Exogenous electrical stimulation in soft tissue wounds healing: mechanism and devices

2.1. Ion channels, transporters, and EF-sensitive membrane receptors in EF

When cells are exposed to an EF, the applied field alters protein conformation by influencing the axial dipole moment of proteins^[16]. This activation mechanism targets voltage-sensitive proteins, including ion channels, transporters, and EF-sensitive receptors.

Among ion channels, Ca²⁺ and Na⁺ channels are the most extensively studied. In cells expressing voltage-gated Ca²⁺ channels, the EF induces channel opening near the cathode, facilitating ion influx, elevating intracellular ion concentration and pH, and ultimately leading to membrane polarization^[17]. Additionally, transporters such as Na⁺/K⁺-ATPase and Na⁺/H⁺ exchanger 3 are locally activated, triggering downstream intracellular signaling pathways. These processes are closely associated with the directed migration of certain cell types in response to EFs^[18].

The EGF receptor is an EF-sensitive receptor that undergoes upregulation and asymmetric redistribution in response to both endogenous and exogenous EFs. Studies have demonstrated that the downstream epidermal growth factor (EGF) receptor–mitogen-activated protein kinase (MAPK) signaling pathway plays a critical role in EF-directed cell migration. Similarly, the acetylcholine receptor (AChR) redistributes under EF stimulation^[19], and its activation facilitates cytoskeletal reorganization, cell polarization, and subsequent electrotactic responses^[20]. Additionally, N-methyl-D-aspartate receptors (NMDARs), which are ligand-gated Ca²⁺-permeable ion channels, are activated by EF stimulation. This activation mediates the NMDAR/Ras-related C3 botulinum toxin substrate 1 (Rac1)/actin signaling pathway, ultimately promoting cell migration^[21] (Figure 2).

Furthermore, electrical stimulation, depending on its voltage intensity and frequency, may also have effects on different plasma membranes, inducing reversible pore formation. These reversible pores, commonly known as electroporation, provide a mechanism for the delivery of biomolecules, including therapeutic drugs. The ability of symmetric alternating current EFs to guide cell migration in a frequency-dependent manner further suggests that nonprotein components of the cell membrane may play a critical role in modulating cellular behavior^[22]. Moreover, studies have demonstrated that lipid rafts respond to EFs, promoting the polarization of membrane proteins and initiating intracellular signaling cascades^[23].

2.2. Signaling pathway in electric field

EFs activate various intracellular signaling pathways by modulating ion channels, transporters, and EF-sensitive membrane receptors, which subsequently influence cellular activity^[24]. Notably, the phosphatase and tensin homolog (PTEN)-phosphoinositide 3-kinase (PI3K) and MAPK pathways have been identified as critical regulators of these processes. Specifically, the PI3K–protein kinase B (Akt) pathway is a central regulator of EF-directed cell migration, while the MAPK pathway plays a significant role in modulating other cellular behaviors.

2.3. Growth factors and cytokines in electric field

Following the initiation of an EF-induced intracellular signaling cascade, the resulting effects propagate through the surrounding tissue via growth factors and cytokines, establishing a cell-to-cell regulatory network. This phenomenon is particularly pronounced in immune cells, such as macrophages. Exogenous EFs modulate macrophage phenotypes, influence their polarization, and subsequently reshape the immune microenvironment, thereby impacting the overall wound healing process. Furthermore, exogenous electrical stimulation induces fibroblasts to secrete fibroblast growth factor 2 and enhances VEGF protein synthesis in human umbilical vein endothelial cells (HUVECs). This activation of the MAPK/ERK signaling pathway promotes HUVEC migration, invasion, and angiogenesis^[38]. In keratinocytes, exogenous electrical stimulation (100–200 mV/mm, 6 hours) increases EGF and VEGF secretion, while reducing interleukin-6 (IL-6) and interleukin-8 (IL-8) levels. These changes indirectly influence physiological processes, such as blood vessel formation, ultimately facilitating wound healing^[39].

In summary, the molecular mechanism of EFs in wound healing is a multifaceted process initiated by the perturbation of voltage-sensitive proteins in the cell membrane. This activation of ion channels, transporters, and receptors triggers well-defined intracellular signaling cascades (e.g., MAPK, PI3K, Rac1) that govern essential cellular functions, most notably electrotaxis and proliferation. These cellular-level events culminate in significant physiological benefits, including enhanced angiogenesis, improved blood perfusion, and modulation of the immune response, which collectively accelerate wound closure.

3.1. Hemostasis and inflammation

Following injury, vascular rupture exposes subendothelial collagen to platelets, triggering platelet aggregation and initiating the intrinsic coagulation cascade. The resulting blood clots, along with locally released cytokines and growth factors, promote cell chemotaxis and tissue cell adhesion during the subsequent inflammatory phase. Inflammation is a critical stage of wound healing, characterized by a vascular-centric response. Upon injury, tissue-resident sentinel cells release inflammatory mediators, activating vascular responses and recruiting inflammatory cells to clear tissue debris and pathogens. This process is gradually replaced by tissue repair^[41]. Notably, macrophage activation is essential for transitioning to the proliferative phase, as it also mediates angiogenesis^[42].

The EF plays a pivotal role in modulating immune cell activity during the inflammatory process. In the initial phase of inflammation, endogenous EFs facilitate the directional migration of macrophages, lymphocytes, and neutrophils to the wound site. Notably, mast cells, which are often implicated in skin pathologies, exhibit a significant reduction in population under electrical stimulation during the acute inflammatory phase^[43]. Furthermore, macrophages demonstrate an EF intensity-dependent anodal migration, with enhanced phagocytic activity under EF exposure, thereby accelerating the clearance of pathogens and necrotic tissue, and promoting soft tissue regeneration^[44]. During the later stages of inflammation, electrical stimulation has been shown to attenuate immune cell infiltration and downregulate pro-inflammatory cytokine secretion, facilitating inflammation resolution. Of particular significance is the role of macrophage polarization in chronic inflammation. Recent studies indicate that electrical stimulation can induce macrophage polarization towards the M2 phenotype, thereby shifting the wound microenvironment from an inflammatory to a reparative state, effectively preventing chronic inflammation^[45].

Simultaneously, the EF enhances vascular responsiveness, augmenting blood flow to the wound site, facilitates the migration of inflammatory cells and the transport of essential nutrients, thereby accelerating wound healing. Additionally, studies have demonstrated that electrical stimulation, particularly through the application of symmetrical biphasic pulsed currents, significantly attenuates posttraumatic edema^[46,47].

3.2. Proliferation

During the proliferation phase, epithelial cells, fibroblasts, and endothelial cells play pivotal roles in tissue repair^[41]. Epithelial cells at the wound margin initiate proliferation and extend projections to re-establish the protective barrier, thereby preventing fluid loss and bacterial infiltration. Activated platelets and macrophages secrete EGF and transforming growth factor-beta, which promote epithelial cell proliferation and chemotaxis^[48]. Concurrently, VEGF, secreted by keratinocytes, macrophages, fibroblasts, platelets, and endothelial cells at the wound periphery, drives the formation of new capillaries. Fibroblasts migrate from adjacent tissues to the wound site, where they synthesize a provisional extracellular matrix comprising type 3 collagen, glycosaminoglycans, and fibronectin. Platelet-derived growth factor and EGF, released by platelets and macrophages, serve as key signaling molecules that stimulate fibroblast proliferation and activity.

The EF facilitates directional cell migration by establishing a stable voltage gradient at the wound site, which provides spatial guidance for the movement of surrounding cells. This process is primarily regulated by the PI3K–PTEN signaling pathway. Additionally, extensive research has demonstrated that exogenous electrical stimulation enhances cell proliferation, thereby accelerating wound healing. Specifically, electrical stimulation activates the TGF-β1/ERK/nuclear factor kappa-light-chain-enhancer of activated B-cell signaling pathway, inducing fibroblast proliferation and upregulating α-smooth muscle actin expression, which drives the differentiation of fibroblasts into contractile myofibroblasts^[49,50]. Myofibroblasts play a critical role in wound closure and extracellular matrix deposition. In vitro studies have further revealed that electrical stimulation at voltages exceeding 3 V/cm significantly increases the expression of fibroblast-derived collagen, elastin, and MMP-1^[51]. Collagen and elastin are essential components of the extracellular matrix, while MMP-1 facilitates matrix degradation, enhances cell migration, and participates in tissue remodeling, collectively promoting soft tissue regeneration. Notably, the effects are more pronounced with short voltage pulses. Moreover, electrical stimulation promotes the migration, invasion, and proliferation of vascular endothelial cells, while stimulating the secretion of key growth factors such as VEGF and fibroblast growth factor 2, which drive angiogenesis and provide essential blood supply for wound healing^[52].

3.3. Maturation

The maturation stage is characterized by the deposition of collagen, which organizes into a well-structured network within the wound. The strength of the resulting scar, a key outcome of soft tissue healing, is determined by the rate, quality, and total quantity of extracellular matrix deposition^[41]. Excessive collagen synthesis, however, can lead to the formation of hypertrophic scars or keloids.

Over time, the composition of the wound matrix undergoes significant changes. Initially, it is predominantly composed of fibrin, fibronectin, and thrombospondin, which are critical for cell adhesion and migration^[53,54]. As healing progresses, the levels of glycosaminoglycans, proteoglycans, and specific structural proteins increase, providing a foundation for subsequent matrix deposition and remodeling. Eventually, collagen emerges as the primary structural protein in the scar tissue. During wound healing, fibroblasts exhibit adaptive responses to dynamic mechanical loads within the matrix. These responses include migration, matrix proteolysis, and other behaviors that collectively establish isometric tension—a state where internal and external mechanical forces are balanced, preventing cell shortening or elongation.

Existing studies demonstrate that electrical stimulation modulates scar thickness and hardness by influencing collagen deposition within the scar tissue. Research on low-voltage pulsed current applied to diabetic mouse models revealed a positive correlation between electrical stimulation intensity and collagen deposition^[55]. Additionally, electrical stimulation regulates the secretion of various MMPs, thereby impacting the maturation of the extracellular matrix at the wound site^[56].

4.1. Battery

The most intuitive idea may be to use a battery. As an efficient energy storage device, the battery can act as a power source and power a variety of wearable or implantable devices. The conventional battery usually has a larger volume, a lack of flexibility, and a possible toxicity, but with the continuous deepening of research, more new types of batteries continue to emerge^[71]. For wound healing, the primary consideration is excellent biocompatibility. Besides, it needs to adapt to the wound environment as much as possible, ensure sufficient electricity, and avoid interfering with wound healing.

Wu et al. have designed a fluid-activated tubular Mg–Mo battery that can effectively discharge after implanted in the intermuscular space and significantly improve the healing rate of full-thickness skin wounds^[72]. It uses body fluid in the intermuscular space as an electrolyte with higher electrical conductivity, and avoids possible corrosion caused by electrolyte leakage. Moreover, the battery featured a simple structure and good stability, providing continuous discharge for up to 5 days to meet the requirements of wound healing. Xiao et al. also chose body fluids as electrolytes^[73]. The battery was composed of an Mg-wire core, a separator, and an outer layer formed by wrapping carbon yarn, which absorbs the wound exudate, owing to activating the battery. The excessive wound exudate formed an electrolyte layer between the Mg wire (anode) and the carbon yarn (cathode) to facilitate the redox reaction. Kim et al. designed an electricity auto-generating glucose-responsive enzymatic biofuel cell as a skin patch^[74]. It converted ubiquitous biological glucose into electrical energy, and then stimulated angiogenesis, fibroblast functionality, and matrix synthesis (Figure 4A–C). Similarly, Wang et al. devised a capacitive dressing with polypyrrole-wrapped carbon cloth electrodes and a bacterial cellulose hydrogel separator^[75]. This dressing is designed to be antibacterial, so it has greater electrical capacity and rechargeability. The experimental results show that the slow discharge process after the rapid discharge can regulate immunity, promote the formation of capillaries, and collagen deposition at the wound site (Figure 4D, E). This dressing enabled continuous and effective sterilization and promoted wound healing through a safe, low-voltage EF. It offered nonantibiotic physical therapy for infected wounds, demonstrating significant clinical potential in an era where drug-resistant bacteria are increasingly prevalent.

4.2. Piezoelectric generator

Piezoelectric materials can convert mechanical energy into electrical energy. When subjected to an external force, these materials undergo internal polarization, resulting in the generation of opposite charges on their specific surfaces. Researchers have explored various methods to generate voltage or current through piezoelectric materials for wound healing, including external stimuli (e.g., ultrasound) and harnessing mechanical energy from bodily movements. Traditionally, piezoelectric materials are categorized into three groups: inorganic piezoelectric materials, organic piezoelectric materials (including natural and synthetic biopolymers), and piezoelectric composites. Inorganic piezoelectric materials typically exhibit stronger piezoelectric effects, superior long-term stability, and high rigidity. In contrast, organic piezoelectric materials, while demonstrating weaker piezoelectric effects, offer advantages in flexibility and biocompatibility. Piezoelectric composites, designed by combining inorganic and/or organic materials with other components, achieve a balance of flexibility and piezoelectric performance. However, their preparation is more complex, and their performance stability may be compromised.

Piezoelectric ceramics are the most widely utilized inorganic piezoelectric materials^[76]. Their individual grains can be uniformly polarized, generating a potential difference. Its high stiffness restricts its application in wound healing. In contrast, polyvinylidene fluoride (PVDF) stands out as a representative organic piezoelectric material, offering excellent piezoelectric properties, workability, and mechanical strength. The piezoelectric performance of PVDF is significantly influenced by its β-phase content, which can be enhanced by optimizing parameters such as spinning distance, applied voltage, speed, and annealing processes^[77]. Sun et al. developed a PVDF-based self-powered wound dressing integrated with antibiotic release. This dressing not only facilitates wound healing through piezoelectric voltage generation but also enables precise control of hydrophilic drug release by modulating the electrostatic balance between the drug carrier and the drug (Figure 5A, B)^[78]. Fu et al. also combined Poly(vinylidene fluoride-co-trifluoroethylene) (P(VDF-TrFE)), TrFE-based nanogenerator and drug delivery system^[79]. This nanogenerator generated a relatively low EF at rest, and an EF exceeding 625 mV/mm promoting the rapid release of PTEN inhibitor in motion. This on-demand amplified cell electric responsiveness and avoided overinhibition of PTEN (Figure 5C, D). In a distinct approach, Ren et al. utilized cell adhesion tension to create a dynamic force–electrical closed-loop feedback system^[80]. They engineered a piezoelectric dual-network nanofiber dressing incorporating copper/epigallocatechin 3-gallate and PVDF. This design circumvents the temporal limitations of magnetic field- or ultrasound-induced electrical stimulation, synchronizes with cellular physiological states, and mimics the extracellular matrix’s piezoelectric effect to enhance intercellular communication. Experimental results demonstrated that the electrical stimulation generated by this dressing activates calcium-related ion channels and significantly accelerates wound healing (Figure 5E, F). On this dressing surface of, cells further modulated the adaptive electrical stimulation generated by the piezoelectric nanofiber network through their inherent adhesiveness, producing a dynamic mechanoelectric closed-loop feedback signal that mimics the electrical microenvironment of natural physiological conditions. Moreover, it exhibited strong antibacterial and anti-inflammatory capabilities, promoting skin repair through multiple biological pathways.

Composite piezoelectric materials are currently a focal point of research^[81]. Xu et al. developed a repetitive mechanical impact-electrical stimulation system by combining barium titanate with polydimethylsiloxane (PDMS)^[82]. PDMS, known for its excellent biocompatibility and flexibility, ensures continuous and stable contact with damaged skin, overcoming the limitations of barium titanate nanoparticles. Studies indicated that this electrical stimulation reduced inflammation, enhanced angiogenesis, and significantly accelerated wound healing. Wang et al. designed 4-octyl itaconate-coated Li-doped ZnO/Ply(L-lactide) piezoelectric composite microfibers^[83]. The incorporation of Li atoms induces lattice distortion in ZnO, enhancing its piezoelectric properties, while aligned Ply(L-lactide) further amplifies the piezoelectric effect. Electrical stimulation, combined with reactive oxygen species generated by microfibers, restores mitochondrial function. Additionally, the acoustic dynamic effect of Li-doped ZnO achieves a 94.2% bactericidal rate against Staphylococcus aureus. These microfibers facilitate infected wound healing through multiple mechanisms, offering a promising approach for managing infected wounds.

4.3. Triboelectric nanogenerators

Triboelectric nanogenerators (TENGs) operate based on the coupling effect of triboelectricity and electrostatic induction. The triboelectric effect induces the accumulation of positive and negative charges on 2 friction layers, respectively. Subsequently, electrical energy is generated between the electrodes through electrostatic induction. The fundamental structure of TENGs consists of 2 dielectric films with distinct electron gain/loss capabilities, connected by back electrodes. As a self-powered device for wearable electronics, TENG has attracted significant attention due to its high efficiency and wide range of material choices^[84].

The output capacity of TENGs is primarily influenced by the surface potential properties of the material, as well as external factors such as ambient temperature and humidity. Venkatesan et al. developed a single-electrode TENG, whose surface charge density and electrical output performance were significantly enhanced through incorporating a TiO₂–MXene–polystyrene nanofiber membrane as a charge-trapping interlayer^[85]. When applied to rat skin, the TENG generated an open-circuit voltage of 1 to 10 V through the rat’s daily activities, delivering electrical stimulation to the wound. In vivo studies demonstrated that this electrical stimulation enhances cell proliferation, promotes angiogenesis, and accelerates wound healing. For TENGs to be effective in wound healing, they must operate in a fully biocompatible environment, such as body fluids present at the wound site. Additionally, the materials used in TENGs must be sufficiently flexible to conform to the wound without causing further damage. Hydrogels, known for their softness and water-absorbing properties, are ideal candidates for wound dressings, as they promote wound closure^[86]. Combining friction materials with hydrogels represents a promising approach. Qin et al. designed a triboelectric stimulator that integrates a TENG with a triboelectric-responsive drug delivery hydrogel (TR-DDH), using the TR-DDH as an electrode in direct contact with the wound^[87]. The TENG generated pulsed currents and triggered volume changes in the polypyrrole within the TR-DDH, releasing curcumin nanoparticles. In vitro and in vivo experiments confirmed that this system enables efficient and controllable drug delivery, significantly promoting the healing of infected wounds (Figure 6A–C). Similarly, Tang et al. fabricated a TENG using electrospun polymer tribo-layers and a chemical vapor-deposited polypyrrole electrode, resulting in a device with excellent flexibility, air permeability, and moisture retention^[88]. In vitro and in vivo experiments demonstrated that the TENG upregulates the expression of growth factor-related genes, enabling diabetic rat skin wounds to heal within 2 weeks (Figure 6D–F).

4.4. Electret

Electret, also known as a permanent electric body, is a dielectric that can store an excess “real” charge or/ and maintain an “oriented” electric dipole for a long time (much longer than the time required to form the polarization). The former means that it is a nonelectric neutral material. The latter is that after the medium containing the intrinsic electric dipole is polarized by the strong external EF, its polarization state does not completely disappear with the removal of the external EF, and the “oriented” electric dipole is maintained “long-term,” forming the “oriented” electric dipole electret.

As a stimulus source of exogenous electrical stimulation, the electret has significant advantages: stability. Electrets can spontaneously generate microcurrent and micro EF in the humoral environment and maintain the charge for a long time in the absence of external energy input. This means that when selecting and designing the electret material, the stable presence of its charge matches the physiological process of healing in time, ΔT especially in deep wounds. Yao et al. combined the electret thin films with a shape memory alloy to construct an electromechanical synergistic dressing^[89]. Biocompatible shape memory alloys can draw the epithelial tissue and provide the appropriate contractile force for wound healing. Electret film could enhance the endogenous EF to promote healing while playing an antibacterial role. In vivo studies in rats showed that this dressing could promote the secretion of EGF and VEGF, regulate the microenvironment of the wound surface, and significantly improve the wound closure rate (Figure 7A–E). Kim et al. applied electrets in the other direction^[90]. They obtained higher voltages via a multilayer stacked electret (MS-electret) to suppress skin scarring. MS-electret have surface potential of 3400 V to generate direct current EF (Figure 7F).

4.5. Thermoelectric generators

Thermoelectric nanogenerators utilize the Seebeck effect to convert thermal energy into electrical power. The Seebeck effect manifests as a voltage gradient between 2 dissimilar conductors or semiconductors when subjected to a temperature differential. In pyroelectric materials exhibiting spontaneous polarization, temperature variations modulate polarization strength, generating opposing surface charges through the primary pyroelectric effect. Pyroelectric nanogenerators harness this temperature-dependent charge separation for energy conversion. Unlike piezoelectric counterparts requiring mechanical strain, pyroelectric nanogenerators generate transient currents solely through thermal fluctuations. Secondary pyroelectric effects emerge in wurtzite-structured materials where thermal expansion induces crystallographic strain, subsequently activating piezoelectric charge separation. This synergistic mechanism enables dual energy harvesting through coupled pyroelectric–piezoelectric phenomena.

While thermoelectric and pyroelectric generators find widespread application in electronic component design^[92], their direct implementation as exogenous electrical stimulation sources remains limited. Zhang et al. recently demonstrated a breakthrough in flexible biocompatible TE device development^[91]. The researchers employed Bi₂Te₃-based compounds, selected for superior near-ambient thermoelectric performance, deposited on flexible polyimide substrates with interdigitated gold electrodes. This configuration achieved exceptional energy conversion efficiency, generating 10 mV output under ΔT = 10 K conditions. When applied topographically to wound sites, the device sustained μV-level potential gradients through dermal thermoelectric coupling. Experimental validation revealed that bioelectrical stimulation derived from physiological (37 °C) to environmental (25 °C) thermal gradients significantly enhanced cellular metabolic activity. Specifically, this is manifested by suppressed secretion of inflammatory cytokines and increased angiogenesis, thereby accelerating wound healing (Figure 7G, H).

Table 2 presents some additional examples.