This document discusses the future of bioelectronics in medicine. It describes how the convergence of biology and electronics could allow for technologies like restoring vision or reversing spinal cord injuries using implanted devices. Key areas that could be impacted include healthcare, homeland security, and protecting the environment. The document outlines some of the materials being researched for bioelectronics like graphene and PEDOT, as well as devices like pacemakers and biosensors. Advances in bioelectronics hold promise for new medical treatments but also challenges in biocompatibility and sensor longevity that researchers are working to address.

1. BIOELECTRONICS: FUTURE OF THE MEDICINE
ABSTRACT
There is an opportunity for dramatically increased synergy between electronics
and biology, fostered by the march of electronics technologies to the atomic scale
and rapid advances in system, cell, and molecular biology. In the next decade, it
may become possible to restore vision or reverse the effects of spinal cord injury
or disease; for a lab-on-a-chip to allow medical diagnoses without a clinic or
instantaneous biological agent detection. Bioelectronics is the discipline resulting
from the convergence of biology and electronics and it has the potential to
significantly impact many areas important to the nation's economy and well-being,
including healthcare and medicine, homeland security, forensics, and protecting
the environment and the food supply. Not only can advances in electronics impact
biology and medicine, but conversely understanding biology may provide
powerful insights into efficient assembly processes, devices, and architectures for
nanoelectronics technologies, as physical limits of existing technologies are
approached. Advances in bioelectronics can offer new and improved methods and
tools while simultaneously reducing their costs, due to the continuing exponential
gains in functionality-per-unit-cost in nanoelectronics. Realizing the promise of
bioelectronics requires research that crosses disciplines, such as electrical
engineering, biology, chemistry, physics, and materials science. Bioelectronic
medicine is a new field but the hope and promise is significant. Bioelectronic
medicine is not an innovation but a revolution. Its concept is simple: use an
electrical current to trick the body into healing itself. Bioelectronic medicine holds
the promise of treating a variety of diseases and illnesses.

2. INTRODUCTION
At the first C.E.C. Workshop, in Brussels in November 1991, bioelectronics was
defined as 'the use of biological materials and biological architectures for
information processing systems and new devices'. Bioelectronics, specifically
bio-molecular electronics, were described as 'the research and development of
bio-inspired (i.e. self-assembly) inorganic and organic materials and of
bio-inspired (i.e. massive parallelism) hardware architectures for the
implementation of new information processing systems, sensors and actuators, and
for molecular manufacturing down to the atomic scale'.[1] The National Institute
of Standards and Technology (NIST), an agency of the U.S. Department of
Commerce, defined bioelectronics in a 2009 report as "the discipline resulting
from the convergence of biology and electronics".[2]:
Nowadays bioelectronics medicines are defined as" A tiny implanted device
treating disease by changing the electric pulses in nerves to and from specific
organ.
It is a branch of science concerned with the application of biological materials and
processes in electronics, or the use of electronic devices in living systems.

3. HISTORY
 1908 Germany Von Berndt, Von Preiss and Von Zeyneck publish a paper on
the treatment of joint disease using high frequency waveform currents.
 1914 England World War I casualties are treated for exercise, pain
management and healing with Faradic, Sinusoidal, Galvanic and Longwave
diathermy currents.
 1920 Worldwide Combined Faradic, Sinusoidal, Galvanic and Switched
Galvanic clinical “switch tables” are produced. Shortwave diathermy devices
are produced.
Figure: 1
 1923 Australia Australian therapists responsible for treating World War I
casualties with electro-medicine can obtain certification.
 1930’s Germany Interferential currents are developed. Two alternating,
medium frequency sinewave current paths are crossed to give pulsed low
frequency modes of electrical stimulation. Interferential currents are much

4. more comfortable than anything else available at the time.
 1950’s onwards Russia “Russian Stimulation” is developed for athletes for
building muscle and increasing power.
 Mid-60s onwards - Modern Electrotherapy Present day TPNS begins with the
landmark paper by Melzack and Wall, entitled “Pain Mechanism: A New
Theory.” An enormous amount of scientific research followed, resulting in the
therapy used up until recent times.
 The “Pain Control Gate” theory suggested that strong afferent nerve
stimulation by chemical, mechanical or electrical means overrides painful
sensations at hypothetical pain control “gates” in the spinal cord.
 When the gate is open pain impulses can pass easily; when the gate is partially
open only some pain impulses can pass and when the gate is closed no pain
impulses are able to pass. They suggested that the position of the gate depends
upon the degree of large or small fiber firing. When large fibers firing
predominates, the gate closes so that no impulses can pass through, where as
when small fiber predominates, the pain message can be transmitted.
 Their work led to the development of the first Transcutaneous Electrical Nerve
Stimulation (TENS) hardware device. Today, frequency specific TPNS
protocol formulations like those developed by NuroKor are used worldwide to
target a vast range of pain conditions without the side effects of drugs.
 1970’s USA Transcutaneous Electrical Nerve Stimulation (TENS) is
acknowledged as a viable method of pain management by America’s Food and
Drug Administration (FDA). Many American companies begin production of
TENS devices. The heart pacemaker is developed.
 1977 Australia Lamers develops the “Biphasic Capacitance Discharge
Micro-pulse” device, with equally active stimulation from both electrodes
instead of just one.
 1970’s & 80’s Sweden Ericsson and Sjolund publish research comparing
constant, high frequency TENS to bursts of high frequency TENS (termed
acupuncture-like TENS), finding that the latter offers better pain relief and
does in fact instigate a release of endorphins into the bloodstream.
 1980’s USA High voltage Galvanic stimulation of up to 500 volts is used in
table-top clinical use devices.

5.  1981 USA Becker electrically induces limb regeneration in frogs and rats.
 1990’s Worldwide Advances in electrically conductive polymers and
self-adhesive, electrically conductive gels allow for production of electrodes
which are much more user-friendly.
 1991 Australia Lammers manufactures the world’s first multi-function
stimulator, combining a TENS (for pain relief, etc.) with EMS (for muscle
strengthening).
 2000 USA John McDonald of Washington University uses Electrical Muscle
Stimulation (EMS) to exercise the muscles of a quadriplegic of 8 years. The
patient defies medical science by regaining limited sensation and movement in
his body.
 Nurokor the body electric - bioelectrical medicine for treatment of pain and
injury the latest breakthrough personal use devices are like smartphones and
have preset treatment apps with a broad range of therapeutic use built in to the
operating system software
MATERIAL
(1) GRAPHENE
It is an allotrope of carbon consisting of a single layer of atoms arranged in
two-dimensional honeycomb lattice. Each atom in graphene sheets each atom in
graphene connected to nearest atom by a Sigma bonds and contributes 1 electron
to conduction band that extend over wall sheet.
FIGURE: 2 FIGURE: 3

6. This is the same type bonding seen in carbon nanotubes and polycyclic aromatic
hydrocarbons, and (partially) in fullerenes and glassy carbon.
These conduction bands make graphene a semimetal with unusual electronic
properties that are best described by theories for massless relativistic particles.
Charge carriers in graphene show linear, rather than quadratic, dependence of
energy on momentum, and field-effect transistors with graphene can be made that
show bipolar conduction. Charge transport is ballistic over long distances; the
material exhibits large quantum oscillations and large and nonlinear diamagnetism.
Graphene conducts heat and electricity very efficiently along its plane. The
material strongly absorbs light of all visible wavelengths, which accounts for the
black color of graphite; yet a single graphene sheet is nearly transparent because of
its extreme thinness. The material is also about 100 times stronger than would be
the strongest steel of the same thickness.
Photograph of a suspended graphene membrane in transmitted light. This
one-atom-thick material can be seen with the naked eye because it absorption of
light .
FIGURE :4
Photograph of a suspended graphene membrane in transmitted light. This
one-atom-thick material can be seen with the naked eye because it absorbs
approximately 23% of light.
The Cambridge Graphene Centre and the University of Trieste in Italy conducted a
collaborative research on use of Graphene as electrodes to interact with brain
neurons. It is shown that applying conductive graphene patterns on flexible
substrates can enable the study on neuronal cells by resolving the reported
mechanical mismatch between biosensors and the soft cell membrane. Researchers
have shown that aqueous graphene patterns do not hinder the viability of
dopaminergic neuronal cells.[27]
And can be used as an interface for establishing a reliable communication pathway
with the neuronal networks. (25)
Researchers at the Graphene Research Centre at the National University of
Singapore (NUS) discovered in 2011 the ability of graphene to accelerate the
osteogenic differentiation of human Mesenchymal Stem Cells without the use of

7. biochemical inducers. (28)
In 2015 researchers used graphene to create sensitive biosensors by using epitaxial
graphene on silicon carbide. The sensors bind to the 8-hydroxydeoxyguanosine
(8-OHdG) and is capable of selective binding with antibodies.
The presence of 8-OHdG in blood, urine and saliva is commonly associated with
DNA damage. Elevated levels of 8-OHdG have been linked to increased risk of
developing several cancers.
The research revealed that uncoated Graphene can be used as neuro-interface
electrode without altering or damaging the neural functions such as signal loss or
formation of scar tissue. Graphene electrodes in body stay significantly more
stable than modern day electrodes (of tungsten or silicon) because of its unique
properties such as flexibility, bio-compatibility, and conductivity. (28-31)
PEDOT
It is a polymer mixture of two ionomers. One component in this mixture is made
up of sodium polystyrene sulfonate which is a sulfonated polystyrene. Part of the
sulfonyl groups are deprotonated and carry a negative charge. The other
component poly(3,4-ethylenedioxythiophene) (PEDOT) is a conjugated polymer
and carries positive charges and is based on polythiophene. Together the charged
macromolecules from a molecular salt.
FIGURE:5 (STRUCTURE OF PEDOT) FIGURE:6
Pedot is also useful in diagnostic bioelectronics, because of its oxidative properties
switching in two PEDOT: PSS electrodes connected by a piece of PhastGel SDS
buffer strips. The electrodes were reversibly and repeatedly oxidized and reduced
by switching the polarity of an applied 1 V potential. This was observed by a color
change between dark (reduced PEDOT) and light (oxidized PEDOT) blue within
the electrodes, demonstrating the transport of ions between and into the electrodes.

8. DEVICES
Bioelectronics has large number of devices available in 21th century. Some
devices are vastly used in general application like pacemaker implantation in
cardiac arrhythmias etc.
(1) PACEMAKER
A pacemaker is a small device that's placed in the chest or abdomen to help control
abnormal heart rhythms. This device uses electrical pulses to prompt the heart to
beat at a normal rate.
Pacemakers are used to treat arrhythmias (ah-RITH-me-ahs). Arrhythmias are
problems with the rate or rhythm of the heartbeat.
FIGURE:7 (WORKING PHENOMENA OF PACEMAKER)

9. (2) BIOSENSORS
Biosensors are developed on theory of biochemical processes in our body.so they
are all Functional devices can successfully convert (bio)chemical information into
electronic one by means of an appropriate transducer which contains specific
molecular recognition structures.
In this way, biosensors can be described as integrated receptor-transducer devices
which provide selective quantitative or semi-quantitative analytical information
using biological recognition elements. The main advantages of biosensors, over
traditional analytical detection techniques, are their cost-effectiveness, fast and
portable detection, which makes in situ and real time monitoring possible.
Implantable biosensors can make a continuous monitoring of metabolites
providing an early signal of metabolic balances and assist in the prevention and
cure of various disorders, for instance diabetes and obesity.
Enzymes are well-known biological sensing materials used in the development of
biosensors due to their specificity. However, since they have poor stability in
solution, enzymes need to be stabilized by immobilization. Enzyme
immobilization can be made by covalent linkage, physical adsorption,
cross-linking, encapsulation or entrapment (52).
The choice of the immobilization method depends on the nature of the biological
element, the type of transducer used, the physicochemical properties of the analyte
and the conditions in which the biosensor should operate. Moreover, it is essential
that the biological element exhibit maximum activity in its immobilized
environment.
FIGURE: 8 (WORKING PHENOMENA OFBIOSENSORES)
As a result, the development of a sensing device based on enzymes is in a good
agreement with the present concerns of Green Chemistry due to inherently being a
clean process. Notwithstanding some shortcomings such as high sensitivity to
environmental factors (like pH, ionic strength and temperature), dependence on
some cofactors and limited lifetime hinder the utilization of enzymes in some

10. specific situations.
To overcome the drawbacks, enzyme-free biosensors have been actively developed
owing to their simple fabrication, stability and reproducible characteristics. Novel
nanoparticle (NP)-modified electrodes and other functionalized electrodes have
been tested in the design of enzyme-free biosensors (53).
Nanostructured materials have the advantage to be easily functionalized exhibiting
high electrocatalytic activity and stability. For instance, carbon-based
nanostructures have been widely studied as a platform which can hybridize with
other functionalized materials, such as metal and metal oxides, forming
nanocomposites with improved electrochemical properties.
Overall, these nanostructures can provide optimal composite electrode materials
for high-performance enzyme-free biosensors.
Drug-enhanced biosensors
A biosensor is an analytical device used to determine the concentrations of
substances in the body. Generally, a biosensor is comprising a biological
recognition element and a transducer that is capable of detecting the particular
biological reaction and converting it into a signal [].
Implantable biosensors are particularly useful in monitoring substances associated
with the physiological condition with respect to chronic diseases. Based on the
detection principle, biosensors can be classified into optical biosensors,
electrochemical biosensors, thermometric biosensors, and piezoelectric biosensors.
The most commonly used commercial biosensors are the blood glucose sensors for
diabetes management.
Different types of glucose sensors are under investigation and these use different
methods of glucose detection and range from noninvasive, to minimally invasive
to invasive. Invasive, totally implantable, sensors are expected to require less
rigorous calibration and exhibit smaller subject-to-subject variability. However,
inflammation and fibrosis associated with tissue injury and the continuous
presence of a foreign object constitutes the main cause of sensor failure in vivo, as
sensors isolated by fibrosis lose their specific connection with the local tissues,
which limits their longevity and functionality, since the sensor is starved of
analyte(s).
In order to enhance biocompatibility and therefore the lifetime of implantable
biosensors, various natural and synthetic polymers have been employed as
coatings, in an effort to mask the surface of implantable biosensors, giving the
sensors a hydrophilic and flexible surface. In particular, collagen, poly ethylene
glycol (PEG) (49), poly vinyl alcohol (PVA) [49], poly lactic acid (PLA) and
PLGA [49-50] have been used. Although these biomaterials are considered to be
relatively biocompatible, a number of studies have shown that such coatings still
have biocompatibility issues and are not able to eliminate the inflammatory
response completely.

11. To suppress inflammation and fibrosis related to the implantation and continuous
in vivo residence of biosensors, drugs such as dexamethasone, which is a potent,
synthetic anti-inflammatory and immunosuppressant member of the corticosteroid
family, have been delivered using different strategies.
For instance, dexamethasone has been incorporated into a hydrogel coating that
surrounds the biosensor. Briefly, PLGA microspheres containing dexamethasone
were incorporated into PVA hydrogels using the freeze–thaw technique which is a
physical cross-linking method and therefore not harmful to
electrochemical-sensing enzymes or the drug eluting polymers (microspheres).
The PVA hydrogel allows rapid diffusion of analytes into the sensor, while the
PLGA microspheres provide controlled release of the dexamethasone. The PVA
hydrogel is soft and flexible, mimicking human soft tissues and is stable under a
wide range of temperature and pH conditions. This composite coating has been
shown to control both acute and chronic inflammation and minimize fibrosis for as
long as dexamethasone is released from the coating [88, 90].
However, administration of corticosteroids alone has the potential to be
anti-angiogenic, which decreases the blood supply around the biosensor site.
Several studies have demonstrated that localized delivery of growth factors (i.e.
VEGF) successfully stimulates new blood vessels and improves circulation around
the implant sites, which can be a strategy to overcome the anti-angiogenic effects
of corticosteroids (51).
Patil and colleagues investigated the co-administration of dexamethasone and
VEGF using a PLGA microsphere/PVA hydrogel composite as a tissue response
modifier in rats [7].
During the 4-week experimental period, implants eluting both VEGF and
dexamethasone successfully suppressed the inflammatory reactions and fibrosis, as
well as stimulated neoangiogenesis. The results suggested these PLGA/PVA
hydrogel composite may be a useful technology for implantable biosensors to
improve biocompatibility and enhance in vivo performance. Following the same
principle, Norton et al. have studied the in vitro pharmacokinetics and in vivo
pharmacological effect of hydrogel coatings directly containing dexamethasone or
dexamethasone and VEFG combinations. The results showed pharmacological
counteractions between dexamethasone and VEGF. Therefore, future studies
should emphasize on minimizing this counteraction and optimizing the dual
delivery doses for these two drugs.
Biosensors have wide application potential for various clinical purposes, such as
diagnosis of diseases, metabolism monitoring and so on. They have the potential to
significantly improve the quality of life for many people, especially diabetic
patients.

12. Many factors beyond sensor design can substantially affect sensor performance,
including patient body condition, sensor insertion protocol and foreign body
responses as discussed before. Many issues associated with implantable sensors
usage remain to be clarified and require further investigation. Drug-enhanced
implantable biosensors have not yet been commercialized.
FIGURE :9
a) Schematic of the biosensor structure and membrane assembly consisting of
cellulose application and absorption pads and electro spun cellulose nitrate
capture pad.
b) Detection scheme of the lateral flow immunosensor based on the antibody
functionalized electro spun capture membrane,
c) Biosensor test results for Escherichia coli O157:H7 bacteria demonstrate the
linear sensor response and lower detection limit of 61 CFU/ml.
d) Biosensor test results for BVDV virus demonstrate the linear sensor response.
(3) CELLULOSE BASED DEVICES
Both cellulose and cellulose derivatives, such as cellulose nitrate, cellulose acetate
and carboxymethyl cellulose, exhibit an excellent biocompatibility which makes
them appropriate for immobilization of biological compounds [33, 34].
As is known, the ideal support for enzymes should be inert, stable and
mechanically resistant making the use of cellulose matrices ideal for adsorption
and covalent bond immobilization.

13. The modification of cellulose with dendritic structures is a novel and interesting
path to synthesize functional and unconventional cellulose-based supports for the
immobilization of enzymes. Moreover, the introduction of reactive groups into the
cellulose structure may allow a covalent nonreversible attachment of
biomolecules.
Maria Montanez and her team suggested the hybridization of cellulose surface
with branched dendritic entities that improves the sensitivity toward biomolecules.
The described methodology delivers a new toolbox for the design of sophisticated
biosensors with advantages such as low detection limit, versatility and suppression
of nonspecific interactions providing highly sophisticated cellulose surfaces with
unprecedented tunability. Dendrimers are synthetic macromolecules with highly
branched structure and globular shape. They possess unique properties such as
high density of active groups, good structural homogeneity, internal porosity, and
good biocompatibility [35] [36].
When addressed to biosensor applications, the well defined dendritic structures
generate surfaces with increased reproducibility and high affinity for biomolecular
immobilization. This is due to the extraordinary control over the architecture
coupled to the possibility of designing a large number of accessible active sites at
the periphery of the dendritic scaffolds.
The solubility of cellulose depends on many factors especially on its structure,
molecular weight and source. Polysaccharides are well-known to manifest a strong
tendency to aggregator to incomplete solubilization due to the formation of
hydrogen bonds. The hydrogen bonding patterns in cellulose are considered as one
of the most relevant factors on its physical and chemical properties. The solubility,
crystallinity and hydroxyl reactivity can be directed affected by intra- and
intermolecular bond formation (figure 9) [31].
FIGURE: 9 FIGURE:10
(THE STRUCTURE OF INTRA AND INETRCHAIN HYDROGEN BONDING PATTERN IN CELLULOSE)

14. A further approach is the modification of cellulose-based structures with ionic
liquids (ILs). Ionic liquids are often used in the preparation of functional materials
by its covalent attachment to the support surface forming a stable composite.
Moccelini [37] have reported the development of a novel polymeric support based
on cellulose acetate and 1-n-butyl-3-methylimidazolium bis (trifluoromethyl
sulfonyl) imide-based IL, BMI.N(Tf)2 IL, for enzyme immobilization. The
introduction of the IL probably causes an increase in the distance between the
cellulose chains due to the interactions of the anion of the IL and the hydrogen
bond networks of the cellulose acetate. Thus, the enzyme can be entrapped within
the interstitial space of the formed composite, which results in a considerable
stabilization of the enzyme structure, and consequently increases its activity. The
study performed demonstrates that this material was able to immobilize Laccase,
leading to highly efficient and robust biocatalysts thus improving the
electrochemical performance of the biosensor.
The use of ILs is an alternative either for cellulose dissolution or to facilitate the
dispersion of carbon nanotubes. For that reason, Xuee Wu [38] describes a method
to immobilize enzymes in a cellulose-multiwalled carbon nanotube (MWCNT)
matrix via the IL reconstitution process. This method consists in the dissolution of
cellulose in the IL, followed by dispersion of MWCNT in the solution and enzyme
addition. Subsequently, the IL is removed by dissolution, leaving the
cellulose-MWCNT matrix with the enzyme encapsulated on the surface. The
cellulose–MWCNT matrix possesses a porous structure which allows the
immobilization of a large amount of enzyme close to the electrode surface, where
direct electron communication between active site of enzyme and the electrode is
enabled. The –OH groups of cellulose can also provide a good environment for the
encapsulation of the enzyme. The authors have employed the resulting porous
matrix in the immobilization of Glucose oxidase (GOx). The encapsulated GOx
showed good bio electrochemical activity, enhanced biological affinity as well as
good stability.
The simple electrode fabrication methodology and the biocompatibility of the
cellulose–MWCNT matrix mean that the immobilization matrix can be extended
to diverse proteins, thus providing a promising platform for further research and
development of biosensors and other bioelectronics devices.
The use of ILs as an intermediary solvent to facilitate the combination of cellulose
and CNTs has been suggested by Jun Wan [39].
A cellulose and single wall carbon nanotube (SWNTs) composite was utilized to
immobilize leukemia K562 cells on a gold electrode to form a cell impedance
sensor.

15. Envisaging the immobilization of other biomolecules, Alpat and Telefoncu [40]
describes the development of a novel biosensor based on the co-immobilization of
TBO (Toluidine Blue O), NADH (Nicotinamide adenine dinucleotide) and ADH
(alcohol dehydrogenase) on a cellulose acetate coated glassy carbon electrode for
ethanol identification. In fermentation and distillation processes, ethanol can reach
toxic concentrations that may cause inflammation and conjunctiva of the nasal
mucous membrane and irritation of the skin. Therefore, proper detection and
quantification of ethanol is of extreme importance. The detector is made by simply
deposition on the surface of a glassy carbon electrode and an active layer was
prepared by covalent linkage between the mediator TBO and a cellulose acetate
membrane. This mediator is commonly used for the oxidation and determination
of NADH. Then, a NADH solution and the ADH were added to the cellulose
acetate-TBO-modified glassy carbon electrode and tested. The developed
biosensor exhibited good thermal stability and long-term storage stability.
The immobilization of proteins on solid surfaces is a key step for the development
of medical diagnostic systems. An alternative approach for the immobilization of
specific proteins is the chemical modification of cellulose.
Stephan Dikeman [41] and his colleagues have described a targeted chemical
modification of cellulose to be used as substrate for proteins and biocatalysts
bonding. A new cellulose derivative obtained by modification of cellulose with
nitrilotriacetic acid (NTA) was used for the complexation of nickel (II). The
complex formed was used to immobilize labeled molecules. In that way, the
Ni-cellulose derivative allows the development of specific and sensitive molecular
diagnostic systems.
Another approach is proposed by Jianguo Juang [42] using protein-functionalized
cellulose sheets. The surface of the individual cellulose nanofibers was coated with
an ultrathin titania gel. The titania coated surfaces were then biotinylated creating
a biotin monolayer on each nanofiber by the coordination of carboxyl group.
Subsequently, bovine serum albumin (BSA) was added to the functionalized
surface to prevent nonspecific adsorption of streptavin. The immobilization of
streptavin molecules on its surface was made through biotin-streptavin interaction.
Streptavidin has two pairs of binding sites for biotin on opposite’s faces of
molecule. When immobilized on the cellulose nanofiber with one pair, the other
pair is available for further attachment of biotinylated species. The cellulose sheet,
composed by numerous nanofibers modified with titania/biotin/BSA layers with
anchored streptavidin molecules, gives a large surface area to detect biotin-tagged
biomolecules. Thus, biofunctionalized cellulose is a promising substract for
specific biomolecular detection.

16. As previously described, the immobilization of biological compounds can be an
important parameter for implantable biosensors due to the fact that it dictates the
sensitivity, selectivity and long-term stability of the device. Thus, cellulose
appears as an easy functionalized material and an ideal support for adsorption and
covalent bond immobilization of biomolecules.
GENERAL MECHANISM OF ACTION
Bioelectronics devices has several applications in pharmaceutical. These devices
also useful for enhancement of efficacy of medicine for many chronic disease
conditions like diabetes, cancer and for diagnostic purposes also.
(1) BIOSENSING OR DIAGNOSTIC
Bioelectronics devices are used for diagnostic purposes ex. In diabetic patients it's
helpful for diagnosis of sugar level.
FIGURE: 11 FIGURE: 12
FIGURE: 13 FIGURE:14

17. (2) APPLICATION AS MEDICINE
1. PARALYSIS
Paralysis is disease condition in which the nervous system get damage and loss of
neurons are observed. So, the electronic signal could not generate by specific
organ and so on the movement of particular organ would not be possible.
Bioelectronic device also help to develop a signal through little electronic current
generation by themselves.
FIGURE: 15
Electrode array location
(a) muscle stimulation
(b)experimental set‐ up
(c) and neural activity
(d and e) for an electronic neural bypass system used to restore movement in a
paralyzed human.
Reprinted from Bouton, Chad E., et al. ‘Restoring cortical control of functional
movement in a human with quadriplegia.’ Nature 533.7602 (2016): (45)
These bioelectronics devices are also work on the concept of neuronal modulation.
With this technique's researchers have found improvement in paralyzed patients.
Report show that the enhancement of activities in patients is also in an ascending
order as per graphical representation.

18. The early work in BCI technology that allowed paralyzed patients to move
computer cursors and wheelchairs paved the way for restoration of movement in
their own limbs. Early nonhuman primate work was completed where temporarily
paralyzed arm muscles were activated under the control of a BCI 33, 34. In these
research studies, neural decoding was combined with functional electrical
stimulation to allow volitional control of temporarily paralyzed muscles. By
comparison, however, paralysis in humans from an actual spinal cord injury can be
quite complex and provides many challenges. Recently, ‘neural bypass’
technology was developed and demonstrated in a first‐ in‐ human study involving
a 23‐ year‐ old male quadriplegic participant. As shown in Fig. 15, a tiny
electrode array (4 x 4 mm across) with 96 electrodes was implanted in motor
cortex and through the use of neural decoding methods, the study participant was
able to move his paralyzed hand under volitional control.
FIGURE: 16
Functional movements achieved by a paralyzed study participant using an
electronic neural bypass linking decoded brain activity to muscle activation in real
time. Reprinted from Bouton, Chad E., et al. ‘Restoring cortical control of
functional movement in a human with quadriplegia.’ Nature 533.7602 (2016):
247–250.
The participant was able to regain volitional wrist and finger movements through
his own thoughts and was able to start and stop those movements when desired.
This allowed the participant to achieve functional movements, using different hand
grasps to manipulate large (glass bottle) and small objects (stirring stick), as those
shown in Fig.16.
Furthermore, the participant was later able to think about static and
dynamic/rhythmic movements, such as flexing and wiggling the finger or wrist,
and switch between the two volitionally as shown in Fig. 17.

19. These results exemplify what is possible with neural decoding and bioelectronic
technology and are paving the way for applications in not only spinal cord injury,
but potentially for stroke, traumatic brain injury, motor neuron disease and other
areas in the future. See Table 1 for a summary of study results for
neuromodulation and bioelectronic medicine studies.
FIGURE: 17
Rhythmic movements achieved by a paralyzed study participant using an
electronic neural bypass. Reprinted from Sharma, G. et al. Using an Artificial
Neural Bypass to Restore Cortical Control of Rhythmic Movements in a Human
with Quadriplegia. Sci. Rep. 6, 33807; doi: 10.1038/srep33807 (2016).
Bioelectronic medicine has already been used to successfully treat inflammatory
diseases such as rheumatoid arthritis 14 and Crohn's disease 15. Neurostimulation
can up‐ /down‐ regulate the immune system in many beneficial ways and even
affect acute inflammation response 12, 16. In one landmark study, it was shown
that efferent vagus nerve signaling could modulate inflammation and the response
to endotoxin and neurostimulation of the peripheral vagus nerve during
endotoxemia in rats inhibited tumor necrosis factor (TNF) synthesis in the liver
and prevented the development of shock 17.

20. Tracing the neurophysiological mechanisms to the spleen revealed that signals
originating in the vagus nerve-controlled lymphocyte release of acetylcholine that
in turn inhibited macrophage production of TNF and other inflammation‐
inducing factors 18. So, we found some interesting results by using bioelectronics
in some disease are given as below.

21. (2) INFLAMMATORY DISEASE
These devices are also available in form of implantable devices. They can
stimulate vagus nerve and help to control inflammation in PNS stimulated organs
like ex. Liver kidney, stomach etc.
Neural reflexes establish homoeostasis in organ systems. Recent advances in
neuroscience and immunology have revealed reflex mechanisms that regulate
innate and adaptive immunity. For example, ‘the inflammatory reflex’, in which
the vagus nerve plays a key role, maintains immunological homoeostasis by
regulating cytokine production and inflammation. Recent clinical trials indicate
that it may be feasible to target the inflammatory reflex in humans to inhibit
cytokine release as treatment of inflammatory diseases, including rheumatoid
arthritis and inflammatory bowel disease [43].
Both afferent and efferent signals in peripheral nerves have been directly
implicated in the reflex control of immunity. Importantly, sensory neurons are
activated by inflammation, and the resulting neural signals modulate cytokine
release and the “inflammatory potential” of infiltrating monocytes and
macrophages [43].
Hence, it may be possible to develop therapeutic devices that both record and
modulate neural signals in inflammation regulating reflex circuits.
FIGURE:19
This figure depicts the general mechanism of action for nervous stimulation.

22. It works in Vegas nerve to peripheral nervous system for stimulation of
inflammation. It reduces cytokinin release and relive inflammation and pain also.
A vagus nerve has more than 100000 neuronal presents in its structure. From these
neurons maybe 80000 neurons are sensory neurons. So, they can conduct a
sensory integration of information via stimulation of charge.
The vagus nerve continues to hold a specific and important place in bioelectronic
medicine. Pioneering research on the role of the vagus nerve in the regulation of
immune responses and inflammation that started more than 20 years ago led to
several important developments in bioelectronic medicine (Borovikova et al., 2000;
Tracey, 2002; Pavlov et al., 2018).
One is the successful use of vagus nerve stimulation (VNS) in the treatment of
human inflammatory and autoimmune diseases (Koopman et al., 2016; Meregnani
et al., 2011; Pavlov & Tracey, 2017).
The current experience with using implanted device-generated VNS in a clinical
trial with patients with inflammatory bowel disease (Crohn’s disease) was
summarized by Bonnaz (Bonnaz, 2018).
The author outlines important findings in the context of our improved
understanding of the functional anatomy of the vagus nerve, new clinical
knowledge of VNS for epilepsy and depression and remaining challenges (Bonnaz,
2018).
These include finding optimal regimens (frequency, pulse width, waive forms, and
duration) of chronic VNS, further miniaturization of the devices and targeting
specificity. He also summarizes the pros and cons of invasive (through implanted
devices) and non-invasive VNS, including transcutaneous VNS of the auricular
branch of the vagus nerve, or the use of devices for cervical vagus nerve
stimulation (Lerman et al., 2016) as therapeutic approaches (Bonnaz, 2018).
Preclinical and clinical research going hand in hand is critical for advancing the
field of Bioelectronic Medicine. Studies on the immunomodulatory role of the
vagus nerve are an excellent example of this symbiotic relationship.
(3) CANCER
Cancer is a severe condition of tissue and treatment of cancer patients is not like a
cup of tea. It is required very accurate treatment in specific areas. Nowadays the
treatment of cancer patients is doing via radiotherapy, chemotherapy etc. But all
these treatments have large area of side effects.
So, hopefully bioelectronics can overcome these all types of side effects and it can
give accurate treatment
Let's draw a distinction here. A material that's part electronic (read: has wires) and
part biological (read: is made of living cells) is certainly bioelectric. But the
ultimate ambition of bioelectronics takes it a stage further.

23. These—largely hypothetical—devices use the principles of biocomputing and the
architecture of biological electronics to do incredible things.
It'll take some time to get there. So far, what we have been successful at doing in
the field of bioelectronics is manipulating the electrical properties of living cells.
Tufts University developmental biologist Michael Levin, for instance, believes he
can tweak the existing electronic signals in cells to spawn new patterns of growth.
This is not dissimilar to tweaking the flow of proteins in a biocomputer to perform
a specific function, except its implications are potentially world-changing.
Just think what it could do for cancer research. Levin's team published a paper last
February that outlines how specific electrical signals are associated with tumor
growth. In effect, if you could identify that unique bioelectric signal early on, you
could spot the tumor before it even starts to grow.
(The first figure depicts the normal cancer cells growth and second figure depict the electrical field
influenced on tumor cell growth.)
By using physics to influence biology, Novocure discovered another way to treat
cancer. Tumor Treating Fields utilizes the natural electrical properties of dividing
cancer cells.
Tumor Treating Fields uses alternating electric fields specifically tuned to target
cancer cells. Once the electric fields enter the cancer cell, they attract and repel
charged proteins during cancer cell division. Cellular proteins such as tubulin and
septin are strongly affected by Tumor Treating Fields because they are highly polar,
containing both positive and negative charges. During cell division, tubulin and
septin must position themselves in a particular way in order for the cell to divide.
Tumor Treating Fields exerts forces on tubulin and septin, preventing them from
moving to their correct locations and disrupting cancer cell division.
FIGURE:20 FIGURE: 21

24. (3) DIABETES
A plethora of studies have confirmed the important role of the nervous system in
maintaining a tight regulation of glucose homeostasis. This has initiated new
research exploring the opportunities of bioelectronic medicine for improving
glucose control in people with diabetes, including regulation of gastric emptying,
insulin sensitivity, and secretion of pancreatic hormones. Moreover, the
development of novel closed-loop strategies aims to provide effective, specific and
safe interfacing with the nervous system, and thereby targeting the organ of
interest. This is especially valuable in the context of chronic diseases such as
diabetes, where closed-loop bioelectronic medicine promises to provide real-time,
autonomous and patient-specific therapies. In this article, we present an overview
of the state-of-the-art for closed-loop neuromodulation systems in relation to
diabetes and discuss future related opportunities for management of this chronic
disease.
Diabetes is a chronic metabolic disease caused by an impairment of the hormone
insulin which results in elevated blood glucose. This disorder currently affects 422
million people worldwide and is forecast to be the 7th leading cause of death in
2030 (World Health Organization, Organization WH 2016).
Therapies involving insulin administration are indispensable for people with type
1 diabetes. For type 2, such therapies are sometimes used in early stages, and are
critical at later stages of the disease. However, the costs associated with the insulin
market are untenable, poised to reach $39.13 billion by 2020 based on the 2016
market research report published by (Markets and Markets 2016).
Moreover, the American Diabetes Association reported in March 2018 that the
total costs of treating people diagnosed with diabetes has risen to $327 billion in
2017 from $245 billion in 2012 (American Diabetes Association AD 2018).
These figures reflect the impact of diabetes on society and encourage the
development of new treatments to improve the control of glucose. The application
of bioelectronic medicine to treat diabetes has been previously criticized by some
members of the scientific community due to the complexity of the underlying
biological processes and the lack of legitimacy of preliminary simulations (Lowe
2016).
However, recent work demonstrates the important role of the vagus nerve in the
pathophysiology of diabetes and its comorbidities (e.g. cardiovascular diseases),
and supports the potential benefits of modulating the peripheral nerve signals to
improve the metabolic dysregulation (Steculorum et al. 2016; Zhang and van den
Pol 2016).
Conversely, research on bioelectronic medicine for direct control of diabetes has
emerged recently, with two main areas of interest: i) recording from the peripheral
nerves to extract metabolic information and ii) modulating their electrical activity
to improve glycemic fluctuations.

25. Regarding the former, recent work aims to use the vagus nerve as a glucometer to
identify hypoglycemic events from neural readings (Bedows 2018; Masi et al.
2019).
In fact, neural activity presents a negatively correlated response to glycemia (Masi
et al. 2019).
The complexity of the recorded data requires advanced strategies to identify and
decode neural signals related to glycemic levels.
In particular, Masi et al. (2019) have developed a decoding algorithm that
recreates blood glucose levels with high accuracy using regression models with
regularization to avoid over-fitting (Masi et al. 2019).
Preliminary results are promising and encourage application of their method for
glucose monitoring and control in the near future, especially for type 1 diabetes.
(CLOSED LOOP NEUROMODULATION)
A depiction of future closed-loop neuromodulation systems for diabetes
management. Metabolic biomarkers and neurophysiological recordings from a
variety of peripheral nerves can be used to automatically control the stimulation
dosage to be delivered back to the peripheral nervous system or directly to the
organs to modulate their function
The impact of neurostimulation on type 1 diabetes has been less explored, but
recent research from Guyot et al. (2019) suggests that stimulation of the pancreatic
sympathetic nerves projecting to the pancreatic lymph nodes inhibits the
progression of the disease, at least in mice (Guyot et al. 2019).
FIGURE:22

26. Activation of these nerves with a stimulation frequency of 10 Hz and 450 μA
amplitude resulted in a reduction of pro-inflammatory cytokines and of the
proliferation of autoreactive T cells, therefore limiting the progression of the
disease. Preliminary optimization of the stimulation parameters eliminated
undesired effects such as blood flow alteration and axonal excitability exhaustion,
hence allowing for therapeutic use.
ADVANTAGES
First, and most important to patients, it holds out the promise of treating conditions
that today’s drugs and medical procedures are either unable to address, such as
severe spinal-cord injuries and blindness or only partially address, such as Crohn’s
disease. Second, miniaturized electric stimulators have the potential to deliver true
precision medicine. Consider patients with paralysis caused by CNS damage in a
stroke or by traumatic brain injury; a bioelectronics therapeutics application to
restore motor transmission by precisely bridging the damaged site is conceptually
simple to imagine, whereas a pharmaceutical approach is too diffuse, lacking the
precision targeting needed. Almost all drugs have the potential for undesired
systemic effects. Some of these effects can even impact compliance, such as a
hypertensive patient reducing medication use because of dizziness. On the other
hand, at least in theory, precise targeting enabled by an electroceutical application
could limit the number and extent of side effects.
TABLE NO: 2 (OUTCOMES OF TREATMENT)

27. FUTURE PERSPECTIVES
The improvement of standards and tools to monitor the state of cells at subcellular
resolutions is lacking funding and employment. This is a problem because
advances in other fields of science are beginning to analyze large cell populations,
increasing the need for a device that can monitor cells at such a level of sight.
Cells cannot be used in many ways other than their main purpose, like detecting
harmful substances. Merging this science with forms of nanotechnology could
result in incredibly accurate detection methods. The preserving of human lives like
protecting against bioterrorism is the biggest area of work being done in
bioelectronics. Governments are starting to demand devices and materials that
detect chemical and biological threats. The more the size of the devices decrease,
there will be an increase in performance and capabilities.
VISION AND CHALLENGES
Bioelectronics has the potential to changes peoples’ lives, but key challenges must
be overcome Input from microelectronics and biotechnology experts, with a
diversity of expertise, was gathered during a wide-ranging discussion of long-term
opportunities at the Bioelectronics Roundtable meeting. Subsequently, the
Roundtable participants where asked to identify the highest priority research need
areas in bioelectronics from a list of over 90 topics. Topics identified by multiple
respondents are shown below as “Highest Priority”, whereas those that received
fewer votes are listed as “Other Topics of Interest”. A more complete summary of
their responses may be found in Appendix D. Even if research is already underway,
realization of any one of the technologies or capabilities listed below is envisioned
to. take ten years or more, based on the ten to twelve-year innovation period that is
typically required to.

28. VISIONS
 Prosthetics, including tissue, i.e. artificial pancreas, and neural implants, i.e.
vision, hearing, etc.
 Disease prevention, including neural degeneration, cancer, etc.
 Disease detection, including neural degeneration, cancer, etc.
 Lab-on-a-chip
 Electronic protein and DNA chips
 Imaging, including cellular
 Tele-monitoring
 Noninvasive physical sensing, e.g. vital functions
 Concentration of analyte and metabolites, etc.
 Real-time and time dependent measurements
 Single bio-molecule detection, including mass, size, chemical, optical, etc.
 Molecular recognition
 Signal processing algorithms
 DNA sequencing
 Nanofabrication (electrodes, devices), including patterning
 Thin film technology
CHALLANGES
 Health monitoring and compliance, real time
 Replacement tissue
 Drug Discovery
 Drug Delivery
 Drug dose, delivery verification
 Energy Scavenging
 Batteries
 Adverse effects
 Nano-delivery and sensing, such as long-term implantable glucose
monitors
 Detection-transduction-signal processing
 High resolution (spatial & temporal) imaging (anatomical, functional, &
molecular)
 Surface characterization
 Protein produced in cells
 Nanopores and nano-membranes
 Neural modeling
 Single-use disposable technologies
 Packaging
 Rehabilitation, including home healthcare and independent living
 Monitoring

29.  Cell Biology
 Novel power generators that will extend the life of implanted devices
 Real time, personalized medicine, via customizable chips
The highest priority challenges, listed above, were categorized within four
cross-cutting topical areas: application drivers, devices, measurements and
analysis, or technologies, as shown in Figure 23.
These topical areas, and the corresponding challenges, align and map into the
framework described as below.
Figure :23
(Cross-cutting drivers address critical challenges, through the creation of new bio-electronic related devices,
measurement capabilities, and technologies.)

30. CONCLUSION
From this review we concluded that the bioelectronics are safe medicines for
future without any side effects. Today, the field of bioelectronics is poised for
exponential growth. The Federal government’s expertise in critical areas of science
and technology, including sensors, nanoelectronics, and metrology should be
harnessed and coordinated, along with expertise from academia and industry to
firmly establish the United States as a leader in this high impact areas of research
and development. The realization of many bioelectronic application opportunities
requires the development of a number of critical technologies. One example of an
ultimate technology target would be extremely scaled intelligent bio-electronic
micro-systems for in vivo operations. This requires the convergence of several
technologies, such as 3D integration, wireless networks, and two-way interfacing
with tissues such as neurons and other cells, as well as organs. In general,
technology encompasses the fabrication and design processes required to construct
a functional bioelectronics system; e.g., semiconductor manufacturing,
computer-aided design, packaging and system integration, etc. An illustrative
example of a driver and related measurements, devices, and technologies is a
personalized medicine system to monitor an individual’s wellness, detect disease
at the earliest stage, and measure the effectiveness of therapies. Using a systems
biology approach, such an application will require the development of massively
parallel bioelectronic sensor systems that have the capability of detecting,
identifying, and quantifying a wide range of biomarkers (e.g., RNA, DNA,
proteins, metabolites, growth factors, hormones, etc.). The convergence of the best
attributes of semiconductor electronics (amplifiers, DSPs, memory, displays,
systems integration, scalability) and biology (specific recognition of biomolecules,
nanometer-length scales, self-assembly, and complexity) could someday
lead to a true personalized medical device that can be implanted in the body.
Similar systems could also be used in the research domain to provide a
fundamental understanding of how single cells and and population of cell works.

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