Skin trauma refers to any injury that disrupts the natural anatomical structure of the skin, ranging from damage to the epidermal layer to deeper injuries involving subcutaneous tissues and organs. As shown in Figure 2A, skin wound healing progresses through four overlapping phases: hemostasis, inflammation, proliferation, and remodeling. The hemostasis phase primarily involves the formation of a “platelet plug” and activation of the “coagulation cascade” to achieve rapid physiological hemostasis. The inflammatory phase entails the activation of the immune system, with immune cells migrating to the wound site to clear necrotic tissue and create conditions for tissue regeneration. The proliferation phase is a critical stage of wound healing, where granulation tissue formation and epithelialization promote wound closure. Finally, during the remodeling phase, fibroblasts proliferate extensively, remodeling the wound with scar tissue to restore strength and further optimize its structure and function to approximate normal tissue.

From a biological perspective, wounds can be classified into acute and chronic wounds based on their healing speed and difficulty. As illustrated in Figure 2B, acute wounds heal through rapid and orderly immune regulation: neutrophils primarily clear pathogens, the dynamic polarization of M1/M2 macrophages balances inflammation and repair, and regulatory T cells (Tregs) suppress excessive immune responses. In contrast, chronic ulcers, depicted in Figure 2C, face healing obstacles due to a persistent inflammatory microenvironment. Mechanisms include aberrant M1 macrophage polarization, residual neutrophil extracellular traps (NETs), Th1/Th17-mediated cytokine storms, and microbial biofilm formation. Additionally, age-related reductions in repair factor secretion exacerbate extracellular matrix degradation and angiogenesis inhibition. The fundamental difference between these two types of wounds lies in the spatiotemporal dysregulation of cellular components and molecular mediators in their immune microenvironments (Raziyeva et al., 2021).

Liang et al. (2022) developed a dual-responsive regulatory model based on a ZnO/PVDF piezoelectric scaffold (ZPFSA), achieving phase-specific modulation: during the inflammatory phase, ZnO nanoparticles exert broad-spectrum antibacterial effects, inhibiting pathogen colonization and shortening the neutrophil-dominated inflammatory response; during the proliferation phase, piezoelectric microcurrents (ES) activate fibroblast migration and VEGF-mediated angiogenesis; and in the remodeling phase, transforming growth factor TGF-β signaling coordinates collagen fiber deposition while suppressing excessive α-smooth muscle actin (α-SMA) expression, enabling scar-free healing within 14 days.

Wound healing involves multiple cell types and is a complex, multi-layered, and coordinated process. Due to factors such as infection, traumatic scarring, systemic diseases, peripheral vascular diseases, and venous insufficiency, wounds often develop abnormal scars or progress into chronic wounds. Successful wound healing should restore normal bodily function while minimizing scar formation (Ibrahim et al., 2019). As shown in Figure 2D, electrical stimulation technology provides a molecular intervention strategy for pathological healing through phase-targeted regulation: during the inflammatory phase, it enhances macrophage chemotaxis by activating Kv channels, promotes neutrophil recruitment via ERK phosphorylation, and suppresses pro-inflammatory cytokines (TNF-α, IL-6) to accelerate inflammation resolution, while anode-mediated pH modulation synergistically inhibits bacterial colonization; during the proliferation phase, endogenous electric fields guide keratinocyte migration through PI3K/PTEN signaling, and microcurrents drive fibroblast proliferation and collagen synthesis via MAPK phosphorylation while upregulating VEGF to promote endothelial angiogenesis; in the remodeling phase, biphasic currents modulate TGF-β signaling to reduce abnormal collagen deposition and improve the biomechanical properties of scars. This multi-dimensional synergistic mechanism establishes a theoretical framework for phase-specific management of chronic wounds and scar regulation (Luo et al., 2021).

In uninjured skin, there are potential differences between the cell membrane and the epithelial tissue layer, known as the “membrane potential” (∼70 mV) and the “trans-epithelial potential” (TEP, ∼10–60 mV), respectively. These potential differences are essential for the maintenance of cellular ion homeostasis. Negatively charged chloride ions at the surface of the skin and positively charged sodium ions in the dermis contribute to electrochemical processes that promote wound healing (Shapira et al., 2023). These potentials play an important role in maintaining tissue homeostasis and cellular function.

When the skin is injured, the balance of the transmembrane potential is disrupted, and the combination of cellular damage, ion channel opening, and inflammation after the injury leads to a decrease in the potential at the wound site, while the TEP around the wound remains unchanged, forming a low-resistance channel, resulting in a “short-circuitat the wound site”, and thus, the TEP drives the electric current flows out of the short-circuit site that occurs at the skin injury (Tai et al., 2009). used a vibration probe to measure the current at the human finger incision, and obtained the potential difference driving current.

The research team led by Zhang Y. et al. (2025) systematically investigated the application mechanisms of electroactive electrospun nanofiber scaffolds in skin wound repair. This study comprehensively explored the biological effects of electric field-regulated tissue regeneration from a bioelectrical perspective. The findings demonstrate that bioelectrical signals, as fundamental characteristics of living organisms, are ubiquitous across various cell types. These signals manifest as endogenous electric fields (EFs), ionic currents, redox potentials, and transmembrane potential differences. During wound healing, such bioelectrical signals play a pivotal regulatory role. As illustrated in Figure 3A, when skin tissue is injured, the transepithelial potential (TEP) is disrupted, resulting in a significant potential gradient (∼200 mV mm^-1) between the wound center and surrounding intact tissue. This lateral electric field directionally guides the electrotactic migration of epithelial cells and multiple repair-associated cells—including neutrophils, lymphocytes, monocytes, macrophages, endothelial cells, and fibroblasts—toward the wound center. Further analysis revealed that the ion dynamics of Cl⁻ and Na⁺ are critical determinants in maintaining wound potential. The concentration gradients of these ions not only regulate potential differences but also ensure the homeostasis of the wound’s electrical microenvironment through active transport via ion pumps. These findings confirm that endogenous electric fields serve as essential biophysical signals, not only orchestrating directional cell migration but also providing a theoretical foundation for novel wound management strategies based on electrical signal transduction.

In the study by Zhang CK. et al. (2025), the researchers developed a multifunctional composite hydrogel (PSMT) to promote infected wound healing through the combined application of near-infrared (NIR) photothermal therapy and ES. The hydrogel was fabricated by incorporating functionalized MXene@TA-Eu nanosheets (NSs) into a matrix composed of polyvinyl alcohol (PVA) and sericin. As demonstrated in Figure 3B, the PSMT hydrogel exhibited synergistic therapeutic effects under NIR-ES co-stimulation, including: Potent antibacterial activity, significantly reducing bacterial load; Modulation of the inflammatory microenvironment, suppressing pro-inflammatory cytokine release; Promotion of macrophage polarization toward the pro-healing M2 phenotype; Enhanced angiogenic capacity. These coordinated effects collectively accelerated the healing process of infected wounds.

As shown in Table 1, power supply devices are primarily categorized into two types: external power sources and self-powered systems. In the field of wound healing, the application of electric field therapy has been limited by the bulky size of traditional external power sources and the output voltage instability of new power sources (Behr et al., 2021). In recent years, chemical micro-batteries have garnered attention due to their portability and cost-effectiveness (Zeng et al., 2022; Zhang et al., 2022). Sun XT. et al. (2024) reported a rechargeable flexible micro Zn-MnO2 battery (mZMB) that employs a ring-shaped circuit configuration to generate a ring-shaped electric field simulating the endogenous electric field (EEF) within the body. This electric field plays a crucial role in regulating cellular activities, thereby accelerating the healing process.

Godwinraj and George (2021) developed a wireless closed-loop smart bandage with low impedance and adjustable adhesion through dual-conductive hydrogel electrodes. This bandage has demonstrated significant efficacy in accelerating wound healing speed and enhancing skin remodeling, with improvements of approximately 25% and 50%, respectively. Experimental studies demonstrate that electrical stimulation significantly accelerates wound closure and induces a marked elevation in wound impedance, facilitating rapid attainment of impedance plateau. This integrated approach enables concurrent real-time monitoring and active therapeutic modulation of wound healing processes.

Self-powered systems have become a research hotspot due to their portability, high safety, and cost-effectiveness. TENGs as a class of innovative energy harvesting devices, have emerged as a preferred solution for numerous electronic applications owing to their excellent flexibility and optimized performance (Cheah et al., 2021). TENGs operate based on the principle of contact electrification, where the contact and subsequent separation of two dissimilar materials induce charge redistribution, generating alternating current (AC) (Long et al., 2018). The independent triboelectric layer design allows TENGs to function without the need for moving parts or direct circuit connections, significantly improving efficiency and enabling non-contact operation. Depending on the materials used, TENGs can be categorized into solid-solid, solid-liquid, and liquid-liquid types, where the effective contact area directly influences the current output.

Meng et al. (2023) developed a novel bioadhesive TENG(BA- TENG) made from novel biocompatible polymer, as shown in Figure 4A, aiming to achieve rapid closure of acute wounds and accelerated healing through electrical stimulation. As shown in Figures 4B-E, the BA-TENG consists of a flexible and biocompatible TENG as the upper layer and a bioadhesive layer as the lower layer, enabling strong adhesion on wet tissues. Under ultrasonic actuation, the device generates a stable electric field (approximately 0.86 kV·m^-1), which accelerates wound healing by promoting cell migration and proliferation. Experimental results demonstrate that the BA-TENG achieves immediate wound closure in an ex vivo porcine colon model within approximately 5 s and significantly reduces blood loss (by about 82%) and hemostasis time in an in vivo rat model. This device showcases potential for application in emergency scenarios, providing new insights and methods for electrical stimulation-enhanced wound healing.

Wang WJ. et al. (2024) developed a novel aqueous-aqueous triboelectric nanogenerator (A-A TENGs)-powered multifunctional wound healing system by combining polyethylene glycol and dextran solutions, creating a 100% contact interface to enhance charge transfer and improve current output. The A-A TENGs generate charges through the contact and separation of two aqueous materials, forming a current through an external circuit. As integrating functionalized conductive hydrogels, the system ensures uniform distribution of the electric field at the wound site, promoting fibroblast migration and proliferation, enhancing angiogenesis, increasing collagen deposition, eliminating bacteria, and reducing inflammatory cells. This significantly accelerates the wound healing speed in infected wounds, demonstrating its potential for electrical stimulation-enhanced wound healing.

In the study by Xiong et al. (2020) as shown in Figure 4F, the researchers developed a gas-solid interactive triboelectric nanogenerator (GS-TENG) based on a viscoelastic porous polydimethylsiloxane-dimethylethylenedioxime polyurethane (PDPU) elastomer. The elastomer, with a thickness of 3 mm and an average pore size of 0.6 mm, features uniformly distributed closed pores that enable efficient gas trapping. A highly transparent and conductive silver nanowire bundle mesh (AgBM) was employed as the electrode material. Through a precision transfer process, the AgBM was tightly integrated with the porous PDPU substrate and subsequently coated with a 0.5 mm-thick dense PDPU protective layer. This structural design ensures excellent conductivity while maintaining 70% optical transmittance. The working mechanism of the GS-TENG relies on periodic gas-elastomer interfacial interactions, which couple triboelectrification, electrostatic induction, and dynamic charge migration in the gas phase. As shown in Figure 4G, this synergistic effect enables instantaneous illumination of dozens of serially connected commercial LEDs. The operational process can be divided into four distinct stages, as shown in Figure 4H: (i) Under external pressure, the PDPU undergoes compressive deformation, enhancing contact between pore surfaces and facilitating charge transfer from the gas to the negatively charged PDPU, forming an electric double layer with a negatively charged surface and positively charged gas; (ii) Upon pressure release, the positively charged gas undergoes potential redistribution via dynamic charge migration. Due to pore structure heterogeneity, transient asymmetric charge distribution occurs, driving free electrons from the top electrode to the bottom electrode through electrostatic induction, generating a forward current; (iii) At full unloading, the system reaches potential equilibrium, resulting in zero output signal; (iv) When pressure is reapplied, reverse charge transfer induces electron backflow, producing a negative current. Continuous alternating current output can thus be achieved under periodic mechanical excitation. As shown in Figure 4I, comparative experiments demonstrate that conventional TENGs using dense PDPU structures only yield weak outputs of 0.2 V, 2.5 nC, and 1.2 nA cm⁻² in terms of voltage, charge quantity, and current density, respectively.

Huang et al. (2024) demonstrated a body fluid (BF)-activated metal-based implantable battery, an ideal self-powered device for wound therapy. They developed a tubular Mg-Mo battery to promote wound healing. By evaluating electrical stimulation under body fluid conditions, the study correlated discharge current, dissolved oxygen (DO) concentration, and serum organics simulated with fetal bovine serum (FBS). Effective stimulation persisted for over 5 days, with a current density of 25–400 μA·cm^-2 in phosphate-buffered saline. The in vivo DO concentration supported normal battery discharge. Although the addition of FBS reduced the voltage (while still meeting effective stimulation levels), it extended the discharge duration. Additionally, a body fluid-driven battery was implanted between the hindlimb muscles to deliver ES, accelerating full-thickness skin wound healing in rats. Compared to the blank control group (75.11% ± 0.41% healing rate at 14 days), rats receiving battery stimulation for 5 days (BS-5 days) exhibited a significantly improved healing rate of 97.50% ± 0.29%. This work proposes an innovative therapeutic strategy for wound healing with potential clinical applications.

Baniya et al. (2023) developed a wearable bioelectronic system composed of a polydimethylsiloxane (PDMS) device and a printed circuit board (PCB). The system features a modular design that continuously drives H⁺ ions through a cation-selective hydrogel-filled capillaries into the wound bed by applying a positive voltage between the working electrode (WE) and reference electrode (RE). This process replaces endogenous sodium ions, reducing the M1/M2 macrophage ratio by 35.86% in a mouse model, demonstrating the system’s efficacy in enhancing wound healing. Kang et al. (2024) developed a fully implantable wireless powered tact sensor system embedded artificial skin (WTSA) that integrates biologically artificial skin and crack based tact sensors, as shown in Figures 4J,K. The system employs a hydrogel coating to reduce foreign body reactions, thereby enhancing the effectiveness of electrical stimulation. The crack-based tactile sensor detects externally applied pressure, converting it into frequency-modulated electrical signals. As shown in Figures 4L-N, these signals stimulate the scientific nerve to induce corresponding muscle responses, effective triggering leg movement. This mechanism promotes the regeneration of the intact skin layer, demonstrating excellent biocompatibility and healing-promoting potential. This work provides novel insights and an empirical foundation for electrical stimulation applications in wound healing. Li et al. (2024) proposed a wearable therapeutic zinc battery that utilizes poly (3,4-ethylenedioxythiophene) (PEDOT) -based polyelectrolyte hydrogel as epidermal stimulation electrodes to eliminate wound infection and promote diabetic wound healing. The battery consists of a zinc anode and a PEDOT-based conductive polymer hydrogel cathode. PEDOT, a cationic polymer, interacts with the negative charges on bacterial cell membranes, disrupting their integrity. The redox reactions of PEDOT generate ROS, such as H2O2, which damage critical bacterial organelles, including DNA, RNA, and proteins. Additionally, PEDOT + reacts with glutathione (GSH), depleting GSH in bacterial cells and reducing their ability to scavenge ROS, thereby enhancing its bactericidal effect. The anode leverages the redox reaction of zinc to produce zinc ions with antibacterial properties, which inhibit bacterial biofilm formation and promote DNA replication, transcription, and cellular damage repair.

The microcurrent generated by the battery mimics the endogenous electric field of the body, promoting fibroblast migration and angiogenesis, while reducing the expression of inflammatory factors. Zinc ions further enhance cell proliferation and migration, and activate the MAPK and PI3K/Akt signaling pathways. The PEDOT-based conductive polymer hydrogel exhibits excellent biocompatibility and mechanical properties, providing an optimal growth environment for cells and facilitating cell-cell interactions, thereby accelerating wound healing.

In recent years, technological advancements have driven the development of specialized therapeutic approaches that extend beyond direct electrical stimulation of wounds. These innovative methods indirectly regulate wound healing by modulating various factors.

Sun YN. et al. (2024) developed a self-powered wound dressing using polyvinylidene fluoride (PVDF) as the substrate, loaded with vancomycin (VAN) and carboxylated carbon nanotubes (c-MWCNTs). This dressing combines a Lock-ON/OFF electric field-driven drug release mechanism with electrical stimulation therapy to accelerate the healing of infected wounds. The dressing was fabricated using electrospinning and soft template methods, maintaining a closed state for drug release under non-stimulated conditions. When mechanical stress is applied, an electric field is generated through the piezoelectric effect, enabling precise drug release under stimulated conditions. The cumulative drug release rate reached 88.57%, representing an 89-fold increase compared to the non-stressed group. Through electrical stimulation, the device effectively promoted wound healing, achieving a healing rate of 100% within 10 days, demonstrating excellent antibacterial efficacy and the ability to accelerate tissue regeneration. Wang H. et al. (2024) investigated a capacitive antibacterial dressing composed of a polypyrrole-wrapped carbon cloth and a bacterial cellulose (BC) hydrogel separator. The device demonstrated a sterilization efficiency of up to 99.97% after applying a 1 V voltage for 10 min, with a kill rate of 99.99% against multidrug-resistant bacteria. Electrical stimulation not only enhanced the antibacterial capability of the dressing but also significantly accelerated wound healing in a mouse model of infected full-thickness skin defects by promoting local collagen deposition and microvascular reconstruction, indicating the promising potential of this capacitive antibacterial dressing in promoting wound healing.

In the study by Zhang Q. et al. (2024), an innovative magneto-mechano-electric (MME) cascade stimulation system for wound healing was developed and validated. As shown in Figure 5A, mechanistic studies revealed that pure PLLA membranes maintained stable surface morphology and roughness parameters (Ra = 1.47 μm, Rq = 1.84 μm, Rt = 19.29 μm) before and after magnetic field stimulation, while PLLA/CFO10 composite membranes exhibited significant reduction in surface roughness (Ra = 1.05 μm, Rq = 1.34 μm, Rt = 17.18 μm) under magnetic field exposure. This system, as illustrated in Figure 5B, employs aligned poly (L-lactic acid)/cobalt ferrite (PLLA/CFO) magnetoelectric nanofiber membranes as the core component, working synergistically with a remotely controllable magnetic field to achieve therapeutic effects. This deformation effect originates from the local mechanical strain induced by the aligned magnetic dipole arrangement of CFO nanoparticles, which is subsequently transferred to the piezoelectric PLLA matrix through interfacial coupling, ultimately leading to surface polarization changes and electrical signal output, as shown in Figure 5C. Regarding material selection, PLLA, as an FDA-approved implantable biomaterial, exhibits excellent biocompatibility, biodegradability, structural stability, and piezoelectric properties; meanwhile, polydopamine (PDA)-modified CFO nanoparticles not only demonstrate outstanding magnetic characteristics but also significantly enhance interfacial bonding strength and biostability with the PLLA matrix. As shown in Figure 5D, the composite membrane can generate magnetic field-driven electrical stimulation output, with its magnetoelectric conversion performance systematically verified. Through systematic in vitro cellular experiments and full-thickness skin defect models in rats, the MME system demonstrated remarkable therapeutic advantages: promoting cell adhesion, proliferation and spreading behavior, accelerating wound healing processes, and enhancing collagen deposition and angiogenesis. Notably, as shown in Figure 5E, quantitative analysis via Masson’s trichrome staining revealed that the magnetic field-treated PLLA/CFO10 experimental group exhibited the most significant collagen deposition, confirming its exceptional performance in tissue regeneration.

Kim SW. et al. (2024) proposed a novel multi-layer stacked electret (MS-electret) patch, which is fabricated using a corona charging system and is capable of self-generating a sustained direct current electric field (DCEF) without an external power source. The design of the MS-electret allows for the modulation of electric field strength by physically stacking dielectric layers, providing stable electrical stimulation. This significantly inhibits the transformation of human dermal fibroblasts (hDFs) into myofibroblasts, reducing fibrotic activity. In the 7-layer MS-electret treatment group, the expression of the COL1A1 gene was significantly reduced by approximately 90%, while the expression of the COL3A1 gene increased, indicating the device’s remarkable efficacy in promoting wound healing and inhibiting scar formation.

Compared to other materials, the OPV cell can generate electricity continuously without the need for battery replacement or connection to a power line. Both the OPV cell and MEMS electrode exhibit excellent flexibility, allowing them to adapt to the movement of the skin surface. The dressing also demonstrates good biocompatibility and antibacterial performance, promoting wound healing and reducing healing time. In vivo experiments and proteomic analysis revealed that the proposed PMH dressing significantly accelerates the healing of infected diabetic wounds by enhancing extracellular matrix regeneration, eliminating bacteria, modulating inflammatory responses, and regulating vascular function. Therefore, the PMH dressing represents a powerful, versatile, and effective solution for diabetic wound care, paving the way for the development of electrical stimulation wound dressings.

Qiu et al. (2020) fabricated a multilayer composite membrane (MC membrane) using electrospinning technology, composed of an antibacterial layer (ABL), a healing-promoting layer (HPL), and a reinforcement layer (RFL) made from zein/ethyl cellulose (zein/EC). By utilizing protoporphyrin (PPIX) as a photosensitizer, the membrane achieved photodynamic antibacterial effects. Additionally, electrical stimulation was employed to promote cell migration and angiogenesis, while reducing inflammatory responses. This approach significantly enhanced the wound healing rate in a mouse skin defect model, achieving a healing rate of 92.4% by the 10th day.

Zhang et al. (2023) developed a piezoelectric generator (PEG) based on poly (L-lactic acid) (PLLA) and vitamin B2 (VB2). Compared to traditional generators, the PLLA/VB2 PEG is made from bio-based materials, offering superior biocompatibility and greater suitability for skin wound treatment. By blending PLLA and VB2, they improved the crystal structure and β-phase orientation, resulting in better biocompatibility and higher piezoelectric output than commonly used polyvinylidene fluoride (PVDF)-based PEGs. The PLLA/VB2 PEG also boasts advantages such as non-invasiveness, biodegradability, and low cost, making it highly promising for future applications.

Liang et al. (2022) utilized 3D printing technology to fabricate a novel ZnO nanoparticles modified PVDF/sodium alginate (SA) piezoelectric hydrogel scaffold (ZPFSA), providing a new therapeutic option for rapid wound healing and scar prevention. The scaffold features a dual piezoelectric release mode in both vertical and horizontal directions, ensuring continuous generation of piezoelectric current. As a bioelectric stimulation signal, it triggers a series of responses, including cell proliferation and migration, ordered collagen deposition, neovascularization, and upregulation of various growth factors related to wound healing. This ultimately achieves rapid and complete wound healing in a rat full-thickness wound model. The material’s swelling properties enable current generation in the vertical direction, making it essential to test its swelling performance. When the concentrations of sodium alginate and PVDF are optimized for printing, the piezoelectric scaffold achieves a swelling rate of approximately 331%, establishing a swelling-based vertical piezoelectric response mode. The material also exhibits high mechanical performance, ensuring stable current generation under high-frequency motion on the skin surface.

Yu et al. (2024) developed a single-electrode TENG skin patch using molybdenum disulfide (MoS2) and biocompatible gelatin methacryloyl (GelMA) hydrogel. MoS2 exhibits excellent electrical conductivity and photothermal conversion properties, while GelMA demonstrates outstanding biocompatibility. The TENG device is capable of harvesting biophysical energy, generating an electric field around damaged tissues, and enhancing wound healing through near-infrared (NIR) photothermal effects. Additionally, the TENG can function as a real-time sensor to monitor physiological signals. The TENG prototype achieved a peak voltage output of 48.80 V and a current output of 0.57 μA.

In vitro experiments using mouse fibroblastsdemonstrated that the TENG accelerates cell migration through the combined effects of photothermal heating and real-time electrical stimulation. Animal studies further confirmed that the TENG effectively promotes collagen deposition and angiogenesis, ultimately enhancing tissue regeneration and wound healing. Notably, this study is the first to report the use of a MoS2-based TENG for accelerating wound healing. This work is expected to not only provide new avenues for the application of self-powered wearable electronics in wound therapy but also highlight their potential in advanced sensing systems.

The research team led by Li CH. et al. (2023) successfully developed a polarized potassium sodium niobate (K₀.₅Na₀.₅NbO₃)-based piezoelectric bioactive glass composite (P-KNN/BG). This innovative material combines a bioactive glass (BG) matrix with lead-free piezoelectric KNN through polarization treatment, integrating BG’s exceptional osteointegration capacity with KNN’s piezoelectric properties. As shown in Figure 5I, field-emission scanning electron microscopy (FE-SEM) analysis revealed uniformly distributed surface morphology across all experimental groups. Through incorporation of KNN piezoelectric components and optimized polarization processing, the composite achieved a significantly enhanced surface potential of 322.04 ± 12.85 mV, representing a 3.2-fold increase compared to pure BG (77.05 ± 15.19 mV),as shown in Figure 5H. This potential enhancement stems from two synergistic mechanisms: (1) KNN doping imparts tunable dielectric properties, and (2) polarization treatment markedly improves piezoelectric performance via domain alignment. Notably, piezoelectric effect-induced electrostatic interactions promote accelerated release of bioactive ions (Ca²⁺, Si⁴⁺, and PO₄ ^3-) from the BG matrix. At optimal concentrations, these ions effectively stimulate secretion of angiogenesis-related factors. The molecular mechanism, illustrated in Figure 5F, demonstrates P-KNN/BG’s dual-mode pro-angiogenic action: Piezoelectricity-induced membrane hyperpolarization establishes electrochemical gradients facilitating ion influx. Sustained ion release activates the eNOS/NO signaling pathway, significantly upregulating expression of angiogenic factors (VEGF, b-FGF, and TGF-β), as shown in Figure 5G. As shown in Figure 5J, in vivo chick chorioallantoic membrane assays confirmed that P-KNN/BG treatment not only exhibited excellent biocompatibility but also increased vascular network density by 2.3-fold while promoting extensive neovascularization. This study provides novel design principles and therapeutic strategies for developing electrically active bone repair materials.

Qi Xu’s research team (Xu Q. et al., 2024) successfully developed a self-powered repetitive mechanical impact-electrical stimulation (RMI-ES) system based on a barium titanate/polydimethylsiloxane (BaTiO₃/PDMS) piezoelectric composite membrane, as shown in Figure 5K. The core component of this system consists of non-centrosymmetric tetragonal-phase BaTiO₃ (T-BTO) nanoparticles uniformly dispersed in a PDMS matrix, which, after polarization treatment, forms a flexible composite membrane with piezoelectric properties. Scanning electron microscopy (SEM) analysis revealed that the T-BTO nanoparticles were homogeneously distributed within the PDMS matrix, a structural design that endows the material with both the excellent biocompatibility and flexibility of PDMS and the highly efficient electromechanical conversion capability of T-BTO, as shown in Figure 5L. Under mechanical stimulation, the composite membrane demonstrated remarkable energy conversion performance, generating an output voltage of approximately 35 V at 2 Hz frequency and 4% strain, as shown in Figure 5N, and 18 V under 5 Hz frequency and 50 N impact loading, as shown in Figure 5O. This mechanoelectrical energy conversion arises from the non-centrosymmetric lattice structure of T-BTO, which produces microscopic piezoelectric polarization under external force, thereby generating a dynamic built-in electric field. As shown in Figure 5M, mechanistic studies demonstrated that the electrical stimulation generated by the piezoelectric membrane exerts therapeutic effects by activating the PI3K/AKT signaling pathway: the electric field promotes PI3K-catalyzed generation of PIP₃, which subsequently activates AKT serine/threonine kinase, triggering a cascade of intracellular events that regulate critical biological processes, including cell survival, proliferation, and migration. Additionally, this pathway participates in modulating angiogenesis and extracellular matrix remodeling. Systematic in vitro and in vivo animal model experiments confirmed the system’s significant pro-healing effects, demonstrating that electrical stimulation not only enhances fibroblast proliferation and collagen deposition but also activates the PI3K/AKT pathway to promote vascular regeneration. This innovative strategy, which converts biomechanical stimuli into therapeutic electrical signals, provides a crucial theoretical foundation and technological pathway for developing novel self-powered wound treatment systems.

In the 2017 study by Bikson et al. (2018), FDA-approved TENS devices (primarily Class II medical devices cleared through the 510(k) premarket notification process) were categorized into two main applications: GZJ devices for pain management (e.g., arthritis, migraine treatment) and NFO devices for cosmetic purposes (e.g., facial rejuvenation). The study noted that these devices could deliver a maximum output current of up to 37.6 mA in head and facial applications (exemplified by the Rejuvenique device) and demonstrated good clinical tolerance, with common side effects limited to transient skin irritation (e.g., erythema resolving within 20 min, as reported in studies on the BMR Face device). A representative study, such as Kavanagh et al.’s 2012 clinical trial on facial rejuvenation, showed that using a TENS device with a peak current of 35 mA (5 sessions per week, 20 min per session, over 12 weeks) resulted in no significant adverse events in the treatment group (n = 56) compared to the control group (n = 52). Notably, although the electrical parameters of TENS devices (e.g., current density of 46.4 mA/cm² for the Rejuvenique OTC device and 2.37 mA/cm² for the prescription device Cefaly) were significantly higher than those of traditional tES technologies, their long-term clinical use had validated their safety.

The 2023 study by Bikson et al. (2023) further clarified that the FDA has established stringent electrical output safety standards for TENS devices (Class II medical devices). Key restrictions include: a charge quantity formula based on phase duration *t* (milliseconds), *Q* = 20 + 28*t* mC (measured at 50% phase amplitude), an average current ≤ 10 mA, depolarization phase duration ≤500 ms, and a DC current ≤ 100 μA under fault conditions. Additionally, the FDA mandates that the RMS electrode current density must be ≤ 2 mA/cm² and the average power density ≤0.25 W/cm². Furthermore, the FDA specifies multiple safety measures, covering dynamic output control, open/short-circuit protection for electrodes, power stability management, and biocompatibility requirements for electrode materials. These measures, enforced through the 510(k) review process, ensure end-to-end safety from device design to clinical application.

The study by Li et al. (2020) systematically analyzed the effects of different electrical stimulations on wound healing: Direct current (DC) leads to voltage concentration due to high epidermal resistance but shows limited efficacy and may even cause necrosis, as observed in diabetic rats where it accelerated wound contraction without significantly improving inflammation. Monophasic pulses (SP), owing to better voltage distribution and the ability to promote α-SMA and TGF-β1 secretion, significantly enhanced healing efficacy. In contrast, biphasic pulses (BP) exhibited poorer therapeutic effects due to charge cancellation, though adjusting frequency (≤187 Hz) and duty cycle (e.g., <50.6%) could improve outcomes. The key factor, charge quantity, has an effective range of 250–500 μC/s in humans and 75–90 μC/s in rats, with the DC component (UDC) optimally ranging between 0.49 and 0.7 V, though experiments showed its safe range could extend to 0.4–1.22 V. These findings provide critical insights for optimizing electrical stimulation therapy.

Lin et al. (2025) developed a hydrogel-based electronic wound dressing patch that enables precise drug release in diabetic wound healing by optimizing electrical stimulation parameters. The study found that applying a −5 V DC voltage allowed the PEDOT:CHC/silk hydrogel to release 60% of the drug within 1 h, far surpassing other samples. However, increasing voltage intensity exacerbated continuous drug outflow. Periodic monophasic constant potential stimulation (−3 V for 2 min) led to burst release with diminishing efficiency, whereas biphasic alternating current (AC) stimulation produced a controllable stepwise release, accelerating responsive release while suppressing continuous diffusion. Experiments demonstrated that continuous biphasic AC cycles were the most effective strategy for regulating ibuprofen release, enabling on-demand drug delivery by adjusting voltage parameters. Thus, selecting the appropriate electrical stimulation mode (particularly biphasic AC) is crucial for optimizing drug release and promoting wound healing.

Xu et al. (2022) found that non-contact electrical stimulation (NCES) at specific intensities significantly enhances wound healing. In HaCaT cells, NCES at 53 and 76 mV mm^-1 boosted cell viability on day 1 and consistently promoted migration and proliferation on days 3 and 5. For human dermal fibroblasts (HDFs), 53 mV mm^-1 was most conducive to migration and uniform healing, while 76 and 104 mV mm^-1 promoted vertical cell alignment. In THP-1 and macrophages, NCES at 53 mV mm^-1 upregulated M2 macrophage markers, optimizing immunomodulation. Animal experiments showed that NCES at 54 mV mm^-1 consistently accelerated healing, reduced scarring, and improved collagen alignment. In summary, NCES at 53–54 mV mm^-1 significantly enhances wound repair by regulating cell behavior, immune response, and tissue remodeling.

A CP is a polymer with a conjugated π-electron system and the ability to conduct electricity. In the field of electrical-stimulation-assisted wound healing, CPs can be used as electrode materials or carriers for active ingredients, etc. It can effectively conduct current when an electrical stimulation is applied and may also have characteristics such as biocompatibility, which helps to promote cell activities, proliferation, etc., at the wound site, thereby accelerating wound healing. They have adjustable conductivity and good biocompatibility. They can be designed to have specific electrical and mechanical characteristics according to needs, making them suitable for wound healing applications.

However, a single application CP is impractical, its mechanical properties are poor, its rigid structure makes it highly intolerant, and it is highly sensitive to moisture and air (Acosta et al., 2022). Long-term implantation also carries the risk of chronic inflammation. Therefore, scientists have found that when CP is mixed with other materials such as silk (Gh et al., 2017), collagen (Qin et al., 2020), gelatin, or prepared into hydrogels based on CPs (Stejskal, 2017), the defects of CP can be effectively improved, and hybrid CP has become a research hotspot at present.

CP materials are widely used in nerve regeneration and bone repair and are capable of controlling the growth of cells and tissues by promoting cell proliferation, simulating electronic or ionic conductivity, and medicating the flow of currents (Dong et al., 2017; Gilmore et al., 2009; Aznar-Cervantes et al., 2017; Qi et al., 2018). At present, the commonly used CPs on the market include polypyrrole (PPy), polythiophene (PT) and its derivatives, polyaniline (PANI), such as poly(3,4-ethylenedioxythiophene) (PEDOT).

Graphene wound dressings are gradually attracting attention in some research and clinical applications. Graphene oxide (GO) is an oxidized form of graphene with single-atomic layers that exhibit excellent conductivity and high chemical stability (Yu et al., 2023). GO exists as a two-dimensional lattice comprising a unique monolayer of sp^2-and sp^3-hybridized carbon atoms. Previous studies confirmed the ability of GO to promote cell proliferation and adhesion (Fu et al., 2017). and that conductive polymer materials containing GO can strengthen the ES, thereby accelerating wound healing (Khan et al., 2015; Senthil et al., 2018). Additionally, GO mediates the formation of extracellular superoxide compounds that can inhibit bacterial activity and reduce the risk of infection (Zhao et al., 2018). Moreover, dispersed GO nanoparticles exhibit low viscosity and cytotoxicity at high concentrations, thereby making them good candidates for local administration. The dispersed nanoparticles can also be converted into membrane materials to prolong their residence time on the skin surface and prevent biotoxicity (Rauti et al., 2016).

Zhong et al. (2024) demonstrated scarless healing of infected wounds using sHA/G-GM conductive hydrogels. The underlying mechanism, systematically illustrated in Figure 7A, involves the sulfated hyaluronic acid component within the material specifically binding IL-4 via sulfonate groups. This binding activates the STAT6 pathway in macrophages, promoting their polarization from the M1 to the M2 phenotype. Concurrently, the graphene network enhances tissue conductivity, amplifying endogenous electrical signals to coordinately regulate fibroblast migration and collagen deposition. Flow cytometry data in Figure 7B confirmed a significantly elevated proportion of CD206+ M2 macrophages within the treated wounds compared to the control group, accompanied by suppressed expression of the pro-inflammatory cytokine TNF-α. These findings validate the sHA-mediated immune remodeling function. The synergistic actions of these mechanisms promote angiogenesis and epithelial regeneration, ultimately culminating in organized collagen arrangement and functional wound healing.

Zhou et al. (2024) developed a conductive polyacrylamide/sodium alginate cross-linked hydrogel composite containing reduced graphene oxide (PAA-SA@rGO). This composite material has antibacterial, anti-inflammatory and antioxidant properties and can serve as a bridge to turn the “short circuit” at the injured site into a “complete circuit”, thereby prompting fibroblasts near the wound site to secrete growth factors and accelerate tissue regeneration. Meanwhile, the PAA-SA@rGO hydrogel can effectively seal the wound to form a barrier, demonstrating antibacterial and anti-inflammatory properties and preventing the invasion of foreign bacteria.

Carbon-based materials such as carbon nanotubes and graphene have high conductivity and mechanical strength. They can be used to make flexible electrodes or incorporated into wound dressings for electrical stimulation. Carbon has high electrical conductivity, good mechanical properties and a large specific surface area. A large specific surface area helps to adsorb some bioactive molecules, etc., and high electrical conductivity can ensure effective electrical-stimulation transmission, thus playing a role in the wound-healing process, such as regulating the electrical environment of cells at the wound site and promoting cell migration and proliferation.

Hydrogel dressing is a new type of medical dressing, which is cross-linked by hydrophilic polymer. Hydrogel dressings have a structure similar to extracellular matrix, and have good biocompatibility. They can absorb wound exudates and provide a humid environment around the wound, so they are widely used in the treatment of skin wounds (Zhou et al., 2019; Zhang et al., 2019). At the same time, hydrogel dressings can also be used as carriers of bioactive factors or antibacterial drugs to improve the skin healing rate (Tahneh et al., 2022). However, due to the poor conductivity and lack of antibacterial properties of individual hydrogels, it is impractical to use hydrogels alone in wound healing. At present, the widespread practice is to introduce conductive polymers, carbon based materials, etc., into hydrogels, which has become a research hotspot in the field of electrostimulation wound healing.

The PMH dressing developed in this study features a sandwich structure with a core comprising a flexible organic photovoltaic module, a microelectromechanical systems electrode, and an HD-Ag₂ conductive hydrogel interface. As illustrated in Figures 7E–K, the hydrogel incorporates in situ synthesized silver nanoparticles via photoreduction, endowing it with both biocompatibility and antibacterial activity. In an infected diabetic wound model, this dressing generates biomimetic electrical stimulation through photoresponsive mechanisms, mimicking the direction of physiological injury currents. Experimental results confirm its triple-action healing acceleration mechanism: first, the HD-Ag₂ hydrogel effectively eliminates MRSA and PAO1 pathogens, exhibiting an inhibition zone diameter of 8.2 ± 0.3 mm; second, it downregulates pro-inflammatory cytokines TNF-α and IL-1β while promoting M2 macrophage polarization, thereby shortening the inflammatory phase; finally, it activates fibroblast migration and upregulates collagen deposition by 320%, concurrently enhancing extracellular matrix reorganization. In vivo studies demonstrate a 97% wound closure rate within 22 days, significantly surpassing the control group (Hu et al., 2024).

Here, Xu RC. et al. (2024) Proposed a porous hydrogel with gas-solid contact separation triboelectric (gshl) as wound dressing with reference to. Their synthesis process began with the preparation of a solution containing deionized water, into which lithium chloride and sodium dodecyl sulfate were dissolved. After the initial reagent was completely dissolved, dodecyl methacrylate was introduced into the solution, which improved the structural integrity and mechanical properties of the hydrogel. Then, acrylamide was added as monomer of self-polymerization reaction and potassium persulfate as initiator of polymerization reaction. The addition of N, N, n’, n’- tetramethylethylenediamine to catalyze the polymerization ensures the rapid and effective crosslinking of hydrogels. During the whole reaction, the mixture was stirred vigorously to promote the formation of uniform porous structure. After the preparation, in order to evaluate the medical application potential of gshl as wound dressing, they evaluated several important indicators, including expansion rate, tensile strength, tensile strain and stability. They showed good swelling rate, which also provided good conditions for the wound not to be exposed. At the same time, it also had good tensile strength and stability. As a wound dressing, it was undoubtedly excellent.

Electrical stimulation techniques have been shown to be effective in reducing bacterial load in wounds while protecting host cells from damage. In the study of Marziyeh Jannesari (Jannesari et al., 2023) a TENG composed of PPy-GO composite material was successfully developed, which showed excellent electrical output performance and significant bactericidal activity. In order to further explore its antibacterial mechanism, Staphylococcus aureus was used as the representative model of gram-positive bacteria, and the antibacterial properties of the prepared TENG electrode were studied in detail. In order to quantitatively evaluate its antibacterial performance, optical-density (DO600) measurements and colony-forming unit-counting methods were used to monitor the inhibition of bacterial growth. The results of experimental significant destructive changes were observed in the incubation process of bacteria on the electrode under the condition of no electrical stimulation. However, when the tapping time was extended from 10 min to 25 min, the bactericidal performance of the electrode was significantly improved, and the bactericidal rate was increased from about 25% to about 75%. This phenomenon can be attributed to the triboelectric effect produced under tapping conditions. According to the morphological observation of bacteria, on the carbon electrode treated without electric field stimulation by TENG, the originally smooth and complete S. aureus became fuzzy and rough after modification by PPy and PPy-GO layers. In the absence of electric field stimulation of TENG, no rupture or collapse of bacterial envelope or cell membrane was observed. However, the bactericidal effect was significantly enhanced by increasing the exposure time of the bacteria on the PPy-GO 2–180# electrode. With the increase of tapping time from 10 min to 25 min, the damage effect of TENG electric field stimulation on bacterial structure became more significant, which was consistent with the results of antibacterial test. Fluorescent dyes such as acridine orange/propidium iodide (AO/PI) were used to stain live/dead cells to investigate the cell viability. It was observed that prolonged finger-tapping of the PPy-GO 2–180# electrode (from 10 to 25 min) further enhanced its bactericidal activity. The results of live/dead staining were consistent with those of OD600 measurements and agar-plate antibacterial-tests. The synergistic effect of electric field stimulation generated by PPy-GO composite TENG is a key factor to enhance the efficacy of bacterial growth inhibition. Electrical stimulation, as a non-traditional antimicrobial means, has demonstrated its potential in the medical field through a variety of mechanisms, especially in promoting wound healing and preventing infection.

As a biological regulatory instrument, ES has demonstrated a profound impact on cell activity, including the promotion of key processes such as proliferation, growth, migration, and stem cell differentiation. Its effects span both normal and pathological states, involving the regulation of ion transport, gene transcription, protein synthesis, and reactive oxygen generation, as well as the release of chemokines and cytokines. To complex physiological activities such as synaptic extension and cell migration. A large number of studies have shown that bioelectrical stimulation has a significant effect on promoting the regeneration and repair of damaged tissues (Meng SY. et al., 2021). Cell proliferation, as a key process of cell number expansion, is an indispensable link in wound healing, which drives new cells to fill tissue defects in the wound area and lays the cytological basis for wound healing. Especially in the early stages of wound healing, such as within 48 h after wound formation, cell proliferation contributes as much as 73% to wound closure of vascular smooth muscle cells (SMCs), highlighting their central role in the process of “filling the gap” (Ammann et al., 2019). When exploring the mechanism of skin injury repair, the importance of cell migration as a key link to cover and seal the wound is self-evident. In particular, the inward directional movement of keratinocytes from the edge of the wound is the cornerstone of rebuilding the epidermal barrier and restoring its physiological protection function. In this process, the mechanical signal transduction inside the cell works in concert with the external traction force to profoundly regulate the healing process and the tight closure of the wound (Holt et al., 2020).

The core of vascularization lies in the mechanism of cell proliferation and directed migration, which provides indispensable nutrition and oxygen support for tissue regeneration and constitutes a crucial link in the wound healing process, directly determining the efficiency of the healing rate (Fu et al., 2023). Specifically, vascular endothelial cells play an important role in the process of angiogenesis and realize the construction and expansion of vascular network through a series of precise regulation. It is worth noting that ES shows its unique repair potential, and significantly upregates the expression levels of VEGF, matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) in the ischemic flap area by effectively alleviating the inflammatory response and apoptosis process triggered by oxidative stress. This regulatory effect further promoted the increase of microvessel density and the significant increase of the number of new vessels, injected strong impetus into the angiogenesis process, and accelerated the process of tissue repair and regeneration (Chen et al., 2024).

VEGF, as the core regulator of physiological angiogenesis in embryonic development, bone construction and reproductive function, plays a crucial role in promoting angiogenesis (Mao et al., 2022).

On this basis, Zhang YX. et al. (2024) innovatively proposed the “cocktail effect” strategy of synergies between electrical simulation and multiple metal ions, and realized the joint intervention of ES and multiple ions by constructing a wearable ionic triboelectric nanogenerator (iTENG) patch. In particular, copper, as a key nutrient for angiogenesis, synergies with iron ions to significantly promote the expression of VEGF, angiopoietin-1 and fibroblast growth factor-2 (FGF2), thereby enhancing the proliferation and migration of endothelial cells and accelerating the reepithelialization process of wound tissue. The accumulation of metal ions in the wound area showed a significant “cocktail effect”, in which endothelial cell adhesion molecule-1 (CD31) was a key evaluation index of angiogenesis. The results of CD31 staining clearly showed a significant advantage in the degree of angiogenesis in the NCs + EP group. The number of CD31 positive cells and the density of microvessels were much higher than those in other controls, thus accelerating the process of wound healing.

Zheng et al. (2024) demonstrated that multifunctional PPTZ hydrogel combined with electrical stimulation significantly promoted tissue regeneration and healing in diabetic wounds. Key evidence for tissue blood flow regulation was observed in Figure 9A, which revealed dense neovascularization indicated by red arrows. Figure 9B quantitatively confirmed via α-SMA immunofluorescence that vascular smooth muscle cell expression reached 304.49%, substantiating that the hydrogel synergistically with electrical stimulation enhanced neovascularization and improved local microcirculation.

Yin et al. (2023) developed a polyaniline-based conductive antibacterial hydrogel PSP for treating infected chronic wounds. Animal experiments confirmed its significant therapeutic efficacy. As shown in Figure 9C, complete wound healing was achieved after 14 days of treatment combining PSP hydrogel with electrical stimulation. Histological analysis further revealed that compared to electrical stimulation alone or conventional dressing groups, this treatment group exhibited a 28% significant increase in re-epithelialization extent, a 100% elevation in collagen deposition, and markedly enhanced neovascularization. This superior efficacy stems from the multifunctional synergy of the PSP hydrogel. Fabricated via in situ polymerization embedding aniline within a polyacrylamide network and stabilized with sulfonated hyaluronic acid as a macromolecular dopant for polyaniline’s conductive state, its preparation process is detailed in Figure 9D. The resulting PSP hydrogel demonstrates skin-comparable conductivity of 1.05 mS/cm. Its antibacterial mechanism relies on polyaniline’s specific binding to Gram-positive bacterial lipoteichoic acid, thereby disrupting cell wall structural integrity.

Chronic wounds, defined as wounds that do not show signs of healing for more than 1 month, are characterized by persistent inflammation, a significant delay in the healing process, and complications associated with a high risk of tissue damage and infection. This type of wound covers a wide range of diabetic foot ulcers, pressure ulcers, venous ulcers and radiation ulcers and other common clinical types. In the pathophysiological process of chronic wounds, the imbalance of inflammatory cytokines, abnormal expression of growth factors and changes in proteolytic enzyme activity jointly lead to the difficulty of wound healing or significant prolongation of healing time. Meanwhile, the treatment process may also induce adverse complications such as infection, which brings great challenges to current medical interventions. Innovative treatment strategies are urgently needed (Li and Zheng, 2024).

VEGF plays a pivotal role in wound healing by regulating angiogenesis and inflammatory responses. Studies confirm that pathological VEGF upregulation leads to aberrant vascular leakage and inflammatory cell infiltration, creating a fibrotic microenvironment that impedes the healing process. As shown in Figure 9E, targeted VEGF therapy, achieved through delivering exogenous VEGF or utilizing tissue-engineered vascular grafts, significantly promotes functional neovascularization in ischemic tissues. This improves local perfusion and oxygenation, accelerating re-epithelialization. Furthermore, research elucidates that stem cell therapy synergistically enhances vascular network reconstruction by inducing the differentiation of pluripotent stem cells into endothelial cells and promoting the secretion of factors like VEGF. This effectively reduces the healing duration of chronic wounds through mechanisms involving suppression of excessive inflammatory responses and mitigation of scar formation (Pérez-Gutiérrez and Ferrara, 2023).

Fibroblasts play a central role in the homeostasis of the ECM, responsible for the synthesis, secretion and remodeling of key components of the ECM, especially collagen and elastin, the two most abundant structural proteins. Collagen, as the cornerstone of skin ECM, gives it excellent elasticity and strength. Of its various types, type I collagen dominates adult skin, but after trauma, its place is temporarily replaced by type III collagen, which then undergoes remodeling to restore homeostasis. Elastin, on the other hand, is synthesized during wound healing and, although it accounts for only a small fraction of ECM (0.6%–7.9%), is essential for reducing scar contraction, promoting skin regeneration and giving the wound area the necessary flexibility. Reconstruction of the elastic fiber network is essential for full recovery of skin function. However, inadequate elastin regeneration, accompanied by excessive accumulation of collagen synthesis, often leads to an undesirable healing outcome-the formation of scars that are significantly less flexible and elastic than normal dermis. When skin is damaged, ECM proteins undergo a series of finely regulated repair processes aimed at restoring skin integrity, structural stability, and internal environmental balance. This process begins in the hemostatic phase, during which extracvascular collagen (mainly type I) activates platelets, interacts with ECM proteins (collagen, fibronectin, von Willebrand factor, etc.) through platelet receptors (e.g., glycoprotein VI), releases soluble mediators such as cyclic AMP, and induces the release of blood cells. Promote platelet adhesion and release of growth factors and adhesion glycoproteins. Following the inflammatory phase, PDGF (platelet-derived growth factor) is activated to recruit fibroblasts to the wound site, prompting them to synthesize collagen and glycosaminoglycan, providing favorable conditions for cell migration. In the growth stage, the temporary fibrin matrix is gradually replaced by a new matrix composed of collagen fibers, proteoglycans and fibronectin. During this process, fibroblasts are stimulated to replace the original fibrin clots with hyaluronic acid, proteoglycan and fibronectin to promote the formation of mature collagen fibril. As the scar matures, type III collagen is gradually replaced by type I collagen, which enhances the tensile strength of the scar. In order to maintain skin elasticity, the reconstruction of elastin in ECM is particularly critical. It is involved in cell migration, matrix construction, protease production, tension regulation and defense response, and actively contributes to wound healing and maintenance of skin homeostasis by enhancing cell adhesion, diffusion, proliferation and signal transduction mechanisms (Gardeazabal and Izeta, 2024; Gajbhiye and Wairkar, 2022).

In the pioneering research of Xiang et al. (2023) successfully generated rectangular pulse single-phase microsecond pulse electric filed (μsPEF) waveforms using their self-developed solid-state Marx generator (SSMG). This wave shape exhibits a rapid rising/falling edge in the nanosecond range to stimulate cells, thereby inducing a microsecond pulsed electric field mediated wound healing mechanism dependent on actin and collagen. It was found that a short duration of 750 V/cm μsPEF induced rapid migration of fibroblasts over a long period of time. In addition, the study demonstrated that μsPEF stimulation can effectively regulate the recombination of actin cytoskeleton and the conversion of focal adhesion, thus significantly promoting the migration rate of fibroblasts in a two-dimensional cell culture system. This accelerated fibroblast migration phenomenon is accompanied by co-alignment with the ECM in a three-dimensional microenvironment, which together drives the final process of wound healing. To investigate the effects of μsPEF stimulation on the secretion of collagen α2 (COL1A2) or FGF-2 from fibroblasts, we used an enzyme-linked immunosorbent assay (ELISA) to measure the levels of these two molecules in the cell supernatant 48 h after stimulation. The results showed that under the stimulation of 750 V/cm and 1500 V/cm μsPEF, the secretion of COL1A2 increased by 137% and 233%, respectively, compared with the control group, indicating that μsPEF can promote the synthesis of new ECM in fibroblasts. Provide the necessary support for other cells associated with effective wound healing. At the same time, Masson staining results of skin tissue slices also showed that the collagen fiber tissues in the 750 V/cm μsPEF group were well arranged, which was consistent with the results of in vitro experiments, and this change was consistent with the characteristics of the remodeling stage of wound healing. Further, to investigate whether μsPEF stimulation leads to collagen degradation, the researchers quantified changes in collagen concentration after electrical stimulation. The results of sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) showed that, at the same initial concentration, the final concentration of collagen gel decreased with the increase of the μsPEF stimulating electric field intensity, which meant that the degradation of collagen gel occurred to different degrees under the stimulation of different μsPEF intensity. In addition, the collagen gel stimulated by μsPEF was significantly twice as hard as that in the unstimulated group. More importantly, μsPEF effectively promoted the closure of skin wounds in vivo, and the closure efficiency along the electric field line was higher. This effect is attributed to faster migration of fibroblasts and better arrangement of collagen fibers. In the end, healing efficiency was significantly improved 2.5 times in the μsPEF stimulated group compared to the unstimulated group. This orderly arrangement of collagen fibers helps to form stable scar tissue, which speeds up the wound healing process.

In the complex physiological process of wound healing, moderate inflammatory response plays an indispensable role, which effectively clears the necrotic tissue and resists the invasion of exogenous pathogens, and is a key link in the healing sequence. However, chronic wounds are often trapped in a continuous inflammatory cycle due to adverse factors such as abnormal differentiation of macrophages, imbalance of neutrophil metabolism, excessive release of pro-inflammatory cytokines and bacterial infection. This long-term inflammatory state is extremely harmful, not only hindering the wound healing process, but also promoting the formation of excessive scar tissue. In view of this, regulating and reducing the level of excessive inflammatory response during wound healing has become an extremely challenging task to accelerate chronic wound healing. In this context, the innovative strategy of integrating electrical stimulation technology with conductive dressing platform has shown significant advantages, which can accurately regulate the expression levels of growth factors and inflammatory factors, and effectively prevent excessive extension of inflammatory period. Furthermore, anti-inflammatory therapy, as an adjunct, plays a crucial role in facilitating the smooth transition of the wound from the inflammatory phase to the proliferative phase. This transformation is a crucial link in achieving full wound healing and functional recovery (Xu et al., 2021). In summary, it is expected to open up a new path for efficient healing of chronic wounds through the comprehensive application of multiple strategies such as electrical stimulation, conductive dressing and anti-inflammatory therapy.

The individual factors of patients influence the efficacy of electrical stimulation. In the study by Zanto et al. (2021), the researchers pointed out that individual differences have a significant impact on the therapeutic effects of transcranial alternating current stimulation (tACS), primarily manifested in two aspects: neuroanatomical structure and neurophysiological characteristics. From a neuroanatomical perspective, variations in skull thickness, cerebrospinal fluid distribution, subcutaneous fat content, gyral morphology, and local tissue heterogeneity among individuals lead to differences in electrical conduction impedance. As a result, the same intensity of tACS can produce significantly varying electric field strengths in the cerebral cortex of different individuals. From a neurophysiological standpoint, due to inherent differences in endogenous neural oscillatory activity, the intervention effect of tACS is most pronounced when the stimulation frequency is close to the individual’s intrinsic peak oscillation frequency. Research data indicate that in long-term theta-band stimulation experiments, subjects whose baseline theta peak frequency was closer to the 6 Hz stimulation frequency exhibited more significant improvements in multitasking ability after the intervention. Further analysis revealed that the synergistic effect of simulated electric field strength and baseline theta peak frequency, these two key factors, could explain 54%–65% of the interindividual variability in tACS intervention outcomes. This finding underscores the importance of considering individual differences in the clinical application and experimental design of tACS.

In the study by Mahmood et al. (2019), ES was proven to effectively improve impaired wound healing in diabetic animals. Using an alloxan-induced diabetic rabbit model, the results showed that diabetic animals receiving ES treatment (T3 group) exhibited a significant acceleration in wound healing, with a reduction in wound area of 0.3–0.2 cm² per treatment session. Although their healing rate was slower than that of non-diabetic animals (T2 group), it was significantly better than that of the diabetic control group receiving only insulin treatment (T4 group). Notably, the T4 group failed to achieve complete wound healing after seven treatment sessions, whereas the T3 group reached full healing within the same timeframe. This result clearly demonstrates the specific therapeutic advantage of ES for diabetic wounds. Mechanistically, ES may promote diabetic wound repair through multiple pathways: first, by simulating endogenous injury electric fields to directionally guide the migration of epithelial cells and fibroblasts; second, by activating the MAP kinase signaling pathway to enhance cell proliferation and improve the recruitment of inflammatory cells (neutrophils and macrophages); additionally, ES exhibits significant metabolic regulatory effects, including lowering blood glucose levels (by enhancing insulin receptor sensitivity and glycogen synthesis), reducing oxidative stress (through the neutralization of free radicals by exogenous electrons), and improving lipid profiles (manifested as a mild increase in HDL and reductions in LDL and triglyceride levels). These findings not only provide a new therapeutic strategy for impaired wound healing in diabetes but also offer important insights into the biological effects of ES.

In the study by Khalil and Merhi (2000), the researchers explored the effects of non-invasive transcutaneous electrical nerve stimulation (TENS) on sensory nerve activation in aged rats and its impact on wound healing. With aging, the regulatory capacity of sensory nerves on cutaneous vascular responses declines, leading to weakened neurogenic inflammation and thereby impairing wound repair efficiency. The experiments found that low-frequency (5 Hz) TENS stimulation significantly enhanced blood flow responses in the hind paw pads of aged rats, with vasodilatory effects similar to those observed in young rats, indicating that the sensory nerves of aged individuals retain responsiveness to low-frequency electrical stimulation. In a thermal injury model, aged rats receiving TENS treatment showed significantly shorter wound healing times (14.7 ± 0.2 days) compared to the sham-treated group (21.8 ± 0.3 days), confirming that low-frequency TENS can promote tissue repair by activating peripheral sensory nerves. Furthermore, the study found that the sympathetic nervous system plays a limited role in the vascular responses induced by low-frequency TENS, as no significant regulatory effect of sympathetic nerves on vasodilation was observed in either young rats with sympathetic blockade by phentolamine and guanethidine or aged rats under low-frequency stimulation conditions.

The cellular microenvironment in wound regions exhibits extreme complexity, encompassing diverse cytokines, GFs, and intricate intercellular interactions. This complexity results in marked variations in ES responsiveness across wound types, as documented in reference. Furthermore, interpatient heterogeneity in local tissue physiology-including circulatory status and neural functionality-may lead to differential responses to identical ES parameters.

ES-mediated effects on wound microenvironments may extend beyond localized areas, potentially inducing systemic physiological alterations. For instance, ES may exert systemic effects through modulating systemic inflammatory responses, immune regulation (IR), or metabolic processes, thereby indirectly influencing patients’ global health status (Gupta and Krasnoslobodtsev, 2024). However, the mechanisms and scope of ES-induced systemic effects-including their spatial distribution and intensity gradients-remain poorly characterized, necessitating further mechanistic investigations. The ES dose-response relationship constitutes a critical research focus. Variations in ES parameters-including current intensity, frequency, waveform, and stimulation duration (SD)-demonstrate differential healing impacts. Establishing optimal ES parameters and their patient-specific adaptation based on wound types and individual variations is paramount for achieving personalized ES therapy (PET) and treatment optimization. Future studies must investigate ES parameter-therapeutic efficacy correlations while developing protocols to optimize ES regimens according to wound characteristics and patient physiology.

Integrative therapeutic strategies significantly enhance wound healing outcomes. ES combined with drug therapy (DT) demonstrates dual benefits: enhancing pharmacological efficacy while reducing drug resistance development. This synergistic effect potentially stems from ES-induced modulation of cell membrane permeability (CMP) that facilitates intracellular drug transport, coupled with enhanced drug action through cellular signaling pathway regulation (Zhao et al., 2020; Ryu et al., 2024). Furthermore, ES-biomaterial integration improves biomaterial performance via controlled release (CR) of bioactive substances and enhanced host tissue integration, collectively elevating healing quality (Ren et al., 2024).

Current research on ES-based combination therapy (CT) remains in the exploratory phase. While existing studies suggest potential synergistic effects between ES and adjunct therapies, their mechanistic foundations (MFs) and optimal implementation protocols (OIPs) require systematic validation. Future investigations must elucidate ES-therapeutic modality interactions and develop CT optimization frameworks to maximize therapeutic outcomes. This necessitates establishing ES parameter optimization matrices, selecting drug therapy/biomaterial components through compatibility screening, and conducting rigorous safety-efficacy (SE) assessments of CT regimens. Furthermore, researchers must systematically investigate AEs and RPs associated with ES-based CT to ensure TS. This safety-centric approach will enable development of precision-engineered CT regimens that optimize ES parameters while mitigating MRs, ultimately providing novel therapeutic strategies for CWs and HHWs.

Traditional implantable medical devices (such as pacemakers) face two core challenges: limited energy supply and insufficient biocompatibility. Currently, such devices primarily rely on disposable batteries or external power sources, which not only have limited endurance but also require secondary surgeries to replace batteries, increasing patients’ medical risks and financial burdens. Additionally, the large size and rigid nature of traditional batteries restrict the miniaturization and flexibility of these devices, while the suboptimal biocompatibility of some materials can trigger immune rejection, chronic inflammation, and tissue fibrosis, thereby affecting device performance and long-term safety.

To overcome these limitations, self-powered technologies have become a research hotspot, among which TENG and PENG show significant potential. These technologies capture mechanical energy from human motion, heartbeat, or respiration and convert it into electrical energy, enabling self-powering of devices. For example, a TENG-based symbiotic pacemaker can directly drive pacing circuits using the mechanical energy of heartbeats, significantly reducing reliance on traditional batteries. Meanwhile, supercapacitors, with their high biocompatibility, rapid charge-discharge characteristics, and ultra-long cycle life, are considered ideal energy storage units, further enhancing system sustainability.

In terms of material design, the development of new electrodes and encapsulation materials has become crucial. Flexible electrodes (such as organic semiconductors, CPs, or hydrogel-based materials) mimic the mechanical properties of biological tissues, significantly reducing the modulus mismatch at the implantation interface and minimizing tissue damage risks. Hydrogel electrodes can also optimize conductivity by incorporating conductive nanomaterials (such as carbon nanotubes or graphene) while maintaining excellent biocompatibility. Encapsulation materials must balance biostability and degradability—for instance, flexible polymer materials like poly(lactic-co-glycolic acid) (PLGA) can protect electronic components while safely degrading after service, eliminating the need for secondary removal surgeries.

However, several technical bottlenecks remain in this field: First, the long-term stability and energy conversion efficiency of TENG/PENG in dynamic physiological environments require further optimization. Second, electrode materials must balance conductivity, flexibility, and biocompatibility, and the long-term interaction mechanisms at the tissue interface still need in-depth exploration. Additionally, systematic research on the degradation rate control of biodegradable materials and their long-term effects on the body is still lacking.

Looking ahead, with the integration of multidisciplinary fields (such as materials science, micro/nano energy, and artificial intelligence), implantable devices will evolve toward intelligence and personalization. By incorporating IoT and remote monitoring technologies, real-time data transmission and adaptive control become possible, driving innovation in precision medicine. Breakthroughs in this field will not only address existing clinical pain points but also expand into emerging applications such as neuromodulation and wearable medical technologies (Cui et al., 2024).

Conventional ES regimens require patients to connect to external power sources (EPSs), which restricts mobility and elevates infection potential (IP) due to wire penetration through wound dressings (WDs) or direct skin contact. To address these limitations, developing self-powered ES devices has become a research priority. Current SPD variants primarily include biofuel cells (BFCs), triboelectric nanogenerators, and piezoelectric materials (PEMs) (Gupta and Krasnoslobodtsev, 2024). These systems enable personalized, continuous energy delivery (CED) while reducing EPS dependence and improving patient mobility (PM).

SPDs face critical technical challenges (CTCs) including limited reactant supply (RS), environmental sensitivity, and suboptimal energy conversion efficiency (ECE) (Preetam et al., 2024). These limitations compromise SPD reliability and practical applicability (PA). Addressing these CTCs requires interdisciplinary integration of materials science (MS), energy technology, and bioengineering to develop next-generation SPDs with enhanced stability, user-friendliness, and biosafety.

Current clinical practice lacks universally accepted macroscopic assessment criteria for WHP. Specialized evaluation systems (SESs) remain underdeveloped for specific wound types (SWTs) including burn wounds and diabetic foot ulcers (DFUs), complicating therapeutic efficacy comparison and analysis. While tissue biopsy techniques enable direct observation of cell proliferation (CPx), differentiation, and extracellular matrix (ECM) synthesis, inconsistent operational protocols (OPs) for sampling locations (SLs), frequency, and analytical methods (AMs) create protocol variability (PV). This PV compromises data accuracy (DAc) and comparability of critical parameters like CPx, ultimately hindering definitive TEE of ES interventions.

To enhance the accuracy and reliability of WHP assessment, future studies must develop and validate standardized assessment tools and methods (SATMs). This includes defining optimal SLs, frequency, and AMs for tissue biopsies to ensure data consistency (DCn) and comparability. Additionally, researchers should integrate non-invasive evaluation techniques such as imaging modalities and biomarker analysis to provide novel perspectives for WHP monitoring. These advancements aim to achieve precise and objective evaluation of the WHP, thereby establishing a robust scientific foundation for therapeutic TEE of interventions like ES. Such progress is critical for optimizing treatment protocols (TOs), improving TOs, and ultimately enhancing patient prognoses.

In the treatment of chronic wounds, the selection of minimally invasive implantable power sources requires comprehensive consideration of energy requirements, biocompatibility, safety, and clinical applicability. For short-term treatment needs, biodegradable primary batteries or supercapacitors are ideal choices due to their no-need-for-removal and minimally invasive characteristics, but their degradation mechanisms and energy density need optimization. For long-term treatment, rechargeable secondary batteries or human energy harvesting technologies (such as nanogenerators and biofuel cells) show greater potential, though challenges like charging convenience, output stability, and biocompatibility must be addressed. Wireless energy transmission technologies (such as near-field wireless charging, ultrasound, or photovoltaic power) can reduce infection risks associated with physical connections, but their efficiency, safety, and device size still require improvement. Clinical decisions should be based on wound type, treatment duration, and patient-specific factors, prioritizing flexible, lightweight power solutions with high tissue compatibility, while integrating dynamic energy management and multifunctional technologies to achieve efficient and safe chronic wound healing. In the future, through material innovation, structural optimization, and intelligent power management, minimally invasive implantable power sources are expected to play a greater role in precision medicine (Xu M. et al., 2024).

Non-invasive Degradative Wave (DW) electrical stimulation has been shown to effectively enhance blood flow and hemoglobin levels in acute skin wounds without affecting wound closure time, indicating its potential application in promoting acute wound healing. Although ES has proven beneficial for wound repair, the mechanisms of DW, optimal device selection, and dosing protocols require further exploration. Using a temporal skin biopsy model combined with non-invasive assessment methods such as spectrophotometric intracutaneous analysis (SIAscopy) and full-field laser perfusion imaging (FLPI), studies have found that DW significantly improves blood flow perfusion and oxygenation in acute wounds. However, due to limitations such as small sample size (n = 20) and insufficient monitoring time points, only more pronounced effect differences could be detected. Future research should expand sample sizes, extend observation periods, and further investigate the role of DW in reducing pathological scars (such as hypertrophic scars and keloids) to facilitate its clinical translation (Ud‐Din et al., 2012).

Electrical stimulation dressings demonstrate significantly superior antibacterial effects in infected wounds compared to traditional dressings. Their antimicrobial mechanisms primarily rely on electrical stimulation, zinc ion release, and the generation of reactive oxygen species. These mechanisms can disrupt bacterial cell membranes or interfere with their metabolism, thereby effectively inhibiting bacterial growth. In contrast, conventional cotton dressings, due to their hydrophilic nature, tend to provide a favorable environment for pathogenic bacteria and lack inherent antibacterial activity. Experiments have shown that they fail to form a noticeable zone of inhibition and exhibit almost no ability to suppress or kill bacteria (Wang S. et al., 2024).

Although electrical stimulation offers numerous advantages in promoting wound healing, such as accelerating tissue repair and reducing infection risks, its application still faces certain limitations, particularly regarding cost. Compared to traditional dressings (e.g., gauze, hydrocolloid dressings, etc.), the procurement and maintenance expenses of electrical stimulation devices and related consumables are considerably higher. Additionally, the treatment process often requires professional operation, further increasing medical costs. Therefore, in routine wound care or resource-limited healthcare settings, economical and convenient traditional dressings remain the more common choice. Moving forward, to facilitate the widespread adoption of electrical stimulation technology, the key lies in reducing costs through technological optimization and large-scale production or developing more affordable portable devices to enhance clinical accessibility (Nicksic et al., 2022).