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org/CR Review

In Vivo Organic Bioelectronics for Neuromodulation

Magnus Berggren,* Eric D. Głowacki, Daniel T. Simon, Eleni Stavrinidou, and Klas Tybrandt

Cite This: Chem. Rev. 2022, 122, 4826−4846 Read Online

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ABSTRACT: The nervous system poses a grand challenge for integration with modern
electronics and the subsequent advances in neurobiology, neuroprosthetics, and therapy which
would become possible upon such integration. Due to its extreme complexity, multifaceted
signaling pathways, and ∼1 kHz operating frequency, modern complementary metal oxide
semiconductor (CMOS) based electronics appear to be the only technology platform at hand
for such integration. However, conventional CMOS-based electronics rely exclusively on
electronic signaling and therefore require an additional technology platform to translate
electronic signals into the language of neurobiology. Organic electronics are just such a
technology platform, capable of converting electronic addressing into a variety of signals
matching the endogenous signaling of the nervous system while simultaneously possessing
favorable material similarities with nervous tissue. In this review, we introduce a variety of
organic material platforms and signaling modalities specifically designed for this role as
“translator”, focusing especially on recent implementation in in vivo neuromodulation. We
hope that this review serves both as an informational resource and as an encouragement and
challenge to the field.

CONTENTS sensory information.1 In vertebrates, the peripheral nervous

system (PNS) consists of nerve bundles that are composed of
1. Introduction 4826
many axon fibers that transport outbound and inbound signals,
2. Coatings for Existing Electrodes 4827
at speeds around 100 m/s, to and from the central nervous
3. Chemical Stimulation and Drug Delivery 4829
system (CNS). In the CNS of a human approximately 1011
3.1. Controlled Delivery Electrodes 4829
somas (neuron cell bodies) together define the central signal
3.2. Iontronic Delivery 4829
processing unit. In the CNS, every soma captures signals via its
4. Photonic Approaches 4831
dendrite branches and releases its signals through its axon
4.1. Photostimulation Mechanisms 4831
4.2. Photoactivated Interfaces In Vivo 4833
cable, ending with the telodendrion. At the boundaries
5. Flexible and Stretchable Stimulating Electrodes 4834 between the telodendrions and “downstream” somas, in total
6. Biohybrid Interfaces 4837 more than 1014 synapses process and transmit neural signals.
6.1. Biohybrid Interfaces in the CNS 4837 This signaling of both the CNS and PNS includes a complex
6.2. Biohybrid Interfaces in the PNS 4837 combination of electric, ionic, chemical, and structural features.
7. Piezoelectric Stimulation 4838 Precise regulation of neuronal function, in both the PNS and
8. Conclusions and Outlook 4839 CNS, is a grand challenge and is highly anticipated as many
Author Information 4839 long-standing questions of neurobiology remain unanswered
Corresponding Author 4839 due to a lack of proper signal triggering technology. For
Authors 4839 example, deep brain stimulation has been available for over 25
Author Contributions 4840 years and is widely used in the clinic,2 but the underlying
Notes 4840 mechanisms of action remain unclear and the devices
Biographies 4840 themselves have seen only marginal technological advances
Acknowledgments 4840 since their introduction.3,4 In addition, several proposed neural
References 4840
Special Issue: Organic Bioelectronics

1. INTRODUCTION Received: May 4, 2021

Published: January 20, 2022
The nervous system consists of various components that
process and transfer signals, which in turn regulate and actuate
internal functions as well as record internal and external
© 2022 The Authors. Published by
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4826 Chem. Rev. 2022, 122, 4826−4846
Chemical Reviews pubs.acs.org/CR Review

prosthetic and therapeutic techniques are hampered since ing conjugated organic molecules. This includes molecular
adequate stimulation, electrode resolution, and multifunctional materials such as macrocycles, up to and including conjugated
interaction with neuronal signaling are still not possible.5,6 To polymers. This definition excludes materials based on
enable such manipulation and control of the signaling cascades allotropes of carbon such as nanotubes, graphene, diamond-
of the PNS and CNS, a technology with proper addressing, like carbon, etc. We hope this review serves both as a source of
complexity, speed, and miniaturization is needed that can information and as a benchmark and encouragement for
“speak the language” of depolarization and neurotransmitters. further developments.
Neuromodulation traditionally relies on the injection of
electrolytic charge from a solid-state electrode. The concept 2. COATINGS FOR EXISTING ELECTRODES
of electrical to ionic transduction is at the center of any
bioelectronic interface. Polymers were first identified in the early 1980s10 as a key
Of all human-made technologies with signaling character- material in neurostimulation applicationsbefore the era of
istics that can match those of the CNS and PNS, organic electronicsowing to their flexible, permeable,11
complementary metal oxide semiconductor (CMOS) based biocompatible, and inert characteristics.12 For instance,
electronics and solid-state photonics are the only ones readily platinum-on-tantalum electrode arrays were photolithograph-
at hand.7 However, there is a fundamental challenge in ically defined and sandwiched between thin polyimide layers,12
connecting analog or digital solid-state Si-based circuitry with access openings produced for electrode stimulation. The
directly8 to the nervous systems due to a lack of signal resulting Kapton device was inserted through the round
translators which can convert an electronic addressing signal window of the inner ear, and successful cochlear prosthesis
into the expression of signal entities that can be received and operation was demonstrated. However, the rise of intrinsically
interpreted by the components of the CNS and PNS, i.e., the conducting polymers,13,14 and stable characteristics while
synapses, nerve bundles, etc. operating in aqueous media, opened up radically new
Organic electronic materials and devices represent a key opportunities of defining electrodes combining several
enabling technology that possesses many of the desired anticipated “plastic” properties with electroactivity and
features for translating electronic signals into the endogenous amalgamating desired mechanical and biochemical features
signaling entities of the PNS and CNS (Figure 1). In this with electronic characteristics and functionalities. Suggestions
for using conjugated polymer electrodes (CPEs) to record or
regulate functions of neurons was suggested and presented as
early as 1991.15 In a few early studies, neuronal cells were
applied to conjugated polymer coatings or electrodes in an
attempt to explore biocompatibility and regeneration of
nervous tissue,16 ultraflexible neural intrafascicular electro-
des,17 and neurite outgrowth.18 In particular, polypyrrole
(PPy) was examined in an in vivo experiment in 1994.16 Here,
various forms of PPy electrodes were examined, such as PPy
added directly onto Pt wires and then implanted into a rat
model with a minimal tissue response observed 4 weeks after
surgery. Further, PPy-based CPEs were also examined to
trigger and regulate angiogenesis (regeneration of blood
vessels) in vivo.19
The achievements listed above blazed the trail for the work
to derive dedicated CPEs applied in vivo to record and regulate
neuronal signaling and tissue (re)growth/generation. A first
step was taken in 2001, when Martin and co-workers reported
surface-modified neural electrodes with improved recording
capability.20,21 Micromachined silicon probes with gold
electrodes were coated with PPy combined with polystyr-
Figure 1. In vivo organic bioelectronic neuromodulation. (a) Multiple, enesulfonate (PSS) or biomolecules from aqueous solutions.
parallel electronic signals can be transduced using (b) organic The PPy phase was galvanostatically grown at a current density
electronic materials, electrodes, and structures. (c) The broad array of of 0.5 mA/cm2, reaching a total passed charge ranging from 60
neuromodulatory signals arising from the organic electronics can to 240 μC (see Figure 2a). The resulting “fuzzy” electrode
include, e.g., electrical, physical/piezoelectric, or biochemical stimuli. morphology, provided by the PPy cladding, exhibited a more
efficient interface for electronic and ionic signal transport, and
paper, we review the early and recent progress on the topic of the biomolecule coating with cell-binding functionality also
developing neurostimulation devices based on organic offered improved cell attachment. Soon after this achievement,
materials, specifically targeting in vivo applications. We focused the Inganäs team reported conducting hydrogel CPEs based on
on reviewing organic bioelectronics9 in the form of electrodes, PEDOT:PSS (poly(3,4-ethylenedioxythiophene) doped with
devices, and systems, with specific features related to elasticity, PSS) manufactured onto a micromachined polydimethylsilox-
signal translation fundamentals, proximity, biostability, bio- ane (PDMS) substrate.22 In this work, the emphasis was aimed
compatibility, self-organization, and more, in an attempt to to develop an all-flexible device expressing a high capacitance
make the technology−nervous system signaling interface value, per area active electrode, optimized for signal recordings,
seamless. Organic bioelectronics are defined as those based along with elastic properties similar to those of the targeted
on organic semiconducting and conducting materials compris- tissue or brain. Several early studies also aimed to investigate
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Figure 2. (a) Surface-modified depth probes with improved recording capability. The charges indicate the amount of electropolymerization of
PPy:PSS. (b) Nerve-cuff electrode featuring nanoparticulate PPy within silicone elastomers. (c) PPy−PCL copolymer degradable tubular electrode
for regeneration of the sciatic nerve. Part a reproduced with permission from ref 20. Copyright 2001 John Wiley and Sons. Parts b and c reproduced
with permission from refs 31 and 32, respectively. Copyright 2007 and 2010 Taylor & Francis.

the overall biocompatibility,23 biostability, and interaction with cladding contained a healthy nerve cable and no inflammatory
proteins under electrical stimulation from CPEs in vivo. response was observed.32 PEDOT-coated PtIr and IrOx
The work on CPEs to regulate and record cell functions and electrodes were also found to have superior signal-to-noise
neuronal signaling was thus established, and several groups recording and charge injection characteristics when they were
subsequently entered this research effort.24 In 2004, the first evaluated by using electrochemical impedance spectroscopy,
steps toward using conjugated polymer electrodes for in vivo both in vitro and when implanted in rat cortex.33 A similar
neurostimulation of the CNS and PNS was reported.25 At the study was conducted for PEDOT coated on bare Pt
same time, it was also shown that electropolymerized PPy on microelectrodes, which confirmed previous reports.34 In an
nylon/spandex fabric electrodes exhibited successful in vivo attempt to further “open up” the electrode structure, vapor
electrotherapeutic results when they were applied to a phase polymerization of PEDOT was applied to a 3D
neuropathic pain animal model.26 Soon after, refined and microparticle assembly. The microparticles were then
dedicated CPEs were frequently developed and explored, such selectively excluded, which rendered the resulting electrode
as for regulating nerve regeneration on biodegradable highly porous with voids defined on the micrometer scale.35 In
composites (PPy doped with butanesulfonic acid)27 and an attempt to derive electrodes that mimic the structure and
improving the nerve−electrode interface of cochlear implants morphology of the targeted neuronal system, to reach a
(PPy doped with p-toluenesulfonate coated on Au).28 Further seamless electro-neuro interface, in situ/in vivo polymerization
work investigated the necessary biostability and biocompati- of PEDOT using iron chloride was conducted.36 The resulting
bility of conducting polymers, such as by investigating the electrode was produced inside acellularized muscle tissue
short-term histocompatibility and signal throughput29 and by constructs, and a resulting tissue−electrode amalgamation was
incorporating polysaccharides (heparin) as dopants to limit thus achieved. A similar approach was later used to
PEDOT’s immunological response in cortical tissue.30 In an electropolymerize EDOT monomers to form a PEDOT
attempt to derive CPEs with tailor-made elastic properties, cloud electrode with a protrusion penetrating brain tissue37
nanoparticulate PPy was polymerized within silicone elas- and the hippocampus of live rats.38
tomers and then shaped into a cuff-electrode configuration Recent work on the development of CPEs for in vivo
(Figure 2b).31 neurostimulation has been devoted to deriving highly
CPE materials can be manufactured and shaped into sophisticated electrode devices and systems. For instance,
mechanical, structural, and functional systems, which provide PEDOT doped with PSS-co-(maleic acid) (PSS-co-MA) was
great freedom to define dedicated electrode settings for specific coated on carbon microfibers (7 μm in diameter) forming an
in vivo neurostimulation applications. PPy−poly(ε-caprolac- intraspinal microstimulation (ISMS) scaffold. The ISMS
tone) (PCL) copolymers were for instance synthesized and electrode was introduced into the cervical spinal cord of
explored as degradable electrodes for regeneration of the anesthetized rats, and successful activation of specific spinal
sciatic nerve (Figure 2c). After 8 weeks from implantation, the motor neurons was achieved, with an increased activation
tubular electrode including the biodegradable PPy−PCL response for PEDOT:PSS-co-MA coated carbon fibers
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compared to noncoated ones.39 New material formulations

have also been explored recently, such as PEDOT:Nafion with
an improved charge injection limit reaching 4.4 mC/cm2.40

3. CHEMICAL STIMULATION AND DRUG DELIVERY

3.1. Controlled Delivery Electrodes
The mixed ionic and electronic properties of organic electronic
materials make them a promising platform of controlled
substance release technologies. In the most straightforward
embodiment of controlled drug release from organic electro-
des, the ions associated with doping and charge compensation
along the polymer backbone can be released from the electrode
during electrochemical switching. For example, in the electro-
chemical switching of the archetypal PPy from its oxidized
(charged) to neutral state, the compensating counterion (A−)
is released into bulk solution: PPy+:A− + e− → PPy0 + A−.
Indeed, chemical delivery has been an integral part of the field
of conducting polymers since the early 1980s. As early as 1984,
Zinger and Miller were investigating the release of the
neurotransmitter glutamate from PPy films.41 The appeal of
such controlled release is obvious: if the bioactive compound
can be contained by the organic electrode and released on
demand by simple voltage pulses, a precise and local drug
delivery system can be achieved and provide an alternative to
problematic systemic dosage (injections, pills, and the
associated side effects) or fluidic delivery (requiring
complicated pumps and plumbing). Such controlled delivery
has been particularly appealing in the realm of neuroscience,
since the target cells and tissue are particularly sensitive to
chemical and physical (e.g., fluidic pressure) changes in their
environment. Over the decades, a variety of such controlled Figure 3. Controlled release via conducting polymer electrodes. (a)
delivery electrodes have been demonstrated, all following the Canonical mechanism with active (left) and passive/diffusion (right)
basic recipe of embedding bioactive substances in the redox- drug release. (b) Combination of controlled release (anti-inflamma-
active conducting polymer film (as counterions in the PPy tory dexamethasone, Dex) and neural recording (large electrode to
example above, or co-ions compensating the counterions) and left) on a single flexible depth probe. (c) Enhancement of controlled
releasing them into the adjacent electrolyte upon redox release using functionalized carbon nanotubes. Parts a and b
switching (Figure 3a). These devices have been extensively reproduced with permission from refs 50 and 54, respectively.
Copyright 2019 and 2017 Elsevier. Part c reproduced with permission
reviewed elsewhere42−45 and have been utilized in a variety of from ref 55. Copyright 2018 John Wiley and Sons.
recent in vitro neuromodulation demonstrations.46−52 How-
ever, such controlled delivery electrodes have seen few
study did prove the concept of relatively long-term
neuromodulation demonstrations in vivo.
implantation of conducting polymer-controlled delivery
In 2016, Wallace et al. demonstrated a “pre in vivo” system
electrodes. Meanwhile, Cui et al. have been experimenting
combining electrocorticography (ECoG) signals associated
with nanostructured additives to enhance delivery performance
with epilepsy as the input signal for controlled release of the
in vivo. In 2018, they used functionalized carbon nanotubes in
antiepileptic drug fosphenytoin (FOS).53 They used prere-
a combined PEDOT and PPy film to deliver 6,7-
corded human ECoG signals to trigger release of FOS from a
dinitroquinoxaline-2,3-dione (DNQX), a competitive agonist
PPy film on a quartz crystal microbalance (QCM) to validate
to glutamate receptors, into the barrel cortex of rats (Figure
the “seizure initiated” system. Using a constant-current delivery
3c).55 Using multielectrode depth probes modified with their
protocol to ensure consistency, they demonstrated a latency
delivery electrode material, they were able to demonstrate the
(between exceeding the ECoG threshold and actual drug
expected neural suppressive effect of DNQX up to 446 μm
release) of only ∼10 s. In 2017, Asplund et al. combined classic
from the release site. More recently, the team has
conducting polymer controlled delivery with flexible neural
demonstrated a PEDOT-based delivery electrode incorporat-
depth probes.54 In that study, they embedded the anti-
ing mesoporous sulfonated nanoparticles for enhanced drug
inflammatory dexamethasone (Dex) in multiple PEDOT
loading.56 With these devices, they increased the charge
electrodes on the same flexible polyimide-based recording
injection limit (for electrical stimulation), increased the drug
probes (Figure 3b). The aim was to mitigate the inflammatory
loading capacity by 16.8 times compared to pure PEDOT, and
response common to such depth probes which, over time,
again demonstrated in vivo neural suppression via DNQX
causes degradation of recording quality. Over the course of 12
delivery (in mouse brain).
weeks, they were able to periodically release Dex precisely at
the implant location and observe that active neurons did 3.2. Iontronic Delivery
indeed remain closer to the recording electrode. While the Another version of drug delivery utilizing the unique ionic
neuron−electrode proximity was only marginally affected, the properties of organic electronics has emerged in the 2000s in
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Figure 4. Iontronic drug delivery. (a) Basic lateral organic electronic ion pump (OEIP) with characteristic length scales. In this depiction, the
source (anodic) electrolyte is on the left and the target (cathodic) electrolyte is on the right. (b) OEIP adapted for delivery of GABA directly to the
relevant nerve junctions on the rodent spinal cord, for pain therapy. (c) Microfluidic ion pump (μFIP) adapted for depth probe implantation. The
scale bar is 1 mm, and the cross section at “×” is depicted below. (d) Freestanding fluidic capillary-based device with “iontronic cap”. Parts a and d
reproduced with permission from refs 57 and 74, respectively. Copyright 2018 and 2021 John Wiley and Sons. Parts b and c reproduced with
permission from refs71 and 72, respectively. Copyright 2015 and 2018 AAAS.

the form of so-called “iontronics”.57,58 Iontronics represent membranes (AEMs) for anionic drug delivery, in a variety of
circuits, circuit branches, and components where the dominant form factors and by various research groups.43,57,61,62 Addi-
or exclusive charge carriers are ions rather than electrons or tional iontronic components and circuits have also been
holes. The concept is an extension of ion exchange systems developed, such as diodes,63 capacitors,64 transistors,65−67
whereby ions are transported through selective membranes by rectifiers,68 and logic circuits.69
the application of electric fields (electrophoresis). Iontronics, In 2009, Simon et al. demonstrated the first in vivo
in this context, are typified by their original demonstration in application of OEIPs, for modulating auditory function in a
2007: the organic electronic ion pump (OEIP),59 effectively an guinea pig model.70 In these experiments, the planar geometry
iontronic resistor (i.e., ionic current directly proportional to of previous OEIPs was encapsulated by using medical-grade
applied voltage). This original OEIP was based on a single thin tubing (over the source and target electrolytes) and PDMS
film of the well-known PEDOT:PSS with regions of the over the tapered “delivery tip”. Devices were mounted on the
PEDOT component “deactivated” by chemical overoxidation, round window membrane of anesthetized guinea pigs, and
leaving ionically conducting (but electronically insulating) auditory function was modulated by delivery of glutamate
regions of polyanionic PSS. In the fully hydrated state, cations which elicited a selective excitotoxic effect on the inner hair
could be “pumped” electrophoretically laterally across the PSS cells of the cochlea. This acute excitotoxic demonstration
region, from a “source” electrolyte to a “target” electrolyte paved the way for a follow-up project focusing on treating
(Figure 4a). The polyanionic nature of the PSS rendered it a neuropathic pain. In 2015, a simplified OEIP implant
lateral (several millimeters) cation exchange membrane specifically designed to match the physiology of the rat spinal
(CEM), blocking the electrophoretic flow of anions from the cord was demonstrated.71 In these experiments, the OEIP was
target toward the source. In this way, the OEIP represents a designed with four outlets connected as a parallel iontronic
platform for charge-selective delivery of small- to medium- circuit and arranged to match the position of the L3−L6 dorsal
sized ionic compounds on demand (no delivery in the absence roots, where the sciatic nerve bundles enter the spinal cord and
of applied voltage) and without liquid flow (aside from relay the pain signal into the CNS (Figure 4b). Delivery of the
hydration sheaths, no liquid is “pumped” along with the ions). inhibitory neurotransmitter γ-aminobutyric acid (GABA) at
As with the controlled delivery electrodes above, such these specific points (to awake animals) resulted in a
spatiotemporally resolved delivery, without liquid flow, is of significant reduction of the pain threshold (von Frey filament
great appeal in the realm of neuromodulation. From the first test in a spared sciatic nerve model) while only requiring
OEIP demonstrations,59,60 delivering neuroactive compounds approximately 1% of the required dosage used in intrathecal
for neuromodulation purposes has been a top priority. Over injection. Around this time, Malliaras and Proctor et al. began
the years, a variety of devices have been demonstrated using development of a hybrid microfluidic ion pump (μFIP)
CEMs for cationic drug delivery and anion exchange architecture combining the long-range versatile delivery of
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fluidics with the high-resolution spatiotemporal delivery of 4. PHOTONIC APPROACHES

OEIPs. In 2017, they demonstrated the first μFIP, based on a Organic semiconducting materials can be highly efficient light
conformable parylene C based microfluidic architecture with absorbers.78 Organic semiconductors have, relative to their
vertical CEM outlets (based on PEDOT:PSS) in the “roof” of inorganic cousins, remarkably high optical absorption co-
the fluidic channel.61 The devices exhibited ideal iontronic efficients. Poly(3-hexylthiophene), P3HT, is an archetypical
performancelow leakage and low voltage operationand polymeric p-type semiconductor used extensively in organic
were successfully used to deliver K+ to the cortex of photovoltaics. In the region of strongest absorption between
anesthetized rats, eliciting the expected hyperexcitability 400 and 600 nm, P3HT has an absorption coefficient of
(increased spiking). In 2018, they demonstrated a μFIP between 1 × 105 and 5 × 105 cm−1. Phthalocyanines, which are
adapted for implant application (depth probe, Figure 4c).72 macrocyclic small molecules deployed in vacuum-processed
This device was used to deliver GABA into the hippocampus organic photovoltaics, have absorption coefficients of the same
of anesthetized mice in a 4-AP epilepsy model. GABA delivery magnitude. Metal-free phthalocyanine, H2Pc, has a peak
via the μFIP successfully suppressed pathological neural absorption coefficient of 3 × 105 cm−1 at 650 nm.79 Silicon,
spiking events (only when actively delivering, not during the standard inorganic photovoltaic material, has an absorption
passive delivery), demonstrating for the first time “deep” in vivo coefficient of 3 × 103 cm−1 at 650 nm, a 100-fold difference.
neuromodulation using ion pump technology. Most recently, Absorption coefficients of organic semiconductors such as
Proctor et al. have demonstrated an integrated sensing and P3HT and H2Pc even exceed those of highly efficient
drug delivery platform using the conformable parylene C based absorbing direct-band-gap materials such as germanium or
μFIP combined with a PEDOT:PSS-based ECoG electrode gallium arsenide by a factor of 2−10. Therefore, organic
array surrounding the ion pump outlets. 73 Using an semiconductors have an intrinsic advantage due to the fact that
anesthetized mouse cortex model, they were able to they are highly efficient light absorbers. As a consequence,
successfully demonstrate the in vivo delivery of various biointerface devices based on organics can be much thinner
neuro-active compounds with simultaneousand importantly, (based on films of tens to hundreds of nanometers) and
colocalizedelectrophysiological recording. The hybrid mi- lightweight and therefore minimally invasive when implanted.
crofluidic ion pump concept has also been demonstrated by This capability of using less absorber material, combined with
using a free-standing capillary fiber form factor. In 2021, the relative mechanical flexibility and possible biocompatibility,
Arbring Sjöström et al. demonstrated a coaxial capillary device makes organic semiconductors promising choices for light-
(for fluid inlet and outlet) with an “iontronic cap” featuring an activated interfaces. Despite these advantages, the use of
AEM ion channel (Figure 4d).74 With the PEDOT-based organic light transducers for neurostimulation applications is a
source electrode (cathode) incorporated onto the surface of young and still emerging field, with examples of in vivo
the inner capillary, a minimal amount of wiring was needed to experiments being promising but still limited. In the following,
drive the device (the anodic counter electrode was a separate we will consider first the mechanisms behind photostimulation,
piece of PEDOT:PSS), making it simple to mount on a followed by discussion of some necessary context from in vitro
micromanipulator and integrate into a standard electro- examples and then, finally, in vivo validations themselves.
physiology setup. Glutamate was delivered (as an anion) into
artificial cerebrospinal fluid and used to demonstrate the 4.1. Photostimulation Mechanisms
spatiotemporal precision (via a glutamate biosensor), paving There are three mechanisms by which organic light absorbers
the way for application in brain slice models or as a depth can transduce an optical signal into a bioelectronic one: (i)
probe. photothermal, (ii) photochemical, and (iii) photovoltaic.
In addition to the basic OEIP functionality described above, Photothermal can be further broken down into “simple”
i.e., operation as an iontronic resistor, the analogy between the photothermal heating of a physiological medium or very rapid
majority cationic and anionic carriers in CEMs and AEMs and temperature changes which cause photothermocapacitive
the holes and electrons in p- and n-type semiconductors has effects. Photovoltaic can likewise be separated into two
enabled the development of a range of iontronic components different processes: photocapacitive, where light induces
including bipolar membrane diodes (CEM−AEM junction)63 reversible formation of electrochemical double layers, and
and bipolar junction transistors (AEM−CEM−AEM stack),65 photofaradaic, where light drives redox reactions which may or
as well as analog64 and digital63,66 ionic circuits. While these may not be reversible. Photovoltaic mechanisms are the only
more complex devices have yet to reach in vivo applications, ones which are analogous to “classic” electrical neuro-
they have enabled significantly advanced functionalities that stimulation. Normal electrical neurostimulation relies on the
pave the way for more advanced neuromodulation. For injection of current from an electrode into a physiological
example, the integration of vertical iontronic diodes along medium, with the goal of altering the membrane potential of
the length of lateral OEIP channels enabled individually nearby excitable cells. To modify membrane potentials, the
addressable neurotransmitter delivery with on/off switching of direction of current flow and the resultant electric field profiles
∼50 ms (as opposed to ≳1 s for lateral or fluidic-based must be carefully considered. These principles for current
OEIPs).75 More recently, purely geometric modifications of injection and flow apply also to the case of designing
the ion channel encapsulation have enabled “polarization photovoltaic stimulation electrodes. As with traditional
diodes” to reach on/off switching of ∼1 ms, finally “wired” neurostimulation, the figure of merit is injected charge,
approaching the temporal dynamics of synaptic transmission.76 or charge density. Charge density is the most useful metric for
Finally, integration of palladium-based “proton traps” along the “macro” electrodes, of greater than 100 μm diameter. For
length of lateral ion channels has enabled a significant increase microelectrodes often used in stimulation, thresholds for action
in delivery efficiency (ratio of delivered neuroactive compound potential usually scale not with density, but with total delivered
to electronic charge in driving circuit, with the ideal case of charge.80 The injected charge (or charge density) is defined as
1:1).77 the integral of current (or current density) over one phase of a
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stimulus waveform.81 Charge must be delivered rapidly, usually organic materials to date.91 Organic photothermal absorbers
within 100−1000 μs, in order to stimulate voltage-gated have been reported in vivo for photothermal cancer
sodium channels. This is because voltage-gated sodium ablation;92,93 however, their deployment has been isolated to
channels, required for evoking action potential, have very in vitro neurostimulation so far.
rapid gating. The threshold values of charge for reproducible If the electrical potential across the semiconductor/electro-
generation of action potentials (APs) will depend on the lyte is high enough, photogenerated electrons and holes can be
stimulation target. For example, in vivo stimulation of APs in transferred to the electrolyte by respectively reducing or
peripheral nerves requires charge densities in the range 1−60 oxidizing molecules. Physiological electrolytes contain various
μC/cm2.80−82 For evoking AP in the retina, small micro- molecules that can participate in redox reactions. Various
electrodes are utilized to maximize spatial resolution of organic molecules can be oxidized, such as sugars, or reduced,
stimulation. Thresholds will vary depending on which types such as quinone molecules.94 Dioxygen, dissolved in water, is a
of excitable cells in the retina are targeted. Thresholds have potent electron acceptor. Moreover, water electrolysis is always
been reported in the range from 0.05 mC/cm2 to as high as 1 a possibility, resulting in hydrogen or oxygen gas evolution. In
mC/cm2, with thresholds generally being lower when larger the case of organic semiconductors, direct water splitting
stimulating electrodes are used.83 without transition metal cocatalysts has proved to be very
Photoexcited semiconductors dissipate absorbed energy via inefficient and detectable only in trace amounts.95 In recent
radiative or nonradiative processes. Nonradiative processes are years, a number of studies have shown that oxygen reduction
either electrical work (as carriers are extracted into an external reactions are very common on organic semiconductor surfaces,
load, as in the case of a photovoltaic under normal operation) and these can have important physiological effects.96 Single-
or heating. Semiconductors can be configured to suppress electron reduction of O2 to superoxide97,98 or the two-electron
radiative and charge-generating effects and dissipate energy reduction yielding hydrogen peroxide,99−101 H2O2, was
primarily as heatwhich leads to a temperature increase of the demonstrated to proceed efficiently on a number of organic
semiconductor and its surrounding medium. There are two semiconductors. Both oxygen reduction reactions are thermo-
mechanisms by which photothermal heating can elicit an dynamically favored over H2 evolution, with two-electron
electrophysiological response: a slow process and a fast oxygen reduction to peroxide occurring at 0.7 V lower
process. The slow process refers to the trivial effect of potential than H2 evolution. The dominance of oxygen
increased local temperature. Absorption of constant illumina- reduction reactions was established in electrochemical,102,103
tion lasting on the order of hundreds of milliseconds to photoelectrochemical,99,104 and photochemical tests98,101 for
seconds causes a temperature increase local to the site of polythiophenes, the biopigment eumelanin,105 and various
illumination. Heat-sensitive ion channels, especially transient crystalline organic molecular materials.104 These oxygen
receptor vanilloid (TRPV) channels, can be activated by heat reduction products are known as reactive oxygen species
and lead to depolarization of excitable cells.84 There are a few (ROS) and have physiological effects ranging from toxicity at
examples in the literature of organic semiconductor/cell high concentration (>100 μM)106 to ion channel modu-
interfaces used to stimulate TRPV channels by photothermal lation107 and signaling effects (1 nM−0.01 mM range)108 at
heating. Colloidal nanocrystals synthesized from the pigment low concentrations. On-demand light-driven ROS generation
quinacridone were found to form close interfaces with cultured by P3HT has been shown by Antognazza and co-workers to
cells and be effective photothermal heating elements.85 yield physiological effects both in vitro109−111 and in vivo.112
Photoactivation of TRPV1 channels was measured with The in vivo model chosen was the freshwater polyp, an eyeless
quinacridone/cell interfaces illuminated with green light pulses animal. It was shown that P3HT colloidal nanoparticles were
of 30 μJ energy dose.85 Photothermal heating in these internalized by the polyp and photoirradiation resulted in
interfaces was also found to increase currents flowing through behavioral changes as well as transcriptional changes in gene
potassium inward rectifier channels. Similar experiments have expression. Though not neuromodulation per se, this experi-
been performed with human embryonic kidney cells expressing ment showed that photogenerated ROS can be delivered by
TRPV1 channels which were photothermally activated with organic semiconductors and produce physiological changes.
longer light pulses (tens to hundreds of milliseconds) using These charge injection mechanisms are completely analo-
P3HT thin films as the light absorber.86 The effects of P3HT gous to traditional neurostimulation; only the provision for
photothermal heating on single cells were evaluated as a light excitation “photo” is added. Currents flowing across an
function of irradiation time and intensity by Martino et al.87 A electrolyte will result in potential differences in the medium,
completely different stimulation mechanism can arise from which can depolarize cell membranes. Photoexcited charges in
highly intense light pulses at a short time scale of 1 ms. Rapid a semiconductor can travel to the semiconductor/electrolyte
local temperature increase of cell membranes causes their interface and cause charging of an electrolytic double layer.
expansion, which results in a transient increase of cell This phenomenon is regarded as photocapacitive charging. If
membrane capacitance. A capacitance increase results in a the potential difference across this interface is sufficiently large,
depolarizing current. This effect was discovered when using this charge can be transferred to a species in solution, resulting
direct heating of cells with intense infrared light pulses by in a redox reaction. This electrical current originating from
Shapiro and Bezanilla et al.88−90 The magnitude of the redox charge transfer is referred to as photofaradaic current.
depolarizing current is proportional to the rate of temperature For neurostimulation applications, both capacitive and faradaic
change and not the absolute change in temperature. For this charge injection processes are acceptable, providing that the
reason, even with extremely intense laser pulses, when they are latter are fully reversible.113 In order for photocapacitive or
very short, they cause nonhazardous rises in temperature. A photofaradaic currents to be injected by a semiconductor
number of inorganic nano/microparticle light transducers have (organic or otherwise) into a physiological electrolyte, there
been used for photothermocapacitive stimulation interfaces; must be a discrete cathode and anode component of the
however, this effect has not been explicitly described for semiconductor/device in contact with the electrolyte. That is,
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Figure 5. (a) P3HT-based retinal stimulation implantable devices which were shown to partially restore visual sensitivity to blind rats. Implantation
was carried out for periods of 6−10 months. (b) P3HT-based photovoltaic pixels integrated into a foldable prosthetic implant for minimally
invasive implantation into the eye. Part a reproduced with permission from ref 119. Copyright 2017 Springer Nature. Part b from ref 122. CC BY
4.0.

there must be a path for the capacitive or faradaic current to these experiments, hippocampal neurons are grown on P3HT
flow through the solution in such a way as to generate potential substrates and then illuminated with 20 ms pulses with an
differences that adjacent cells will experience. A number of intensity of 15 mW/mm2, corresponding to a light energy dose
photovoltaic configurations for photocapacitive114 and photo- of 30 mJ/cm2. Action potentials are generated reproducibly
faradaic115 charge injection have been reported. with stimulation frequencies of 1−20 Hz, with the action
4.2. Photoactivated Interfaces In Vivo potential probability falling from +90% for 1 Hz stimulation to
around 70% by 20 Hz. Degenerated retinal tissues were then
Organic electronics for photo-driven neurostimulation appli- measured ex vivo, and action potentials were reliably triggered
cations is a relatively young field, with the first examples of in with light intensities at 4 mW/mm2. Follow-up work from
vitro work being reported within the past decade. Examples in 2015 showed that P3HT interfaces had a concurrence of three
vivo remain rare, though with the speed of developments at the different effects: photocapacitive, photothermal, and photo-
in vitro level this is likely to change in the near future. Organic thermocapacitive. The photocapacitive effect and photo-
photointerfaces deployed to date in vivo can be divided into thermocapacitive effect could both be implicated in the
two application targets: the retina of the eye and subcutaneous depolarization of cells and therefore stimulation of action
implants for stimulation of peripheral nerves. Light-driven potentials.
stimulation approaches have been explored the most in the In 2017, the P3HT photoelectrode system was reported in
context of artificial stimulation of the retina. Retinal prosthetic vivo, with the possibility of stimulation of retinal tissues tested
devices are aimed to restore partial visual sensitivity to patients for the first time. The photostimulation implant consisted of a
afflicted with blindness conditions which are caused by trilayer of silk fibroin serving as a biocompatible substrate,
degeneration of photosensitive cells but where the neuronal PEDOT:PSS as an underlying conducting layer, and P3HT as
cells of the retina remain viable. Synthetic light-absorbing a charge-generating material and capping layer (Figure 5a).
elements can be imagined to convert light into signals which The devices were implanted subretinally in dystrophic rats.
stimulate the intact neurons of the retinal tissue and restore This animal model shows vision impairment in terms of both
visual perception. Several retinal prosthetic devices are on the light sensitivity and spatial acuity and is an established model
market and at various phases of clinical trials. There remains a for degenerative blindness. The efficacy of stimulation by the
substantial interest in making retinal stimulation approaches device was validated using recording of visually evoked
simple and more efficacious than the state of the art, and potentials (VEPs), measuring pupillary reflex, as well as
organic semiconductors have attracted interest to achieve this. behavior assessments. Implantation was tracked over 6 months,
P3HT, by virtue of its widespread use as a photovoltaic after which devices were explanted and characterized. The
polymer, ease of solution processability, and aforementioned explanted devices were found to preserve a similar level of
high absorbance coefficient, is the most explored organic photoelectrical charging and upon microscopic inspection
photoactive material for neurostimulation interfaces to date. appeared to be fully intact and undegraded. In parallel, there
Lanzani, Benfenati, Antognazza and colleagues published a was exploration of using colloidal P3HT nanoparticles (in the
comprehensive volume of work from 2009 to 2020, detailing range of hundreds of nanometers in diameter) for neuro-
the deployment of P3HT for neurostimulation in various in stimulation. In 2020, it was reported that subretinally injected
vitro settings and in vivo for retinal stimulation.86,116−121 This colloidal dispersions of P3HT could achieve similar in vivo
series of studies began with detailing the fabrication and effects as the planar devices published in 2017. The approach is
measurement of organic photoelectrodes in contact with attractive as such injection is surgically more facile. On one
electrolyte. These photoelectrodes were characterized in the hand, the in vivo compatibility of P3HT appears promising,
context of photovoltaic stimulation, with the hypothesis that and there is evidence that neurostimulation can be induced by
photocapacitive currents would be injected into the physio- P3HT, at least at relatively high light intensities. On the other
logical electrolyte. In 2013, Ghezzi et al. reported that films of hand, there are still open questions related to the mechanisms
P3HT (230 nm thickness) on conducting ITO substrates at play: whether P3HT can stimulate via a photovoltaic
could elicit action potentials reliably in cultured neurons. In mechanism or whether photochemical mechanisms or photo-
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Figure 6. (a) Organic electrolytic photocapacitor (OEPC) capacitive coupling to adjacent cell membranes. The OEPC consists of a charge-
generating p−n junction atop a return electrode. Ionic currents short-circuit the device over the electrolyte during charging/discharging. (b) In vivo
OEPC implants for stimulation of the sciatic nerve prove that organic photovoltaic implants can function under chronic conditions and can be
powered using tissue-penetrating red light. Part b reproduced with permission from ref 127. Copyright 2020 Silverå-Ejneby et al.

thermal mechanisms are predominantly responsible for the layers are charging up. Ionic current can only flow in solution
observed electrophysiological effects ex vivo and in vivo. An at time periods shorter than the charging time of the double
important point of distinction is that the to-date-reported layers and will necessarily be limited by the double layer with
P3HT devices do not incorporate a structure of a primary the smaller capacitance.114 Sustained ionic direct currents
electrode and return electrode as normal neurostimulation would only be possible if both cathode and anode components
configurations do; therefore, there is not a clear current path support faradaic reactions.124,125
for photovoltaic faradaic or capacitive currents to flow. The OEPC was tested for stimulation in vitro with single
Commercial availability, ease of processability, and indications cells, primary neuronal cultures, and explanted retinal
for biocompatibility make P3HT and related polythiophenes tissues.114,123,126 In these applications, the OEPC device was
an interesting choice for functional photostimulation inter- able to stimulate via a photovoltaic mechanism that was
faces. Issues that remain to be solved are engineering devices to photocapacitive, using light intensities on the order of 1−8
deliver high currents/current densities and also material mW/mm2 which generated 1−2 μC/cm2 over 1 ms of
stability, which under photoirradiation conditions may not illumination. OEPCs were reported in vivo in 2020 for
be sufficient for chronic stimulation. Recently, P3HT-based transcutaneous stimulation of peripheral nerves.127 Silverå-
organic photovoltaic cells have been incorporated into a soft Ejneby et al. showed how OEPCs can be fabricated on
multielectrode array of stimulation electrodes of 130 μm parylene (3 μm thick) modified with thin, semitransparent
diameter (Figure 5b).122 The entire array is foldable, enabling gold (Figure 6b). These flexible OEPC stimulators were
a minimally invasive implantation into the eye. This was only integrated into a zip-tie locking mechanism so as to be
carried out on surgical phantoms as yet; however, the idea, chronically implanted around the nerve. In this study, the
combined with higher-performance organic photovoltaic pixels, sciatic nerve in rat served as a model to validate direct
holds high potential for future implantable stimulators. photoelectrical stimulation. The OEPC devices could be
The OEPC was introduced in 2018 as a thin film implanted at a depth of roughly 1 cm below the surface of
photoelectrode device to mimic established bipolar electrode the skin and actuated transcutaneously by using a 638 nm laser
stimulators.123 The original OEPC features a bilayer donor− diode over the course of 100 days. Validation was performed
acceptor photovoltaic structure, fabricated via vacuum by shining impulses of light at the implant (100−1000 μs pulse
sublimation of H2Pc as the electron donor, and a perylene length) and measuring electromyography (EMG) of the leg
tetracarboxylic diimide derivative, PTCDI, as an electron and paw. EMG signals were accompanied by clear leg
acceptor. The system of materials was chosen as such movements, evidencing direct photoelectrical stimulation of
evaporated bilayers are well-established in the literature and the sciatic nerve. This approach to ultrathin nerve stimulators
stand out for operational stability. The OEPC p−n donor− is an application where the mechanical and optical properties
acceptor junction functions as the charge-generation layer as of organic semiconductors can be highly competitive.
well as the primary stimulation electrode. The OEPC
transduces impulses of light into ionic currents flowing in 5. FLEXIBLE AND STRETCHABLE STIMULATING
solution. The process proceeds as follows: A light impulse is ELECTRODES
absorbed by the p−n layer and electrons travel to the n-type The mechanics and form factor of neuromodulation devices
material/electrolyte interface, while holes are injected into an are of general importance for all types of devices, ranging from
underlying metallic electrode (Figure 6a). As a consequence, conventional electrodes to photoactivated electrodes and drug
two electrolytic double layers are formed: one on the n-type/ delivery devices. When the mechanical aspects of various
electrolyte interface and the other at the back contact/ devices are described, the terms “soft”, “flexible”, and
electrolyte interface. The former is cathodically polarized, “stretchable” are often used, sometimes interchangeably.
while the latter is anodically polarized. Ionic current will flow “Soft” refers to a material property, often the elastic modulus,
in the surrounding solution while the two respective double while “flexibility”, the ability to bend, is the result of both
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Figure 7. Flexible and stretchable conducting polymer based devices for neuromodulation. (a) PEDOT:PSS electrodes and OECTs were
integrated into the bending plane of a 4 μm thick parylene C device. (b) The ultraflexible probe was inserted with a stiff shuttle.140 (c) The
viscoplastic PEDOT:PSS electrode could expand along with the growing tissue. (d) The viscoplastic electrode (MorphE) induced little
inflammation (inflammatory biomarker ED1) in comparison to a conventional cuff electrode. (e) Soft and stretchable microwire based on a
silicone/PEDOT−PEG/CNTs composite. (f) Histology of chronically implanted nerves with the soft microwire (SW, left) and polyimide wire
(PW, right). The soft wire induced less scar tissue around the wire. Parts a and b reproduced with permission from ref 140. Copyright 2015 John
Wiley and Sons. Parts c and d reproduced with permission from ref 147. Copyright 2020 Springer Nature. Parts e and f reproduced with permission
from ref 149. Copyright 2019 John Wiley and Sons.

softness and geometry. A stretchable material or device can be PEDOT:PSS films and improve their stretchability, for
elongated, often in an elastic manner, while remaining example, polyethylene glycol. 136 To reach really soft
functional. This typically requires tolerance to higher levels mechanical properties, conductive hydrogel formulations are
of strain within the materials than for flexible devices. To employed.137,138
achieve a chronically stable neural interface, flexibility or Parylene, polyimide, and SU-8 have been the most popular
stretchability is often required for surface electrodes interfacing substrate and insulation materials for flexible neural interfaces.
peripheral nerves or the spinal cord.128,129 In the case of The total device thickness plays an important role here, as the
penetrating neural probes, they should not induce a severe bending stiffness is 1000 times higher for a 20 μm thick device
tissue response or migrate within the tissue over time. It is in comparison to a ultraflexible 2 μm139 thick device.
known that a mechanical mismatch between the neural probe Williamson et al. developed a 4 μm thick parylene probe
and the soft neural tissue (E < 10 kPa for brain) can cause both with gold conductors and PEDOT:PSS electrodes and
issues, as natural bodily movements, respiration, and vascular electrochemical transistors (Figure 7a,b).140 Due to its
pulsatility induce movements within the tissue.130−132 The ultraflexibility, the probe had to be attached to a rigid shuttle
compliance of a rectangular probe is characterized by its axial during insertion, after which it was delaminated and the shuttle
stiffness kA = Ewt/l and bending stiffness kB = Ewt3/l (elastic was removed. The device could stimulate local populations of
modulus E, width w, thickness t, length l). The advantage of neurons and record activity with the transistor, while limiting
thin polymer probes can be understood on the basis of the the tissue response due to its outstanding flexibility. Boehler et
bending stiffness, as thickness is the most important property al. developed an alternative approach for flexible neural probes
to achieve low bending stiffness, i.e., flexibility. For axial as they included Dex-loaded PEDOT electrodes onto the
stiffness (elongation), thickness is less important, and a low probes.54 The Dex could be actively released by electrical
elastic modulus is necessary to accommodate tissue mo- addressing of the drug-loaded PEDOT electrodes, which
tions.133 The tunability of the mechanical properties of showed a positive effect during 12 weeks of implantation with
conducting polymers makes them attractive for flexible and respect to the proximity of neurons to the electrodes.
stretchable neural interfaces. Various formulations of PE- Flexibility also allows for the development of nonplanar device
DOT:PSS have gained the most attention, likely due to their geometries for various applications. Ferrari et al. combined ink
superior chemical stability. Pristine dry PEDOT:PSS is rather jet printing of PEDOT:PSS with a heat-shrinkable polymer
hard and brittle, with an elastic modulus in the gigapascal range substrate to form cuff electrodes for nerve regeneration
and a fracture strain around 2−6%.134 The swelling behavior of applications.141 The device was able to stimulate regenerated
PEDOT:PSS in water depends strongly on the processing motor axons to induce a muscular response 3 months after
conditions and additives. PEDOT:PSS with the addition of 5% implantation. In another approach, Tian et al. used the
ethylene glycol has been reported to have an elastic modulus in flexibility of their parylene C−PEDOT:PSS microelectrodes to
the 100 MPa range in the swollen state.135 The addition of create a flexible tubular electrode with drug delivery
GOPS (3-glycidoxypropyltrimethoxysilane), a common stabi- capability.142
lization additive, increases the wet elastic modulus to ∼300 A recent trend is to go beyond the limitations of flexibility by
MPa.135 A variety of additives can be used to soften developing soft and stretchable conducting polymer based
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Figure 8. Examples of biohybrid neural interface devices. (a) Cell-seeded electrode consisting of Pt, conducting hydrogel, and hydrogel for culture
of neuroprogenitor and glia cells. (b) (left) Living electrode concept where a neuronal axonal electrode is cultured in vitro within a columnar
hydrogel with the potential to be injected in the brain and interfaced with a neuromodulation device. (right) Confocal reconstruction of a
unidirectional, cerebral cortical neuronal living electrode at 11 days of culture in vitro, immunolabeled for axons (β-tubulin-III; red) and synapses
(synapsin; green) with a nuclear counterstain (Hoechst; blue). The surrounding hydrogel microcolumn is shown in purple. (c) (left) Regenerative
peripheral nerve interface (RPNI) that is based on a scaffold of acellular muscle coated with PEDOT that contains myoblasts and is wrapped
around the end of the peripheral nerve. A section of the distal common peroneal nerve is removed (A), and the residual nerve (B) is implanted into
the RPNI (C) for a minimum of 2 months. (right) In situ image of RPNI 4 months after implantation. (d) (right) Tissue engineered electronic
nerve interface (TEENI): 16-channel device attached to the ends of a transected nerve. Insets show 1 mm diameter cross-sectional views of the
construct with a single thread set (4) and a multiple thread set (3−4−3) arrangement. (left) Histological analysis of a TEENI device after a 6 week
implantation. (left) Optical microscope image of an explanted nerve that regenerated through a TEENI hybrid scaffold with the microfabricated
device visible inside the nerve. (top right) Light-sheet microscope image of a TEENI device (red) and the vasculature (green) inside a regenerated
nerve. (center bottom) Image of regenerated axons within a TEENI device. Part a from ref 181. CC BY 3.0. Part b reproduced with permission
from ref 182. Copyright 2018 John Wiley and Sons. Part c from ref 164. CC BY 4.0. Part d reproduced with permission from ref 183. Copyright
2019 IEEE.

stimulation devices. To achieve stretchability, all device layers stretchable electrode arrays, Liu et al. developed PEDOT-based
must be stretchable or arranged geometrically so that they are hydrogel conductors (∼50 S/cm) by dissolving an ionic liquid
isolated from strain. A special class of highly elastic polymers, additive out of the conductors after the film formation. Soft
elastomers, are therefore used as substrates and encapsulation (∼30 kPa) cuff electrodes were developed, based on the
for such devices. There exist a variety of different elastomers, conductive hydrogel and a fluorinated substrate material, and
although only a small portion of those are suitable for chronically implanted around the sciatic nerve in mice. The
biomedical use and implantation.143 Stretchable conducting soft cuff electrodes showed less tissue response and lower
polymers can be achieved by tailoring the material structure in stimulation threshold than the commercial reference cuff
combination with swelling in water137 or by forming electrode. By instead using glycerol as an additive to
conducting polymer−elastomer composites.144 However, PEDOT:PSS, Liu et al. developed viscoplastic hydrogel
even modified conducting polymers typically have inferior electrodes (∼1 S/cm).147 Together with a viscoplastic
robustness and stretchability in comparison to many polymer, electrodes that could expand along with growing
elastomers. It is therefore of the utmost importance to create tissue were achieved and implanted around the sciatic nerve of
good adhesion between the substrate/encapsulation and the growing rats (Figure 7c,d). Penetrating probes are necessary to
conducting polymer layer to achieve robust and stretchable achieve higher specificity in peripheral nerve stimulation, but
devices. As many elastomers are hydrophobic and have low such probes typically induce a severe tissue response.148 Zheng
surface energy, activation by, e.g., oxygen plasma is often used et al. addressed this issue by developing stretchable microwire
to improve the adhesion between the layers.145 Qi et al. electrodes based on a silicone/PEDOT−PEG/CNTs (<5 S/
developed stretchable highly conductive (∼800 S/cm) PPy− cm) composite with an elastic modulus below 1 MPa (Figure
toluenesulfonic acid conductors by the use of prestrained 7e).149 The implant could evoke force and compound muscle
PDMS substrates.146 The anchoring of the PPy conductors to action potentials in the tibial nerve of rats and showed less scar
the PDMS was facilitated by the fabrication of PPy nanowires tissue encapsulation after 1 month of implantation in
as an adhesion layer, which greatly improved the adhesion to comparison to a polyimide wire (Figure 7f). The above
the PDMS substrate. Stretchable multielectrode arrays were examples demonstrate the benefits of soft and stretchable
used for acute recording of electrocorticographic signals and conducting polymer electrodes for neuromodulation; however,
stimulation of the sciatic nerve in rats. To achieve even softer a limiting factor is the relatively low conductivities of these
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materials. It might therefore be beneficial to combine while the electrical performance of the electrode was
stretchable conducting polymers with high-performance promising, the cell growth within the hydrogel scaffold
stretchable inorganic conductors129,150 for the next generation requires further optimization. Furthermore, the dimensions
of soft and stretchable devices for neural modulation. of the electrode should be miniaturized for in vivo testing.
The first in vivo evaluation of a cell-seeded probe was
6. BIOHYBRID INTERFACES presented by Purcell et al.156 The probe was based on SU-8
encapsulated in parylene C and had an opening along its length
Biohybrid neural interface devices combine principles of tissue
where NSCs were seeded in an alginate hydrogel. The study
engineering with bioelectronic technologies,151−153 aiming to
focused only on the cell viability, and the probe had no active
minimize or even eliminate the foreign body response and to
sites. The tissue response after implantation in the cortex of
improve the communication and signal transduction between
rats was evaluated at four time points over 3 months. Up to 1
the biotic and abiotic interfaces. Tissue regeneration principles
week post implantation, higher neural density was observed
can be used to restore the damaged tissue but also to form a
around the cell-seeded probe in comparison with controls, but
more natural connection between the device and the target
after 6 weeks increased neuronal loss and glial encapsulation
tissue. For example, the use of autologous iPSCs, induced
were observed. The initial positive effect could be a result of
pluripotent stem cells, that are harvested from the patient will
in principle suppress any immune response at the implantation the neurotrophic and neuroprotective factors that are released
site. However, studies have shown that iPSCs can have low by the NSCs,159 while the later negative effect could be due to
viability after transplantation and even form tumors.154 On the reduced viability of the NSCs and/or a delayed immune
other hand, neural stem cells (NSCs) have shown better response from the host tissue. In another work, NPCs were
viability and the ability to differentiate into both neurons and immobilized on laminin-coated Si neural probes.160 The cells
glia cells.155 In addition, NSCs secrete neurotrophic factors were cultured in vitro for 14 days, showing growth and
that promote the axonal regeneration in the host neurons while differentiation along the probe, and then the probe was
at the same time reducing glial formation and enhancing implanted in murine cortex. At 1 and 7 days post implantation
healing.156 Although the two fields have made significant viable NSCs were detected on the probe and in its proximity.
progress independently over the past decades, biohybrid neural Furthermore, the authors observed a reduced glial response
interface devices are at a very early stage of development with that could be the effect of secreted neurotrophic factors from
only a few examples in the literature for both the central and the NSCs. Cell-seeded probes are still at a very early stage of
peripheral nervous systems. development. While these examples show promise in terms of
host tissue response, a more in-depth investigation is still
6.1. Biohybrid Interfaces in the CNS required in order to demonstrate how the seeded cells and the
Green et al. were the first to demonstrate the concept of a host tissue integrate and communicate over time.
biohybrid electrode based on organic electronic materials157,158 Taking the idea of cell-seeded probes a step further is the
(Figure 8a). The living electrode construct, as they named it, concept of the living electrode introduced by Cullen et al.161
was a Pt electrode with a conducting hydrogel that supported The idea is to form an axon-based electrode consisting of a
neural progenitor and glia cell growth.158 The study focused on neuronal tissue engineered construct that can be injected into
evaluating the electrode performance and cell viability in vitro. the brain and act as a transducer between the host tissue and
A PVA-based hydrogel was initially cross-linked on top of the an external electrical or optical neuromodulation device that
Pt electrode, and then PEDOT was electropolymerized will lie on the surface of the brain (Figure 8b). Depending on
through the hydrogel in order to induce electronic the nature of the engineered neurons, the living electrode can
conductivity. Then a macromer solution that contained have excitatory, inhibitory, or modulatory effect as it will be
neuroprogenitor or glia cells was deposited on top of the determined by the type of synapses that will be formed with
conducting hydrogel and cross-linked with UV in order to the host tissue. The motivation behind this approach is to
encapsulate the cells. Hydrogels are widely used materials for enhance neuromodulation through a biological interface that
tissue engineering as they can mimic the mechanical properties can have high specificity, high synaptic density, and long-term
of the in vivo environment and they can support cell growth integration. So far living electrodes have been demonstrated in
with diffusion of nutrients and other signaling molecules. The vitro based on columnar hydrogels that support neural growth
electrode had initially a relatively high modulus of 140 kPa, but and longitudinal axonal outgrowth of glutamatergic, dopami-
over time it became softer due to swelling, reaching 1.5 kPa nergic, and GABAergic neuron subtypes.162,163 On the basis of
after 21 days in an aqueous environment. In comparison with a the cell culture conditions and hydrogel composition, the
neat Pt electrode, the living electrode construct had lower length of the axons can vary between submillimeter and
impedance (1−1000 Hz), higher charge storage capacity, and centimeter and, therefore, can target different areas in the brain
higher charge injection limit. Glia cells showed high viability, after injection. In a preliminary in vivo study living electrodes
reaching 80% in the course of 7 days, while the viability of the with GFP-modified cortical neurons were microinjected
neural progenitor cells was low. The neuroprogenitor cells between the cerebral cortex and the thalamus in rats.163 At 7
were encapsulated immediately after harvest, and the authors and 28 days post implantation the implanted neurons survived,
speculate that the presence of cell debris might have negatively maintaining the engineered architecture, while there were
impacted the cells. The authors also evaluated the extracellular indications of formed synapses with host neurons based on the
matrix production in an additional study and showed that both presence of the presynaptic protein synapsin in the proximity
laminin and collagen were produced, with laminin distributed of the transplanted neurons.
throughout the hydrogel while collagen was present only at the
surface of cells. The cells, although they were distributed 6.2. Biohybrid Interfaces in the PNS
throughout the hydrogel, mostly formed aggregates. In this Biohybrid devices for interfacing with the peripheral nervous
work the biohybrid electrode was only evaluated in vitro, and system also exist. Similarly to the CNS devices, the goal is to
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Figure 9. Piezoelectric thin films coupled with magnetostrictive materials allow for transduction of oscillating magnetic fields to resonant
mechanical vibrations which in turn are converted by piezoelectric PVDF into alternating AC currents capable of direct neurostimulation. By using
two different resonant frequencies and a diode bridge circuit, biphasic stimulation can be accomplished. Reproduced with permission from ref 169.
Copyright 2020 Elsevier.

suppress the host response, in this case to minimize neuroma electrophysiological activity over 6 weeks.166 The TEENI was
formation and axonal damage and to enhance device well integrated into the tissue with vascularization and axons
integration. Advanced prosthetics for example require high throughout the scaffold. A more detailed immunohistochem-
fidelity control with multiple channels of independent motor ical analysis was performed in another work and showed the
control and sensory feedback that can be achieved via a high- presence of regenerated axons and Schwann cells but also a
density cell connection. foreign body response related to the presence of the PI
In a proof-of-concept study Urbanchek et al. presented the electrode threads.167
regenerative peripheral nerve interface (RPNI), a device that is
composed of a scaffold that supports differentiation of 7. PIEZOELECTRIC STIMULATION
myoblasts and regeneration of nerves as a new strategy for
connecting divided peripheral nerves with artificial limbs164 Piezoelectric materials generate a voltage upon mechanical
(Figure 8c). The scaffold consisted of an acellular muscle with deformation, resulting in current flow. It is possible therefore
chemically polymerized PEDOT. The distal end of a divided to extract power from a piezoelectric material. Periodic
peroneal nerve was inserted in the cylindrical scaffold where mechanical vibration can thus be transduced to alternating
myoblasts were cultured. The RPNI was evaluated on average electrical currents, which can then be applied for neuro-
93 days after implantation. EMG activity was recorded from stimulation. A number of organic polymeric materials are well-
the RPNI, and the myoblasts within the construct developed established piezoelectrics. The most prominent is PVDF
into mature muscle that was reinnervated and revascularized (polyvinylidene fluoride),168 which is used in numerous
without any indication of neuroma formation. Furthermore, commercial electronic products and has likewise found its
neuromuscular junctions were detected, indicating formation way into in vivo stimulation devices. Singer and co-workers
of synapses between the regenerated axon and the myoblast recently reported the concept of magnetoelectric transduction
derived muscle fibers. The PEDOT electrode surrounding the for neurostimulation (Figure 9).169 The process relies on
cultured cells opens the possibility for parallel stimulation/ PVDF for generating an AC current. PVDF is coupled with a
recording, but that was not explored in this initial study. magnetic strip which in turn vibrates with a resonant frequency
Another hybrid approach for the PNS is the tissue excited by an external magnetic field. Therefore, a magnetic
engineered electronic nerve interface (TEENI) that aims to field generates a mechanical vibration, which is transduced by
integrate soft and flexible electrode arrays into a hydrogel PVDF into AC current. Due to the excellent tissue-penetrating
matrix that can act as scaffold for regeneration of nerves properties of magnetic fields, this kind of wireless stimulator
(Figure 8d).153 In this case the scaffold does not include any has the potential for interfacing to deep targets, for example in
cells, but the idea is that host cells will grow within the scaffold the brain. The device consists of a thin film of PVDF which is
and make an intimate connection with the electrode array. It laminated with Metglas SA1, a magnetostrictive alloy, and is
was first presented by Desai et al.165 with an electrode array encapsulated in parylene C, giving a minimal mechanical form
based on flexible polyimide (PI) electrodes integrated within a factor. An alternative pathway is to couple acoustical waves
pro-regenerative scaffold that was then wrapped in decellular- directly to activate a piezoelectric material, which is the
ized small intestinal submucosa. In a following work the concept behind actuating implanted piezoelectric stimulators
TEENI was implanted in a damaged rat sciatic nerve with the with focused ultrasound.170,171 The focused ultrasound/
distal and proximal nerves placed at the two ends of the device. piezoelectric approach has gained increasing attention recently;
After only 4 days of implantation, the authors recorded single however, inorganic piezoelectric crystals are used. The thin
unit activity at the distal electrodes and were able to record film form factors enabled by polymeric piezoelectrics such as
4838 https://doi.org/10.1021/acs.chemrev.1c00390
Chem. Rev. 2022, 122, 4826−4846
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PVDF may enable more minimalistic and biocompatible constitutes an attractive complement to high-frequency
stimulators in the future. electrical stimulation. Organic electronic ion pumps have
shown considerable promise for in vivo deployment, yet
8. CONCLUSIONS AND OUTLOOK important questions must be answered regarding chronic
Using organic electronic materials for in vivo bioelectronic stability and compatibility. Solutions for the replenishment of
interfaces offers a high degree of versatility due to the synthetic reservoirs must also be found, or the ion pump technology
tunability of material properties. There is an increasing amount must focus on applications that require relatively low doses
of experimental indications that organic electronic materials and/or only short-term application.
have good potential biocompatibility. The mechanical softness, Overall, the field of in vivo organic bioelectronics is just
relative to traditional ceramic, inorganic materials, can reduce beginning to gain larger interest and acceptance, as many
the foreign body response upon implantation. On the other materials and device concepts are validated at the in vitro stage
hand, bioorthogonality is desired. The chemical similarity and mature to the level of in vivo applications. Indeed, medical
between organic conductors and biology may not always be devices incorporating organic electronic materials (coatings)
ideal for the living system. To date, the long-term effects of have just recently been awarded FDA and CE approval, e.g.,
implanting organic electronic materials remain poorly under- Acutus Medical’s AcQMap system178 incorporating Heraeus’s
stood. The most important outlook for this field of research is Amplicoat PEDOT formulation.179 Heraeus (one of the largest
to establish the suitability of organic electronic materials for producers of PEDOT and related derivatives) has confirmed180
chronic applications. PEDOT-based materials have shown very that they are currently working on commercialization of several
promising performance for in vivo recording, for example in the additional applications for Amplicoatincluding neuromodu-
CNS. Likewise, the use of organic electrodes like PEDOT has lationbut only the AcQMap system has reached the level of
seen increased attention for stimulation applications in recent FDA/CE approval. An important caveat to the push for
years,172 with efforts focusing on understanding stimulation medical approval and in vivo or even in-human testing is that
efficiency,173 material stability,174−176 and improving long-term scientists working in this field should consider thorough
device performance.177 However, due to the lack of large characterization of materials and devices ex vivo, especially with
patient studies utilizing such organic material systems, chronic regard to stability and reliability. This is important from the
safety remains an open question. point of view of ethical use of laboratory animals, where
While organic materials have advantages as active bioelec- scientists should optimize their approaches as much as possible
tronic interface components, their mechanical properties, and before planning in vivo experiments.
the role of organic substrates and encapsulants, are equally Altogether, organic electronics materials and systems already
critical for successful neural interfaces. A wide range of elastic present promising capabilities for neuromodulation technol-
moduli can be achieved for conducting polymers, from ogy. As preclinical demonstrators are translated into clinical
gigapascal in the pristine state to kilopascal in conductive devices, we feel certain that patients in the not-too-distant
hydrogel formulations. This enables matching of the future will benefit from such organic bioelectronic technolo-
mechanical properties of interfaced tissues, which is of especial gies. This being said, the in vivo chronic test of time is the next
importance when interfacing deforming tissues in the PNS. frontier for organic bioelectronics to prove itself for wide-scale
The chemical structure of organic electronic materials also acceptance in neuromodulation protocols.
enables innovative approaches for the deployment of
stimulation electrodes. Conducting polymers can be formu- AUTHOR INFORMATION
lated into injectable dispersions that solidify in situ. The Corresponding Author
molecular nature of the conductors can also enable specific
interactions with, and the bridging of, biological structures. Magnus Berggren − Laboratory of Organic Electronics,
Furthermore, gentle polymerization approaches may allow for Department of Science and Technology, Linköping University,
in situ formation of integrated conductive structures. 601 74 Norrköping, Sweden; orcid.org/0000-0001-5154-
Altogether, organic electronics promise unparalleled integra- 0291; Email: [email protected]
tion with tissue and thereby specific neuromodulation and
recording. Authors
The neurostimulation field is increasingly pushing toward Eric D. Głowacki − Laboratory of Organic Electronics,
wireless solutions to enable less invasive stimulation in vivo. In Department of Science and Technology, Linköping University,
line with this, the possibility of exploiting efficient light 601 74 Norrköping, Sweden; Bioelectronics Materials and
absorption by organic semiconductors has created the nascent Devices, Central European Institute of Technology, Brno
field of organic optobioelectronic interfaces and stimulators. University of Technology, 612 00 Brno, Czech Republic;
The amount of work in vivo remains very limited; however, the orcid.org/0000-0002-0280-8017
increasing diversity of organic stimulation devices tested under Daniel T. Simon − Laboratory of Organic Electronics,
in vitro conditions indicates that this field is set to grow. A Department of Science and Technology, Linköping University,
major question which must be confronted by the field is, once 601 74 Norrköping, Sweden; orcid.org/0000-0002-2799-
again, stability. Researchers often publish validations of 3490
successful performance but fail to carry out and report device Eleni Stavrinidou − Laboratory of Organic Electronics,
stability. Department of Science and Technology, Linköping University,
Organic electronic materials have great potential for 601 74 Norrköping, Sweden
controlled delivery of drugs and biomolecules, as their Klas Tybrandt − Laboratory of Organic Electronics,
structure allows for the incorporation and transport of Department of Science and Technology, Linköping University,
molecular entities. As chemical stimulation is very versatile 601 74 Norrköping, Sweden; orcid.org/0000-0002-9845-
and typically operates in the low-frequency regime, it 446X
4839 https://doi.org/10.1021/acs.chemrev.1c00390
Chem. Rev. 2022, 122, 4826−4846
Chemical Reviews pubs.acs.org/CR Review

Complete contact information is available at: same year she was awarded the Future Research Leaders grant by the
https://pubs.acs.org/10.1021/acs.chemrev.1c00390 Swedish Foundation for Strategic Research. Her research interests
focus on organic electronics for plant monitoring and optimization,
Author Contributions energy applications, and biohybrid systems.
The manuscript was written through contributions of all Klas Tybrandt received his Ph.D. in organic electronics in 2012 at the
authors. All authors contributed equally and are listed Laboratory of Organic Electronics (LOE) at Linköping University.
alphabetically by last name. His work was focused on the development of ionic components and
Notes circuits, including the highlights of inventing the first ionic transistor
functional at physiological salt concentrations and the first
The authors declare no competing financial interest. complementary ionic circuits. He continued to work as a postdoc at
Biographies LOE for 1 year and then received a postdoc fellowship from the
Swedish Research Council to join the Laboratory of Biosensors and
Magnus Berggren received his Ph.D. in applied physics in 1996 from Bioelectronics at ETH Zurich. From this point forward he changed
Linköping University. He then joined Bell Laboratories as a postdoc his research topic to stretchable electronics, with focus on soft and
in Murray Hill, NJ, USA. Since 2002, he has been professor in organic stretchable materials for bioelectronics. In 2016, he returned to LOE
electronics at Linköping University and the founding director of the as an assistant professor, received the Ingvar Carlsson Award, and
Laboratory of Organic Electronics (LOE), today including more than established the Soft Electronics group. In 2018, he became an
100 scientists. Magnus Berggren is one of the pioneers of printed
associate professor, and in 2020 he was awarded the Future Research
organic electronics and organic bioelectronics. In 2012, he was elected
Leaders grant from the Swedish Foundation for Strategic Research.
member of the Royal Swedish Academy of Sciences, in 2014 he
received the Marcus Wallenberg Price, in 2016 he was awarded the
IVA Gold Medal, and in 2018 he was elected member of the Royal ACKNOWLEDGMENTS
Swedish Academy of Engineering Sciences. He is the cofounder of The authors wish to thank Caroline Lindholm for compiling
nine companies. the manuscript and assisting with the content. Funding for the
Eric D. Głowacki completed his Ph.D. in chemistry in 2013 at the time committed to compiling this review was provided by the
Johannes Kepler University (JKU) in Linz, Austria, working on Knut and Alice Wallenberg Foundation, the Swedish
bioelectronic semiconductors and flexible electronic devices. He Foundation for Strategic Research, the Swedish Research
continued at JKU working on devices for electrophysiology. In 2016, Council, the European Research Council (ERC, Advanced
he was awarded a Wallenberg Molecular Medicine Fellowship, which Grant for M.B.), and the Ö nnesjö Foundation. E.D.G. is
allowed him to start a research group in 2017 at Linköping University grateful for support from the ERC under the European Union’s
(LiU) in Sweden. His group has worked on devices for stimulation of Horizon 2020 research and innovation program (Grant
the nervous system, as well as reactive oxygen species generation. In Agreement No. 949191). K.T. and E.S. received additional
2020, he was awarded the European Research Council Starting Grant, support from the Swedish Government Strategic Research
with which he established a new research group dedicated to Area in Materials Science on Advanced Functional Materials at
bioelectronics research at CEITEC, Brno University of Technology, Linköping University (Faculty Grant SFO-Mat-LiU No. 2009-
in the Czech Republic. 00971).
Daniel T. Simon received his Ph.D. in physics in 2007 from the
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