4 Biohybrid Neural Interfaces - Improving The Biological Integratio

Biohybrid neural interfaces: improving the
biological integration of neural implants
Abstract
Implantable neural interfaces (NIs) have emerged in the clinic as outstanding tools
for the management of a variety of neurological conditions caused by trauma or
disease. However, the foreign body reaction triggered upon implantation remains
one of the major challenges hindering the safety and longevity of NIs. The
integration of tools and principles from biomaterial design and tissue engineering
has been investigated as a promising strategy to develop NIs with enhanced
functionality and performance. In this Feature Article, we highlight the main
bioengineering approaches for the development of biohybrid NIs with an emphasis
on relevant device design criteria. Technical and scientific challenges associated
with the fabrication and functional assessment of technologies composed of both
artificial and biological components are discussed. Lastly, we provide future
perspectives related to engineering, regulatory, and neuroethical challenges to be
addressed towards the realisation of the promise of biohybrid neurotechnology.
Biohybrid design enables the engineering of neural interfaces with enhanced

functionality and performance.
Introduction
Neural interfaces (NIs) are devices that enable direct communication with the
nervous system by leveraging the electrical excitability of nervous tissues to
stimulate and/or record neural activity. NIs have been widely implemented in the
management of neurological disorders affecting either the central (CNS) or the
peripheral nervous systems (PNS).1–6
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit1)
They have also been extensively
used to develop brain–machine interfaces (BMIs) to control neuroprostheses and
other assistive devices.7,8 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit7) In
general, NIs rely on the use of arrays of electrodes that can be implantable or non-
implantable.9 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit9) Non-implantable
electrodes can be used to monitor brain signals from the scalp via
electroencephalography (EEG),10
which circumvents the need for
surgical implantation but limits spatial and temporal resolution.11
In contrast, implantable devices
such as the Utah electrode array (UEA) or electrode leads for deep brain stimulation
(DBS) are implanted into the cortex or deep brain structures, providing higher
resolution for electrical stimulation (ES) and recording due to the intimate contact
with the host tissues.12 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit12) Despite
these advantages, conventional implantable NIs often undergo poor biological
integration into the surrounding tissues, which in turn hinders long-term
applications and clinical translation.
The implantation of an electrode array into the neural parenchyma triggers an

inflammatory process mediated by the immune system, leading to a biological
response known as the foreign body reaction (FBR) (Fig. 1
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/figure/fig1/)). The
initial trauma and the disruption of the blood brain barrier (BBB) result in the release
of circulating blood cells and proteins that trigger an acute inflammatory response
at the implant site13,14 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit13) (Fig. 1A
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/figure/fig1/)). Early
after implantation (0–24 h), migratory neutrophils increase vascular permeability
and mediate monocyte recruitment and differentiation into macrophages via
soluble pro-inflammatory cytokines. Activated macrophages attempt to
phagocytose and degrade the implant, which results in electrode damage,15
increased impedance,16
and overall reduced device
performance (Fig. 1C
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/figure/fig1/)). Resident
cells in the CNS such as microglia and astrocytes also become activated and
contribute to this acute immune response.17–20
For chronically implanted
devices (>4 weeks), the sustained inflammation gives way to a fibrotic process that
ultimately leads to the formation of a fibrous scar that encapsulates and isolates
the implant21–23 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit21) (Fig. 1B
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/figure/fig1/)). In the
context of ES, this physical barrier increases the level of charge injection required to
elicit tissue activation, which induces further tissue damage and electrode
degradation.24 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit24) Local tissue
trauma may also be exacerbated due to mechanical mismatches and implant
micromotion caused by normal respiratory and cardiovascular functions.25,26
This is mainly because
conventional NIs rely on electrode arrays made from stiff and inert materials such
as platinum (Pt), platinum–iridium (Pt–Ir) or stainless steel,27,28
which are mechanically distinct
from the soft and viscoelastic neural tissues. The perpetuation of local tissue
damage further aggravates neuronal depletion leading to a reduction of
approximately 40% in the number of viable neurons at the device–tissue interface.29
Tissue responses to neural implants and their impact on device performance. (A) The acute
immune response. Upon implantation, plasma proteins adhere to the electrode surface
triggering PRR-mediated signalling pathways in microglial cells, astrocytes, and infiltrating
neutrophils. Activated cells secrete pro-inflammatory cytokines (TNF, IL1β, IL2) and
chemokines (CCL2) increasing BBB permeability, as well as macrophage infiltration, activation,
and polarization into an M1 pro-inflammatory phenotype. ROS and the activation of the
complement cascade further contribute to neurotoxicity. (B) The chronic immune response.
Macrophages polarize into an M2 phenotype and release anti-inflammatory cytokines (TGFβ,
IL4, IL10). Astrocytes, microglia, and macrophages fused into multi-nucleated giant cells form
a scar that encapsulates the implant. Pro-angiogenic factors such as VEGF and PDGF are
involved in the vascularisation of the capsule surrounding the electrode. (C) Electrical model of
the electrode–tissue interface. The FBR increases electrode impedance and decreases CSC
over time, resulting in reduced SNR and increased risk of overpotential. BBB (blood brain
barrier), CCL (chemokine ligand), CCR (chemokine receptor), CSC (charge storage capacity), IL
(interleukin), ILR (interleukin receptor), PDGF (platelet-derived growth factor), PRR (patter
recognition receptor), ROS (reactive oxygen species), SNR (signal-to-noise ratio), TGFβ
(tumour-growth factor β), TGFβR (tumour-growth factor β receptor), TNFα (tumour necrosis
factor α), TNFR (tumour necrosis factor receptor), VEGF (vascular endothelial growth factor).
Chronic inflammatory responses have been shown to hinder implant biointegration,
longevity, and performance, and constitute one of the main limitations precluding
the long-term applications of implantable NIs. The large majority of studies
describing the negative effects of the FBR on implant performance have relied on
research performed on animal models. However, clinical evidence has shown that
the long-term implantation of NIs is also associated with the onset of inflammatory
and fibrotic responses in human patients. For instance, post-mortem analysis has
revealed that a UEA retrieved 7 months after implantation exhibited signs of fibrotic
encapsulation and peri-implant tissue damage.30
Electrode tip degradation has
also been observed following post-mortem explantation of UEAs after 987 and 182
days, with higher degrees of electrode damage corresponding to longer
implantation timelines.15 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit15)
Therefore, strategies aimed at mitigating the negative effects of the FBR and
improving the long-term safety and performance of NIs have gathered significant
research interest.
The biomechanical mismatch between soft living tissues and stiff implants is a
major factor influencing the degree of the FBR. Therefore, implant design strategies
are moving away from conventional stiff materials towards flexible and
conformable alternatives based on biomimetic design.31–39
A variety of novel electrode
substrates made from elastomers or organic materials combined with conductive
polymers (CPs),40 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit40) carbon
nanotubes (CNTs), or graphene (GF) have been developed for this application.41
Bio-integrative strategies based
on surface modification or the incorporation of biomaterial coatings that provide a
more biomimetic interface have also been widely explored.37,42,43
Lastly, as the field of NIs
continues to evolve, there has been a shift towards alternate modalities for neural
interfacing. For instance, neural recording through intracranial blood vessels via
endovascular stentrode arrays has emerged as a promising alternative to
conventional implantation techniques.44,45
Strategies that improve implant resolution and selectivity are also needed to
enhance the discrimination of neuronal activity and to enable the stimulation of
specific cells or cell populations. To this end, it has been hypothesised that
biohybrid design approaches may be used to engineer high-resolution and
chronically-stable bioelectronic interfaces by promoting the integration of
implantable devices into the host tissues at the cellular level.46
This feature article will focus on
the main experimental strategies in bioelectronics research aimed at engineering
the device–tissue interface through the integration of biomaterial- and cell-based
strategies. First, the use of biochemical and biophysical cues to guide the fate of
endogenous cells at the implant site is discussed. Second, strategies based on
biomaterial carriers for the delivery of exogenous cells to mediate implant
biointegration are reviewed. Overall, biohybrid approaches may provide safer,
longer-lasting, and more efficacious alternatives to conventional NIs by
incorporating tools and principles from regenerative medicine and tissue
engineering into bioelectronic development.
Modulation of endogenous host cells
Implant surface modification strategies have been explored to instruct the growth
and development of endogenous cells that could in turn mediate device
biointegration. Moreover, the controlled release of biochemical cues and the
delivery of biophysical stimuli has also been explored to elicit specific biological
responses towards ameliorating the FBR and enhancing implant longevity and
performance.
Biochemical cues: surface functionalisation, bioactive coatings, and

controlled release
Inert materials such as Pt or graphite remain the most commonly used electrode
substrates for NIs, while polymers such as polyimide (PI) or poly(dimethylsiloxane)
(PDMS) are often used for insulation and encapsulation.27
Due to the lack of biological
cues, these devices are intrinsically unable to support cell development to establish
intimate contact with the host tissues. Because of this, the incorporation of
biological cues to guide the fate of endogenous cells upon implantation has been
widely investigated in the literature. One approach to present biological cues to
endogenous cells relies on the functionalisation of the implant surface with
bioactive molecules. For instance, the immobilization of cell adhesion proteins such
as laminin47 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit47) or neural adhesion
protein L148 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit48) on the electrode
surface has been shown to promote the growth and development of endogenous
cells at the interface (Fig. 2A
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/figure/fig2/)). Neuronal
survival and neurogenesis can be promoted via specific growth factors involved in
neuroplasticity, such as brain-derived neurotrophic factor (BDNF).49,50
Molecules aimed at reducing
microglial activation and gliosis can also be integrated at the interface to
ameliorate neurotoxic responses.51,52
Moreover, bioactive patterns
can be formed on the electrode surface by alternating cell adhesion inhibitors and
cell-adhesive motifs53 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit53) to mimic
tissue architectures found in vivo. Different strategies to functionalise the electrode
surface with bioactive molecules have been reported in the literature. Although
physical absorption is a versatile and facile approach, this often results in the
formation of weak, non-specific, and reversible non-covalent bonds.54
In contrast, techniques based
on chemical absorption such as silane chemistry produce covalent bonds that are
comparatively stronger and can be used to graft proteins to different substrates.55
Surface pre-treatment with
oxygen plasma has been explored to enhance biomolecule functionalisation by
modifying implant hydrophilicity. However, this type of approach could result in
unwanted effects such as etching of the underlying materials.53
Alternatively, surface
hydrophilicity can be modulated to augment the adhesion of bioactive molecules
without compromising implant integrity.56
Surface functionalisation via
grafting of bioactive molecules directly to the implant surface enables the
preservation of device footprint. However, this strategy is limited by the
concentration of molecules that can be grafted, as well as the type of chemistry
needed and the surface area available for functionalisation.
Biochemical cues to modulate endogenous cell fate. (A) Biomolecule surface functionalisation
strategies. Schematic depicting the functionalisation of silicone electrode arrays with neural
adhesion molecule L1 (middle) and fluorescence micrograph showing neuronal attachment on
L1-coated probes (β-tubulin III is shown in green and cell nuclei in blue) (right) (reproduced
with permission from ref. 48
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit48)). (B) Biomaterial coating
strategies for controlled release. Schematic showing PVA-PEDOT CHs biofunctionalized with
NGF (middle) and fluorescence micrographs showing neurite outgrowth on CHs with soluble
NGF (top) NGF-functionalised CHs (bottom) (reproduced with permission from ref. 57
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit57)). (C) Microfluidic delivery.
Schematic of a flexible penetrating microelectrode arrays with integrated microfluidic
structures (middle) and fluorescence micrograph showing local delivery of Dextran Texas Red
(red) at the interface (cell nuclei shown in blue) (right) (reproduced with permission from ref.
68) (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit68). (D) Biomaterial-based
electrode constructs. Schematic of ECM-based microelectrodes composed of collagen I and
fibronectin (middle) and fluorescence micrograph showing cortical neurons growing on ECM-
based electrodes (top), compared to parylene controls (bottom) (β-tubulin III is shown in green
and cell nuclei in blue) (reproduced with permission from ref. 69
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit69)).
Another approach to deliver bioactive stimuli to the implant site relies on the
encapsulation of soluble cues into biodegradable material-based coatings (Fig. 2B
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/figure/fig2/)). In this
context, hydrogels provide several advantages owing to their high-water uptake
capacity and their similarity to the native extracellular matrix (ECM). Hydrogels have
been widely employed as reservoirs for the controlled release of neurogenesis-
promoting drugs and growth factors, such as BDNF or nerve growth factor (NGF),57
as well as anti-inflammatory
drugs such as dexamethasone.58,59
Moreover, biological cues could
also be integrated into coatings that enhance the electrochemical performance of
electrodes. CPs such as polypyrrole (Ppy) or poly(3,4-ethylenedioxythiophene)
(PEDOT) have been functionalised with biological cues such as laminin-derived
peptides60 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit60) or RGD motifs61
to produce coatings that could
tune both charge transduction and cell development at the interface. For instance,
Ppy films doped with hyaluronic acid (HA) with high molecular weight were used as
electrode coating and exhibited reduced cell attachment.62
Such coating could be used to
diminish scar tissue formation. Ppy has also been used in conjunction of
polydopamine (PDA) to form conductive biomaterial coating supporting cell
adhesion.63 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit63) Furthermore,
research from our group has shown that the co-incorporation of laminin peptide
dopants and neurotrophic growth factor (NGF) into PEDOT-based coatings could
effectively promote neurite outgrowth in vitro.64,65
However, this
biofunctionalization strategy was also shown to disrupt the PEDOT matrix,
rendering it more brittle and subject to delamination.64
To overcome this, our group
and others have reported the engineering of interpenetrating conductive hydrogels
(CHs) via electrochemical polymerisation of the CP chains using an immobilized
dopant.66 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit66) CHs hold great
potential to develop controlled release systems for the delivery of drugs and other
charged molecules via electroactive release.57,58,67
However, non-electroactive
hydrogels could also be implemented for this application by fine-tunning the
polymer composition, the degree of crosslinking, or the degradation rate of the
scaffold. Despite these advantages, hydrogel coatings are susceptible to
delamination during implantation, and they can only be loaded with a finite
concentration of molecules. Furthermore, hydrogel swelling could significantly
increase device footprint, resulting in greater tissue displacement upon
implantation.
Despite the advantages of ECM-based coatings, these nanoscale structures are

often rapidly biodegraded in vivo, which largely precludes their ability to modulate
tissue responses across chronic timeframes. One approach to address this
limitation is the integration of microfluidic structures within NIs to enable sustained
and prolonged delivery of neurogenic factors or anti-inflammatory drugs68
(Fig. 2C
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/figure/fig2/)).
However, the integration of a microfluidic component could greatly increase the
footprint of the device, which increases tissue displacement and compression
during implantation. To address this limitation, previous groups have explored the
engineering of electrode constructs that are predominantly composed of native
ECM components. For instance, a study by Shen et al. reported the fabrication of
ECM-encapsulated microelectrodes, which possessed similar dimensions and
exhibited comparable performance to conventional silicon-based arrays in vivo.
These ECM-based microelectrodes were shown to support the formation of a dense
layer of viable neurons on the implant surface, while also undergoing reduced
neuroinflammation and glial scarring following chronic implantation in rats69
(Fig. 2D
Furthermore, the ability of biological materials to be effectively biodegraded in vivo
could be leveraged to engineer transient bioelectronics that could be cleared from
the body after the therapeutic effect has been achieved. This approach could
address issues related to chronic tissue damage associated with persistent NIs,
while also circumventing the need for surgical retrieval.70,71
Physical cues: implant architecture, surface topography, and device

form factor
The physical structure of the ECM provides specific architectures that influence cell
migration and differentiation in vivo. Therefore, the recapitulation of biophysical
cues found in the native ECM has been explored to influence the fate of
endogenous cells at the interface56,72
(Fig. 3A
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/figure/fig3/)). Based
on this biomimetic approach, the modulation of implant surface nano-roughness
has been shown to increase neural cell attachment in vitro.73,74
As neurons and glial cells
exhibit unique responses to different surface topographies, this strategy has been
employed to modulate the neuron-to-glia coverage along the implant surface.75,76
Surface topography could be
used to modulate the fate of immune cells such as macrophages by promoting their
polarization towards pro- or anti-inflammatory phenotypes.77,78
Furthermore, increasing the
electrode surface roughness also increases the active surface area, thus reducing
impedance and enhancing the charge storage capacity (CSC).79
Biophysical cues to modulate endogenous cell fate. (A) Topographical cues to direct cell
adhesion and differentiation (reproduced with permission from ref. 56
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit56)) (right). Fluorescence
micrographs of β-tubulin positive (red) and GFAP positive cells (green) on nanoporous-Au
surfaces (left) (adapted with permission from ref. 75
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit75) Copyright 2023 American
Chemical Society). (B) Open and perforated electrode arrays and immunohistochemical
staining showing tissue ingrowth into perforated parylene sheath electrodes (NeuN is shown in
brown and GFAP in blue) (reproduced with permission from ref. 84
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit84)). (C) Schematic of NeuE
arrays mimicking subcellular neuronal structures and fluorescence micrograph showing the
interaction between NeuE electrodes (red) and neurons (green) (reproduced with permission
from ref. 90) (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit90). (D)
Schematic showing the delivery of injectable mesh electronics and fluorescence micrograph of
cortical brain slices at 12 weeks post-injection (neurofilaments shown in red and NeuN in
yellow, mesh electronics are shown in blue) (reproduced with permission from ref. 98
NIs with novel form factors have been designed to promote tissue integration by
incorporating open or perforated device architectures80
(Fig. 3B
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/figure/fig3/)). For
instance, a pioneering study by Kennedy et al. reported the engineering of cone
electrodes comprised of an insulated gold wire fixed inside a hollow glass cone.81
These glass structures were
loaded with sciatic nerve segments, which promoted tissue ingrowth into the
electrodes following intracortical implantation in rats and monkeys.81,82
Although long-term
electrophysiological recordings could be obtained for up to 15 months after the
implantation of single- and multi-electrode units, the low scalability of this approach
greatly limits clinical implementation. More recently, polymeric materials such as
parylene C (PaC) have been explored to fabricate electrode arrays using
manufacturing techniques such as surface micromachining. For instance, PaC
arrays with perforated sheath structures have been shown to improve tissue
integration and the exchange of oxygen and nutrients upon implantation.83
These arrays were also shown
to produce stable neural recordings for up to 12 months following implantation into
the rat motor cortex, while also enabling tissue ingrowth within the perforated
structures.84 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit84) Open architectures
and compliant polymeric materials thus offer the possibility to establish more
intimate contact with target cells by guiding tissue ingrowth within the device or
reducing tissue damage at the interface. Despite these advantages, the
preservation of structural integrity during and after implantation is critical to ensure
optimal device performance. In addition, bespoke insertion methods such as shuttle
devices35 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit35) or transient coatings
for probe stiffening are often required to aid the implantation of these types of
NIs.85,86 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit85)
A variety of biomorphic designs that recapitulate tissue architecture and mechanics

have been explored to improve the long-term stability of NIs. For instance, the
reduction of implant footprint has been shown to diminish macrophage activation
and the FBR by minimising tissue damage upon implantation87
(Fig. 3C
Millimetre-sized wireless NIs termed neural dust have been explored for the
recording of electrical signals from nerves and muscles.88,89
In another study by Yang et al.,
nano-scaled bioinspired electrodes were fabricated with recording sites that
matched the size of the soma of pyramidal neurons.90
These neuron-like electronics
(NeuE) were implanted into mouse brains and produced stable recordings for up to
90 days post-implantation. However, one challenge associated with device
miniaturization is the preservation of electrode properties, as reducing the surface
area also increases electrode impedance. To overcome this limitation, surface
roughening91,92 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit91) and electrode
coatings93,94 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit93) could be employed
to increase the surface area and reduce impedance, while also enhancing electrode
performance and recording selectivity.
Another strategy to enhance electrode–tissue interaction is the design of mesh or
cloud electronics that can spread within and establish intimate contacts with
nervous tissues.95 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit95) For instance,
Liu et al. developed syringe-injectable mesh electronics, which were shown to
support cell migration along the mesh when injected into rodent brains96,97
(Fig. 3D
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/figure/fig3/)). These
mesh electrodes were shown to enable long-term stimulation and recording,98
while also resulting in reduced
FBR when compared to flexible thin-film probes.99
Another iteration of cloud
electrodes was developed based on in situ electro-polymerisation of PEDOT.100,101
PEDOT monomers could be
polymerized upon injection to form a polymer cloud that could spread beyond areas
affected by neuronal depletion and interact with healthy neurons distal to the
implant site.102 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit102) The long-term
effects of in situ PEDOT deposition were investigated following injection into the
hippocampus of rodents,103 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit103)
which showed no impairment in neural function. Similarly, deployable intracortical
electrode arrays have been developed based on liquid crystal elastomers (LCEs),
which also enabled recording from viable neurons away from the insertion site and
the FBR-induced glial sheath.104
Delivery of exogenous cell effectors
The functionalisation of NIs with live cells has emerged as a promising strategy to
engineer biohybrid technologies that better approximate the properties and
functionality of biological tissues.105
It has been hypothesised that
transplanted cells could establish physiological connections with the host nervous
system and mediate implant biointegration at the device–tissue interface.
Physiological communication between neurons mainly relies on chemical and
electrical synapses.106 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit106) While
chemical communication is mediated by neurotransmitter release at the synaptic
cleft, electrical communication is transmitted by cytoplasmic connections such as
gap junctions. It can be hypothesised that mature endogenous cells would secrete
factors guiding and directing the neurite extension of transplanted cells. This would
mediate the establishment of chemical synapses between endogenous neurons
and exogenous neurons.107 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit107)
Furthermore, because of physical vicinity, cell-to-cell connections could be initiated
between the two cell populations, thus mediating electrical communication and
promoting neuronal integration.108
This approach may enable
more natural mechanisms of neuromodulation,109
which in turn could reduce the
risk of faradaic charge injection and the associated tissue damage.110
Different approaches to
engineer biohybrid NIs have been reported in the literature,111
including grafting cells directly
to the implant surface via immobilised ECM adhesion proteins (Fig. 4A
instance, Azemi et al., investigated the functionalisation of silicon probes with
laminin and murine neural progenitor cells (NPCs) to improve the biointegration of
neural implants.55 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit55) Their results
showed that NPCs on the probes remained viable after implantation into the murine
cortex, and that the implants underwent reduced fibrotic encapsulation compared
to the controls. A different strategy currently under development by our group relies
on the selective engraftment of biotinylated cells to streptavidin-functionalised
implant surfaces. This molecular anchoring approach has already been used in the
clinic to enhance the endothelialisation of arterial stents following angioplasty112
and to increase neural cell
attachment to biomaterial scaffolds.113
Although directly attaching
cells to the electrode surface does not increase the footprint of the device, cell
viability could be compromised due to shear stress experienced upon
implantation.25 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit25)
Delivery of exogenous cells to engineer the device–tissue interface. (A) Schematic showing
direct cell engraftment via ECM adhesion proteins. Fluorescence micrographs of GFP-positive
NPCs (green) cultured for 14 days on laminin-functionalised probes (autofluorescence in red)
(middle) and 1 day after implant retrieval (right) (reproduced with permission from ref. 55
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit55)). (B) Cell-laden
biomaterial-based coatings. Schematic of layered living electrodes developed by Green et al.
(reproduced with permission from ref. 116
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit116)) (right). (C) Cellularised
polymeric electrode constructs. SEM micrograph of a porous alginate scaffold embedded with
carbon nanomaterials (middle) and fluorescence micrographs of encapsulated NPCs after 6
weeks in culture (Tuj1 shown in green, MBP in white, NPCs in red, and cell nuclei in blue) (right)
(reproduced with permission from ref. 185
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit185)). (D) Schematic of micro
tissue-engineered neural networks (μTENN). Fluorescence micrograph of μTENN retrieved 1
month after implantation (GFP shown in green, NF200 in red, synapsin in purple, and cell nuclei
in blue) (right) (adapted with permission from ref. 186
Implant micro-displacement due to cardiorespiratory function induces constant
mechanical stress and increases the severity of scaring around the implant.25,38
Owing to their tuneable
mechanical properties, hydrogel scaffolds can be used to attenuate noxious
responses induced by tissue micromotion and mechanical mismatches.
Furthermore, hydrogels constitute ideal carriers to enhance the viability of
exogenous cells delivered to the device–tissue interface due to their biomimetic
properties114 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit114) (Fig. 4B
instance, Faveri et al., reported the development of wire microelectrodes coated
with a fibrin hydrogel containing encapsulated neurons or glial cells.115
Their results showed that both
cell types were able to develop within the hydrogel, and that the biohybrid coating
did not negatively impact the electrochemical performance of the electrodes.
Another iteration of biohybrid NIs developed by our group consists of a tissue-
engineered layered electrode coating. These living electrodes (LEs) are composed
of a CH layer and a cell-laden biosynthetic hydrogel layer formed on top of a Pt
electrode substrate.109 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit109) The CH
enhances the electrochemical properties of the underlying electrode, while the
biosynthetic hydrogel enables the combined delivery of relevant bioactive cues to
control the fate of the encapsulated cells.116
This approach highlights the
versatility and modularity of biomaterial systems for the development of tissue-
engineered components that could be incorporated into biohybrid NIs.
Tissue-engineering design criteria for biohybrid NIs
Although neurons constitute the main functional cell type in the nervous system,
glial cells such as astrocytes and oligodendrocytes are key modulators of neural
function.117–119 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit117) Because of
this, the engineering of functional neural constructs in vitro has been shown to rely
heavily on the contribution of a functional glial component.120,121
For instance, work from our
group showed that hydrogel carriers composed of poly(vinyl alcohol) (PVA) co-
polymerised with sericin and gelatin (PVA-SG) could effectively support the
differentiation of PC-12 cells.122,123
However, the restrictive
polymer network failed to support the development of primary astrocytes, which in
turn compromised the survival of co-encapsulated murine NPCs.124
These observations highlight
the relevance of the cell phenotypes employed and the conditions in which they are
maintained in vitro to fabricate complex heterocellular neural constructs. In recent
years, patient-derived induced pluripotent stem cells (iPSCs)125
have emerged as a promising
resource for personalized tissue-engineered technologies.126–129
As iPSC-derived NPCs have
been shown to differentiate into various neural phenotypes,130
they represent an ideal
platform to engineer immunocompatible biohybrid NIs. Issues related to the
sourcing of cells with limited or aberrant functionality may hinder this strategy in
patients affected by trauma or disease.131,132
However, genome editing and
cell reprograming technologies may be employed to engineer designer cell
phenotypes tailored to specific applications.133,134
Furthermore, bio-instructive
materials could be rationally designed to deliver synergistic combinations of
physicochemical cues for biofabrication. In this regard, four main design aspects
may be considered for the development of tissue-engineered constructs for
biohybrid NIs.135 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit135)
Biological stimuli
The recapitulation of native cues found in biological tissues through the use of
material-based scaffolds is fundamental for neural tissue engineering.136
Although synthetic materials
such as PVA or poly(ethylene glycol) (PEG)137
enable precise control over the
physical properties of scaffolds, the lack of physiological cues often hinders cell
development. To address this, synthetic polymers could be functionalised with ECM
adhesion cues, such as the widely used arginine-glycine-aspartic (RGD) motif.138–
141 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit138)
They could also be used in
combination with natural polymers such as gelatin and collagen to produce
biosynthetic composites with enhanced bioactivity.142,143
The use of biosynthetic
materials also enables scaffold remodelling and biodegradation via cell-secreted
proteases such as matrix metalloproteinases (MMPs).144
In the context of biohybrid NIs,
the precise modulation of scaffold biodegradability is fundamental to support the
maturation of tissue-engineered constructs in vitro. This property is also critical to
allow endogenous tissue ingrowth to form a chronically-stable interface upon
implantation. For instance, a biosynthetic hydrogel system developed by our group
has been shown to support the development of primary NPCs into synaptically
active neural constructs.145 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit145)
Moreover, these scaffolds could also support neural tissue ingrowth ex vivo, which
highlights the potential of this biomaterial system as a platform to engineer bio-
integrative NIs.
Biophysical features
Scaffold micro-architecture greatly influences the determination of cell fate through
the modulation of cell morphology and the promotion of specific gene expression
pathways.146 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit146) The porosity of
the polymer network also determines the movement of nutrients, bioactive factors,
and metabolic by-products, as well as the ability of cells to migrate and spread
across the scaffold.147 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit147)
Biomaterial scaffolds with specific fibre alignments and diameters have been
shown to guide neurite extension and the differentiation of neural stem cells (NSCs)
into neurons.148 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit148) In turn, this
property may be leveraged to engineer biohybrid NIs with bio-instructive
architectures. For instance, Tang-Shomer et al., reported the engineering of a
biohybrid NI based on thin and micro-patterned silk films.149
Their results showed that
micro-grooves on the films could promote the alignment of astrocytes and nascent
neuronal processes, but had no effect on the alignment of mature axons. Therefore,
scaffolds with defined biophysical features hold great potential to elicit cell-specific
responses without the need for soluble factors. This approach could also reduce
manufacturing costs and complexity and overall help facilitate clinical translation.
Mechanical properties
As multiple cellular pathways are influenced by mechanoresponsive mechanisms,
the modulation of scaffold stiffness and viscoelasticity has been explored to guide
neural proliferation and differentiation.150,151
Previous studies have shown
that soft biomaterial substrates could enhance neuronal maturation and
branching.152–156 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit152) They have
also been shown to support optimal morphological development of encapsulated
brain organoids.157 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit157) Soft and
viscoelastic biomaterials have thus been widely explored to mimic the properties of
nervous tissues and enable targeted cell mechanoregulation.158
Hydrogels are remarkably
advantageous in this regard, as their mechanical properties can be readily modified
by varying the polymer type and concentration, as well as the crosslinking
strategy.137 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit137) Although soft
hydrogels (0.1–10 kPa) have been shown to be more permissive for neuronal
culture, glial cells generally require stiffer substrates (0.5–10 kPa) for adequate
development in vitro.159 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit159)
Furthermore, NSCs have been shown to preferentially differentiate into neuronal
lineages when cultured on softer substrates (0.1–0.5 kPa), whereas stiffer
scaffolds (1–10 kPa) are often conducive to glial differentiation.160
The mechanical properties of
biomaterials are also of particular importance when designing biohybrid NIs in
order to prevent noxious tissue responses.161
Therefore, there is a need to
develop tailorable and multi-functional biomaterials to meet the mechanical
requirements associated with different aspects of biohybrid design.
Electrical cues
Neural cell populations, including neurons, glia, and NSCs have been shown to
respond to a wide range of electroconductive substrates and stimulation regimes in
vitro.162 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit162) Similarly, the intrinsic
electrical activity of neurons has been shown to play a role in the maturation of
cortical networks in vivo.163–166
Because of this, there has
been a growing interest in the development of electroconductive materials for a
variety of applications in neural engineering.167,168
Conductive scaffolds could be
used to enhance intrinsic neuronal activity and strengthen newly formed synapses
without the need for exogenous electrical stimuli.169
Different conductive materials
have been explored for this application, including gold nanostructures170,171
and carbon allotropes such as
GF and CNTs.167,172 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit167) For
instance, CNT grids for neuronal culture have been shown to promote the formation
of neural networks with enhanced neurite outgrowth and synaptic activity in
vitro.173,174 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit173) Conductive
scaffolds are also ideal substrates to study the effect of exogenous ES on neural
growth and differentiation. A study by Koppes et al. demonstrated that ES resulted
in enhanced neurite outgrowth in scaffolds loaded with single-walled CNTs,
compared to controls without ES.175
Similarly, ES of human NSCs
cultured on graphene oxide foams has been shown to promote cell proliferation and
neuronal differentiation.176 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit176)
CPs have also been used to engineer composite scaffolds for neuronal culture177
and have been widely used as
coatings to improve electrode performance in biomedical implants.178
Although this approach has
been widely explored for the fabrication of CHs, the incorporation of nanomaterials
could significantly alter the mechanical properties of hydrogels. Moreover, concerns
related to nanotoxicity and the fate of nanomaterials upon scaffold biodegradation
remain. Therefore, there is a need to increase our understanding on the
pharmacokinetics of nanomaterials and their interactions with proteins and cells in
vivo in order to prevent potential neurotoxic effects.
Considerations for biohybrid NI fabrication
The integration of cellular components into the design of implantable NIs could
enable the possibility of directly interfacing devices with the nervous system by
harnessing intrinsic physiological mechanisms. However, the technological and
biological complexity of biohybrid implants raises multiple challenges related to
their fabrication, functional characterisation, and clinical translation. One
challenging aspect of biohybrid fabrication are the potential compromises between
device functionality and the viability of the tissue-engineered components. For
instance, while soft biomaterial coatings may promote neuronal survival at the
interface and help alleviate the FBR, they are susceptible to swelling and
delamination and may be lost upon tissue insertion.14,179
Several studies reported
swelling-induced delamination of hydrogels bound to rigid substrates.180,181
CH coating loss was also
observed following implantation of CH-coated cochlear implants182
and DBS electrode arrays.183
As the use of stiffer materials
that could better withstand implantation could compromise cell development at the
interface, alternative strategies may be explored. Multiple techniques are available
to enhance the adhesion of biohybrid coatings to electrode substrates, which
include surface roughening to increase hydrogel grip115
or chemical pre-treatment to
form functional handles.184 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit184) For
instance, biohybrid LEs developed by our group rely on an electrochemically
deposited pre-layer of PEDOT/p-toluenesulfonate (pTS) to enhance the mechanical
grip of the CH to the underlying electrode substrate.66
Biohybrid NI design should aim to maximise the synergy between different

experimental approaches according to the intended application in order to
streamline technology development. For instance, the use of growth factors or
cytokines to instruct cell fate for biofabrication may be circumvented by tailoring
scaffold mechanics and architecture, or via targeted ES. The neurotrophic support
provided by accessory feeder cells could be leveraged to avoid the need for growth
factor or cytokine supplementation. Moreover, the delivery of exogenous cell
effectors may be bypassed all together in some cases by exploiting instead the
capabilities of resident host cells or migratory cells recruited to the implant site.
Therefore, biohybrid NIs could be designed to leverage the complexity of the in vivo
environment in order to simplify technology development and streamline clinical
translation.
As the field of bioelectronics continues to shift towards the use of flexible organic
materials for device fabrication, the direct integration of cellular components into
the NI structure has been explored (Fig. 4C
instance, neuron–electrode interfaces composed of silk films co-patterned with
cells and electrodes have been used for neural recording and ES in vivo.149
Viscoelastic CHs composed of
alginate and carbon allotropes have been shown to support the growth and
differentiation of NPCs into both neurons and glia.185
As these CHs exhibited
conductivities ranging between 4–10 S m−1, they hold great promise to fabricate
implantable NIs for targeted ES. Micro-tissue engineered neural networks (μTENNS)
have been engineered based on agarose hydrogel microcolumns filled with collagen
and laminin to guide the ingrowth of neural 3D aggregates across the lumen105,186
(Fig. 4D
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/figure/fig4/)). These
tubular constructs may be used to modulate target tissues via synaptic connections
established de novo between NIs and the host nervous system.187,188
Pre-clinical evaluation
Technical challenges may be encountered when evaluating the performance of

active devices composed of both artificial and biological components. Although in
vitro models have been developed to mimic some aspects of chronic
implantation,189 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit189)in vivo models
remain the gold standard as they provide the highest physiological relevance.
Multiple transgenic models of neurological disorders have also been established,190
which provide more accurate
platforms for the assessment of theragnostic NIs. Although post-mortem analysis
of explants has been traditionally used for functional evaluation, this usually
requires extensive tissue processing and is only representative of discrete
endpoints. Non-invasive imaging techniques are therefore required for real-time
evaluation of device performance and to monitor tissue responses in vivo. Intravital
imaging techniques such as two-photon microscopy191,192
and clinical imaging
techniques such as magnetic resonance imaging (MRI) and computed tomography
(CT) may be used for this application. These techniques could not only be used to
monitor the development of biohybrid implants in situ, but also to assess the degree
of biointegration and FBR without the need for implant retrieval.193,194
To achieve this, our group and
others have focused on the development of advanced biomaterials for soft
bioelectronics that are compatible with clinical imaging techniques such as MRI.
Alternatively, emerging neuroimaging techniques based on functional ultrasound
have been shown to enable large-scale and high-resolution neural imaging in human
patients.195,196 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit195) In addition,
near-infrared fluorescent (NIR) imaging197
or MRI198
may be used in combination
with labelling techniques to monitor the fate of exogenous cells across chronic
timeframes.
Electrochemical characterisation via electrochemical impedance spectroscopy (EIS)

or cyclic voltammetry (CV) may be carried out to assess electrode performance and
the degree of fibrotic encapsulation.199,200
When performed in vivo, faster
CV scan rates may be used in order to reduce anaesthesia time, as well as the risk
of charge build-up and faradaic damage. It is also important to consider the impact
of the stimulation delivered for electrochemical characterisation on the biology of
the tissue-engineered components and the host tissues. Moreover, as cellularised
constructs are closely integrated with active electrode systems for biohybrid
fabrication, it is crucial to better understand the influence of electrical stimuli on the
fate of complex neural constructs. To this end, multi-electrode array (MEA) systems
have been developed to enable real-time, label-free and high-throughput
electrophysiological monitoring in vitro.201
In addition, custom-built
devices could be developed to better approximate specific physiological scenarios
or to accommodate the requirements of NIs with bespoke formats.202
However, experimental
findings from in vitro ES studies remain poorly translatable, which is due in part to
the lack of standardised set-ups and protocols. To address this limitation,
computational in silico models have been explored to enhance the reproducibility of
ES protocols and streamline clinical translation.203
Future perspectives
The realisation of biohybrid NIs that could one day be delivered to human subjects
presents multiple engineering hurdles that need to be addressed to ensure implant
and patient safety. For instance, the integration of wireless and battery-free
capabilities for transcutaneous operation could help ameliorate surgical risks, while
also extending device longevity and improving user experience.204,205
Wireless brain–computer
interface (BCI) systems such as the one developed by the BrainGate research
consortium are already being implemented in the clinic to allow tetraplegic patients
to control point-and-select interfaces.206
However, despite the
advantages of wireless interfacing, this approach may hinder information transfer
rates and raise concerns related to data safety and protection.207
In addition, several
neuroscientific questions remain unanswered, such as the long-term effects of
neuromodulatory devices on brain function. Adverse effects such as depression,
cognitive decline, and personality changes have been reported in Parkinson's
Disease patients undergoing DBS.208
Although these effects could
be partly attributed to medication or disease progression, the impact of chronic
implantation and ES regimes remains to be elucidated. Moreover, if transplanted
cells are able to establish synaptic connections with the host, they could potentially
disturb endogenous neural activity due to ectopic activation or inhibition.
Exogenous stem or progenitor phenotypes could also migrate out of the device and
proliferate or differentiate in an uncontrolled way at off-target sites.209
Although conventional
neuromodulatory devices may be switched off or surgically removed if needed, the
modulation and removal of tissue-engineered components bring forward several
challenges in this regard. Strategies derived from regenerative medicine and
immunotherapy may be explored to address these issues, such as engineering cells
sensitive to custom external stimuli or with a built-in “kill switch”.210
Therefore, there is a need to
increase our understanding on the long-term adaptations that biohybrid implants
and the host nervous system undergo across chronic timeframes to pre-emptively
mitigate any potential risks.
Although biohybrid technologies are still in their infancy, the translation of

implantable neurotechnologies is rapidly becoming a reality. This is exemplified by
the increasing number or clinical trials approved by the Food and Drug
Administration (FDA) that are being carried out by companies such as Synchron and
Neuralink. As of 2023, more than 400 clinical trials related to neural interfaces were
registered in the Cochrane database. Governments have been involved in the surge
for neurotechnology research by launching multiple funding opportunities, such as
the BRAIN initiative launched under Obama mandate, or the Stimulating Peripheral
Activity to Relieve Conditions (SPARC) common fund. International collaborations
have also been established such as the Human Brain Project supported by the
European Union. The steady increase in private investment coupled with the rapid
growth in artificial intelligence (AI) and machine-learning have greatly accelerated
progress in the field of NIs. A growing number of studies have explored the
implementation of deep-learning algorithms to enhance the speed and accuracy of
speech neuroprostheses driven by implantable BCIs.211,212
However, despite this rapid
technological advancement, current regulatory, ethical, and legal frameworks are
lacking and should be revisited to adapt to these emerging developments. From the
regulatory perspective, new categories of medical devices may need to be defined
to capture biohybrid technologies with combined traits of active implants, drugs,
and cell transplants. Regulatory agencies have already begun to establish specific
guidelines for combination products containing two or more regulated components
from different categories.193 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit193)
Moreover, the standardisation of criteria from different international agencies is
crucial to ensure that clear regulatory pathways are in place.
As biohybrid technologies continue to mature, the development of biointegrative NIs

that could remain implanted across the entire lifetime of the user raises several
ethical concerns related to privacy, responsibility, agency, and identity.213
Neural data recorded by NIs is
highly sensitive since it can be used to decode the thoughts, feelings, or emotions
of the user. It is therefore essential to ensure secure storage and controlled access
to this information to prevent misuse by third parties, such as advertisers,
employers or governments.214 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit214)
Whether it is perceived as dystopic or utopic, the digitalisation of some aspects of
the human mind is becoming a reality, and regulatory and legal frameworks must be
pre-emptively defined. The increasing use of AI and closed-loop systems that could
operate without input from the user raises multiple issues related to agency and
autonomy.215 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit215) Clinical evidence
has shown that ES could influence behaviour and self-determination, which could
potentially compromise patient consent.216
DBS implantees have reported
alterations in perception and embodiment,217,218
with some users describing
NIs becoming a part of themselves.219
Biohybrid NIs also pose
several ontological questions that challenge the neuroessentialist view of human
identity and consciousness. For instance, neuroethicists have postulated that some
form of morally relevant consciousness might develop in complex neural constructs
grown in vitro, such as brain organoids or assembloids.220
Moreover, it has been
previously postulated that technology could become so utterly intertwined with our
cognitive machinery that it could be considered part of the machinery of thought
itself.221 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10720954/#cit221) Moving forward, these
and other metaphysical notions are particularly relevant in the context of biohybrid
NIs, as technological progress continues to outpace our fundamental
understanding of what it is to be human.
Author contributions
The paper was written by MB with editing by RPL and RG. Funding was obtained by
RG.
Acknowledgments
The authors acknowledge funding support from the ERC Consolidator Grant in
Living Bionics (771985-1). The figures were created with https://BioRender.com
(https://biorender.com/).
Biography
Marjolaine Boulingre :
Marjolaine Boulingre is a PhD student in the Department of Bioengineering at
Imperial College London. She received her Master’s degree in Life Sciences
Engineering from Ecole Polytechnique Fédérale de Lausanne (EPFL) in 2022. Before
joining the Green lab, she conducted her Master Thesis at Harvard School of
Engineering and Applied Sciences (SEAS) within the Mooney lab, where she was
involved in the development of soft conductive hydrogel scaffold for neural tissue
engineering. Her current research interest focuses on developing next-generation
bioelectronic devices that integrate cellular components to improve tissue
integration.
Biography
Roberto Portillo Lara :

Dr Roberto Portillo Lara is a biomedical scientist and bioengineer whose research
focuses on the development of tissue engineering and regenerative medicine
technologies for theragnostic applications. Throughout his career, he has been
involved in variety of projects with a strong translational component, ranging from
engineering smart wound dressings, surgical bioadhesives and systems for
controlled drug release, to cardiovascular, orthopaedic, and musculoskeletal tissue
analogues. At Imperial College, he leads the “Living Electrode” project, a multi-
disciplinary effort aimed at developing tissue-engineered neural interfaces that
could be biologically integrated into the host in order to drive the next generation of
implantable bioelectronics.
Biography
Rylie A Green :
Prof Rylie Green, FIET, is the Head of Bioengineering at Imperial College London.
Prof. Green has developed a range of innovative materials to address the limitations
that hinder the development of next-generation bioelectronic devices. Her focus has
been in developing electrode technologies that are stretchable and mediate
improved electrical charge transfer with the body, including pioneering living
bioelectronics. She has also developed wearable diagnostic devices and drug
delivery systems for localised chemotherapy. This research has initiated
collaborations with Galvani Bioelectronics, Cochlear Ltd and the US Department of
Defense. She is an Associate Editor for APL Bioengineering, Advanced
Bionanomedicine and Biomaterials.
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Biohybrid neural interfaces: improving the

biological integration of neural implants

Biohybrid design enables the engineering of neural interfaces with enhanced

The implantation of an electrode array into the neural parenchyma triggers an

Modulation of endogenous host cells

Biochemical cues: surface functionalisation, bioactive coatings, and

Despite the advantages of ECM-based coatings, these nanoscale structures are

Physical cues: implant architecture, surface topography, and device

A variety of biomorphic designs that recapitulate tissue architecture and mechanics

Delivery of exogenous cell effectors

Tissue-engineering design criteria for biohybrid NIs

Considerations for biohybrid NI fabrication

Biohybrid NI design should aim to maximise the synergy between different

Technical challenges may be encountered when evaluating the performance of

Electrochemical characterisation via electrochemical impedance spectroscopy (EIS)

Although biohybrid technologies are still in their infancy, the translation of

As biohybrid technologies continue to mature, the development of biointegrative NIs

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