nanomaterials (Figure 5). Scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS) evidenced the porous structure of the gelatin scaffold loaded with a homogeneous dispersion of molybdenum in the matrix. Interestingly, MoS₂ ensured material conductivity and acted as covalent cross-links for the hydrogel, ensuring its printability and stability. The material displayed sensitivity to strain, and potentially to pH and biological interactions. As such, it is foreseen to be of high interest for wearable electronics, and for the development of conformable implanted sensors that would necessitate minimal intervention, thanks to the injectability of the materials. Kim et al. (2023b) developed a thermoplastic tungsten-based conductive paste (7 10⁵ S cm⁻¹) composed of a mixture of beeswax (as resorbable matrix), tungsten nanoparticles (as electrical conductor, 500 nm–10 µm size), and glycofurol (as formulation aid). The paste can be filled at moderate temperature (approximately 70°C) into molds and screen-printed, and remains stable at body and room temperatures; it gets degraded in PBS buffer in approximately 80 days. To design resorbable bioelectronic systems, both the substrate and conductive ink patterns should be resorbable. Wang et al. (2019d) designed wearable devices based uniquely on graphene and silk. They combined calcium-plasticized fibroin with graphene (Ca/fibroin/graphene) to directly write or print conductive patterns onto a Ca²⁺/silk stretchable film. Interestingly, the Ca/fibroin/graphene ink displayed self-healing properties that facilitated printing.

Following deposition of the conductive material (ink or paste) onto the substrate, it is often necessary to post-process the material so that the conductive patterns cannot be subsequently washed out or be rapidly dissolved in biological fluids. This post-treatment should, however, not compromise the material functionality, biocompatibility, or resorbability. Depending on the materials, post-processing can include chemistry, light, or heat treatment. Thermal and UV cross-linking are particularly interesting due to their ease of implementation.

This section has evidenced the wide range of processes that can be used to combine scaffolds/substrates and electrical conductors to obtain resorbable conductive materials with a variety of chemical structures, morphologies, properties, and shapes. The next section is dedicated to the description of the applications of such materials in the biomedical field.

# 4 Applications in the biomedical field

Various applications of resorbable conductive materials are emerging and are foreseen to expand in the near future; they require different specifications and shall comply with different regulations. After a short section dedicated to material biocompatibility requirements, we will review the different domains of applications of resorbable conductive materials.

## 4.1 Biocompatibility and other requirements

Wearable devices require sufficient biocompatibility to avoid skin irritation and intradermal sensitization (biocompatibility standard ISO 10993-Part 10: Tests for skin sensitization),

whereas implantable devices and tissue substitutes may require the full list of biocompatibility tests required by ISO 10993-1, depending on the contact duration and their invasiveness, in particular ISO 10993-6 (Part 6: Tests for local effects after implantation). In the case of biodegradable materials, the identification and safety of degradation products are also of paramount importance. To this aim, the investigator shall refer to ISO 10993-13 and ISO 10993-15, dedicated to the degradation of products from polymer-based medical devices and metal alloys, respectively. Then, according to the risk analysis, the investigator shall evaluate the tolerable intake (TI) based on the maximum amount of substances below the threshold of adverse effects [the no-observed-adverse-effect-limit (NOAEL)] and modifying factors according to ISO 10993-17. Other material requirements, such as mechanical and conductive properties, also strongly depend on the targeted application. Tissue engineering and 3D cell culture applications demand high biocompatibility because of the intimate contact between materials and cells and require suitable mechanical properties (for instance, soft but stable dynamic hydrogels), but do not require high conductivity (Xu et al., 2021; Gao et al., 2022). On the contrary, a highly conductive material like metal should be used to fabricate the electrical tracks of a resorbable bioelectronic system.

## 4.2 Medical devices for sensing and recording

### 4.2.1 Wearable bioelectronic systems

In these applications, resorbable conductive materials are essentially obtained by 2D patterning processes on a flexible, sometimes stretchable, substrate (typically an elastomer or polyester film). Wearable bioelectronic systems are mainly dedicated to sensing, display, and stimulation. Electrical stimulation for wound healing will be specifically addressed in the tissue engineering section since the conductive materials employed can serve both as stimulation electrodes and tissue substitutes.

Most of the described resorbable wearable systems concern physical sensing (strain, temperature) and display. For instance, Wang et al. (2019d) designed a Ca/fibroin/graphene ink whose resistivity was sensitive to strain, temperature, and humidity and that could be printed onto Ca²⁺/silk stretchable films to design wearable devices. The bioelectronic systems were applied onto the skin as sensing tattoos (Figure 6A). A hydrogel dynamic network composed of PVA, borate, and GO particles partially reduced by dopamine oxidative self-polymerization was applied on the skin as a strain-sensing material (Wang et al., 2019c). Held et al. (2022) designed Galinstan serpentine tracks (approximately 2 mm thick) entrapped between two layers of resorbable PGS/ PGS-acrylate or gelatin films. Galinstan is a liquid metal, an eutectic mixture of 68% Ga, 22% In, and 10% Sn (mass%), whose biocompatibility has been assessed (Foremny et al., 2021). The high elongation at a break that can withstand the films was used to design strain sensors to monitor elbow bending (Figure 6B). Feng et al. (2019) developed resorbable, temperature-sensitive, and optically transparent Zn electrodes patterned onto PVA films for temperature sensing or wearable heaters. Using the same
nanomaterials (Figure 5). Scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS) evidenced the porous structure of the gelatin scaffold loaded with a homogeneous dispersion of molybdenum in the matrix. Interestingly, MoS₂ ensured material conductivity and acted as covalent cross-links for the hydrogel, ensuring its printability and stability. The material displayed sensitivity to strain, and potentially to pH and biological interactions. As such, it is foreseen to be of high interest for wearable electronics, and for the development of conformable implanted sensors that would necessitate minimal intervention, thanks to the injectability of the materials. Kim et al. (2023b) developed a thermoplastic tungsten-based conductive paste (7 $10^5$ S cm⁻¹) composed of a mixture of beeswax (as resorbable matrix), tungsten nanoparticles (as electrical conductor, 500 nm–10 µm size), and glycofurol (as formulation aid). The paste can be filled at moderate temperature (approximately 70°C) into molds and screen-printed, and remains stable at body and room temperatures; it gets degraded in PBS buffer in approximately 80 days. To design resorbable bioelectronic systems, both the substrate and conductive ink patterns should be resorbable. Wang et al. (2019d) designed wearable devices based uniquely on graphene and silk. They combined calcium-plasticized fibroin with graphene (Ca/fibroin/graphene) to directly write or print conductive patterns onto a $Ca^{2+}$/silk stretchable film. Interestingly, the Ca/fibroin/graphene ink displayed self-healing properties that facilitated printing.

Following deposition of the conductive material (ink or paste) onto the substrate, it is often necessary to post-process the material so that the conductive patterns cannot be subsequently washed out or be rapidly dissolved in biological fluids. This post-treatment should, however, not compromise the material functionality, biocompatibility, or resorbability. Depending on the materials, post-processing can include chemistry, light, or heat treatment. Thermal and UV cross-linking are particularly interesting due to their ease of implementation.

This section has evidenced the wide range of processes that can be used to combine scaffolds/substrates and electrical conductors to obtain resorbable conductive materials with a variety of chemical structures, morphologies, properties, and shapes. The next section is dedicated to the description of the applications of such materials in the biomedical field.

# 4 Applications in the biomedical field

Various applications of resorbable conductive materials are emerging and are foreseen to expand in the near future; they require different specifications and shall comply with different regulations. After a short section dedicated to material biocompatibility requirements, we will review the different domains of applications of resorbable conductive materials.

## 4.1 Biocompatibility and other requirements

Wearable devices require sufficient biocompatibility to avoid skin irritation and intradermal sensitization (biocompatibility standard ISO 10993-Part 10: Tests for skin sensitization),

whereas implantable devices and tissue substitutes may require the full list of biocompatibility tests required by ISO 10993-1, depending on the contact duration and their invasiveness, in particular ISO 10993-6 (Part 6: Tests for local effects after implantation). In the case of biodegradable materials, the identification and safety of degradation products are also of paramount importance. To this aim, the investigator shall refer to ISO 10993-13 and ISO 10993-15, dedicated to the degradation of products from polymer-based medical devices and metal alloys, respectively. Then, according to the risk analysis, the investigator shall evaluate the tolerable intake (TI) based on the maximum amount of substances below the threshold of adverse effects [the no-observed-adverse-effect-limit (NOAEL)] and modifying factors according to ISO 10993-17. Other material requirements, such as mechanical and conductive properties, also strongly depend on the targeted application. Tissue engineering and 3D cell culture applications demand high biocompatibility because of the intimate contact between materials and cells and require suitable mechanical properties (for instance, soft but stable dynamic hydrogels), but do not require high conductivity (Xu et al., 2021; Gao et al., 2022). On the contrary, a highly conductive material like metal should be used to fabricate the electrical tracks of a resorbable bioelectronic system.

## 4.2 Medical devices for sensing and recording

### 4.2.1 Wearable bioelectronic systems

In these applications, resorbable conductive materials are essentially obtained by 2D patterning processes on a flexible, sometimes stretchable, substrate (typically an elastomer or polyester film). Wearable bioelectronic systems are mainly dedicated to sensing, display, and stimulation. Electrical stimulation for wound healing will be specifically addressed in the tissue engineering section since the conductive materials employed can serve both as stimulation electrodes and tissue substitutes.

Most of the described resorbable wearable systems concern physical sensing (strain, temperature) and display. For instance, Wang et al. (2019d) designed a Ca/fibroin/graphene ink whose resistivity was sensitive to strain, temperature, and humidity and that could be printed onto $Ca^{2+}$/silk stretchable films to design wearable devices. The bioelectronic systems were applied onto the skin as sensing tattoos (Figure 6A). A hydrogel dynamic network composed of PVA, borate, and GO particles partially reduced by dopamine oxidative self-polymerization was applied on the skin as a strain-sensing material (Wang et al., 2019c). Held et al. (2022) designed Galinstan serpentine tracks (approximately 2 mm thick) entrapped between two layers of resorbable PGS/ PGS-acrylate or gelatin films. Galinstan is a liquid metal, an eutectic mixture of 68% Ga, 22% In, and 10% Sn (mass%), whose biocompatibility has been assessed (Foremny et al., 2021). The high elongation at a break that can withstand the films was used to design strain sensors to monitor elbow bending (Figure 6B). Feng et al. (2019) developed resorbable, temperature-sensitive, and optically transparent Zn electrodes patterned onto PVA films for temperature sensing or wearable heaters. Using the same
<figure><img src="image_13.png" /><figcaption>**FIGURE 6**
Examples of resorbable wearable sensors. (A) *Wearable resorbable tattoo sensors based on silk and graphene materials:* i) silk fibroin (SF) was extracted from *B. mori* cocoons and mixed with $Ca^{2+}$ and graphene aqueous suspension to obtain a conductive ink that could be used to directly write or mask-print conductive patterns onto a SF/$Ca^{2+}$ cross-linked membrane. ii) The resistivity of the obtained devices was sensitive to strain, humidity, and temperature, which makes them useful in designing an electrocardiogram (ECG) recording device (a,b), or respiration (c,d) and temperature (e,f) sensors. Interestingly, the materials presented self-healing properties that made it possible to continue signal recording with conductive pattern fracture and healing. Reproduced with permission, Copyright 2019, John Wiley and Sons, (Wang Q. et al., 2019). (B) *Strain sensors based on Galistan metal liquid tracks embedded in gelatin or PGS acrylate (PGSA) films:* (i) the gelatin-based sensor was then applied on a volunteer subject to monitor elbow bending. (ii) The device withstood important bending without rupture. (iii) The motion could be monitored by recording the resistivity of the conductive track. Reproduced with permission, Copyright 2022, John Wiley and Sons (Held et al., 2022).</figcaption></figure>

materials but different patterns obtained by laser sintering, they designed a partially resorbable device for near-field communication and display.

Electrochemical-based sensors hold great potential for sensing and biosensing, and if processed as resorbable, can be used as transient devices deposited onto the skin or injected into the dermis. Liang et al. (2014) obtained a 70-µm-thick graphene/silk conductive composite film using the vacuum filtration of a graphene oxide and silk fibers suspension, followed by the chemical reduction of GO. Platinum nanospheres were then grown onto the film by cyclic voltammetry electrodeposition in order to obtain an $H_2O_2$ sensor or a glucose biosensor after immobilization of glucose oxidase (GOx) on Pt nanoparticles. Though no resorbability study was reported, the employed sensing materials could be resorbable and serve to design a transient wearable bioelectronic system. Kurland et al. (2013) developed a PEDOT:PSS/sericin ink loaded with glucose oxidase enzyme that they printed onto a UV-cross-linked fibroin-methacrylate substrate in order to obtain highly sensitive and

selective glucose electrochemical sensors that could withstand 30° bending and be resorbed in approximately 4 weeks. Devices comprising PEDOT- or PANI-based inks loaded with enzymes and printed on different substrates for the analysis of a few metabolites (glucose, lactate, and cholesterol) extracted from sweat (Bilbao et al., 2023) hold great promises. The use of micro- or nanostructured patterns (nanotubes and microcups) of conducting polymers combined with GOx or laminin cell adhesion peptide could further enhance the sensitivity of the sensors in comparison to plain films by increasing the sensing surface (Yang et al., 2014). 3D-printed patterns of a conductive resin could further enhance the recognition sensitivity of the conductive hydrogel. Dadras-Toussi et al. (2022) developed a photosensitive resin comprising poly(ethylene glycol diacrylate), PEDOT:PSS, a photosensitizer, and GOx or laminin cell adhesion peptide (Figure 5). 3D multiphoton lithography was used to obtain self-standing 3D patterns of cell-adhesion conductive materials or GOx-coated patterned microelectrodes that exhibited high
<figure><img src="image_13.png" /><figcaption>FIGURE 6
Examples of resorbable wearable sensors. (A) Wearable resorbable tattoo sensors based on silk and graphene materials: i) silk fibroin (SF) was extracted from *B. mori* cocoons and mixed with Ca²⁺ and graphene aqueous suspension to obtain a conductive ink that could be used to directly write or mask-print conductive patterns onto a SF/Ca²⁺ cross-linked membrane. ii) The resistivity of the obtained devices was sensitive to strain, humidity, and temperature, which makes them useful in designing an electrocardiogram (ECG) recording device (a,b), or respiration (c,d) and temperature (e,f) sensors. Interestingly, the materials presented self-healing properties that made it possible to continue signal recording with conductive pattern fracture and healing. Reproduced with permission, Copyright 2019, John Wiley and Sons, (Wang Q. et al., 2019). (B) Strain sensors based on Galistan metal liquid tracks embedded in gelatin or PGS acrylate (PGSA) films: (i) the gelatin-based sensor was then applied on a volunteer subject to monitor elbow bending. (ii) The device withstood important bending without rupture. (iii) The motion could be monitored by recording the resistivity of the conductive track. Reproduced with permission, Copyright 2022, John Wiley and Sons (Held et al., 2022).</figcaption></figure>

materials but different patterns obtained by laser sintering, they designed a partially resorbable device for near-field communication and display.

Electrochemical-based sensors hold great potential for sensing and biosensing, and if processed as resorbable, can be used as transient devices deposited onto the skin or injected into the dermis. Liang et al. (2014) obtained a 70-µm-thick graphene/silk conductive composite film using the vacuum filtration of a graphene oxide and silk fibers suspension, followed by the chemical reduction of GO. Platinum nanospheres were then grown onto the film by cyclic voltammetry electrodeposition in order to obtain an H₂O₂ sensor or a glucose biosensor after immobilization of glucose oxidase (GOx) on Pt nanoparticles. Though no resorbability study was reported, the employed sensing materials could be resorbable and serve to design a transient wearable bioelectronic system. Kurland et al. (2013) developed a PEDOT:PSS/sericin ink loaded with glucose oxidase enzyme that they printed onto a UV-cross-linked fibroin-methacrylate substrate in order to obtain highly sensitive and

selective glucose electrochemical sensors that could withstand 30° bending and be resorbed in approximately 4 weeks. Devices comprising PEDOT- or PANI-based inks loaded with enzymes and printed on different substrates for the analysis of a few metabolites (glucose, lactate, and cholesterol) extracted from sweat (Bilbao et al., 2023) hold great promises. The use of micro- or nanostructured patterns (nanotubes and microcups) of conducting polymers combined with GOx or laminin cell adhesion peptide could further enhance the sensitivity of the sensors in comparison to plain films by increasing the sensing surface (Yang et al., 2014). 3D-printed patterns of a conductive resin could further enhance the recognition sensitivity of the conductive hydrogel. Dadras-Toussi et al. (2022) developed a photosensitive resin comprising poly(ethylene glycol diacrylate), PEDOT:PSS, a photosensitizer, and GOx or laminin cell adhesion peptide (Figure 5). 3D multiphoton lithography was used to obtain self-standing 3D patterns of cell-adhesion conductive materials or GOx-coated patterned microelectrodes that exhibited high
sensitivity and specificity. These electrically conductive resins therefore appeared appealing for the design of biosensors and sensing in organ-on-chip devices.

However, the development of resorbable sensors is still limited by
several barriers that are yet to be overcome. A main limitation is the poor
conductivity of some materials, especially conducting polymers when
combined with resorbable hydrogels. CPs' conductivity can potentially
be improved by combining them with other conductive fillers such as
carbon nanotubes or graphene derivatives although it could stiffen the
materials and decrease their flexibility and stretchability. When
designing ion-selective electrodes, another important limitation is the
present use of non-safe and non-degradable materials in the design of the
sensing part (Cánovas et al., 2019). Therefore, the design of fully
resorbable electrochemical-based wearable sensors still largely remains
an unmet challenge.

Although a few examples of resorbable wearable sensors have
been described in the literature, the fact that the devices are laid onto
the skin and can be easily removed after use limits their applications.
However, the development of wearable resorbable devices can
appear as the first step and proof-of-concept toward the
development of resorbable implanted bioelectronic systems and
presents high environmental interest in reducing electronics
waste (Feng et al., 2019).

## 4.2.2 Implanted microelectrode arrays and bioelectronic systems

The field of cardiac or neural tissue recording or stimulation is a good example to describe the evolution of materials and processes used through the last 25 years, with the objective to progress toward softer, more conformable, and flexible bioelectronic systems intended for use in the heart, brain, spinal cord, peripheral nerve, muscle, and skin (Tringides et al., 2021). Ultimately, it has now turned its attention toward device resorbability, particularly for specific applications such as short- to medium-term monitoring for epilepsy seizure (Yu et al., 2016; Xu et al., 2019a), neural stimulation for temporary pain relief (Lee et al., 2022), or intracranial pressure monitoring (Shin et al., 2019).

The first electrode arrays cleared by the FDA were the renowned
Utah array (Rousche et al., 1998). These arrays comprised a hundred
silicon cones, each covered by an insulator (silicon dioxide and/or
parylene), except for their apex. These devices sparked considerable
interest as they offered the possibility of concurrent neural
recordings from up to a hundred channels, thus initiating the
development of implantable devices for brain-computer
interfaces (Hochberg et al., 2006). However, the risks of
damaging blood vessels and triggering microhemorrhages, along
with inflammatory response and the eventual formation of glial scar,
remain very high (Kozai et al., 2015). In response to this challenge,
Neuralink has developed a specialized sewing machine capable of
gently introducing flexible polyimide shanks into the cortex while
avoiding blood vessels, with the assistance of medical imaging.
Owing to the substantial difference between Young's modulus of
polyimide and the stiffness of the brain tissue, the thickness of the
shank was decreased to attain a targeted range of 1 µm (Lycke et al.,
2023). However, for insertion into the brain tissue, as the thinned
structure was no longer stiff enough to prevent buckling, the authors
utilized a 75-µm tungsten wire affixed to the shank via a
biodissolvable PEG adhesive.

Alternately, to reduce the mechanical mismatch with the brain
tissue, using softer materials that closely resemble it, such as
hydrogels, is a viable approach. A transient microarray for the
recording of electrophysiological signals from the cortex was
designed by the group of Rogers (Yu et al., 2016). It involved the
utilization of thin silicon tracks transferred onto a PLGA film and
coated with a SiO₂ dielectric layer (Yu et al., 2016). More recently,
the same research group introduced a bioresorbable device designed
for the transient electrostimulation of the sciatic nerve to act as an
electronic pain blocker (Figure 7A) (Lee et al., 2022). In this
bioelectronic system, fast-resorbable magnesium was used to
design tracks in contact with the external connector (kilo-hertz
frequency alternating current pulses sent during treatment), whereas
slowly degrading Mo was used to make contact with the nerve. Thin
strips of Mo were put in contact with Mg strips using a conductive
resorbable carbon wax (C-wax) in a woven electrode pattern. The
primary objective of this design was to ensure that the rapid
resorption of the 50-µm-thick Mg patterns after the
electrostimulation treatment (approximately 10 days in phosphate
buffer, 2 months when implanted in rodents) did not impose any
constraints on the nerve. The nerves were in contact with 700-nm-
thick Moelectrodes that were resorbed over a longer time scale
(approximately 2 months in phosphate buffer). Note that different
substrate materials were also tested and selected for the fabrication
of the system to achieve suitable kinetics of bioresorption.
Conducting polymers were shown to improve the bioelectronic
interface between metals (gold and platinum) and neural tissues,
especially by decreasing the electrical impedance and increasing the
charge transfer capacity (Ludwig et al., 2006; Richardson-Burns
et al., 2007; Khodagholy et al., 2015). CP nanotubes (70–175 nm
diameter) (Abidian et al., 2008; Abidian et al., 2009; Abidian et al.,
2010) and microstructures (Antensteiner et al., 2017a; Khorrami
et al., 2017) advantageously enhanced the surface roughness of the
CP films and improved the cellular response of neurons for chronic
stimulation and recording. Our group recently developed a
resorbable PEDOT:HA ink that can be inkjet-printed and UV-
cross-linked on molybdenum tracks patterned onto a flexible
PLGA substrate, to serve as a transient recording device of visual
stimuli (Leprince et al., 2023b). The conductivity of the tracks and
signal recording was maintained for approximately 4 months of
implantation on rat cortex, correlated with the system
resorption in vivo.

Other microelectrode arrays have been designed for various
applications, for instance, interacting with bones. Yao et al. (2021)
described a bioresorbable and self-powered implant to stimulate and
monitor the resorption of bone fracture. The device was composed
of two parts: a self-powering generator with micro-pyramid-shaped
PLGA structures between two Mg conductive islands and an
interdigitated electrode dressing for bone electrical stimulation
and healing monitoring (Figure 7B). It can be foreseen that
transient electrochemical sensors (for instance, monitoring pH,
lactate, and inflammation) can be of high interest in assessing
infection risks during the few months following prosthesis
implantation (Dai et al., 2023). A thermoresponsive and
injectable self-supporting conductive hydrogel made of collagen
and polypyrrole was described to detect glucose by amperometry
(Ravichandran et al., 2018). The key issue of connectivity was
however not addressed or described, and the demonstration of
sensitivity and specificity. These electrically conductive resins therefore appeared appealing for the design of biosensors and sensing in organ-on-chip devices.

However, the development of resorbable sensors is still limited by
several barriers that are yet to be overcome. A main limitation is the poor
conductivity of some materials, especially conducting polymers when
combined with resorbable hydrogels. CPs' conductivity can potentially
be improved by combining them with other conductive fillers such as
carbon nanotubes or graphene derivatives although it could stiffen the
materials and decrease their flexibility and stretchability. When
designing ion-selective electrodes, another important limitation is the
present use of non-safe and non-degradable materials in the design of the
sensing part (Cánovas et al., 2019). Therefore, the design of fully
resorbable electrochemical-based wearable sensors still largely remains
an unmet challenge.

Although a few examples of resorbable wearable sensors have
been described in the literature, the fact that the devices are laid onto
the skin and can be easily removed after use limits their applications.
However, the development of wearable resorbable devices can
appear as the first step and proof-of-concept toward the
development of resorbable implanted bioelectronic systems and
presents high environmental interest in reducing electronics
waste (Feng et al., 2019).

4.2.2 Implantable microelectrode arrays and
bioelectronic systems

The field of cardiac or neural tissue recording or stimulation is a good example to describe the evolution of materials and processes used through the last 25 years, with the objective to progress toward softer, more conformable, and flexible bioelectronic systems intended for use in the heart, brain, spinal cord, peripheral nerve, muscle, and skin (Tringides et al., 2021). Ultimately, it has now turned its attention toward device resorbability, particularly for specific applications such as short- to medium-term monitoring for epilepsy seizure (Yu et al., 2016; Xu et al., 2019a), neural stimulation for temporary pain relief (Lee et al., 2022), or intracranial pressure monitoring (Shin et al., 2019).

The first electrode arrays cleared by the FDA were the renowned
Utah array (Rousche et al., 1998). These arrays comprised a hundred
silicon cones, each covered by an insulator (silicon dioxide and/or
parylene), except for their apex. These devices sparked considerable
interest as they offered the possibility of concurrent neural
recordings from up to a hundred channels, thus initiating the
development of implantable devices for brain-computer
interfaces (Hochberg et al., 2006). However, the risks of
damaging blood vessels and triggering microhemorrhages, along
with inflammatory response and the eventual formation of glial scar,
remain very high (Kozai et al., 2015). In response to this challenge,
Neuralink has developed a specialized sewing machine capable of
gently introducing flexible polyimide shanks into the cortex while
avoiding blood vessels, with the assistance of medical imaging.
Owing to the substantial difference between Young's modulus of
polyimide and the stiffness of the brain tissue, the thickness of the
shank was decreased to attain a targeted range of 1 µm (Lycke et al.,
2023). However, for insertion into the brain tissue, as the thinned
structure was no longer stiff enough to prevent buckling, the authors
utilized a 75-µm tungsten wire affixed to the shank via a
biodissolvable PEG adhesive.

Alternately, to reduce the mechanical mismatch with the brain
tissue, using softer materials that closely resemble it, such as
hydrogels, is a viable approach. A transient microarray for the
recording of electrophysiological signals from the cortex was
designed by the group of Rogers (Yu et al., 2016). It involved the
utilization of thin silicon tracks transferred onto a PLGA film and
coated with a SiO₂ dielectric layer (Yu et al., 2016). More recently,
the same research group introduced a bioresorbable device designed
for the transient electrostimulation of the sciatic nerve to act as an
electronic pain blocker (Figure 7A) (Lee et al., 2022). In this
bioelectronic system, fast-resorbable magnesium was used to
design tracks in contact with the external connector (kilo-hertz
frequency alternating current pulses sent during treatment), whereas
slowly degrading Mo was used to make contact with the nerve. Thin
strips of Mo were put in contact with Mg strips using a conductive
resorbable carbon wax (C-wax) in a woven electrode pattern. The
primary objective of this design was to ensure that the rapid
resorption of the 50-µm-thick Mg patterns after the
electrostimulation treatment (approximately 10 days in phosphate
buffer, 2 months when implanted in rodents) did not impose any
constraints on the nerve. The nerves were in contact with 700-nm-
thick Moelectrodes that were resorbed over a longer time scale
(approximately 2 months in phosphate buffer). Note that different
substrate materials were also tested and selected for the fabrication
of the system to achieve suitable kinetics of bioresorption.
Conducting polymers were shown to improve the bioelectronic
interface between metals (gold and platinum) and neural tissues,
especially by decreasing the electrical impedance and increasing the
charge transfer capacity (Ludwig et al., 2006; Richardson-Burns
et al., 2007; Khodagholy et al., 2015). CP nanotubes (70–175 nm
diameter) (Abidian et al., 2008; Abidian et al., 2009; Abidian et al.,
2010) and microstructures (Antensteiner et al., 2017a; Khorrami
et al., 2017) advantageously enhanced the surface roughness of the
CP films and improved the cellular response of neurons for chronic
stimulation and recording. Our group recently developed a
resorbable PEDOT:HA ink that can be inkjet-printed and UV-
cross-linked on molybdenum tracks patterned onto a flexible
PLGA substrate, to serve as a transient recording device of visual
stimuli (Leprince et al., 2023b). The conductivity of the tracks and
signal recording was maintained for approximately 4 months of
implantation on rat cortex, correlated with the system
resorption in vivo.

Other microelectrode arrays have been designed for various
applications, for instance, interacting with bones. Yao et al. (2021)
described a bioresorbable and self-powered implant to stimulate and
monitor the resorption of bone fracture. The device was composed
of two parts: a self-powering generator with micro-pyramid-shaped
PLGA structures between two Mg conductive islands and an
interdigitated electrode dressing for bone electrical stimulation
and healing monitoring (Figure 7B). It can be foreseen that
transient electrochemical sensors (for instance, monitoring pH,
lactate, and inflammation) can be of high interest in assessing
infection risks during the few months following prosthesis
implantation (Dai et al., 2023). A thermoresponsive and
injectable self-supporting conductive hydrogel made of collagen
and polypyrrole was described to detect glucose by amperometry
(Ravichandran et al., 2018). The key issue of connectivity was
however not addressed or described, and the demonstration of
<figure><img src="image_14.png" /><figcaption>FIGURE 7</figcaption></figure>

Examples of resorbable implanted medical devices. (A) *Bioresorbable nerve cuff as a stimulator to electronically block pain.* i) Schematic representation of the device, showing the Mg/Mo woven electrode structure connected through C-wax. ii) Schematic of the process of the nerve conduction block in the cuff-geometry device. iii) Illustration of the functioning and progressive bioresorption of the device through various stages of its lifetime. iv) Illustration of the *in vivo* implantation: a subcutaneous pathway for the placement of nerve cuffs and wire interconnects (top) and cuffs wrapping around nerves for stimulation, blockage, and recording (bottom). v) Representative compound nerve action potential (CNAP) measurements at days 1, 5, and 9 after implantation, without (w/o) or with electrical stimulation of the pain-blocking device. Copyright 2022, the Authors, published by Science Advances (Lee et al., 2022). (B) *Self-powered implant to stimulate and monitor the resorption of bone fracture.* i) Representative scheme of the device, showing the two parts: the self-powering generator (top) and the interdigitated electrode dressing for electrical stimulation (bottom). ii) Triboelectric working principle of the self-powering generator part. iii) X-ray photographs of bone fracture healing (right tibia) with time in rodents, when treated with an active device (i.e., implantation of the fully active device, top row), when treated with the inactive device (i.e., implantation of the device for which the self-powering unit has been disconnected from the interdigitated electrode pattern, middle row), when not treated (no device implantation, bottom row). Reproduced with permission, Copyright 2021, the Authors, published by PNAS (Yao et al., 2021). (C) *Resorbable microneedle-based device for in-depth and wireless electrotherapy and drug delivery into injured muscle tissue.* i) The device is composed of a drug-loaded PLGA microneedle array assembled with a PLGA sheet comprising magnesium coils acting as an antenna for wireless power transmission. ii) Invasive surgical procedure for the implantation of the device in rat muscle injury models. Scale bar: 1 cm. iii) Muscle healing assessment with (+ES) or without (−ES) electrostimulation at days 5 (D5) and 9 (D9) after treatment: representative H&E staining section images (scale bar: 500 µm) and statistical analysis of muscle injury depth. iv) Photographs of microneedle-based devices implanted in rats at different times after therapy (9 days, 2 weeks, 8 weeks, and 12 weeks). Scale bar: 5 mm. Adapted with permission from Huang et al. (2022), Copyright 2022, the American Chemical Society.
<figure><img src="image_14.png" /><figcaption>FIGURE 7</figcaption></figure>

Examples of resorbable implanted medical devices. (A) *Bioresorbable nerve cuff as a stimulator to electronically block pain.* i) Schematic representation of the device, showing the Mg/Mo woven electrode structure connected through C-wax. ii) Schematic of the process of the nerve conduction block in the cuff-geometry device. iii) Illustration of the functioning and progressive bioresorption of the device through various stages of its lifetime. iv) Illustration of the *in vivo* implantation: a subcutaneous pathway for the placement of nerve cuffs and wire interconnects (top) and cuffs wrapping around nerves for stimulation, blockage, and recording (bottom). v) Representative compound nerve action potential (CNAP) measurements at days 1, 5, and 9 after implantation, without (w/o) or with electrical stimulation of the pain-blocking device. Copyright 2022, the Authors, published by Science Advances (Lee et al., 2022). (B) *Self-powered implant to stimulate and monitor the resorption of bone fracture.* i) Representative scheme of the device, showing the two parts: the self-powering generator (top) and the interdigitated electrode dressing for electrical stimulation (bottom). ii) Triboelectric working principle of the self-powering generator part. iii) X-ray photographs of bone fracture healing (right tibia) with time in rodents, when treated with an active device (i.e., implantation of the fully active device, top row), when treated with the inactive device (i.e., implantation of the device for which the self-powering unit has been disconnected from the interdigitated electrode pattern, middle row), when not treated (no device implantation, bottom row). Reproduced with permission, Copyright 2021, the Authors, published by PNAS (Yao et al., 2021). (C) *Resorbable microneedle-based device for in-depth and wireless electrotherapy and drug delivery into injured muscle tissue.* i) The device is composed of a drug-loaded PLGA microneedle array assembled with a PLGA sheet comprising magnesium coils acting as an antenna for wireless power transmission. ii) Invasive surgical procedure for the implantation of the device in rat muscle injury models. Scale bar: 1 cm. iii) Muscle healing assessment with (+ES) or without (−ES) electrostimulation at days 5 (D5) and 9 (D9) after treatment: representative H&E staining section images (scale bar: 500 µm) and statistical analysis of muscle injury depth. iv) Photographs of microneedle-based devices implanted in rats at different times after therapy (9 days, 2 weeks, 8 weeks, and 12 weeks). Scale bar: 5 mm. Adapted with permission from Huang et al. (2022), Copyright 2022, the American Chemical Society.
functionality was made in a piece of meat, evidencing the long pathway to human applications.

Microneedle (MN)-based devices to measure or stimulate in a minimally invasive way through the skin have emerged in the last 10 years (Huang et al., 2022; GhavamiNejad et al., 2023). If the benefit of microneedles essentially relies on their skin-anchoring function, which minimizes potential artifacts due to body movements, they still remain invasive systems for microneedle heights above 80 µm, which makes us consider them as implanted devices. If the anchoring function and improvement of measure quality and reliability can counterbalance the regulatory issue due to the invasiveness of such systems, they should expand rapidly for minimally invasive transdermal sensing in the coming years. Microneedles have so far been made mainly from non-resorbable materials, and intended to be removed at the end of their use. For instance, GhavamiNejad et al. (2023) designed an MN patch for glucose sensing based on a blend of hyaluronic acid, dopamine, PEDOT:PSS, Pt nanoparticles, and glucose oxidase. They associated this MN patch as the working electrode with two other patches made of polycarbonate, coated with a Pt layer (counter-electrode) and Ag/AgCl (reference electrode) for glucose transdermal sensing. In the future, the use of long-term (1–2 months) fully resorbable materials can be a real asset to improve the safety of such devices, as well as their disposal after use. In this perspective, Huang et al. (2022) very recently described a resorbable implantable electronic system composed of a drug-loaded PLGA microneedle array (25 MN of 900 µm height) coated by a tungsten layer (1 µm thick), assembled through a conductive paste (mixture of W nanoparticles and candelilla wax) with a PLGA sheet comprising square-shaped magnesium coils (41 µm thick) acting as the antenna for wireless power transmission (Figure 7C). This device was used for the in-depth electrostimulation conjugated to the delivery of anti-inflammatory drugs (aspirin or ibuprofen) into injured muscle tissue. While the Mg coils resorbed in approximately 8 weeks, the degradation of the PLGA material was slower, within 12 weeks. However, the bioelectronic system was not implanted onto the skin surface but directly onto the muscle tissue using an invasive surgery procedure. The microneedle structuration of the device was therefore used for its tissue-anchoring function but not to reduce the invasiveness of the implantation.

## 4.3 Tissue engineering

Tissue engineering has emerged as a promising therapeutic approach, aiming to replace damaged tissue with a functional one that is generally grown within a biologically functional scaffold. Notably, efforts have been focused on constructing biomaterials-based scaffolds that resemble the extracellular matrix to promote cellular regrowth, differentiation, and tissue regeneration. However, designing scaffolds that achieve optimal cellular responses and integration with the host tissue remains a challenge. Recently, there has been growing interest in incorporating both electroconductive and bioresorbable properties into biomaterials used for tissue engineering. Electroconductive materials can mimic the natural electrical microenvironment of living tissues, facilitating accurate cell responses and tissue

development. Meanwhile, bioresorbable materials gradually degrade and are absorbed by the body, reducing the need for invasive procedures and potential complications associated with permanent implants. Therefore, the combination of electroconductive and bioresorbable properties in tissue engineering scaffolds holds promise for tissue regeneration and functional organ restoration. The following section will primarily focus on exploring the latest advancements in electroconductive scaffolds for understanding the fundamental mechanisms underlying *in vitro* cellular monitoring and stimulation in the presence of electroconductive elements. Subsequently, the latest advancements in electroconductive and biodegradable materials in tissue engineering will be treated, with a particular focus on the functional restoration of four of the major electroactive tissues: the heart, nervous system, skin, and bones.

### 4.3.1 Engineered *in vitro* culture systems for cellular monitoring and stimulation

Nowadays, advanced *in vitro* culture systems have emerged as valuable tools for studying the intricate structure and functionality of human tissues, bridging the gap between *in vitro* and *in vivo* investigations. These systems enable the recreation of physiologically relevant microenvironments, in particular the 3D native extracellular matrix (ECM) that serves as a dynamic scaffold that supports cell adhesion, migration, and differentiation. This capability is crucial to accurately recapitulate complex pathophysiological phenomena and support various applications, such as tissue engineering, regenerative medicine, and drug discovery. In this context, the integration of physiologically relevant electroconductivity into 3D *in vitro* cell culture models adds a new dimension to their capabilities, as several tissues, such as the heart, nerves, skin, and brain, are known to display electrical properties (Xu et al., 2021). By incorporating conductive materials into hydrogel matrices, it becomes possible to develop scaffolds that not only support cell growth but also provide electrical stimulation to mimic the natural electrical cues found in living tissues. This unique combination of physicochemical support and electrical conductivity promotes cell proliferation, differentiation, and tissue regeneration, making electroconductive hydrogels a promising tool for the development of functional, biomimetic tissue constructs (Min et al., 2018).

Electroconductive hydrogels play a significant role in the monitoring of cell growth *in vitro*. These hydrogels offer the unique capability of integrating electrical monitoring within the 3D culture systems. The electrical properties of the culture, such as impedance, capacitance, and electrical resistance, can be measured and monitored, which can provide insights into cellular behaviors such as proliferation, viability, and metabolism (De León et al., 2020). The electrical monitoring of cell growth in electroconductive hydrogels allows for real-time and non-invasive assessment of cell behavior. Changes in electrical signals can reflect alterations in cell morphology, cell adhesion, and cellular responses to environmental cues. These electrical cues can serve as indicators of cell growth, functionality, and response to external stimuli (Khan et al., 2019). In particular, impedance measurements at the cell-material interface offer non-invasive and real-time monitoring of cellular behavior and allow to correlate and quantify cell viability over time. Inal et al. (2017) developed a conducting polymer scaffold, made of
functionality was made in a piece of meat, evidencing the long pathway to human applications.

Microneedle (MN)-based devices to measure or stimulate in a minimally invasive way through the skin have emerged in the last 10 years (Huang et al., 2022; GhavamiNejad et al., 2023). If the benefit of microneedles essentially relies on their skin-anchoring function, which minimizes potential artifacts due to body movements, they still remain invasive systems for microneedle heights above 80 µm, which makes us consider them as implanted devices. If the anchoring function and improvement of measure quality and reliability can counterbalance the regulatory issue due to the invasiveness of such systems, they should expand rapidly for minimally invasive transdermal sensing in the coming years. Microneedles have so far been made mainly from non-resorbable materials, and intended to be removed at the end of their use. For instance, GhavamiNejad et al. (2023) designed an MN patch for glucose sensing based on a blend of hyaluronic acid, dopamine, PEDOT:PSS, Pt nanoparticles, and glucose oxidase. They associated this MN patch as the working electrode with two other patches made of polycarbonate, coated with a Pt layer (counter-electrode) and Ag/AgCl (reference electrode) for glucose transdermal sensing. In the future, the use of long-term (1–2 months) fully resorbable materials can be a real asset to improve the safety of such devices, as well as their disposal after use. In this perspective, Huang et al. (2022) very recently described a resorbable implantable electronic system composed of a drug-loaded PLGA microneedle array (25 MN of 900 µm height) coated by a tungsten layer (1 µm thick), assembled through a conductive paste (mixture of W nanoparticles and candelilla wax) with a PLGA sheet comprising square-shaped magnesium coils (41 µm thick) acting as the antenna for wireless power transmission (Figure 7C). This device was used for the in-depth electrostimulation conjugated to the delivery of anti-inflammatory drugs (aspirin or ibuprofen) into injured muscle tissue. While the Mg coils resorbed in approximately 8 weeks, the degradation of the PLGA material was slower, within 12 weeks. However, the bioelectronic system was not implanted onto the skin surface but directly onto the muscle tissue using an invasive surgery procedure. The microneedle structuration of the device was therefore used for its tissue-anchoring function but not to reduce the invasiveness of the implantation.

## 4.3 Tissue engineering

Tissue engineering has emerged as a promising therapeutic approach, aiming to replace damaged tissue with a functional one that is generally grown within a biologically functional scaffold. Notably, efforts have been focused on constructing biomaterials-based scaffolds that resemble the extracellular matrix to promote cellular regrowth, differentiation, and tissue regeneration. However, designing scaffolds that achieve optimal cellular responses and integration with the host tissue remains a challenge. Recently, there has been growing interest in incorporating both electroconductive and bioresorbable properties into biomaterials used for tissue engineering. Electroconductive materials can mimic the natural electrical microenvironment of living tissues, facilitating accurate cell responses and tissue

development. Meanwhile, bioresorbable materials gradually degrade and are absorbed by the body, reducing the need for invasive procedures and potential complications associated with permanent implants. Therefore, the combination of electroconductive and bioresorbable properties in tissue engineering scaffolds holds promise for tissue regeneration and functional organ restoration. The following section will primarily focus on exploring the latest advancements in electroconductive scaffolds for understanding the fundamental mechanisms underlying in vitro cellular monitoring and stimulation in the presence of electroconductive elements. Subsequently, the latest advancements in electroconductive and biodegradable materials in tissue engineering will be treated, with a particular focus on the functional restoration of four of the major electroactive tissues: the heart, nervous system, skin, and bones.

### 4.3.1 Engineered in vitro culture systems for cellular monitoring and stimulation

Nowadays, advanced in vitro culture systems have emerged as valuable tools for studying the intricate structure and functionality of human tissues, bridging the gap between in vitro and in vivo investigations. These systems enable the recreation of physiologically relevant microenvironments, in particular the 3D native extracellular matrix (ECM) that serves as a dynamic scaffold that supports cell adhesion, migration, and differentiation. This capability is crucial to accurately recapitulate complex pathophysiological phenomena and support various applications, such as tissue engineering, regenerative medicine, and drug discovery. In this context, the integration of physiologically relevant electroconductivity into 3D in vitro cell culture models adds a new dimension to their capabilities, as several tissues, such as the heart, nerves, skin, and brain, are known to display electrical properties (Xu et al., 2021). By incorporating conductive materials into hydrogel matrices, it becomes possible to develop scaffolds that not only support cell growth but also provide electrical stimulation to mimic the natural electrical cues found in living tissues. This unique combination of physicochemical support and electrical conductivity promotes cell proliferation, differentiation, and tissue regeneration, making electroconductive hydrogels a promising tool for the development of functional, biomimetic tissue constructs (Min et al., 2018).

Electroconductive hydrogels play a significant role in the monitoring of cell growth in vitro. These hydrogels offer the unique capability of integrating electrical monitoring within the 3D culture systems. The electrical properties of the culture, such as impedance, capacitance, and electrical resistance, can be measured and monitored, which can provide insights into cellular behaviors such as proliferation, viability, and metabolism (De León et al., 2020). The electrical monitoring of cell growth in electroconductive hydrogels allows for real-time and non-invasive assessment of cell behavior. Changes in electrical signals can reflect alterations in cell morphology, cell adhesion, and cellular responses to environmental cues. These electrical cues can serve as indicators of cell growth, functionality, and response to external stimuli (Khan et al., 2019). In particular, impedance measurements at the cell-material interface offer non-invasive and real-time monitoring of cellular behavior and allow to correlate and quantify cell viability over time. Inal et al. (2017) developed a conducting polymer scaffold, made of
macroporous PEDOT:PSS integrated with collagen and dodecylbenzenesulfonic acid (DBSA) for the growth and monitoring of MDCK-II cells in a 3D system via electrochemical impedance spectroscopy. The presence of collagen provides cells with a biologically supportive, biomimetic environment to grow. On the other hand, the intimate contact of cells with the electroactive material allows a highly efficient signal transduction at the electrode interface, providing valuable, quantitative insights into MDCK-II growth and migration when compared to the bare collagen scaffold condition (Inal et al., 2017). Furthermore, the possibility to create seamless interfaces between cells and tissues and electronics is gaining significant interests in the contexts where intimate and long-lasting contact is required for monitoring complex *in vitro* systems. Ferlauto et al. (2018) developed a soft electroconductive interface through the selective electrodeposition of a hybrid material made from alginate and PEDOT:PSS onto platinum microelectrodes within a planar microelectrode array (MEA). The integration resulted in a substantial reduction of both mechanical and electrical mismatch at the tissue/electrode interface. Notably, it significantly reduced the electrical noise during recording when iPSC-derived neurospheres were encapsulated within these hydrogels, in contrast to using bare alginate hydrogels. Additionally, it provided a soft, supportive microenvironment for the long-term growth of organoids.

In addition to cell and tissue monitoring, the possibility to electrically stimulate cells *in vitro* (via endogenous or exogenous routes) has been shown to deeply influence cell behavior and stem cell differentiation, offering a potential strategy for generating tissue-specific cell types in regenerative medicine and tissue engineering applications (Chen et al., 2019). In a seminal study, a biohybrid hydrogel composed of collagen, alginate, and PEDOT:PSS was shown to induce *in vitro* maturation and beating properties of hiPSCs-derived cardiomyocytes, upon external electrical stimulations (Figure 8A) (Roshanbinfar et al., 2018). Similarly, the *in vitro* electrical stimulation of neural stem cells (NSCs) embedded in a collagen-based network containing PPy showed NSC proliferation and differentiation into astrocytes, provoking NSC transcriptome alternation, such as genes involved in cell proliferation and synaptic remodeling (Xu et al., 2022).

The molecular mechanisms underlying electrically induce cell growth and differentiation involves intricate cellular signaling pathways and gene expression regulation (Thrivikraman et al., 2018; Chen et al., 2019; Katoh, 2022). Electrical stimulation triggers the activation of specific ion channels and transporters on the cell membrane, leading to changes in intracellular ion concentrations, particularly calcium ions. These changes initiate downstream signaling cascades, such as activation of protein kinases, phosphorylation of transcription factors, and modulation of gene expression. This ultimately regulates cell growth and differentiation by influencing cell cycle progression, proliferation, and the activation of lineage-specific genes. Additionally, electrical stimulation can modulate the activity of growth factors and cytokines, further contributing to cell growth and differentiation processes. It is however worth noting that the specific molecular mechanisms underlying electrically induced cell growth and differentiation are still partially unclear and can greatly vary depending on the cell type and on the specific characteristics of the conductive material in contact with cells.

It is also evident that cellular differentiation in such systems relies on the combination of mechanical and electrical stimulations through a concert of biochemical and mechanobiological pathways (Bielfeldt et al., 2022). The possibility to independently investigate the two stimuli might give further insight into the biological processes underpinning cell type formation and help develop a more accurate platform for regenerative medicine applications. In a recent study, Tringides et al. (2023) developed a porous conductive scaffold by incorporating carbon nanomaterials (CNTs and carbon flakes) into an alginate hydrogel matrix with tunable mechanical and electrical properties in the range of the typical neural tissue values (Figure 8B). By varying the degree of matrix viscoelasticity and CNT content, the authors could study and characterize the ability of encapsulated neural progenitor cells to grow and differentiate under different electrical and mechanical environments. Notably, it was found that the more viscoelastic and conductive scaffolds produced denser neurite networks and differentiated into astrocytes and myelinating oligodendrocytes. These findings were consistent with previous studies examining the influence of matrix viscoelasticity and conductivity associated with carbon nanotubes (CNTs) on the maturation of neural cells (Chaudhuri et al., 2015; Chen et al., 2019; Samanta et al., 2022). Importantly, this study provides novel insights into the individual contributions of each stimulus, shedding light on their independent effects.

Interestingly, the dynamic rearrangement of the internal matrix nanostructure, as a result of the continuous cell–environment interaction, was shown to further alter the endogenous conductivity of the system. This phenomenon was particularly evident upon cell encapsulation in dynamic hydrogel networks. In an electroconductive PEDOT:PSS/peptide-PEG hydrogel, the assembly of peptide-PEG and negatively charged PEDOT:PSS nanostructure resulted in a dynamic non-covalent network, prone to structural rearrangements under cellular action, such as growth and maturation (Figure 8C) (Xu et al., 2018). Despite that the underlying biological and chemical mechanisms remained undetermined, the increase in conductivity after 5 days of mesenchymal stromal cell culture was associated with a simultaneous marked change in the matrix network structure, with the presence of nanofiber bundles around the cells.

In conclusion, the exploration of the underlying biological processes governing cellular differentiation and phenotypic expression in the presence of electroconductive elements is crucial for advancing regenerative medicine applications. Further investigation of these intricate mechanisms offers an opportunity to develop refined and precise platforms that can accurately replicate the complex cellular environments found *in vivo*. By unraveling the intricacies of cell–biomaterial interactions at a fundamental level, new insights can be gained into cellular fate determination, lineage commitment, and the modulation of cellular functions, thereby enhancing *in vitro* modeling capabilities and driving the development of innovative therapeutic approaches for tissue engineering applications.

### 4.3.2 Cardiac tissue engineering

Cardiovascular diseases, such as myocardial infarction, occur with imparted electrical activity and alteration of the heart's mechanical function, which causes severe damage to the heart tissue, such as the loss of cardiomyocytes (CMs). The infarcted
macroporous PEDOT:PSS integrated with collagen and dodecylbenzenesulfonic acid (DBSA) for the growth and monitoring of MDCK-II cells in a 3D system via electrochemical impedance spectroscopy. The presence of collagen provides cells with a biologically supportive, biomimetic environment to grow. On the other hand, the intimate contact of cells with the electroactive material allows a highly efficient signal transduction at the electrode interface, providing valuable, quantitative insights into MDCK-II growth and migration when compared to the bare collagen scaffold condition (Inal et al., 2017). Furthermore, the possibility to create seamless interfaces between cells and tissues and electronics is gaining significant interests in the contexts where intimate and long-lasting contact is required for monitoring complex *in vitro* systems. Ferlauto et al. (2018) developed a soft electroconductive interface through the selective electrodeposition of a hybrid material made from alginate and PEDOT:PSS onto platinum microelectrodes within a planar microelectrode array (MEA). The integration resulted in a substantial reduction of both mechanical and electrical mismatch at the tissue/electrode interface. Notably, it significantly reduced the electrical noise during recording when iPSC-derived neurospheres were encapsulated within these hydrogels, in contrast to using bare alginate hydrogels. Additionally, it provided a soft, supportive microenvironment for the long-term growth of organoids.

In addition to cell and tissue monitoring, the possibility to electrically stimulate cells *in vitro* (via endogenous or exogenous routes) has been shown to deeply influence cell behavior and stem cell differentiation, offering a potential strategy for generating tissue-specific cell types in regenerative medicine and tissue engineering applications (Chen et al., 2019). In a seminal study, a biohybrid hydrogel composed of collagen, alginate, and PEDOT:PSS was shown to induce *in vitro* maturation and beating properties of hiPSCs-derived cardiomyocytes, upon external electrical stimulations (Figure 8A) (Roshanbinfar et al., 2018). Similarly, the *in vitro* electrical stimulation of neural stem cells (NSCs) embedded in a collagen-based network containing PPy showed NSC proliferation and differentiation into astrocytes, provoking NSC transcriptome alternation, such as genes involved in cell proliferation and synaptic remodeling (Xu et al., 2022).

The molecular mechanisms underlying electrically induce cell growth and differentiation involves intricate cellular signaling pathways and gene expression regulation (Thrivikraman et al., 2018; Chen et al., 2019; Katoh, 2022). Electrical stimulation triggers the activation of specific ion channels and transporters on the cell membrane, leading to changes in intracellular ion concentrations, particularly calcium ions. These changes initiate downstream signaling cascades, such as activation of protein kinases, phosphorylation of transcription factors, and modulation of gene expression. This ultimately regulates cell growth and differentiation by influencing cell cycle progression, proliferation, and the activation of lineage-specific genes. Additionally, electrical stimulation can modulate the activity of growth factors and cytokines, further contributing to cell growth and differentiation processes. It is however worth noting that the specific molecular mechanisms underlying electrically induced cell growth and differentiation are still partially unclear and can greatly vary depending on the cell type and on the specific characteristics of the conductive material in contact with cells.

It is also evident that cellular differentiation in such systems relies on the combination of mechanical and electrical stimulations through a concert of biochemical and mechanobiological pathways (Bielfeldt et al., 2022). The possibility to independently investigate the two stimuli might give further insight into the biological processes underpinning cell type formation and help develop a more accurate platform for regenerative medicine applications. In a recent study, Tringides et al. (2023) developed a porous conductive scaffold by incorporating carbon nanomaterials (CNTs and carbon flakes) into an alginate hydrogel matrix with tunable mechanical and electrical properties in the range of the typical neural tissue values (Figure 8B). By varying the degree of matrix viscoelasticity and CNT content, the authors could study and characterize the ability of encapsulated neural progenitor cells to grow and differentiate under different electrical and mechanical environments. Notably, it was found that the more viscoelastic and conductive scaffolds produced denser neurite networks and differentiated into astrocytes and myelinating oligodendrocytes. These findings were consistent with previous studies examining the influence of matrix viscoelasticity and conductivity associated with carbon nanotubes (CNTs) on the maturation of neural cells (Chaudhuri et al., 2015; Chen et al., 2019; Samanta et al., 2022). Importantly, this study provides novel insights into the individual contributions of each stimulus, shedding light on their independent effects.

Interestingly, the dynamic rearrangement of the internal matrix nanostructure, as a result of the continuous cell–environment interaction, was shown to further alter the endogenous conductivity of the system. This phenomenon was particularly evident upon cell encapsulation in dynamic hydrogel networks. In an electroconductive PEDOT:PSS/peptide-PEG hydrogel, the assembly of peptide-PEG and negatively charged PEDOT:PSS nanostructure resulted in a dynamic non-covalent network, prone to structural rearrangements under cellular action, such as growth and maturation (Figure 8C) (Xu et al., 2018). Despite that the underlying biological and chemical mechanisms remained undetermined, the increase in conductivity after 5 days of mesenchymal stromal cell culture was associated with a simultaneous marked change in the matrix network structure, with the presence of nanofiber bundles around the cells.

In conclusion, the exploration of the underlying biological processes governing cellular differentiation and phenotypic expression in the presence of electroconductive elements is crucial for advancing regenerative medicine applications. Further investigation of these intricate mechanisms offers an opportunity to develop refined and precise platforms that can accurately replicate the complex cellular environments found *in vivo*. By unraveling the intricacies of cell–biomaterial interactions at a fundamental level, new insights can be gained into cellular fate determination, lineage commitment, and the modulation of cellular functions, thereby enhancing *in vitro* modeling capabilities and driving the development of innovative therapeutic approaches for tissue engineering applications.

### 4.3.2 Cardiac tissue engineering

Cardiovascular diseases, such as myocardial infarction, occur with imparted electrical activity and alteration of the heart's mechanical function, which causes severe damage to the heart tissue, such as the loss of cardiomyocytes (CMs). The infarcted
<figure><img src="image_15.png" /></figure>

<figure><img src="image_16.png" /></figure>

<figure><img src="image_17.png" /></figure>

<figure><img src="image_18.png" /><figcaption>FIGURE 8
Cell-conductive material interactions in advanced hydrogels and scaffolds for *in vitro* 3D culture models. (A) *Biohybrid hydrogel composed of collagen, alginate, and PEDOT:PSS for in vitro hiPSCs-derived cardiomyocyte maturation.* (i) Schematic of the conductive biohybrid hydrogel formation (eCA-gel). (ii) Maturation of hiPSC-derived cardiomyocytes in the non-conductive hydrogel control (CA-gel) and electroconductive hydrogels (eCA-gel). Confocal images projection of tissue constructs stained for cardiomyocyte-specific markers troponin I, sarcomeric-α-actin, and connexin 43. Scale bars: 25 µm. Adapted with permission, Copyright 2018, John Wiley and Sons (Roshanbinfar et al., 2018). (B) *Porous, conductive scaffold made of alginate and carbon nanomaterials (CNTs and carbon flakes) for the electromechanical differentiation of neural progenitor cells (NPCs).* (i) Schematic of the porous scaffold and scanning electron microscopy (SEM) images of the internal structure, showing the entrapment of carbon flakes (red) and CNT (blue) into alginate (gray). Scale bar: 1 µm. (ii) 3D reconstruction of NPC micrographs in scaffolds of different mechanical properties (viscoelastic and elastic) and carbon content (%) after 6 weeks in culture. Staining for oligodendrocyte markers TuJ1 (green), myelin basic protein (MBP, magenta), and NPC (red). Scale bars: 180 µm. (iii) Quantification of the length of myelin for different carbon contents (%) and mechanical properties (viscoelastic, elastic) of the scaffolds. Adapted with permission, Copyright 2022, John Wiley and Sons (Tringides et al., 2023). (C) *Characteristics of PEDOT:PSS/peptide-PEG conductive dynamic hydrogels.* (i) Self-assembling and representative hydrogel formation through reversible and non-covalent interactions. (ii) Transmission electron microscopy (TEM) images of MSCs encapsulated in the PEDOT:PSS/peptide-PEG hydrogel showing the formation of nanofiber bundles around cells. Scale bars: 500 nm (left) and 1 µm (right). Adapted with permission from Xu et al. (2018), Copyright 2018, the American Chemical Society.</figcaption></figure>

myocardial tissue triggers a pro-fibrotic response, which is
responsible for the stiffening of the tissue and loss of
contractility. Compared to other tissues, the cardiac regenerative
capacity is really limited. In this context, cardiac tissue engineering
aims at assembling tissue patches, adhesives, or injectable materials,
which can intrinsically integrate with the cardiac tissue. Notably,
apart from being biocompatible and biodegradable, those scaffolds

should match the mechanical and electrical behavior of the
myocardium ECM in order to mimic and transduce the
heartbeat. Moreover, as the heart has a low inherent regenerative
capacity, it is crucial that these systems allow for the maturation and
differentiation of implanted cells into conductive and contractile
CMs. The conductivity range of native myocardium, which can be
used as reference values for designing electroconductive hydrogels
<figure><img src="image_15.png" /><figcaption>FIGURE 8</figcaption></figure>

Cell-conductive material interactions in advanced hydrogels and scaffolds for *in vitro* 3D culture models. (A) *Biohybrid hydrogel composed of collagen, alginate, and PEDOT:PSS for in vitro hiPSCs-derived cardiomyocyte maturation*. (i) Schematic of the conductive biohybrid hydrogel formation (eCA-gel). (ii) Maturation of hiPSC-derived cardiomyocytes in the non-conductive hydrogel control (CA-gel) and electroconductive hydrogels (eCA-gel). Confocal images projection of tissue constructs stained for cardiomyocyte-specific markers troponin I, sarcomeric-α-actin, and connexin 43. Scale bars: 25 µm. Adapted with permission, Copyright 2018, John Wiley and Sons (Roshanbinfar et al., 2018). (B) *Porous, conductive scaffold made of alginate and carbon nanomaterials (CNTs and carbon flakes) for the electromechanical differentiation of neural progenitor cells (NPCs)*. (i) Schematic of the porous scaffold and scanning electron microscopy (SEM) images of the internal structure, showing the entrapment of carbon flakes (red) and CNT (blue) into alginate (gray). Scale bar: 1 µm. (ii) 3D reconstruction of NPC micrographs in scaffolds of different mechanical properties (viscoelastic and elastic) and carbon content (%) after 6 weeks in culture. Staining for oligodendrocyte markers TuJ1 (green), myelin basic protein (MBP, magenta), and NPC (red). Scale bars: 180 µm. (iii) Quantification of the length of myelin for different carbon contents (%) and mechanical properties (viscoelastic, elastic) of the scaffolds. Adapted with permission, Copyright 2022, John Wiley and Sons (Tringides et al., 2023). (C) *Characteristics of PEDOT:PSS/peptide-PEG conductive dynamic hydrogels*. (i) Self-assembling and representative hydrogel formation through reversible and non-covalent interactions. (ii) Transmission electron microscopy (TEM) images of MSCs encapsulated in the PEDOT:PSS/peptide-PEG hydrogel showing the formation of nanofiber bundles around cells. Scale bars: 500 nm (left) and 1 µm (right). Adapted with permission from Xu et al. (2018), Copyright 2018, the American Chemical Society.

myocardial tissue triggers a pro-fibrotic response, which is
responsible for the stiffening of the tissue and loss of
contractility. Compared to other tissues, the cardiac regenerative
capacity is really limited. In this context, cardiac tissue engineering
aims at assembling tissue patches, adhesives, or injectable materials,
which can intrinsically integrate with the cardiac tissue. Notably,
apart from being biocompatible and biodegradable, those scaffolds

should match the mechanical and electrical behavior of the
myocardium ECM in order to mimic and transduce the
heartbeat. Moreover, as the heart has a low inherent regenerative
capacity, it is crucial that these systems allow for the maturation and
differentiation of implanted cells into conductive and contractile
CMs. The conductivity range of native myocardium, which can be
used as reference values for designing electroconductive hydrogels
for cardiac repair, varies from $5 \times 10^{-5} \text{ S cm}^{-1}$ (transversally) to $0.0016 \text{ S cm}^{-1}$ (longitudinally) (Gao et al., 2022).

The main strategy used in cardiac tissue engineering consists of the addition of carbon nanotubes, gold nanoparticles, and graphene and its derivatives, or conducting polymers such as PPy, PANI, and PEDOT, to hydrogels. The electrically conductive properties of the materials incorporated in ECM-mimic hydrogels have been shown to improve in vivo cardiac function and electrical impulse propagation in the absence of external stimulation (Morsink et al., 2022). On the other side, it is widely accepted that the inclusion of nano- or microstructured materials, regardless of their conductivity, also changes the stiffness and topography of the scaffold, influencing the maturation and irritability of the heart tissue. It has been argued that the incorporation of intrinsic conductive materials results in the formation of tight connections between cell membranes and the scaffold, forming a hybrid conductive network that, in turn, facilitates signal propagation and excitability of heart cells. Furthermore, the presence of nano- or microelectrical conductors has been shown to promote cell attachment and the expression of cardiac-specific markers (e.g., sarcomeric alpha-actin striations and connexin 43 (cx-43) (Morsink et al., 2022). Lee et al. (2019) have characterized the effects of the addition of CNTs, GO, and rGO in gelatin methacrylate (GelMA) hydrogels on cardiomyocytes' function and behavior, underlying the importance of directing cardiac tissue regeneration through mechanical and electrical cues of carbon derivatives. GelMA-CNT and GelMA-rGO scaffolds resembled typical stiffness values of the heart, featured electrophysiological properties, and displayed electrical conductivity. Surprisingly, the different types of carbon functionalization direct different types of *in vitro* tissue maturation. While GelMA-CNT hydrogels led to ventricular-like tissue, GelMA-GO hydrogels guided to atrial-like tissue. This is likely the result of the integrin-mediated differentiation of the CMs, which was stimulated differently by using different carbon nanoparticles and thus different gel topography.

Injectable electroconductive hydrogels can be deployed into the infarct site and surrounding area to promote myocardial tissue function restoration, providing an effective and minimally invasive method. Once injected into the myocardium, the hydrogel undergoes fast *in situ* polymerization, not only acting as a structural support for the damaged tissue but also bridging the electrical mismatch between healthy and damaged CMs, promoting cardiac resynchronization (Gao et al., 2022). Liang et al. (2018) developed a series of electroconductive hydrogels by combining PPy with gelatin and PEGDA via a two-step Michael addition reaction. The injectable material was directly painted into the infarcted area in a myocardial infarction rat model, and *in situ* polymerization occurred in less than 10 s, avoiding any adverse hydrogel leakage and creating a seamless interface between the hydrogel and the tissue. Four weeks post-implantation, the PPy-containing hydrogels were mostly degraded, likely due to enzymatic and hydrolysis degradation, and the cardiac tissue presented a remarkably improved electrophysiological signal restoration and reconstruction. Injectable hydrogels could also load cells, drugs, and biomolecules into the tissues, further boosting myocardial restoration and cardiac function. Bao et al. (2017) developed an injectable PEGDA-melamine/hyaluronan-thiol

(HA-SH)/GO hydrogel, where GO interacted with the melamine core through π-π conjugation, and this was loaded with adipose-derived stem cells. The flowable behavior of the hydrogel allowed the safe injection of the cells into the myocardial infarction area in rats, by mitigating the injection-associated shear stress. *In vivo* results have shown a remarkable improvement in heart function, characterized by an increase in ejection fraction and reduction of the infarcted area together with enhanced angiogenesis (Bao et al., 2017).

Among other electrically conductive nanoparticles, AuNPs are widely employed for cardiac tissue engineering due to the ease of producing particles with different sizes, shapes, and surface properties, allowing for tunable electrical and mechanical properties. Saravanan et al. (2018) incorporated graphene oxide gold nanosheets (GO-Au) into degradable chitosan polymer. *In vitro*, the scaffold exhibited Go-Au concentration-dependent degradation properties, supported cell attachment and maturation, displayed no cytotoxicity, and increased electrical conductivity and signal propagation. When tested *in vivo*, in a rat model of myocardial infarction, the cardiac patch showed improved heartbeat, contractility, conductivity, and restoration of the ventricular function. However, despite low levels of inflammation, contrary to the *in vitro* tests, after 5 weeks post-implantation, the patch was still present in the heart, suggesting the need for more elaborative studies on the long-term fate of this class of implanted scaffolds and their long-term effects on cardiac function (Saravanan et al., 2018). In general, to be clinically relevant, cardiac patches should withstand the continuous, dynamic-stress environment of the heart and should hold great tissue adhesion, enabling tissue restoration while providing mechanical and electrical support to the infarction site. As such, conductive dynamically bonded hydrogels, featuring self-healing behaviors, are the desired materials to mimic the ability of native cardiac tissue to regenerate through the continuous formation of new chemical bonds (Rogers et al., 2020). To further enhance hydrogel wet-adhesion to tissues, conductive dopamine-based materials have been widely employed due to their notable gluing properties. To this end, Jing et al. (2017) developed electroconductive chitosan-based hydrogels functionalized with GO and featuring dynamic, self-healing, and self-adhesive behavior, by the incorporation of poly(dopamine). *In vitro* cell culture results showed enhanced viability and proliferation of human stem cell-derived fibroblasts and CMs in the conductive chitosan-dopamine/GO hydrogels, as well as faster, spontaneous, and physiologically relevant beating rate when compared to the non-conductive control.

Interestingly, Wu et al. (2020) developed a combined approach therapy, by synthetizing two types of biodegradable and bio-conductive hydrogels for the co-administration of a self-adhesive conductive hydrogel patch and injectable and self-healable hydrogel to the infarcted myocardium (Figure 9A). The dynamic, injectable hydrogel, obtained via Schiff-base hydrazone bonds between oxidized HA and hydrazide-functionalized HA, was first injected at the infarcted area in order to provide mechanical support and promote angiogenesis. Subsequently, the self-adhesive hydrogel patch, obtained by combining gelatin-dopamine and dopamine-modified PPy upon $Fe^{3+}$ trigger, was painted and rapidly bound to the outermost layer of the beating myocardium in order to provide
for cardiac repair, varies from $5 \times 10^{-5} \text{ S cm}^{-1}$ (transversally) to $0.0016 \text{ S cm}^{-1}$ (longitudinally) (Gao et al., 2022).

The main strategy used in cardiac tissue engineering consists of the addition of carbon nanotubes, gold nanoparticles, and graphene and its derivatives, or conducting polymers such as PPy, PANI, and PEDOT, to hydrogels. The electrically conductive properties of the materials incorporated in ECM-mimic hydrogels have been shown to improve *in vivo* cardiac function and electrical impulse propagation in the absence of external stimulation (Morsink et al., 2022). On the other side, it is widely accepted that the inclusion of nano- or microstructured materials, regardless of their conductivity, also changes the stiffness and topography of the scaffold, influencing the maturation and irritability of the heart tissue. It has been argued that the incorporation of intrinsic conductive materials results in the formation of tight connections between cell membranes and the scaffold, forming a hybrid conductive network that, in turn, facilitates signal propagation and excitability of heart cells. Furthermore, the presence of nano- or microelectrical conductors has been shown to promote cell attachment and the expression of cardiac-specific markers (e.g., sarcomeric alpha-actin striations and connexin 43 (cx-43) (Morsink et al., 2022). Lee et al. (2019) have characterized the effects of the addition of CNTs, GO, and rGO in gelatin methacrylate (GelMA) hydrogels on cardiomyocytes' function and behavior, underlying the importance of directing cardiac tissue regeneration through mechanical and electrical cues of carbon derivatives. GelMA-CNT and GelMA-rGO scaffolds resembled typical stiffness values of the heart, featured electrophysiological properties, and displayed electrical conductivity. Surprisingly, the different types of carbon functionalization direct different types of *in vitro* tissue maturation. While GelMA-CNT hydrogels led to ventricular-like tissue, GelMA-GO hydrogels guided to atrial-like tissue. This is likely the result of the integrin-mediated differentiation of the CMs, which was stimulated differently by using different carbon nanoparticles and thus different gel topography.

Injectable electroconductive hydrogels can be deployed into the infarct site and surrounding area to promote myocardial tissue function restoration, providing an effective and minimally invasive method. Once injected into the myocardium, the hydrogel undergoes fast *in situ* polymerization, not only acting as a structural support for the damaged tissue but also bridging the electrical mismatch between healthy and damaged CMs, promoting cardiac resynchronization (Gao et al., 2022). Liang et al. (2018) developed a series of electroconductive hydrogels by combining PPy with gelatin and PEGDA via a two-step Michael addition reaction. The injectable material was directly painted into the infarcted area in a myocardial infarction rat model, and *in situ* polymerization occurred in less than 10 s, avoiding any adverse hydrogel leakage and creating a seamless interface between the hydrogel and the tissue. Four weeks post-implantation, the PPy-containing hydrogels were mostly degraded, likely due to enzymatic and hydrolysis degradation, and the cardiac tissue presented a remarkably improved electrophysiological signal restoration and reconstruction. Injectable hydrogels could also load cells, drugs, and biomolecules into the tissues, further boosting myocardial restoration and cardiac function. Bao et al. (2017) developed an injectable PEGDA-melamine/hyaluronan-thiol

(HA-SH)/GO hydrogel, where GO interacted with the melamine core through π-π conjugation, and this was loaded with adipose-derived stem cells. The flowable behavior of the hydrogel allowed the safe injection of the cells into the myocardial infarction area in rats, by mitigating the injection-associated shear stress. *In vivo* results have shown a remarkable improvement in heart function, characterized by an increase in ejection fraction and reduction of the infarcted area together with enhanced angiogenesis (Bao et al., 2017).

Among other electrically conductive nanoparticles, AuNPs are widely employed for cardiac tissue engineering due to the ease of producing particles with different sizes, shapes, and surface properties, allowing for tunable electrical and mechanical properties. Saravanan et al. (2018) incorporated graphene oxide gold nanosheets (GO-Au) into degradable chitosan polymer. *In vitro*, the scaffold exhibited Go-Au concentration-dependent degradation properties, supported cell attachment and maturation, displayed no cytotoxicity, and increased electrical conductivity and signal propagation. When tested *in vivo*, in a rat model of myocardial infarction, the cardiac patch showed improved heartbeat, contractility, conductivity, and restoration of the ventricular function. However, despite low levels of inflammation, contrary to the *in vitro* tests, after 5 weeks post-implantation, the patch was still present in the heart, suggesting the need for more elaborative studies on the long-term fate of this class of implanted scaffolds and their long-term effects on cardiac function (Saravanan et al., 2018). In general, to be clinically relevant, cardiac patches should withstand the continuous, dynamic-stress environment of the heart and should hold great tissue adhesion, enabling tissue restoration while providing mechanical and electrical support to the infarction site. As such, conductive dynamically bonded hydrogels, featuring self-healing behaviors, are the desired materials to mimic the ability of native cardiac tissue to regenerate through the continuous formation of new chemical bonds (Rogers et al., 2020). To further enhance hydrogel wet-adhesion to tissues, conductive dopamine-based materials have been widely employed due to their notable gluing properties. To this end, Jing et al. (2017) developed electroconductive chitosan-based hydrogels functionalized with GO and featuring dynamic, self-healing, and self-adhesive behavior, by the incorporation of poly(dopamine). *In vitro* cell culture results showed enhanced viability and proliferation of human stem cell-derived fibroblasts and CMs in the conductive chitosan-dopamine/GO hydrogels, as well as faster, spontaneous, and physiologically relevant beating rate when compared to the non-conductive control.

Interestingly, Wu et al. (2020) developed a combined approach therapy, by synthetizing two types of biodegradable and bio-conductive hydrogels for the co-administration of a self-adhesive conductive hydrogel patch and injectable and self-healable hydrogel to the infarcted myocardium (Figure 9A). The dynamic, injectable hydrogel, obtained via Schiff-base hydrazone bonds between oxidized HA and hydrazide-functionalized HA, was first injected at the infarcted area in order to provide mechanical support and promote angiogenesis. Subsequently, the self-adhesive hydrogel patch, obtained by combining gelatin-dopamine and dopamine-modified PPy upon $Fe^{3+}$ trigger, was painted and rapidly bound to the outermost layer of the beating myocardium in order to provide
<figure><img src="image_19.png" /><figcaption>FIGURE 9
Conductive hydrogels for tissue engineering applications. (A) Co-administration of an injectable hydrogel (HA-CHO/HA-CDH) and an adhesive conductive hydrogel patch (Gel-DA/DA-PPy) to treat myocardial infarction. (i) Schematic depicting the synthesis and co-administration of the two hydrogels. (ii) Masson's trichrome-stained sections showing infarct size and related fibrotic tissue (blue stained infarct scar) of the myocardium for the untreated group (top) and the hydrogels co-administration group (bottom). Scale bars: 1 mm. Adapted with permission from Wu et al. (2020), Copyright 2020, the American Chemical Society. (B) Injectable, conductive, self-healing hydrogel (ICH) scaffold for spinal cord injury repair. (i) Schematic illustration of the hydrogel, based on amino-modified gelatin (NH₂-gelatin) and aniline tetramer-grafted oxidized hyaluronic acid (AT-OHA), loaded with exogenous neural stem cells (NSCs) and its administration in a rat model of total spinal cord injury (SCI). (ii) Total spinal cord resection samples 6 weeks after implantation of ICH, NSCs-loaded ICH (ICH-NSCs), and without any treatment (control group). (iii) Semi-quantitative analysis of the proportion of neurofilament 200 (NF200)-positive regions in rats by immunofluorescence staining. Adapted with permission from Liu H. et al. (2023), Copyright 2023, the American Chemical Society. (C) Conductive hydrogels for skin repair and wound dressing. (Top) Trans-epithelial potential and electric field at the wound site before and after the healing process. Reproduced with permission, Copyright 2020, John Wiley and Sons (Korupalli et al., 2021). (Bottom) (i) Diagrammatic sketch of soft hemostatic antioxidant conductive HA-DA/rGO@polydopamine (PDA) hydrogel preparation, macroscopic characteristics, and implantation at the wound site. Scale bar: 5 mm. (ii) Pictures of wounds at days 3, 7, and 14 post-implantation. (iii) Granulation tissue (red arrows) thickness for the different groups on day 14 post-implantation. Scale bar: 500 µm. Tegaderm: commercial film dressing (control); HA-DA/rGO0: HA-DA hydrogel in the absence of rGO, HA-DA/rGO3; HA-DA hydrogel cross-linked with rGO@PDA, HA-DA/rGO3/Doxy: doxycycline-loaded HA-DA/rGO@PDA hydrogel. Adapted with permission, Copyright 2019, John Wiley and Sons (Liang et al., 2019). (D) In vivo study of conductive 3D-printed PCL/MWCNTs scaffolds for bone tissue engineering. (i) Schematic illustration of the experimental setup: synthesis of the conductive scaffolds and their implantation with electrical stimulation (ES) treatment. (ii) Bone defect formation in the animal model and bone tissue formation with and without conductive scaffold after 60 days. (iii) Cross-section histological images of bone tissue formation at the bone defect for all groups (PCL, PCL/MWCNTs 0.75% wt and PCL/MWCNTs 3% wt) after 60 and 120 days, with and without electrical stimulation (ES). Adapted from eSilva et al. (2021), Copyright 2022, Springer Nature.</figcaption></figure>

high hydrogel-tissue integration and homogenous electrical conductivity. These combined hydrogel/patch approaches featured good biodegradability of both materials upon in vivo implantation and a more pronounced improvement of the conductive functions, in terms of electrophysiological, histological, and antigenic outcomes when compared to single-mode systems (cardiac patch or injectable hydrogel) (Wu et al., 2020).

### 4.3.3 Nerve tissue engineering

Nerves' regrowth upon injury can be slow and often results in incomplete functional recovery as a consequence of the limited nervous tissue regenerative capacity. Endogenous and external electrical stimulations have been shown to promote nerve growth, enhance axonal regeneration, and guide the direction of nerve growth. Similar to cardiac tissue, recent studies have shown that conductive hydrogels can be used as electrical stimulators and
<figure><img src="image_16.png" /><figcaption>FIGURE 9
Conductive hydrogels for tissue engineering applications. (A) Co-administration of an injectable hydrogel (HA-CHO/HA-CDH) and an adhesive conductive hydrogel patch (Gel-DA/DA-PPy) to treat myocardial infarction. (i) Schematic depicting the synthesis and co-administration of the two hydrogels. (ii) Masson's trichrome-stained sections showing infarct size and related fibrotic tissue (blue stained infarct scar) of the myocardium for the untreated group (top) and the hydrogels co-administration group (bottom). Scale bars: 1 mm. Adapted with permission from Wu et al. (2020), Copyright 2020, the American Chemical Society. (B) Injectable, conductive, self-healing hydrogel (ICH) scaffold for spinal cord injury repair. (i) Schematic illustration of the hydrogel, based on amino-modified gelatin (NH₂-gelatin) and aniline tetramer-grafted oxidized hyaluronic acid (AT-OHA), loaded with exogenous neural stem cells (NSCs) and its administration in a rat model of total spinal cord injury (SCI). (ii) Total spinal cord resection samples 6 weeks after implantation of ICH, NSCs-loaded ICH (ICH-NSCs), and without any treatment (control group). (iii) Semi-quantitative analysis of the proportion of neurofilament 200 (NF200)-positive regions in rats by immunofluorescence staining. Adapted with permission from Liu H. et al. (2023), Copyright 2023, the American Chemical Society. (C) Conductive hydrogels for skin repair and wound dressing. (Top) Trans-epithelial potential and electric field at the wound site before and after the healing process. Reproduced with permission, Copyright 2020, John Wiley and Sons (Korupalli et al., 2021). (Bottom) (i) Diagrammatic sketch of soft hemostatic antioxidant conductive HA-DA/rGO@polydopamine (PDA) hydrogel preparation, macroscopic characteristics, and implantation at the wound site. Scale bar: 5 mm. (ii) Pictures of wounds at days 3, 7, and 14 post-implantation. (iii) Granulation tissue (red arrows) thickness for the different groups on day 14 post-implantation. Scale bar: 500 µm. Tegaderm: commercial film dressing (control); HA-DA/rGO0: HA-DA hydrogel in the absence of rGO, HA-DA/rGO3; HA-DA hydrogel cross-linked with rGO@PDA, HA-DA/rGO3/Doxy: doxycycline-loaded HA-DA/rGO@PDA hydrogel. Adapted with permission, Copyright 2019, John Wiley and Sons (Liang et al., 2019). (D) In vivo study of conductive 3D-printed PCL/MWCNTs scaffolds for bone tissue engineering. (i) Schematic illustration of the experimental setup: synthesis of the conductive scaffolds and their implantation with electrical stimulation (ES) treatment. (ii) Bone defect formation in the animal model and bone tissue formation with and without conductive scaffold after 60 days. (iii) Cross-section histological images of bone tissue formation at the bone defect for all groups (PCL, PCL/MWCNTs 0.75% wt and PCL/MWCNTs 3% wt) after 60 and 120 days, with and without electrical stimulation (ES). Adapted from eSilva et al. (2021), Copyright 2022, Springer Nature.</figcaption></figure>

high hydrogel-tissue integration and homogenous electrical conductivity. These combined hydrogel/patch approaches featured good biodegradability of both materials upon in vivo implantation and a more pronounced improvement of the conductive functions, in terms of electrophysiological, histological, and antigenic outcomes when compared to single-mode systems (cardiac patch or injectable hydrogel) (Wu et al., 2020).

### 4.3.3 Nerve tissue engineering

Nerves' regrowth upon injury can be slow and often results in incomplete functional recovery as a consequence of the limited nervous tissue regenerative capacity. Endogenous and external electrical stimulations have been shown to promote nerve growth, enhance axonal regeneration, and guide the direction of nerve growth. Similar to cardiac tissue, recent studies have shown that conductive hydrogels can be used as electrical stimulators and
greatly promote neural cell proliferation, elongation, orientation, and neuronal differentiation, making these scaffolds promising for tissue repair (Rogers et al., 2020; Gao et al., 2022). Notably, conductive hydrogels employed as structural and electrical “functional bridges” at the lesion site could stimulate new neurogenesis and subsequent functional neural network formation. Such hydrogels are also the most suitable candidates for delivering stem cells, retaining and protecting cells after injection at the target tissue, and even directing the differentiation of neural stem cells by fine-tuning the modulus and conductivity of hydrogels. Notably, electrical stimulation in the presence of neural stem cells (NSCs) has been demonstrated to enhance their differentiation toward a neuron-like phenotype, as evidenced by a general increase in TuJ1 expression and the development of longer neurites, promoting neuronal differentiation over astrocyte differentiation (lower GFAP levels of expression) (Zhu et al., 2019; Sordini et al., 2021).

Spinal cord injury is a serious and disabling health issue that causes loss of motor functioning and sensing. It causes neural necrosis and axonal disruption with a low to null regenerative capacity. Implantation of injectable conductive hydrogels can restore the spinal cord by providing physiologically relevant electrical signal pathways (estimated to be 8–100 S cm⁻¹ for the spinal cord). The promotion of specific cell proliferation and differentiation at the injured site has been shown to be a promising clinical treatment. Liu et al. (2023) developed injectable, biodegradable, and self-healing hydrogel scaffolds based on aniline tetramer grafted onto oxidized hyaluronic acid and amino-modified gelatin, eventually loaded with NSCs (Figure 9B). The resulting hydrogels displayed electroconductive (134 S cm⁻¹) and mechanical (G' = 446 Pa) properties that matched the natural spinal cord values. When injected into the back skin tissue of Sprague-Dawley rats, it showed good compatibility and complete degradation after 16 days (aniline tetramer is generally metabolized in physiological environments). Furthermore, when injected in a rat model of total spinal cord resection, the loaded NSCs differentiated into neurons and further grew into new nerve axons. The self-healing properties, together with the good conductivity of the hydrogel scaffold promoted endogenous neurogenesis, by providing continuous tissue electro-activity, which finally led to nerve regeneration and locomotor function recovery. Notably, the controlled degradation rate of the hydrogel allowed the complete axon integration within the tissue, without hindering their prior growth and connection (Liu H. et al., 2023). Similarly, Luo et al. (2022) developed an ECM-mimic hydrogel composed of borax-functionalized oxidized chondroitin sulfate, PPy, and gelatin, featuring injectable, self-healing properties (Schiff-base and borate-diol ester dynamic bonds), as well as physiologically relevant electrical (50 S cm⁻¹ conductivity) and mechanical (G' = 930 Pa) properties. The injection of such hydrogels into the injury site to fill the lesion cavity promoted endogenous neural stem cells’ neurogenesis and induced myelinated axon regeneration into the lesion site, thereby achieving significant locomotor function restoration in rats with spinal cord injury. Hydrogel degradation occurred within 21 days post-implantation (into rat subcutaneous tissue) with no histological damage to major organs (kidney, heart, liver, and spleen) (Luo et al., 2022). Furthermore, external electrical stimulation was proven to

enhance recovery of nerve injuries. Zhang et al. (2021) developed a wireless method for spinal cord regeneration by developing magneto-metric Fe₃O₄ Ba TiO₃ NP loaded with biodegradable ECM-like HA/collagen hydrogels and used an external magnetic field to induce electrical stimulation. Transplantation of this scaffold with wireless stimulation in the rat hemi-section spinal cord injury model showed the promotion of neural regeneration and paved the way for non-invasive remote control electrical devices for soft tissue stimulation. Contrary to the central nervous system, the peripheral nervous system has a good regenerative capacity after injury. Nevertheless, the complete restoration of nerve defects remains a big clinical challenge due to the side effects related to the use of autologous grafts as the golden standard, such as donor shortages, rejection, and infection risks. In the framework of tissue engineering, nerve guidance conduits (NGCs) are promising alternatives to nerve auto-grafting (Vijayavenkataraman, 2020). NGCs are generally tubular polymeric scaffolds that act as functional bridges between the injured nerve endings, providing structural and trophic support for the axon reconstruction along the conduit. As such, the requirements for an ideal NGC include suitable mechanical properties and structural support for promoting the longitudinal alignment of the new axons, high porosity, biocompatibility, and electrical conductivity. In this regard, an NGC made of PEDOT NPs incorporated in a tetrapeptide-modified chitin hydrogel was developed (Huang et al., 2021). The incorporation of PEDOT NPs, together with the highly porous structure of the hydrogel film, significantly promoted sciatic nerve regeneration after 20 weeks, featuring gastrocnemius muscle restoration and thickness of myelinated axon, similar to the auto-graft control groups. Despite the promising results, data on the conductive hydrogel degradation rates were reported only for in vitro experiments. Park et al. (2020) developed conductive NGCs by polymerizing in situ a GelMA/GO composite hydrogel using an annulus mold and further chemically reducing it to the r(GO/ GelMA) form under mild conditions. The obtained material featured suitable mechanical stability (57 kPa Young’s modulus), permeability, flexibility, and electrical conductivity (90 S cm⁻¹) for nerve restoration. In vitro, the hydrogel at its reduced form r(GO/ GelMA) displayed remarkable neurogenesis capacity compared to the non-reduced form and pristine GelMA hydrogel, likely due to the electroactive interaction of rGO within the hydrogel. In vivo studies with a 10-mm peripheral defect model showed that the r(GO/GelMA) material significantly promotes neural regrowth, myelination, and functional regeneration of muscle and nerve tissues within 8 weeks post-implantation, without significant toxicity to other major organs. Nevertheless, at week 8, the r(GO/GelMA) hydrogel was only partially degraded at the implantation site (Pyarasani et al., 2019). Despite encouraging in vitro data on the degradation kinetics of hydrogel, future long-term investigations on material degradation and its systemic toxicity are necessary.

### 4.3.4 Wound dressing and skin repair

Similar to the myocardium and nerves, the skin also exhibits sensitivity to electrical signals, characterized by a conductivity ranging from 2.6 to $1 \times 10^{-7}$ S cm⁻¹. In intact skin, the epithelial tissue transports ions to the epidermis to form a transdermal potential (~10–60 mV). When a wound occurs, the homeostatic
greatly promote neural cell proliferation, elongation, orientation, and neuronal differentiation, making these scaffolds promising for tissue repair (Rogers et al., 2020; Gao et al., 2022). Notably, conductive hydrogels employed as structural and electrical “functional bridges” at the lesion site could stimulate new neurogenesis and subsequent functional neural network formation. Such hydrogels are also the most suitable candidates for delivering stem cells, retaining and protecting cells after injection at the target tissue, and even directing the differentiation of neural stem cells by fine-tuning the modulus and conductivity of hydrogels. Notably, electrical stimulation in the presence of neural stem cells (NSCs) has been demonstrated to enhance their differentiation toward a neuron-like phenotype, as evidenced by a general increase in TuJ1 expression and the development of longer neurites, promoting neuronal differentiation over astrocyte differentiation (lower GFAP levels of expression) (Zhu et al., 2019; Sordini et al., 2021).

Spinal cord injury is a serious and disabling health issue that causes loss of motor functioning and sensing. It causes neural necrosis and axonal disruption with a low to null regenerative capacity. Implantation of injectable conductive hydrogels can restore the spinal cord by providing physiologically relevant electrical signal pathways (estimated to be 8–100 S cm⁻¹ for the spinal cord). The promotion of specific cell proliferation and differentiation at the injured site has been shown to be a promising clinical treatment. Liu et al. (2023) developed injectable, biodegradable, and self-healing hydrogel scaffolds based on aniline tetramer grafted onto oxidized hyaluronic acid and amino-modified gelatin, eventually loaded with NSCs (Figure 9B). The resulting hydrogels displayed electroconductive (134 S cm⁻¹) and mechanical (G' = 446 Pa) properties that matched the natural spinal cord values. When injected into the back skin tissue of Sprague-Dawley rats, it showed good compatibility and complete degradation after 16 days (aniline tetramer is generally metabolized in physiological environments). Furthermore, when injected in a rat model of total spinal cord resection, the loaded NSCs differentiated into neurons and further grew into new nerve axons. The self-healing properties, together with the good conductivity of the hydrogel scaffold promoted endogenous neurogenesis, by providing continuous tissue electro-activity, which finally led to nerve regeneration and locomotor function recovery. Notably, the controlled degradation rate of the hydrogel allowed the complete axon integration within the tissue, without hindering their prior growth and connection (Liu H. et al., 2023). Similarly, Luo et al. (2022) developed an ECM-mimic hydrogel composed of borax-functionalized oxidized chondroitin sulfate, PPy, and gelatin, featuring injectable, self-healing properties (Schiff-base and borate-diol ester dynamic bonds), as well as physiologically relevant electrical (50 S cm⁻¹ conductivity) and mechanical (G' = 930 Pa) properties. The injection of such hydrogels into the injury site to fill the lesion cavity promoted endogenous neural stem cells’ neurogenesis and induced myelinated axon regeneration into the lesion site, thereby achieving significant locomotor function restoration in rats with spinal cord injury. Hydrogel degradation occurred within 21 days post-implantation (into rat subcutaneous tissue) with no histological damage to major organs (kidney, heart, liver, and spleen) (Luo et al., 2022). Furthermore, external electrical stimulation was proven to

enhance recovery of nerve injuries. Zhang et al. (2021) developed a wireless method for spinal cord regeneration by developing magneto-metric Fe₃O₄ Ba TiO₃ NP loaded with biodegradable ECM-like HA/collagen hydrogels and used an external magnetic field to induce electrical stimulation. Transplantation of this scaffold with wireless stimulation in the rat hemi-section spinal cord injury model showed the promotion of neural regeneration and paved the way for non-invasive remote control electrical devices for soft tissue stimulation. Contrary to the central nervous system, the peripheral nervous system has a good regenerative capacity after injury. Nevertheless, the complete restoration of nerve defects remains a big clinical challenge due to the side effects related to the use of autologous grafts as the golden standard, such as donor shortages, rejection, and infection risks. In the framework of tissue engineering, nerve guidance conduits (NGCs) are promising alternatives to nerve auto-grafting (Vijayavenkataraman, 2020). NGCs are generally tubular polymeric scaffolds that act as functional bridges between the injured nerve endings, providing structural and trophic support for the axon reconstruction along the conduit. As such, the requirements for an ideal NGC include suitable mechanical properties and structural support for promoting the longitudinal alignment of the new axons, high porosity, biocompatibility, and electrical conductivity. In this regard, an NGC made of PEDOT NPs incorporated in a tetrapeptide-modified chitin hydrogel was developed (Huang et al., 2021). The incorporation of PEDOT NPs, together with the highly porous structure of the hydrogel film, significantly promoted sciatic nerve regeneration after 20 weeks, featuring gastrocnemius muscle restoration and thickness of myelinated axon, similar to the auto-graft control groups. Despite the promising results, data on the conductive hydrogel degradation rates were reported only for in vitro experiments. Park et al. (2020) developed conductive NGCs by polymerizing in situ a GelMA/GO composite hydrogel using an annulus mold and further chemically reducing it to the r(GO/ GelMA) form under mild conditions. The obtained material featured suitable mechanical stability (57 kPa Young’s modulus), permeability, flexibility, and electrical conductivity (90 S cm⁻¹) for nerve restoration. In vitro, the hydrogel at its reduced form r(GO/ GelMA) displayed remarkable neurogenesis capacity compared to the non-reduced form and pristine GelMA hydrogel, likely due to the electroactive interaction of rGO within the hydrogel. In vivo studies with a 10-mm peripheral defect model showed that the r(GO/GelMA) material significantly promotes neural regrowth, myelination, and functional regeneration of muscle and nerve tissues within 8 weeks post-implantation, without significant toxicity to other major organs. Nevertheless, at week 8, the r(GO/GelMA) hydrogel was only partially degraded at the implantation site (Pyarasani et al., 2019). Despite encouraging in vitro data on the degradation kinetics of hydrogel, future long-term investigations on material degradation and its systemic toxicity are necessary.

### 4.3.4 Wound dressing and skin repair

Similar to the myocardium and nerves, the skin also exhibits sensitivity to electrical signals, characterized by a conductivity ranging from 2.6 to 1 × 10⁻⁷ S cm⁻¹. In intact skin, the epithelial tissue transports ions to the epidermis to form a transdermal potential (~10–60 mV). When a wound occurs, the homeostatic
balance of the transdermal potential is disrupted, resulting in a potential decrease at the wound site and the formation of positive currents flowing toward the wound center. As a result, the formation of these endogenous electric fields promotes cellular recruitment and proliferation at the wound site, following the electrical gradient (electrotaxis), until complete wound healing is achieved, and the initial transdermal potential is restored (Shaner et al., 2023).

Therefore, to enhance such a regenerative capacity of the skin and accelerate the healing process, conductive hydrogel dressings can be employed. Such materials applied at the wound site should possess multifunctional properties. Notably, conductive dressings should exhibit adhesiveness to secure the dressing, possess antibacterial properties to prevent infections, scavenge radicals to minimize oxidative stress, and have sufficient conductivity and good mechanical properties to support cell migration, proliferation, and tissue regeneration. In this context, a series of soft hemostatic antioxidant conductive hydrogels based on HA-graft-dopamine and rGO have been developed (Liang et al., 2019) (Figure 9C). *In vivo*, the injected hydrogels showed high tissue adhesive properties, viscoelasticity, conductivity, and hemostatic ability. The hydrogel dressing showed substantial tissue repair after 7 days of treatment in a mouse full-thickness skin defect repair model, accelerating epidermal remodeling and promoting neovascularization at the lesion site. Furthermore, *in vitro* drug release studies in physiological conditions and zone of inhibition tests of antibiotics-loaded hydrogels showed a promising sustained drug release capacity of these hydrogels (Liang et al., 2019).

Apart from the re-establishment of the skin's endogenous electrical field through conductive dressing, the application of an external electrical field can also improve wound healing. Lei et al. (2021) developed an adaptive conductive hydrogel by incorporating tannic acid and human-like collagen into a polyvinyl alcohol and borax hydrogel dynamic cross-linking network. The dynamicity of the bonds imparted the hydrogel with self-healing and self-adaptive behavior at the wound site, which facilitated cell-to-cell signaling, promoted hemostatic repair, and maintained hydrogel structural and functional capacity. Furthermore, such adaptive behavior allowed endogenous and external current conduction, promoting electrostimulation in wound tissue. The combination of electrostimulation and hydrogel greatly promoted L929 cell migration and proliferation and *in vivo* wound healing, with subcutaneous tissue (blood vessels and pores) reconstruction. *In vivo* degradability tests showed gradual and complete hydrolytic degradation of the hydrogel in accordance with wound repair, avoiding any possible secondary damage due to adhesive peeling (Lei et al., 2021). Interestingly, the incorporation of additional characteristics into these electroconductive hydrogels could impart them with superior regenerative capabilities for a broad range of tissue engineering applications. In this context, Li et al. (2020) developed biomechanically active conductive hydrogels that could promote wound healing through the combination of biomechanical and biochemical functions. By combining quaternized chitosan, poly(dopamine)-coated reduction graphene oxide and poly(N-isopropylacrylamide), a series of multifunctional, injectable hydrogels have been developed. While the biochemical characteristics provided the hydrogels with self-healing, antioxidant, and adhesive properties, as well as good conductivity, the self-

contraction ability of the poly(N-isopropylacrylamide) in response to temperature changes played a crucial role in wound closure, leading to a significant improvement in tissue restoration in an *in vivo* full-thickness skin defect (Li et al., 2020).

### 4.3.5 Bone tissue engineering

Bone has a naturally good regenerative capacity to recover small bone defects; however, larger fractures generally require external intervention to restore the damaged tissue (Schemitsch, 2017). In this context, bone tissue engineering demands the creation of biocompatible, osteogenic scaffolds, which can sustain the dynamic nature and irregular structure of the microenvironment of the bone. These scaffolds should allow bone tissue remodeling and regeneration, providing physicochemical properties for osteoblast attachment, strong mechanical properties, and scaffold mineralization. Bone tissue engineering undergoes a process initiated by the migration and recruitment of bone cells, subsequently followed by proliferation, differentiation, and matrix formation (calcium deposition) (Mostafavi et al., 2020). Electrical stimuli play a key role in a broad spectrum of biological processes involved in bone regeneration, such as angiogenesis, cell division, and signaling. In this context, conductive hydrogels have been shown to effectively stimulate and sustain the effect of endogenous electric fields in bone tissue repair (Arambula-Maldonado et al., 2022).

In order to increase scaffold elastic modulus, roughness, and conductivity, the main strategy consists of the development of functional hybrid hydrogel/fiber composites. Notably, the combination of fibrous PANI in a graphene-containing hydrogel demonstrated that the inclusion of conducting fibers yielded materials that better supported human osteoblast-like cell adhesion, proliferation, and morphology when compared to hydrogel alone (Khorshidi et al., 2018). However, considerations on the *in vivo* biological toxicity of PANI, especially in the form of fiber, must be taken into account. On the other hand, the introduction of GO to porous hydrogel matrices was shown to significantly improve the efficiency of the mineralization process through electrostatic interactions, which sustained crystal growth and apatite deposition. In another study, β-cyclodextrin (β-CD)-functionalized rGO was used as a conductive component and mixed with GelMA/acryloyl-β-cyclodextrin (Ac-CD)-based photo-cross-linked hydrogel (Li et al., 2022). Such a hydrogel was shown to accelerate the *in vivo* defect repair in a rat skull defect model by promoting collagen deposition and mineralization. *In vitro* degradation tests confirmed the ability of the hydrogels to provide adequate mechanical and structural support in the early stages and to subsequently undergo gradual degradation, providing a good foundation for *in vivo* bone repair (Li et al., 2022).

Recently, conductive scaffolds were also obtained through the incorporation of multi-walled carbon nanotubes (MWCNTs) in a biodegradable PCL hydrogel and cut to fit the bone defect in rat skull models (eSilva et al., 2021) (Figure 9D). Upon exogenous electrical stimulation over a period of 120 days, thicker bone tissue reformation was observed, along with angiogenesis and mineralization. In particular, the combination of conductive hydrogel and electrostimulation was shown to play an important role in bone remodeling, inducing osteoclast formation and functioning.
balance of the transdermal potential is disrupted, resulting in a potential decrease at the wound site and the formation of positive currents flowing toward the wound center. As a result, the formation of these endogenous electric fields promotes cellular recruitment and proliferation at the wound site, following the electrical gradient (electrotaxis), until complete wound healing is achieved, and the initial transdermal potential is restored (Shaner et al., 2023).

Therefore, to enhance such a regenerative capacity of the skin and accelerate the healing process, conductive hydrogel dressings can be employed. Such materials applied at the wound site should possess multifunctional properties. Notably, conductive dressings should exhibit adhesiveness to secure the dressing, possess antibacterial properties to prevent infections, scavenge radicals to minimize oxidative stress, and have sufficient conductivity and good mechanical properties to support cell migration, proliferation, and tissue regeneration. In this context, a series of soft hemostatic antioxidant conductive hydrogels based on HA-graft-dopamine and rGO have been developed (Liang et al., 2019) (Figure 9C). *In vivo*, the injected hydrogels showed high tissue adhesive properties, viscoelasticity, conductivity, and hemostatic ability. The hydrogel dressing showed substantial tissue repair after 7 days of treatment in a mouse full-thickness skin defect repair model, accelerating epidermal remodeling and promoting neovascularization at the lesion site. Furthermore, *in vitro* drug release studies in physiological conditions and zone of inhibition tests of antibiotics-loaded hydrogels showed a promising sustained drug release capacity of these hydrogels (Liang et al., 2019).

Apart from the re-establishment of the skin's endogenous electrical field through conductive dressing, the application of an external electrical field can also improve wound healing. Lei et al. (2021) developed an adaptive conductive hydrogel by incorporating tannic acid and human-like collagen into a polyvinyl alcohol and borax hydrogel dynamic cross-linking network. The dynamicity of the bonds imparted the hydrogel with self-healing and self-adaptive behavior at the wound site, which facilitated cell-to-cell signaling, promoted hemostatic repair, and maintained hydrogel structural and functional capacity. Furthermore, such adaptive behavior allowed endogenous and external current conduction, promoting electrostimulation in wound tissue. The combination of electrostimulation and hydrogel greatly promoted L929 cell migration and proliferation and *in vivo* wound healing, with subcutaneous tissue (blood vessels and pores) reconstruction. *In vivo* degradability tests showed gradual and complete hydrolytic degradation of the hydrogel in accordance with wound repair, avoiding any possible secondary damage due to adhesive peeling (Lei et al., 2021). Interestingly, the incorporation of additional characteristics into these electroconductive hydrogels could impart them with superior regenerative capabilities for a broad range of tissue engineering applications. In this context, Li et al. (2020) developed biomechanically active conductive hydrogels that could promote wound healing through the combination of biomechanical and biochemical functions. By combining quaternized chitosan, poly(dopamine)-coated reduction graphene oxide and poly(N-isopropylacrylamide), a series of multifunctional, injectable hydrogels have been developed. While the biochemical characteristics provided the hydrogels with self-healing, antioxidant, and adhesive properties, as well as good conductivity, the self-

contraction ability of the poly(N-isopropylacrylamide) in response to temperature changes played a crucial role in wound closure, leading to a significant improvement in tissue restoration in an *in vivo* full-thickness skin defect (Li et al., 2020).

### 4.3.5 Bone tissue engineering

Bone has a naturally good regenerative capacity to recover small bone defects; however, larger fractures generally require external intervention to restore the damaged tissue (Schemitsch, 2017). In this context, bone tissue engineering demands the creation of biocompatible, osteogenic scaffolds, which can sustain the dynamic nature and irregular structure of the microenvironment of the bone. These scaffolds should allow bone tissue remodeling and regeneration, providing physicochemical properties for osteoblast attachment, strong mechanical properties, and scaffold mineralization. Bone tissue engineering undergoes a process initiated by the migration and recruitment of bone cells, subsequently followed by proliferation, differentiation, and matrix formation (calcium deposition) (Mostafavi et al., 2020). Electrical stimuli play a key role in a broad spectrum of biological processes involved in bone regeneration, such as angiogenesis, cell division, and signaling. In this context, conductive hydrogels have been shown to effectively stimulate and sustain the effect of endogenous electric fields in bone tissue repair (Arambula-Maldonado et al., 2022).

In order to increase scaffold elastic modulus, roughness, and conductivity, the main strategy consists of the development of functional hybrid hydrogel/fiber composites. Notably, the combination of fibrous PANI in a graphene-containing hydrogel demonstrated that the inclusion of conducting fibers yielded materials that better supported human osteoblast-like cell adhesion, proliferation, and morphology when compared to hydrogel alone (Khorshidi et al., 2018). However, considerations on the *in vivo* biological toxicity of PANI, especially in the form of fiber, must be taken into account. On the other hand, the introduction of GO to porous hydrogel matrices was shown to significantly improve the efficiency of the mineralization process through electrostatic interactions, which sustained crystal growth and apatite deposition. In another study, β-cyclodextrin (β-CD)-functionalized rGO was used as a conductive component and mixed with GelMA/acryloyl-β-cyclodextrin (Ac-CD)-based photo-cross-linked hydrogel (Li et al., 2022). Such a hydrogel was shown to accelerate the *in vivo* defect repair in a rat skull defect model by promoting collagen deposition and mineralization. *In vitro* degradation tests confirmed the ability of the hydrogels to provide adequate mechanical and structural support in the early stages and to subsequently undergo gradual degradation, providing a good foundation for *in vivo* bone repair (Li et al., 2022).

Recently, conductive scaffolds were also obtained through the incorporation of multi-walled carbon nanotubes (MWCNTs) in a biodegradable PCL hydrogel and cut to fit the bone defect in rat skull models (eSilva et al., 2021) (Figure 9D). Upon exogenous electrical stimulation over a period of 120 days, thicker bone tissue reformation was observed, along with angiogenesis and mineralization. In particular, the combination of conductive hydrogel and electrostimulation was shown to play an important role in bone remodeling, inducing osteoclast formation and functioning.
# 5 Challenges and perspectives

As shown in this review, the field of resorbable conductive materials applied to biomedical applications is emerging and already fast expanding, giving rise to a growing interest in the community of advanced medical devices and tissue engineering. This is shown by the large number of publications in the domain reported in this review, and their novelty (>75% in the last 5 years, >95% since 2013). The field of resorbable bioelectronic systems is relatively young compared to chronic implantable devices such as pacemakers, deep brain stimulators, neural stimulators, or cochlear implants. However, there exist already several proofs of concept at the *in vitro* and preclinical (mainly in rodents) stages. The fact that implanted systems may be designed as resorbable is expected to extend their use to non-chronic pathologies requiring transient therapy and/or monitoring. Tissue engineering applications are quite novel in general, and the use of conductive materials will help address important applications (for instance tissue healing and heart and nerve reconstruction) that are still at the proof-of-concept stage. Therefore, it can be foreseen that the requirement for resorbable conductive materials that can optimally interface with tissues or act as tissue substitutes will quickly expand in the coming decades.

Another striking point that appears through this overview is the variety of employed polymer substrates/scaffolds, electrical conductors, and processes, which can be used to obtain resorbable conductive materials. This is largely accounted for by not only the large range of addressed biomedical applications but also the wide panoply of available components (scaffolds and electrical conductors) that allow choosing different strategies to design and fabricate resorbable bioelectronic systems, implants, or tissue substitutes. The variety of proposed approaches in the domain is interesting in order to meet the different challenges yet to be addressed.

Technical challenges concern the fabrication processes, stretchability and conformability of the devices, as well as material conductivity. In addition, communication of the implanted device with the external world has to be addressed in terms of electric and power connectivity, as well as for eventual information transfer. Concerning the fabrication process, the adhesion between different device layers, or at the interface between metals and polymers, for instance, can still be an issue, with poor adhesion or delamination being a source of low electrical contact (and hence low device performance) and/or premature degradation. For certain applications, such as spinal cord stimulation or recording, the stretchability of the device is key. The more stretchable it is, the better it can withstand large displacements and torsions in the spine during movements. In this perspective of high stretchability/conformability to tissues, conducting polymer-based materials, thanks to their mechanical and structural properties, appear very interesting in designing electrical tracks or contact electrodes. However, their electrical conductivity is still several orders of magnitude below the ones of resorbable metals. Therefore, innovative chemical designs are still intensively sought to achieve conductive materials presenting simultaneously features of high conductivity, stretchability, and biocompatibility.

Another challenge concerns the identification of relevant medical applications that will boost scientific and technical developments, in particular in the field of resorbable implanted bioelectronic systems. For instance, if the resorbable pacemaker prototype proposed by the group of Rogers (Choi et al., 2021) is a remarkable technical achievement,

doubt can exist concerning its medical relevance. However, relevant applications of resorbable implanted bioelectronic systems are foreseen in the fields of i) minimally invasive transient monitoring (wearable devices and microneedle-based devices), ii) post-surgery transient monitoring and drug delivery [e.g., for the prevention/detection of infections, the follow-up of orthopedic surgery (bone fracture and prosthesis implantation), and the assessment of flaps resection and anastomosis], and iii) electrical stimulation for the healing of the skin or internal tissue wounds, or for muscular recovery and reinforcement. At the present time, the reported studies mainly appear to be supported by technical research groups rather than by medical teams. The technical signs of progress and first preclinical proofs of concept of devices, implants, and tissue substitutes based on resorbable conductive materials will hopefully pique clinicians' interest and will lead to the emergence of new applications of these materials.

Concerning the clinical translation challenge, in addition to the identification of relevant medical applications that are already emerging, the main task remains the demonstration of the full resorbability of devices or full integration of tissue substitutes, without any acute or long-term side effects, and the safety of the employed materials. The scaffolds/substrates and electrical conductors that have been described in Section 2 of this review have been reported as “biocompatible” and “resorbable,” but it has to be reminded that material safety has to be evaluated according to its dose, its precise preparation process, its location of implantation into the body and its residence time, its metabolism pathway, its degradation products, and possible migration away from its site of implantation. Some of the described materials are highly questionable, such as CNTs (Mishra et al., 2018) and ZnO or Zn (that will oxide in zinc oxide during its degradation process) (Xia et al., 2008; Jin et al., 2021). In presently reported studies, the resorbability of the materials is mainly assessed qualitatively by photographs or/and indirectly by the measurement of physical parameters such as impedance for an electrical contact, or a quality factor for an antenna. Safety evaluations involve the immunostaining and histology of tissue sections that come into contact with the devices or tissue substitutes. If such preliminary results, which already represent a huge amount of work, can be satisfactory in the first stage of the development of a resorbable material or device, further investigations will be required to enable the translation to the clinic. They include i) the evaluation of the dissolution rate of the material and the comparison of the employed dose with the toxicity intake limits given in meta-analysis databases such as https://pubchem.ncbi.nlm.nih.gov/; ii) the study of the metabolism pathways and identification of the degradation products of the conductive material; iii) the assessment of the biodistribution and the clearance of the material components and degradation products with time in the different organs; and iv) the study of potential side effects in the short and long terms. Another consideration to take into account is that the degradation rate of the material should be aligned as best as possible to its targeted use to minimize risks.

In conclusion, resorbable conductive materials already appear to have a bright future in biomedical applications and serve different purposes in the design of tissue substitutes and optimized interfaces between tissues and medical devices. This already very active research field should expand in the coming years, with intensive work to improve the performances of the materials to simultaneously present features of high conductivity, stretchability/conformability, and
# 5 Challenges and perspectives

As shown in this review, the field of resorbable conductive materials applied to biomedical applications is emerging and already fast expanding, giving rise to a growing interest in the community of advanced medical devices and tissue engineering. This is shown by the large number of publications in the domain reported in this review, and their novelty (>75% in the last 5 years, >95% since 2013). The field of resorbable bioelectronic systems is relatively young compared to chronic implantable devices such as pacemakers, deep brain stimulators, neural stimulators, or cochlear implants. However, there exist already several proofs of concept at the *in vitro* and preclinical (mainly in rodents) stages. The fact that implanted systems may be designed as resorbable is expected to extend their use to non-chronic pathologies requiring transient therapy and/or monitoring. Tissue engineering applications are quite novel in general, and the use of conductive materials will help address important applications (for instance tissue healing and heart and nerve reconstruction) that are still at the proof-of-concept stage. Therefore, it can be foreseen that the requirement for resorbable conductive materials that can optimally interface with tissues or act as tissue substitutes will quickly expand in the coming decades.

Another striking point that appears through this overview is the variety of employed polymer substrates/scaffolds, electrical conductors, and processes, which can be used to obtain resorbable conductive materials. This is largely accounted for by not only the large range of addressed biomedical applications but also the wide panoply of available components (scaffolds and electrical conductors) that allow choosing different strategies to design and fabricate resorbable bioelectronic systems, implants, or tissue substitutes. The variety of proposed approaches in the domain is interesting in order to meet the different challenges yet to be addressed.

Technical challenges concern the fabrication processes, stretchability and conformability of the devices, as well as material conductivity. In addition, communication of the implanted device with the external world has to be addressed in terms of electric and power connectivity, as well as for eventual information transfer. Concerning the fabrication process, the adhesion between different device layers, or at the interface between metals and polymers, for instance, can still be an issue, with poor adhesion or delamination being a source of low electrical contact (and hence low device performance) and/or premature degradation. For certain applications, such as spinal cord stimulation or recording, the stretchability of the device is key. The more stretchable it is, the better it can withstand large displacements and torsions in the spine during movements. In this perspective of high stretchability/conformability to tissues, conducting polymer-based materials, thanks to their mechanical and structural properties, appear very interesting in designing electrical tracks or contact electrodes. However, their electrical conductivity is still several orders of magnitude below the ones of resorbable metals. Therefore, innovative chemical designs are still intensively sought to achieve conductive materials presenting simultaneously features of high conductivity, stretchability, and biocompatibility.

Another challenge concerns the identification of relevant medical applications that will boost scientific and technical developments, in particular in the field of resorbable implanted bioelectronic systems. For instance, if the resorbable pacemaker prototype proposed by the group of Rogers (Choi et al., 2021) is a remarkable technical achievement,

doubt can exist concerning its medical relevance. However, relevant applications of resorbable implanted bioelectronic systems are foreseen in the fields of i) minimally invasive transient monitoring (wearable devices and microneedle-based devices), ii) post-surgery transient monitoring and drug delivery [e.g., for the prevention/detection of infections, the follow-up of orthopedic surgery (bone fracture and prosthesis implantation), and the assessment of flaps resection and anastomosis], and iii) electrical stimulation for the healing of the skin or internal tissue wounds, or for muscular recovery and reinforcement. At the present time, the reported studies mainly appear to be supported by technical research groups rather than by medical teams. The technical signs of progress and first preclinical proofs of concept of devices, implants, and tissue substitutes based on resorbable conductive materials will hopefully pique clinicians' interest and will lead to the emergence of new applications of these materials.

Concerning the clinical translation challenge, in addition to the identification of relevant medical applications that are already emerging, the main task remains the demonstration of the full resorbability of devices or full integration of tissue substitutes, without any acute or long-term side effects, and the safety of the employed materials. The scaffolds/substrates and electrical conductors that have been described in Section 2 of this review have been reported as "biocompatible" and "resorbable," but it has to be reminded that material safety has to be evaluated according to its dose, its precise preparation process, its location of implantation into the body and its residence time, its metabolism pathway, its degradation products, and possible migration away from its site of implantation. Some of the described materials are highly questionable, such as CNTs (Mishra et al., 2018) and ZnO or Zn (that will oxide in zinc oxide during its degradation process) (Xia et al., 2008; Jin et al., 2021). In presently reported studies, the resorbability of the materials is mainly assessed qualitatively by photographs or/and indirectly by the measurement of physical parameters such as impedance for an electrical contact, or a quality factor for an antenna. Safety evaluations involve the immunostaining and histology of tissue sections that come into contact with the devices or tissue substitutes. If such preliminary results, which already represent a huge amount of work, can be satisfactory in the first stage of the development of a resorbable material or device, further investigations will be required to enable the translation to the clinic. They include i) the evaluation of the dissolution rate of the material and the comparison of the employed dose with the toxicity intake limits given in meta-analysis databases such as https://pubchem.ncbi.nlm.nih.gov/; ii) the study of the metabolism pathways and identification of the degradation products of the conductive material; iii) the assessment of the biodistribution and the clearance of the material components and degradation products with time in the different organs; and iv) the study of potential side effects in the short and long terms. Another consideration to take into account is that the degradation rate of the material should be aligned as best as possible to its targeted use to minimize risks.

In conclusion, resorbable conductive materials already appear to have a bright future in biomedical applications and serve different purposes in the design of tissue substitutes and optimized interfaces between tissues and medical devices. This already very active research field should expand in the coming years, with intensive work to improve the performances of the materials to simultaneously present features of high conductivity, stretchability/conformability, and
biocompatibility and to assess their safe use. These are the necessary conditions for their adoption into the clinics.

## Author contributions

MS: conceptualization, visualization, writing—original draft, and writing—review and editing. FS-S: conceptualization, writing—original draft, and writing—review and editing. PM: writing—review and editing and conceptualization. IT: conceptualization, visualization, writing—original draft, and writing—review and editing.

## Funding

The authors that declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the CEA internal funding "Organoids on chip" focus program (PhD grant for MS). LETI-DTIS was supported by the French National Research Agency in the framework of the

STRETCH project (ANR- 8-CE19-0018-01), the LabEx Arcane (grant ANR-17-EURE-0003) and Glyco@Alps (ANR-15-IDEX-02) programs.

## Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

## Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

## References

Abidian, M. R., Corey, J. M., Kipke, D. R., and Martin, D. C. (2010). Conducting-polymer nanotubes improve electrical properties, mechanical adhesion, neural attachment, and neurite outgrowth of neural electrodes. *Small* 6 (3), 421–429. doi:10.1002/smll.200901868

Abidian, M. R., Kim, D.-H., and Martin, D. C. (2006). Conducting-polymer nanotubes for controlled drug release. *Adv. Mater.* 18 (4), 405–409. doi:10.1002/adma.200501726

Abidian, M. R., Ludwig, K. A., Marzullo, T. C., Martin, D. C., and Kipke, D. R. (2009). Interfacing conducting polymer nanotubes with the central nervous system: chronic neural recording using poly(3,4-ethylenedioxythiophene) nanotubes. *Adv. Mater.* 21 (37), 3764–3770. doi:10.1002/adma.200900887

Abidian, M. R., and Martin, D. C. (2008). Experimental and theoretical characterization of implantable neural microelectrodes modified with conducting polymer nanotubes. *Biomaterials* 29 (9), 1273–1283. doi:10.1016/j.biomaterials.2007.11.022

Abu Ammar, A., Abdel-Haq, M., Abd-Rbo, K., and Kasem, H. (2021). Developing novel poly(lactic-Co-glycolic acid) (PLGA) films with enhanced adhesion capacity by biomimetic mushroom-shaped microstructures. *Biotribology* 27, 100184. doi:10.1016/j.biotri.2021.100184

Aghazadeh, M. R., Delfanian, S., Aghakhani, P., Homaeigohar, S., Alipour, A., and Shahsavarani, H. (2022). Recent advances in development of natural cellulosic non-woven scaffolds for tissue engineering. *Polymers* 14 (8), 5376. doi:10.3390/polym14081531

Alhashmi Alamer, F., and Almalki, G. A. (2022). Fabrication of conductive fabrics based on SWCNTs, MWCNTs and graphene and their applications: a review. *Polymers* 14 (24), 5376. doi:10.3390/polym14245376

Anand, P., Llewelyn, J. G., Thomas, P. K., Gillon, K. R. W., Lisk, R., and Bloom, S. R. (1988). Water content, vasoactive intestinal polypeptide and substance P in intact and crushed sciatic nerves of normal and streptozotocin-diabetic rats. *J. Neurological Sci.* 83 (2), 167–177. doi:10.1016/0022-510X(88)90066-4

Ansari, S., Sami, N., Yasin, D., Ahmad, N., and Fatma, T. (2021). Biomedical applications of environmental friendly poly-hydroxyalkanoates. *Int. J. Biol. Macromol.* 183, 549–563. doi:10.1016/j.ijbiomac.2021.04.171

Antensteiner, M., and Abidian, M. R. (2017b). "Tunable nanostructured conducting polymers for neural interface applications," in Proceedings of the 39th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), Jeju Island, South Korea, July 11-15, 2017, 1881–1884.

Antensteiner, M., Khorrami, M., Fallahian-bijan, F., Borhan, A., and Abidian, M. R. (2017a). Conducting polymer microcups for organic bioelectronics and drug delivery applications. *Adv. Mater.* 29 (39), 1702576. doi:10.1002/adma.201702576

Arambula-Maldonado, R., and Mequanint, K. (2022). Carbon-based electrically conductive materials for bone repair and regeneration. *Mater. Adv.* 3 (13), 5186–5206. doi:10.1039/d2ma00001f

Baker, A. E. G., Cui, H., Ballios, B. G., Ing, S., Yan, P., Wolfer, J., et al. (2021). Stable oxime-crosslinked hyaluronan-based hydrogel as a biomimetic vitreous substitute. *Biomaterials* 271, 120750. doi:10.1016/j.biomaterials.2021.120750

Balfourier, A., Luciani, N., Wang, G., Lelong, G., Ersen, O., Khelfa, A., et al. (2020). Unexpected intracellular biodegradation and recrystallization of gold nanoparticles. *Proc. Natl. Acad. Sci.* 117 (1), 103–113. doi:10.1073/pnas.1911734116

Ban, G., Hou, Y., Shen, Z., Jia, J., Chai, L., and Ma, C. (2023). Potential biomedical limitations of graphene nanomaterials. *Int. J. Nanomedicine* 18, 1695–1708. doi:10.2147/IJN.S402954

Bano, K., Pandey, R., and Roohi, J. (2018). New advancements of bioplastics in medical applications. *Int. J. Pharm. Sci. Res.* 9 (2), 402–416. doi:10.13040/IJPSR.0975-8232.9(2).402-16

Bao, R., Tan, B., Liang, S., Zhang, N., Wang, W., and Liu, W. (2017). A π-π conjugation-containing soft and conductive injectable polymer hydrogel highly efficiently rebuilds cardiac function after myocardial infarction. *Biomaterials* 122, 63–71. doi:10.1016/j.biomaterials.2017.01.012

Bashir, S., Hina, M., Iqbal, J., Rajpar, A. H., Mujtaba, M. A., Alghamdi, N. A., et al. (2020). Fundamental concepts of hydrogels: synthesis, properties, and their applications. *Polymers* 12 (11), 2702. doi:10.3390/polym12112702

Battigelli, A., Almeida, B., and Shukla, A. (2022). Recent advances in bioorthogonal click chemistry for biomedical applications. *Bioconjugate Chem.* 33 (2), 263–271. doi:10.1021/acs.bioconjchem.1c00564

Beygisangchin, M., Abdul Rashid, S., Shafie, S., Sadrolhoseini, A. R., and Lim, H. N. (2021). Preparations, properties, and applications of polyaniline and polyaniline thin films—a review. *Polymers* 13 (12), 2003. doi:10.3390/polym13122003

Bhat, M. A., Rather, R. A., and Shalla, A. H. (2021). PEDOT and PEDOT:PSS conducting polymeric hydrogels: a report on their emerging applications. *Synth. Met.* 273, 116709. doi:10.1016/j.synthmet.2021.116709

Bielfeldt, M., Rebl, H., Peters, K., Sridharan, K., Staehlke, S., and Nebe, J. B. (2022). Sensing of physical factors by cells: electric field, mechanical forces, physical plasma and light—importance for tissue regeneration. *Biomed. Mater. Devices* 1, 146–161. doi:10.1007/s44174-022-00028-x

Bilbao, E., Garate, O., Rodríguez Campos, T., Roberti, M., Mass, M., Lozano, A., et al. (2023). Electrochemical sweat sensors. *Chemosensors* 11 (4), 244. doi:10.3390/chemosensors11040244

Boehler, C., Agrawe, Z., and Asplund, M. (2019). Applications of PEDOT in bioelectronic medicine. *Bioelectron. Med.* 2 (2), 89–99. doi:10.2217/bem-2019-0014

Borriello, A., Guarino, V., Schiavo, L., Alvarez-Perez, M. A., and Ambrosio, L. (2011). Optimizing PANi doped electroactive substrates as patches for the regeneration of cardiac muscle. *J. Mater. Sci. Mater. Med.* 22 (4), 1053–1062. doi:10.1007/s10856-011-4259-x

Borschel, G. H., Kia, K. F., Kuzon, W. M., and Dennis, R. G. (2003). Mechanical properties of acellular peripheral nerve. *J. Surg. Res.* 114 (2), 133–139. doi:10.1016/S0022-4804(03)00255-5

Boutry, C. M., Kaizawa, Y., Schroeder, B. C., Chortos, A., Legrand, A., Wang, Z., et al. (2018). A stretchable and biodegradable strain and pressure sensor for orthopaedic application. *Nat. Electron.* 1 (5), 314–321. doi:10.1038/s41928-018-0071-7
biocompatibility and to assess their safe use. These are the necessary conditions for their adoption into the clinics.

## Author contributions

MS: conceptualization, visualization, writing—original draft, and writing—review and editing. FS-S: conceptualization, writing—original draft, and writing—review and editing. PM: writing—review and editing and conceptualization. IT: conceptualization, visualization, writing—original draft, and writing—review and editing.

## Funding

The authors that declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the CEA internal funding "Organoids on chip" focus program (PhD grant for MS). LETI-DTIS was supported by the French National Research Agency in the framework of the

STRETCH project (ANR- 8-CE19-0018-01), the LabEx Arcane (grant ANR-17-EURE-0003) and Glyco@Alps (ANR-15-IDEX-02) programs.

## Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

## Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

## References

Abidian, M. R., Corey, J. M., Kipke, D. R., and Martin, D. C. (2010). Conducting-polymer nanotubes improve electrical properties, mechanical adhesion, neural attachment, and neurite outgrowth of neural electrodes. *Small* 6 (3), 421–429. doi:10.1002/smll.200901868

Abidian, M. R., Kim, D.-H., and Martin, D. C. (2006). Conducting-polymer nanotubes for controlled drug release. *Adv. Mater.* 18 (4), 405–409. doi:10.1002/adma.200501726

Abidian, M. R., Ludwig, K. A., Marzullo, T. C., Martin, D. C., and Kipke, D. R. (2009). Interfacing conducting polymer nanotubes with the central nervous system: chronic neural recording using poly(3,4-ethylenedioxythiophene) nanotubes. *Adv. Mater.* 21 (37), 3764–3770. doi:10.1002/adma.200900887

Abidian, M. R., and Martin, D. C. (2008). Experimental and theoretical characterization of implantable neural microelectrodes modified with conducting polymer nanotubes. *Biomaterials* 29 (9), 1273–1283. doi:10.1016/j.biomaterials.2007.11.022

Abu Ammar, A., Abdel-Haq, M., Abd-Rbo, K., and Kasem, H. (2021). Developing novel poly(lactic-Co-glycolic acid) (PLGA) films with enhanced adhesion capacity by biomimetic mushroom-shaped microstructures. *Biotribology* 27, 100184. doi:10.1016/j.biotri.2021.100184

Aghazadeh, M. R., Delfanian, S., Aghakhani, P., Homaeigohar, S., Alipour, A., and Shahsavarani, H. (2022). Recent advances in development of natural cellulosic non-woven scaffolds for tissue engineering. *Polymers* 14 (8), 5376. doi:10.3390/polym14081531

Alhashmi Alamer, F., and Almalki, G. A. (2022). Fabrication of conductive fabrics based on SWCNTs, MWCNTs and graphene and their applications: a review. *Polymers* 14 (24), 5376. doi:10.3390/polym14245376

Anand, P., Llewelyn, J. G., Thomas, P. K., Gillon, K. R. W., Lisk, R., and Bloom, S. R. (1988). Water content, vasoactive intestinal polypeptide and substance P in intact and crushed sciatic nerves of normal and streptozotocin-diabetic rats. *J. Neurological Sci.* 83 (2), 167–177. doi:10.1016/0022-510X(88)90066-4

Ansari, S., Sami, N., Yasin, D., Ahmad, N., and Fatma, T. (2021). Biomedical applications of environmental friendly poly-hydroxyalkanoates. *Int. J. Biol. Macromol.* 183, 549–563. doi:10.1016/j.ijbiomac.2021.04.171

Antensteiner, M., and Abidian, M. R. (2017b). "Tunable nanostructured conducting polymers for neural interface applications," in Proceedings of the 39th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), Jeju Island, South Korea, July 11-15, 2017, 1881–1884.

Antensteiner, M., Khorrami, M., Fallahian-bijan, F., Borhan, A., and Abidian, M. R. (2017a). Conducting polymer microcups for organic bioelectronics and drug delivery applications. *Adv. Mater.* 29 (39), 1702576. doi:10.1002/adma.201702576

Arambula-Maldonado, R., and Mequanint, K. (2022). Carbon-based electrically conductive materials for bone repair and regeneration. *Mater. Adv.* 3 (13), 5186–5206. doi:10.1039/d2ma00001f

Baker, A. E. G., Cui, H., Ballios, B. G., Ing, S., Yan, P., Wolfer, J., et al. (2021). Stable oxime-crosslinked hyaluronan-based hydrogel as a biomimetic vitreous substitute. *Biomaterials* 271, 120750. doi:10.1016/j.biomaterials.2021.120750

Balfourier, A., Luciani, N., Wang, G., Lelong, G., Ersen, O., Khelfa, A., et al. (2020). Unexpected intracellular biodegradation and recrystallization of gold nanoparticles. *Proc. Natl. Acad. Sci.* 117 (1), 103–113. doi:10.1073/pnas.1911734116

Ban, G., Hou, Y., Shen, Z., Jia, J., Chai, L., and Ma, C. (2023). Potential biomedical limitations of graphene nanomaterials. *Int. J. Nanomedicine* 18, 1695–1708. doi:10.2147/IJN.S402954

Bano, K., Pandey, R., and Roohi, J. (2018). New advancements of bioplastics in medical applications. *Int. J. Pharm. Sci. Res.* 9 (2), 402–416. doi:10.13040/IJPSR.0975-8232.9(2).402-16

Bao, R., Tan, B., Liang, S., Zhang, N., Wang, W., and Liu, W. (2017). A π-π conjugation-containing soft and conductive injectable polymer hydrogel highly efficiently rebuilds cardiac function after myocardial infarction. *Biomaterials* 122, 63–71. doi:10.1016/j.biomaterials.2017.01.012

Bashir, S., Hina, M., Iqbal, J., Rajpar, A. H., Mujtaba, M. A., Alghamdi, N. A., et al. (2020). Fundamental concepts of hydrogels: synthesis, properties, and their applications. *Polymers* 12 (11), 2702. doi:10.3390/polym12112702

Battigelli, A., Almeida, B., and Shukla, A. (2022). Recent advances in bioorthogonal click chemistry for biomedical applications. *Bioconjugate Chem.* 33 (2), 263–271. doi:10.1021/acs.bioconjchem.1c00564

Beygisangchin, M., Abdul Rashid, S., Shafie, S., Sadrolhoseini, A. R., and Lim, H. N. (2021). Preparations, properties, and applications of polyaniline and polyaniline thin films—a review. *Polymers* 13 (12), 2003. doi:10.3390/polym13122003

Bhat, M. A., Rather, R. A., and Shalla, A. H. (2021). PEDOT and PEDOT:PSS conducting polymeric hydrogels: a report on their emerging applications. *Synth. Met.* 273, 116709. doi:10.1016/j.synthmet.2021.116709

Bielfeldt, M., Rebl, H., Peters, K., Sridharan, K., Staehlke, S., and Nebe, J. B. (2022). Sensing of physical factors by cells: electric field, mechanical forces, physical plasma and light—importance for tissue regeneration. *Biomed. Mater. Devices* 1, 146–161. doi:10.1007/s44174-022-00028-x

Bilbao, E., Garate, O., Rodríguez Campos, T., Roberti, M., Mass, M., Lozano, A., et al. (2023). Electrochemical sweat sensors. *Chemosensors* 11 (4), 244. doi:10.3390/chemosensors11040244

Boehler, C., Agrawe, Z., and Asplund, M. (2019). Applications of PEDOT in bioelectronic medicine. *Bioelectron. Med.* 2 (2), 89–99. doi:10.2217/bem-2019-0014

Borriello, A., Guarino, V., Schiavo, L., Alvarez-Perez, M. A., and Ambrosio, L. (2011). Optimizing PANi doped electroactive substrates as patches for the regeneration of cardiac muscle. *J. Mater. Sci. Mater. Med.* 22 (4), 1053–1062. doi:10.1007/s10856-011-4259-x

Borschel, G. H., Kia, K. F., Kuzon, W. M., and Dennis, R. G. (2003). Mechanical properties of acellular peripheral nerve. *J. Surg. Res.* 114 (2), 133–139. doi:10.1016/S0022-4804(03)00255-5

Boutry, C. M., Kaizawa, Y., Schroeder, B. C., Chortos, A., Legrand, A., Wang, Z., et al. (2018). A stretchable and biodegradable strain and pressure sensor for orthopaedic application. *Nat. Electron.* 1 (5), 314–321. doi:10.1038/s41928-018-0071-7
Boutry, C. M., Müller, M., and Hierold, C. (2012). Junctions between metals and blends of conducting and biodegradable polymers (PLLA-PPy and PCL-PPy). *Mater. Sci. Eng. C* 32 (6), 1610–1620. doi:10.1016/j.msec2012.04.051

Caliari, S. R., and Burdick, J. A. (2016). A practical guide to hydrogels for cell culture. *Nat. Methods* 13 (5), 405–414. doi:10.1038/nmeth.3839

Cánovas, R., Padrell Sánchez, S., Parrilla, M., Cuartero, M., and Crespo, G. A. (2019). Cytotoxicity study of ionophore-based membranes: toward on-body and *in vivo* ion sensing. *ACS Sensors* 4 (9), 2524–2535. doi:10.1021/acssensors.9b01322

Cao, Y., and Wang, B. (2009). Biodegradation of silk biomaterials. *Int. J. Mol. Sci.* 10 (4), 1514–1524. doi:10.3390/ijms10041514

Cassano, D., Summa, M., Pocoví-Martínez, S., Mapanao, A.-K., Catelani, T., Bertorelli, R., et al. (2019). Biodegradable ultrasmall-in-nano gold architectures: mid-period *in vivo* distribution and excretion assessment. *Part. Part. Syst. Charact.* 36 (2), 180046. doi:10.1002/ppsc.201800464

Chatterjee, S., Saxena, M., Padmanabhan, D., Jayachandra, M., and Pandya, H. J. (2019). Futuristic medical implants using bioresorbable materials and devices. *Biosens. Bioelectron.* 142, 111489. doi:10.1016/j.bios.2019.111489

Chaudhuri, O., Gu, L., Darnell, M., Klumpers, D., Bencherif, S. A., Weaver, J. C., et al. (2015). Substrate stress relaxation regulates cell spreading. *Nat. Commun.* 6 (1), 6365. doi:10.1038/ncomms7365

Chaudhuri, O., Gu, L., Klumpers, D., Darnell, M., Bencherif, S. A., Weaver, J. C., et al. (2016). Hydrogels with tunable stress relaxation regulate stem cell fate and activity. *Nat. Mater.* 15 (3), 326–334. doi:10.1038/nmat4489

Chen, C., Bai, X., Ding, Y., and Lee, I.-S. (2019). Electrical stimulation as a novel tool for regulating cell behavior in tissue engineering. *Biomaterials Res.* 23 (1), 25. doi:10.1186/s40824-019-0176-8

Chen, G., Matsuhisa, N., Liu, Z., Qi, D., Cai, P., Jiang, Y., et al. (2018a). Plasticizing silk protein for on-skin stretchable electrodes. *Adv. Mater.* 30 (21), 1800129. doi:10.1002/adma.201800129

Chen, L., Wang, W., Lin, Z., Lu, Y., Chen, H., Li, B., et al. (2022). Conducting molybdenum sulfide/graphene oxide/polyvinyl alcohol nanocomposite hydrogel for repairing spinal cord injury. *J. Nanobiotechnology* 20 (1), 210. doi:10.1186/s12951-022-01396-8

Chen, X., Park, Y. J., Kang, M., Kang, S.-K., Koo, J., Shinde, S. M., et al. (2018b). CVD-grown monolayer MoS2 in bioabsorbable electronics and biosensors. *Nat. Commun.* 9 (1), 1690. doi:10.1038/s41467-018-03956-9

Chen, Z., Chen, Y., Hedenqvist, M. S., Chen, Cai, Cai, Li, H., et al. (2021). Multifunctional conductive hydrogels and their applications as smart wearable devices. *J. Mater. Chem. B* 9 (11), 2561–2583. doi:10.1039/d0tb02929g

Chen, Z., Lin, Z., Obaid, S. N., Rytkin, E., George, S. A., Bach, C., et al. (2023). Soft, bioresorbable, transparent microelectrode arrays for multimodal spatiotemporal mapping and modulation of cardiac physiology. *Sci. Adv.* 9 (27), eadi0757. doi:10.1126/sciadv.adi0757

Chiulan, I., Heggset, E. B., Voicu, Ş. I., and Chinga-Carrasco, G. (2021). Photopolymerization of bio-based polymers in a biomedical engineering perspective. *Biomacromolecules* 22 (5), 1795–1814. doi:10.1021/acs.biomac.0c01745

Choi, C., Choi, M. K., Liu, S., Kim, M., Park, O. K., Im, C., et al. (2017). Human eye-inspired soft optoelectronic device using high-density MoS2-graphene curved image sensor array. *Nat. Commun.* 8 (1), 1664. doi:10.1038/s41467-017-01824-6

Choi, C., Lee, Y., Cho, K. W., Koo, J. H., and Kim, D.-H. (2019). Wearable and implantable soft bioelectronics using two-dimensional materials. *Accounts Chem. Res.* 52 (1), 73–81. doi:10.1021/acs.accounts.8b00491

Choi, Y. S., Yin, R. T., Pfenniger, A., Koo, J., Avila, R., Lee, K. B., et al. (2021). Fully implantable and bioresorbable cardiac pacemakers without leads or batteries. *Nat. Biotechnol.* 39 (10), 1228–1238. doi:10.1038/s41587-021-00948-x

Choi, Y. Y., Ho, D. H., and Cho, J. H. (2020). Self-healable hydrogel-liquid metal composite platform enabled by a 3D printed stamp for a multimodular sensor system. *ACS Appl. Mater. Interfaces* 12 (8), 9824–9832. doi:10.1021/acsami.9b22676

Chor, A., Gonçalves, R. P., Costa, A. M., Farina, M., Ponche, A., Sirelli, L., et al. (2020). *In vitro* degradation of electrospun poly(lactic-Co-glycolic acid) (PLGA) for oral mucosa regeneration. *Polymers* 12 (8), 1853. doi:10.3390/polym12081853

Christenson, E. M., Anderson, J. M., and Hiltner, A. (2007). Biodegradation mechanisms of polyurethane elastomers. *Corros. Eng. Sci. Technol.* 42 (4), 312–323. doi:10.1179/174327807x238909

Cong, Y., and Fu, J. (2022). Hydrogel–tissue interface interactions for implantable flexible bioelectronics. *Langmuir* 38 (38), 11503–11513. doi:10.1021/acs.langmuir.2c01674

Czubacka, E., and Czerczak, S. (2019). Are platinum nanoparticles safe to human health? *Med. Pr.* 70 (4), 487–495. doi:10.13075/mp.5893.00847

Dadras-Toussi, O., Khorrami, M., Louis Sam Titus, A. S. C., Majd, S., Mohan, C., and Abidian, M. R. (2022). Multiphoton lithography of organic semiconductor devices for 3D printing of flexible electronic circuits, biosensors, and bioelectronics. *Adv. Mater.* 34 (30), 2200512. doi:10.1002/adma.202200512

Dai, C., Kong, D., Chen, C., Liu, Y., and Wei, D. (2023). Graphene transistors for *in vitro* detection of health biomarkers. *Adv. Funct. Mater.* 33, 2301948. doi:10.1002/adfm.202301948

Dash, M., Chiellini, F., Ottenbrite, R. M., and Chiellini, E. (2011). Chitosan—a versatile semi-synthetic polymer in biomedical applications. *Prog. Polym. Sci.* 36 (8), 981–1014. doi:10.1016/j.progpolymsci.2011.02.001

De León, S. E., Pupovac, A., and McArthur, S. L. (2020). Three-Dimensional (3D) cell culture monitoring: opportunities and challenges for impedance spectroscopy. *Biotechnol. Bioeng.* 117 (4), 1230–1240. doi:10.1002/bit.27270

Deo, K. A., Jaiswal, M. K., Abasi, S., Lokhande, G., Bhunia, S., Nguyen, T.-U., et al. (2022). Nanoengineered ink for designing 3D printable flexible bioelectronics. *ACS Nano* 16 (6), 8798–8811. doi:10.1021/acsnano.1c09386

Dorishetty, P., Balu, R., Gelmi, A., Mata, J. P., Quigley, A., Dutta, N. K., et al. (2022). Microporosity engineered printable silk/graphene hydrogels and their cytocompatibility evaluations. *Mater. Today Adv.* 14, 100233. doi:10.1016/j.mtadv.2022.100233

Duan, X., Gao, R., Xie, P., Cohen-Karni, T., Qing, Q., Choe, H. S., et al. (2012). Intracellular recordings of action potentials by an extracellular nanoscale field-effect transistor. *Nat. Nanotechnol.* 7 (3), 174–179. doi:10.1038/nnano.2011.223

Eglin, D., and Alini, M. (2008). Degradable polymeric materials for osteosynthesis: tutorial. *Eur. Cells Mat.* 16, 80–91. doi:10.22203/ecm.v016a09

Eitel, I., and Friedrich, M. G. (2011). T2-weighted cardiovascular magnetic resonance in acute cardiac disease. *J. Cardiovasc. Magnetic Reson.* 13 (1), 13. doi:10.1186/1532-429x-13-13

Elosegui-Artola, A. (2021). The extracellular matrix viscoelasticity as a regulator of cell and tissue dynamics. *Curr. Opin. Cell Biol.* 72, 10–18. doi:10.1016/j.ceb.2021.04.002

eSilva, E. P., Huang, B., Helaehil, J. V., Nalesso, P. R. L., Bagne, L., de Oliveira, M. A., et al. (2021). *In vivo* study of conductive 3D printed PCL/MWCNTs scaffolds with electrical stimulation for bone tissue engineering. *Bio-Design Manuf.* 4 (2), 190–202. doi:10.1007/s42242-020-00116-1

Eslamian, M., Mirab, F., Raghunathan, V. K., Majd, S., and Abidian, M. R. (2021). Organic semiconductor nanotubes for electrochemical devices. *Adv. Funct. Mater.* 31 (49), 2105358. doi:10.1002/adfm.202105358

Fattahi, P., Yang, G., Kim, G., and Abidian, M. R. (2014). A review of organic and inorganic biomaterials for neural interfaces. *Adv. Mater.* 26 (12), 1846–1885. doi:10.1002/adma.201304496

Feig, V. R., Tran, H., and Bao, Z. (2018). Biodegradable polymeric materials in degradable electronic devices. *ACS Central Sci.* 4 (3), 337–348. doi:10.1021/acscentsci.7b00595

Feng, S., Cao, S., Tian, Z., Zhu, H., and Kong, D. (2019). Maskless patterning of biodegradable conductors by selective laser sintering of microparticle inks and its application in flexible transient electronics. *ACS Appl. Mater. Interfaces* 11 (49), 45844–45852. doi:10.1021/acsami.9b14431

Ferlauto, L., D'Angelo, A. N., Vagni, P., Airaghi Leccardi, M. J. I., Mor, F. M., Cuttaz, E. A., et al. (2018). Development and characterization of PEDOT:PSS/alginate soft microelectrodes for application in neuroprosthetics. *Front. Neurosci.* 12, 648. doi:10.3389/fnins.2018.00648

Fleischer, S., Shevach, M., Feiner, R., and Dvir, T. (2014). Coiled fiber scaffolds embedded with gold nanoparticles improve the performance of engineered cardiac tissues. *Nanoscale* 6 (16), 9410–9414. doi:10.1039/c4nr00300d

Foremny, K., Nagels, S., Kreienmeyer, M., Doll, T., and Deferme, W. (2021). Biocompatibility testing of liquid metal as an interconnection material for flexible implant technology. *Nanomaterials* 11 (12), 3251. doi:10.3390/nano11123251

Gandhi, B., and Raghava, N. S. (2020). Fabrication techniques for carbon nanotubes based ECG electrodes: a review. *IETE J. Res.*, 1–20. doi:10.1080/03772063.2020.1768909

Gao, C., Song, S., Lv, Y., Huang, J., and Zhang, Z. (2022). Recent development of conductive hydrogels for tissue engineering: review and perspective. *Macromol. Biosci.* 22 (8), 2200051. doi:10.1002/mabi.202200051

GhavamiNejad, P., GhavamiNejad, A., Zheng, H., Dhingra, K., Samarikhalaj, M., and Poudineh, M. (2023). A conductive hydrogel microneedle-based assay integrating PEDOT:PSS and Ag-Pt nanoparticles for real-time, enzyme-less, and electrochemical sensing of glucose. *Adv. Healthc. Mater.* 12 (1), 2202362. doi:10.1002/adhm.202202362

Ghosh, S., Haldar, S., Gupta, S., Bisht, A., Chauhan, S., Kumar, V., et al. (2020). Anisotropically conductive biodegradable scaffold with coaxially aligned carbon nanotubes for directional regeneration of peripheral nerves. *ACS Appl. Bio Mater.* 3 (9), 5796–5812. doi:10.1021/acsabm.0c00534

Gillispie, G., Prim, P., Copus, J., Fisher, J., Mikos, A. G., Yoo, J. J., et al. (2020). Assessment methodologies for extrusion-based bioink printability. *Biofabrication* 12 (2), 022003. doi:10.1088/1758-5090/ab6f0d

Glasser, A., Cloutet, É., Hadzioioannou, G., and Kellay, H. (2019). Tuning the rheology of conducting polymer inks for various deposition processes. *Chem. Mater.* 31 (17), 6936–6944. doi:10.1021/acs.chemmater.9b01387
Boutry, C. M., Müller, M., and Hierold, C. (2012). Junctions between metals and blends of conducting and biodegradable polymers (PLLA-PPy and PCL-PPy). *Mater. Sci. Eng. C* 32 (6), 1610–1620. doi:10.1016/j.msec2012.04.051

Caliari, S. R., and Burdick, J. A. (2016). A practical guide to hydrogels for cell culture. *Nat. Methods* 13 (5), 405–414. doi:10.1038/nmeth.3839

Cánovas, R., Padrell Sánchez, S., Parrilla, M., Cuartero, M., and Crespo, G. A. (2019). Cytotoxicity study of ionophore-based membranes: toward on-body and *in vivo* ion sensing. *ACS Sensors* 4 (9), 2524–2535. doi:10.1021/acssensors.9b01322

Cao, Y., and Wang, B. (2009). Biodegradation of silk biomaterials. *Int. J. Mol. Sci.* 10 (4), 1514–1524. doi:10.3390/ijms10041514

Cassano, D., Summa, M., Pocoví-Martínez, S., Mapanao, A.-K., Catelani, T., Bertorelli, R., et al. (2019). Biodegradable ultrasmall-in-nano gold architectures: mid-period *in vivo* distribution and excretion assessment. *Part. Part. Syst. Charact.* 36 (2), 180046. doi:10.1002/ppsc.201800464

Chatterjee, S., Saxena, M., Padmanabhan, D., Jayachandra, M., and Pandya, H. J. (2019). Futuristic medical implants using bioresorbable materials and devices. *Biosens. Bioelectron.* 142, 111489. doi:10.1016/j.bios.2019.111489

Chaudhuri, O., Gu, L., Darnell, M., Klumpers, D., Bencherif, S. A., Weaver, J. C., et al. (2015). Substrate stress relaxation regulates cell spreading. *Nat. Commun.* 6 (1), 6365. doi:10.1038/ncomms7365

Chaudhuri, O., Gu, L., Klumpers, D., Darnell, M., Bencherif, S. A., Weaver, J. C., et al. (2016). Hydrogels with tunable stress relaxation regulate stem cell fate and activity. *Nat. Mater.* 15 (3), 326–334. doi:10.1038/nmat4489

Chen, C., Bai, X., Ding, Y., and Lee, I.-S. (2019). Electrical stimulation as a novel tool for regulating cell behavior in tissue engineering. *Biomaterials Res.* 23 (1), 25. doi:10.1186/s40824-019-0176-8

Chen, G., Matsuhisa, N., Liu, Z., Qi, D., Cai, P., Jiang, Y., et al. (2018a). Plasticizing silk protein for on-skin stretchable electrodes. *Adv. Mater.* 30 (21), 1800129. doi:10.1002/adma.201800129

Chen, L., Wang, W., Lin, Z., Lu, Y., Chen, H., Li, B., et al. (2022). Conducting molybdenum sulfide/graphene oxide/polyvinyl alcohol nanocomposite hydrogel for repairing spinal cord injury. *J. Nanobiotechnology* 20 (1), 210. doi:10.1186/s12951-022-01396-8

Chen, X., Park, Y. J., Kang, M., Kang, S.-K., Koo, J., Shinde, S. M., et al. (2018b). CVD-grown monolayer MoS2 in bioabsorbable electronics and biosensors. *Nat. Commun.* 9 (1), 1690. doi:10.1038/s41467-018-03956-9

Chen, Z., Chen, Y., Hedenqvist, M. S., Chen, Cai, Cai, Li, H., et al. (2021). Multifunctional conductive hydrogels and their applications as smart wearable devices. *J. Mater. Chem. B* 9 (11), 2561–2583. doi:10.1039/d0tb02929g

Chen, Z., Lin, Z., Obaid, S. N., Rytkin, E., George, S. A., Bach, C., et al. (2023). Soft, bioresorbable, transparent microelectrode arrays for multimodal spatiotemporal mapping and modulation of cardiac physiology. *Sci. Adv.* 9 (27), eadi0757. doi:10.1126/sciadv.adi0757

Chiulan, I., Heggset, E. B., Voicu, Ş. I., and Chinga-Carrasco, G. (2021). Photopolymerization of bio-based polymers in a biomedical engineering perspective. *Biomacromolecules* 22 (5), 1795–1814. doi:10.1021/acs.biomac.0c01745

Choi, C., Choi, M. K., Liu, S., Kim, M., Park, O. K., Im, C., et al. (2017). Human eye-inspired soft optoelectronic device using high-density MoS2-graphene curved image sensor array. *Nat. Commun.* 8 (1), 1664. doi:10.1038/s41467-017-01824-6

Choi, C., Lee, Y., Cho, K. W., Koo, J. H., and Kim, D.-H. (2019). Wearable and implantable soft bioelectronics using two-dimensional materials. *Accounts Chem. Res.* 52 (1), 73–81. doi:10.1021/acs.accounts.8b00491

Choi, Y. S., Yin, R. T., Pfenniger, A., Koo, J., Avila, R., Lee, K. B., et al. (2021). Fully implantable and bioresorbable cardiac pacemakers without leads or batteries. *Nat. Biotechnol.* 39 (10), 1228–1238. doi:10.1038/s41587-021-00948-x

Choi, Y. Y., Ho, D. H., and Cho, J. H. (2020). Self-healable hydrogel-liquid metal composite platform enabled by a 3D printed stamp for a multimodular sensor system. *ACS Appl. Mater. Interfaces* 12 (8), 9824–9832. doi:10.1021/acsami.9b22676

Chor, A., Gonçalves, R. P., Costa, A. M., Farina, M., Ponche, A., Sirelli, L., et al. (2020). *In vitro* degradation of electrospun poly(lactic-Co-glycolic acid) (PLGA) for oral mucosa regeneration. *Polymers* 12 (8), 1853. doi:10.3390/polym12081853

Christenson, E. M., Anderson, J. M., and Hiltner, A. (2007). Biodegradation mechanisms of polyurethane elastomers. *Corros. Eng. Sci. Technol.* 42 (4), 312–323. doi:10.1179/174327807x238909

Cong, Y., and Fu, J. (2022). Hydrogel-tissue interface interactions for implantable flexible bioelectronics. *Langmuir* 38 (38), 11503–11513. doi:10.1021/acs.langmuir.2c01674

Czubacka, E., and Czerczak, S. (2019). Are platinum nanoparticles safe to human health? *Med. Pr.* 70 (4), 487–495. doi:10.13075/mp.5893.00847

Dadras-Toussi, O., Khorrami, M., Louis Sam Titus, A. S. C., Majd, S., Mohan, C., and Abidian, M. R. (2022). Multiphoton lithography of organic semiconductor devices for 3D printing of flexible electronic circuits, biosensors, and bioelectronics. *Adv. Mater.* 34 (30), 2200512. doi:10.1002/adma.202200512

Dai, C., Kong, D., Chen, C., Liu, Y., and Wei, D. (2023). Graphene transistors for *in vitro* detection of health biomarkers. *Adv. Funct. Mater.* 33, 2301948. doi:10.1002/adfm.202301948

Dash, M., Chiellini, F., Ottenbrite, R. M., and Chiellini, E. (2011). Chitosan—a versatile semi-synthetic polymer in biomedical applications. *Prog. Polym. Sci.* 36 (8), 981–1014. doi:10.1016/j.progpolymsci.2011.02.001

De León, S. E., Pupovac, A., and McArthur, S. L. (2020). Three-Dimensional (3D) cell culture monitoring: opportunities and challenges for impedance spectroscopy. *Biotechnol. Bioeng.* 117 (4), 1230–1240. doi:10.1002/bit.27270

Deo, K. A., Jaiswal, M. K., Abasi, S., Lokhande, G., Bhunia, S., Nguyen, T.-U., et al. (2022). Nanoengineered ink for designing 3D printable flexible bioelectronics. *ACS Nano* 16 (6), 8798–8811. doi:10.1021/acsnano.1c09386

Dorishetty, P., Balu, R., Gelmi, A., Mata, J. P., Quigley, A., Dutta, N. K., et al. (2022). Microporosity engineered printable silk/graphene hydrogels and their cytocompatibility evaluations. *Mater. Today Adv.* 14, 100233. doi:10.1016/j.mtadv.2022.100233

Duan, X., Gao, R., Xie, P., Cohen-Karni, T., Qing, Q., Choe, H. S., et al. (2012). Intracellular recordings of action potentials by an extracellular nanoscale field-effect transistor. *Nat. Nanotechnol.* 7 (3), 174–179. doi:10.1038/nnano.2011.223

Eglin, D., and Alini, M. (2008). Degradable polymeric materials for osteosynthesis: tutorial. *Eur. Cells Mat.* 16, 80–91. doi:10.22203/ecm.v016a09

Eitel, I., and Friedrich, M. G. (2011). T2-weighted cardiovascular magnetic resonance in acute cardiac disease. *J. Cardiovasc. Magnetic Reson.* 13 (1), 13. doi:10.1186/1532-429x-13-13

Elosegui-Artola, A. (2021). The extracellular matrix viscoelasticity as a regulator of cell and tissue dynamics. *Curr. Opin. Cell Biol.* 72, 10–18. doi:10.1016/j.ceb.2021.04.002

eSilva, E. P., Huang, B., Helaehil, J. V., Nalesso, P. R. L., Bagne, L., de Oliveira, M. A., et al. (2021). *In vivo* study of conductive 3D printed PCL/MWCNTs scaffolds with electrical stimulation for bone tissue engineering. *Bio-Design Manuf.* 4 (2), 190–202. doi:10.1007/s42242-020-00116-1

Eslamian, M., Mirab, F., Raghunathan, V. K., Majd, S., and Abidian, M. R. (2021). Organic semiconductor nanotubes for electrochemical devices. *Adv. Funct. Mater.* 31 (49), 2105358. doi:10.1002/adfm.202105358

Fattahi, P., Yang, G., Kim, G., and Abidian, M. R. (2014). A review of organic and inorganic biomaterials for neural interfaces. *Adv. Mater.* 26 (12), 1846–1885. doi:10.1002/adma.201304496

Feig, V. R., Tran, H., and Bao, Z. (2018). Biodegradable polymeric materials in degradable electronic devices. *ACS Central Sci.* 4 (3), 337–348. doi:10.1021/acscentsci.7b00595

Feng, S., Cao, S., Tian, Z., Zhu, H., and Kong, D. (2019). Maskless patterning of biodegradable conductors by selective laser sintering of microparticle inks and its application in flexible transient electronics. *ACS Appl. Mater. Interfaces* 11 (49), 45844–45852. doi:10.1021/acsami.9b14431

Ferlauto, L., D'Angelo, A. N., Vagni, P., Airaghi Leccardi, M. J. I., Mor, F. M., Cuttaz, E. A., et al. (2018). Development and characterization of PEDOT:PSS/alginate soft microelectrodes for application in neuroprosthetics. *Front. Neurosci.* 12, 648. doi:10.3389/fnins.2018.00648

Fleischer, S., Shevach, M., Feiner, R., and Dvir, T. (2014). Coiled fiber scaffolds embedded with gold nanoparticles improve the performance of engineered cardiac tissues. *Nanoscale* 6 (16), 9410–9414. doi:10.1039/c4nr00300d

Foremny, K., Nagels, S., Kreienmeyer, M., Doll, T., and Deferme, W. (2021). Biocompatibility testing of liquid metal as an interconnection material for flexible implant technology. *Nanomaterials* 11 (12), 3251. doi:10.3390/nano11123251

Gandhi, B., and Raghava, N. S. (2020). Fabrication techniques for carbon nanotubes based ECG electrodes: a review. *IETE J. Res.*, 1–20. doi:10.1080/03772063.2020.1768909

Gao, C., Song, S., Lv, Y., Huang, J., and Zhang, Z. (2022). Recent development of conductive hydrogels for tissue engineering: review and perspective. *Macromol. Biosci.* 22 (8), 2200051. doi:10.1002/mabi.202200051

GhavamiNejad, P., GhavamiNejad, A., Zheng, H., Dhingra, K., Samarikhalaj, M., and Poudineh, M. (2023). A conductive hydrogel microneedle-based assay integrating PEDOT:PSS and Ag-Pt nanoparticles for real-time, enzyme-less, and electrochemical sensing of glucose. *Adv. Healthc. Mater.* 12 (1), 2202362. doi:10.1002/adhm.202202362

Ghosh, S., Haldar, S., Gupta, S., Bisht, A., Chauhan, S., Kumar, V., et al. (2020). Anisotropically conductive biodegradable scaffold with coaxially aligned carbon nanotubes for directional regeneration of peripheral nerves. *ACS Appl. Bio Mater.* 3 (9), 5796–5812. doi:10.1021/acsabm.0c00534

Gillispie, G., Prim, P., Copus, J., Fisher, J., Mikos, A. G., Yoo, J. J., et al. (2020). Assessment methodologies for extrusion-based bioink printability. *Biofabrication* 12 (2), 022003. doi:10.1088/1758-5090/ab6f0d

Glasser, A., Cloutet, É., Hadzioioannou, G., and Kellay, H. (2019). Tuning the rheology of conducting polymer inks for various deposition processes. *Chem. Mater.* 31 (17), 6936–6944. doi:10.1021/acs.chemmater.9b01387
Gong, Y., Cheng, Y. Z., and Hu, Y. C. (2022). Preparation of polymer conductive hydrogel and its application in flexible wearable electronic devices. *Prog. Chem.* 34 (3), 616–629. doi:10.7536/pc210329

Gottschalk, A., Scafidi, S., and Toung, T. (2021). Brain water as a function of age and weight in normal rats. *PLoS ONE* 16 (9), e0249384. doi:10.1371/journal.pone.0249384

Grosjean, M., Gangolphe, L., and Nottelet, B. (2023). Degradable self-healable networks for use in biomedical applications. *Adv. Funct. Mater.* 33 (13), 2205315. doi:10.1002/adfm.202205315

Gueye, M. N., Carella, A., Faure-Vincent, J., Demadrille, R., and Simonato, J.-P. (2020). Progress in understanding structure and transport properties of PEDOT-based materials: a critical review. *Prog. Mater. Sci.* 108, 100616. doi:10.1016/j.pmatsci.2019.100616

Guo, B., Glavas, L., and Albertsson, A.-C. (2013). Biodegradable and electrically conducting polymers for biomedical applications. *Prog. Polym. Sci.* 38 (9), 1263–1286. doi:10.1016/j.progpolymsci.2013.06.003

Guo, B., and Ma, P. X. (2018). Conducting polymers for tissue engineering. *Biomacromolecules* 19 (6), 1764–1782. doi:10.1021/acs.biomac.8b00276

Guo, X., and Facchetti, A. (2020). The journey of conducting polymers from discovery to application. *Nat. Mater.* 19 (9), 922–928. doi:10.1038/s41563-020-0778-5

Gupta, P., Agrawal, A., Murali, K., Varshney, R., Beniwal, S., Manhas, S., et al. (2019). Differential neural cell adhesion and neurite outgrowth on carbon nanotube and graphene reinforced polymeric scaffolds. *Mater. Sci. Eng. C* 97, 539–551. doi:10.1016/j.msec.2018.12.065

Gutiérrez de la Rosa, S. Y., Muñiz Diaz, R., Villalobos Gutiérrez, P. T., Patakfalvi, R., and Gutiérrez Coronado, Ó. (2022). Functionalized platinum nanoparticles with biomedical applications. *Int. J. Mol. Sci.* 23 (16), 9404. doi:10.3390/ijms23169404

Hall, C. M., Moeendarbary, E., and Sheridan, G. K. (2021). Mechanobiology of the brain in ageing and Alzheimer's disease. *Eur. J. Neurosci.* 53 (12), 3851–3878. doi:10.1111/ejn.14766

Han, W. B., Yang, S. M., Rajaram, K., and Hwang, S.-W. (2022). Materials and fabrication strategies for biocompatible and biodegradable conductive polymer composites toward bio-integrated electronic systems. *Adv. Sustain. Syst.* 6 (2), 2100075. doi:10.1002/adsu.202100075

Hébert, C., Mazellier, J. P., Scorsone, E., Mermoux, M., and Bergonzo, P. (2014). Boosting the electrochemical properties of diamond electrodes using carbon nanotube scaffolds. *Carbon* 71, 27–33. doi:10.1016/j.carbon.2013.12.083

Held, M., Pichler, A., Chabeda, J., Lam, N., Hindenberg, P., Romero-Nieto, C., et al. (2022). Soft electronic platforms combining elastomeric stretchability and biodegradability. *Adv. Sustain. Syst.* 6 (2), 2100035. doi:10.1002/adsu.202100035

Hochberg, L. R., Serruya, M. D., Friehs, G. M., Mukand, J. A., Saleh, M., Caplan, A. H., et al. (2006). Neuronal ensemble control of prosthetic devices by a human with tetraplegia. *Nature* 442 (7099), 164–171. doi:10.1038/nature04970

Hu, W., Wang, Z., Xiao, Y., Zhang, S., and Wang, J. (2019). Advances in crosslinking strategies of biomedical hydrogels. *Biomaterials Sci.* 7 (3), 843–855. doi:10.1039/c8bm01246f

Huang, L., Yang, X., Deng, L., Ying, D., Lu, A., Zhang, L., et al. (2021). Biocompatible chitin hydrogel incorporated with PEDOT nanoparticles for peripheral nerve repair. *ACS Appl. Mater. Interfaces* 13 (14), 16106–16117. doi:10.1021/acsmami.1c01904

Huang, W.-J., and Wang, J. (2023). Development of 3D-printed, biodegradable, conductive PGSA composites for nerve tissue regeneration. *Macromol. Biosci.* 23 (3), 2200470. doi:10.1002/mabi.202200470

Huang, X., Liu, Y., Hwang, S.-W., Kang, S.-K., Patnaik, D., Cortes, J. F., et al. (2014a). Biodegradable materials for multilayer transient printed circuit boards. *Adv. Mater.* 26 (43), 7371–7377. doi:10.1002/adma.201403164

Huang, X.-W., Wei, J.-J., Zhang, M.-Y., Zhang, X.-L., Yin, X.-F., Lu, C.-H., et al. (2018). Water-based black phosphorus hybrid nanosheets as a moldable platform for wound healing applications. *ACS Appl. Mater. Interfaces* 10 (41), 35495–35502. doi:10.1021/acsmami.8b12523

Huang, Y., Li, H., Hu, T., Li, J., Yiu, C. K., Zhou, J., et al. (2022). Implantable electronic medicine enabled by bioresorbable microneedles for wireless electrotherapy and drug delivery. *Nano Lett.* 22 (14), 5944–5953. doi:10.1021/acs.nanolett.2c01997

Huang, Z.-B., Yin, G.-F., Liao, X.-M., and Gu, J.-W. (2014b). Conducting polypyrrole in tissue engineering applications. *Front. Mat. Sci.* 8 (1), 39–45. doi:10.1007/s11706-014-0238-8

Humpolicek, P., Kasparkova, V., Saha, P., and Stejskal, J. (2012). Biocompatibility of polyaniline. *Synth. Met.* 162 (7), 722–727. doi:10.1016/j.synthmet.2012.02.024

Hwang, S.-W., Tao, H., Kim, D.-H., Cheng, H., Song, J.-K., Rill, E., et al. (2012). A physically transient form of silicon electronics. *Science* 337 (6102), 1640–1644. doi:10.1126/science.1226325

Inal, S., Hama, A., Ferro, M., Pitsalidis, C., Oziat, J., Iandolo, D., et al. (2017). Conducting polymer scaffolds for hosting and monitoring 3D cell culture. *Adv. Biosyst.* 1 (6), 1700052. doi:10.1002/adbi.201700052

Jacot, J. G., Martin, J. C., and Hunt, D. L. (2010). Mechanobiology of cardiomyocyte development. *J. Biomechanics* 43 (1), 93–98. doi:10.1016/j.biomech.2009.09.014

Jensen, B. E. B., Dávila, I., and Zelikin, A. N. (2016). Poly(vinyl alcohol) physical hydrogels: matrix-mediated drug delivery using spontaneously eroding substrate. *J. Phys. Chem. B* 120 (26), 5916–5926. doi:10.1021/acs.jpcb.b6b01381

Jiang, D.-H., Satoh, T., Tung, S. H., and Kuo, C.-C. (2022). Sustainable alternatives to nondegradable medical plastics. *ACS Sustain. Chem. Eng.* 10 (15), 4792–4806. doi:10.1021/acssuschemeng.2c00160

Jiang, Y., Xu, M., and Yadavalli, V. K. (2019). Silk fibroin-sheathed conducting polymer wires as organic connectors for biosensors. *Biosensors* 9 (3), 103. doi:10.3390/bios9030103

Jin, M., Li, N., Sheng, W., Ji, X., Liang, X., Kong, B., et al. (2021). Toxicity of different zinc oxide nanomaterials and dose-dependent onset and development of Parkinson's disease-like symptoms induced by zinc oxide nanorods. *Environ. Int.* 146, 106179. doi:10.1016/j.envint.2020.106179

Jing, X., Mi, H.-Y., Napiwocki, B. N., Peng, X.-F., and Turng, L.-S. (2017). Mussel-inspired electroactive chitosan/graphene oxide composite hydrogel with rapid self-healing and recovery behavior for tissue engineering. *Carbon* 125, 557–570. doi:10.1016/j.carbon.2017.09.071

Kalra, A., Lowe, A., and Al-Jumaily, A. M. (2016). Mechanical behaviour of skin: a review. *J. Mat. Sci. Eng.* 5 (4), 1–7. doi:10.4172/2169-0022.1000254

Karimi, A., Shojaei, A., and Tehrani, P. (2017). Mechanical properties of the human spinal cord under the compressive loading. *J. Chem. Neuroanat.* 86, 15–18. doi:10.1016/j.jchemneu.2017.07.004

Karmakar, R. S., Chu, C.-P., Liao, Y.-C., and Lu, Y.-W. (2022). PVA tactile sensors based on Electrical Contact Resistance (ECR) change mechanism for subtle pressure detection. *Sensors Actuators A Phys.* 342, 113613. doi:10.1016/j.sna.2022.113613

Katoh, K. (2022). Effects of electrical stimulation on the signal transduction-related proteins, c-src and focal adhesion kinase, in fibroblasts. *Life* 12 (4), 531. doi:10.3390/life12040531

Kayser, L. V., and Lipomi, D. J. (2019). Stretchable conductive polymers and composites based on PEDOT and PEDOT:PSS. *Adv. Mater.* 31 (10), 1806133. doi:10.1002/adma.201806133

Keefer, E. W., Botterman, B. R., Romero, M. I., Rossi, A. F., and Gross, G. W. (2008). Carbon nanotube coating improves neuronal recordings. *Nat. Nanotechnol.* 3 (7), 434–439. doi:10.1038/nnano.2008.174

Keller, T. S., Mao, Z., and Spengler, D. M. (1990). Young's modulus, bending strength, and tissue physical properties of human compact bone. *J. Orthop. Res.* 8 (4), 592–603. doi:10.1002/jor.1100080416

Khan, M. A., Cantù, E., Tonello, S., Serpelloni, M., Lopomo, N. F., and Sardini, E. (2019). A review on biomaterials for 3D conductive scaffolds for stimulating and monitoring cellular activities. *Appl. Sci.* 9 (5), 961. doi:10.3390/app9050961

Khodagholy, D., Gelinas, J. N., Thesen, T., Doyle, W., Devinsky, O., Malliaras, G. G., et al. (2015). NeuroGrid: recording action potentials from the surface of the brain. *Nat. Neurosci.* 18 (2), 310–315. doi:10.1038/nn.3905

Khorrami, M., and Abidian, M. R. (2018). "Aligned conducting polymer nanotubes for neural prostheses," in Proceedings of the 40th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), Honolulu, HI, USA, July 18-21, 2018, 6080–6083.

Khorrami, M., Antensteiner, M., Fallahianbijan, F., Borhan, A., and Abidian, M. R. (2017). "Conducting polymer microcontainers for biomedical applications," in Proceedings of the 39th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), Jeju Island, South Korea, July 11-15, 2017, 1869–1872.

Khorshidi, S., and Karkhaneh, A. (2018). Hydrogel/fiber conductive scaffold for bone tissue engineering. *J. Biomed. Mater. Res. Part A* 106 (3), 718–724. doi:10.1002/jbm.a.36282

Kim, B. C., Spinks, G., Too, C. O., Wallace, G. G., and Bae, Y. H. (2000). Preparation and characterisation of processable conducting polymer–hydrogel composites. *React. Funct. Polym.* 44 (1), 31–40. doi:10.1016/S1381-5148(99)00074-7

Kim, D.-H., Kim, Y.-S., Amsden, J., Panilaitis, B., Kaplan, D. L., Omenetto, F. G., et al. (2009). Silicon electronics on silk as a path to bioresorbable, implantable devices. *Appl. Phys. Lett.* 95 (13), 133701. doi:10.1063/1.3238552

Kim, D.-H., Viventi, J., Amsden, J. J., Xiao, J., Vigeland, L., Kim, Y.-S., et al. (2010). Dissolvable films of silk fibroin for ultrathin conformal bio-integrated electronics. *Nat. Mater.* 9 (6), 511–517. doi:10.1038/nmat2745

Kim, J., Campbell, A. S., de Ávila, B. E.-F., and Wang, J. (2019). Wearable biosensors for healthcare monitoring. *Nat. Biotechnol.* 37 (4), 389–406. doi:10.1038/s41587-019-0045-y

Kim, K. S., Maeng, W.-Y., Kim, S., Lee, G., Hong, M., Kim, G.-B., et al. (2023a). Isotropic conductive paste for bioresorbable electronics. *Mater. Today Bio* 18, 100541. doi:10.1016/j.mtbio.2023.100541

Kim, S., Baek, S., Sluyter, R., Konstantinov, K., Kim, J. H., Kim, S., et al. (2023b). Wearable and implantable bioelectronics as eco-friendly and patient-friendly integrated nanoarchitectonics for next-generation smart healthcare technology. *EcoMat* 5, e12356. doi:10.1002/eom2.12356
Gong, Y., Cheng, Y. Z., and Hu, Y. C. (2022). Preparation of polymer conductive hydrogel and its application in flexible wearable electronic devices. *Prog. Chem.* 34 (3), 616–629. doi:10.7536/pc210329

Gottschalk, A., Scafidi, S., and Toung, T. (2021). Brain water as a function of age and weight in normal rats. *PLoS ONE* 16 (9), e0249384. doi:10.1371/journal.pone.0249384

Grosjean, M., Gangolphe, L., and Nottelet, B. (2023). Degradable self-healable networks for use in biomedical applications. *Adv. Funct. Mater.* 33 (13), 2205315. doi:10.1002/adfm.202205315

Gueye, M. N., Carella, A., Faure-Vincent, J., Demadrille, R., and Simonato, J.-P. (2020). Progress in understanding structure and transport properties of PEDOT-based materials: a critical review. *Prog. Mater. Sci.* 108, 100616. doi:10.1016/j.pmatsci.2019.100616

Guo, B., Glavas, L., and Albertsson, A.-C. (2013). Biodegradable and electrically conducting polymers for biomedical applications. *Prog. Polym. Sci.* 38 (9), 1263–1286. doi:10.1016/j.progpolymsci.2013.06.003

Guo, B., and Ma, P. X. (2018). Conducting polymers for tissue engineering. *Biomacromolecules* 19 (6), 1764–1782. doi:10.1021/acs.biomac.8b00276

Guo, X., and Facchetti, A. (2020). The journey of conducting polymers from discovery to application. *Nat. Mater.* 19 (9), 922–928. doi:10.1038/s41563-020-0778-5

Gupta, P., Agrawal, A., Murali, K., Varshney, R., Beniwal, S., Manhas, S., et al. (2019). Differential neural cell adhesion and neurite outgrowth on carbon nanotube and graphene reinforced polymeric scaffolds. *Mater. Sci. Eng. C* 97, 539–551. doi:10.1016/j.msec.2018.12.065

Gutiérrez de la Rosa, S. Y., Muñiz Diaz, R., Villalobos Gutiérrez, P. T., Patakfalvi, R., and Gutiérrez Coronado, Ó. (2022). Functionalized platinum nanoparticles with biomedical applications. *Int. J. Mol. Sci.* 23 (16), 9404. doi:10.3390/ijms23169404

Hall, C. M., Moeendarbary, E., and Sheridan, G. K. (2021). Mechanobiology of the brain in ageing and Alzheimer's disease. *Eur. J. Neurosci.* 53 (12), 3851–3878. doi:10.1111/ejn.14766

Han, W. B., Yang, S. M., Rajaram, K., and Hwang, S.-W. (2022). Materials and fabrication strategies for biocompatible and biodegradable conductive polymer composites toward bio-integrated electronic systems. *Adv. Sustain. Syst.* 6 (2), 2100075. doi:10.1002/adsu.202100075

Hébert, C., Mazellier, J. P., Scorsone, E., Mermoux, M., and Bergonzo, P. (2014). Boosting the electrochemical properties of diamond electrodes using carbon nanotube scaffolds. *Carbon* 71, 27–33. doi:10.1016/j.carbon.2013.12.083

Held, M., Pichler, A., Chabeda, J., Lam, N., Hindenberg, P., Romero-Nieto, C., et al. (2022). Soft electronic platforms combining elastomeric stretchability and biodegradability. *Adv. Sustain. Syst.* 6 (2), 2100035. doi:10.1002/adsu.202100035

Hochberg, L. R., Serruya, M. D., Friehs, G. M., Mukand, J. A., Saleh, M., Caplan, A. H., et al. (2006). Neuronal ensemble control of prosthetic devices by a human with tetraplegia. *Nature* 442 (7099), 164–171. doi:10.1038/nature04970

Hu, W., Wang, Z., Xiao, Y., Zhang, S., and Wang, J. (2019). Advances in crosslinking strategies of biomedical hydrogels. *Biomaterials Sci.* 7 (3), 843–855. doi:10.1039/c8bm01246f

Huang, L., Yang, X., Deng, L., Ying, D., Lu, A., Zhang, L., et al. (2021). Biocompatible chitin hydrogel incorporated with PEDOT nanoparticles for peripheral nerve repair. *ACS Appl. Mater. Interfaces* 13 (14), 16106–16117. doi:10.1021/acsmami.1c01904

Huang, W.-J., and Wang, J. (2023). Development of 3D-printed, biodegradable, conductive PGSA composites for nerve tissue regeneration. *Macromol. Biosci.* 23 (3), 2200470. doi:10.1002/mabi.202200470

Huang, X., Liu, Y., Hwang, S.-W., Kang, S.-K., Patnaik, D., Cortes, J. F., et al. (2014a). Biodegradable materials for multilayer transient printed circuit boards. *Adv. Mater.* 26 (43), 7371–7377. doi:10.1002/adma.201403164

Huang, X.-W., Wei, J.-J., Zhang, M.-Y., Zhang, X.-L., Yin, X.-F., Lu, C.-H., et al. (2018). Water-based black phosphorus hybrid nanosheets as a moldable platform for wound healing applications. *ACS Appl. Mater. Interfaces* 10 (41), 35495–35502. doi:10.1021/acsmami.8b12523

Huang, Y., Li, H., Hu, T., Li, J., Yiu, C. K., Zhou, J., et al. (2022). Implantable electronic medicine enabled by bioresorbable microneedles for wireless electrotherapy and drug delivery. *Nano Lett.* 22 (14), 5944–5953. doi:10.1021/acs.nanolett.2c01997

Huang, Z.-B., Yin, G.-F., Liao, X.-M., and Gu, J.-W. (2014b). Conducting polypyrrole in tissue engineering applications. *Front. Mat. Sci.* 8 (1), 39–45. doi:10.1007/s11706-014-0238-8

Humpolicek, P., Kasparkova, V., Saha, P., and Stejskal, J. (2012). Biocompatibility of polyaniline. *Synth. Met.* 162 (7), 722–727. doi:10.1016/j.synthmet.2012.02.024

Hwang, S.-W., Tao, H., Kim, D.-H., Cheng, H., Song, J.-K., Rill, E., et al. (2012). A physically transient form of silicon electronics. *Science* 337 (6102), 1640–1644. doi:10.1126/science.1226325

Inal, S., Hama, A., Ferro, M., Pitsalidis, C., Oziat, J., Iandolo, D., et al. (2017). Conducting polymer scaffolds for hosting and monitoring 3D cell culture. *Adv. Biosyst.* 1 (6), 1700052. doi:10.1002/adbi.201700052

Jacot, J. G., Martin, J. C., and Hunt, D. L. (2010). Mechanobiology of cardiomyocyte development. *J. Biomechanics* 43 (1), 93–98. doi:10.1016/j.biomech.2009.09.014

Jensen, B. E. B., Dávila, I., and Zelikin, A. N. (2016). Poly(vinyl alcohol) physical hydrogels: matrix-mediated drug delivery using spontaneously eroding substrate. *J. Phys. Chem. B* 120 (26), 5916–5926. doi:10.1021/acs.jpcb.b6b01381

Jiang, D.-H., Satoh, T., Tung, S. H., and Kuo, C.-C. (2022). Sustainable alternatives to nondegradable medical plastics. *ACS Sustain. Chem. Eng.* 10 (15), 4792–4806. doi:10.1021/acssuschemeng.2c00160

Jiang, Y., Xu, M., and Yadavalli, V. K. (2019). Silk fibroin-sheathed conducting polymer wires as organic connectors for biosensors. *Biosensors* 9 (3), 103. doi:10.3390/bios9030103

Jin, M., Li, N., Sheng, W., Ji, X., Liang, X., Kong, B., et al. (2021). Toxicity of different zinc oxide nanomaterials and dose-dependent onset and development of Parkinson's disease-like symptoms induced by zinc oxide nanorods. *Environ. Int.* 146, 106179. doi:10.1016/j.envint.2020.106179

Jing, X., Mi, H.-Y., Napiwocki, B. N., Peng, X.-F., and Turng, L.-S. (2017). Mussel-inspired electroactive chitosan/graphene oxide composite hydrogel with rapid self-healing and recovery behavior for tissue engineering. *Carbon* 125, 557–570. doi:10.1016/j.carbon.2017.09.071

Kalra, A., Lowe, A., and Al-Jumaily, A. M. (2016). Mechanical behaviour of skin: a review. *J. Mat. Sci. Eng.* 5 (4), 1–7. doi:10.4172/2169-0022.1000254

Karimi, A., Shojaei, A., and Tehrani, P. (2017). Mechanical properties of the human spinal cord under the compressive loading. *J. Chem. Neuroanat.* 86, 15–18. doi:10.1016/j.jchemneu.2017.07.004

Karmakar, R. S., Chu, C.-P., Liao, Y.-C., and Lu, Y.-W. (2022). PVA tactile sensors based on Electrical Contact Resistance (ECR) change mechanism for subtle pressure detection. *Sensors Actuators A Phys.* 342, 113613. doi:10.1016/j.sna.2022.113613

Katoh, K. (2022). Effects of electrical stimulation on the signal transduction-related proteins, c-src and focal adhesion kinase, in fibroblasts. *Life* 12 (4), 531. doi:10.3390/life12040531

Kayser, L. V., and Lipomi, D. J. (2019). Stretchable conductive polymers and composites based on PEDOT and PEDOT:PSS. *Adv. Mater.* 31 (10), 1806133. doi:10.1002/adma.201806133

Keefer, E. W., Botterman, B. R., Romero, M. I., Rossi, A. F., and Gross, G. W. (2008). Carbon nanotube coating improves neuronal recordings. *Nat. Nanotechnol.* 3 (7), 434–439. doi:10.1038/nnano.2008.174

Keller, T. S., Mao, Z., and Spengler, D. M. (1990). Young's modulus, bending strength, and tissue physical properties of human compact bone. *J. Orthop. Res.* 8 (4), 592–603. doi:10.1002/jor.1100080416

Khan, M. A., Cantù, E., Tonello, S., Serpelloni, M., Lopomo, N. F., and Sardini, E. (2019). A review on biomaterials for 3D conductive scaffolds for stimulating and monitoring cellular activities. *Appl. Sci.* 9 (5), 961. doi:10.3390/app9050961

Khodagholy, D., Gelinas, J. N., Thesen, T., Doyle, W., Devinsky, O., Malliaras, G. G., et al. (2015). NeuroGrid: recording action potentials from the surface of the brain. *Nat. Neurosci.* 18 (2), 310–315. doi:10.1038/nn.3905

Khorrami, M., and Abidian, M. R. (2018). "Aligned conducting polymer nanotubes for neural prostheses," in Proceedings of the 40th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), Honolulu, HI, USA, July 18-21, 2018, 6080–6083.

Khorrami, M., Antensteiner, M., Fallahianbijan, F., Borhan, A., and Abidian, M. R. (2017). "Conducting polymer microcontainers for biomedical applications," in Proceedings of the 39th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), Jeju Island, South Korea, July 11-15, 2017, 1869–1872.

Khorshidi, S., and Karkhaneh, A. (2018). Hydrogel/fiber conductive scaffold for bone tissue engineering. *J. Biomed. Mater. Res. Part A* 106 (3), 718–724. doi:10.1002/jbm.a.36282

Kim, B. C., Spinks, G., Too, C. O., Wallace, G. G., and Bae, Y. H. (2000). Preparation and characterisation of processable conducting polymer–hydrogel composites. *React. Funct. Polym.* 44 (1), 31–40. doi:10.1016/S1381-5148(99)00074-7

Kim, D.-H., Kim, Y.-S., Amsden, J., Panilaitis, B., Kaplan, D. L., Omenetto, F. G., et al. (2009). Silicon electronics on silk as a path to bioresorbable, implantable devices. *Appl. Phys. Lett.* 95 (13), 133701. doi:10.1063/1.3238552

Kim, D.-H., Viventi, J., Amsden, J. J., Xiao, J., Vigeland, L., Kim, Y.-S., et al. (2010). Dissolvable films of silk fibroin for ultrathin conformal bio-integrated electronics. *Nat. Mater.* 9 (6), 511–517. doi:10.1038/nmat2745

Kim, J., Campbell, A. S., de Ávila, B. E.-F., and Wang, J. (2019). Wearable biosensors for healthcare monitoring. *Nat. Biotechnol.* 37 (4), 389–406. doi:10.1038/s41587-019-0045-y

Kim, K. S., Maeng, W.-Y., Kim, S., Lee, G., Hong, M., Kim, G.-B., et al. (2023a). Isotropic conductive paste for bioresorbable electronics. *Mater. Today Bio* 18, 100541. doi:10.1016/j.mtbio.2023.100541

Kim, S., Baek, S., Sluyter, R., Konstantinov, K., Kim, J. H., Kim, S., et al. (2023b). Wearable and implantable bioelectronics as eco-friendly and patient-friendly integrated nanoarchitectonics for next-generation smart healthcare technology. *EcoMat* 5, e12356. doi:10.1002/eom2.12356