Electroactive Biomaterials and Systems For Cell Fate Determination and Tissue Regeneration: Design and Applications

Review
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Electroactive Biomaterials and Systems for Cell Fate

Determination and Tissue Regeneration: Design and
Applications
Zhirong Liu, Xingyi Wan, Zhong Lin Wang,* and Linlin Li*
of suitable biomaterial scaffolds, their
During natural tissue regeneration, tissue microenvironment and stem cell compatibility with native tissue microen-
niche including cell–cell interaction, soluble factors, and extracellular matrix vironment, and the delivered biochemical
(ECM) provide a train of biochemical and biophysical cues for modulation and biophysical cues that might influence
of cell behaviors and tissue functions. Design of functional biomaterials the host or laden cells.[1] That is to say,
smart biomaterials act not only as inert
to mimic the tissue/cell microenvironment have great potentials for tissue
structural support for damaged area, but
regeneration applications. Recently, electroactive biomaterials have drawn also as active modulators for endogenous
increasing attentions not only as scaffolds for cell adhesion and structural cell adhesion and functions. Additionally,
support, but also as modulators to regulate cell/tissue behaviors and function, they could provide biochemical and bio-
especially for electrically excitable cells and tissues. More importantly, physical cues to trigger cell differentiation
electrostimulation can further modulate a myriad of biological processes, from into tissue-specific cell lineages.[2] Phys-
icochemical characteristics of biomaterials
cell cycle, migration, proliferation and differentiation to neural conduction,
including chemical composition, struc-
muscle contraction, embryogenesis, and tissue regeneration. In this review, tural feature, stiffness/elasticity, porosity,
endogenous bioelectricity and piezoelectricity are introduced. Then, design and adhesion-ligand density might provide
rationale of electroactive biomaterials is discussed for imitating dynamic appropriate biophysical cues for guiding
cell microenvironment, as well as their mediated electrostimulation and stem cell differentiation into specific lin-
eages and tissue regeneration.[3] Some
the applying pathways. Recent advances in electroactive biomaterials
preliminary review papers on tissue engi-
are systematically overviewed for modulation of stem cell fate and tissue neering biomaterials have summarized
regeneration, mainly including nerve regeneration, bone tissue engineering, the effect of biomaterials’ morphology,
and cardiac tissue engineering. Finally, the significance for simulating the composition, and mechanical properties
native tissue microenvironment is emphasized and the open challenges and on stem cell differentiation.[3b,4]
future perspectives of electroactive biomaterials are concluded. In human body, bioelectricity is an inte-
gral part of organism. At the cell level, cell
membrane potential plays an important
1. Introduction role in the regulation of cell cycle, migration, proliferation and
differentiation. And action potential determines cellular excit-
Tissue engineering aims to regenerate damaged tissues as ability especially for neurons and cardiomyocytes.[5] Bioelec-
alternative of cell replacement therapy, autografts, and organ tricity is a ground base of the functions of electroactive organs/
transplantation. It is a comprehensive discipline that incorpo- tissues, including central and peripheral nervous systems,
rates multiple considerations, including design and fabrication muscles, heart and inner ear sensory epithelium. Specifically, it
modulates a myriad of biological processes, such as functional
Z. Liu, X. Wan, Prof. Z. L. Wang, Prof. L. Li and structural refinement of synapses/neuronal networks,
Beijing Institute of Nanoenergy and Nanosystems neural conduction, synchronous contraction of cardiomyocytes,
Chinese Academy of Sciences as well as muscle contraction.[6] Disruption of the steady-state
Beijing 100083, P. R. China electrical milieu of embryos might cause serious developmental
E-mail: zhong.wang@mse.gatech.edu; lilinlin@binn.cas.cn
defects, such as lack of cranium, misshapen head, abnormal or
Z. Liu, X. Wan, Prof. Z. L. Wang, Prof. L. Li
School of Nanoscience and Technology
absent brachial development, and incomplete closure of neural
University of Chinese Academy of Sciences folds in focused areas.[7] In addition, endogenous piezoelec-
Beijing 100049, P. R. China tricity widely exists in low-symmetry biomacromolecules and
Prof. Z. L. Wang biomolecular assemblies, which is considered to be closely
School of Materials Science and Engineering associated with tissue growth and remodeling, especially for
Georgia Institute of Technology bone regeneration.[8]
Atlanta, GA 30332-0245, USA
Recently, a range of electroactive biomaterials, including
The ORCID identification number(s) for the author(s) of this article
can be found under https://doi.org/10.1002/adma.202007429.
conductive and piezoelectric biomaterials, and their mediated
electrostimulation have been developed to mimic the nature
DOI: 10.1002/adma.202007429 bioelectricity as a biophysical cue for modulation of stem cell
Adv. Mater. 2021, 2007429 2007429 (1 of 33) © 2021 Wiley-VCH GmbH

www.advancedsciencenews.com www.advmat.de
fate and regenerative medicine.[9] Electroactive biomaterials are We finally summarize the prospects of electroactive biomate-
considered to be a new generation of smart biomaterials that rials for modulation of cell fate and tissue regeneration, and
allow directly deliver electrostimulation to target cells/tissues, highlight the challenges that might be faced in future espe-
or adjust their own characteristics under electrostimulation cially for clinical translation.
to adapt to the cell microenvironment. Electroactive biomate-
rials have the potentials to integrate the topological, chemical,
mechanical cues, as well as electrical properties to meet the 2. Endogenous Bioelectricity and Piezoelectricity
specific biological application requirements. Specifically, con-
ductive materials enable charge transport at the cellular mem- In human body, bioelectricity is an integral part of organism.
brane interface, and regulate the interactions at cell–cell or cell/ At the nanoscale and molecular level, electrical signal gener-
tissue–biomaterial interfaces.[10] Additionally, electrostimula- ated from piezoelectric biomacromolecules under mechanical
tion delivered through conductive and piezoelectric materials stress acts as a stimulus for controlling the precipitation of
can further modulate cell and tissue behavior.[5,11] More impor- bone apatite for calcification, thereby promoting bone growth
tantly, electroresponsive biomaterials under electrostimulation and remodeling.[16] At the cellular level, cell action potential
could adjust their own characteristics, such as redox state,[12] determines cellular excitability especially for neurons and car-
hydrophobic/hydrophilic property,[13] conformation of surface diomyocytes, thus modulating a myriad of tissue function, such
ligand[14] and mechanical property.[15] The adjustable character- as functional and structural refinement of synapses/neuronal
istics are beneficial to build a dynamic cells/tissues microenvi- networks, neural conduction, cardiomyocytes contraction, as
ronment at different developing periods, in collaboration with well as muscle contraction.[6] At the tissue level, steady endog-
other factors (e.g., growth factor, mechanical stimulation, and enous electric fields within embryos provide an overall template
surface structure). for tissue development during ontogeny.[17] In addition, it can
The reviews of electroactive biomaterials have appreciated mediate cell communication, and regulating important elec-
in recent years,[9] which summarize electroactive biomate- trophysiological processes, such as synaptic plasticity and syn-
rials for tissue regeneration, and provide an overview on the chronization, myocardial contraction and rate, as well as tissue
current progresses of the electroactive biomaterials for drug repairing and wound healing.[18]
delivery and regenerative medicine. For tissue engineering
application, an in-depth understanding of how the cell micro-
environment evolves over time is critical for development of 2.1. Endogenous Bioelectricity
smart tissue engineering biomaterials. Another important
aspect that should be paid attention is the pathways that might 2.1.1. Membrane Potential and Action Potential
be used to impose electricity on cells/tissues via those con-
ductive biomaterials. Currently, convenient and safe delivery Almost all mammalian cells have a long-term, steady-state
of electrostimulation is an urgent requirement for tissue voltage potential (ca. -10 to -90 mV for different cell types)
regeneration, especially for transforming basic researches across the plasma membrane, called membrane potential (Vm)
into clinical applications. This review outlines recent devel- (Figure 1). The Vm arises from the presence of different trans-
opments of electroactive biomaterials for cell fate determi- membrane ion channels, pumps, and gap junction complexes,
nation and tissue regeneration. First, we unveil the intrinsic which help for the transport of specific ions and molecules
nature of endogenous bioelectricity and piezoelectricity, as across the cytomembrane.[19] Generally, terminally differenti-
well as their crucial roles in tissues/organs development and ated cells tend to be hyperpolarized (strongly polarized with
regeneration. Then, the design rationale of electroactive bio- more negative Vm), whereas developing cells including embry-
materials via imitating the natural bioelectricity in bodies is onic, stem, and tumor cells tend to be depolarized.
discussed. Based on this understanding, we mainly focus on Electrically excitable cells such as neurons and myocytes
conductive and piezoelectric biomaterials, and their applicable can rapidly depolarize away from resting membrane poten-
electrostimulation pathways especially with recently devel- tial, namely excitability. It results in millisecond propagated
oped implantable energy harvesters (IEHs). In this paper, action potentials (AP) mediated by the change in Vm. In neural
the system that integrates both electroactive biomaterials and system, the AP propagation shapes neuronal circuit via neural
electrostimulation devices or pathways is named as electroac- transmission, and also induces functional and structural refine-
tive system. Instead of just summarizing recent progresses in ment of synapses/neuronal networks.[6a] In 1970s, exogenous
electroactive biomaterials, our review also reveals the mecha- electric field (EF) was first found to be able to stimulate neuron
nism of electrostimulation in modulating cell activity via cell survival, migration,[20] and increase neurite outgrowth.[21]
signaling and downstream biochemical responses and tissue Although the mechanism is not fully understood up to now,
regeneration, according to the dynamic microenvironment of rearrangement of cell membrane receptors/channels and intra-
respective cells and tissues. We also discuss the concurrent cellular cytoskeletal proteins are involved in the process.[22]
effect of electrostimulation with other biophysical cues of the In clinic, electrostimulation has been applied to manipulate
biomaterials (i.e., stiffness, topology, and mechanical stimu- central nervous system (CNS) as early as 1750s. Now, electro
lation) and electricity-reinforced biochemical cues. Then, stimulation has been used in clinic to treat a wide range of
the applications of electroactive biomaterials in tissue regen- neurological diseases, disorders, and injuries, including essen-
eration, particularly for electrically sensitive tissues (nerve tial tremor, Parkinson’s disease (PD), epilepsy, and spinal cord
system, bone tissue, cardiac tissue, and others) are presented. injuries.[23] For cardiomyocytes (CMs), their APs regulated by

Figure 1. Endogenous bioelectricity (right) and piezoelectricity (left).
ion channels and gap junctions contribute to the spontaneous (iPSCs).[29b] It is expected that rational exogenous regulation of
beating of the cells. The rhythmic AP continuously propagates Vm might provide significant opportunities for therapeutic pur-
in multicellular cardiac tissues, and traverses to the myocar- pose including regenerative medicine.[19]
dium via Purkinje fibers to induce myocardial contractility.[6b]
Thus, electrostimulation has been applied for heart failure
therapy and myocardium rebuilding.[24] 2.1.2. Endogenous Electric Field in Tissues
Beyond electrically excitable cells, it is exciting that Vm as a
cell-autonomous bioelectric regulator is also important in non- When we shift from a single cell to multicellular collections
excitable cells for modulating a train of cellular activities such and tissues, striking parallel is found. Cells are regulated not
as cell cycle and proliferation.[25] It is also found Vm fluctuation, only by their own Vm, but also Vm of their neighboring cells via
an outcome of combined activities of various ion channels and gap junctions.[32] More importantly, endogenous electric fields
transporters, can functionally regulate tumorigenesis, cancer (EFs) have been found for more than a half century. During
progression and metastasis.[19] Generally, cancer cells are in a embryogenesis, there is an endogenous electric current with
depolarized state, and the membrane depolarization might be a voltage gradient from 40 to 140 mV mm−1,[33] which plays a
importance for stemness maintenance of cancer stem cells. key role in regulating cell behaviors and tissue development,
In addition to their roles as a maker of cell differentiation such as asymmetric left-right organs.[34] It has been reported
and maturation state, Vm and related signals also play instruc- that disruption of normal electrical milieu of embryos would
tive roles in the differentiation process and linage commitment cause serious developmental defects such as lack of cranium,
of stem cells.[26] Hyperpolarization is an instructive trigger for loss of eyes, misshapen head, abnormal or absent brachial
accelerating stem cell differentiation. Conversely, Vm depo- development, and incomplete closure of neural folds in focused
larization maintains stem cells in an undifferentiated state.[27] areas.[7] Steady voltage gradients within embryos provide an
Accordingly, the expression and function of transmembrane overall template for tissue development during ontogeny.[17] In
ion channels may influence the stem cell differentiation. Induc- addition, endogenous EFs mediate the communication of elec-
tion of cells with a more negative Vm, namely hyperpolarization, trically excitable cells, thereby regulating important physiolog-
is considered to be a promising therapeutic pathway. With the ical processes, such as synaptic plasticity and synchronization,
intrinsic cellular excitability especially for neurons and CMs, as well as myocardial contraction and rate.[18]
electrostimulation has been used for guiding maturation of these Endogenous EFs also play important roles in tissue
cells. Additionally, electrostimulation has also been applied to repairing and wound healing for a wide range of wounded
induce differentiation of stem cells into neuron,[28] CMs,[29] and and regenerated tissues/organs, including limbs, bone frac-
nonexcitable osteoblasts (OBs)[30] from multipotent/pluripotent tures, corneal, and skin wounds.[35] Taken skin wound as
stem cells,[29a] progenitors,[28b] bone-marrow-derived mesen- an example, a cross transepithelial potential ranging from
chymal stem cells (MSCs)[31] and induced pluripotent stem cells 15 to 60 mV would be formed mainly due to the polarized

distribution of ion channels in the epithelial cells. A wound and molecular level, many biomacromolecules possess high
would disrupt ion flux across leaky cell membranes and epi- structural order with intrinsic helical or chiral asymmetry,
thelial barrier, and also short-circuit the transepithelial poten- which cause low symmetry inherent polarization and piezo-
tials for generating a lateral EF, or called leakage current electricity. For instance, a single collagen fibril with polar hex-
(Figure 1). The magnitude of this lateral EF ranges between agonal crystalline unit and spiral structure has been proven to
40 and 200 mV mm−1 in mammalian wounds.[36] It acts as a have piezoelectric effect by piezoforce microscopy (PFM).[48]
directional cue for directing cell migration into the wound Collagen molecules in the form of a spiral triple helix self-
location for wound healing, called galvanotaxis.[37] Many kinds assemble through the hydrogen bonding of amine and carbonyl
of cells including epithelial cells, embryonic cells, and fibro- functional groups and pack into a quasi-hexagonal (C6) lattice
blasts have be found to have the ability to sense external EFs of crystal fibrils. When a mechanical stress is applied, the dis-
at physiological strength and migrate along the field gradients, placement of hydrogen bonds redistributes dipole moments to
most of them towards the negative pole.[38] This phenomenon the longitudinal axis of the collagen molecules, causing perma-
of galvanotaxis may be related the redistribution of membrane nent polarization (Figure 1).[9c] The piezoelectric heterogeneity
components, intracellular organelles and activated intracel- within collagen fibrils correlates with the periodic variation of
lular signaling pathways.[39] The electrical currents present in their overlap and gap regions. Other biomolecules and bioas-
the body after injury are responsible for various biological pro- semblies including proteins/peptides,[49] deoxyribonucleic acids
cesses mediated by non-excitable cells, for early responses to (DNA),[50] and virus[51] have also been found to have piezo-
wound healing and tissue regeneration.[40] In addition, since electric effect. Generally, the piezoelectric coefficients of natural
the function of resident stem cells is often determined by biomacromolecules are relatively low, typically in the range of
their in vivo location within tissues, the targeting of stem cells 0.1–10 pm V−1,[52] but the piezoelectric effect might play a vital
toward injury would be a crucial key for tissue regeneration. role in tissue regeneration and physiological processes.
Beyond biochemical cues, bioelectricity guides the homing of
stem cells. Under the physiological EF gradients, cells could
migrate to wounds and recreate the necessary tissues by the 2.2.2. Piezoelectricity in Tissues
coordination of cell secretion, proliferation, and differentia-
tion.[41] Based on these notions, exogenous simulated bioelec- Within body, the electrical, mechanical, and chemical activities
trical EF has been applied for promoting would healing[42] and are inevitably coupled with each other. At the macroscale and
tissue regeneration for bone, limb, muscle, and nerve system tissue level, piezoelectric effect has been found in a number
in clinical studies.[43] of plant and animal tissues. Collagen as an ECM protein con-
tributes to the piezoelectric effect of many animal tissues,
including bones, hairs, tendons, ligaments, skins, callus and
2.2. Endogenous Piezoelectricity cartilages.[8a,b,53] Elastin as another ECM protein contributes to
the piezoelectricity in blood vessels.[49b,54] The function of nat-
2.2.1. Piezoelectric Biomacromolecules ural piezoelectricity remains elusive, but it is generally consid-
ered to be closely associated with many physiological processes,
Piezoelectricity means electricity resulted from mechanical tissue growth and remodeling.
pressure. In detail, a certain material (nanocrystals, ceramics, Taking bone as an example (Figure 1), it could be consid-
and biological matters) generates and accumulates electric ered as a natural piezoelectric composite, in which the non-
charges with opposite symbols on the surface when it is sub- centrosymmetric collagenous matrix (≈22 wt%) is densely
jected to a mechanical stress or strain.[44] The generated electric fibrillar packed and embedded in hydroxyapatite (HAp) crystals
charges are proportional to the applied stress according to the (≈69 wt%).[55] Due to the structural anisotropy, bone shows an
linear theory of piezoelectricity:[45] anisotropic piezoelectric response. The highest piezoelectric
coefficient (d14) of the femur could reach 0.7 pC N−1 in a shear
Ppe = d × T (1) mode.[56] Bone deformation causes a spontaneous polarization
and electric potential, mainly contributed from the piezoelec-
where Ppe, d, and T are the generated polarization vector, piezo- tricity of collagen (along with HAp) and streaming potential.[57]
electric strain coefficient, and the mechanical stress, respec- It is generally believed that piezoelectricity is the cause of dry
tively. Vice versa, the exposure to an electrical bias induces a bone stress evoked potential, while the mechanism responsible
deformation of the material, namely inverse piezoelectric effect: for wet bone is streaming potential. The theory of streaming
potential indicates that the potential generated by stress in wet
Spe = d × E (2) bone is mainly due to the flow of ion containing interstitial fluid
through bone caused by pressure.[58] According to the Wolff’s
where Spe and E are the induced mechanical deformation of the law, electrical signal generated from mechanical stress acts
material and the applied external EF strength, respectively. as a stimuli for promoting bone growth and remodeling.[16a]
Piezoelectricity in biosystems was first observed from a The switchable surface potential of bone under physiological
bundle of wool in 1940s.[46] The main component of hairs, deformation controls the precipitation of bone apatite for
wools, and horns is keratin in the form of right-handed calcification.[16b] Furthermore, OBs and osteoclasts that are
α-helices, and its piezoelectricity is due to natural polariza- responsible for bone formation and reabsorption, respectively,
tion and ordered arrangement of the α-helix.[8b,47] At nanoscale can response to piezoelectricity that acts as a signal of cell

mechanotransduction and mechanosensation.[8c] Based on the Traditionally, bulk metals including titanium (Ti), magne-
endogenous piezoelectric effect, exogenous electrostimulation sium, and stainless steel have been employed as bone repair
has been used to induce a positive effect on bone regeneration implants due to their high mechanical properties, fatigue
and enhancement of osteogenic activity.[59] resistance, and conductivity.[64] Porous metals scaffolds were
also designed to increase stress conduction, load therapeutic
drugs, and increase vascularization in the scaffolds.[65] Recently,
3. Electroactive Biomaterials and metal-based biomaterials with micro-/nanostructures, espe-
cially Au nanomaterials (AuNMs) have been developed for
Electrostimulation
biomedical applications.[66] AuNMs (such as Au nanoparticles,
Not very long after the discovery of natural bioelectricity and Au nanorods, Au nanowires)[67] with good biocompatibility are
biopiezoelectricity, development of biomaterials that could considered to be an appropriate reinforcing material that can
guide cell behavior and tissue regeneration have attracted improve electrical conductivity and stiffness of tissue engi-
growing interest as an interdiscipline of molecular chemistry neered scaffolds by adjusting AuNMs concentrations.[1b,67a,68] In
and physics, engineering material, biology and medicine. Great addition, their advantages of high surface areas and facile sur-
endeavors have been devoted to the design and fabrication of face modification via gold-thiol chemistry are beneficial to con-
biomaterial scaffolds from electroactive biomaterials, including venient drug loading. Besides Au nanostructures, other metal/
biocompatible conductive and piezoelectric materials. It is metal oxide, such as nanostructured Ag, Zn, Ti, B, Sr, Mg, Cu,
more challenging and comprehensive for delivery of efficient Pt, and MoS2 have also been employed in tissue engineering,
electrostimulation via these biomaterials, according to different especially for bone repair.[69]
requirements of respective tissues and lineage commitment of Compared with carbon-based materials and metals, conduc-
stem cells. tive polymers not only have electrically conductive properties, but
also possess attractive properties as common polymers, especially
flexibility and low stiffness. Thus, they have striking advances in
3.1. Conductive Biomaterials the area of biomedical applications. The conductivity of conduc-
tive polymers (oxidized and reduced states) is in the range of
For tissue engineering involving electrically excitable cells/ 10−7 to 103 S cm−1.[70] Their electrical conductivity origins from
tissues, electrically conductive materials enable charge trans- the conjugated double bond throughout the polymer matrix.[71]
portation at the cell–substrate interface and regulate the inter- Figure 2 lists the typical conducting polymers commonly used
actions at the cell–substrate or cell-cell interfaces.[10b,c] Cell in biomedical field, including polypyrrole (PPy), polyaniline
behaviors including adhesion, proliferation, self-renewal or dif- (PANi), polythiophene (PTh), poly(3,4-ethylenedioxythiophene)
ferentiation, and cellular signaling could be modulated on these (PEDOT), etc. Size, functional groups, and charge distribution
conductive biomaterials.[60] Recent studies have reported the of dopants (counterions) have great influence on the conduc-
fabrication of conductive biomaterial scaffolds with proper bio- tivity and performance of conducting polymers. Besides, some
physical properties (e.g., micro-/nanostructures, stiffness, and emerging conductive materials, such as MXene quantum dots,[72]
conductivity) for mimicking natural tissue microenvironment nanosheets,[73] and composite scaffolds[74] are also employed to
and stem cell niche. In some researches, simple culture of stem promote tissue regeneration.
cells on conductive biomaterials without electrical stimulation Composite conductive biomaterials can integrate the advan-
could regulate the cell self-renewal or differentiation and ECM tages of multiple materials. In addition to adjusting the conduc-
regeneration. The references of electrically conductive biomate- tivity to match the target tissue, the stiffness of the composite
rials for cell regulation are outlined in Table 1. They are divided biomaterial could also be tuned to be comparable to ECM of
into three categories: carbon-based biomaterials, metal/metal specific tissues/organs, from soft brain tissue (≈1 kPa) and myo-
oxide, and conductive polymers (Figure 2). cardial tissue (≈10 kPa) to stiff bone tissue (25-50 kPa).[75,76] The
Carbon-based biomaterials have aroused considerable integrated functions of adjustable surface topography, surface
research interests in biomedical science, from 3D graphite, energy, drug release, and electricity-driven actuation are being
2D graphene, 1D carbon nanotubes (CNTs), to 0D carbon exploited to coregulate cell/tissue behaviors and function.[77]
dots (C-dots), fullerene and nanodiamonds.[61] Although these Although there are various conductive biomaterials, as well as
carbon-based materials are all mainly composed of carbon ele- many processing techniques, the challenge of designing a bio-
ment, the carbon allotropic forms, sizes, mechanical properties, compatible and conductive microenvironment for tissue regen-
and surface chemistry endow them with diverse properties.[10a,62] eration is still open. Inorganic conductive additives (e.g., CNTs,
Among them, graphene and CNTs based materials are most rGO, and AuNMs) exhibit excellent conductivity even at low
widely employed in tissue engineering, due to their inimitable concentrations, while their poor dispersion in polymer matrix
mechanical features, chemical stability, large specific surface reduces the uniformity of the composite biomaterials and
area, and high electrical conductivity. For tissue engineering limits large-scale fabrication. In addition, due to the unmatched
application, carbon-based biomaterials are commonly used as mechanical properties between the inorganic additives and
reinforcing agents to increase the mechanical performance and polymer matrix, tension and bending induced deformation of
conductivity of polymer matrix.[62,63] In addition, their large sur- the composite biomaterials would affect their conductivity.
face area and abundant functional groups facilitate the loading Generally, rationally designed conductive biomaterials have
and releasing of bioactive species, including chemical drugs, good biocompatibility.[78] However, long-term biosafety and bio-
growth factors, genes and proteins.[61a] distribution should not be ignored. It is reported that toxicity

Table 1. Stem/progenitor cells differentiation and cell function modulation on electrically conductive biomaterials.
Conductive biomaterials Conductive scaffolds Electrostimulation Stem/progenitor cells Outcome cell line Refs.
Graphene and derivatives Graphene film/3D scaffold / NSCs/MSCs Neurons [197f,199h–j,197l,m,202]
Graphene 0.1–0.5 V, 1 ms, 1–5 Hz, 1–3 d hBMSCs Neurons/OBs [301]
Graphene 0.1 V, 50 Hz, 10 min/d for 15 d rMSCs SCs [302]
Graphene−polyelectrolyte / Neural progenitor cells Neurons [196c]
multilayer (NPCs)
Graphene–NP film / NSCs Neurons [197g]
PDA/RGD–graphene–PCL / SCs Neuron/astrocyte [10b]
Graphene/silk fibroin films / miPSCs Neuron/astrocyte [303]
Graphene/PEDOT Biphasic, 30 µA, 1 Hz, 3000 rMSCs Neurons [119b]
pulses/day for 21 d
Graphene substrate / NSCs/MSCs/hiPSC CMs [280–281,304]
Collagen/graphene Monophasic, 2.5 V cm−1, 1 Hz, 48 h Alignment and maturation of the ESC-CMs [286]
Graphene hydrogel Differentiation of the new bone from the host bone [243b]
Graphene/poly(trimethylene Biphasic, 0.01 mA, 2.5 ms, MSCs OBs [305]
carbonate) (PTMC) 100 Hz, 4 h/d for 7 d
GO coated nanofiber / NSCs Oligodendrocytes [203]
GO/methacryloyl-substituted <15 V, 50 ms, 0.5–3 Hz CM growth and maturation [306]
tropoelastin
GO/alginate / hMSC OBs [241d]
GO/chitosan / hADSCs OBs [241c]
rGO sheet / NSCs Neurons [197k]
rGO/collagen / MSCs Neurons [197n]
rGO/PCL PC12 Neurons [307]
rGO/GelMA Biphasic, 3–6 V cm−1, 50 ms, Synchronous contraction of cardiac [282]
0.5, 1, 2, and 3 Hz tissue constructs
rGO/PAAm (polyacrylamide) 5 V, 10 ms, 1 Hz, 4 h/d for 3–7 d C2C12 Myotubes [294a]
rGO/poly (citric acid-octanediol- / C2C12 Myotubes [294b]
polyethylene glycol)(PCE)
CNTs Thin film or substrate / NSCs Neurons [197a,b,216,197c,217b]
MWCNTs/chondroitin sulphate / NPCs Neurons [198]
MWCNTs/PET fibrous matrices / ESC Neurons [199]
CNTs/collagen / MSCs Neurons [197e]
MWCNTs/PEGDA Biphasic, 0.1–1 mA, 100 ms, mNSCs Neuron/astrocyte [308]
100 Hz, 4 d
CNTs 3 V cm−1, 10 ms, 1 Hz, 2 d mESCs CMs [309]
CNTs hybrid hydrogel −1, mMSCs CMs [310]
3 V cm 10 ms, 1 Hz, 2 d
CNTs/PCL/silk fibroin / Aligned, elongated, maturation of CMs [278b]
CNT-GelMA/Au/PEG Square waveform, 50 ms, Control the beating behavior of the [15a]
0.5–6 V, 0.5, 1.0, and 2.0 Hz pseudo-3D cardiac tissue construct
CNTs-GelMA / CMs maturation [285]
MWCNTs/PLLA 1.5 V, 1.5 h per d for 7 d rBMSCs OBs [311]
CNT/collagen 0.5–0.6 mA, 20 min hMSCs OBs [312]
MWCNT/PEDOT Sine wave, 60–80 V, 10 ms, C2C12 Myotube [296a]
0.5–8 Hz
Pyrolysed 3D carbon / NSCs Neurons [198]
Silk fibroin/carbon nanofiber / MSC OBs [313]
PEDOT PEDOT:PEG film / NSCs Neurons [209a]
PEDOT/chitosan/gelatin / rNSCs Neuron/astrocyte [314]
PEDOT-HA/Cs/gel / rNSCs Neuron/astrocyte [315]

Table 1. Continued.
Conductive biomaterials Conductive scaffolds Electrostimulation Stem/progenitor cells Outcome cell line Refs.
Polyurethane (PU)/PEDOT:PSS/ Biphasic, 0.25 mA cm−2, 100 ms, NSC Neurons [316]
liquid crystal GO 250 Hz, 8 h per d for 3 d
Collagen/alginate/PEDOT:PSS / Maturation and beating of hiPSC-CMs [60a]
PEDOT:PSS / MC3T3-E1 OBs [246]
PEDOT–COOH / C2C12 Myotube [317]
PPy PPy (DBS) film / NSCs Neurons [208a]
Laminin/PPy / ESCs, NSCs Neurons [208b]
Polyphenol/TA/PPy / NSCs Neurons [60b]
PPy/poly (l-lactic 0.1 V cm−1, 4 h per d for 7 d PC12 Neurons [318]
acid-co-ε-caprolactone) (PLCL)
PPy/PLA Rectangular wave, 0.04 V, 30 min PC12 Neurons [319]
DOPA/PPy/PGA Springs / Maturation and synchronous contraction of CMs [277]
HPAE-Py/Geln / Reconstruction of cardiac function, revascularization [275]
of the infarct myocardium
PPy 2 V, 4 h/2 d for 12 d MSCs OBs [250c]
PPy Biphasic, 15/500/1200 mV, 10 ms, MC3T3-E1 OBs [320]
1 Hz, 1 h per d for 2 d
PPy/PCL 0.2 mA, 4 h per d for 21 d MSCs OBs [321]
PPy/chitosan 0.2 mA, 4 h per d for 21 d MSCs OBs [10a]
PPy-PDA-HAp 300 mV BMSCs OBs [322]
PPy/PTMC Biphasic, 50 µA, 0.25–1 ms, Adipose stem cells (ASCs) Smooth muscle cells [323]
10 Hz, 4 h per d for 14 d (SMCs)
PANi PANi/collagen/HA / Longer contraction time, higher contractile [10c]
amplitude, and lower beating rates
PANi/PLA / rbBMSCs OBs [248]
ANi/chitosan/HAp 2 V, 100 Hz, 2 h per d for 14 d hbBMSCs OBs [324]
PANi/gelatin Square wave, 6 V, 1 ms, 1 Hz, 1 d C2C12 Myotube [295]
Gold Gold NPs/PCL/gelatin / PC12 Neurons [204]
PDA-gold/PCL / BMSCs/SCs Neurons [205]
Gold nanorod/gelatin / Rhythmic contraction of the CMs [320]
Gold nanorod/GelMA 2–10 V, 2 ms, 1–3 Hz Synchronous tissue-level beating of CMs 130
Au/PCL-gelatin 3V, 50 ms, 1 and 2 Hz Synchronized contraction of CMs [271]
Si NWs Si NWs 3.75 V cm−1, 1 Hz, 9 d hiPSC CMs [325]
of carbon-based biomaterials depends on their size, doses/ metal ions could promote osteogenesis by serving as structural
concentrations, and surface oxygen contents.[79] The possible components of bone forming enzymes and proteins,[69b,85] there
mechanism involved in their cytotoxicity include induction of are still concerns about the potential toxicity of those metal
protein aggregation through abnormally strong interactions ions and nanoparticles. For instance, the metal ions can pro-
with proteins, and destruction of cell membrane structures.[80] duce hydroperoxide radicals and cause cytotoxicity.[86] Au nano-
In vivo animal experiments showed that CNTs can induce reac- structures have high chemical stability and been considered
tive oxygen species (ROS)-mediated inflammation, epithelioid to have good biocompatibility, but their long-term metabolism
granulomas and fibrosis that lead to lung malfunction.[81] And also needs further evaluation due to its inactivity to biodegrade.
carbon-based materials, especially C-dots, could accumulate in The biological toxicity of conductive polymers mainly originates
multiple organs, including liver, spleen, stomach, kidney, brain, from low-molecular-weight toxic impurities generated during
and heart,[82] and cause neurotoxicity, neuronal behavioral defi- the synthesis process and degradation products,[87] which may
cits and damages, heart and dopaminergic alterations and affect produce oxidative stress and change the intracellular mito-
neuronal gene expression.[83] While some studies have shown chondrial membrane potential (MMP).[88] Thus, it is urgent
carbon-based materials could specifically distribute in vivo and to evaluate the biocompatibility, cytotoxicity, and biometabolic
rapidly excrete from the body through kidney.[84] For metallic physiology of conductive biomaterials after different adminis-
implants, although some studies have shown that the released tration pathways to ensure the biosafety.

Figure 2. Typical conductive biomaterials used in the field of tissue engineering.
3.2. Conductive Biomaterial-Based Electrostimulation embryogenesis, and tissue regeneration.[5a] The external elec-
trostimulation not only provides a tool to regulate cell thera-
For a long history, exogenous electrostimulation was directly peutic response, but also accelerates to reveal the underlying
applied to cell culture media or local tissues including deep mechanism of endogenous bioelectricity.
brain stimulation, activation of neurons and CMs, modulation Electrostimulation can be delivered to cells/tissues through
of stem cell differentiation, and activation of tissue repairing. DC or alternating current (AC) (Figure 3a). DC stimulation is
However, these plate electrodes have many limitations. First, it the most basic electrostimulation method. The amplitude of
lacks selectivity and spatial resolution. The presupposed non- voltage, current, and stimulus duration can be adjusted. It is
target cells/tissues might be greatly influenced. Second, the widely applied in biomedical field probably because it can be
cell culture media or surrounding tissues would weaken the easily generated by batteries.[91] It was found that DC stimula-
voltage that is ultimately applied to the target cells/tissues.[89] tion (30–250 mV mm−1) can promote migration of neural stem/
Conductive biomaterials with micro-/nanostructure could not progenitor cell toward the cathode.[92] In another report, both
only deliver extra electrostimulation according to physiolog- strong DC EFs (10–15 V cm−1) and weak DC EFs (≤5 V cm−1)
ical needs, but also act as biological scaffolds on which cells were able to cause intracellular calcium elevation, promote cell
adhere tightly,[90] thus reducing the voltage loss caused by the elongation, and guide motility of osteoblast-like cells.[93] DC
surrounding media. And reasonable morphology, chemical, electrostimulation has some disadvantages, such as the forma-
mechanical properties of conductive biomaterial can synergisti- tion of capacitive bilayer near the electrodes. In addition, pH
cally directing cell adhesion, proliferation, and differentiation. alteration and by-products from electrolysis might also cause
Thus, conductive biomaterial-based electrical stimulation can biological toxicity. For AC stimulation, in addition to voltage
provide a diverse platform for regulating cell behavior and stem and stimuli duration, waveform (monophase or biphase; square
cell fate in tissue engineering. wave, sine wave, triangle wave, and pulse wave, etc.), fre-
quency and pulse width can also be varied (Figure 3a). Among
them, biphasic electrostimulation can maintain a charge bal-
3.2.1. Direct Electrostimulation for Tissue Regeneration ance, thereby minimizing cell damage.[94] AC stimulation with
low frequencies (<1 Hz) can regulate behavior of neuron that
Enlightened by the bioelectricity in human bodies, biomimetic derived from ESCs and iPSCs[95] and evoke network matura-
electrostimulation has become a spotlight of research for the tion in the cortical neuron.[96] The contraction and maturation
modulation of a myriad of biological processes, such as stem of CMs derived from human ESCs, iPSCs, and cardiac pro-
cell differentiation, neural conduction, muscle contraction, genitor cells were also modulated by endogenous AC electrical

Figure 3. a) Electrostimulation waveforms for tissue regeneration. b) Possible pathways involved in the biological response to electrostimulation.
Electrostimulation could act through intracellular calcium ions, membrane receptors, ATP, ROS, gap junctions and ECM compositions. Subsequently,
the essential signaling pathways are triggered to modulate cell proliferation, migration, and differentiation. GF, growth factor; GR, growth receptor;
CaM, calmodulin; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; ERK, extracellular signal regulated kinase; FAK,
focal adhesion kinase; JNK, c-jun N-terminal kinase; MAPK, mitogen activated protein kinase; PI3K, phosphatidylinositol-3 kinase; PTEN, phosphate
and tensin homolog; Src, steroid receptor coactivator; YAP, yes-associated protein; TAZ, transcriptional coactivator with PDZ-binding motif; ROCK,
Rho-associated protein kinase; MAP, microtubules-associated protein; mTOR, mammalian target of rapamycin; FOX1: forkhead box protein 1; GSK3β,
glycogen synthase kinase-3. c) Devices to apply direct electrostimulation.

fields (1–10 Hz).[18b,97] Moreover, AC stimulation can signifi- can change the cell gap junctions, affect exchange of signaling
cantly promote osteogenic differentiation even in the absence molecules such as calcium, potassium, cyclic nucleotides and
of exogenous drugs and/or growth factors.[98] Although most of inositol phosphates, and promote the development and com-
works apply electrostimulation with fixed voltage or electrical munication of electroactive cells.[109] 6) ECM compositions:
field, current is also a key parameter that cannot be ignored. Electrostimulation can alter ECM compositions by affecting
It is found that current above the threshold might cause cell proteins, soluble ions or charged groups, which could be per-
death,[99] such as 20 mA in case of treating nonunions.[100] ceived by cells through integrins.[110]
Electrostimulation has been proven to play an important Subsequently, the original biophysical electrostimulation can
role in modulating cell activity both in vitro and in vivo, while be converted into biochemical cues for cells to read through
the exact mechanisms of these electrical-induced biochemical intracellular signaling cascades, which matters in regulating
responses are still obscure. The electrical activity of cells and cell behaviors including cell lineage commitment. Protein
conductive materials is based on ionic processes and electron activation via phosphorylation nearly runs through the whole
flow or transfer, respectively. It is vital to clarify the electrical signaling pathways. Typically, phosphorylation of FAK, a linker
interaction between materials and cells. The cell membrane bridging integrins and cytoskeleton, can be passively turned
potential is regulated by the inflow and outflow of ions, which on by electrostimulation. Then it can further stimulate actin
can be simulated by an equivalent circuit using a voltage source, remodeling together with downstream mechano-signaling like
a capacitor, and a resistor.[89] In which, the voltage source rep- MAPK pathways and ERK1/2 that are closely related to cell pro-
resents the cellular resting membrane potential; the capacitor liferation and differentiation, and JNK required for subsequent
represents the intracellular and extracellular charge separated MAP activation and neurogenesis.[111] Studies also reveal that
by the nonconductive cell membrane; and the variable resistors electrically induced intracellular calcium concentration increase
represent ion channels. An external electrical stimulation gener- reinforces the activation of unique calcium/calmodulin pathway
ated by piezoelectric or conductive materials can be modeled by in cardiomyogenic differentiation.[112] Additionally, pulsed elec-
another voltage source. Thus, external electrostimulation would trical fields can promote the secretion of growth factors and
affect cell membrane potential, membrane receptors, ion chan- further get involved in p38 signaling transduction to induce
nels, gap junctions, etc. There are several pathways that might myogenic lineage choice.[113] Moreover, other associated path-
be potentially involved (Figure 3b): 1) Intracellular calcium ways that collectively constitute the intricate signaling networks
ions and calcium signaling: Electrostimulation is able to locally to synergistically mediate cell regulation have been extended to
change the Vm and activate the voltage-gated calcium channels Wnt signaling pathway for osteogenesis, PI3K/PTEN signaling
(VGCC), allowing an influx of extracellular Ca2+ into cytoplasm. and its downstream Ark for cell survival and apoptosis. All of
In addition, electrostimulation can induce recombination of these are responsible for the expression of proliferative and dif-
membrane proteins via phospholipase C, subsequently causing ferentiative genes.[112,114]
Ca2+ release from intracellular calcium reservoirs.[89,101] The
Ca2+ transients in both cases would activate the cytoskeletal
calmodulin, and further accelerate cell proliferation and change 3.2.2. Devices to Apply Direct Electrostimulation
growth factors expression.[9c,99a,102] 2) Membrane receptors:
Electrostimulation can induce asymmetric assembly and dis- There are several different pathways to impose electrostimula-
assembly of F-actin filaments, and regulate the distribution, tion on cells/tissues, including direct stimulation, capacitive
expression or conformation of transmembrane receptors (e.g., stimulation, inductive stimulation, and combined stimulation.[5b]
growth factor receptors, integrin-β molecules, and adeno- For capacitive stimulation and inductive stimulation, cells indi-
sine A2A receptors),[103] thereby influencing related intracel- rectly perceive electric field or electromagnetic field, and do not
lular signaling pathways in cell migration or differentiation directly contact with biomaterial electrodes. Thus, we mainly
via ligand-receptor binding. 3) Adenosine triphosphate (ATP): focus on direct electrostimulation via conductive biomaterials
Electrostimulation may promote cell metabolism and accelerate in this section. Commercial electrical stimulators are mostly
ATP depletion, thus altering membrane related behaviors, such applied for direct electrostimulation, especially for in vitro cell
as endocytosis and exocytosis, adhesion, and migration.[104] experiments.[94] Their electrical parameters (voltage, current,
However, some reports suggested that DC electrostimula- waveform, frequency, and stimulation time) can be fine-tuned,
tion ranging from 10 to 1000 µA promoted membrane-bound helpful to screen out the most suitable electrostimulation con-
ATP synthesis,[105] and then these ATP would be consumed ditions for different cells/tissues. For in vivo applications, they
for conversion of monomeric G-actin to polymeric F-actin for are bulky and require wire connections between stimulators
reorganization of actin cytoskeleton.[106] 4) ROS: Electrostimu- and electrodes. It is inconvenient, and might increase potential
lation controlled ROS generation at a physiologic level can safety risks after implantation. Implantable batteries have been
trigger essential signaling pathways related to cell prolifera- successfully used in implantable medical electronic devices,
tion and differentiation, including MAPK pathways and subse- such as cardiac pacemakers, deep brain stimulators, and coch-
quent ErK1,2, JNK, and p38 signaling cascades.[107] It has been lear implants.[115] Combined with the corresponding electrodes,
reported that a mild rise in hypoxia-induced ROS enhancement they have produced positive therapeutic effects in clinical applica-
can promote proliferation and differentiation of MSC.[107a,108] tion. Unfortunately, regular replacement of battery is needed due
5) Gap junctions: Gap junctions not only enable adjacent cells to limited battery capacity (e.g., lifetime of cardiac pacemakers
to exchange small molecules, but also form electrical coupling = 7–10 years),[116] which not only increases financial burden of
and metabolic coupling between those cells. Electrostimulation patients, but also increases the risk of postoperative infection.
Recently, implantable energy harvesters (IEHs) have been the premise of not interfering with normal cochlea function,
proposed, which can harvest power from organisms or sur- the low EP voltage and extractable power are two major chal-
rounding environment, such as human mechanical energy, lenges for harvesting net positive energy.
in vivo redox reaction, endocochlear potential and ambient In addition to harvesting mechanical and electrochemical
light and temperature.[117] Therefore, a series of self-powered energy in body, researchers also utilize energy in environment,
electrostimulation devices has been developed (Figure 3c), such as light and heat. Thus PVC and PYENGs are employed to
including piezoelectric nanogenerators (PENGs),[118] triboelec- generate electricity for in vivo electrostimulation.[135] Due to its
tric nanogenerators (TENGs),[119] mass imbalance oscillation nature of photoelectricity, most PVCs are used in eyes or under
generator (MIOG),[120] enzymatic biofuel cells (EBFCs),[121] the skin where light is easily transmitted.[136] And PYENGs gen-
untracochlear potential (EP) collector,[122] photovoltaic cell erally need to artificially create a temperature gradient to meet
(PVC),[123] and pyroelectric nanogenerators (PYENGs).[124] the temperature difference required to generate electricity.[124]
Human mechanical motions in daily life, such as limb In general, researchers have developed a variety of elec-
movement, heartbeat, and respiration, could produce abun- trostimulation devices that could be applied for in vitro and
dant kinetic energy. PENGs convert mechanical energy in vivo electrostimulation. Their practical application is deter-
into electricity based on piezoelectric materials, which have mined by the specific tissue microenvironment. Mechanical
been designed as an energy harvester to generate electricity energy harvesters (PENG, TENG, and MIOG) are more suitable
and applied to the electrodes. In 2006, Wang and Song first for the application in heart and bone tissue, due to the regular
designed a ZnO nanowire-based PENG to harvest tiny vibra- mechanical heartbeats and joints movement in bodies. High
tional energy.[125] Recently, the output performance has been compatibility with corresponding tissues is the foundation
improved up to 20 V/1 µA for implantable PENG,[126] and requirement for the implantable devices. Thus, biocompatible
130 V/800 nA for wearable PENG.[127] TENG could convert materials are used directly to fabricate or encapsulate IEHs.
mechanical energy into electricity based on the coupling High energy conversion efficiency and stable output also need
effects of triboelectrification and electrostatic induction, to be further optimized. For harsh stimulation conditions, it is
which was first proposed by Wang and co-workers in necessary to charge the generated electricity from IEHs into the
2012.[128] In order to be applied in different scenarios, TENGs battery and then control the electrical output when needed. In
with four fundamental working modes have been developed, addition, high flexibility, and suitable size, mechanical strength,
including vertical contact-separation mode, lateral sliding and elastic modulus are also important for easy adhesion to
mode, single electrode mode, and freestanding triboelectric- different biological tissues, reducing interference with sur-
layer mode.[129] Generally, humidity seriously affects output rounding tissues.
of the TENG due to its nature of electrostatic induction.
Thus, encapsulation is a necessary step for stable output of
implantable TENG.[130] Driven by cardiac motion of a pig, the 3.3. Piezoelectric Biomaterials and Electrostimulation
open-circuit voltage and short-circuit current of an implant-
able TENG reached up to 65.2 V and 0.5 µA, respectively.[130] Piezoelectric biomaterials can generate piezopotential to regu-
Hinchet et al. designed a thin vibrating TENG that can har- late the behaviors and fate of stem cells. It is generally believed
vest external mechanical energy delivered by an ultrasound. that its electrostimulation mechanism is similar to that of
The output generated by the ultrasound ex vivo reached 2.4 V electrical stimulation via a conductive material, which mainly
and 156 µA under the porcine tissue.[131] MIOG is another focuses on the membrane potential, ion channels, membrane
mechanical energy harvester based on the conventional auto- receptors, and ECM compositions.[14b,89] Micro-/nano-structured
matic watch mechanism.[132] By affixing MIOG to a sheep scaffolds from piezoelectric materials are independently
heart for 1 h, the generator produced 330 impulses with a discussed because of the special physiochemical and electrome-
mean power of 16.7 µW that was translated into 11.1 µJ per chanical coupling properties of piezoelectric materials different
heartbeat.[120] from conductive materials. Piezoelectric materials are charac-
EBFCs are hybrid systems that combine the electrochemical terized by two opposite effects: direct piezoelectric effect (gen-
energy conversion with biocatalysis.[121a] They can utilize redox eration of electricity under an applied pressure), and reverse
reaction in the body, such as glucose, to generate low-intensity piezoelectric effect (deformation of material in response to an
direct current (DC) for electrostimulation or powering bioelec- applied EF). Responsive to respective physical stimuli, both
tric devices.[121b,133] The advantages of mild operating conditions effects can act as determinant cue for regeneration of different
and simple device structure promote EBFCs to be a desirable tissues.
implantable power source. A modified biocatalytic buckypaper
electrode with millimeter-scale size of 2 × 3 × 2 mm3 generated
electrical power of 2–10 µW when implanted in a living gray 3.3.1. Piezoelectricity and Piezopotential
garden slug.[134] As another electrochemical energy in body, EP
arises from the electrochemical gradient between endolymph Piezoelectricity origins from the noncentrosymmetric nature
and perilymph, which is the largest positive DC electrochem- of material, including noncentrosymmetric crystal structure
ical potential in mammals (70–100 mV).[122] This potential has in inorganic piezoelectric materials and noncentrosymmetric
been utilized to power implanted devices. For example, Mer- molecular structure and orientation in organic piezoelectric
cier et al.[122] designed a chip to extract a minimum of 1.12 nW materials.[137] Due to the special electromechanical coupling
from the EP of a guinea pig to power a wireless radio. Under properties, electricity is generated when the piezoelectric
Figure 4. a) Atomic model of the wurtzite-structured ZnO, and schematic illustrations of stress induced electric dipole moment. Reproduced with
permission.[140] Copyright 2012, Wiley-VCH. b) Numerical piezopotential distribution along a ZnO NW under axial stretch or compress. Reproduced
with permission.[143a] Copyright 2009, American Institute of Physics. c) Atomic model of the perovskite structured ceramics (ABO3). d) Molecular
structure of α- and β-phase PVDF.
material is deformed and vice versa, which is piezoelectric effect conformation (TGTG′) for α and δ phases, all trans (TTTTT)
and converse piezoelectric effect, respectively. Piezoelectric for β phase, and T3GT3G′ for γ and ε phases.[142] Among them,
effect is a molecular phenomenon that induces a macroscopic α and β phases are predominant (Figure 4d). The dielectric
potential through continuous overlay of the dipole polarization, property of PVDF derives from the different electronegativity
which is the piezoelectric potential (piezopotential).[125,138] of F and H atoms, generating a dipole moment along the F→H
Piezoelectricity in inorganic materials arises from the non- direction.[9c] The α phase exhibits no piezoelectricity, because
centrosymmetric crystal structure. When the crystal is under the chains are packed in the unit cell resulting in a net cancel-
a mechanical stress, the displacement of positive and negative lation of dipole moments. The β phase has the highest piezo-
ions inside the crystal produces a dipole moment. It could not electricity due to the parallel orientation of dipole moments
be cancelled out by other dipoles.[139] Figure 4a depicts piezo- causing the highest net electric dipole moment.[137,143]
electric effect of wurtzite-structured ZnO semiconductor.[140]
In an unstrained hexagonal ZnO crystal structure, positive
Zn2+ and negative O2− are tetrahedrally coordinated and the 3.3.2. Pathways for Generating Piezopotential
centers of anions and cations overlap with each other, so there
is no polarization. When a stretched or compressive stress is Ferroelectric materials can produce permanent polarized
applied, the relative displacement of Zn and O atoms causes potential even without strain. For other piezoelectric mate-
the transfer of positive and negative charges centers to the rials, mechanical deformation (elongation, twisting, bending,
opposite directions, resulting in a dipole moment in the unit or compression) is an indispensable requirement for the gen-
cell. Hence, there appears a macroscopic piezopotential in the eration of piezopotential. Piezopotential have been widely
ZnO crystal due to the continuous overlay of dipole moments employed to regulate carrier transmission in transistors,[144]
(Figure 4b).[141] For perovskite structured ferroelectric ceramics photocatalysis,[145] solar cells,[146] and light-emitting diodes
(ABO3), it has a nonzero net charge in the unit cells even if no (LED).[147] Different methods, such as speed-controlled motor,
mechanical stress is applied. And an external stress can further ultrasound wave, mechanical brushing/sliding, internal strain
shift the relative position of the B site inside the unit cell and of crystal by thermal stress and water flow have been developed
change its electrical polarity (Figure 4c). to induce mechanical deformation to generate piezopotential.
Piezoelectricity in organic materials origins from the ori- And intriguing helical structure was designed to amplified the
entation and arrangement of molecular dipoles. Taking deformation.[139] For tissue engineering applications, pathways
PVDF [(CH2CF2)n] as an example, it has five crystal phases for exerting mechanical stress are more limited. It is neces-
with three chain conformations: trans−gauche−trans−gauche sary to take into account cell viability and adhesion during
deformation of the piezoelectric biomaterials. As well, for in nanostripe array structures, which could generate a surface
vivo application, the availability and biosafety of the pathway piezopotential about +3.4 mV according to finite element simu-
should be considered. lation by cell traction (10 nN), which was over 3500 times com-
Recently, to control the material deformation accurately, a pared with the flat PVDF film. This high surface piezopotential
custom vibrating platform with selectable frequency and ampli- could efficiently promote neuron-like differentiation of rbMSCs
tude was employed to generate vibration, and a sensor attached (Figure 5e,f).[160]
to the culture plate bottom was used to quantify the vibration In addition, some tissue activities or human body move-
amplitude.[148] Dynamic bioreactor was also designed to apply ments can also be utilized to generate piezopotential for in vivo
cyclic compression.[149] A speaker was attached on the bottom tissue repair, such as heartbeats for cardiac tissue engineering
of the bioflex culture plate, and the frequency and intensity and joint activities for bone tissue engineering.[157a,161] Reason-
of vibration were controlled by function generator and power able design of morphology and structure of piezoelectric bio-
amplifier.[150] material enables it to more efficiently utilize biomechanical
Ultrasonic wave is sound wave with a frequency higher than energy in cells, tissues and organs, generating a feedback elec-
20 000 Hz. Due to its high tissue penetration and good direc- trostimulation on corresponding matters.
tionality, it has been used for diagnostic imaging, promotion of
drug delivery, and sonodynamic therapy.[151] When using ultra-
sound as a mechanical force source, both acoustic pressure and 3.3.3. Piezoelectric Biomaterials for Tissue Regeneration
ultrasonic cavitation effect play major roles in driving deforma-
tion of the piezoelectric materials. Sound pressure causes tiny In this section, piezoelectric biomaterials are introduced with
bubble nuclei expansion and closure rapidly to generate shock categories of i) inorganic piezoelectric materials, ii) organic
waves. And ultrasonic cavitation is a dynamic process including piezoelectric materials (including natural and synthetic biopoly-
expansion, closure and oscillation.[153b] Furthermore, ultrasonic mers), and iii) piezocomposites. Their biomedical applications
power, frequency and periodically turn on/off can be adjusted in stem cell determination and tissue regeneration is high-
precisely by ultrasonic transducers.[152] lighted in the next section.
Interestingly, magneto-electric (ME) materials have been The first piezoelectric material with single crystal α-quartz
designed to induce piezopotential of piezoelectric materials by was observed by the Curie brothers in 1880, whereas its appli-
a magnetic field. A magnetic stimulus causes strain of mag- cation was limited to acoustic devices due to low piezoelectric
netic material, and the strain is further transferred to inti- coefficient and inefficient signal transduction. Perovskite
mately connected piezoelectric material to produce an electrical structured ceramics (ABO3), such as BTO, SrTiO3, LiTaO3 and
response. This is the magnetoelectric coupling in two-phase LiNbO3, exhibit high electromechanical coupling and good
ME materials.[153] Magnetic field has been widely applied for biocompatibility.[9c] For example, BTO nanoparticles have a low
magnetic resonance imaging, magnetic hyperthermia, and tar- cytotoxicity even at high concentrations.[162] Lead-containing
geted drug delivery. It has a deep tissue penetration and high piezoceramics such as PZT has high piezoelectricity. The piezo-
precision in controlling the motion of magnetic materials.[154] electric constant of ternary solid solutions of perovskites such
CoFe2O4@BaTiO3 (CFO@BTO) core–shell ME nanoparti- as Pb(Zn1/3Nb2/3)O3 (PZN) and PbTiO3 (PZN-PT) could reach
cles,[155] ME nanowires, and nanoeels[156] have been prepared as high as 2000 pC N−1, but potential toxicity of lead limits their
to trigger the ME effect electric dipole by applying a AC mag- biomedical application.[9c] To reduce cytotoxicity of lead-based
netic field. The nanoeel consisted of a flexible piezoelectric tail piezoceramics, researchers have encapsulated biocompatible
(PVDF-based copolymer), linked to a nickel rings decorated PPy materials on them, such as Ti,[163] but the leakage of Pb2+ ions
nanowire for magnetic actuation.[156c] By changing the external still cannot be ignored.
magnetic field, the nanoeel can be switched from a tumbling Recently, the third-generation semiconductors, most of
motion to a wobbling motion (Figure 5a). And the actuation which have wurtzite structure, such as ZnO, AlN, BN, and
of nanoeel deformed the soft PVDF-based tail, which induced GaN, have been proven to have semiconductor properties and
its electric polarization changes and realized controlled drug piezoelectric effect, simultaneously.[141b] Although their piezo-
release based on electrostatic repulsion (Figure 5b). electric coefficients are always lower than the above-mentioned
In nature tissues, the mechanical force generated by cell piezoelectric ceramics, they can generate piezopotential com-
activity is continuously applied to ECM. Nanowire-based plat- parable to cell membrane potentials, which is enough to regu-
forms have been employed as force sensors to monitor cell late cell behavior.[137,164] Besides, 2D odd-layered MX2 (M = Mo,
traction forces through quantitatively analyzing the bending W, etc.; X = S, Se, or Te), MX (M = Ga, In, Sn or Ge; X = Se
of the nanowires (Figure 5c).[157] It was found cell traction- or S), GaP, GaAs, GaSb and black phosphorus also have piezo-
mediated soft fibers realignment and gel contraction,[158] as electric effect.[165]
well as cellular contraction caused breakage of the fiber cross- Compared with piezoceramics, although piezopolymers have
links, allowing the cells to recruit more fibers (Figure 5d).[159] relatively low piezoelectric coefficients, their advantages of high
Although the materials mentioned above are not piezoelectric, flexibility and relatively low stiffness meet the requirements
these studies suggested cell activities (i.e., cell spreading, of tissue engineering biomaterials, especially for soft tissue
migration, contraction, and CMs beating) and corresponding applications. A variety of structures including microspheres,
cell traction forces can induce deformation of piezoelectric bio- nanofibers, films, and hydrogels have been fabricated through
materials with special structure or suitable hardness. Inspired different preparation technics, such as electrospinning, spin
by this, our group has fabricated piezoelectric PVDF films with coating, and template method.[52b] PVDF and P(VDF-TrFE)
Figure 5. a) Time-lapse image showing a single hybrid nanoeel transition from a surface-walking swimming mode to a wobbling motion upon changing
the parameters of magnetic fields. b) The corresponding pulsatile release of rhodamine (RhB) with (Mon) and without (Moff) a magnetic field. Repro-
duced with permission,[158c] Copyright 2019, Wiley-VCH; c) Cell migration-induced nanowire deflections. Reproduced with permission.[157c] Copyright
2018, American Chemical Society. d) Tensile forces generated by cellular contraction lead to breakage of the fiber cross-links, which allowed the cells
to recruit more fibers. Reproduced with permission,[159] Copyright 2017, National Academy of Sciences. e) The electric potential generated on the
nanostriped PVDF when strained by a tangential force of 10 nN. f) Inherent cell forces of living cells grown on the surface of PVDF with nanoscaled
stripe arrays. Reproduced with permission.[160] Copyright 2019, Wiley-VCH.
(d33 = − 38 pC N−1)[166] are widely investigated due to their high improve the crystallinity and piezoelectricity of PLLA, and its
piezoelectric response and good mechanical properties. Among shear piezoelectric constant d14 can reach ≈10 pC N−1 with the
the five crystal phases of PVDF, the β phase exhibits the draw ratio increases.[169] Polyhydroxyalkanoate (PHA) is another
highest piezoelectricity (d33 = −33 pC N−1; d31 = 23 pC N−1).[137] commonly used biodegradable piezopolymer, including
As mentioned above, piezoelectricity of PVDF origins from poly(3-hydroxybutyrate) (PHB) and poly(3-hydroxybutyrate-3-hy-
orientation and arrangement of the F→H dipoles. To increase droxyvalerate) (PHBV).[170] It is a bacterial synthetic polyester as
piezoelectricity, the materials could be processed via poling a carbon source and energy storage substance in the organism.
at a high electrical field, annealing, mechanical stretching, PHA has twisted radial lamellar structure and exhibits different
melt-recrystallization and incorporation of graphene.[47,167] orientations when aggregated to films,[9b] thus possessing pie-
Electrospinning is the most common method for fabricating zoelectricity (1.6–2.0 pC N−1).[52b,171] Although the piezoelectric
piezoelectric PVDF. Both high applied voltage and high-speed coefficient of PHA is relatively low, its unique biodegradable,
rotating collector cause micro-/nanofibers stretching, conducive biocompatible, and mechanical properties allow it to be used to
to increase polarity. In addition, to reduce its hydrophobicity for fabricate scaffold and biosensor.
better cell adhesion and tissue affinity, PVDF has been modi- Natural piezopolymers attract more attention in tissue engi-
fied by incorporation of inorganic nanomaterials, mixing with neering due to their low toxicity and biodegradability. In gen-
hydrophilic polymers, or treated with oxygen plasma.[160,168] Poly eral, many biomacromolecules have piezoelectricity, as we have
(l-lactic acid) (PLLA), a biodegradable and bioabsorbable piezo- introduced in the section of endogenous piezoelectricity. In
polymer, shows promise as a functional biomaterial in tissue addition to collagen and other proteins, cellulose, chitin, and
engineering applications. Mechanical stretching is effective to chitosan are also widely investigated as natural piezopolymers.
Cellulose is a linear homopolymer of glucose with a low piezo- To overcome this restriction, conducting polymers films are
electric coefficient of ≈0.1 pC N−1.[172] Chitin is a natural polysac- employed as nanoswitches to gate nonelectroactive materials as
charide with a piezoelectric coefficient of ≈0.2–1.5 pC N−1.[173] It the drug container.[180] For example, a thin PPy layer (≈1.5 µm)
is widely existed in shells of crustaceans, mollusks, insects, and was covered on nanoporous anodized aluminum oxide mem-
cell wall of fungus. Since its hydrophilicity, chitin is benefit to brane (Figure 6b).[12b] The ON/OFF release of model protein
promoting cell adhesion and spreading.[47] Chitosan is a biode- drug was realized by shrank of PPy chains in the oxidation state
gradable linear polysaccharide by partial deacetylation of chitin, (0.1 V, the expulsion of hydrated sodium ions) and expanded
and its solubility is greatly improved. Due to their low toxicity, to cover the pores in the reduced state (−1.1 V). To improve the
good biocompatibility, biodegradability and flexibility, natural drug loading and release rate, nanoscaled dispersed/colloidal
piezopolymers have been used in nerve and cartilage tissue systems, such as nanoparticles, micelles, and vesicular struc-
engineering for stem cells adhesion, proliferation, differentia- tures are also developed.[181] Electrostimulation can also indi-
tion, and functional cell growth.[174] More recently, researchers rectly control drug release from pH-responsive scaffolds via
have synthesized biomimetic piezoelectric supramolecules and electro-induced pH changes.[182]
micro-/nanostructures especially with polypeptides and pep- Electroresponsive interfaces can control cell adhesion,
tide crystals.[175] Recently, a higher piezoelectric coefficient over release, migration, as well as stem cell differentiation via
200 pm V−1 has been realized.[176] With good biocompatibility electrically induced conformational changes of RGD.[14a,183]
and low immunogenicity, we vision that these piezoelectric RGD as a tripeptide sequence (Arg-Gly-Asp) generally exists
molecules would open up a wide avenue for the development of in ECM proteins that mediates integrin-mediated cell adhe-
new generations of biomimetic piezoelectric materials. sion. Lashkor et al.[184] directly exposed (open circuit condi-
Moreover, piezocomposites integrate the advantages of tions) or concealed (−0.4 V) RGD by folding and stretching
piezoceramics and piezopolymers, thus exhibiting high the RGD-grafted charged backbone of oligopeptide. Another
piezoelectric coefficient, good flexibility, biocompatibility, research[14a] indirectly exposed or concealed RGD by electro-
and improved mechanical stability. A common compounding static attraction and repulsion of negatively charged sulfonate
method is to disperse the piezoceramic nanostructures into moiety without RGD modification (Figure 6c). In addition,
polymer matrix to fabricate polymer matrices-based compos- surface electrical potential generated by piezoelectric materials
ites, such as microspheres, fibers, films, and hydrogels.[48,52b] is also used to in situ induce conformational change of the
The improved performance of piezocomposites further pro- adsorbed proteins to fit different physiological needs. According
motes the application of piezoelectric biomaterials in tissue to molecular dynamics simulation (Figure 6d), a higher RGD
engineering field. exposure was observed on the material surface with a 53 mV
electrostatic potential, which was more conducive to cell adhe-
sion. When the surface potential was 88 mV, the height of RGD
3.4. Electroresponsive Biomaterials decreased, and the distance between RGD and synergy domain
of fibronectin decreased from 41 to 33 Å. Under this dynamic
Triggered by environmental variations (e.g., temperature, pH, modulation, a fast cell proliferation was observed.[14b]
electricity, light, and magnetic field), stimuli-responsive bio- Furthermore, electrically induced mechanical forces or
materials exhibit specific changes of their own characteristics, motion of electroresponsive biomaterials have been used to
which have attracted considerable interest due to their bionic regulate cells/tissues behavior. Polyelectrolyte hydrogels gen-
nature and widespread biomedical application potentials.[177] erate deformation by repeatedly swelling and deswelling under
Among them, electrostimulation has several attractive advan- an EF. It is due to osmotic pressure changes inside and out-
tages, including noninvasiveness, high spatiotemporal con- side of the hydrogel caused by charged ion transferring to the
trollability, and rapid and reversible induction.[178] For tissue anode or cathode sides.[185] A biocompatible and electrorespon-
engineering, a spectrum of functional biomolecules (e.g., sive hydrogel-based smart scaffold composed of acrylic acid
growth factors, therapeutic drugs, genes, and proteins) could and fibrin was developed to mechanically stimulate cells. The
play important roles in regulating cell behaviors, cell fate pulsatile electrostimulation (± 0.06 V mm–1) induced dynamic
determination, and tissue regeneration. Electroresponsive alternation of the scaffold and significantly enhanced cell
biomaterials can release therapeutic agents on-demand with growth-in and alignment.[186] Electrically driven biorobots have
predetermined magnitude and time schedule, when actuated been widely studied as engineering biohybrid tissue actuators,
by an appropriate electrical stimulus. Most of current elec- especially for regulating the motion of cardiac tissue and skel-
troresponsive drug delivery systems are based on electrically etal muscle.[15,187] For example, a biohybrid valveless pump-bot
induced redox reaction of conducting polymers. Taking PPy as was proposed, which was consisted of a soft hydrogel tube
an example (Figure 6a), its oxidized form has abundant positive with both ends connected to a stiffer polydimethylsiloxane
charge along the carbon backbone, serving as active sites for (PDMS), and a skeletal muscle ring wraps around the soft tube
complexing negatively charged drugs by electrostatic and hydro- (Figure 6e).[188] Triggered by spontaneous muscle contraction or
phobic interactions.[12a] When PPy is electro-reduced to neutral, electrostimulation (9 V; 4 Hz), this pump-bot established a net
the loaded drugs are expelled from the PPy matrix, thereby trig- unidirectional fluid flow up to 22.5 µL min−1 (Figure 6f,g).
gering drug release. Electroresponsive drug-release systems are In general, electroresponsive scaffolds are composed of
commonly designed in the form of thin films or hydrogels, in a class of electroactive biomaterials that can adjust their own
which drugs are directly incorporated.[179] This drug loading biochemical and biophysical properties or environmental con-
and release is limited by the chargeability of the loaded drugs. ditions through external electrostimulation to adapt cells and
Figure 6. a) The electrodynamic character of PPy. b) Electrically responsive nanoporous PPy membrane: Reversible change of pore size between oxidation/
reduction states, and in situ AFM height images corresponding to the oxidation and the reduction states. Reproduced with permission.[12b] Copyright 2011,
American Chemical Society. c) Potential-responsive surfaces for the dynamic manipulation of cell behavior. Reproduced with permission.[14a] Copyright 2019,
Wiley-VCH. d) Molecular dynamics simulation for conformation of FN-III7−10 on the CFO/P(VDF-TrFE) composite film with 53 and 88 mV. Reproduced with
permission.[14b] Copyright 2018, American Chemical Society. e) Schematic illustration of the biohybrid pump-bot. Muscle contraction along the circumferential
direction compresses the hydrogel tube in the radial direction which drives a unidirectional flow. f) Time-varying deformation of hydrogel tube induced by
muscle rings at electrical stimulation frequencies with a voltage of 9 V. g) Flow patterns along cross-section of the hydrogel tube in the middle at an electrical
stimulation voltage of 9 V. Reproduced with permission.[188] Copyright 2019, National Academy of Sciences.
tissues at different periods. Therefore, electrostimulation acts electrophysiological environment. In mature nervous system,
on cells indirectly, and it is mainly from the effect of the adjust- neurons form synapses to transmit electrical signals and inte-
able properties of the material (mechanical property, redox state, grate into neuronal circuits. After axonal injury, neurons switch
hydrophobic/hydrophilic property, and conformation of surface from an active electrical transmission state back to an electri-
ligand) on cells, including membrane deformation, ion chan- cally silent and growth-competent state.[190] Similarly, native
nels activation, integrin-mediated cytoskeleton remodeling, and myocardium is an electrically excitable tissue with a conductivity
nucleartransduction, etc.[189] They are appealing candidates in from 1.6 × 10−3 to 5 × 10−5 S cm−1.[191] After myocardial infarction
transforming basic researches into clinical applications. (MI), beating CMs are replaced by a fibrotic scar with higher
stiffness and electric resistivity,[75] thus hindering the synchro-
nous contraction of myocardial tissue and inhibiting ventricular
4. Application in Tissue Regeneration function. As for bone tissue, it could be considered as a natural
piezoelectric composite, and its highest piezoelectric coeffi-
Electroactive biomaterial-mediated stem cell differentiation/ cient (d14) could reach 0.7 pC N−1.[56] The endogenous bioelec-
trans-differentiation into specific cell lineages is of great sig- tric potential in bone defect walls range from −52 to −87 mV.[192]
nificance for tissue regeneration. Although the underlying For tissue regeneration, determination of favorable changes in
molecular events and mechanism of electroactivation are natural tissue repair, and biomimetic construction of matched
not completely clear, there are some general guidelines for microenvironment along with biochemical/biophysical cues are
the design of smart biomaterials. Besides that morphology important for long-term tissue regeneration. In this section, we
and mechanical properties of biomaterials should match mainly focus on the applications of electroactive biomaterials in
tissue microenvironment, it is important to imitate tissue stem cell determination and tissue regeneration, particularly in
Table 2. Stem/progenitor cells differentiation and cell function modulation on piezoelectric biomaterials.
Piezoelectric Piezoelectric scaffold Electrical features Deformation Stem/progenitor cells Outcome cell line Refs.
biomaterial
PVDF PVDF / / NSC Neuron/astrocyte [326]
PVDF d33 = −30 ± 2 pC N−1 Ultrasound PC12 Neurons [327]
PVDF / Cell traction rbMSCs Neuron-like cells [160]
PVDF/PCL d33 = 13.2 pm V−1 / SCs Neurons [227a]
P(VDF-TrFE) / / SCs neurite extension and myelination [328]
P(VDF-TrFE)/BTO d31 = 53.5 pm V−1 Ultrasound SH-SY5Y Neurons [225]
g31 = 0.24 mV N−1
P(VDF-TrFE)/CFO / Ultrasound PC12 Neuron-like cells [156a]
P(VDF-TrFE) / / mESC CMs/endothelial cells [291]
P(VDF-TrFE) / Cardiac contractile hiPSC CMs [161a]
PVDF/Ti d33 = -28 pC N−1 / BMSCs OBs [329]
PVDF / / hBMSCs OBs [330]
PVDF / Cell adhesion forces Calcium transients of OBs [168]
PVDF d33 = -32 pC N−1 / C2C12 Myotube [296b]
P(VDF-TrFE) / Bioreactors MSCs OBs/chondrocytes [149]
P(VDF-TrFE) d33 = 10 pC N−1, / BM-MSCs OBs [107c]
surface potential = −53 mV
P(VDF-TrFE)/BTO / / MSCs OBs [331]
PVDF/CFO / Magnetic fields Proliferation of preosteoblasts [262]
P(VDF-TrFE)/Dopa@BTO Surface potential = −76.8 mV / BM-MSCs OBs [259]
BaTiO3(BTO) BTO NPs / Ultrasound Neural stimulation [183]
PLGA/BTO / / H9C2 Myotubes [290]
S. platensis@Fe3O4@ BTO / Ultrasound PC12 Neurons [228]
BTO/PHBV d33 = 1.4 ± 0.03 pC N−1 / Cartilage regeneration [332]
BiFeO3 (BFO) BFO Surface potential = +75 mV / MSCs Osteoblast [263]
CFO@BFO/GelMA / Magnetic fields SHSY5Y Neuron-like cells [11]
ZnO ZnO/PDMS / Cyclic bending / hMSCs CMs [293]
stretching
KNN KNN 220.2 pm V−1 / BMSCs Osteoblast [263]
PHB PHB-PANi / Ultrasound hBMSCs Osteoblast [251]
Nylon-11 Nylon-11 NPs / Ultrasound Dental pulp stem cells Osteoblast [333]
electrically sensitive tissues. Detailed conductive biomaterials ability is relatively stronger, permanent neurological deficits are
and electrostimulation parameters, as well as corresponding cell still usual accompanied by failure of nerve regeneration and
responses are listed in Table 1. Piezoelectric biomaterials and development of chronic pain.[190] For neural regeneration, it is
their mediated cell modulation are listed in Table 2. a challenge for repairing large lesions in both CNS and PNS
that cannot be directly reconnected by end-to-end surgery. It
is helpful to committed differentiation of stem cells into func-
4.1. Nerve Regeneration tional neurons, guidance of neural cell growth, promotion of
axonal elongation, and signal propagation.[9a,195] Since nerves
During neuronal development, the growth ability of axons are electrogenic cells, electroactive biomaterials and nerve guid-
gradually decreases. Neurons in an active electrically transmit- ance channels (NGCs) are explored for this purpose.
ting state would form synapses to transmit information and Conductive graphitic-based materials[196] are found to
integrate them into functional neuronal circuits.[193] In adult be capable to support neuron survival, neurite outgrowth,
tissue microenvironment of CNS, the inherent poor regenera- and cellular electrical signaling. Their good conductivity is
tive ability of neurons and the existence of inhibitory factors are favorable for synaptic connection and signal transmission.
the main obstacles to axons regeneration and functional recon- CNTs[196c,197] have been used to fabricate electrically conduc-
struction. For the individuals suffering from spinal cord injury tive biomaterials for promoting neural differentiation from
or stroke, it might lead to a permanent disability.[193a,194] For NSCs,[199a,d,f–k,198] ESCs,[197o,199] MSCs,[197e,199l–n] and iPSC.[197b] A
peripheral nervous system (PNS), although its self-repairing varieties of techniques including layer-by-layer method,[196c,197a]
electrospinning,[197b] self-assembly,[197e,198] chemical vapor Compared with conductive inorganic materials, 3D scaffolds
deposition,[197i] pyrolysis,[198] and 3D printing[197m] have been made of electrically conductive polymers have the advantages
used to fabricate carbon-based conductive scaffolds for neural of flexibility and low stiffness with low Young’s modulus, thus
differentiation and nerve regeneration. The conductive scaf- more suitable for soft nervous systems. Scaffolds composed of
folds with 3D porous structure[199m,n,198] are advantageous for CPs including PPy,[62b,210] PEDOT,[209] and PANi[210] have been
cell growth-in, providing cells with a mimic tissue microen- used to fabricate neural scaffolds. Due to the versatility for
vironment. It is interesting that without addition of any exog- synthesis of conductive polymers, a range of bioactive surface
enous biochemical factors, hMSCs could be differentiated was designed. Zhu et al. reported a cell membrane-mimicking
into neuron-like cells on graphene (3DG) composite scaffold conducting polymer capable of electrically interfacing with
by 3D printing with a high graphene content (60 vol%),[197m] neurons selectively and efficiently. It can promote neurite
although the mechanism is still not clear. An graphene loaded outgrowth while minimizing immune recognition, thereby
polycaprolactone (PCL) nanostructured scaffold was fabricated avoiding immunogenic scar formation.[94] PEDOT-carbon
for peripheral nerve restoration, with polydopamine (PDA) and microfibers modified with PLL/heparin/bFGF/fibronectin also
RGD coating to improve cell adhesion. This conductive 3D gra- showed good integration, establishing contraction with neu-
phene scaffold can significantly enhance neural-related proteins ronal somas, axons, dendrites and glial cells, with little even no
and neurotrophic factors expression, promote axonal regrowth scarring response.[211] Zhou et al. designed a soft conducting
and remyelination after peripheral nerve injury.[10b] polymer hydrogel based on a plant-derived polyphenol, tannic
Currently, some contradictory conclusions still exist from dif- acid (TA), cross-linking and doping conducting PPy chains,
ferent studies. Yang and co-workers found multiwalled carbon which significantly promoted new endogenous neurogenesis in
nanotubes (MWCNTs) in polyethylene terephthalate (PET) a hemisection model of spinal cord injury.[60b]
matrix could promote neural differentiation of ESCs.[199] How- In addition, integration of conductive polymers with other
ever, another study by Le and co-workers found only GO had softer polymers can further improve the flexibility, biodegra-
the promotion effect, whereas graphene and CNTs had not.[197o] dability and processability.[212] For example, incorporation of
Along with conductivity, the complicated physicochemical fac- temperature-sensitive hydrogels can fabricate injectable conduc-
tors of scaffolds including surface chemical property,[200] stiff- tive 3D scaffolds.[213] Aligned micro-/nanofibers can enhance
ness,[201] alignment,[202] and micro-/nanoscaled topography may cell anisotropy and neurite length.[214] It should be noted that
have combined influence on cell fate. In addition to induced topographical features, surface hydrophobicity–hydrophilicity,
differentiation into neuron, GO coated nanofibers were also mechanical strength, protein adsorption, and biomolecules
used for guiding NSCs into oligodendrocytes, a kind of myeli- incorporation[215] of the scaffolds may also play concurrent key
nating cells in CNS.[203] roles.[197c,i,216,217] For instance, embryonic hippocampal neurons
Other conducting inorganic nanomaterials are also used to cultured on patterned PPy microchannels (1 and 2 µm wide)
increase the conductivity of scaffolds. AuNPs were decorated polarized faster, with a twofold increase in the number of cells
onto the surface of electrospun nanofibers for promoting with axons compared to the cells cultured on the unpatterned
axonal elongation of neurons.[204] A PDA-coated gold/PCL PPy film.[218]
nanostructured scaffold was fabricated via multilayer molding, Although the biomaterials with good electrical conductivity
and the fabricated conductive NGCs exhibited satisfactory have a positive effect on neurite outgrowth and neural differen-
recovery of sciatic nerves and angiogenesis.[205] Interestingly, tiation, those effects related therapeutic outcome is still limited.
electromagnetized AuNPs along with reprograming factor can Furthermore, in most of cases, the promotion effect on cell dif-
facilitate an efficient direct lineage conversion to induced dopa- ferentiation could not be orientated into the specific cell linages.
minergic (iDA) neurons under specific electromagnetic field Biological and chemical differentiation-inducing agents are gen-
(EMF) conditions (Figure 7a).[206] AuNPs were modified with erally required, concurrently, in the differentiation process.
thiol-containing ligands to induce magnetic polarization by the Given the tremendous roles of the endogenous bio-
“Fermi hole effect.” After in vivo treatment, PD mice exhib- electric signals, electrostimulation, matched to the tissue
ited a remarkable restoration of movement in an open-field, electrophysiological environment and delivered from conduc-
including increased total travel distance and a higher prob- tive biomaterials to cells/tissues, has been developed for neural
ability of activity in the center zone of the open field. Addition- regeneration, treatment of neurological disease by promotion
ally, dopamine (DA) levels and electrophysiological properties of neurite extension[219] and neural differentiation of stem cells.
were significantly enhanced compared with the untreated PD It has been reported that even without addition of any differ-
mice (Figure 7b), indicating the formation of synapses with entiation-inducing agents, those effects could be realized.[28a]
neurons of the host brain. Eight weeks after the treatment, Sun et al.[220] reported that PPy-coated nanofibers scaffold can
EMF/AuNP exposure along with reprograming factor converted enhance proliferation of Schwann cells (SCs), while not induce
astrocytes into iDA neurons in the brain. differentiation of PC12 cells. Importantly, electrostimulation
Li and co-workers fabricated a porous film assembled (100 mV cm−1; 1 h per day) could further induce SCs differentia-
from MoS2 nanoflakes. The film has a high conductivity of tion without neural growth factor, and the neurite length was
2.5 × 10−4 S cm−2. With the electrical conductivity and nanopo- increased with increasing PPy content in the scaffold. Based on
rous structure, the film efficiently increased cell proliferation these results, they designed a PPy-coated NGC, which showed
and attachment of NSCs. After 15 d differentiation, cells on the a similar performance of nerve regeneration to an autograft.[221]
MoS2 conductive film have a 1.85-fold neurite outgrowth com- Indispensability of electrostimulation in neural differentiation
pared with that on cell culture plate.[207] was also verified.[222]
Figure 7. Rescue of Parkinsonian phenotypes in MPTP- and 6-OHDA-induced PD mouse models by in vivo direct lineage reprogramming using
the EMF-induced magnetized AuNPs system. a) A schematic diagram of in vivo experiment. b) DA measurement of iDA neurons in the striatum of
6-OHDA-lesioned mice and EMF-AuNPs-treated 6-OHDA-lesioned (top). Spontaneous postsynaptic currents of GFP+ in vivo converted iDA neurons
after EMF-treating (bottom). Reproduced with permission.[206] Copyright 2017, Springer Nature. c) The current of TENG driven by human walking steps.
d) The nucleus (blue) and neural-specific antibodies Tuj1 (red) and GFAP (green) of cells with TENG electrostimulation for 21 d on the rGO−PEDOT
microfiber. Reproduced with permission.[119b] Copyright 2016, American Chemical Society. e) Schematic illustration of a micromotor to induce the dif-
ferentiation of the targeted neural stem-like cell. f) Ca2+ imaging of target PC12 cell stimulated by the S. platensis@Fe3O4@tBTO with ultrasound for 50 s.
g) Fluorescence image of differentiated PC12 cells stimulated by S. platensis@Fe3O4@tBTO under ultrasound (target cell in red arrow). Reproduced
with permission.[228] Copyright 2020, Wiley-VCH.
With rational designed scaffolds to support cells and rebuild BTO nanoparticles,[183,225] and boron nitride nanotubes
tissue structures, safe and convenient approach of electrostim- (BNNTs).[226] Under ultrasound stimulation, the generated piez-
ulation is equally crucial for potential clinical translation. Our opotential from both BTO nanoparticles on cytomembrane and
group designed a self-powered wearable TENG that can gen- piezoelectric polymer scaffolds attached to cells can stimulate
erate a stable output of 30 µA driven by human walking steps neuron-like cells or promote neuronal differentiation of stem
for electrostimulation (Figure 7c).[119b] Delivery of this electrical cells in vitro.[183,225] For in vivo applications, soft and flexible
signal through rGO-PEDOT hybrid microfibers can induce piezoelectric polymer (e.g., 3D PVDF-based scaffolds) as NGCs
MSCs differentiation into neuron-like cells (Figure 7d). exhibited significant electrophysiological, morphological and
Specifically, piezoelectric biomaterials can be employed as functional nerve restoration through electromechanical interac-
both scaffold and electrical stimulation source, realizing nonin- tions under cell traction.[227] In addition, ME composite mate-
vasive neuronal stimulation without requiring additional wires rials, such as P(VDF-TrFE)/CFO,[156a] GelMA/CFO@ BTO,[11]
and electrodes.[9c,223] Several kinds of piezoelectric biomaterials Streptomyces platensis@Fe3O4@BTO,[228] were designed for
have been used for neuronal differentiation and nerve regen- precise neural stem-like cell stimulation and neuronal differen-
eration, such as PVDF and its copolymer (P(VDF-TrFE)),[148,224] tiation. ME materials can generate electricity by manipulation
of magnetic field based on magnetostriction/magnetomotion osteogenesis. Especially, graphene was compounded with cal-
and piezoelectric effect. For example, Liu et al.[228] sequentially cium phosphates (e.g., HAp and β-tricalcium phosphate), inte-
coated Fe3O4 and BTO nanoparticles onto S. platensis to obtain grating good conductive of the former and osteoconductivity of
a helical-shaped biohybrid micromotor. Owing to the mag- the later.[242] The possible reasons for promotion of osteogenic
netism of Fe3O4, this micromotor can autonomously move to a differentiation are the π–π stacking interactions between the
target PC12 cell under the guidance of a low-intensity rotating basal plane of graphene-based materials and aromatic rings in
magnetic field. Then, in situ piezopotential of BTO was gen- the osteogenic inducer molecules,[241c] thus increasing the con-
erated by an ultrasound stimulation to induce intracellular centration of osteogenic inducer at the scaffold surface. Addi-
Ca2+ transients and neuronal differentiation of the target cells tionally, the abundant functional groups in GO facilitate the
(Figure 7e–g). Then, the cells were treated with different inhibi- adsorption and hydrogen bonding of proteins[243] and calcium
tors to investigate the potential mechanisms, and found that deposition/biomineralization.[241d]
the activation of Ca2+ channels may play a crucial role in the Currently, the results for CNTs in bone regeneration is con-
piezoelectricity-dependent differentiation of neural stem-like troversial. In one study, CNTs promoted osteogenic differentia-
cells. Dong et al.[11] fabricated helical microswimmers of GelMA tion of MSCs and ectopic bone formation in vivo.[217a] However,
hydrogel modified with CFO@BTO core–shell ME nanoparti- it has also been reported that carboxylated CNTs had no signifi-
cles, and utilized magnetic fields for both actuating the micro- cant effect on adipogenesis, osteogenesis and chondrogenesis
swimmer and triggering piezopotential of BTO. The rotating of human MSC.[244] And a contradictory result was reported that
magnetic fields actuated microswimmers rotating around their carboxylated CNT inhibited proliferation, osteogenic differen-
long axis, and generating a translational motion. Also, alter- tiation, and adipogenic differentiation of mouse MSCs.[245] It is
nating magnetic fields caused magnetostriction of CFO core, deduced that their difference in size, concentrations, and sur-
which was then exerted on the BFO shell to induce transient face oxygen contents and stem cell source may responsible for
change of its surface charges, thus promoting cell differentia- the discrepant results.
tion. Without additional mechanical energy input, mechanical Conductive polymers show great potential in bone regen-
stress from cell traction could direct impose on and induce eration due to their responsivity of electrical signal.[9b] Several
surface piezopotential of PVDF.[162,224a] With combination of studies demonstrated that conductive polymers, including
aligned nanoscaled stripe array structure, it could manipulate porous PEDOT:PSS,[246] PEDOT/PCL,[247] PANi/PLA nanofi-
neuron-like differentiation of rbMSCs. brous scaffolds,[248] and PHB-PANi,[249] could induce osteogenic
differentiation of stem cells and bone regeneration, some-
times with an external electrical stimulation.[10a,242d,250] Notably,
4.2. Bone Tissue Engineering postoperative inflammation might lead to high ROS level for
1–2 weeks,[251] which not only is harmful to cells, but also
Since primary bone cells are not electrically excitable,[5a] the inhibits osteogenesis.[252] The ability of conductive polymers to
design of electroactive biomaterials for bone tissue engineering scavenge and control ROS[253] also promotes bone regeneration
is mainly inspired by the piezoelectric features of bone tis- during inflammation in the initial stage of bone regeneration.
sues.[229] As aforementioned, bone could be considered as a nat- Scaffolds and growth factors are two critical factors affecting
ural piezoelectric composite, mainly composed of piezoelectric bone regeneration in bone tissue engineering, while wide appli-
collagen matrix and HAp crystals. Streaming potential is the cation of growth factors is limited by their poor stability.[254]
primary drive for strain-generated potential in wet bone.[230] Cui et al.[255] constructed a nonviral plasmid vector (phBMP-4)
Surface electric potential caused by mechanical bone strain can that can control expression of human bone morphogenetic
accumulate charged macromolecules, inducing conformational protein-4 (hBMP-4) under the trigger of doxycycline (Dox)
changes of adsorbed proteins[231] and facilitating apatite depo- (Figure 8a). This vector was controlled released from an electro-
sition from Ca2+ and PO43− ions,[232] thereby promoting bone active triblock copolymer of PLA-block-aniline pentamer-block-
growth and remodeling. Both OBs and osteoclasts play an irre- PLA (PLA-AP) with poly(lactic-co-glycolic acid) (PLGA)/HA.
placeable role in bone repair process. OBs are responsible for the Electrostimulation (500 mV, 100 Hz, and 50% duty cycle)
formation and organization of bone ECM and subsequent min- caused movement and release of the charged gene carrier com-
eralization.[233] A proportion of OBs are trapped as osteocytes in plex and thus resulting in an acceleration of phBMP-4 release
the lacunae of the bone matrix, which are mainly responsible for (Figure 8b). This multifunctional scaffold enhanced cell prolif-
intercellular communication.[234] Osteoclasts are polarized cells eration and osteogenesis differentiation in vitro, and as well as
with a ruffled border region of cell membrane. Osteoclastic bone accelerated bone repair of rabbit radial defect in vivo.
resorption involves mineral dissolution and followed degradation Inspired by the bone piezoelectric features, design of
of the organic phase.[235] In bone regeneration, electric signal is piezoelectric biomaterials is a promising biomimetic strategy
considered as an important cue for promoting osteoblast prolif- for bone regeneration. Piezoelectric biomaterials, such as
eration[236] and osteodifferentiation of stem cells.[237] Thus, con- PVDF,[168,256] P(VDF-TrFE),[107c,149] BN nanotube/P(VDF-
ductive bone grafts are desired for promoting bone regeneration. TrFE),[257] PLLA,[258] PDA@ BTO/P(VDF-TrFE),[259] HA/
In addition, biodegradability, high mechanical strength and oste- PLLA,[260] BTO/HAp,[261] BiFeO3/SrTiO3,[192] PVDF/CFO,[262]
ointegration are beneficial for bone graft materials.[238] K0.5Na0.5NbO3 (KNN)[263] have been used for promoting cell
Graphene containing micro-/nanostructured scaffolds proliferation, osteogenic differentiation, HAp deposition, and
including film,[239] 3D foam,[240] hydrogel,[241] have been bone formation. Ultrasound,[264] magnetism-driven magneto-
reported to be able to promote osteogenic differentiation and striction,[262] and cell traction forces[168] have been employed to
Figure 8. a) A smart electroactive tissue engineering scaffold for efficient bone repair. b) Gene release profiles from different scaffolds with or without
electrostimulation (ES). Reproduced with permission.[255] Copyright 2020, Elsevier Ltd. c) Illustration of biomimetic electric microenvironment created
by BTO NP/P(VDF-TrFE) composite membranes for bone defect repair. d) Representative micro-CT images and sagittal view images of critical-sized
rat calvarial full-thickness defects at 12 weeks postimplantation. Blue arrows denote the residual membrane materials. Yellow arrows denote the regen-
erated new bone. Yellow dotted lines denote the boundary between nascent bone and host bone. Reproduced with permission.[259] Copyright 2016,
American Chemical Society. e) Schematic diagram of the formation process of minerals on the PVDF scaffold. f) The material showed a self-adapting
mechanical property by increasing modulus under dynamic loading. g) Images of the PVDF scaffold after submerged in SBF showing the formation of
minerals, scale bar is 10 µm. Reproduced with permission.[265] Copyright 2020, Wiley-VCH.
trigger the deformation of piezoelectric biomaterials for gen- the positive and negative charges caused more electronegative
eration of surface piezopotential, while some reports did not fibronectin (isoelectric point of pH 4.8–6.4) to cluster on the
clearly indicate the mechanical force source that caused their nanofilm. Thus, there are more cellular binding sites to facili-
deformation.[107c,263] For example, after corona polarization tate cell adhesion and migration, thereby triggering implant
treatment of 5 vol % PDA@BTO incorporated P(VDF-TrFE), osseointegration and bone healing. Both of the two opposite
the polarized film had a surface potential of −76.8 mV, which electric potentials could promote bone repair, which might be
was in the range of natural endogenous biopotential.[259] This related to the different structures of the bone defect in animals.
film was more conducive to promoting osteogenic differentia- Moreover, the negative potential film utilized galvanotaxis of
tion in vitro than the P(VDF-TrFE) with a surface potential of MSCs to recruit cells; while the positive potential film attracted
−42 mV, and achieved a rapid repair of bone defects because electronegative fibronectin to promote cell adhesion.
of sustainable maintenance of the electric microenvironment Inspired by the natural bone mineralization process, a
in vivo (Figure 8c,d). Oppositely, An electropositive BiFeO3 piezoelectric material that can respond to external mechan-
nanofilm (BFO+, +75 mV) was designed, which can establish ical stimulation was designed to induce mineral deposition
a built-in EF between the BFO+ nanofilm and electronegative (Figure 8e).[265] After immersing PVDF films (d31 ≈ 23 pC N−1)
bone defect walls (−52 to −87 mV).[192] The attraction between in a simulated body fluid (SBF) for one week, HAp minerals
were preferentially deposited onto the negatively charged sur- implantation is indispensable for cardiac tissue engineering.
face, which was consistent with the natural endogenous biolog- Feiner et al.[271] integrated gold electrode-based device with
ical potential. This phenomenon indicates that the biomimetic electrospun fibers as hybrid cardiac patches for online moni-
electrical signals are more conducive to tissue repair. And toring electrical activities of cardiac tissues. Besides, according
an external mechanical loading can induce higher electrical to physiological needs, the system can manipulate and reverse
charges, thereby enhancing mineral growth rate. Because tissue contraction and release soluble biofactors by electrostim-
further biomineralization of the scaffold could increase its ulation for regulation of cardiac function (Figure 9a).
mechanical property, this system can dynamically adjust its Conductive polymer containing scaffolds have been
own mechanical stiffness depending on the external loading fabricated to deliver electrical pulses to increase synchro-
(Figure 8f,g). This process facilitated the development of smart nized beating of CMs, enhancing cell–cell communica-
coatings on bone implants to alleviate problems brought by tion[272] and cardiomyogenic differentiation,[273] such as
mechanical mismatch. PANi/PLGA nanofibrous meshes,[269a] collagen/hyaluronic
Besides osteogenic differentiation, PVDF,[266] acid/PANi,[10c] PPy film,[274] hyperbranched poly(amino ester)
P(VDF-TrFE), [149] and BTO/PHBV [267] have also been used (HPAE)–Py/gelatin hydrogels,[275] PPy-chitosan hydrogel,[270]
to promote cartilage regeneration. Damaraju et al. reported poly(thiophene-3-acetic acid) (PTAA)/ethacrylated aminated
that the fate of MSC was determined by piezoelectricity gelatin hybrid hydrogel network,[273] and collagen/alginate/
of the scaffold, where P(VDF-TrFE) with streaming poten- PEDOT:PSS.[60a] In a composite DA/methacrylated-gelatin/
tial of 25.2 ± 2.5 µV promoted chondrogenesis and annealed poly(ethylene glycol) diacrylate (PEGDA) cryogel incorporating
P(VDF-TrFE) (61.1 ± 1.5 µV) promoted osteogenesis.[149] PPy NPs, the PPy NPs can be transferred from donor patch to
Interestingly, converse piezoelectric effect of piezoelectric the infarcted tissue, stimulating the immigration of neomyo-
materials is also utilized to induces bone formation in vivo. A cardium to the infarcted area and eventually yield an improve-
Li-battery powered piezoelectric PVDF actuator was designed ment in cardiac function.[276] Recently, injectable biomaterials
to mechanically stimulate bone.[268] After implanting actuators have shown great potential in cardiac tissue engineering
in sheep femur and tibia osteotomy cuts for one-month, the by preventing ventricular dilation, improving conduction
rates of bone deposition and new bone generation were signifi- velocity, and enhancing angiogenesis. Song et al.[277] developed
cantly higher under a sinusoidal AC stimulation (5 V, at 1 Hz an injectable DA-coated PPy/poly(glycolic acid) (PGA) spring
and 3 Hz for 15 min) compared to the static controls. These (Figure 9b). After injection, tangled coils formed an elastically
progresses suggest that both piezoelectric effect and converse conductive 3D network, which can not only modulate car-
piezoelectric effect of piezoelectric biomaterials could be used diac function, but also measure the contractile force of CMs
to effectively promote bone growth and remodeling. (Figure 9c–e).
CNT-incorporated hydrogels as scaffolds can promote car-
diac cell adhesion and maturation, and improve cell electrical
4.3. Cardiac Tissue Engineering and Others coupling.[278] SWCNTs incorporated injectable thermosensitive
hydrogel was applied for cardiac tissue engineering with the
Native myocardium is an electroactive tissue (1.6 × 10−3 S cm−1 ability of promoting cardiomyogenic differentiation of brown
(longitudinally) to 5 × 10−5 S cm−1 (transversally)) capable of ADSCs.[279] Shin et al. constructed a batoid-fish-shaped pseudo-
transferring electrical signals and allowing heart to beat.[191] 3D cardiac tissue,[15a] which consisted of two micropatterned
For global heart function restore, it is necessary to restore the hydrogel layers: a PEG hydrogel substrate as a mechanically
impulse propagation. Electrical connection of the isolated CMs stable structure and a GelMA layer embedded with CNTs as
to an intact tissue could synchronize contraction and restore a cell attachment substrate (Figure 9f). This biomimetic scaf-
ventricular function. In cardiac tissue engineering especially fold facilitated high myofiber organization and self-actuating
for repairing myocardial tissues in MI, electrically conductive motions aligned with the cell contraction (Figure 9g). In addi-
biomaterials have positive contribution in electrical signal prop- tion, applying electrostimulation (0.5–6 V, 0.5–2.0 Hz) through
agation, enhancement in cardiomyocyte function, increase of the embedded Au microelectrodes can further control the
cell-cell interaction for coordinating the beatings of the CMs, beating behavior of this pseudo-3D cardiac tissue (Figure 9h,i).
and cardiomyocyte commitment of stem cells. The underling Graphene was reported to be able to promote cardiomyo-
molecular mechanism mainly includes the stimulation of gap genic differentiation of ESCs[280] and MSCs.[281] CMs showed
junction protein Connexin 43 expression[269] and Ca2+ signal stronger contractility and faster spontaneous beating rate on
conduction.[270] In addition to fundamental requirement of bio- rGO-incorporated GelMA.[282] Interestingly, graphene flake was
compatibility and biodegradability, morphology, electrical con- incorporated into a stem cell spheroid for improving cardiac
ductivity, and elasticity matching with cardiac tissue (≈10 kPa) function[283] and cardiomyogenic differentiation.[284] Lee et al.[285]
are favorable for the cardiac scaffolds or patches to mimic the reported that compared to low conductive GO-GelMA, electri-
native ECM.[75,270] For instance, gold nanowires incorporated in cally conductive CNT- and rGO- GelMA scaffolds were more
alginate scaffold bridged the electrically resistant pore walls of conducive to promote desirable morphology of CMs and ele-
alginate and improved electrical communication between adja- vated expression of functional cardiac markers. More impor-
cent cardiac cells.[67b] AuNPs impregnated thiol-2-hydroxyethyl tantly, the biohybrids of collagen and pristine graphene with
methacrylate have tunable conductivity and elasticity, facilitating stiffness and electrical conductivity matching the native cardiac
cardiomyocyte function.[269b] In vitro assessment of the engi- tissue significantly increased metabolic activity of CMs and
neered-tissue performance and control of their function after cross-striated sarcomeric structures. And electrostimulation
Figure 9. a) Schematics of the microelectronic cardiac patch integrated with sensor of tissue electrical activity, electrical stimulation and controlled
release of biomolecules within the tissue microenvironment. Reproduced with permission.[271] Copyright 2016, Springer Nature. b) SEM image and
photograph of the DOPA-coated Ppy/PGA spring scaffold. Scale bars in a1: 0.5 cm. c) The α-actinin (green) and cx43 (red) protein levels in CMs
on spring scaffold at day 7 detected by immunofluorescent staining. d) Myocardium (red) and fibrous tissues (blue) in heart sections after 4 weeks.
The springs could be observed in the scar zone (green arrows). e) The mechanism interpretation of conductive spring for monitoring cell contractile
force. Reproduced with permission.[277] Copyright 2019, American Chemical Society. f ) Schematic illustration of the layer-by-layer structure of the
construct. g) Photographs of the freestanding bioinspired soft robot cultured for 5 d taken at 1.6, 1.8, and 2.5 s. The blue and green line represents
the longitudinal axis and transverse axis displacement, respectively. h) Beating response of the bioinspired soft robot when stimulated with an AC
external electrical field at 1 V cm−1 and with various frequencies from 0.5 to 2.0 Hz. i) Excitation threshold voltage required at different frequencies
(0.5, 1.0, and 2.0 Hz) when electrical stimulation was applied via the embedded Au microelectrodes. Reproduced with permission.[15a] Copyright
2018, Wiley-VCH.
that was consistent with the beating frequency of CMs preventing deterioration.[130] Microscopically, the contraction of
(2.5 V cm−1 monophasic stimulation at 1 Hz) based on biohy- CMs also can be utilized to trigger the deformation of piezo-
brid collagen/graphene composite can enhance the alignment electric materials, thereby inducing piezopotential for in situ
and maturation of ESC-derived CMs.[286] electrostimulation of the cells. Cardiomyocyte contraction force
In body, heartbeat is a spontaneous biomechanical force that (20–140 nN)[288] was significantly higher than the cell traction
has been collected by TENG or PENG to generate electrical force (1–10 nN).[160] Liu et al. demonstrated a contractile cardio-
energy as a pulse sensor[118,287] or power to drive implanted myocyte-driven PVDF piezoelectric nanofiber as a biogenerator,
cardiac pacemaker.[130] Recently, Ouyang et al. designed a self- which generated an output of 200 mV (open-circuit voltage) and
powered symbiotic pacemaker, which integrated energy har- 45 nA (short-circuit current).[289] Piezoelectric PLGA/BTO,[290]
vesting (TENG) and storage as well as cardiac pacing together. electrospun P(VDF-TrFE),[161a,293] PCL/P(VDF-TrFE),[292] ZnO
The energy harvested from each cardiac motion cycle of pig nanorods/PDMS[293] have also been explored for promoting CMs
reached 0.495 µJ, successfully correcting sinus arrhythmia and proliferation, alignment, contraction, cell-cell communication,
and myocardial differentiation. Not only that, piezoelectric scaf- stimulation time duration) that match the electrophysiological
folds can also monitor contractile activity of CMs and heart characteristics of target tissue. For specific cells, tissues or
based on the voltage transients, simultaneously.[161] organs, although the adjustment range of electrostimulation
Similarly, electroactive biomaterials (both conductive and parameter is relatively narrow, small changes might cause dif-
piezoelectric materials) have been employed in skeletal muscle ferential cell/tissue responses. Due to the complexity of the
tissue regeneration for promoting myogenic differentiation,[294] electrophysiological environment of cells and tissues, it is vital
myotube formation, maturation,[295] and myotube fusion.[296] to clarify the interaction between the electron-based electrical
And extra AC electrostimulation can cause calcium transients stimulation of conductive/piezoelectric materials and the ion-
and regulate myotube contraction.[295–297] For other applica- based electrical activity of living organisms. And the avail-
tions, electroactive biomaterials were also used for the main- able voltage reaching cell membrane is not only determined
tenance of undifferentiated state of multi-potent cells instead by the EF and electrodes, but also related to the conductivity
of using feeder cells or ECM,[298] as well as reprogramming of of the biomaterials, the media and the electrical property of
somatic cells into iPSCs.[299] cytomembrane.[164] In addition, the interaction and feedback
between cells/tissues and electroactive biomaterials, as well as
exact mechanisms and intracellular signaling pathways are still
5. Conclusions and Outlook obscure. It is urgent to reveal the interplay between cells/tissues
and biomaterials, thereby identifying the universal design prin-
Electroactive biomaterials and their delivered electrostimulation ciples of electroactive biomaterials and electrostimulation at
have made impressive progresses in regenerative medicine, tissular, cellular, molecular, and genetic levels. Moreover, con-
from promoting cell migration, proliferation and differentia- venience and patient compliance for electrostimulation should
tion, to modulating nerve conduction, muscle contraction, and be kept in mind for possible clinic translation. With rational
tissue regeneration. Currently, there are still great challenges design and full consideration of biocompatibility, wearable and
and broad space for optimal integration of biomaterials, donor implantable energy harvesters that can harvest power from
cells and host microenvironment, finally translating the labora- organisms or surrounding environment has great potential to
tory findings to clinic applications. impose electrostimulation via electroactive biomaterials.
An in depth understanding of cell dynamic microenviron- For both in vitro and in vivo applications, it is important to
ment is conducive to specifying the criteria of biomaterials real-time feedback the cell activities and tissue recovery so as to
design. Throughout human life, cell and tissue microenviron- optimize cell dynamic microenvironment and external stimula-
ments change at different periods, especially during organ tion. Electroactive materials have great potential in integration
development and tissue repair. For tissue regeneration, determi- of electrostimulation and monitor of physiological signal. For
nation of favorable changes in tissue repair, and biomimetic con- example, conductive biomaterials could serve as both electrodes
struction of those changing microenvironment is important for to realize the input of external electrostimulation and the output
adapting long-term repair process. Stimuli-responsive biomate- of electrical transients of electroactive cells and tissues, simul-
rials are considered as potential 4D tissue engineering scaffolds, taneously.[271,300] Based on their electromechanical coupling
which can exhibit specific characteristic changes when triggered properties, piezoelectric biomaterials also can be employed as
by endogenous or exogenous environmental variations (such sensors to monitor mechanical activity of motile cells/tissues,
as temperature, pH, electrical potential, light, mechanical force such as myocardial contraction and heartbeats.
or magnetic field). Moreover, it is worth noting that cells them- In the design of biomaterial systems, coordination of elec-
selves are also dynamic. Changes in cell membrane potential, tronic properties with other biophysical and biological cues
tissue electrophysiological environment, cell adhesion, migra- are very important. Multifunctional integration (e.g., chemical
tion and tissue mechanical activities are always existing. If the composition, morphology, mechanical stiffness, biological fac-
endogenous changes can be utilized to stimulate biomaterials tors, external stimuli, sensing and dynamic response) should
and induce their favorable changes, it is possible to realize cell- be considered. In bodies, immune system has a crucial role
regulated dynamic biomaterials to imitate cell microenviron- in clean up damaged tissues and recruit endogenous cells for
ment without any external stimuli. For electrostimulation, in modulation of innate regeneration. It is attractive to design
this respect, cell/tissue traction activated piezoelectric effect from biomaterials with ability to regulate immune response toward
rational designed piezoelectric biomaterials is a good example. tissue regeneration. It is still an unknown and open field that if
The biocompatibility of biomaterials should be paid sufficient electro-activity of biomaterials would interact with the immune
attention, especially the long-term biosafety and compatibility system and influence immune response. Totally, with current
with the host tissues. Now, the results for some nanomaterials progresses and huge space for development, electroactive bio-
are still controversial (e.g., CNTs).[79d] To analyze the safety and materials show tremendous potential for tissue regeneration.
biological effects of biomaterials, high-throughput assay is
expected to realize a multifactorial evaluation and selection in
parallel.[4a] The influence and metabolism of degradation prod- Acknowledgements
ucts of electroactive materials should also be considered.
The work was supported by the National Key R&D project from Minister
Excitatory transmission in nerve and heart system is a com-
of Science and Technology, China (2016YFA0202703), the National
plex process, which can happen within a few ms (nerve) to 0.1 s Nature Science Foundation (No. 82072065, 81471784), the Nature
(heart). It is of great significance to optimize electrostimula- Science Foundation of Beijing (2172058), and the National Youth Talent
tion conditions (including voltage, frequency, pulse width and Support Program.
Conflict of Interest A. Khademhosseini, Adv. Mater. 2018, 30, 1704189; b) S. R. Shin,

C. Shin, A. Memic, S. Shadmehr, M. Miscuglio, H. Y. Jung,
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Zhirong Liu received her B.S. degree from China University of Geosciences in 2016. Currently she is
a Ph.D candidate with Prof. Linlin Li at Beijing Institute of Nanoenergy and Nanosystem, Chinese
Academy of Science. Her research mainly focuses on bioactive nanomaterials/nanodevices for
biomedical applications in drug delivery, stem cell manipulation, and tissue regeneration.
Xingyi Wan received her B.S. degree in bioengineering from Wuhan University of Science and
Technology, China in 2018. Now she is a Ph.D. candidate with Prof. Linlin Li at Beijing Institute of
Nanoenergy and Nanosystem, Chinese Academy of Science. Her current research focuses on the
manipulation of cell adhesion on electroactive biomaterials and synthesis of smart materials for
cell stimulation and further biomedical applications.
Zhong Lin Wang received his Ph.D. from Arizona State University in physics. He now is the
hightower chair in materials science and engineering, regents’ professor, engineering distinguished
professor and director, Center for Nanostructure Characterization, at Georgia Tech. His discoveries
and breakthroughs in developing nanogenerators established the principle and technological road
map for harvesting mechanical energy from environment and biological systems for powering a
personal electronics. He coined and pioneered the field of piezotronics and piezophototronics by
introducing piezoelectric potential gated charge transport process in fabricating new electronic and
optoelectronic devices.
Linlin Li received her M.S. degree in biochemistry and molecular biology from Beijing Normal
University in 2005, and Ph.D. degree in physical chemistry from Technical Institute of Physics and
Chemistry, Chinese Academy of Sciences in 2008. Currently, she is a professor at Beijing Institute
of Nanoenergy and Nanosystems, CAS. Her research interests include biomedical application of
biomaterials and devices (nanogenerator and piezotronic device) in cancer therapy, biosensing,
and tissue regeneration.

Electroactive Biomaterials and Systems For Cell Fate Determination and Tissue Regeneration: Design and Applications

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Electroactive Biomaterials and Systems for Cell Fate

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Figure 1. Endogenous bioelectricity (right) and piezoelectricity (left).

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Figure 2. Typical conductive biomaterials used in the field of tissue engineering.

Adv. Mater. 2021, 2007429 2007429 (8 of 33) © 2021 Wiley-VCH GmbH

Adv. Mater. 2021, 2007429 2007429 (9 of 33) © 2021 Wiley-VCH GmbH

Conflict of Interest A. Khademhosseini, Adv. Mater. 2018, 30, 1704189; b) S. R. Shin,

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