REVIEW ARTICLE

Recent Progress of Soft and Bioactive Materials

in Flexible Bioelectronics Citation: Wu X, Ye Y, Sun M, Mei Y,
Xiaojun Wu1,2†, Yuanming Ye3,4†, Mubai Sun1,5, Yongfeng Mei1,2,6,7, Ji B, Wang M, Song E. Recent Progress
of Soft and Bioactive Materials in
Bowen Ji3*, Ming Wang1,8*, and Enming Song1,2,6* Flexible Bioelectronics. Cyborg Bionic
Syst. 2025;6:Article 0192. https://
1
Institute of Optoelectronics & Department of Materials Science, Shanghai Frontiers Science Research doi.org/10.34133/cbsystems.0192
Base of Intelligent Optoelectronics and Perception, State Key Laboratory of Integrated Chips and Systems
Submitted 14 May 2024
(SKLICS), Fudan University, Shanghai 200438, China. 2State Key Laboratory of Medical Neurobiology and Revised 22 August 2024
MOE Frontiers Center for Brain Science, State Key Laboratory of Molecular Engineering of Polymer, Fudan Accepted 22 September 2024
Published 29 April 2025
University, Shanghai 200438, China. 3Unmanned System Research Institute, National Key Laboratory of
Unmanned Aerial Vehicle Technology, Integrated Research and Development Platform of Unmanned Aerial Copyright © 2025 Xiaojun Wu et al.
Vehicle Technology, Northwestern Polytechnical University, Xi’an 710072, China. 4Queen Mary University of Exclusive licensee Beijing Institute of
Technology Press. No claim to original
London Engineering School, Northwestern Polytechnical University, Xi’an 710072, China. 5Institute of Agro- U.S. Government Works. Distributed
food Technology, Jilin Academy of Agricultural Sciences (Northeast Agricultural Research Center of China), under a Creative Commons

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Attribution License (CC BY 4.0).
Changchun, China. 6International Institute for Intelligent Nanorobots and Nanosystems, Neuromodulation
and Brain-machine-interface Centre, Fudan University, Shanghai 200438, China. 7Yiwu Research Institute
of Fudan University, Yiwu, Zhejiang 322000, China. 8Frontier Institute of Chip and System, Fudan University,
Shanghai 200433, China.

*Address correspondence to: [email protected] (B.J.); [email protected] (M.W.); sem@fudan.

edu.cn (E.S.)
†These authors contributed equally to this work.

Materials that establish functional, stable interfaces to targeted tissues for long-term monitoring/stimulation
equipped with diagnostic/therapeutic capabilities represent breakthroughs in biomedical research and clinical
medicine. A fundamental challenge is the mechanical and chemical mismatch between tissues and implants
that ultimately results in device failure for corrosion by biofluids and associated foreign body response. Of
particular interest is in the development of bioactive materials at the level of chemistry and mechanics
for high-performance, minimally invasive function, simultaneously with tissue-like compliance and in vivo
biocompatibility. This review summarizes the most recent progress for these purposes, with an emphasis on
material properties such as foreign body response, on integration schemes with biological tissues, and on their
use as bioelectronic platforms. The article begins with an overview of emerging classes of material platforms
for bio-integration with proven utility in live animal models, as high performance and stable interfaces with
different form factors. Subsequent sections review various classes of flexible, soft tissue-like materials, ranging
from self-healing hydrogel/elastomer to bio-adhesive composites and to bioactive materials. Additional
discussions highlight examples of active bioelectronic systems that support electrophysiological mapping,
stimulation, and drug delivery as treatments of related diseases, at spatiotemporal resolutions that span
from the cellular level to organ-scale dimension. Envisioned applications involve advanced implants for brain,
cardiac, and other organ systems, with capabilities of bioactive materials that offer stability for human subjects
and live animal models. Results will inspire continuing advancements in functions and benign interfaces to
biological systems, thus yielding therapy and diagnostics for human healthcare.

Introduction while that of electronic materials is up to 100 GPa [6]. The

state-of-the-art electrocardiogram (ECG) signal acquisition
Flexible bioelectronics can bridge the gap between mechanical relies heavily on in vitro wearable devices, e.g., Holter devices,
devices and living organisms and play critical roles in real- whose accuracy feedback is impacted by dynamic movement
time monitoring, sensing, recognizing, and actuating [1–5]. and transdermal transport manner [7,8]. Next-generation
However, the mechanical mismatch between electrodes and bioelectronics is characterized with advantages including
soft tissue hinders their conformable usage. For example, the soft, ultrathin, light weight, and microscale, which can be
Young’s modulus of myocardial tissue ranges from 10 to 15 kPa, used for implantable application to avoid those drawbacks

Wu et al. 2025 | https://doi.org/10.34133/cbsystems.0192 1

[9,10]. Meanwhile, they can contribute to the development In this review, the development and application of implant-
of precise and personalized medicine by supporting continuous able bioelectronics over the past few years is reviewed. We
long-term monitoring [11,12]. highlight the promising material design that contributes to bio-
Material engineering and structure engineering, which focus electronics progress from the viewpoint of mechanical and bio-
on silicon thin film and its configuration design, are the crucial logical. Specially, soft, flexible, and self-healing materials that
foundation of next-generation bioelectronics. The wide opera- benefit reliability of bioelectronics in dynamic environment from
tion temperature range (Tm ~ 1,420 °C) of monocrystalline sili- the aspect of mechanical match are introduced systemically.
con allows it to undergo various doping and manufacturing Bioadhesive and bioactive materials that favor the robust, bio-
processes that enable its application in the integrated semicon- safe, and multifunctional bioelectronics from the aspect of bio-
ductor device [13]. Since bulk silicon is rigid and high energy logical research are also summarized. Applications of implantable
consuming, silicon-based thin-film membranes with a nano- bioelectronics in monitoring and sensing, modulation of physi-
meter scale structural dimensions emerge to meet the soft and ological and pathological conditions via smart response, and
conformal requirements [11,14–16]. In addition to the thickness tissue regeneration via electrical stimulation are summarized
reduction of silicon substrates, their configuration can be fab- later. Furthermore, we discuss the remaining challenges and
ricated into open-mesh/honeycomb porous structures, serpen- opportunities for application of bioelectronics in precise diag-
tine patterns, and kirigami/origami structures with intrinsic nosis and treatment. We expect to provide comprehensive refer-
stretchability, further benefiting the mechanical match of ences for researchers who are seeking a roadmap toward the de
bioelectronics and living organisms [2,10,17–21]. Other novel novo design of bioelectronics for in vivo application.
materials have shown their competitiveness in intrinsically
stretchable bioelectronics design, e.g., rubber, polyurethane Flexible and Implantable Bioelectronics
(PU), and hydrogel scaffolds [22–25]. Recently, advanced manu-
facturing technologies also contribute to the flourishing devel- Currently, in vivo implantation of bioelectronics has gained great
opment of bioelectronics, e.g., 3-dimensional (3D) printing and attention due to the high signal-to-noise ratio (SNR) and precise

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microfluidic technologies, which endow bioelectronics with information feedback on target tissues. Fig. 1 demonstrates typi-
sophisticated module design in both components and structures cal applications of implantable bioelectronics toward differ-
and can be integrated with therapeutic capabilities [26–28]. ent organs/tissues for healthcare. Organs and tissues, including
Silicon can offer the in situ growth of insulation layer SiO2 brain, heart, muscle, neural, and retina, possess different biome-
by thermal oxidation, which is water-insoluble and possesses chanical features, giving distinct requirements for bioelectronics
excellent chemical stability and insulation properties [29]. In [6,43–45]. For their different implantable purposes, chronic and
general, bioelectronics encapsulated by SiO2 thin film would transient bioelectronics need distinct encapsulation strategies.
work stably in practical applications, while the local environ- However, flexible bioelectronics is the main development ten-
ment change over implanting makes it vulnerable. The interface dency due to its advantages in mechanical match and conformal
of implanted devices is first attacked by foreign body response intact with soft tissues [2,8,46,47]. In this section, based on the
(FBR), followed by congregation of proteins, neutrophils, fibro- latest progress in soft, flexible, stretchable bioelectronic devices,
blasts, macrophages, and so on [20,30]. Under the electric field, we discuss the general principle recognized in their design and
the encapsulation layer becomes sensitive to water and ions, limitations in practical application.
accelerating the failure of devices. With prolonged implanta-
tion, fibrous capsule formation and inflammation would decrease Design principle of flexible and
the monitoring reliability and lead to device failure eventually stretchable bioelectronics
[31,32]. Many efforts have been devoted into guaranteeing the Metals and their oxides or nitrides, such as platinum, gold,
chronic implantable signal acquisition of bioelectronic from iridium, and iridium oxide, are commonly employed to give a
several aspects: (a) mechanical match is necessary to minimize low impedance and biocompatibility interface with tissue and
the mechanical damage of target tissue during implanting and bioelectronics [48]. Utah array and Michigan probes represent
enhancing the conformable contact; (b) the chemical interface the 2 mature implants for recording signals from the brain.
is biocompatible or immune shielding to avoid FBR; (c) anti- In particular, Utah array becomes the “gold standard” for
inflammatory or immunosuppressant is adopted to modulate high-channel brain–computer interface (BCI) and has been
an immune response. Besides chronic application, some bio- implanted in rats, monkeys, and even patients [48–51]. Yet,
electronics are designed with short-term service, where pro- the rigid probes might fail for the dynamic nature and FBR of
grammable biodegradability is highly demanding [33–35]. In tissues over chronic implantation [52]. Considering the local
both cases, the degradation products should be bioabsorbable environment of bioelectronics, strategies including surface
or metabolized by the host. modification, soft encapsulation, and bio-glue have been
Nowadays, bioelectronics using multifunctionalization adopted to prolong the lifetime of bioelectronics.
(BUMF) is blooming, and based on this, the integration of diag- As shown in Fig. 2, we systemically summarize the recent
nosis (monitoring) and therapy (stimulation) has emerged development of bioelectronics from viewpoints of electrode,
[36–38]. For example, hydrogels have been applied as a tensile encapsulation layer, and substrates. Novel materials can boost
encapsulation material for bioelectronics, and they can also be remarkably the soft and stretchable performance of bioelec-
used as drug carriers with sustained release [39–42]. Considering tronics. Carbon-based materials [e.g., graphene, MXenes, and
that novel active materials can benefit bioelectronic innovations carbon nanotubes (CNTs)] and conducting polymers (CPs)
(e.g., intrinsic stretchable, chronic implantable, and program- [e.g., poly (3-4, ethylenedioxythiophene) (PEDOT), polypyr-
mable biodegradable) and play a vital role in the construction role (PPy), and polyaniline (PNAi)] have been applied to
of BUMF, we would give a systemic review of the materials construct flexible and stretchable bioelectronics [36,53–63].
design and development. Moreover, conductive polymer, hydrogel, semi-dry hydrogel,

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Fig. 1. Typical applications of implantable bioelectronics for healthcare toward organs/tissues with different biomechanical feature. E, elastic modulus; EEG, electroencephalography;
ECoG, electrocorticography; WC, water content; COF, coefficient of friction; IOP, intraocular pressure; ECG, electrocardiogram; EMG, electromyography.

Fig. 2. Brief overview of recent development of implantable bioelectronics. (A to C) Encapsulation layers. (A) Chronic encapsulation: SiO2. PDMS: Reproduced with permission
from [42]. Copyright 2023, Wiley-VCH. (B) Bioactive polymer for biodegradable encapsulation: PLGA: Reproduced with permission from [72]. Copyright 2024, Wiley-VCH.
PA-SiON: Reproduced with permission from [73]. Copyright 2024, Wiley-VCH. (C) Hydrogel encapsulation: Hydrogel/polymer coating: Reproduced with permission from [74].
Copyright 2023, Wiley-VCH. (D to F) Electrode. (D) Conductive nanomaterials as electrode: CNT: Reproduced with permission from [244]. Copyright 2024, Springer Nature
Limited. Graphene: Reproduced with permission from [53]. Copyright 2023, Wiley-VCH. MXene: Reproduced with permission from [54]. (E) Conductive polymer as soft
electrode: PEDOT:PSS: Reproduced with permission from [55]. Copyright 2022, AAAS. PPy: Reproduced with permission from [56]. Copyright 2017, Wiley-VCH. (F) Conductive
hydrogel as soft electrode: BC-CPH: Reproduced with permission from [26]. Copyright 2023, Springer Nature Limited. PP-P-A-Zr: Reproduced with permission from [245].
Copyright 2024, Wiley-VCH. (G to J) Substrate. (G) Silicon-based elastomer: Ecoflex: Reproduced with permission from [76]. Copyright 2024, Elsevier. (H) Stretchable polymer
semiconductors: SBS fiber: Reproduced with permission from [77]. Copyright 2023, AAAS. Self-adhesive SBES: Reproduced with permission from [75]. Copyright 2023, AAAS.
BASC film crosslinked by p(g2T-T) and BAP: Reproduced with permission from [78]. Copyright 2023, AAAS. (I) Biodegradable polymer: PLGA: Reproduced with permission
from [79]. Copyright 2024, Wiley-VCH. (J) Substrate free: Reproduced with permission from [80]. Copyright 2023, AAAS.

Wu et al. 2025 | https://doi.org/10.34133/cbsystems.0192 3

or elastomers are developed and employed as replacements or Combined with structural design such as waves, helices,
coatings of rigid electrodes for improved mechanical match and open-mesh serpentine, and island-bridge structures, the
conformability with tissues [18,41,56,64–71]. Insulators and resulting flexible 3D structure can afford stretch deformation
encapsulation layer mainly determine the lifetime and mechani- [11]. Brainmask with fractal serpentine design and bacterial
cal performance of bioelectronics. In addition to SiO2, soft poly- cellulose (BC) substrate was reported [87]. The Brainmask
mers such as polydimethylsiloxane (PDMS), Ecoflex, polyimide device kept the structure intact after attaching to the agar gel
(PI), and parylene C are used for chronic flexible thin-film cylinder (5 mm in radius). Meanwhile, high moisture of BC
encapsulation, while polycaprolactone (PCL), polylactic-glycolic film makes it easily attach to the nonplanar epidural surface
acid (PLGA), and polyglycolic (PGA) are applied to biodegrad- that favors the precise recording of in vivo electrocortico­
able and bioabsorbable bioelectronic encapsulation [42,72–75]. graphy (ECoG) signals. 3D structures that show more accom-
Substrates for bioelectronics are limited by the processing condi- modation to curved surface of organ/tissues can also be the
tions; hence, rubbery, PU, and stretchable polymer semiconduc- target of transfer printing. Combined with structural design
tors with intrinsic stretchable and self-healing properties are such as waves, helices, open-mesh serpentine, and island-
also proposed [75–81]. In addition, wireless data transmission bridge structures, the resulting flexible 3D structure could
and energy supply are also in hot research for implantable bio- afford stretch deformation. Yu and colleagues [89] report a
electronics, although they are not covered in this review [2,20]. biaxially stretchable curvy, shape-adaptive imager with bal-
These efforts contribute to the development of implantable bio- loon stamp transfer, and kirigami structural design. Under
electronics with good biocompatibility, designable lifetime, high 30% biaxial strain, the optoelectronic 32 × 32-pixel array can
signal quality, and high reliability. maintain 78% of its electrical performance.
Although material systems with unique feature can meet Elastomers such as PU, rubbery, and stretchable polymer
the requirement of application of bioelectronics toward a semiconductors [e.g., poly-thieno[3,2-b]thiophene-diketopyr-
specific condition, their composition shall be adjustable con- rolopyrrole (DPPTT)] are promoted with intrinsically high
sidering the overall performance about mechanical, electrical, elasticity and low hysteresis [89]. Deformable bioelectronics

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biochemical, and so on. Mechanical properties such as tensile based on those elastomers can be applied for conditions with
strength, Young’s modulus, and fracture toughness shall in large deformations, like beating heart. Epicardial bioelectronic
similar level with “soft and wet” tissues to eliminate mechani- patch based on rubbery presents suitable mechanical softness
cal mismatch. Besides high electrical conductivity for signal to heart tissue that can realize spatiotemporal mapping of elec-
sensing and amplification, the circuit can provide additional trophysiological activity [18]. Hydrophilic PU composited with
modulation via external stimulus such as force, photo, acous- conductive fillers [e.g., CNT, poly(3,4-ethylenedioxythiophene)-
tic, and magnetic. Biochemical properties, especially the sur- polystyrene sulfonate (PEDOT:PSS), and liquid metal] can be
face biochemistry, account for the direct interaction with engineered to be multifunctional bioelectronics [90,91]. A tis-
tissues and can also provide surface sensing and shielding sue adhesive ink consisting of PU, poly(acrylic acid) N-hydroxy
function. Nowadays, all-soft bioelectronics that are promising succinimide ester (PAA-NHS), and ethanol/water mixture was
in connect tissue engineering and bioelectronics may provide fabricated into tissue adhesive patches with conformable,
a platform for seamless HMI. We inferred it as the main ten- stretchable, and robust adhesion with wet tissues within sec-
dency for bioelectronics. onds [92]. Conductive silver ink was employed to construct a
simple LED circuit to explore the bioadhesive bioelectronic
patch application of the 3D printing platform. Meanwhile,
Design and fabrication of flexible and modification of elastomers to improve their reliability is ongo-
stretchable bioelectronics ing. Very recently, a hydrophilic polyurethane (RPU) sub-
Soft and stretchable materials strate was reported with high binding strength to wet gold
Rigid and thick implants cause more serious FBR and mechani- (Au) grains (1,243.4 N/m), which is superior to pervious elas-
cal mismatch than the soft and thin ones; thus, implantable tomeric polymers [PDMS, styreneethylene-butylene-styrene
bioelectronics are moving toward thinner and flexible implants. (SEBS), and Ecoflex] [86].
Silicon-on-insulator (SOI) technologies bring a thin platform Hydrogel is another representative material for soft and
for the fabrication of the hyperflexible device [33,82]. With the stretchable bioelectronics, and has shown outstanding per-
development of nearly 40 years, SOI wafers can be polished formance for its extracellular matrix (ECM)-like structure and
with a thickness of less than 100 nm. Devices based on those composition. Hydrogel-based cardiac patch can not only pro-
wafers can stand deformation such as bending, twisting, and vide real-time monitoring of myocardium electrical activity
folding [83]. For instance, ultrathin neuroelectronic array but also modulate tissue damage via drug delivery or elec-
based on n-doping of Si nanomembrane with a thickness of tronic stimulation [60,93,94]. Despite promising mechanical
~140 nm demonstrated negligible performance degradation strength of hydrogel-based bioelectronics, the chronic implan-
after 10,000 bending cycles (bend radius ~ 4 mm) [4]. With the tation of hydrogel is difficult as it is prone to the attack or
aid of transfer printing, devices can be integrated on soft corrosion by surrounding body fluid.
substrate, e.g., PDMS, PI, and other polymer films [cel-
lulose, silk fiber, poly(vinyl alcohol) (PVA), and so on] [84–87]. Self-healing materials
Eye-implantable probe (width: 190 μm, thickness: 110 μm) was Self-healing materials rapidly and spontaneously restore their
fabricated via transfer printing by PDMS stamp to PI panel with structures and functionalities upon encountering damage under
SU-8 as adhesive layer [88]. The flexible, small size, and probe- external stimulations, which can enhance the anti-fatigue per-
type pressure-sensitive transistor can selectively and pre- formance of devices, extend their lifespans, and improve their
ciously monitor intraocular pressure (IOP), without the risk of reliability [95–97]. These materials offer numerous advantages
eye damage and measurement errors. for minimally invasive surgeries aiming at tissue regeneration,

Wu et al. 2025 | https://doi.org/10.34133/cbsystems.0192 4

including nerve regeneration, wound healing, implantable pros- commercial glues (Fig. 3Ai). When a strain of 500% was applied
thetics, bone repair, and tendon repair [62,98–101]. Restoration to the 7% (w/v) HA-PEG hydrogel, both storage modulus (G′)
of the original structure, mechanical properties, and electrical and loss modulus (G″) values were fully recovered after the
conductivity is achieved through various mechanisms, such as strain was reduced to 1% at 5-min time intervals (Fig. 3Aii).
noncovalent bonds (e.g., electrostatic interactions, metal coor- Moreover, Xu et al. [104] introduced a bioactive hydrogel fea-
dination interactions, and hydrogen bonding interactions) or turing Schiff base bonding between tannic acid-modified gold
dynamic reversible covalent chemical bonds (such as Diels– nanocrosslinkers and chitosan, which rapidly recovered within
Alder reactions and Schiff base reactions) [95]. Materials capable 30 min. Injection of the hydrogel into the brains of Parkinson’s
of spontaneous and rapid repair in the in vivo environment are disease (PD) rats significantly mitigated irregular neuronal cell
particularly suited for practical applications. Implantable self- discharges in the subthalamic nucleus, thereby aiding in the
healing materials are primarily categorized into hydrogels, elas- restoration of motor function.
tomers, and conjugated polymers. However, self-healing hydrogels relying on weak dynamic
Hydrogels have gained extensive attention owing to their bonds often suffer from low toughness and susceptibility to
tissue-like properties, including a similar Young’s modulus and in vivo breakage [99]. Elastomers represent another common
compatibility with physiological microenvironments and tis- class of self-healing materials characterized by adaptive mechani-
sues, which promote favorable biocompatibility and molecular cal properties and exceptional resilience. PDMS- and PU-based
transport [38,102]. Particularly, injectable self-healing hydro- self-healing elastomers are prevalent in implantable devices,
gels have garnered considerable attention due to their effective- leveraging segment mobility, reversible covalent bonds, and
ness in filling irregular defects. The basis for the self-repairing hydrogen bonds to achieve self-healing capabilities [105–107].
properties of hydrogels is the reversibility of the crosslinked The first stage for the self-healing of devices is the self-healing
network bonds. Self-healing hydrogels can be prepared by func- of elastomer substrates. Zhou et al. [108] developed catechol-
tionalizing conventional polymers, such as the natural polymer functionalized polyurethane (C-PU-PTMEG) elastomers. By
protein, cellulose, sodium alginate, chitosan, gelatin, and hyal- adjusting the molecular weight of poly(tetramethylene ether

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uronic acid (HA), as well as the synthetic polymers including glycol) (PTMEG), they modulated the mobility of chain seg-
polyethylene glycol, polyetherimide, and polyethylene oxide. ments and dynamic hydrogen bonding to enhance material
For example, Ren et al. [103] polymerized hydrazide-modified self-healing. At 37 °C, C-PU-PTMEG exhibited self-healing
HA and o-phthalaldehyde (OPA)-terminated 4-armed poly properties in air and phosphate-buffered saline (PBS) solution
(ethylene glycol) (4ApeG-OPA) into an injectable, self-healing (Fig. 3Bi). When used as a cardiovascular scaffold coating on the
hydrogel, which showed better wound healing efficiency than inner wall of a commercial trigeminal vessel after connecting

Fig. 3. Self-healing hydrogels and elastomers. (A) Self-healing hydrogels. (i) Dynamic cross-linking in the hydrogel between HA and 4ApeG-OPA. (ii) Step–strain test for
7% (w/v) HA-PEG hydrogel. Reproduced with permission from [103]. (B) Self-healing elastomers. (i) The self-healing of the family of C-PU-PTMEG elastomers in PBS.
(ii) Less thrombus coverage for the C-PU-PTMEG-treated group at the cross-section of the catheter. Reproduced with permission from [108]. Copyright 2022, AAAS.
(C) (i) Fracture capacitor (left) and healed capacitor with layer realignment (right). (ii) Initial (top) and healed (bottom) pressure-sensing performance of the
capacitor. Reproduced with permission from [110]. Copyright 2023, AAAS.

Wu et al. 2025 | https://doi.org/10.34133/cbsystems.0192 5

arteriovenous vessels in rabbits, it showed improved patency structures [121]. Furthermore, materials with both mechanical
with reduced thrombus formation compared to commercial property and electrical conductivity similar to those of tissues
thermoplastic polyurethane (TPU) (Fig. 3Bii). Besides the have been developed. In particular, electroactive materials with
elastomer substrate, the self-healing of conductive component high strength, which have been made into artificial muscles
is equally important in bioelectronic applications. Son et al. or artificial tendons, have received much attention. Artificial
[109] embedded CNTs within a self-healing PDMS–MPU0.4– muscles have achieved a wide range of applications in mimick-
IU0.6 elastomer. The fractured conductive network autono- ing muscle contraction to generate force, mechanical actuating
mously regenerated, demonstrating complete restoration of robotics, and prosthetic limb. For instance, Pan et al. [122]
the resistance–strain behavior after 12 h of self-healing, and proposed a supertough spider silk composites for artificial
capable of withstanding 100% tensile strain. Moreover, achiev- tendon, with a toughness of 420 MJ/m3 and a conductivity
ing self-healing of complex device shapes and functionalities of 1,077 S/cm. The electro-tendon, which is composed of
also necessitates self-healing behavior between different func- spider silk, single-walled carbon nanotubes (SWCNTs), and
tional layers. Cooper et al. [110] achieved automatic reorga- PEDOT:PSS, showed no change in conductivity after more than
nization and healing between layers by alternately arranging 40,000 bending and stretching cycles.
PDMS-based polymer and polypropylene glycol (PPG)-based Moreover, in terms of functionality, materials mimicking
polymer multilayer films (Fig. 3Ci), utilizing post-damage tissue properties, such as drug delivery, self-healing, and
surface energy differences. When applied in capacitive pres- stimulus-responsive materials, have been developed [40,97,123].
sure sensors, the drifted and hysteresis changes in device capaci- Conductive hydrogels, which have high softness, tissue-like
tance after self-repair were minimal (Fig. 3Cii), with 96% mechanical properties, high water content, mimicry of the
recovery of initial capacitance after heating and the full recov- extracellular environment, and potential for multifunctionality,
ery of mechanical and conductive properties after 72 h of are emerging as promising candidates for tissue-like materials
annealing at 70 °C. Such interlayer co-self-healing character- [112]. Park et al. [123] introduced an injectable, degradability-
istics prevent misalignment from constraining device func- tunable conductive hydrogel. This hydrogel combines poly(ethylene

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tionality restoration. However, its self-healing capacity remains glycol)-tetrathiol and thiol-functionalized reduced graphene oxide
limited at room temperature. (rGO) with hydrolyzable poly(ethylene glycol)-diacrylate and
Lastly, the self-healing properties of conjugated polymers poly(ethylene glycol)-dimaleimide, respectively. The resulting
have been studied to promote the development of devices based hydrogels exhibit a Young’s modulus of 15 to 17 kPa and an
on organic semiconductors, including organic thin-film field- electrical conductivity of 21 to 22 mS/cm. Hydrolyzable con-
effect transistors. Oh et al. [111] designed a 3,6-di(thiophen- ductive hydrogels vanish within 3 d after in vivo injection, while
2-yl)-2,5-dihydropyrrolo[3,4-c]pyrrole-1,4-dione (DPP)-based bioelectrodes based on stabilized conductive hydrogels can
conjugated polymer containing 2,6-pyridine dicarboxamide record electromyographic signals in vivo for up to 21 d, achiev-
(PDCA). Through thermal annealing and solvent vapor annealing ing an SNR of 7.03 ± 1.7.
treatments, the mobility of damaged polymer films recovered Biocompatibility of the material with tissues also requires con-
from 0.024 to 1.13 cm2/Vs. sideration for minimizing inflammatory or immune response to
host tissue. Natural biomaterials including natural polysaccharide
Tissue-like performance: Mechanical and (such as chitosan, cellulose, starch, alginate, sodium hyaluronate,
functional properties and dextran) and protein (such as silk, collagen, elastin, reflectin,
Tissue-like materials have been developed to create seamless and keratin) benefit the progress of stable bioelectronic interfaces
and adaptive interface between electronic devices and human [124,125]. Additionally, the structure and composition of bioac-
tissues, aiming to minimize mismatch [112]. Extensive research tive materials are similar to the natural ECM, which facilitates cell
has focused on reducing the mechanical mismatch between proliferation and differentiation, and has great advantages in
implanted materials and surrounding tissues to mitigate immune promoting tissue repair and wound healing. Wang et al. [126]
responses, implant rejection, and foreign body reactions, thus designed bilayer hydrogels based on NHS ester-modified sodium
enhancing biocompatibility [65,113,114]. Parameters such as alginate and chitosan. The hydrogel could spontaneously curl
hardness, tensile strength, toughness, viscoelasticity, relaxation into microtubules from its initial film form to form an adaptive
time scale, adhesion, and solute diffusivity are crucial for char- and conformal bioelectronic interface. Cells on its surface have
acterizing mechanical suitability, among which Young’s modu- very high cellular activity and proliferation ability, and are also
lus is of primary interest [115]. Recent material advancements able to form adhesion spots and further fully form intercellular
have enabled implants to not only possess Young’s modulus linkages.
similar to that of tissues but also adjust their mechanical prop-
erties as needed by employing strategies such as intrinsic soft- Implantable bioelectronics systems
ness and the design of soft interlayer structures [56]. Foreign body response
Additionally, many tissues in the human body, including The FBR governed by immune system can impend the lifetime
muscles, tendons, and articular cartilage, exhibit anisotropic and quality of implantable bioelectronics [31]. FBR is a process
structural characteristics [116,117]. Developing materials capa- that can be divided into 3 stages: protein adsorption, matrix
ble of effectively mimicking such anisotropic mechanical prop- deposition, and fibrous encapsulation. Proteins from surround-
erties is crucial for preserving, replacing, and repairing these ing body fluids can contact and adsorb onto implants within
biological tissues. Recent strategies to achieve mechanical anisot- several seconds and trigger an immune response. Protein aggre-
ropy involve stretching nanofibers, combining stretching and gation is related to the surface property such as surface wet-
compression, waving, supramolecular assembly, and stretching tability, topography, and roughness, driving numerous works
polymer chains [118–122]. Additionally, bio-3D printing has that focus on surface modification [30]. The superhydrophobic,
emerged as a promising approach for fabricating anisotropic superhydrophilic, and superwetting surface has been reported

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to resist the nonspecific binding of proteins and thus escape The hydrogel realized a conformal contact with brain tissue for
the subsequent immunorecognition [127,128]. Materials includ- its low modulus (<1 kPa) and high adhesion strength (~10 kPa).
ing PEG, zwitterionic, polypeptides, and polysaccharides have The catechol groups on the hydrogel help to integrate electronic
been employed in surface modification in the form of coating, device and soft brain tissue for both scalp electroencephalogram
hydrogel, membrane, polymer brush, and so on [129–131]. (EEG) and intracranial ECoG signal recording, with an SNR of
Drugs with anti-inflammation or immunosuppressive activity ~10.19 dB for the ECoG signal. With the development of the
can also modulate FBR at implanted regions [132]. However, wet adhesion mechanism, hydrophobic interaction is empha-
FBR is a continuous process where matrix deposition and fibrous sized. They report a short alkyl chain-modified hydrogel in
encapsulation occur after blood protein adsorb, loading anti- addition to dopamine. The PDA-PAM-C2 hydrogel composed
inflammation drugs cannot prevent fibrous capsule formation of acrylamide (AM), dopamine, and ethyl acrylate (C2) possessed
eventually. the highest adhesive strength to wet glass surfaces (23.5 ±
Matrix deposition is the result of protein adsorption, which 1.9 kPa) and reproducible adhesive strength to porcine skin
consisted of acute and chronic inflammation [133]. Acute (~8 kPa) [146]. Molecular dynamics (MD) simulation revealed
inflammation exists at the early stage of implantation (<7 d), that the hydration layer broken by C2 strengthened the interac-
during which polymorphonuclear neutrophils (PMNs) recruited tion between the hydrogel and glass surfaces. A conductive
by aggregated proteins are the primary cell types. PMNs would hydrogel was fabricated by introducing a PDA-functionalized
secrete proteolytic enzymes and reactive oxygen species (ROS) CNT (pCNT) for in vivo epicardial ECG signal detection, show-
to defend against microorganisms, as well as chemoattractant ing a potential for in vivo physiological signal monitoring and
[e.g., interleukin-8 (IL-8)] to appeal monocytes and macro- stimulation.
phages migrated and polarized into pro-inflammatory M1 mac- In terms of the dynamic process of wet adhesion, Yu et al.
rophages [134]. Chronic inflammation starts when monocytes [147] fabricated a chronological adhesive cardiac patch (CAHP)
and macrophages become predominant and fade over time crosslinked by functionalized polyaniline (f-PANi) and poly-
(~21 d) [135]. During this period, M1 macrophages release vinyl alcohol (PVA). The dynamic covalent borate ester bonds

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ROS continuously and adhere and spread onto the implant and noncovalent hydrogen bonds among them ensure the
surface to “engulf ” it. Therefore, the implant device is wrapped in situ gelation mechanism and further benefit internal cohe-
with infused macrophages, which are called multinucleated sion and interfacial interlocking to firmly anchor with the myo-
foreign body giant cells (FBGCs) [136]. FBGCs work together cardium (Fig. 4A). CAHP demonstrates an enhanced mechanical
with other immune cells to attract fibroblasts by secreting pro- interlocking adhesion with tissue by penetrating the wet epi-
fibrotic factors [including transforming growth factor-β (TGF-β), cardium and forming tiny and dense pore channels at the tissue
IL-6, platelet-derived growth factor (PDGF), and connective interface (Fig. 4B and C). Bioadhesive motifs can also be incor-
tissue growth factor (CTGF)]. Fibroblasts infiltrate and pro- porated into polymer brush for wet tissue adhesion. By means
liferate gradually, and deposit collagen to reconstruct the of a polyethylene backbone with long linear side chains, carboxylic
surroundings of devices, and capsules are formed by taking acid (COOH) and NHS ester show a synergistic effect in bio-
fibroblasts as major cells [137]. A stiffer and thicker capsule can adhesive polymer (BAP) [78]. Specifically, COOH groups absorb
be sensed and causes pain of adjacent tissues, even requiring water for temporarily cleaning and forming electrostatic inter-
secondary surgery [138,139]. Considering the cascade nature actions with tissue surfaces, while NHS covalently bonds with
of FBR, materials with inherent histocompatibility, immuno- the primary amine groups on the tissue surface. An intrinsic
suppression, and self-cleaning capability play a prominent role bioadhesive polymer semiconductor (BASC) film was devel-
in the development of implantable bioelectronics. We would oped by crosslinking with semiconducting polymer poly(3,3′-
discuss the recent advances in facilitating HMI from the per- bis(2-(2-(2-methoxyethoxy) ethoxy) ethoxy)-2,2′:5′,2″-terthiophene)
spective of biomedical materials. [p(g2T-T)], whose interfacial toughness was significantly higher
than that of merely p(g2T-T). The soft and bioadhesive BASC
Tissue adhesive materials and architectures film provides a direct attachment to tissues without gaps and
Tissue adhesion ensures a seamless bioelectronics–tissue inter- high impedance. Organic electrochemical transistors (OECTs)
action, which favors the reliability and validity of bioelectronics. equipped with BASC were fabricated for electrophysiological
Generally, strategies to construct tissue adhesive interface include recording (Fig. 4D). They have a stable and conformable con-
surface chemistry and topography modification. Mussel-inspired tact with isolated rat-heart surface even bearing mechanical
chemistry provides an efficient tool for preparation of wet tissue perturbation, while nonbioadhesive OECT was detached from
adhesive materials [140,141]. Dopamine, a typical catechol- heart and ECG recording was ceased (Fig. 4E and F). Very
based derivative, has been widely employed in the form of recently, a polymer hydrogel bioadhesive (PHB) consisting
dopamine-grafted polymers or self-assembly polydopamine of poly(2-hydroxyethyl methacrylate-co-N-vinylpyrrolidone)
nanoparticles (PDA NPs) to supply material-independent adhe- [poly(HEMA-NVP)] hydrogel layer for swelling-resistant and
sion [142,143]. Lu and colleagues [144,145] have focused their PAA-NHS brush for adhesive was reported [148]. The laminated
researches on the adhesive hydrogel with tough, self-healing, PHB formed conformal interfaces with PLGA and porcine tis-
conductive, antifreezing, antioxidizing properties to monitor sue, contributed by noncovalent interactions (i.e., hydrogen
physiological signals and treat diseases. Considering the impor- bonding and electrostatic interactions) and covalent bonding
tant role in implantable bioelectronics, they designed an ultrasoft, between the NHS (hydrogel adhesive side) and amine moieties
bioadhesive, transparent, conductive, and immune evasive hydro- (tissue side) (Fig. 4G). Furthermore, the PHB was integrated
gel as brain–machine interface (BMI) by incorporating dopamine with a wireless pressure device for intracranial pressure (ICP)
methacrylate-hybridized poly(3,4-ethylenedioxythiophene) monitoring. The robust interface supports a more widely sens-
nanoparticle (dPEDOT NP) into the carrageenan (CA) inter- ing range (0 to 40 mmHg) and higher sensitivity (1 MHz/
penetrated PDA-polyacrylamide (CA-PDA-PAM) network [145]. mmHg) of ICP than sutures, which can be potentially used for

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Fig. 4. Wet tissue adhesive materials. (A) Chronological adhesion mechanism of the CAHP. (B) Scanning electron microscopy images of the hydrogel–tissue interface.
(C) Adhesion strength between CAHPs and porcine myocardium. Reproduced with permission from [147]. Copyright 2023, Springer Nature Limited. (D) Direct adhesive
attachment achieved by a BASC channel and a wet tissue surface. The double-network design of the BASC contains a semiconducting polymer and an adhesive polymer
that achieves covalent bonding with tissue surfaces. (E) Shear strength of the adhesion between a fully bioadhesive OECT on the pig muscle tissue. (F) Conformable and
stable contact of bioadhesive OECT enables continuous ECG signal recording than nonbioadhesive OECT [78]. Copyright 2023, AAAS. (G) Schematic illustration of the
PHB layer for establishing a robust biointerface between the wireless sensors and biological tissues. Reproduced with permission from [148]. Copyright 2024, Wiley-VCH.

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real-time physiological and clinical investigations. To sum up, ion-gated organic electrochemical transistor (IGT) and nonvola-
motifs with both physical or chemical interaction with tissue tile memory device as channel materials, as well as optoelectrode
can both enhance the adhesive performance. They can drive arrays and neural probes as encapsulation materials [157–159].
bioelectronics anchored tightly to neighboring tissues. With strong intramolecular hydrogen bonding, chitosan is a
Topological modification is gaining more and more con- promising candidate to fabricate anti-swelling hydrogel. Qi and
cerns for wet tissue adhesion, owing to its high efficiency in colleagues [160] reported a nonswelling, wet adhesion hydrogel
building and enhancing interface interaction via topological (PAACP) composed of poly(vinyl butyral), acrylic acid, gelatin,
interlock or entanglement [23,149,150]. Tissue topology such and chitosan-grafted N-acetyl-l-cysteine for bioelectronics. After
as pore size, wrinkles, and roughness guided the adhesive archi- implantation for 14 d in vivo, PAACP preserved the tough adhe-
tectural design. In addition, inspired by biological wet adhesive sion performance, supporting the long-term monitoring of elec-
surfaces such as octopus, gecko, and Boston ivy, a series of trode array and strain sensor. Cellulose is the most abundant
biomimetic structures have emerged [151]. Suckers, polygonal biopolymer on earth, which can be extracted from forests or
patterns, nanopillar arrays, hook arrays, seta arrays, and so on secreta by microbes [161]. Similar to chitosan, cellulose with
have been reported with enhanced adhesion force than the flat many -OH groups possesses strong intramolecular hydrogen
surface. In terms of topological entanglement, cellulose, algi- bonding, making it promising to fabricate tough film and
nate, and chitosan were employed as stitch polymers to pene- hydrogel. Compared with other biomaterials, cellulose is less
trate into the 2 adherends [152]. Once triggered by pH, a stitch immunogenic but is biodegradable since it is plant-originated.
network formed and strong adhesion was achieved among Cellulose nanocrystals (CNCs), cellulose nanofibers (CNFs), and
wet materials. With the same strategy, polyacrylic acid (PAA), BC, which have high aspect ratio, are the main derivates of cel-
PAM, poly(n-isopropylacrylamide) (PNIPAM), and cyanoac- lulose, and they have been used as substrates for several bioelec-
rylate polymers were also proved to have the potential for topo- tronics (e.g., neural probe, conductive biopatches, and biosensor)
hesive [108,153]. The synergistic effect of combined surface [162]. Alginate is a soluble, brown seaweed-extracted polysac-
chemistry and topography modification has been confirmed, charide with alternated mannuronic acid (M unit) and gulu-

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e.g., a stitch-bonding strategy proposed by Lu and colleagues ronic acid (G unit). It can be crosslinked by divalent cations
[23]. Dopamine-grafted PAA and NaIO4 were used as glue (e.g., Ca2+, Cu2+, and Sr2+) and forms a unique “egg-shell” struc-
polymer and the trigger, respectively, for intermolecular cross- ture. Alginate has been reported to possess multiple bioactivities
linking, demonstrating universal adhesion performance (adhe- (e.g., antioxidation and anticoagulation), which provide many
sion energies, ~200 to 400 J/m2) to a series of representative benefits for its biomedical application, such as cargoes for drug
adherends [glass, aluminum oxide (Al2O3), PDMS, porcine and cell delivery and scaffolds for tissue engineering [163–165].
liver, and skin]. Till to now, most works about topography Complexed with conductive filler [MXene, graphene oxide (GO)
modification for better tissue adhesion were presented in mate- CNTs, silver nanowires (AgNWs), PEDOT:PSS, PANi, and
rials level instead of device. Thus, it is urgently demanded to so on], alginate-based conductive hydrogel has drawn a lot of
integrate novel materials and topological design with bioelec- attention owing to its soft and stretchable advantages [58]. Fig.
tronics to facilitate its practical application in dynamic environ- 5B displays a sutureless bioelectronic (SAFIE) composed of
ment. Hydrogel is a promising platform to eliminate the 3 layers: an ionically conductive tissue adhesive, a viscoelastic
gap between materials and devices. Recently, Liu et al. [154] networked film, and a fatigue-resistant conducting composite
reported a stickleback fish-inspired Janus zwitterionic hydrogel (E-SHN) [166]. Alginate modified with dopamine (Alg-CA) was
patch with microstructures to minimize the likelihood of slip- coated and penetrated into E-SHN to provide an instantaneous
page and detachment from the cecum surface. The concept (<60 s), robust (adhesive strength ~ 7.2 kPa), stretchable (strain
Janus hydrogel is very suitable to provide specific bioadhesive ~ 660%), and conformal adhesion with heart. Moreover, metal
layers for bioelectronics. We inferred that the combination of coordination between carboxylate/catechol groups in Alg-CA
Janus hydrogel with bioelectronics may promote the application and Ga3+ and/or In3+ of EGaIn results in an electrical pathway,
of topological modification in bioelectronics. which benefits the durable and real-time cardiac monitoring.
Polysaccharides with different mechanical and biological features
Bioactive materials for integrated bioelectronics can work together as bioelectronic–tissue interface materials
with multifunctionalization (BTIM), e.g., the formula consisted of bioresorption polyethyl-
Although the mechanism is unclear, bioactive materials are ene glycol-lactide acid diacrylate (PEG-LA-DA), alginate, and
promising since they provide multifunction, including anti- chitosan. PEG-LA-DA possesses photopolymerization nature that
immunity, antioxidant, and anti-inflammation, to implant bio- accounts for sol–gel transformation, alginate forms ionic network
electronics that favor the long-term implantation. Polysaccharides with Ca2+ to enhance the electrical conductivity, and chitosan
and proteins are the main components of ECM, which have been mixed with coupling reagents functions as a primer for the tissue
extensively investigated and applied in biomedicine with or with- surfaces and forms a covalent bond (-CO-NH-) as well as physical
out chemical modification [155]. To improve the soft tissue chain entanglement with alginate. The synergistic effect of them
integration, polysaccharides or protein-based bioelectronics enables a high-adhesion and low-impedance BTIM for optoge-
have emerged. Fig. 5A shows the chemical structure of repre- netic electronic platforms and electrical cardiac pacing.
sentative bioactive materials for bioelectronics. Chitosan is a Collagen, gelatin, and silk are the main natural proteins that
polyanion polysaccharide that comes from shellfish waste con- have been reported for bioelectronics application, specifically
taining -NH2, -OH, and -NHCOCH3 groups. Chitosan and its as encapsulation layer or substrate of implantable bioelectronics
derivates have been reported with antibacterial, antioxidant, [167]. Collagen and gelatin extracted from connective tissues
immune, and antitumor properties [156]. The chitosan-based of pig and bovine species, fish species, and so on have distinct
film has been employed to fabricate bioprotonic field-effect amino acid composition and physical and chemical properties.
transistor (proton mobility of ~4.9 × 10−3 cm2/(V·s)), internal The pig and bovine species are mostly adopted to construct

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Fig. 5. Bioactive materials. (A) Chemical structures of representative bioactive materials for bioelectronics. (B) Sutureless bioelectronic (SAFIE) with Alg-CA for conformal
adhesion with heart. Reproduced with permission from [166]. Copyright 2023, Springer Nature Limited. (C) Genipin cross-linked gelatin thin film (i) as electrode substrate via
(ii) aqueous-phase transfer printing strategy and (iii) exploded view of the thin-film electrode arrays. Reproduced with permission from [171]. Copyright 2023,
Wiley-VCH. (D) SF-based bioelectronics where SF was employed as (i) photoresist (reproduced with permission from [246]; Copyright 2020, National Academy
of Science) and (ii) substrates including SF-based thin film (left) (reproduced with permission from [153]; Copyright 2019, Wiley-VCH) and SF-based conductive hydrogel
(right) (reproduced with permission from [173]; Copyright 2022, Royal Society of Chemistry).

Wu et al. 2025 | https://doi.org/10.34133/cbsystems.0192 10

film and hydrogels due to their easy chemical modification, and tannic acid–CNTs were introduced to bring conductivity.
better processability, and wide availability. Collagen with 3 long The soft electrode can record epicardial ECG signals with a
helix-shaped chains is water-insoluble, while its next hydrolysis higher SNR than rigid Pt electrode (37 and 15, respectively)
product gelatin presents a temperature-controlled solubility and causes fewer immune responses and biological toxicity
[168]. In addition to biocompatibility and biodegradability, after implantation.
gelatin has cell binding motifs [arginine–glycine–aspartic acid Apart from biopolymer, nanomaterials such as PDA NPs,
(RGD) sequence] in nature, making it appealing in the bio- graphene, and MXene have been reported to possess antioxi-
medical field. Gelatin-based bioelectronics has demonstrated dizing activity; thus, incorporation of them would benefit the
several advantages such as flexibility, self-healing, biodegrad- in vivo performance of implantable bioelectronics. Dopamine
ability, self-adherence, and recyclability [23,169]. Recently, has demonstrated its outstanding performance in alleviating
Zhang et al. [170] reported a 10-μm-thick gelatin-based hydro- the inflammatory response in addition to bioadhesion. In a
gel skin sensor reinforced by PU nanomesh. The ultrathin brain injury model, bioelectronics containing dopamine sup-
sensor has high stretchability (strain ~ 700%), high adhesion presses inflammation and prevents further fibrosis by regulat-
(adhesion energy ~ 176.8 μJ/cm2), low impedance (~31.3 kΩ), ing the activity of macrophages. To sum up, bioactive materials
and good biocompatibility, which can be used for long-term are mainly employed as substrates for bioelectronics to enhance
monitoring of electrophysiological signals without causing skin their biocompatibility. Although their bioactivity has been
irritation, itches, or inflammation. As a common food additive, verified in other fields such as tissue engineering and drug
gelatin can also be fabricated into ingestible soft bioelectronics. delivery, the role in bioelectronics needs more profound
After chemical crosslinking by genipin and changing the sol- investigation.
vent from water to water:glycerol, the resulting soft gelatin
hydrogel (elastic modulus ~ 33.32 kPa; toughness ~ 39.32 J/m3) Application of Implantable Bioelectronics
was employed as the substrate (Fig. 5Ci) [171]. To integrate
with multielectrode arrays, a wet transfer printing process was Monitoring and sensing of physiological signals

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conducted (Fig. 5Cii). Parylene-C and thin-film metal-based With the advancement of implantable sensors, various physi-
multielectrode arrays were detached from rigid silicon wafers ological signals have been acquired for healthcare monitoring,
via capillary forces of water and transferred to another clean including electrophysiological signals [electroencephalography,
substrate. After being cleaned by plasma, the gelatin precursor electrocardiography, electromyography (EMG), etc.], tempera-
was drop-casted on the back surface of the electrode arrays. ture, pH, and pressure [10,174–177]. This section will focus on
The lamination structure and optical image of the transferred devices for monitoring electrophysiological signals, following
device are shown in Fig. 5Ciii. Furthermore, the device was the order of electroencephalography, electrocardiography,
applied as impedance sensor for epithelial barriers via electro- and EMG.
chemical impedance measurements.
Silk fibroin (SF) that originated from silkworm silk has EEG monitoring
been applied in our daily life since ancient times. In recent Brain signals reflect neuronal activity in the brain, and obtaining
decades, SF-based biomaterials (e.g., hydrogel, film, scaffolds, high-fidelity, high-resolution brain signals is crucial for brain
and NPs) are drawing great attention for their good in vivo research and for diagnosing neurological diseases [67,178,179].
biocompatibility, biodegradability, cell affinity (RGD sequences), Depending on their location, electrodes record EEG on the
tunable biomechanical properties, and a variety of chemical scalp, ECoG on the surface of the cortex using subdural grid
modifications [e.g., SF-methacrylate (SFMA)] [172]. With electrodes, and localized field potentials (LFPs) in the brain with
high compliance with the nanofabrication process, SF-based small-sized electrodes [180]. Advances in signal recording
flexible bioelectronics is blooming. Fig. 5D presents the devices aim to capture electrophysiological signals with high
most typical application of SF in bioelectronics: SF-based pho- quality. Conventional implantable brain signal acquisition uses
toresist, where SF functions as the substrate in the form of rigid implantable electrodes, of which silicon-based Utah elec-
thin film and bulk conductive hydrogel. By means of chemi- trodes and Michigan electrodes fabricated by microelectrome-
cal modification, SF can be developed to be photoactive, chanical system (MEMS) fabrication are typical representatives,
which has been adopted for high-resolution micropatterns which can record multipoint signals and local field potentials
via photolithography. By mixing with electroactive compo- [181]. Utah electrodes have the advantages of high channel
nent, SF-based bioelectronics was constructed. Transfer print- count, safety, and excellent short-term recording stability [182].
ing is another method to construct SF-based thin-film devices. Whereas Michigan electrodes have high design flexibility and
As shown in Fig. 5Dii, Mao and colleagues [153] reported an high spatial resolution [183]. However, there is a mechanical
SF-supported/delivered soft bioelectronics for the investiga- mismatch between the rigid probe and the soft brain tissue,
tion of spatiotemporal epileptiform activities and multimodal which causes an immune response in the surrounding neural
neural encoding/decoding. The biocompatible SF substrate tissue upon implantation and leads to tissue scarring in long-
can not only spontaneously form conformal coupling with the term experiments, thus affecting the long-term stability of the
cortical surface but also work as vehicle for in vivo drug deliv- device [12,184]. Therefore, flexible probes based on polymer
ery. SF-based conductive hydrogel can be constructed by substrates have been studied to reduce tissue responses.
introducing electroactive materials (e.g., PEDOT, CNT, and Recently, pioneering advancement has been made in flexible
MXene). On the left of Fig. 5Dii, it demonstrates a mechani- probes. Jiao et al. [174] introduced a multimodal device employ-
cally adaptive hydrogel crosslinked by SF and aldehyde- ing shape memory polymers. This device, with controllable
hyaluronic acid (HA-CHO) for high-efficiency neural activity stiffness and shape, integrates multiple sensors in the rigid state,
recording [173]. The dynamic crosslink network provides a enabling minimally invasive implantation in the soft state and
soft and tissue-compatible hydrogel for immune modulation, conformal adherence to tissue after shape recovery (Fig. 6Ai).

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Fig. 6. Flexible electrodes for electrophysiological signal recording and monitoring. (A) (i) Rigidity switch and shape recovery of the electrode during minimally invasive surgery.
(ii) Recorded ECoG signals and (iii) ECG signals. Reproduced with permission from [174]. Copyright 2023, Wiley-VCH. (iv) Optical image of the OECT array. (v) μ-ECoG signals
recorded by 3 channels of the transient OECT array on days 1 and 6. Reproduced with permission from [33]. Copyright 2023, Wiley-VCH. (B) (i) Structure of the electrode
featured by submicrometer-thick graphene. (ii) ECG signals recorded by commercial Ag/AgCl electrodes and (iii) graphene electrodes. Reproduced with permission from
[53]. Copyright 2023, Wiley-VCH. (C) (i) Tetrode-like arrangement of microelectrodes. (ii) Electrode recordings of EMG signals on day 1. Reproduced with permission from
[193]. Copyright 2023, Wiley-VCH.

The impedance modulus of the integrated electrode at 1 kHz similar waveforms and spectra to those of commercial electrodes.
was 1.35 kΩ, enabling the recording of ECoG and ECG signals The characteristic ECoG signals of epilepsy were recorded near
in vivo (Fig. 6Aii and iii). The recorded ECoG signals had the frequencies of 12.5 and 25 Hz. Furthermore, it diagnosed

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ischemic, primary, and hemorrhagic epilepsy by combining metal interconnects, and CNT nanocomposite electrodes
ECoG and temperature signals and identified inflammatory, reached ultrahigh elongation up to 400% and exhibited excellent
hemorrhagic, and non-inflammatory pericardial effusions using conductivity of 3.8 × 104 S/cm. Meanwhile, reliable wet adhe-
collected ECG signals along with pH signals. sion of the device is necessary for the sensitivity and stability of
In order to obtain signals with higher resolution, minimiz- the signal. Yu et al. [147] proposed a CAHP whose precursor
ing the size of the electrode has been a trend in device design. solution contained amphiphilic side chain-modified polyaniline
Viana et al. [185] presented a graphene-based nanoporous thin- (f-PANi), which rapidly absorbed anti-adhesive pericardial
film microelectrode (EGNITE, 25 μm in diameter) and inte- fluid, actively diffused, and autonomously formed cross-links
grated a 64-channel microelectrocorticography (μ-ECoG) array and mechanical interlocks at the interface, allowing the patch
of EGNITE, with a pitch of 300 μm and a thickness of about to conformally attach directionally to moist and curved epicar-
12 μm. These electrodes exhibit low impedance (25 kΩ) and dial membranes with an interfacial toughness of up to 443.4 J/
high charge injection (3 to 5 mC/cm2). Positioned on the audi- m2. Lin et al. [53] employed a submicrometer-thick graphene
tory cortex, the electrodes record neural signals with high fidel- bio-interface on the heart surface for ECG signal acquisition
ity and spatial resolution, achieving an SNR greater than 10 dB and stimulation (Fig. 6Bi). The electrocardiogram (gEG)
for the local field potential signal. R-waves recorded with graphene electrodes exhibit good tem-
Moreover, sensitivity is also required for precise neural poral correlation with conventional far-field ECG R-waves
recording. Liu et al. [186] developed a neuroelectrode based acquired with commercial Ag/AgCl electrodes and effectively
on nano-enzymes, which utilized quantum transport and bio- attenuate the electrical noise from the mechanical beats of the
catalytic processes to achieve both electron and ion conductive heart (Fig. 6Bii).
at the electrode tissue interface. The SNR of single-neuron
recording in vivo can reach 14.7 dB, and the impedance of the EMG monitoring
nano-enzyme electrode is 1/26 of conventional silver electrodes. Myoelectric electrodes are capable of extracting electrical sig-
Additionally, the SNR for epilepsy detection is 3.2 times higher nals from muscles and of great importance in prosthetic control

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than that of silver electrodes, and it is at least 9.3 times more [190]. First, obtaining high amplitude and sustainable EMG
sensitive than the silver electrode at the second month after signals can better reflect the fatigue level and excitation state
implantation, and the nano-enzyme electrode exhibits good of the muscles and enhance the function of the prosthesis,
sensitivity stability. Wu et al. [33] presented a multichannel which has become one of the goals for electrode development.
neural interface for high-fidelity mapping of μ-ECoG signals The PEDOT-coated stainless steel electrodes for EMG record-
(Fig. 6Aiv). The OECT-based network with 200 × 20 μm2 ing were developed. Using galvanostatic electrodeposition,
conductive channel size enabled stable recording at 100 sites, PEDOT doped with lithium perchlorate was coated onto stain-
which realized the SNR up to 37 dB for in vivo μ-ECoG signals. less steel with a diameter of 76.2 mm. Electrodes were inserted
Furthermore, the biodegradable device can be degraded into into the mice neck muscles to measure EMG activity for 6 weeks.
micro-nanoparticles after immersion in PBS, which avoids the Higher SNR and amplitude were attained with PEDOT-coated
risks associated with secondary surgery. One week after implan- electrodes in comparison to bare electrodes, thus improving
tation, the recorded μ-ECoG signal was attenuated due to the signal quality. Second, in order to obtain localized muscle
degradation of PEDOT:PSS (Fig. 6Av). potential signals, miniaturized electrodes have been devel-
oped to obtain higher spatial resolution EMG signal record-
ECG monitoring ings [191,192]. However, miniaturization reduces the contact
On the other hand, the ECG reflects the contraction and dias- area of the electrode with the muscle tissue, resulting in a rise
tole of heart muscle, aiding in arrhythmia prevention and in contact impedance. To address this issue, Boys et al. [193]
diagnosing cardiovascular diseases (CVDs) [1,48]. Myocardial mimicked the structure of muscle fibers and designed myo-
tissue has a Young’s modulus of around 10 kPa, exhibits regular electric electrodes containing 32 electrode sites. The arrange-
contraction and diastole, and requires efficient blood supply ment of the electrodes was tetrode-like, and the diameter of the
for oxygen and nutrients [187]. Therefore, in order to achieve recording pads was 20 μm (Fig. 6Ci). In terms of material
a seamless and stable interface, the bioelectronic device should design, the recording electrodes were gold electrodes with
be soft enough and have high stretchability, toughness, and PEDOT:PSS coating with parylene-C encapsulation. The lead
conductivity simultaneously, as well as wet adhesion properties arrays were formed in a fibrillar collagen gel by injection of
[188]. At the same time, the materials used should be biocom- type I collagen extracted from rat tail tendon. The average
patible and able to reduce immune response and promote the impedance of the electrodes was measured to be 48.9 kΩ at
growth of cardiomyocytes in order to record ECG signals in 1,000 Hz, allowing the recording of intramuscular EMG with
real time, track cardiac function, and promote the growth and high spatial resolution (Fig. 6Cii).
healing of damaged myocardial tissue [156,189]. In consider-
ation of ultrasoft materials, Sim et al. [18] reported an submil- Modulation of physiological and
limeter thickness epicardial patch, which contained PDMS pathological conditions
substrate and encapsulation, conductive rubbery paste, and Bioelectronics serving as implantable medical device can mod-
PDMS conductor with embedded AgNWs, possessing inher- ulate the conditions around implant sites or host by deliver-
ent porcine heart tissue-like modulus and conductivity. ing drugs, namely, the bioelectronic drug delivery systems
Besides, many efforts have been devoted into balancing the (bEDDSs) [41,194]. Here, we focus on the implantable bEDDS,
mechanical and electrical properties of the bioelectronics. For which works in vivo instead of in vitro (transdermal). For
instance, Wang et al. [19] introduced an intrinsically stretch- instance, heparin-doped polypyrrole electrodes (PPy/Hep) can
able patch for conformal adhesion on the beating heart. The deliver anti-inflammatory cytokines (IL-4) in vivo that miti-
16-channel device composed of the SEBS substrate, liquid gate FBR around implants [30]. Local delivery of inhibitory

Wu et al. 2025 | https://doi.org/10.34133/cbsystems.0192 13

neurotransmitter γ-aminobutyric acid (GABA) in a neuro- and monitor the wound healing via photothermal antibacterial
pathic pain (NP) model via organic electronic ion pump (OEIP) and anisotropic sensing. The in vivo delivery of light/photo can
can significantly decrease the pain response after implantation realize the application of PDT/PTT in deep tissue of inside
for 2 d [195]. Microneedle-integrated bioelectronics with local- organ. An endoscope combined with laser light [near-infrared
ized delivery of theragnostic NPs and drugs has been used for (NIR), red, and visible light], transparent bioelectronics, associ-
precise treatment of lesions [196]. However, active control of ated sensors (temperature, pH, contact, viability sensor), mul-
drug release along with implant bioelectronics needs further tifunctional NPs [chlorin e6 (Ce6), gold nanorods (Au NRs)],
integration of material science and bioelectronics. and chemo-drug DOX was fabricated (Fig. 7Ci) [201]. Thermo­
Similar to DDS, biodegradable or smart responsive materials sensitive PNIPAM (upper critical solution temperature ~ 32 °C)
(thermal, light, electrical, and so on) are promising candidates was employed to respond to NIR laser and release DOX. The
for drug storage and release system. PLGA, a Food and Drug “all-in-one” platform can sense, ablate, and kill tumor cells, and
Administration (FDA)-approved biodegradable polymer, was the combination of PDT (ROS), PTT (heating), and chemo-
frequently employed to load drugs. For example, an implantable therapy performs best in the colon cancer treatment.
and bioresorbable microneedle (IBMN) device was fabricated Optogenetics is a neuromodulation technique that can
by combining wireless electrostimulation (ES) and drug deliv- manipulate neurons at millisecond-order temporal accuracy
ery, which had microneedles made of PLGA to load and release through optical stimulation by expressing photoactive micro-
drugs [197]. The loaded aspirin and ibuprofen can continuously bial opsin proteins in the desired nerve cells [202,203]. A gene-
be released over 15 d, along with hydrolysis and erosion of embedded optoelectrode array aiming at neural implantation
PLGA. Magnesium (Mg) can react with surrounding biofluids to enable spatiotemporal electroporation (EP) was fabricated
(Mg → Mg2++ 2e−) and degraded gradually [14]. Such an elec- with multifunctions, including gene delivery/transfection,
trochemical etching process was employed by using Mg as gate photo modulation, electrical monitoring, and light stimulation
to control the release of liquid drug storage in a bioresorbable of neural tissue [204]. The nanostructural hydrogel consisting
polyanhydride polybutanedithiol 1,3,5-triallyl-1,3,5-triazine- of rGO and 3,4-ethylenedioxythiophene-modified amphi-

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2,4,6(1H,3H,5H)-trione penteonic anhydride (PBTPA) [33]. philic chitosan was used as neural interface (called PG) for
Under the similar mechanism, a Mg-gated biodegradable mul- controllable gene delivery with electrically inductive electro-
tifunctional bioelectronic system (ADDS) was fabricated (Fig. permeabilization. The in vivo implantation of the “all-in-one”
7A) [34]. The biodegradable ADDS consisted of a drug-carrying optoelectrode enables targeting and on-demand spatiotemporal
PLGA membrane, tandem Mg valves, and poly(lactic acid) gene transfection. Integrated with optical waveguide, photo-
(PLA) membrane aligning in the z-axis direction for drug stor- evoked extracellular spikes were detected on day 7, convincing
age and pulsatile/sequential deliver (Fig. 7Ai). The flat soft the success of optical stimulation. Recently, a fully biodegrad-
ADDS can be bent/folded into tubular, which meets the appli- able opto-electronic neural implant system was developed
cation of subcutaneous or intravascular drug delivery (Fig. based on molybdenum/silicon (Mo/Si) electrode array and
7Aii). Under electronical stimulation, Mg valve was corroded PLGA waveguide (Fig. 7Cii) [205]. The soft and flexible device
and drugs encapsulated in the PLA membrane started to release caused negligible immune responses and completely dissolved
in a controlled and sequential manner (Fig. 7Aiii). Drug deliv- by day 50. Chronic in vivo optogenetics experiment was carried
ery to local brain tissues that bypasses the blood–brain barrier in Thy-1: ChR2 transgenic mice. Induced by optical stimulation
(BBB) is important for malignant brain disease [glioblastoma with 460-nm pulses, evoked local field potentials were enhanced
(GBM)] treatment [40]. A chemo- and thermo-coupled therapy and exhibited periodicity until day 28, confirming the ability
was carried out via wireless biodegradable electronic patch of optogenetic stimulation.
(BEP) (Fig. 7Bi) [198]. The BEP consisted of 3 components: bEDDS device integration relies heavily on the responsive
wireless temperature sensor for thermal control, wireless heater materials for drug storage and release. However, the existing
for heat production, and drug reservoir for thermal response. works mainly deliver drugs in a passive way, and the sophisti-
The materials used to construct them were biodegradable cated materials design and the combination of smart bioelec-
PLA, PLGA, Mg, and oxidized starch (OST), ensuring the tronics need further exploration. Besides, electrical simulation
little potential neurological side effects. Hydrophilic OST dis- itself can also play roles in pathological modulation [72,112].
plays more sustained drug release than unmodified starch, as Magnetic resonance imaging (MRI) compatibility transparent
well as a conformal contact with brain surgery site (Fig. 7Bii). PEDOT:PSS-based ECoG grid for NP relief via motor cortex
In a canine GBM model, the group treated with combinate stimulation (MCS) was developed [61]. We would discuss it
“OST + heating” presents the best therapeutic efficacy (Fig. in detail in terms of deep brain stimulation (DBS) in the next
7Biii). Thus, apart from the long-lasting doxorubicin (DOX) section.
delivery to the target region, mild-thermic actuation increases
drug penetration and thus suppresses tumor growth. Tissue engineering
Light-related modulation is gaining more and more concerns Bioelectronics are appealing in electroactive tissue engineering
in theragnostic recently, e.g., photodynamic therapy (PDT), as electrical stimulation contributes to the regeneration of
photothermal therapy (PTT), and optogenetics [39,199,200]. cells and secretion of cytokines and growth factors [206,207].
Many conductive nanomaterials (e.g., GO, CNTs, and MXene) Tissues or organs including muscle, heart, brain, and so on that
can also work as photo-thermal conversion agents, which take electronic signals for information transfer have benefited
expands their biomedical applications. Limited by the penetra- from electronic stimulation for a long time, such as DBS, spinal
tion depth of light, PTT mainly focuses on surface wound man- cord stimulation (SCS), cardiac pacemaker, and electrical mus-
agement. Li et al. [63] reported a gelatin-oxidized dextran cle stimulation (EMS) [20,206,208]. Besides facilitating repair,
(Gel-ODex) hydrogel-based bioelectronics containing magne- implant bioelectronics are also promising in replacing the natu-
toelectric nanosheets (Fe3O4-PDA-rGO), which can proceed ral tissue with function reconstruction, e.g., electronic skin

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Fig. 7. Implantable bioelectronics with DDS application triggered via (A) electronical stimulation, (B) temperature, and (C) light. (A) Biodegradable multifunctional active-
controlled drug delivery system (ADDS) (i) for pulsatile (ii) and sequential (iii) release of multiple drugs. Reproduced with permission from [34]. Copyright 2023, Wiley-VCH.
(B) Bioresorbable electronic patch (BEP) with wireless mild-thermic actuation (i) consisting of OST to load DOX (ii) for efficient treatment of brain tumor (iii). Reproduced
with permission from [198]. Copyright 2019, Springer Nature Limited. (C) Multifunctional endoscope system combined with PDT, PTT, and chemotherapies for colon cancer
treatment (i). Reproduced with permission from [201]. Copyright 2015, Springer Nature Limited. (ii) Bioresorbable neural implant system for simultaneous electrophysiology
and optogenetics stimulation. Reproduced with permission from [205]. Copyright 2024, Springer Nature Limited.

Wu et al. 2025 | https://doi.org/10.34133/cbsystems.0192 15

(e-skin) [209]. In this section, we mainly focus on the applica- ultrasound energy-harvesting (PUEH) device can also be used
tion of implantable bioelectronics in nerve/brain tissue engi- for DBS (Fig. 8Aiii) [200]. Flexible PUEH was constructed by
neering and myocardial tissue engineering. Sm-doped Pb(Mg1/3Nb2/3)O3-PbTiO3 (Sm-PMN-PT) single
crystal with high piezoelectric coefficient (4,000 pC N−1). Under
Nerve/brain tissue engineering US, output power can be up to 280 mW so that DBS can be
Neurodegenerative disease [e.g., Alzheimer disease (AD) and realized. In vivo rat electrophysiological experiments under
PD] and traumatic brain injury (TBI) result in low quality of anesthesia and behavioral experiments further confirmed that
life (losing control of recognition and behavior) or longevity the produced current by PUEH activated the periaqueductal
[172,193]. The treatment of brain-related diseases is hindered gray (PAG) to reach the aim of analgesia. Recently, soft piezo-
by the complex structure of the nerve network. Fortunately, electric-triboelectric hybrid nanogenerators (PTNGs) were
BCI provides a technology for neurophysiological and neuro- fabricated by employing trimethyl chloromethyl ammonium
logical disease researches, based on monitoring, recording, trichloro manganese (TMCMMnCl3) molecular crystals [223].
decoding, and modulating neuron activities [210]. For example, With programmable US pulses, the soft PTNGs generate a
based on the BCI device, paralyzed patients can restore move- stimulation current of ~0.9 mA. The biocompatible PTNG
ment, touch, and speech [210–213]. However, those devices device was implanted in Parkinson’s rat where US stimulation
are commonly based on rigid platinum–iridium electrode/ was performed. Results of electrophysiological study, immuno-
probe with risk (e.g., secondary brain injury) for implantable histochemical staining, and behavior test confirm that the soft
application. Soft bioelectronics with mechanical match with high-performance bioelectronic device can meet the require-
brain tissues are desirable in neuromodulation. Fig. 8Ai illus- ment of DBS electroceutical application.
trates stretchable organic bioelectronics based on the topologi-
cal supramolecular conducting polymer network (PR) for both Myocardial tissue engineering
recording and modulation [55]. It allows direct photopattern- CVDs are becoming the main diseases that endanger human
ing at cellular-level feature sizes and withstands over 100% health [224]. Chronic monitoring of CVD-related parameters

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strain without crack. The high conductivity of PR-based micro- such as heart rate and blood pressure can predict the health
electrode array ensures stable electrophysiological monitoring state of cardiovascular system [225]. Under the malignant con-
and precise neuromodulation at low-voltage (100 μV) electrical ditions such as atrioventricular (AV) block and myocardial
stimulation. Upon localized brainstem stimulation, evoked infarction (MI), therapeutic interventions are necessary [226].
muscle activities at tongue, whisker, and neck were recorded Cardiac pacemaker consisted of pacing leads (electrodes), and
with distinct signals. pulse generator is a common device with history over 60 years
Direct electronic stimulation is also facing several limits, that aimed for cardiac rhythm dysfunction. However, implanta-
such as complex circuitry, large body, and high-power con- tion of stiff pacing electrodes causes several complications
sumption [214,215]. To improve the accuracy and convenience including detaches or fracture of electrodes and infection,
of neuromodulation, laser or ultrasound (US)-based DBS has hematoma, as well as erosion into the tissue. In addition, energy
also been presented [216–218]. For instance, multifunctional supply of cardiac pacemaker limits its permanent application.
neural probes with integration of optogenetics and electro- Thus, the next generation of pacemakers with battery-free,
physiology for optogenetic manipulation are equipped with wireless, and good biocompatibility is urgently needed. Until
microscale light-emitting diodes (μLEDs), optic fiber, or now, biomaterials that can regulate cardiac microenvironment
adeno-associated virus [82,200,202]. Hong and colleagues (e.g., scavenging ROS, suppressing inflammation, and promot-
[219] reported macromolecular infrared nano-transducers for ing angiogenesis) and contribute to the regeneration of fibrotic
deep brain stimulation (MINDS). In the irradiation of sec- tissue with satisfying electrical conduction and mechanical
ond near-infrared (NIR-II; wavelength, 1,000 to 1,700 nm), toughness are emerging [227–229]. Among them, soft and
MINDS can generate heat (photothermal conversion efficiency stretchable bioelectronics that offer real-time dynamic monitor
~ 71%), followed by the activation of a nonselective cation and simultaneous electrocoupling therapy stands for the smart
channel with a high permeability to calcium (TRPV1). MINDS and efficient platform [230]. For instance, stretchable nanocom-
were injected into the mouse hippocampus, motor cortex, and posite nanowires containing Ag–Au–Pt core–shell–shell struc-
ventral tegmental area (VTA), and under NIR-II illumination, ture and Pt NPs, cardiac peacemakers based on implantable
and TRPV1 was activated with minimal thermal damage. triboelectric nanogenerator (TENG), acoustic energy transfer
Fig. 8Aii displays the application of the temporal interfer- and communication device (AECD), transparent microelec-
ence (TI) technique in wireless DBS based on organic elec- trode arrays, and so on have been reported [231–233]. Recently,
trolytic photocapacitors (OEPCs) that possess optical-electronic bioresorbable metal Mo was integrated with the poly(1,8-
transfer ability [220]. The OEPCs were implanted in the cortex, octamethylene-citrate-co-octanol) (POCO) elastic polymer
while the neuronal response evoked by the TI technique was substrate and bioadhesive PEG-LA-DA hydrogel as elastic
comparable to direct deep brain implanted electrodes. cardiac patch (BCEP) for MI therapy (Fig. 8Bi) [234]. The
US containing mass energy can be transformed into electric sophisticated Mo mesh and elastic POCO can withstand elastic
power via the piezoelectric effect [216,221]. Implantable high- deformation of ~15% (13% of cardiac surface), and PEG-LA-DA
performance hydrogel nanogenerators (HENGs) have been hydrogel served as adhesion layer with low impedance of
reported to be capable of stimulating vagus nerves for anti- BCEP and tissue (peeling force ~ 0.3 N, resistance ~ 14 kΩ).
inflammatory therapy [222]. Short-circuit current (1.6 mA) The biocompatible BCEP facilitates human to induce pluripo-
with comparable output to commercial bulky neurostimulators tent stem cell-derived cardiomyocyte (hiPSC-CM) maturation
was induced by US (power density of 0.3 W/cm2). The in vivo with enhanced cell contraction behaviors for the conductive
application of HENG shows great effectiveness in the inhibition path of Mo mesh, indicating their potential application in
of pro-inflammatory cytokines. Likewise, the piezoelectric heart function reconstruction.

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Fig. 8. Application of implantable bioelectronics in (A) brain, (B) cardiac, and (C) bone tissue repair. (A) Brain tissue engineering via (i) stretchable multielectrode array for
bidirectional electronic stimulation with high precision (left) to evoke and record muscle activities at the tongue, whisker, and neck (right). Reproduced with permission from [55].
Copyright 2022, AAAS. (ii) Laser-driven wireless DBS by TI technology (left) with comparable ability to evoke electrophysiological epileptiform activities as direct DBS (right).
Reproduced with permission from [220]. Copyright 2022, Wiley-VCH. (iii) Ultrasound energy-harvesting (Sm-PUEH) device (left) for pain relief via DBS. Reproduced with permission
from [200]. Copyright 2022, AAAS. (B) Cardiac tissue engineering via (i) bioresorbable cardiac patches (left) with the ability to facilitate cell proliferation via electronic stimulation
(right). Reproduced with permission from [234]. Copyright 2023, Wiley-VCH. (ii) 3D-printed hydrogel electronics for electrophysiological monitoring and electrical modulation.
Reproduced with permission from [9]. Copyright 2023, Wiley-VCH. (iii) Microchanneled hydrogel suture to diagnose, treat, and monitor the infarcted heart. Reproduced with
permission from [237]. Copyright 2024, Springer Nature Limited. (C) Bone regeneration via (i) Fully implantable battery-free BD-ES system and possible mechanism involved in
the osteogenesis process. (ii) Performance of BD-ES system in promoting bone repair via electrical stimulation. Reproduced with permission from [239]. Copyright 2024, AAAS.

Hydrogel-based bioelectronics possesses unique advantages treatment potential. However, its bioavailability is limited by
in MI repair for its ECM-like “soft and wet” properties and mul- poor water solubility. Hou and colleagues [94] fabricated cur-
ticompatibility to bioactivates [60]. Curcumin is a molecule cumin@polydopamine nanoparticles (CUR@PDA NPs) with
that has been reported to possess anti-inflammatory and CVD typical bilayer core–shell structure and introduced them into

Wu et al. 2025 | https://doi.org/10.34133/cbsystems.0192 17

conductive hydrogel (called PCP) crosslinked by gelatin and significantly accelerate the wound repair (>1.0 mm without ES
PAM for synchronous MI repair and real-time monitoring. The and <0.5 mm with ES) [139]. Bone and cartilage are avascular
PCP hydrogel is hyperelastic with negligible hysteresis (elonga- tissues, and their self-regeneration needs external assistance
tion at break ~1,300%) and mechanoelectrical sensitivity (37 ms) for cell migration or recruitment and vascularization to supply
for cardiac signal monitoring. In addition, PCP hydrogels inherit essential oxygen and nutrient [238]. Apart from biomaterials
the bioactivity of CUR@PDA NPs, which benefits MI repair that can provide biological cues, previous researches have proved
by regulating the inflammatory microenvironment, promoting that ES can benefit chondrogenesis and cartilage regeneration
angiogenesis, and reducing myocardial fibrosis. In MI model by promoting extracellular protein adsorption, facilitating cell
based on Sprague–Dawley rats, PCP hydrogel implanted groups migration or recruitment, and inducing endogenous TGF-β via
showed the lowest left ventricular internal diameter at diastole the calcium signaling pathway [237,239,240]. Recently, Wang
(LVIDd), left ventricular internal diameter at systole (LVIDs), et al. [239] reported their works about the fully implantable bone
and fibrosis area (reduced from ~70% to 20%) as well as highest defect electrical stimulation (BD-ES) system, which contains a
ejection fraction (EF), fractional shortening (FS) values, and hybrid tribo/piezoelectric nanogenerator (HTP-NG) to provide
infarct thickness (increased from ~0.8 mm to 2.0 mm). biphasic electric pulses and a conductive injectable hydrogel
3D bioprinting brings a facile way to construct hydrogel bio- (EABP) to construct an osteogenic microenvironment (Fig. 8Ci).
electrode arrays with geometrically complex materials and struc- The EABP was prepared by incorporating polydopamine-
tures [70,235]. By incorporating PEDOT:PSS with the hydrogel modified black phosphorus nanosheets (BP@PDA) and alginate
precursor ink (mixture of PVA, chitosan, and PAA-NHS), 3D methacryloyl (AlgMA) substrate for electroactive tissue repair.
printable conducting (3DP) 3-layered hydrogel bioelectronics The high electromechanical conversion efficiency of HTP-NG
was fabricated (Fig. 8Bii) [9]. The outer substrate layer endows makes the BD-ES system independent of charging and circuit.
3DP hydrogel with bioadhesion to various biological tissues The fully implantable battery-free BD-ES system would promote
(porcine skin, heart, blood vessel, and sciatic nerve) that benefits bone regeneration via several aspects, such as enriched signaling
in vivo ECG monitoring. The 3DP hydrogel can provide electri- pathways, enhanced mechanosensitive ion channel activity, acti-

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cal modulation for MI treatment. With a pulse stimulation vation of calcium channel, and activation of osteogenic genes.
(50 mV, frequency of 8 Hz, duration of 4 ms), isoproterenol- Immunohistochemical and immunofluorescence staining con-
induced MI was recovered with normal synchronized pacing firmed that EABP in response to ES from HTP-NG could up-
traces and autonomous rhythm, validating its potential applica- regulate the expression of angiogenesis/osteogenesis-related
tion as integrated diagnosis and treatment bioelectronics. markers that promote bone repair (Fig. 8Cii).
Post-surgery real-time monitoring would provide messages Gastric electrical stimulation (GES) has been proved by FDA
and accelerate the healing process. For example, multifilament for gastroparesis under a humanitarian device exemption (HDE)
surgical sutures were reported with ability to monitor physico- via electrical impulses (0.3 ms, 14 Hz) [241]. However, implan-
chemical states of deep surgical sites such as wound integrity, tation of GES was commonly through endoscopic placement.
gastric leakage, and tissue micromotions [236]. Such monitoring Ingestible electroceutical capsules may provide a noninvasive
of post-MI is necessary for its reusability, and it is better to be device for GES without off-target effects. Inspired by the water
combined with on-demand therapy. A hydrogel suture (DTMS) wicking skin of Moloch horridus, a capsule for active stimula-
with the capability to diagnose, treat, and monitor the infarcted tion and hormone modulation (FLASH) was developed, which
heart was presented recently [237]. The DTMS is a conductive consisted of internal batteries, printed circuit boards, external
PPy deprotonated PVA microchannel hydrogel with adjustable electrodes, and grooved surface for fluid-wicking to remain
sizes (depending on mold), large breakage strength, low friction, robust electrode–mucosa contact in the presence of gastric juice
high conductivity (1.47 S/cm), and bidirectional perfusion func- [242]. It was confirmed that the FLASH was able to modulate
tion. By adding force-luminescent agent ZnS:Cu into the hydrogel ghrelin and glucagon-like peptide 1 (GLP-1) in plasma under
precursor, the DTMS demonstrates the force-induced lumines- ES. Furthermore, bioelectronics has also shown potential in
cence and photothermal conversion effect, which may provide fully artificial tissues, e.g., neuromorphic sensorimotor loop
additional bacterial clearance function. N-acetyl-3-nitrososulfanyl- control of leg twitching was realized by artificial skin [209]. By
valine (SNAP) was incorporated into DTMS via microfluidic using a metal–polymer conductor consisting of poly(l-lactide-
channels as nitric oxide (NO) donor drug to construct the ther- co-ε-caprolactone) (PLC) and liquid metal [gallium–indium
anostic platform. Specifically, DTMS was used for bioelectric sig- alloy (EGAIn)] (MPC-PLC), the biodegradable and biocompat-
nal biosensor and incorporated into mobile phone by Bluetooth ible MPC-PLC membrane seeded with blood vessel cells
module (e.g., EMG and ECG) and SNAP for treatment by inhibit- [human umbilical vein endothelial cells (HUVEs), smooth
ing inflammation and fibrosis, as well as promoting cell infiltra- muscle cells (SMCs), and fibroblasts] was rolled with a mandrel
tion and vascular regeneration. The cardiac repair function of the to form electronic blood vessel. After implantation in rabbit,
theranostic platform was further investigated in MI minipig model the endothelialization process was facilitated by electrical
(Fig. 8Biii). Characterization [cardiac magnetic resonance stimulation. The diameter of electronic blood vessel remained
imaging (cMRI), immunofluorescence staining, and ECG] unchanged, and it exhibited excellent patency and biosafety
results confirmed that S-DTMS can promote cardiac tissue after implantation for 3 months [243].
recovery, indicating the promising application of S-DTMS as
the “diagnosing–treating–monitoring” closed-loop system.
Conclusion and Perspectives
Other electronic responsive tissues Implantable bioelectronics is facing barriers including material
Apart from brain and cardiac tissue, some other tissues/organs and function mismatch, despite that more and more flexible and
can also respond positively to electronic pulse. In a muscle injury stretchable materials have been incorporated to construct soft
model, the IBMN device that provides periodic in vivo ES can and tough bioelectronics from the aspect of electrode, substrate,

Wu et al. 2025 | https://doi.org/10.34133/cbsystems.0192 18

encapsulation, and adhesive layers. For in vivo application, pro- multilayer electronic arrays for multiplexed sensing
grammable stability is also important for bioelectronics apart and actuation during cardiac surgery. Nat Biomed Eng.
from biocompatibility, while smart triggered biodegradable 2020;4(10):997–1009.
materials are rarely adopted. Bioelectronics loaded with drugs 5. Zhang J, Li J, Huang Z, Huang D, Yu H, Li Z. Recent progress
to modulate FBR or local disease of implant site has been in wearable brain–computer interface (BCI) devices based
reported, yet application of bioactive materials such as polysac- on electroencephalogram (EEG) for medical applications:
charide and protein in this area needs more profound researches. A review. Health Data Sci. 2023;3:0096.
Injectable bioelectronics causes less injury during implantation; 6. Guimarães CF, Gasperini L, Marques AP, Reis RL. The
however, seamless fitting with the target tissue or organ depends stiffness of living tissues and its implications for tissue
mostly on shape-changing ability of bioelectronics. Living syn- engineering. Nat Rev Mater. 2020;5:351–370.
thelectronics is emerging, which takes metabolite as driving 7. Akintola AA, van de Pol V, Bimmel D, Maan AC,
forces for in vivo processing of soft bioelectronics. The in situ van Heemst D. Comparative analysis of the equivital
fabrication can acquire substrate-free bioelectronics while meet- EQ02 lifemonitor with holter ambulatory ECG device for
ing the specific topological requirement of target biological sub- continuous measurement of ECG, heart rate, and heart rate
structures. To sum up, designing implantable bioelectronics shall variability: A validation study for precision and accuracy.
be more closely linked with the dynamic nature of in vivo envi- Front Physiol. 2016;7:391.
ronment. The combination of biomedical materials with bioelec- 8. Hong YJ, Jeong H, Cho KW, Lu N, Kim DH. Wearable and
tronics system can be further enhanced. implantable devices for cardiovascular healthcare: From
monitoring to therapy based on flexible and stretchable
electronics. Adv Funct Mater. 2019;29(19):1808247.
Acknowledgments 9. Wang F, Xue Y, Chen X, Zhang P, Shan L, Duan Q, Xing J,
Funding: This work is supported by the STI2030-Major Lan Y, Lu B, Liu J. 3D printed implantable hydrogel
Project (2022ZD0209900, 2022ZD0208601, and 2022Z­ bioelectronics for electrophysiological monitoring and

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D0208600), the National Natural Science Foundation of China electrical modulation. Adv Funct Mater. 2023;34(21):2314471.
(62204057, 62204204, U2341218, and 62104042), Science and 10. Ye Y, Wang H, Tian Y, Gao K, Wang M, Wang X, Liang Z,
Technology Commission of Shanghai Municipality (22ZR­ You X, Gao S, Shao D, et al. Smart epidermal
1406400), Shanghai Sailing Program (grant no. 21YF1451000), electrophysiological electrodes: Materials, structures, and
Lingang Laboratory (LG-QS-202202-02), State Key Labora­ algorithms. Nanotechnol Precis Eng. 2023;6:Article 045001.
tory of Integrated Chips and Systems (SKLICS-Z202306, 11. Song E, Li J, Won SM, Bai W, Rogers JA. Materials for flexible
SKLICS-Z202315), and the Young Scientist Project of MOE bioelectronic systems as chronic neural interfaces. Nat Mater.
Innovation Platform. 2020;19(6):590–603.
Author contributions: X.W.: Investigation, visualization, and 12. Xie C, Liu J, Fu TM, Dai X, Zhou W, Lieber CM. Three-
writing original draft. Y.Y.: Investigation, visualization, and writ- dimensional macroporous nanoelectronic networks
ing original draft. M.S.: Investigation and data curation. Y.M.: as minimally invasive brain probes. Nat Mater.
Validation and resources. M.W.: Conceptualization, resources, 2015;14(12):1286–1292.
and supervision. B.J.: Conceptualization, methodology, resources, 13. Wang W, Xu Y, Shen H. Polycrystalline silicon thin-film
supervision, and writing—review and editing. E.S.: Concep­ solar cells on various substrates. Phys Status Solidi A.
tualization, methodology, resources, supervision, and writing— 2006;203(4):721–731.
review and editing. 14. Koo J, Kim SB, Choi YS, Xie Z, Bandodkar AJ, Khalifeh J,
Competing interests: The authors declare that they have no Yan Y, Kim H, Pezhouh MK, Doty K, et al. Wirelessly
competing interests. controlled , bioresorbable drug delivery device with active
valves that exploit electrochemically triggered crevice
Data Availability corrosion. Sci Adv. 2020;6(35):eabb1093.
15. Mariello M, Kim K, Wu K, Lacour S, Leterrier Y. Recent
Data sharing is not applicable to this article, as no new data advances in encapsulation of flexible bioelectronic implants:
were created or analyzed in this study. All data presented in Materials, technologies, and characterization methods.
this review were reused under permission. Adv Mater. 2022;34(34):2201129.
16. Abyzova E, Dogadina E, Rodriguez RD, Petrov I,
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