposable but low 80mg/dL is .com/support/
rechargeable,6- not available which indicate
the shortest clearly and is not how to work an
warmup time of suitable, while insert, recharg
any CGM on the Dexcom accuracy battery.
market (within is better than this
25minute).7- one in low
predictive 80mg/dl.
readings up to 20
minutes in
advance, with
 alarms to alert the
user before any
Low or High
actually occurs. 8-
the lowest prices
compared to
others. 9- it is real
time continuous
glucose
monitoring.

7 DiaMonTech Based on mid-infrared Easy to use in a N/A

(German Company) technique, which light is device like watch,
emitted to skin and then necklace, etc.- not
light is converted to heat, disposable
More probably will be caused by interaction and accessories.
released by 2021. absorption of glucose.

Website: Relative all patents of this

https:// company are based on
www.diamontech.d optical approach.
e/
hauptversammlung

Note 1: N/A indicates that information is not available.

Note 2: The companies’ name was written in Red, which they are so practical and on a fast track in success.

Note 3: All electrodes of Reverse Iontophoresis and also Minimally invasive systems were made of reference
electrode: Ag/AgCl, working electrode: Ti, or Pt, and Pt electron counter electrode.

2- Noninvasive continuous glucose monitoring:

All methods of noninvasive glucose monitoring, which are mentioned in this report, have
indicated in Fig 1, followed by advantages and challenges of each technique has been
introduced in Table 2,3,4. In fact, this figure was modified because these methods are being
studied much more and are seen in more patent studies and research, which may indicate
perspective of principle devices for non-invasive continuous glucose monitoring and it outlooks
future and be considered for future company’s products.

Figure 1 Different classification of non-invasive blood glucose measurement, plot was adopted by [4].
Table 2 Table indicates advantages and disadvantages of spectroscopic techniques [5].
Table 3 Advantages and challenges in non-invasive glucose monitoring for transdermal glucose extraction techniques [5].
 Table 4 Advantages and challenges in non-invasive glucose monitoring for other techniques [5].

2-1 Optic
According to Figure 1, it shows different techniques for optical-based sensors. Optical methods
have diverse techniques for non-invasive continuous glucose monitoring and this method has
made significant progress, for example as can be seen in table 1 number of 2,3,7 are non-
invasive devices based on optic that 7 is under developing among others.
2-1-1 Dia Mon Tech company
According the earlies related patent in 2021[6], number 7 (DiaMonTech) Fig 2 is made of body
materials such as Si, Ge, ZnS, ZnSe as an optical medium, which is adhered on the skin to detect
and absorb light beam directly without wasting light energy in interface of device and sensor,
laser light due to its absorption and excitation are high resolution, iris diaphragm, mirror for
increasing accuracy of defection, and optical chopper, etc. It is supposed to be used different
modulation frequencies between 5-2000 Hz in pulse waves to send light either in deep layer or
nearer layer for interaction with glucose molecules if they exist in ISF or vascular and then heat
and light are returned back to analyze. Unfortunately, despite this product is not still available
in the market and is coming soon, more detailed information including accuracy, reliability and
etc. don’t exist.

Figure 2 the figure A, B indicate structure of optical sensor adopted by https://www.diamontech.de/#product , figure C
illustrates the inner and infrastructure of the optical sensor of this company which number’ names are able to be found in
patent[6].

3-2-2 challenge of optical method

Although the optical method is very user friendly with quick response, its selectivity is low
because a large number of metabolites are present in the human body which have similar
optical signature as glucose, for example [4]. Moreover, disadvantages and advantages of other
optical methods are mentioned in detail in Table2. Even though optical technologies for glucose
determination are available, most of them are for laboratory use due to the size, cost, and
complexity of operation [7]. Sometimes optical technique is not suitable because of low
sensitivity and reliability of spectral signal-to-noise level and skin thickness and the skin color or
sweating causes problems in receiving optical information.[7]. As seen in table 5, some
commercial products for glucose monitoring based on optics were compared together their
beneficial and drawbacks [4]. For mentioning the main challenges, first, this method shows less
accuracy except the first one because it was built with a combination of three radio waves as a
multisensory makes it better accuracy but it has more varieties and complex to manufacture
and high cost, it will be mentioned in the multisensory section. In addition, creating heat by
metabolic and its absorption is needed for highly precise devices because thermally biological
metabolism is negligible and is taught to detect and it also needs a lot of electronic tools and it
makes it hard to achieve a small portable device. Therefore, this is the reason in this study
would prefer to focus on other non-invasive alternative methods.
Table 5 Companies which produce CGM based on Optical methods.

2-2 Multisensory
For ideal noninvasive devices, a convenient, accurate, easy-to-use, portable, and low-cost
diagnostic tool for diabetes is highly demanded. It is highly recommended that a sensor will
show a lot of analytical information to patients and doctors or by using multisensory help to
make sure for their diagnosis and even each parameter confirms each other and it is made to
achieve high accuracy.
2-2-1Challenge
In multisensory there are a lot of versatile sensors which makes it more sophisticated and
complex and increases numbers of variables. So according to the above, it is really difficult to
manufacture multisensory devices, which can be seen in Fig 3 although this sensor is highly
suggested for the future of sensors to detect all variations of health care. The latest research
has introduced multisensory based on temperature, humidity, and impedance [8]. But this
system is complex to develop, costly, and also not easy to carry. This is why this study does not
focus on it and multisensory needs huge progress to be miniaturized and be simplified and this
system will be too sensitive and has some lots of variables towards other environmental
factors, such as temperature, humidity, etc.

Figure SEQ Figure \* ARABIC 3 The multisensory-based noninvasive

figure 3 illustration that one an example of experimental multisensory.

2-3 Electromagnet
Electromagnetic approach is one promoting approach of non-invasive methods. The
importance of the electromagnet approach in sensors and their bright future made us examine
them separately. According to Table 1, number 2 and 4 are examples of applying
electromagnets into devices. Interestingly, with regard a patent belongs to 2020 (Fig 4),
electromagnetic and using a magnet with 0.234 Tesla with small size and shape allows it to be
placed in a necklace, arm, wrist, use in watchband, and other parts of body. This radiation
including infrared (IR) or MR with narrow wavelength is safe for skin and body tissue and its
detection is associated with glucose via blood vessels through surrounding tissue, known as
target area. Following, its detection is precisely and follows ISO 15197 1[9]. It’s substrate should
be enough strength and stretchable, which can be in silicon (Fig 4, part 100), for example.

Figure 4 Infrastructure of sensor based on electromagnet [9].

2-3-1 Beneficial
The first benefit of continuous glucose monitoring based on electromagnetics is that it has
solved the time lag of detection of glucose through ISF [10]. This novel article introduced a
useful wearable noninvasive multisensory system that measures glucose level precisely with no
time lag. The accurate real-time responses of the sensors are attributed to their unique
vasculature anatomy–inspired tunable electromagnetic topologies [11]. But owing to having
multi sensors and being not portable (Fig 5) is not appropriate, maybe this technique could be
inspiring for small sized devices and costly [11]. The second benefit of this is to be enzyme-less
approach (Fig 5), it can be restored for long terms and in relatively everywhere [11].
2-3-2 Challenge
Despite its advantages and bright future, finding suitable algorithms and evaluating them in
vivo and patient case studies are desperately needed. Another challenge of the electromagnetic
method is mentioned in Table 4.

1
ISO 15197: specifies requirements for in vitro glucose monitoring systems that measure glucose concentrations in
capillary blood samples, for specific design verification procedures and for the validation of performance by the
intended users. These systems are intended for self-measurement by lay persons for management of diabetes
mellitus. In other word, this ISO is in vitro diagnostic test systems — Requirements for blood-glucose monitoring
systems for self-testing in managing diabetes mellitus
Table 4 Advantages and challenges in non-invasive glucose monitoring for other techniques [5]
 Figure 5 Schematic of wearable sensory system[11].

2-4 Reverse Iontophoresis

Most patents and commercial products of Table 1 such as 1 and 6 are based on Reverse
iontophoresis (RI) from ISF of the skin for detection of GL due to it being easy to manufacture,
non-invasive approach, and low cost. Additionally, change in GL concentration in ISF is obvious
during diabetic disorder and its output data is more reliable Fig 9.
2-4-1 Challenge
According to the latest search, Table 4 and 6, despite this method is better and has advantages
in Table 4 and 6, suffers from several difficulties. For instance, interstitial fluid GL
measurements carry a serious time delay compared to the plasma GL because device is placed
on the skin and it takes time to GL response to electricity field applied and move through the
vascular and derm to reach patch, indeed the major challenge for the measurement of blood
glucose non-invasively is the physiological lag between ISF and blood glucose [4]. It often takes
5-10 or sometimes 45 min delayed that glucose will diffuse to ISF through blood vessels and this
issue becomes extremely challenging as glucose is changing fast, so this obstacle may be
tackled with developing software. In addition, the stability, safety, and portability of the
underlying technologies constitute their main challenges [11]. Top layer of the skin is a big
problem and it might stop extracting large molecules and applying all of the current fiend into
the skin [12].
On the other hand, there are various factors that may affect the extraction effect of RI. In terms of
extraction of glucose molecules, the main factors are as follows:

1- skin thickness, 2- the increase of current intensity can increase the ion migration, so make high
extraction of speed glucose and low lag time 3- If direct current is applied to the skin continuously, it
may cause tingling and erythema on the epidermis. Although the sensitivity of the sensor is improved in
proportional to high current intensity, other problems such as skin irritation, a long warm-up time, the
need to change the gaskets every 12 h, the device cannot be used during sweating, and prolonged
electric current can cause skin damage to users, etc. Pulsed current can effectively reduce this side
effect in RI. 4- the current intensity should be between 0.1 to 0.3 mA, and the duration of each time
should not exceed 20 min, unless irritation is observed. 5- The size, shape and location of electrodes are
also crucial factors for RI and Ag/AgCl electrodes as a reference and count electrodes and Ti or Pt for
working electrode.

2-4-2 Saliva sample for RI

Choosing sampling for achieving high accuracy alongside non-invasive is another outlook of scientists.
Saliva and contact lenses (tear) attract attention as another way to count the amount of GL in non-
invasive. In saliva there are more and different types of biological and enzymes than can help for
detection. As before, the mechanism of RI and Fig 6 shows relationship of both. Following discussion
about saliva GL detection:

2-4-2-1 saliva glucose based on patch for electrochemical reaction

It contains glucose oxidized enzyme (GOD) and its method is based on electrochemical
(Amperometry measurements), it has on-chip disposable patch, the working electrode is
functionalized with single-walled carbon nanotubes (SWNT) and multilayers of chitosan (CS),
gold nanoparticles (GNp) and glucose oxidase (GOx), using a layer-by-layer (LBL) assembly
technique (Fig 6)[7]. According to Fig 6 saliva pours on the surface of the kit, the biosensor can
detect glucose down to 0.1 mg/dL and provide noninvasive, reliable (high resolution), highly
reproducible, convenient, fast, and continuous salivary glucose monitoring for personal and
point-of-care use[7].

Figure 6 Schematic of Saliva as non-invasive continues GL.

2-4-2-2 Challenge of Saliva sampling based RI
The first of all, summary of disadvantages and challenging of saliva sampling are mentioned in
Table 6 and Fig 8. The second, each patch needs to be stored in a certain conditional
environment due to containing Glucose oxidase. By using filters (software AND/OR membrane
of PVDF (polyvinylidene fluoride) for avoiding big, iron and other ions molecular attributes to
reach high signal/noise. Moreover, it also decreases the viscosity of saliva samples. This case is
able to detect low 0.1 mg/dL and as high as 20 mg/ dL glucose in saliva, which is sufficient to be
medically applicable for diabetic diagnosis and health surveillance [7]. This patch is detected on
healthy people but no extreme high/low glucose values detected, so it is also needed further
search [7]. Although the last patent belonging 2020[13] is about saliva for attain to high success
and signal/noise, above challenges still exist and it is not suggested for nowadays commercial
products and on the other hand, according its fig7 is not really continuous monitoring.

Figure 7schematic of novel patent for saliva sampling and its non-invasive continuous GL monitoring[13].

2-4-3 Nemaura Med Company (SugarBeat patch system)

Since this patch is a new product and unfortunately more information is not available including website,
patents, article. The Company anticipates filing multiple additional patents over the course of the next
18 months based on ongoing findings and improvements. The Company has several patent families
spanning the following: 1. Sensor related 2. Algorithm and methods of using the CGM data 3. Devices &
methods to enhance glucose sensing 4. Methods to enhance glucose sensing 5. Devices and methods to
extract glucose Fig 8.
Fig 8 Illustration of Sugar BEAT product as a novel non-invasive continuous glucose detection.

2-5 enzyme-less based sensor for glucose monitoring

New approach of sensor for detecting non-invasively continuous blood glucose has been
changed toward enzyme-less sensors, and more new relevant patents are seen and more
research is being carried out to make them more reliable with high accuracy. Fig 9 is an
example non-enzymatic sensor based on bronze for monitoring of glucose in saliva [1]. The
electrocatalytic oxidation of glucose on the bronze electrode occurs on the bronze electrode
without any additional reagent and also with no GOD on bronze, is involved for the
electrochemical determination. Therefore, the electrode can also be simply polished for
regeneration and be maintained for long-term.
This has many frequent uses for long term, selectivity of metal toward glucose, with no
correction, it has a linear range 0- 320 μM, sensitivity is 480 μA mM-1 cm-2, detection limit is
6.6 μM, signal-to-noise rate is 3[1]. Fortunately, glucose level of blood and saliva are relatively
the same level in before, after meals [1].
Figure (a) A photograph of the smart toothbrush with electrochemical sensor for determination of saliva glucose.
Fig 9 illustration of enzyme-less brush teeth for glucose detection.

2-5-1 Beneficial
Long-term usage [1], no stick conditional resorting place, low cost for production from the point
of view of GOD are its advantages, which makes it an advanced method for future.
2-5-2 Challenge
Choice of metal and material facing to blood glucose and also detection and accuracy in each situation
are challenges of this method. In addition, another challenge of this method is sampling. All kind of
sampling are saliva, tear, sweat, that negligible changes in diabetic disease and it is extremely needed in
highly tendency of receptor for reaction with low concentration of GL in these places (Fig 10), and there
are many disadvantages for these sampling as well, which make them achieve low accuracy and
challenging (Table 6). Therefore, this study has been dropped further. If the above obstacles were
solved, it would be a great idea to design a device as small as a coin and then it would be placed
alongside the dental, or adhered into mouth (on a dental) forever, following, it would detect
glucose level constantly.
Figure 10 Contrast of glucose concentrations in different physiological fluids between healthy and diabetic people.

Table 6 Saliva, tears, sweat and interstitial fluids (ISF)-based glucose monitoring devices comparison [2].
2-6 Contact Lens
2-6-1 Contact lens for glucose monitoring:
Contact lens is a new attractive overlook for developing non-invasive techniques. Because of
the development of various non-invasive methods, it’d better discuss all new techniques here
so it is why this was mentioned here.
Because of the reasons below, they are not studied in this study, this kind of commercial
products will not be seen in the near future in the market.
2-6-1-1 Challenge
Continuous glucose monitoring based on contact lens (Fig 11) is not affordable and complex to
be fabricated. It is why this study is not focused on it. Table 6 and Fig 9 have enough crucial
information not to trust them nowadays as commercial products.

Figure 11 An example illustration of contact lens for continuous GL monitoring adopted by google.
 3- Commercial minimally invasive products:
Table 7 A few commercial product information for minimally continuous blood glucose monitoring:

# Device Technology advantages Disadvantages Image Ref

/
Challenges

1  Dexcom Company Reverse iontophoresis 1-detect every N/A site

method by ISF 5min, 2-
wearable patch
USA for up to 10
Device Explanation: days of use. 3-
minimal
Alerts can be
1-auto-applicator: invasive
customized
One-button push to
individually; an
insert small thin
app is like
sensor beneath the
Instagram that
skin
lets others
2-Sensor and follow you for
Transmitter view glucose
level.
patch on skin, slim
sensor continuously
measures glucose
levels just beneath
the skin and sends
data wirelessly to a
display device
through a transmitter,
and it has a delivery
pump.
3- The reader or
smart device is
monitoring
continuously in real
time.

2 Eversense® Fluorescent light Continuous Implanted [3]

detection, sensor
underneath
3 Abbott Company Electrochemical Unsurpassed N/A Its
method, ISF 14 days’ Site
accuracy for
USA adults and
children, can
Insert sensor
be customized
(minimally
to notify you if
invasive)
you want,
compared to
Dexcom’s
patch is
smaller.
approved by
FDA.

Sensor filament
is less than 0.4
mm thick.

4 K’Watch ISF, microneedle 1-continuous We

array monitoring 2- b
PK vitality company
detecting
everywhere N/A
even
It is a pre-clinical trials step, so
showering, 3-
more information is not
adhesive Minimally
available. Its price was
consumable is invasive
estimated at $149.
changed every
week, 3-get
discreet
vibration alerts
in case of hypo
or
hyperglycemia,
4- A pump
 embedded into
device for
creating a
negative
pressure to
decrease ISF
delayed time,
in addition,
multi-needles
improve
accurate and
its delayed. 5-
0.5mm(500µm)
needles (0.5-
1mm is
standard of
microneedle
length.). 6-
according to in
vivo :99.9% of
accuracy. 7-it is
no time.

4- Minimally invasive continuous glucose monitoring:

4-1 Introduction:
Modern technology has introduced micro/Nano needles as a new minimal invasive approach in medical
therapy and diagnosis. Minimal invasive microneedle has diverse structure with versatile application (Fig
11). These days they are being used for sensing biological biomarkers as a continuous sensor. The used
materials can be divided into polymers, metals, and hydrogel. Their choice depends on the kind of uses.
Although in Fig 12 indicates microneedles, study of single needles is increasing, as well. Therefore, this
study has been investigated in two categories: 1- microneedles 2- single needle.
 Figure 12 Schematic of microneedles for sensing biomarkers (left side) and drug delivery application (right side).

4-2 Single needles

4-2-1 Dexcom Company
Dexcom company advances toward producing CGM in a minimal invasive way Fig 13. This company is
grounded its effort on miniaturized devices with high accuracy and they are also seeking for achieving
the best user friendly with cost-effective for diabetic patients. So, this company has upgraded their
product from G5 to G7 version. Some differences between G5 as a first product and G6 is mentioned in
Table 8. In addition, the size of devices for Dexcom G5 and G6 is different (Fig 13). Moreover, unlike
DexcomG5, Dexcom G6 does not need to fingerstick calibrations, the first of all it needs to finger stick
calibration to input data to device and then device starts to work.). Dexcom G7 (Fig 13, B) will use a
totally new platform to what we are used to now with the G6 and G5 platforms. It is planned to be the
smallest and slimmest of any CGM on the market at 30% smaller than the current system (it will become
as small as a coin). It is being compared to the size of a quarter. G7 is coming in 2021. Unlike other
versions of Dexcom products, DexcomG7 has a 1-hour warm-up. It will be able to be worn until 14days.
In addition, it is expected to be fully disposable, with the sensor and transmitter as one piece.
(Unfortunately, more information is not available.)

According to their earlies patents, which belong 2020, it is taken to consideration some general
information following below:

The length of needle must be less than 1 mm because the needle should not reach the dermal layer,
otherwise it causes pain and damage to the vascular and nerve root in the deep layer of dermal. So, it
can be seen all microneedles that build needles in 0.5mm length. The second, there is a single multiple
layer which is implanted into the skin, with an adhesive patch made of elastomer polymer such as
silicone, epoxy, rubber, and acrylate. Materials of sensor carriers in housing are made of PLA+ graphene/
carbon/ or other conductive material. This system is like Fig 14 cylindrical coaxial solid needle which has
multi-layer conductive (Ti, Pt metal as a core of needle) and non-conductive materials (polystyrene,
polyimide, and other isolate ones) and one layer containing GOD or conductive core of needle coated by
GOD [14, 15]. In fact, the needle insertion into the skin is a working electrode with an electroactive
surface and it has a pump delivery for enhancing glucose immigration towards electrodes. In fact,
housing has a delivery pump (just creates a negative pressure to push all glucose to reach to electrode.)
to increase exchanging of glucose. Interestingly, an article has also introduced a hollow single needle
with parallel electrode array other option [15-17].

4-2-1-1 Challenge:
Limitation of CGM especially Dexcom products is not to be used for pregnant and dialysis or critically ill.
It is not known how different conditions or medications common to these populations may affect
performance of the system. G6 readings may be inaccurate in these populations. All commercial minimal
invasive microneedles are being produced in solid-way almost with metal material, which are mentioned
above, causing a little skin irritation, especially this product is adhered for at least 10-14 days.
Table 8 Compares famous commercial products, which are available in the market.

Note: Adopted from https://www.proactiveinvestors.com/companies/news/925727/nemaura-medical-expands-painless-

sugarbeat-glucose-monitor-footprint-in-europe-and-eyes-entry-into-us-market-925727.html#:~:text=SugarBEAT%20consists
%20of%20a%20daily,allows%20for%20better%20glucose%20management.
 Figure 13 Comparing three versions of Dexcom’s products.

Figure 14 Figure illustrates the infrastructure of the device and its sensor and whole package of product. Figure is adopted by its
2020’s patent [16] and website.
4-2-2 Abbott Company
Its needle is a single metal hollow needle and 3electrodes located into the hollow needle and length of
needle makes contact to ISF or middle of dermal tissue.it looks like Fig 15. (Ref electrode is Ag/AgCl).
Carbon + Pt working electrode is coated by conductive materials for speed reactions and immobilizing
GOD on it. There are no particular limited polymers for coating and using all of which can be polyvinyl
pyridine, acrylates, PLA, PANI, Vinyl ferrocene (VF), poly HEMA, poly (ethylene glycol) diacrylate
(PEGDA), etc. [18, 19]. As be seen Fig 14, The sensor is small and discreet, measuring approximately the
size of a quarter. Thus, patients can wear it for 10–14 days with minimal disturbance of their activities of
daily living [20]. Patients can use the data in daily life to get on demand glucose readings without having
to perform a fingerstick to obtain blood for use with a glucose meter [20].

Figure 15 Abbott’s infrastructure product as a minimal invasive device for continuous glucose monitoring. Figures were adopted
by 2020’s patent [18, 19].

4-2-2-1 Challenge
Freestyle Libre Pro and Freestyle Libre are not approved in children <18 years of age or for patients who
are pregnant, on dialysis, or critically ill. Patients who are dehydrated or have high levels of vitamin C or
salicylic acid may not get accurate readings with the system [20].

4-3 Multi-needles
Novel article has introduced a sensor patch containing 4 needles (patch contains Silicone hollow
microneedles) 1-referenses 2- counting electrons 3- working electrode for Glucose, 4 th needle for other
sensing analytic [21]. It is supposed to enhance time reactions with biological analysts with high
accuracy in real time.
4-3-1 Multi-functional Microneedle
Some recent articles have introduced advanced sensory patches including multi-sensor, which
was placed on the right side of patch, work based on reverse iontophoresis [21, 22]. Right side
sensors include sensing temperature, glucose level, relative humidity, etc., while the left side of
patch includes microneedles contacting insulin which is stimulated and released by
temperature of glucose interaction, which was received from the right side relevant sensor
[23]. Although this multi-sensing will be a favorite of future research, complex to manufacture
and limited dose of trapped insulin in each needle are still challenges in this way.

Sensor + Needle with

microneedle insulin
Patch composed by
acrylate/silicone gel, etc.
Connection

4-3-2 Single-functional Microneedle

Single-functional microneedle means microneedle just works as a sensory of one item or delivery of
drug, this system seems to be simple with a few varieties makes them be produced and developed
easily.

4-3-2-1 K’Watch Glucose

One prospective commercial product will be seen in 2021 is K’Watch glucose monitoring Fig 16. This
product is a microneedle array. It is still a pre-clinical trials step, so more information is not available. Its
price was estimated at $149. It has been claimed that this system has no delay but due to unavailable
data it is hard to find out principles. It is guessed that microneedle has more possibility to be exposed to
GLs instead of single needle, moreover, it has a pump delivery for pumping GLs quickly into a sensor
embedded into a device, other guess is that it may be used highly sensitive materials on electrode to
have more tendency toward GL.
 Figure 16 Structure and principle of K’Watch glucose monitoring as a microneedle array.

5-Discussion
Discussion of both methods have been mentioned below separately and other promising ideas have
been written for future, as well.

5-1 Non-invasive Discussion & Author’s Idea for Non-invasive Discussion

Currently, non-invasive blood glucose monitoring methods are generally divided into three categories:
optical methods, microwave methods and electrochemical methods. In general, the advantages of
optical and microwave (especially electromagnetic) methods lie in their highly non-invasive nature and
continuous monitoring without stimulating discomfort to the human body. However, as far as the
research status goes, the measured value may be not highly correlated with the actual blood glucose
value and the linear range is narrow, so subsequent algorithm correction should be required. In
addition, spectroscopy methods are extremely dependent on the skin thickness, which is really different
and diverse between people due to their skin, age, gender, and disease. Electromagnetic approach has
lower energy per photon and is less scattered in the atmosphere, suggesting that they can penetrate
deeper into the tissues, without ionization, portability, long-term storage, user-friendly for insertion in
any device, low cost, and obtain more realistic blood glucose data. Despite the Electromagnetic
approach compared to other optical methods is much better, future noninvasive sensors will be
emerging for optic and microwave ones. However, their poor sensitivity and selectivity are still the core
factors limiting their development, and further efforts should be made towards these two aspects in the
future. For dealing with this problem multi-sensor integration, big data computing and machine-learning
techniques may weaken the influence of internal and external factors to some extent, which is worth
thinking about.
Among transdermal method, although Reverse iontophoresis needs multi patches for sensor and there
are disposable and they have a few limitations mentioned above, consumers have to buy them and
brings for a company a profit and it might have more precise detection owing to electrochemical of
glucose and GOD directly on patch. This detection and LOD (limit of detect)could be more precise by
using Cu and Nano-gold particles and Nano-tube carbon on working electrode and its lag time can be
improved by choice of appropriate polymer as a patch and metal for electrode, this best hydrogel-patch
and conductive material for adhesive patch on skin and on electrode, respectively is followed
protocol[24]or other way for improving is software/ algorithm, applying current (mA) and inserting
pump, using other biological variables such as temperature, sweat, etc. to confirm accuracy and
compromise lagging time. For decreasing the skin irritation, using herbal materials into patches could be
helpful.

-In previous we described choice of RI for detection of GL from ISF is more logical, here we talked openly
in detail:

Electrochemical methods mainly make use of the correlation between some biofluids (such as saliva,
tears, sweat, and ISF) and blood glucose concentration, and indirectly obtain the blood glucose value by
measuring the glucose content in these body fluids. Reverse iontophoresis is measurement based on ISF,
which is more reliable (Fig 10) and it is considered as a current commercial product, but in order to
improve its sensitivity of glucose sensors at the electrochemical level, nanometer electrodes (such as
nano-gold electrode, graphene or carbon nanotube electrode, etc.) are commonly used. Nano-gold,
graphene or carbon nanotube electrode, Cu, conductive polymer coated electrode for working. But for
reducing irritation, which is caused by metal, appropriate micro-distance, the scale and space between
device and skin, from the skin surface can be considered. Patch could be (acrylate, silicone gel, PET), also
by algorithm, software and curve fitting are more practical for making devices precise in terms of
delayed time. However, compared with optical and microwave methods, electrochemical methods have
more advantages in the prospect of commercialization of non-invasive or minimally invasive blood
glucose detection. In future research, if more physical parameters (such as pH, temperature, humidity,
frequency) and other biomarkers associated with blood glucose can be combined to correct
measurement results, to improve the accuracy of non-invasive skin glucose measurement and relevance
to their blood glucose levels, and to achieve continuous monitoring of patients with hyperglycemia and
hypoglycemia, this might be a more mainstream and feasible direction for the solution. Interestingly,
with adding green tea extraction, aloe Vera extraction, other herbal material and their extraction to
substrate and glue will make less obvious for the skin irritation. Unfortunately, I am not sure about its
effect on accuracy and sensitivity and cost of the sensor. It will be needed for further studies. It should
be added that patch/gel materials candidates are silicone gel or other hydrogel, cellulose base gel,
acrylate gel.

-Diagram of the near future steps for non-invasive continuous GL monitoring:

Improved Iontophoresis Electromagnet

Next step
5-2 Minimal invasive discussion
According to review articles, we have figured out what is going on at laboratories for microneedles
development for future from material, advanced process point of view. Following famous products of
CGM, only not their methods and process of manufacturing are the same and be able to predict, but
also based on materials principle, article, and available materials in our situation will be different and
chosen. Indeed, no limitation exists. Here a question arises: what makes professional products? Its
algorithm.

Minimally invasive is direct detection of glucose with less errors. With low time lagging for detection is
one of the advantages of minimally invasive. Now challenging is still a type of needle and materials for
reducing skin irritation and redness, also an appropriate choice triggers us to know about longevity of
sensor/patch life. Most microneedles have been built as a solid-metal material with layer–by-layer like
Dexcom and Abbott's products. Hollow needle is also worked but holes of the needle are probably filled.
In future progress, we will witness a multisensory of microneedle for diagnosis and therapy with ability
of drug delivery. Moreover, it will contain sensors for temperature, humidity, glucose, lactic acid, etc.
Interestingly, for reducing cost process manufacturing and long sensor life, it may address non-
enzymatic methods, not for microneedle, but also for other sensors.

Substrate sensing candidate materials are PTFE, PEEK, PVC, polyurethane, PMMA, PP, silicone, polyester,
polycarbonate, PEO, PBT, PET, and PVDF.

Microneedle electrode materials can be coated by gold nanoparticle, gold porous film coated
microneedles [25], immobilizing of GOD with chitosan, HEMA, etc. or manufacturing needle based on
glass or polymer which coated by conductive material for reducing redness and the skin allergy but
longevity and strength of needle will face a challenges. Another the latest patent has been worked on a
non-enzymatic sensor [26], which showed how to manufacture this system with innumerable
advantages.

Microneedle for continuous glucose monitoring is much reliable ISF diffusion into hollow microneedle
for detection is within real time. Moreover, noninvasive does not breach the skin’s stratum-corneum
barrier, and hence extracts low levels of biomarker. In contrast, microneedle arrays cross the stratum
corneum, and can thereby directly and selectively capture ISF biomarkers. Hollow microneedle or closed
needle within hollow inside which is made by porous polymer. Pores size of the needle body, which is
made of polymer, should be the same as glucose molecules. It leads to high selectivity and hole of the
needle is not filled by other biological analytic ISF (Filtering). Into a hollow microneedle, electrodes are
inserted in parallel. In addition, a pump exists into an adhesive patch for extraction or injection analytic
elements through the skin. Instead of pump insertion, reverse iontophoresis (IR) can be used (this
means a combination of figure17 a +b. In fact, most commercial products are like Fig 17, g & d. Applying
RI with a needle makes the system have a prompt response.

OR microneedle (metal) modified with sensors and biological agents on its surface and then it is exposed
to analysts, its signal will be sent to detectors Fig 17, g. Second one has longer lifespan in skin owing to
metal instinct of needles but it is more likely to face irritation of the skin. Moreover, selectivity of GL
could be very lower than early mentioned. All in all, despite advanced progress and future of
noninvasive glucose monitoring, minimally invasive is more highly recommended and more reliable.
Both length needles must be 70-200 µm. Metal with surface modification for start and the first work of a
company should be better because it is easy to manufacture and polymer-based needs to investigate its
behavior and degradability and its lifespan, which is proportional to sensor life. Next generation of
sensor is to search for non-enzymatic microneedles, the time is desperately needed. Although some
articles and patents are available and they showed enough evidence for its performance, I believe that it
is not enough for marketing yet.

Interestingly, we could build a detection system with insulin delivery for the company's future products.
It needs two separate sensor systems and two groups of microneedles which should be connected
together. Although it outlines prospective sensors, I am not sure of the high cost and complexity and
other coming challenges for the first years of official work of the company and its products.

Figure 17 a, Non-invasive sampling via reverse iontophoresis. b, Collection of ISF via hollow microneedles. c,
Vacuum-assisted ISF collection from micropores created by microneedles or via laser light. d, ISF collection into a
paper reservoir by the repeated ‘pumping’ of microneedles into the skin.  e, ISF collection by swelling hydrogel
microneedles. f, Direct capture of a biomarker in ISF via a biorecognition element (typically, an antibody) bound to
microneedles. g, Real-time monitoring of a biomarker via electrode sensors embedded in microneedles.  h,
Microneedles for closed-loop sensing and drug delivery [27].
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