Med-X (2024) 2:7

[Link]

REVIEW

Biomaterials‑enabled electrical stimulation for tissue healing

and regeneration
Han‑Sem Kim1 · Tanza Baby1,2 · Jung‑Hwan Lee1,2,3,4,5 · Ueon Sang Shin1,2 · Hae‑Won Kim1,2,3,4,5

Received: 29 November 2023 / Revised: 20 February 2024 / Accepted: 26 March 2024

© The Author(s) 2024

Abstract
The electrical microenvironment is considered a pivotal determinant in various pathophysiological processes, including tissue
homeostasis and wound healing. Consequently, extensive research endeavors have been directed toward applying electricity
to cells and tissues through external force devices or biomaterial-based platforms. In addition to in situ electroconductive
matrices, a new class of electroactive biomaterials responsive to stimuli has emerged as a focal point of interest. These elec-
troactive materials, in response to intrinsic biochemical (e.g., glucose) or external physical stimuli (e.g., light, magnetism,
stress), hold significant potential for cell stimulation and tissue regeneration. In this communication, we underscore this
distinct category of electroactive biomaterials, discussing the currently developed biomaterial platforms and their biological
roles in stimulating cells and tissues during the healing and regeneration process. We also critically evaluate the inherent
limitations and challenges of these biomaterials while offering forward-looking insights into their promise for future clini-
cal translations.

Han-Sem Kim and Tanza Baby contributed equally to this work.

* Ueon Sang Shin

usshin12@[Link]
* Hae‑Won Kim
kimhw@[Link]
1
Institute of Tissue Regeneration Engineering (ITREN),
Dankook University, Cheonan 31116, Republic of Korea
2
Department of Nano‑Biomedical Science & BK21 NBM
Global Research Center for Regenerative Medicine, Dankook
University, Cheonan 31116, Republic of Korea
3
Department of Biomaterials Science, College of Dentistry,
Dankook University, Cheonan 31116, Republic of Korea
4
Mechanobiology Dental Medicine Research Center, Dankook
University, Cheonan 31116, Republic of Korea
5
UCL Eastman‑Korea Dental Medicine Innovation Center,
Dankook University, Cheonan 31116, Republic of Korea

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Graphical Abstract

Keywords Electricity · Mechano-electroactive materials · Physical stimuli · Cell stimulation · Tissue regeneration

Introduction electrically activated biological events remain unclear,

diverse signaling pathways, such as Wnt/GSK3β, PI3K/
Cells encounter a diverse array of in vivo tissue microen- AKT, MEK/ERK, and TGF1/ERK/NF-BB, may contrib-
vironments [1, 2]. The dynamic interaction of cells with ute to those effects [17–19]. Consequently, electrical sig-
physical and chemical cues of extracellular matrix (ECM) nals emerge as facile biophysical cues to regulate cellular
determines cellular behaviors, including anchorage, motil- functions, particularly in the tissue healing and regenera-
ity, differentiation, and survival [2–4]. Among the cues, tion process. In fact, biophysical cues encompass various
electrical stimulation has emerged as a prominent deter- modalities, including surface topography, matrix stiffness,
minant in modulating cellular functions. The electrically ultrasound, light, magnetism, and electricity [2]. Among
active milieu exerts discernible effects on diverse cell these biophysical cues, electricity has played unique roles
responses, such as alignment, proliferation, and differen- in modulating diverse cellular behaviors and tissue func-
tiation, which often synergize with biochemical signals, tions, such as stimulating cell motility, proliferation, and
thereby fostering tissue healing and regeneration [5–8]. differentiation as well as wound healing, pain relief, and
Electrical stimulation has been demonstrated to exert tissue regeneration.
diverse in vivo effects, including pain relief, improved As such, recent scientific attention has centered on the
blood circulation, reduced tension in vascular and skel- development of biomaterials with appropriate electrical
etal muscles, and reabsorption of edema and joint fluid conductivity, thereby establishing electrical microenviron-
[9]. It also has a profound influence on cell behaviors ments for the transmission of biophysical signals to cells
in vitro. For instance, pulsed single-phase current signifi- [20–29]. The electrical microenvironments are crucial
cantly alters the shape, viability, structure, and adhesion of for various biological processes, encompassing cellular
mouse myocytes, while dynamic electric field conditions metabolism, ion transport for maintaining homeostasis,
favorably regulate osteoblast proliferation and differentia- and tissue repair. Electrical fields guide cell migration,
tion [10, 11]. Specific electrical parameters can enhance directing them to get involved in acute wound repairing
neural cell growth and control neural stem cell differen- process. For instance, Zhao et al. reported that endogenous
tiation [12, 13]. Moreover, electrical stimulation activates electrical field serves as a primary directional cue for cell
­ a2+, ­Na+, ­K+, ­Cl−), leading to ion flow
ion channels (e.g., C migration during wound healing [30]. Also, Liang et al.
and cytoskeletal changes that directly influence cell migra- created an electrical microenvironment to investigate the
tion [14–16]. While the exact mechanisms underlying the impact on epidermal cells during wound healing, where

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Med-X (2024) 2:7 Page 3 of 27 7

100 mV/mm electrical field applied could accelerated oxidase (GOx), lactate oxidase (LOx), and glucose dehydro-
wound healing [31]. Additionally, electrical signals were genase (GDH) for anions [55, 56], and enzymes like biliru-
observed to promote angiogenesis, facilitating the forma- bin oxidase (BOD), platinum (Pt), and laccase for cations, to
tion of new blood vessels and enhancing nutrient supply produce electricity through their interactions [56–58].
to the healing site of tissues [32]. Furthermore, materials responsive to external stimuli
As such, the biomaterials with appropriate electrical have recently been highlighted to be electrically active.
conductivity can serve as implantable materials and devices These materials are often semiconductor-based. Some rep-
to augment defective and degenerative tissues, regulating resentative examples are the composites with poly(3-hex-
cell–matrix interactions and ultimately improving tissue ylthiophene) (P3HT) nanoparticles [59], thin-film Si mesh
regeneration [4, 22, 33–38]. Furthermore, more recently, structure [60, 61], and titania nanowire arrays deposited with
advanced platforms that can function through external Au nanoparticles [61, 62]. For example, when exposed to
energy, such as light, magnetism, and stress (e.g., employing light, these materials undergo structural changes, affecting
piezoelectric materials) as well as via biochemical reactions their conductivity. Additionally, photoconductive nanoma-
(e.g., glucose) have also been explored to provide electrical terials, like graphene or semiconducting nanoparticles, can
signals and promote tissue healing [39–42]. experience changes in charge carrier mobility or concentra-
With these in mind, this review underscores the signifi- tion when illuminated. Specific light-sensitive proteins are
cance of electro-stimulating biomaterials, including conduc- utilized to modulate the electrical activity of cells, which can
tive materials and various stimulus-responsive biomateri- trigger conformational changes in these proteins. Moreover,
als, designed to facilitate efficient electrical conduction. We researchers have pioneered electroactive materials leverag-
investigate stimulation parameters that can optimally induce ing magnetic fields, namely the effects of electromagnetic
cellular activation and explore the mechanisms underpinning fields (EMF). When a conductive biomaterial, such as a
the electrically stimulated events. We further highlight the magnetic nanoparticle-loaded material, is exposed to an
potential limitations and challenges of existing approaches external magnetic field, magnetic nanoparticles tend to align
and offer forward-looking perspectives for the clinical appli- along the field. This alignment changes the spatial distribu-
cability of optimally designed electrical stimulation systems tion of charges, leading to generating an electric field within
in the future. the biomaterial. Similarly, when an external stress or force is
applied to the piezoelectric biomaterial, it distorts the crys-
talline lattice structure. The mechanical deformation leads
Strategies for biomaterial‑enabled electrical to the displacement of positive and negative charges within
stimulation the crystal lattice, resulting in the development of electric
potential across the material. Such piezoelectric materials
Electroactive biomaterials possessing high electrical con- have been developed with inorganic materials such as ZnO,
ductivity facilitate the efficient transfer of electrical stimula- ­BaTiO3, and Whitlockite [63–65], or polymers like polyvi-
tion. These materials often feature π bond-based backbones nylidene fluoride (PVDF) and poly-L-lactic acid (PLLA)
characterized by extended chains of loosely bound electrons. [39, 66–69]. These piezoelectric materials were formulated
Upon reduction or oxidation through dopant molecules, they into scaffolds or hydrogels for a diverse range of cell and
exhibit enhanced electron mobility. Such materials often tissue stimulations.
comprise a composite of inorganic substances, including Many studies have reported that the voltage ranges for
carbon nanotubes (CNT) [43–45], graphene oxide (GO) cell stimulation and tissue healing typically span from mil-
[46–48], black phosphorus (BP) [49, 50], Mxene [51, 52], livolts (mV) to volts (V), where the selection of a specific
with polymers such as polypyrrole (PPy) [28, 48] and poly- voltage depends on the intended applications, target tissues,
aniline (PANI) [53, 54]. After being processed into conduits and experimental parameters. This spectrum encompasses
or scaffolds by mold casting or 3D printing, these compos- very low voltages, sometimes below the mV threshold,
ites provide high electrical conductivity, enabling efficient which are often harnessed to investigate in vitro activation of
electrical stimulation to cells. cells, such as intracellular ion influx and related signalings
Beyond external power sources for electrical stimulation, [70]. Alternatively, higher voltages, ranging from hundreds
active research is ongoing concerning materials capable of of mV to several V, find utility in the in vivo tissue activa-
self-electricity generation in response to internal and exter- tion, such as cardiac pacing, muscle stimulation, and brain
nal body environments. Building on the effective and stable stimulation [71]. The corresponding current stimuli typically
electron transfer facilitated by these conductive materials, fall within the range of approximately 1 µA down to several
significant emphasis is placed on the development of biofuel nA [72, 73].
cells. These devices harness organic fuels present in body In summary, electrical stimulation approaches lever-
fluid, predominantly employing enzymes such as glucose age the in situ electrical conductivity of materials or the

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Fig. 1  Illustration depicting

various electrical stimulation
approaches utilizing biomateri-
als: in situ electroconductive
materials linked to external
electric sources, environmen-
tally electroactive methods like
enzymatic biofuel cells, and
materials responsive to external
stimuli (light, magnetic, stress).
The generated electricity acti-
vates various cells and tissues
(nerve, muscle, skin, and bone),
contributing to the healing and
regeneration process

stimuli-responsiveness of semiconducting, magnetism, and nanomaterials, and metal nanomaterials, have thus been
piezoelectric materials, which can generate appropriate potentially employed [75–78], as discussed in this section.
electricity for the activation of cells and tissues (e.g., nerve,
muscle, bone, and skin). This contributes significantly to Providing microcurrent with electroconductive
the healing and regeneration process, as illustrated in Fig. 1. biomaterials

Conductive biomaterials, typically composed of hydrophilic

Electrical stimulation based on in situ polymer matrix with conductive polymer or inorganic fillers
conductive biomaterials [50, 76, 77], have been developed into hydrogels or tissue
scaffolds that exhibit tunable electrical and mechanical prop-
The effectiveness of materials exhibiting electrical conduc- erties. The incorporation of conductive elements empowers
tivity akin to native tissue has been extensively validated, a diverse range of conductivity, closely mirroring tissue-
underscoring their potential to serve as a viable electrical specific electrical conductivity, while the polymeric matrix
stimulation source in specific environments to promote cell allows shape formability to satisfy the mechanical proper-
proliferation, motility, and differentiation. These conductive ties. Table 1 lists the conductive biomaterials developed
materials possess a unique combination of electrical conduc- to provide microcurrent for the repair and regeneration of
tivity and biocompatibility, enabling biomedical usages for diverse tissues, including skin, bone, muscle, and nerve.
diverse tissues [2, 3, 74–76]. Specifically, they provide elec- For skin regeneration, various conductive materials
trical stimulation for tissue regeneration, serve as electrodes have been developed. For instance, PPy-combined gelatin
in bioelectrochemical systems and implantable devices, and methacryloyl (GelMA) hydrogels could accelerate skin
contribute to the development of biosensors for sensing tissue regeneration [19]. The conductive hydrogels modu-
and diagnostics. A diverse array of materials that possess ­ a2+ concentrations, stimulating protein
late intracellular C
intrinsic electrical conductivity, spanning polymers, carbon phosphorylation in PI3K/AKT and MEK/ERK pathways,

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Table 1  Summary of representative studies on electrically conductive biomaterials, including their electrical properties, biocompatibility,
mechanical properties, and the applications, with or without the external electrical field
Ref Conductive materi- Conductivity/cur- Applied electrical Cytotoxicity Mechanical properties Applications
als rent/voltage range field

[19] oxidized chondroitin 0.312 ± 0.03 S ­m−1 Not applied Biocompatible - Neurovascular
sulfate regeneration
[79] polypyrrole 3.75 × ­10–2 S ­m−1 Not applied < 9.7 μg/mL 64 MPa (flexible) Spinal cord injury
[80] polyaniline 1.18 S m­ −1 Not applied < 10 μg/mL 38.2 ± 2.2 MPa Myogenic differen-
(Elastic) tiation
[53] Graphene oxide 0.87 ± 1.6 S ­m−1 Not applied < 20 μg/mL 18.64–24.59 MPa Peripheral nerve
(Highly stretchable) regeneration
[81] Silver nanowire 1.54 × ­105 S ­m−1 Not applied < 1 μg/mL ~ 2.6 × ­103 MPa Accelerated wound
(AgNW) (Flexible/ stretchable) healing
[82] Mxene 4 × ­10–2 S ­m−1 0.35 V 10-400 μg/mL 436 MPa Osteogenic differen-
(Weak mechanical flex- tiation
ibility)
[83] Polypyrrole 5.62 ± 0.38 × ­10–2 4–8 × ­10–3 V - - Myocardium infarc-
­Sm−1 tion (MI)
[38] Polydopamine, GO 5 × ­10–1 S ­m−1 0.1 V Up to 250 μg/mL ~ 200 ± 180.32 × ­10–3 MPa Accelerated wound
(Stretchable) healing
[84] Polydopamine, GO 1.6 × ­102 S ­m−1 0.3 V - - Periodontal bone
tissues
[85] Titanium disc 7.4 × ­105 S ­m−1 0.2 V Up to 10 μg/mL ~ 130 MPa Osteogenic differen-
(very flexible) tiation
[86] Bacterial cellulose 10–6 -1 S ­m−1 - ~ 100 μg/mL (flexible) Cardiomyocyte dif-
(BC)-PPy ferentiation
[87] PPy 5–18 S ­m−1 - - - Spinal cord injury
repair
[88] PCL-CNT 15.69–178.63 S ­m−1 - 0.8–10 μg/mL ~ 25 × ­103 Mpa (CNT), Nerve regeneration
(CNT) 38.7 Mpa (PCL)
(Highly flexible)
[89] PPy-Silk fibroin - 5V Biocompatible 70 ± 6 MPa Cardiac tissue Engi-
(SF) (SF) neering
[90] PPy - ~ 2.5 A - - Neurite outgrowth
[91] Cellulose /PPy 8 S ­m−1 - - 25 × ­103 MPa Nerve regeneration
(Cellulose)
[92] PPy-Polyurethane 2.3 × ­10–4 S ­m−1 - Biocompatible 30–150 × ­103 MPa Myoblast differen-
(PU) (Polyurethane, elastic& tiation
flexible)
[93] Polypyrrole (PPy) - 10–5 A - - Neurite outgrowth
[94] PCL/Cellulose - 0.5 V Biocompatible - Nerve regeneration
[95] PPy/PLLA - ~ 50–200 V < 9.7 μg/mL ~ 80 MPa (PLLA, low Wound healing
ductility)
[96] PLLA/PANi - 100 V - - Nerve regeneration
[97] PPy - 5 × ­10–5 A - - Muscle regeneration
[98] Mg(OH)2/GO/HA - 0.1 A, 120 V ~ 10 μg/mL ~ 174 MPa (HA, highly Bone regeneration
(HA) stretchable)

ultimately assisting in the recovery of full-thickness dia- prevention in skin wounds (Fig. 2c). Furthermore, when PPy
betic skin wounds (Fig. 2a,b). In addition, conductive sil- was made into a nanofiber form with silk fibroin or cellulose
ver nanowires were combined with alginate-based gels [47] the conductive nanofiber scaffolds were effective in cardiac
to provide a flexible and formable electrode, considered tissue regeneration [86, 89]. Likewise, PANI nanofiber with
to be alternative to conventional metal electrodes, which poly(ε-caprolactone-gelatin (PCL-Gelatin) [99] supported
could promote wound healing by improving re-epithelial- effective cardiac tissue regeneration, and the PANI hydro-
ization, vascular formation, immune control, and infection gel with hyaluronic acid [53] also demonstrated potential

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Fig. 2  a Illustration detailing the mechanism by which conductive hydrogel enhances neurovascular regeneration in vivo. The conductive hydro-
gels modulate intracellular C ­ a2+ concentrations, stimulating protein phosphorylation in PI3K/AKT and MEK/ERK pathways. (b) Photographs
showing PI3K/AKT and MEK/ERK pathways assisting in the recovery of full-thickness diabetic skin wounds. Adapted with permission from
[19], copyright 2022, John Wiley & Sons. (c) Diagram illustrating the fabrication of epatch and the double-crosslinked network of AgNW-MA-
Alginate-based gel to provide a flexible electrode for wound healing Adapted with permission from [81], copyright 2022, Elsevier. (d) Scanning
electron microscope (SEM) images displaying the morphology of synthesized GelMA, GO/GelMA, and r(GO/GelMA) conduits (scale bar: 500
μm) meant for neural repair Adapted with permission from [80], copyright 2020, John Wiley & Sons. (e) Bar graph depicting the conductivity
of hydrogels made from conductive polymers. Adapted with permission from [53], copyright 2023, Elsevier. (f) Schematic image and charac-
teristics of the carbon nanotube (CNT) platform designed for interaction with astrocytes. Adapted with permission from [101], copyright 2022,
Springer nature

for skeletal muscle regeneration. Furthermore, bone bioac- super-aligned CNT sheets [55, 103], and composite scaffolds
tive materials were combined with conductive materials for consisting of reduced graphene oxide and PANI have shown
bone regeneration. For the sample, hydroxyapatite-GO com- promise in enhancing neural function and promoting nerve
posites with biopolymers were effective in enhancing bone regeneration (Fig. 2f). These materials exert the effects by
regeneration through the effects of electrical conductivity influencing astrocyte function, facilitating spiral ganglion
and ionic release from the inorganic elements [98, 100]. neuron growth, and improving microstructural properties.
The most widely studied area of conductive biomaterials The use of these conductive substances has the potential to
is neural repair, such as spinal cord [79] and peripheral nerve impact nerve survival, adhesion, neurological development,
injuries [80] (Fig. 2d). These nerve conduits incorporate var- and synaptic formation. This opens up exciting possibili-
ious conductive materials, such as CNT, graphene (oxide), ties for therapeutic interventions in the field of neurological
and conductive polymers, facilitating remarkable electri- diseases and nerve regeneration.
cal conductivity (Fig. 2e). The conductive mechanisms are While the electrically conductive biomaterials have dem-
also proven to be diverse, including electrode integration, onstrated remarkable repair capacity of diverse tissues by
ion migration, and the piezoelectric effect, which effec- offering microcurrents to cellular environments, connect-
tively deliver electrical signals to damaged nerves enabling ing external electrical sources can potentially enhance the
axonal growth and functional recovery. Various conductive transfer of electricity, thereby intensifying the stimulation of
substrates, including length-specific MWCNT [101, 102], cells and tissues induced by electrical currents [4, 104, 105].

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Med-X (2024) 2:7 Page 7 of 27 7

Polypyrrole has been a superior choice due to its high elec- consider various factors, including long-term stability, bio-
trical conductivity, good biocompatibility with a cytotoxic- compatibility, and electrical conductivity.
ity limit of up to 9.7 µg/mL, and versatile synthesis meth-
ods enabling diverse structures. Nevertheless, it is prone to Connecting electric field to electroconductive
oxidative degradation over time. Polyaniline shares similar materials
properties but lacks long-term stability in smart devices. On
the other hand, carbon-based materials, specifically carbon Electrical stimulation can be enhanced by applying exter-
nanotubes (CNTs) and graphene oxide (GO), exhibit out- nally induced impulses to the electroconductive materials,
standing electrical conductivity and provide a large surface ultimately accelerating tissue recovery [109]. External elec-
area for cell attachment and growth [106]. Their long-term tric field applications amplify the electrical current output
electrochemical stability is typically superior to metal- of the electrically conductive materials.
based materials like silver nanowires (AgNW) because sil- Various methods exist for electrical stimulation by apply-
ver nanowires can corrode and degrade with a cytotoxicity ing external electrical circuits, including direct, capaci-
limit of < 1 µg/mL, particularly in corrosive environments or tive, and inductive coupling. Direct coupling represents
under repeated mechanical stress [107, 108]. This distinc- a commonly used approach. One notable application was
tion underscores the preference for carbon-based materials observed in transcutaneous electrical nerve stimulation. In
in applications where long-term stability is critical. How- this approach, conductive electrodes establish direct physi-
ever, there are cytotoxicity concerns with these materials at cal contact with the target tissue. For instance, neurite out-
higher concentrations. Therefore, the selection of materi- growth could elongate when cultured on scaffolds made of
als for electrical stimulation applications should carefully electrospun PLLA/PANI fibers [110] or gold nanoparticle

Fig. 3  a Schematic image showing fabrication of SP(silk fibroin and polypyrrole) and its response to external ES, (b) application of electroac-
tive cardiac patch SP50 ECP showing improved electrical integration of host heart under external ES of 5 V/cm to myocardial cells, Adapted
with permission from [83], copyright 2022, John Wiley & Sons. (c) illustrative image of SNF/CNT based E-tattoo, based on silk nanofibers
and MWCNT Adapted with permission from [118], copyright 2021, John Wiley & Sons (d) schematic illustrating preparation of PLA/rGO
and PLA/rGO/PPy, with cellulose for improved neurite outgrowth. Adapted with permission from [119], copyright 2021, Elsevier (e) electrically
conductive pathways created by RSF and Mxene/RSF double-crosslinked network nanocomposite hydrogel that incorporates horseradish peroxi-
dase and hydrogen peroxide to illuminate an LED, which under an applied voltage to promote bone regeneration. (f) electrical conductivities of
various concentrations of Mxene, (g) real-time resistance response measurement tested for Mxene/RSF hydrogel using the cut-contact method.
Adapted with permission from [82], copyright 2023, Elsevier

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composites [111] through direct coupling. Capacitive cou- demonstrated to be effective for skeletal muscle tissue upon
pling is another method involving capacitors to transmit external electrical activation [118].
electrical energy to a target tissue or device. Capacitors, For nerve regeneration, scaffolds were also used in
capable of storing and releasing electrical energy upon volt- combination with electrical stimulation [96]. For instance,
age fluctuations, facilitate the delivery of stimulating signals PANI-based scaffolds, often hydrogels, have proven effec-
via one capacitor plate while positioning the other in prox- tive in enhancing nerve regeneration by stimulating neuron
imity to the target tissue. This system obviates the need for a proliferation and neurite growth, primarily through efficient
conductive scaffold. Gonzalez and colleagues, for instance, electrical delivery [120, 121]. Scaffolds based on PPy were
employed capacitive coupling to administer a 4 mV/cm elec- also employed to enhance neurite outgrowth. For instance,
trical stimulation to chondrocytes, resulting in significant Shi et al. developed nano-porous scaffolds by incorporat-
augmentation of cell proliferation [112]. On the other hand, ing DBSA-doped PPy with cellulose, resulting in improved
inductive coupling harnesses a tunable electromagnetic field neurite outgrowth [91]. Conductive composite fibers that
generated by a conductive coil encompassing the cell culture incorporate GO also demonstrated the ability to enhance
system, commonly referred to as pulse electromagnetic field cell proliferation and promote neurite growth, as observed
stimulation. in PC12 cells incorporating DBSA-doped PPy-cellulose as
Conductive materials, when subjected to an applied elec- nano-porous scaffolds [122] (Fig. 3d). These studies under-
trical field, have demonstrated remarkable potential for tis- score the versatility of electrically conductive polymeric
sue regeneration. For instance, in the context of wound heal- scaffolds, in combination with external electrical stimulus,
ing, PPy integrated with PLLA was utilized with external for the regeneration of neural tissues.
electric fields ranging from 50 to 200 mV/mm [95]. Regen- For bone regeneration, various types of conductive
erated bacterial cellulose/MXene hydrogels, under electric composites were used. For instance, Chao et al. developed
fields of 0–400 mV/mm, also enhanced skin wound healing Mxene nanosheet/silk fibroin double-crosslinked network
[113]. In addition, Li et al. employed a controlled electri- nanocomposite hydrogel that incorporates horseradish
cal stimulation technique using an approximate DC voltage peroxidase and hydrogen peroxide to enhance bone repair
of 10 V for wound healing [114]. In comparison, Brown [82] (Fig. 3e). This conductive scaffold, under an applied
et al. applied higher voltage pulse stimulation (30–60 V) to voltage ~ 100 mV/mm, was proven to promote bone regen-
induce a high rate of wound closure in rabbits and guinea eration with concurrent electrical activity, fostering elec-
pigs [115]. trophysiological microenvironment assessment in vitro,
For skeletal muscle regeneration, PPy-based electrically such as evaluations of cell suitability, electrical conductiv-
conductive scaffolds, upon stimulation with an external ity, bone inductivity, bone immunomodulatory capability,
electrical current of 50 μA, showed higher expression of and angiogenesis (Fig. 3f, g). In vivo studies also showed
contractile proteins [97]. Furthermore, conductive scaffolds bone regeneration and neovascularization treatment using a
were instrumental in producing functional heart tissue and critical-sized longitudinal bone defect model. In addition to
promoting tissue reconstruction for the treatment of heart the inherent electrical signals found within bones, external
attacks [83] (Fig. 3a). By applying an electrical stimula- electrical stimulation has been shown to exert various osteo-
tion of 5 V/cm to myocardial cells upon these scaffolds, genic responses, including enhanced ion mobility and bone
engineered cardiac patches with precise thickness and elec- growth [119, 123–125].
trical activity could be created (Fig. 3b). This direct elec- Some of the representative studies on electrically conduc-
trical stimulation has resulted in the expression of crucial tive biomaterials, including their electrical properties and
cardiac markers, improved resistance to shrinkage, and applications, with or without the external electrical field,
enhanced electrical coupling performance. In vivo studies are outlined in Table 1. Direct electrical stimulation can
demonstrated their effectiveness in enhancing left ventricu- significantly boost cell activity and regeneration, enhanc-
lar remodeling, restoring cardiac function, and improving ing regeneration efficiency. However, it carries risks such
the propagation of electrical signals. Carbon-based con- as apoptosis and the release of toxic substances (e.g., COx,
ductive materials such as MWCNT and GO have also been NOx, SOx) when applied at higher-than-optimal energy lev-
used for muscle regeneration. For instance, the integration els [126–128].
of MWCNT with PPy could promote myoblast differentia- In clinical contexts, rigorous testing and standardiza-
tion [116] under electrical stimulation of 0.125 mA/cm 2. tion are essential to validate the reliability and reproduc-
Recently, an electronic tattoo (E-tattoo, Fig. 3c) based on ibility of these materials. Biocompatibility stands out as a
silk nanofibers and MWCNT (SNF/MWCNT) was devel- supreme concern, thus the conductive biomaterials need to
oped for therapeutic purposes, which could be activated be carefully evaluated for their biocompatibility with the
by the low level of electrical signals (3.5 nA to 0.3 μA) physiological environment, ensuring minimal inflamma-
[117]. MWCNT-doped gelatin-cellulose scaffolds were also tion, immune response, or rejection [129]. Furthermore,

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Fig. 4  Representative examples of electroactive materials in response to intrinsic microenvironmental cues: (a) Illustration showing the elec-
tricity-generation working principle of flexible, miniaturized biofuel-inspired glutamate sensor that can monitor glutamate release in the nerv-
ous system within the cerebral spinal fluid and cyclic voltammetry performed from 0.2 mM to 0.5 mM, Adapted with permission from [135],
copyright 2023, John Wiley & Sons (b) current density change of bioelectrical plaster with different concentrations from actual mouse skin
images after 7 days of hydrogel application, Adapted with permission from [136], copyright 2017, John Wiley & Sons (c) electricity self-gen-
erating enzymatic-biofuel-cell (EBC) skin patch for wound healing, consisting of anodic enzyme and cathodic counterpart, which is developed
into a hydrogel form of polyacrylamide (PAA) containing glucose and EBC, (d) the in vivo wound healing efficacy, Adapted with permission
from [133], copyright 2021, Elsevier and (e) design of self-electrified miniaturized conduit device incorporating dissolvable galvanic cells that
generates open circuit voltage. Adapted with permission from [138], copyright 2020, Science Advances, AAAS

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the long-term stability of these materials is a critical factor, precursor cells. The glucose oxidase-based EBC was also
especially when considering their integration into chronic proven to stimulate neural cells [137].
medical interventions. Degradation over time can compro- One recent study by Kim et al. [132] has further devel-
mise the effectiveness of the biomaterial and pose risks to oped the EBC system for in vivo skin patches and demon-
patient health. Additionally, the integration of these technol- strated the biological electroactive mechanisms (Fig. 4c).
ogies with existing medical practices necessitates particular The EBC system could be powered by enzymes such as
efforts, such as consideration of long-term stability in the GDH and BOD, generating an in situ electrical current.
electrical connections. Also, practical limitations, includ- Electricity generated by EBC was shown to activate the
ing power sources and wiring constraints, can reduce the mechanosensitive ion channel Piezo1, inducing calcium
feasibility of direct electrical connections [130, 131], which influx in endothelial cells and fibroblasts, thereby stim-
warrants further developments. ulating cell motility and migration ability. This study
highlights the critical role of self-generating electricity
Electroactive materials in response to intrinsic in the tissue regenerative process, specifically for skin
microenvironmental cues wound healing (Fig. 4d), by stimulating cell viability
and mobility in vivo while supporting vascular forma-
Enzymatic biofuel cells (EBC) harness biological fuels such tion, collagen deposition, and re-epithelialization. While
as glucose and oxygen to efficiently convert chemical energy the EBCs have shown great promise in activating cells
into electrical energy, resulting in the generation of electric- and repairing diverse tissues in the form of electricity-
ity. Mainly utilizing microorganisms or enzymes to facilitate autogenerating implantable devices, there is a need for
chemical reactions, these biofuel cells enable the conversion further improvements in materials and device designs to
of electrons in these reactions into electric current as they optimize their effectiveness, such as electrical lifetime
traverse from positive to negative poles in external circuits. and degradability. Addressing one of these challenges,
Some recent works have highlighted the potential of these Liu et al. [139] introduced biodegradable, self-electrified,
biofuel cell principles as tissue regeneration devices through ultra-miniaturized conduit devices that incorporate dis-
in situ electrical stimulation of cells and tissues. solvable galvanic cells (Fig. 4e). These recent works on
The development of self-powered, autogenerating elec- EBC systems demonstrate well the in situ responsiveness
trical devices has opened up possibilities for establishing to tissue microenvironmental cues, such as glucose and
localized electrical microenvironments within tissues, with glutamate, thereby self-generating electricity, offering the
potential applications in tissue repair and wound healing. possible uses as wireless innovative biomedical materials
These devices can take various forms, including the glucose- and devices for wound healing and recovery of damaged
responsive EBC skin patch [132] and miniaturized galvanic tissues.
cell-based devices seamlessly integrated into biodegrad- In discussing the three approaches to ES generation,
able scaffolds, as demonstrated in recent biofuel cell stud- the effectiveness depends on specific application require-
ies [133]. ments. The efficacy of using in situ conductive biomateri-
The functional glucose-responsive EBC can serve as a als is contingent upon the particular biomaterial utilized.
biocompatible tool that converts glucose in the body into For instance, materials like PPy, exhibiting a conductivity
electrical energy, finding biomedical applications like range of 5–8 S­ m−1, can enhance neurite outgrowth when
implantable artificial organs and drug delivery biosen- coupled with an external current of ­10−5A. While diverse
sors. For instance, Prasad et al. [134] developed a mil- designs of conductive materials lead to varied applica-
limeter-sized biofuel cell (Fig. 4a) to monitor glutamate tions, their enhanced conductance generally synergizes
release in the nervous system within the cerebral spinal with electrical stimulation [2, 138]. The EBC system
fluid (CSF). Inspired by this, Kai et al. [135] generated introduces a novel means of applying in situ electricity
ionic current along the skin surface through an EBC that without external wires, promising more patient-friendly
is firmly attached to the skin (Fig. 4b). These biocompat- medical devices. However, its power outputs are typically
ible materials act as wearable power sources, maintaining low and short-term, necessitating improvements in mate-
flexibility, excellent skin contact, biocompatibility, and rials. Conversely, external connections offer higher elec-
long-term current stability, contributing to wound closure. trical efficiency and greater controllability with desired
Furthermore, Lee et al. [136] demonstrated the potential stimulation parameters. Therefore, choosing between
of EBC as a promising power source for in vivo implant- these approaches requires considering factors such as
able biomedical devices because the device possesses an power needs, stimulation duration, biocompatibility, and
intrinsic ability to generate electrical stimulation, enhanc- practicality in the intended biological environment.
ing proliferation, migration, and differentiation of muscle

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Med-X (2024) 2:7 Page 11 of 27 7

On‑demand electrical stimulation electron transport or structural rearrangements, providing

through external stimuli‑responsive a basis for responsive behavior at the atomic level [148].
biomaterials This wireless and remote-controlled stimulation approach
offers non-invasive and versatile interfaces, making them
Previously, many studies aimed to address the constraints valuable for various applications from tissue engineering
associated with materials requiring direct electrical con- to human–machine interaction.
nections. Prominent among the active investigations are Another notable category is piezoelectric biomaterials,
employing materials capable of generating electricity in which generate electrical signals in response to mechanical
response to external stimuli, such as light, magnetic field, deformation or pressure. These materials possess intrinsic
and mechanical stress. This strategy enables the controlled piezoelectric properties, allowing them to convert mechani-
delivery of microcurrents to enhance cellular activity cal energy into electrical energy [63–69]. When an external
without direct electrical contacts, instead functioning ‘on mechanical stress is applied, the basic structural arrange-
demand’ control over the electricity [107, 140–142]. These ment deforms, producing a net dipole, i.e., the separation
on-demand stimuli-responsive biomaterials are designed of the molecular positive and negative centers. As a result,
to exhibit tailored responses to diverse cues, effectively the electrons within the materials re-equilibrate, and fixed
converting them into electrical signals [68, 107, 142]. This charges emerge on opposing surfaces of the materials, with
innovative approach has brought a paradigm shift to tra- the materials becoming electrically polarized, producing
ditional electrical stimulation methods by eliminating the electric current [16, 107].
need for direct physical connections, rather enabling wire- These biomaterials can generate electrical stimulation
less and remote-controlled electrical stimulation, possibly that can find diverse applications, including tissue regenera-
offering minimally invasive applications. tion, biosensing, and neural interfaces, by applying external
One such category of biomaterials is optoelectric mate- mechanical forces or vibrations. This section highlights the
rials, which are capable of converting light into electrical potential of these externally induced electrical stimulation
signals. By incorporating light-responsive components using responsive biomaterials, offering promising avenues
like photoactive molecules or semiconductor nanoparti- for advanced biomedical applications.
cles into the matrix, these materials can generate elec-
trical stimulation when exposed to specific wavelengths Photoreactive biomaterials for electrical stimulation
of light [54, 59, 60]. This allows targeted and controlled
stimulation of cells and tissues, opening promising ave- The photoelectric effect, an intriguing phenomenon exten-
nues for therapy and interfaces with electronic devices. sively applied in various technologies like photodetectors
The molecular-level mechanism of action for light-induced and solar cells, harnesses both inorganic semiconductor
responses can vary based on the specific properties of the materials, such as silicon and titanium, and organic semi-
materials. Photoexcited molecules generate electron–hole conductor polymers, like poly(3-hexylthiophene) (P3HT).
pairs by promoting electrons to higher energy levels [143]. When these materials absorb light at specific frequencies,
These charge carriers can contribute to increased electri- their electrons become excited, forming electron–hole pairs.
cal conductivity. Biomaterials with conjugated systems, These electrons are subsequently segregated into the con-
such as pi-bonded systems and aromatic rings can undergo duction band, while the holes occupy the valence band,
electron delocalization upon light absorption which can ultimately generating an electrical current (Fig. 5a) [142].
increase materials conductivity. Moreover, light energy Ongoing research endeavors are focused on developing
can be transferred between molecules within the biomate- materials that can maximize the efficiency of this electrical
rials. Excitons (bound electron–hole pairs) form as a result stimulation process. The evolution of wireless and remote
of this energy transfer, affecting the electronic state and light stimulation represents significant advances from tradi-
conductivity of materials. tional wired electrical stimulation methods. It offers mini-
Similarly, magneto-responsive biomaterials harness mally invasive, enduring interfaces, holding considerable
magnetic fields to generate electrical signals. These mate- promise for addressing tissue damage and degenerative dis-
rials can convert applied magnetic fields into electrical orders [149].
stimulation by incorporating magnetic nanoparticles or In this context, semiconductor polymer nanoparticles,
other magnetically responsive components [144–147]. particularly p-type polymer nanoparticles utilizing P3HT,
At the molecular level, magnetic moments in nanoparti- have gained substantial attention. These high-performance
cles align in the direction of the external magnetic field, conjugated polymers exhibit exceptional photoelectric prop-
influencing the overall properties of the biomaterials. This erties and desirable solubility in organic solvents. Notably,
alignment can modulate conductivity through changes in scaffolds based on P3HT have demonstrated the ability to
promote neuronal maturation upon exposure to green light.

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Fig. 5  Representative studies on electrical stimulation by light-responsive materials: (a) Schematic illustration showing mechanism when a
photoconductive scaffold is illuminated by light, (b) schematic illustration depicting electrical impulses in neurons influencing the treatment
of nerve injuries and neurodegenerative diseases and creating a bioactive platform for remote and wireless optoelectrical stimulation through
the integration of photoconductive P3HT NPs into the biomimetic hydrogel, (c) mean photocurrents produced by hydrogels on green light illu-
mination, (d) illustrative image showing green light irradiation on hydrogel patch and its photocurrent response, Adapted with permission from
[59], copyright 2022, John Wiley & Sons (e) schematic of 3D Si-based hybrid scaffold for photocurrent measurement and photocurrent response
for 3D Si-based scaffolds, Adapted with permission from [60], copyright 2023, Science Advances, AAAS. (f) schematic illustration comparing a
blind retina, which lacks natural photoreceptors, and its interface with a retina featuring nanowire (NW) arrays. The blind retina's necrotic photo-
receptor layer (rod and cone cells) is substituted with an Au-TiO2 NW array serving as artificial photoreceptors. Adapted with permission from
[61], copyright 2018, Springer Nature

However, due to their high reactivity in the presence of into a biomimetic hydrogel matrix for neuronal maturation.
moisture, it is anticipated to degrade soon, which is a signifi- The composition of the hydrogel matrix and cross-linking
cant drawback. A novel approach was implemented by Wu degree were adjusted to meet various applications. P3HT
et al. [59], who integrated hydrophilic P3HT nanoparticles nanoparticles within the hydrogels efficiently converted

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Med-X (2024) 2:7 Page 13 of 27 7

Table 2  Summary of representative studies that report electrical properties, biocompatibility, mechanical properties, and the range of generated
currents of tissue regeneration materials that generate microcurrents in response to light or magnetic fields
Ref Responsive materials External sources (opti- Generated current or Cytotoxicity Mechanical properties Applications
mal conditions) voltage range

[59] P3HT 500–550 nm of green ~ 6.0 × ­10–11 A ~ 0.4 μg/mL Flexible Neurogenesis
light
[60] Silicon ~ 808 nm of near- No mention ~ 10 μg/mL 120 MPa Bone regeneration
infrared light (High elasticity)
[61] Silicon 200–550 nm of UV, UV- 1.45 × ­10–9 A Biocompatible - Artificial retinal
green–blue light Blue-1.08 × ­10–10 A prosthesis
Green- 8.7 × ­10–11 A
[154] 3-(4,5-dimethoxy- 350–365 nm of light No mention - - Cell adhesion,
2-nitrophenyl)-2-bu- inflammation,
tyl ester (DMNPB) vascularization
[155] Neodymium boron Magnetism 10.5 × ­10–3 V 100 μg/mL 850–1050 MPa Conversion of fibro-
(NdFeB) (Elastic) blasts into neurons
[156] CoFe2O4, ­BaTiO3 Magnetism 10 V 0.630 μg/mL 1.5–125 MPa Cell proliferation,
(Co2+ ion) ­(CoFe2O4) differentiation,
upregulated gene
expression
[144] CoFe2O4, ­BaTiO3, Magnetism 8–10 V - - Bone repair, osteo-
PVDF-TrFE genesis

light signals into electrical signals under pulsed green light cells (RGCs) (Fig. 5f). The functional preservation of the
exposure, generating tens of picoamperes of photocurrent rest of the retinal circuit was indicated by the blockage of
(Fig. 5b-d). This phenomenon promoted the growth of corti- ON responses in RGCs using glutamatergic antagonists.
cal neurons surrounded by the hydrogels and stimulated neu- Furthermore, neurons in the primary visual brain responded
ronal differentiation of bone marrow MSCs encapsulated in to light following nanowire array subretinal implantation, as
the hydrogels. This study emphasized the potential for devel- demonstrated by the improvement in pupillary light reflex,
oping future neural electrodes and scaffolds that respond indicating behavioral recovery of light sensitivity. These
to external stimuli beyond traditional electrical stimulation. findings highlight a new optoelectronic tool kit for retinal
A similar concept of 3D biomimetic optoelectronic scaf- lower prosthetic devices, demonstrating significant potential
folds responsive to external infrared light was explored by for vision recovery in visually impaired patients.
Wang et al. (Fig. 5e) [60]. The Si-based 3D biomimetic Table 2 presents the biomaterials systems that generate
scaffolds not only provided a 3D hierarchical structure electricity upon optimal external light sources. The technol-
for directing cell growth but also modulated cell activity ogy of generating electrical currents within light-respon-
through photo-induced electrical impulses. The scaffolds, sive materials constitutes an active research area, which
remotely controlled by infrared light, could electrically alter frequently faces several challenges. First, operational volt-
the membrane potential and intracellular calcium dynamics ages are notably low, yielding the generation of exceedingly
of stem cells, effectively promoting cell proliferation and modest electrical currents, and operating parameters remain
differentiation. The Si-integrated scaffolds demonstrated constrained [150]. In this context, recent studies demonstrate
improved osteogenesis in a mouse model upon light stimula- the ability of hair regeneration by body movement and its
tion. The wirelessly powered optoelectronic scaffolds elimi- applicability in wearable epidermal areas through integrat-
nated the need for tethered electrical implants and degraded ing light and external electrical energy. Despite the apparent
completely in a biological environment. Integrating topo- benefits of generating electricity from light, the system still
graphical and optoelectronic cues in Si-based 3D scaffolds relies on additional external electrical energy to generate
is considered to offer more effective biological modulation voltages ranging from several hundred mV to 10 V [6, 117].
with broad biomedical applications. Moreover, optoelectric systems show high sensitivity to
In another study by Jing et al. [61], artificial photorecep- environmental perturbations within biological environments,
tors were created based on gold nanoparticle-decorated tita- including variances in pH levels and fluctuations in the pres-
nia nanowire arrays for restoring visual responses in blind ence of diverse biochemical agents [151], which often exert
mice with degenerated photoreceptors. These photoreceptors a detrimental influence on electrical performance. Further-
showed spatial resolution of more than 100 μm and exhibited more, sustaining consistent electrical output over prolonged
green, blue, and near UV light responses in retinal ganglion durations within the complex and dynamic environment of

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Fig. 6  Representative studies on electrical stimulation by magnetic-responsive materials: (a) Schematic of magnetic responsive platforms illus-
trating the mechanism of magnetic field effect on magnetic nanoparticles (MNP) containing scaffolds, (b) image showing magnetic nanoparticles
dispersed in the polymeric matrix and magnetic dipole alignment changing magnetic flux density and its compressed state, (c) current and volt-
age outputs under initial and final days from magnetoelastic generator, Adapted with permission from [156], copyright 2022, John Wiley & Sons
(d) diagram showing magnetoelectric coefficient test system and magnetization hysteresis loop where CFO nanoparticles undergo deformation,
Adapted with permission from [157], copyright 2022, Elsevier (e) interface polarization due to applied magnetic field and transition of PVDF
from α to β phase. Adapted with permission from [145], copyright 2023, Springer Nature. (f) The process of the ME-BIT implant receives power
and converts the magnetic field to an electric field by the magnetoelectric film, transfers strain to the piezoelectric layer, PZT, and induces a volt-
age. Adapted with permission from [161], copyright 2022, Springer Nature

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Med-X (2024) 2:7 Page 15 of 27 7

the human body remains a significant challenge [152]. In by growing a piezoelectric platform (PLLA) just above
instances where these technologies are intended for in vivo self-constrained ­CoFe2O4 (CFO) nanoparticles. The CFO
applications, internal light transmission is also limited, core undergoes deformation when exposed to an external
which is further compounded by the barrier posed by the magnetic field (Fig. 6d) resulting from the movement and
multi-layered human epidermis [153]. Therefore, overcom- rotation of magnetic domains. This strain is transmitted
ing these multifaceted hurdles can satisfy the electrical through the ­B aTiO 3-bound region within the interface.
performance of optoelectric biomaterials under a spectrum Recent experiments conducted by Wenwen et al. [144]
of physiological conditions encountered within the human integrated polarized ­C oFe 2O 4@BaTiO 3/polyvinylidene
body. Consequently, extensive research endeavors are under- fluoride trifluoroethylene (PVDF-TrFE) core–shell par-
way to address these intricate and pressing concerns. ticles into these approaches (Fig. 6e). The efficiency of
converting magnetic and electrical energy was signifi-
Electricity generation by biomaterials in response cantly enhanced, leading to activated bone regeneration.
to magnetic field Furthermore, in vivo experiments demonstrated that the
complex membrane could create an electrically conduc-
The generation of electromagnetic energy relies on the fun- tive environment promoting bone regeneration, even in
damental principle of electromagnetic induction, as eluci- inflammatory conditions.
dated by Faraday’s law. This principle postulates that when The work by Joshua et al. [168] further highlighted the
a conductor is subjected to the influence of a magnetic field, magneto-electrics with wireless technology for data and
mainly when there is relative motion or variation in the mag- power transfer, offering high power density, tolerance for
netic field strength, it induces an electromotive force within misalignment, and deep tissue operation (Fig. 6f). The
the conductor. This induced force, in turn, facilitates the flow miniature MagnetoElectric-powered Bio ImplanT (ME-
of electric current through the conductor, thereby generat- BIT) delivered stimulation using a bioelectronic implant
ing electrical energy [157]. Magnetic responsive platforms of millimeter-size. The ME-BITs maintained functional
have thus been developed in biomedical applications to har- power levels over a broader range of misalignment com-
ness this principle effectively (Fig. 6a). In these platforms, pared to ultrasound-powered devices and did not require
the materials or devices experience alterations in their elec- ultrasound gels or foams for energy coupling. These min-
tromagnetic environment, thereby inducing electromotive iature ME-BITs demonstrated sufficient power density
force and consequent electrical signals. These signals can to stimulate large animal models within a blood vessel,
be employed for various applications, including electrical surpassing other wireless power technologies for bioel-
stimulation within biological systems [158–160]. ectronic implants.
Some recent studies have utilized the giant magnetoelas- The biomaterial systems generating micro-electrical
tic effect in soft systems [155, 162–167] to create scal- energy under a magnetic field are summarized in Table 2.
able electrical stimulation platforms. The magnetoelastic The materials that utilize magnetic fields to generate min-
effect originates from the alignment of magnetic dipoles ute electrical currents and provide electrical stimulation
within soft systems, showcasing a more powerful magneto- typically encounter limitations in biocompatibility, neces-
mechanical coupling compared to traditional rigid metal sitating consideration for potential biotoxicity concerns
alloys. Libanori et al. [155] invented a magnetoelastic [2]. Furthermore, the generated electrical power is often
generator (MEG) by dispersing magnetic nanoparticles constrained, and the efficiency of microcurrent generation
like neodymium boron (NdFeB) within liquid silicon through magnetic fields tends to be relatively low, limit-
rubber and applying gentle air pressure (Fig. 6b). The ing the overall efficacy [161]. External factors such as
magnetoelastic generator could convert disturbances into environmental conditions and magnetic interference can
significant electrical currents and voltages (Fig. 6c). This also significantly influence electrical output [169]. More-
electrical stimulation platform demonstrated a remarkable over, within the biological environment, these materials
increase in fibroblast conversion into neurons (104%) and can experience performance degradation due to chemi-
enhancement in neuronal maturation (251%), showing cal oxidation, leading to diminished long-term stability
potential for organ-on-a-chip systems and future neural [170]. Consequently, designing materials for microcur-
engineering applications. rent generation using a magnetic field necessitates stable
Another intriguing approach, as explored by Fangwei and consistent electrical production [171]. For clinical
et al. [156], demonstrated magnetic-electrical coupling applications, consistent performance within the biological
effects to generate electrical stimulation remotely. This environment without showing degradation and toxicity is
method involves the creation of a core–shell structure necessary [172–174], warranting future studies.

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Fig. 7  Representative studies on electrical stimulation by piezoelectric materials: (a) Schematic illustration showing mechanism of piezoelectric effect, (b) inherent
cell forces acting on ZnO nanosheets based piezoelectric nanogenerators and SEM images of NGs, Adapted with permission from [63], copyright 2017, John Wiley
& Sons (c) image showing the construction of piezoelectric PLLA nanofiber scaffold which acts as an electrical stimulator under mechanical stress, Adapted with
permission from [67], copyright 2022, AAAS (d) mechanism showing ultrasound-driven ES enhancing peripheral nerve repair by implantable PHBV/PLLA/KNN
nanogenerator film and the in vivo delivery, Adapted with permission from [66], copyright 2022, Elsevier (e) schematic of US-triggered photocatalytic therapy
involving BT-OHA/THM-APMH hydrogel which exhibits self-healing and adhesion properties for wound healing, Adapted with permission from [64], copyright
2023, Elsevier and (f) PWH-PCL composite scaffold using 3-D printing technology designed to establish an endogenous electric field at bone defect sites facilitat-
ing ­Mg2+ release to increase bone bioactivity. Adapted with permission from [65], copyright 2023, Elsevier

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Med-X (2024) 2:7 Page 17 of 27 7

Piezoelectric biomaterials generating separation within the crystalline structure of ZnO generates
stress‑responsive electricity an electric field via the piezoelectric effect. This self-stim-
ulating mechanism effectively regulates cell activity with-
The operational principle of piezoelectric materials for gen- out external stimuli, enhancing macrophage movement and
erating delicate electrical stimulation involves shifts in the ion channel activation in osteoblast-like cells. Noteworthy
distances between molecules or atoms, typically achieved attributes of these nanoscale voltage generators include their
through changes in applied pressure [175]. Consequently, small size (smaller than a cell), voltage output compara-
these alterations result in variations in the internal charge ble to typical cell membrane potential, and instant electric
distribution and electrical imbalance, ultimately generating power utilization for cell stimulation, eliminating the need
an electrical field (Fig. 7a). for energy storage [39]. While significant progress has been
Piezoelectric materials hold promise for addressing made with piezoelectric nanogenerators, recent attention has
challenges related to invasive electrical signal delivery in shifted towards remotely induced ultrasound activation of
regenerative therapy. They exhibit electromechanical cou- these generators. Self-powered piezoelectric nanogenerators
pling and flexibility, allowing them to serve as self-powered incorporating ZnO have considerable potential in advancing
stimulators that harness mechanical force from organisms motor recovery and neural function. This was substantiated
and external stimuli without wired connections [176, 177]. by Yun et al. [182] through the creation of ZnO-loaded PCL
Recent advancements in nanostructured piezoelectric energy nanogenerator scaffolds designed to address peripheral nerve
harvesters, such as piezoelectric nanogenerators, have ena- injuries (PNIs).
bled active sensing, electrical stimulation therapy, and the Barium titanate (­BaTiO3, BTO) is a compound with
passive harvesting of biomechanical energy to power on- exceptional dielectric and ferroelectric properties that have
body devices from external sources [178]. Moreover, the shown promise in promoting bone regeneration with piezo-
use of wireless electrical cues via electrospun piezoelectric electric properties. For instance, Wu et al. [183] have dem-
polymeric nanofibers presents a non-invasive and cellular- onstrated that coating piezoelectric scaffolds with BTO stim-
level approach to generate localized electrical stimulation ulates osteogenic differentiation in MSCs and angiogenesis
[179, 180]. The emergence of piezoelectric nanogenerators in endothelial cells. Similarly, BTO-coated scaffolds were
represents significant advancements in intelligent regenera- also developed to enhance osteogenesis and vascularization
tive therapy. Over the past decade, these devices have made in vitro. Additionally, multifunctional hydrogels embedded
rapid progress and are positioned to play a fundamental role with BTO nanoparticles were developed [64]. The BTO
in future state-of-the-art personalized healthcare [181]. Due nanoparticles respond to ultrasound, generating reactive
to their highly efficient conversion of mechanical energy to oxygen species (ROS) and thus effectively eliminating bac-
electrical energy, ease of implementation, and capacity for teria, while the hydrogels exhibit self-healing and adhesion
self-powering, these nanogenerators facilitate a broad spec- properties, demonstrating therapeutic efficacy for wound
trum of potential healthcare applications. healing (Fig. 7e).
Recent exploration of piezoelectric materials for self- While in vivo transcutaneous devices have faced signifi-
powered, miniaturized applications has witnessed signifi- cant challenges through conventional approaches, a recent
cant growth since their discovery. Zinc oxide has become a study by Wu et al. [66] addressed this issue. They proposed
central focus due to its compatibility with low-temperature in vivo electrical stimulation utilizing ultrasound-driven bio-
nano-structuring, contrasted with several ferroelectric mate- degradable piezoelectric nanogenerators made of biodegrad-
rials that demand high-temperature processing. However, able PLLA, potassium sodium niobate (KNN), nanowires,
specific synthesis methods for ZnO nanostructures have and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV)
limitations, including their low quantity and physical sta- (Fig. 7d). The inclusion of biodegradable encapsulation lay-
bility. Moreover, materials like lead zirconate titanate (PZT) ers and electrodes further enhances the safety. By harnessing
and barium titanate, known for their high piezoelectric coef- ultrasound as an energy source, these implantable nanogen-
ficients, have gained considerable interest. Recent research, erators provide flexible electrical stimulation to peripheral
mainly focused on PZT-based studies, seeks to develop high- nerves, promoting nerve regeneration and tissue repair.
performance PZT stretchable piezoelectric nanogenerators. As such, PLLA platforms have been actively used for
Gonzalo and colleagues [63] have demonstrated that piezoelectric nanogenerators. Zhu et al. [184] engineered
interactions between living cells and 2D ZnO nanosheets a PENG (Piezoelectric Nanogenerator) device using PLLA
in piezoelectric nanogenerators establish a local electric electrospun nanofibers, which yielded a voltage output of
field (Fig. 7b). This electric field arises from the unique 0.55 V and a current of 230 pA. Also, Smith et al. [185]
properties of ZnO nanosheets characterized by the reduced proposed PLLA nanowires as nanogenerators, harnessing
thickness (< 20 nm) and high aspect ratio (> 100), enabling shear piezoelectricity where the material generates current in
bending in response to cellular forces. Consequently, charge response to shear stress. A fully biodegradable triboelectric

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Table 3  Summary of representative studies on piezoelectric biomaterials that can generate electricity upon applied external stress, including the
type of materials, range of electricity generated, biocompatibility, mechanical properties, and application areas
Ref Materials Generated current/volt- Cytotoxicity Mechanical properties Applications
age range for ES

[66] PHBV/PLLA/KNN 0.6 × ­10–6 A - - Nerve tissue repair

[67] PLLA nanofiber 3.6 V Biocompatible - Cartilage, subchondral bone
regeneration
[65] Whitlockite (PWH) 0.7–2.3 pC/N ~ 100 μg/mL ~ 0.306 ± 0.039 MPa Cell proliferation, migration,
and differentiation in bone
tissue
[110] PVDF nanofiber, Carbonized 6.0 × ­10–8 A Biocompatible 70–100 MPa Wound healing
polydopamine (CPDA) (PVDF, low strength
&stretchability)
[112] PVA-PVDF 2.82 V, 248.16 × ­10–9 A Biocompatible 3–6 MPa (PVA) Diabetic wound repair
[191] ZnO-PCL 0.04–0.12 V Up to 100 μg/ml (ZnO) 30–38 MPa Peripheral nerve regeneration
Highly tensile
[192] PCL-PVDF ~ 0.4 V Biocompatible 38.7 MPa (PCL) Peripheral nerve regeneration
(Highly flexible)
[193] PVDF/ZIF-8 (60–90) ­10−9A Up to 30 μg/ml (ZIF-8) 100 MPa (ZIF-8) Angiogenesis, osteogenesis
[194] PVDF-GO 1.36–2.64 V Nerve tissue engineering
[195] BaTiO3 (0.07–0.19) × ­10–3 V Up to 50 μg/ml 486 ± 75 MPa Neuronal Stimulation
[196] P(VDF-TrFE)/BaTiO3 ~ 2 × ­10–3 V - - Neuroblastoma cells differ-
entiation
[197] ZnO/PDMS 0.3–0.9 V - - Enhanced cell migration,
metabolic activity, and dif-
ferentiation
[198] Poly(vinylidene fluoride–trif- 0.011–0.026 V - - Promoted cardiomyocyte
luoroethylene)/PCL attachment, proliferation,
and alignment
[186] PLLA nanofiber 45 V, 9 × ­10−6A - - Green energy harvesting
machine
[183] BaTiO3 coated Ti6Al4V 10.8 × ­10–6 ± 0.97 A - - Bone repair
scaffold

nanogenerator (TENG) comprising aligned PLLA fibers results, suggesting potential applications in osteoarthritis
and chitosan, gelatin, and polyhydroxybutyrate (PHB) was treatment and tissue repair.
also devised as an energy harvesting machine [186]. These Similarly, PVDF, characterized by piezoelectricity, was
aligned PLLA fibers outperformed random PLLA fibers, developed into nanofiber scaffolds for tissue repair. PVDF
achieving approximately 5.5 times higher voltage and 2 combines high piezoelectric attributes with exceptional
times higher current. In another work, Deokjae et al. have mechanical strength, high thermal stability, desirable flex-
devised a self-enhanced electrostatic discharge TENG (SED- ibility, and biocompatibility. It exhibits a significant piezoe-
TENG) capable of producing around 2200 V peak voltage lectric coefficient, with d­ 33 = 49.6 pm/V, and a dielectric con-
and 7 A peak current, transferring 50 μC of charge per cycle. stant ranging from 6 to 12, surpassing many other organic
The SED-TENG holds significant capability as an ultrahigh polymers [188]. Of note was the increase in β-phase crystal-
output energy harvesting tile for practical applications [187]. line structure during electrospinning, significantly increasing
Furthermore, Liu et al. [67] discovered that a biodegradable the piezoelectric effect [110, 189]. A recent study demon-
piezoelectric scaffold made of PLLA can act as an electrical strated that electrospun PVDF-based fibers could enhance
stimulator when subjected to mechanical force or joint stress the osteogenic differentiation of human MSCs into osteo-
(Fig. 7c). Piezoelectric charge of the scaffold facilitated pro- blast cells and promote early matrix mineralization, primar-
tein adsorption, cell migration, and the release of endog- ily due to the presence of a higher piezoelectric β-phase
enous TGF-β, aiding in tissue regeneration. In vivo testing [190]. While electrospun PVDF fiber shows limitations
on rabbits undergoing exercise treatment yielded promising due to its inherent hydrophobic nature, which is not ideal

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Med-X (2024) 2:7 Page 19 of 27 7

for tissue engineering, the hydrophilicity can be enhanced these drawbacks to achieve higher power generation and
through simple modifications using co-polymers or surface improved efficiency. Moreover, piezoelectric materials are
functionalization. Along with polymers, Whitlockite was susceptible to environmental factors, making the preserva-
another material shown to be piezoelectric. Recently, Wang tion of their long-term stability and consistent performance
et al. [65] developed composite 3D printed scaffolds made challenging. Research into material design and stability is
of piezoelectric Whitlockite and PCL (Fig. 7f). This scaffold crucial to address these issues effectively [200]. Further-
was designed to establish an endogenous electric field at more, the physical stress induced by the piezoelectric effect
bone defect sites while facilitating ­Mg2+ release to increase can impact cells and tissues, especially under high-loading
bone bioactivity. The scaffolds showed inhibition of osteo- conditions. Minimizing such physical stress and developing
clasts while promoting MSC differentiation into neurogenic, safe designs and applications for cells and tissues is thus
angiogenic, and osteogenic lineages. The scaffolds facili- imperative. Addressing these is vital to maximize the poten-
tated neo-bone formation in a rat calvarial defect model, tial of piezoelectric materials and facilitate future clinical
highlighting its potential for regenerating neuro-vascularized applications.
bone tissue. In Table 3, the piezoelectric biomaterials that Implementing technologies for clinical electrical stimu-
can generate electricity upon applied external stress are lation with external stimuli (light, magnetism, piezoelectric
listed, including the type of materials, the range of electric- force) may face challenges like precision in targeting, bio-
ity generated, and the application areas. compatibility, safety assessment, regulatory approval, patient
While holding great promise, these piezoelectric materi- variability, treatment integration, long-term stability, and ethi-
als present notable limitations that require attention. First, cal considerations—these must be finely adjusted to achieve
their biocompatibility remains a critical concern, necessitat- precise and targeted electrical stimulation without unintended
ing further research and development to make these materi- consequences. The need for standardized testing becomes even
als more suitable for in vivo applications [199]. Second, the more pronounced to validate the reliability and reproducibil-
electrical energy generated by external stimuli is limited, and ity of these external stimuli across diverse clinical scenarios.
the efficiency of the piezoelectric effect is currently relatively Interdisciplinary collaboration between materials scientists,
low, restricting potential applications for medical devices engineers, and medical professionals is essential to address
[68]. Future research efforts should focus on overcoming these challenges effectively.

Fig. 8  Schematic illustrating the

current developments and future
trends in biomaterials-enabled
ES systems, including advanced
ES therapies like electrochemi-
cal therapy (EchT), implantable
ES-based systems for advanced
therapy, smart and self-powered
devices for noninvasive ES
production, and smart devices
employing novel electroactive
nanomaterials

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Conclusion and perspectives control and monitoring capability can expand the applica-
tions. It is also imperative to underscore that transitioning
As witnessed, biomaterials-based electrical stimulation from these cutting-edge materials to clinical practice neces-
has played significant roles in healing damaged and dis- sitates a rigorous evaluation of biocompatibility and specific
eased tissue, harnessing the distinctive attributes of con- functions, mainly through relevant animal models.
ductivity and responsiveness of materials. These biomate- From a clinical perspective, advanced ES therapies have
rials, whether facilitating direct electrical connectivity or captured considerable attention in cancer treatment, encom-
auto-generating micro-electric fields in response to various passing direct methodologies like irreversible electropora-
stimuli, hold immense promise for medical applications. tion and electrochemical therapy (EchT), as well as indirect
In principle, two primary strategies have been devel- approaches involving self-powered devices [202] (Fig. 8).
oped to allow electrical stimulation through biomateri- Moreover, self-powered neurostimulation via biomateri-
als. The first entails in-situ electroconductive biomate- als and bioelectronics has become a promising approach to
rials, wherein conductive elements are integrated into exploring, repairing, and modulating neural systems [203,
tissue scaffolds to facilitate intercellular electrical signal 204]. Specific conductive polymers have been employed to
propagation and stimulation. However, ensuring clinically facilitate electrical communication with neurons, showing
applicable conditions necessitates careful consideration of promise in restoring damaged neural pathways. The clini-
external power sources. Therefore, an effort was made to cal severity of spinal cord injuries (SCIs) varies from AISA
explore a wireless system that generates electrical power grade A (most severe, with complete motor and sensory loss)
within the in vivo milieu, such as biofuel cells. to grade E (typical motor and sensory function). Ongoing
The second strategy centres on external stimulus- trials explore combined therapies, such as a collagen scaf-
responsive biomaterials endowed with the remarkable fold with EES (Electrical Epidural Stimulation), umbilical
capability to self-generate electricity in response to diverse cord blood mononuclear cells with lithium carbonate, and
external cues, such as light, magnetic fields, or mechani- locomotor training [205, 206]. Although in vivo studies are
cal stress. The future of this field is continuously evolving limited [207], they reveal enhanced motor recovery in rats
with the development of more biocompatible materials with a combination of NT-3 loaded PCLEEP scaffold and
that can efficiently convert various stimuli, even in combi- rehabilitation, surpassing results from the scaffold alone.
nation. This is expected to enhance the efficiency of elec- Furthermore, for cardiac applications, conductive scaffolds
tricity generation. Notable examples include thermoelec- have enhanced electrical signal propagation in cardiac tissue
tric conversion via body heat sources, electric conversion engineering. These case studies not only highlight the ver-
triggered by pH changes, and the integration of multiple satility of conductive biomaterials but also provide valuable
stimuli. Employment of in situ electroconductive biomate- insights into their safety, efficacy, and feasibility in clinical
rials can be more effective compared to a second strategy scenarios, thereby contributing to the ongoing evolution of
in specific applications. In situ stimulation with conduc- bioelectronic therapies. Through continued efforts, biomate-
tive materials allows for targeted and localized delivery of rials-enabled ES systems will open new horizons in the field
electrical impulses directly to the desired area, minimiz- of tissue healing and regeneration.
ing energy loss and improving efficiency. External stimuli
sources may encounter impedance and dispersion issues,
Authors’ contributions Kim HS and Baby T contributed equally to
potentially reducing their effectiveness. this work as co-first authors. Lee JH, Shin US, Kim HW drafted and
Recent strides in biomaterials for ES have opened new finalized the manuscript, and Kim HW supervised this study. The
avenues for tissue healing and regeneration. Future trends manuscript was written through the contributions of all authors, and
suggest a deeper integration of smart materials with sen- all authors have approved the final version of the manuscript.
sors to monitor real-time physiological responses, allowing Funding This work was supported by grants from the National
adaptive and personalized ES [201]. With the continuous Research Foundation of Korea (MRC 2021R1A5A202231, RS-2023-
development of material science, nanotechnology, micro/ 00220408, 2022R1C1C2010863).
nano processing techniques, novel electroactive nanomate-
rials, and delicately designed devices, the possibilities to Declarations
realize innovative ES therapies have significantly increased. Competing interests Kim HW is an Associate Editor for Med-X. The
For instance, the emergence of new technologies like nano- paper was handled by another Editor and has undergone a rigorous peer
generators has broken the limitations of traditional technolo- review process. Kim HW was not involved in the journal’s peer review
gies. Of note, fine-tuning electrical stimulation parameters, or decisions related to this manuscript.
optimizing bioactive factors, and developing non-invasive, Open Access This article is licensed under a Creative Commons Attri-
implantable electrical stimulation devices with precise bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long

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