Thermoelectric materials for skin wound healing

2.1 Classification of thermoelectric materials

Recent studies have logically demonstrated the key role of the Seebeck effect in biomedical applications. From a microscopic perspective, the Seebeck effect originates from the behavior of charge carriers within a material under a temperature gradient. For a single, standalone material, when the temperature inside it is uniform, the distribution of charge carriers is also relatively uniform. Once a temperature difference (ΔT) arises, the charge carriers at the hot end possess higher kinetic energy, so they diffuse toward the cold end and accumulate there. The nonuniform distribution of charge carrier concentration generates a built-in EF inside the material, which induces charge drift motion within the material. The direction of this charge drift motion is opposite to that of the charge diffusion motion driven by the temperature field, thus preventing further diffusion of charge carriers. When these 2 movement tendencies reach equilibrium, there is no net charge flow inside the material, and a stable electric potential U is formed across the 2 ends of the material. The Seebeck coefficient ($S$) of a single material under a temperature difference (ΔT)can be expressed as:

For a circuit composed of 2 different materials (A and B), its Seebeck coefficient (S) can be expressed as:

To evaluate the energy conversion efficiency of TE materials, the dimensionless figure-of-merit (ZT)^[18,19] is defined as:

where $\sigma$ is electrical conductivity, $T$ is absolute temperature, $\kappa$ is thermal conductivity, and $PF$ is the power factor. The values of $S$, σ, and T are highly coupled, so decoupling them poses the main challenge in enhancing the performance of the composite material.

TE materials are categorized into n-type and p-type based on their dominant charge carriers, and differences in the dominant mobile charge carriers between these 2 types result in variations in the direction of current flow within the TE materials^[20]. The main carriers in n-type TE materials are electrons, whose migration and motion play a key role in the TE properties of the material. Under the action of EF, the electrons can move rapidly and directionally to form an electric current, thus generating the TE effect^[21]. It usually has high conductivity, which is favorable for the transport of electrons and can reduce the Joule heat loss, thus improving the TE conversion efficiency of the material. And the absolute value of its Seebeck coefficient is relatively high; a higher Seebeck coefficient means that under the same temperature difference conditions, the material can produce a larger voltage, which is very important for the improvement of TE conversion efficiency. The main carriers in p-type TE materials are holes, whose migration and motion lead to the generation of electric current and the TE effect. The mobility of holes is usually relatively low compared with electrons in n-type TE materials^[22]. P-type TE materials generally have positive Seebeck coefficients, which are comparable or slightly lower in absolute value than the Seebeck coefficients of n-type TE materials. In terms of conductivity, p-type TE materials may have a slightly lower conductivity relative to n-type materials^[23].

Based on the type of material, they can be categorized into inorganic TE materials, organic TE materials, and their composite materials in Table 1. Inorganic TE materials have better TE properties than organic TE materials. Bismuth telluride (Bi₂Te₃)-based flexible TE devices possess the characteristics of being lightweight, compact in size, and highly deformable. These devices are capable of harvesting electrical energy from temperature gradients, thereby serving as an energy source for wearable devices^[32], as shown in Figure 2. Additionally, they can function as miniature TE cooling pads for localized refrigeration applications^[34]. Lead telluride-based semiconductors^[35], skutterudites^[36], and Half-Heusler alloys^[37] have the ability to convert thermal energy into electrical energy. These materials can be applied in scenarios such as power generation from industrial waste heat and the recovery of waste heat from automotive exhaust. By doing so, not only is the energy utilization efficiency enhanced, but emissions can also be reduced. Organic TE materials have been widely applied due to their abundant resources, low cost, excellent flexibility, and high biocompatibility^[38]. Poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS), characterized by its relatively high electrical conductivity and excellent flexibility, is one of the organic TE polymer materials that have been extensively investigated and demonstrate outstanding performance. It holds potential application values in fields such as flexible TE devices^[39] and wearable electronic devices^[40]. Polyaniline (PANI) exhibits excellent electrical conductivity and a notable TE effect. It can be prepared through simple processes such as the solution method, and its relatively low production cost makes it advantageous^[41]. PANI is applicable for the fabrication of various materials and devices, including biosensors and electrode materials. Composite materials integrate the respective advantages of organic and inorganic materials. To a certain extent, they can achieve a synergistic enhancement of electrical conductivity and the Seebeck coefficient, thereby improving the TE properties of the materials, which is manifested as an increase in the power factor (PF). Consequently, this leads to an improvement in the TE conversion efficiency^[42]. Some TE materials have been applied in the medical field, such as Bi₂Te₃, PEDOT:PSS, and others; while other TE materials are expected to be further extended to multiple research and application directions in the biomedical field through systematic performance-enhancement strategies, such as rational material design, optimization, or the doping of other substances.

2.2 Interaction mechanisms of thermoelectric materials with skin wounds

TE materials exploit the Seebeck effect to directly convert the small temperature gradient between a skin wound and the surrounding environment into a microcurrent, forming the physical basis for the electrical signal interaction between the device and the wound. When a temperature gradient exists across the material, charge carriers diffuse from the high-temperature side (wound) to the low-temperature side (environment), generating a potential gradient whose magnitude depends on both the material’s Seebeck coefficient and the temperature gradient^[43]. Enhancing conversion efficiency requires materials with a high Seebeck coefficient and optimized interfacial thermal resistance^[42]. Crucially, this process does not require an external power source, achieving a self-powering operation that provides a solid foundation for continuous treatment.

As shown in Figure 3A, normal epithelial tissue establishes a transepithelial potential (≈10–60 mV) through sodium, potassium, and chloride ion transport (Na⁺, K⁺, Cl⁻)^[44]. Following epithelial disruption, ion pumps in epithelial cells generate an extracellular EF, termed the endogenous EF (≈40–200 mV/mm, directed from wound edge to center) in Figure 3B and C^[45]. Chronic wounds exhibit persistent inflammation and excessive matrix degradation, reducing endogenous EF strength and impairing fibroblast migration;^[16] electrolyte loss at the wound site further attenuates the endogenous EF, hindering cell migration/proliferation and significantly impeding skin regeneration^[46]. Consequently, EF modulation represents a promising therapeutic strategy. When a temperature differential (ΔT = 10 K, simulating body-environment variance) is applied, the TE material generates a microcurrent (5–35 μA/cm²) that reconstructs the impaired endogenous EF—rendering wound-site field intensity approximately physiological—while directing cell adhesion and migration toward the wound center^[47]. This process simulates physiological electrical signals, compensates for the endogenous EF deficiency in chronic wounds, and activates electrophysiological behavior in injured cells/tissues to achieve treatment.

The inflammatory response in skin wound healing manifests phased characteristics^[48]. The acute inflammatory phase commences with the release of histamine by mast cells. Neutrophils infiltrate rapidly and peak within 24 hours. The concentration of the pro-inflammatory cytokine tumor necrosis factor-α surges promptly, facilitating the clearance of pathogens and necrotic tissues^[49]. If inflammation fails to resolve in a timely fashion, the transition to the chronic inflammatory phase occurs. During this stage, M1-type macrophages constitute over 70% of the cell population, continuously secreting the pro-inflammatory cytokine IL-6. Concurrently, the activity of matrix metalloproteinase-9 escalates by a factor of 3 to 5, culminating in the over-degradation of the extracellular matrix^[50]. This phase is accompanied by pronounced oxidative stress, with the level of ROS being tens of times higher than that in normal tissues^[51]. Consequently, protein carbonylation modification increases by 40%, further inhibiting the repair process^[52]. In physiological wound healing, the concentration of vascular endothelial growth factor (VEGF) peaks at 72 hours after injury, driving sprouting angiogenesis. Nevertheless, in chronic wounds, the expression of VEGF diminishes by 40%^[53]. Simultaneously, there is a disruption in the balance of vascular stabilization signals, thereby establishing a repair-destruction vicious cycle, which ultimately obstructs reepithelialization and functional restoration. Electrical signals trigger multidimensional repair effects by activating related signaling pathways. As shown in Figure 4, the EF generated by silver selenide (Ag₂Se) notably downregulates the expression of prolyl hydroxylase 2, thereby enhancing the stability of hypoxia-inducible factor-1α (HIF-1α) and preventing its ubiquitin-mediated degradation. As a transcription factor, HIF-1α promotes the expression of VEGF-A, a key mediator of angiogenesis that facilitates endothelial cell proliferation, migration, and vessel formation^[54]. Furthermore, Qin’s study indicates that the electrical signals generated by Ag₂Se activate voltage-gated calcium channels on the cell membrane, thereby increasing intracellular Ca²⁺ concentration. Ca²⁺ activates calmodulin-dependent kinase β, which in turn phosphorylates adenosine monophosphate-activated protein kinase. This phosphorylation event subsequently triggers the activation of the nuclear factor-erythroid 2 related factor 2, enhancing mitochondrial function while improving mitochondrial dynamics. Collectively, these cascades promote endothelial cell proliferation and tube formation, accelerate fibroblast migration, and facilitate angiogenesis and tissue regeneration^[55]. The TE device fabricated by Zhang et al.^[56] that not only promotes wound healing but also demonstrates that the microvolt-level electrical signals it generates activate the mechanosensitive ion channel Piezo1. The microvolt-level electrical signals generated by TE materials can also activate the mechanosensitive ion channel Piezo1. Piezo1, in turn, upregulates the expression of HIF-1α and VEGF, thereby enhancing fibroblast migration and proliferation as well as endothelial tube formation^[56]. Numerous studies have demonstrated that endogenous EF at wound sites is attenuated due to electrolyte loss. Leveraging the temperature difference between the wound and the surrounding environment to generate a continuous compensatory EF restores the impaired endogenous EF. The EF directs the directional migration of keratinocytes and fibroblasts via ion directional migration induced by the Soret effect, while modulating cell proliferation and adhesion^[16,57,58]. These pathways are centered on the simulation and restoration of endogenous EFs via electrical signals, which precisely regulate 3 key wound healing processes: fibroblast migration, fibroblast proliferation, and accelerated angiogenesis. Accordingly, aiding epithelial regeneration and matrix remodeling through material design has emerged as a cutting-edge research focus in the fields of biomaterials and regenerative medicine.

3.1 Flexibility for thermoelectric wound dressing

TE materials and devices are crucial in wearable technology for converting body heat into usable electrical energy to treat skin wounds. However, they must adapt to the complex deformations of human skin. During daily activities, the skin undergoes movements, including joint flexion/extension, muscle contraction, and changes from wound swelling or inflammation^[59]. Flexible design is therefore paramount for effective integration into wearable systems, ensuring functionality maintenance while accommodating natural body motion and contours.

In wound dressing applications, hydrogels, owing to their 3-dimensional (3D) structure with a large number of pores inside (Figure 5A), not only enhance physical adsorption but also facilitate permeation of water, nutrients, and bioactive molecules, imparting excellent permeability^[60]. This characteristic is vital for wound healing and showcases significant application potential. Notably, Figure 5B–D demonstrates that hydrogels also exhibit exceptional flexibility^[61,63]. Hydrogels exhibit remarkable stretchability and elasticity, enabling deformation synchronized with skin movement to ensure continuous contact with the wound. Regardless of joint articulation or bodily motion, hydrogel dressings conform without detaching or tearing during skin stretching/flexion. This flexibility significantly enhances patient comfort—preventing dressing-induced secondary trauma—while crucially maintaining a stable wound microenvironment to facilitate healing. Furthermore, hydrogels’ inherent flexibility allows fabrication into diverse shapes/sizes, enabling customization for specific wound characteristics to meet varied clinical needs^[64]. In recent years, hydrogel materials, owing to their distinctive properties, particularly the TE behavior, have been replicating the inherent EF^[65]. This endeavor has propelled the research, development, and evolution of TE hydrogels. Figure 5J depicts Tan et al.^[64] synthesized a TE hydrogel with excellent flexibility, which achieves the simulation of the endogenous EF by virtue of material design and temperature difference-driven mechanisms, thereby addressing the problem of EF deficiency caused by electrolyte loss in diabetic ulcers. The monomer polyether F127 incorporated in this hydrogel demonstrates remarkable stretchability, endowing it with the capacity to modulate the mechanical properties of the hydrogel system. Evident from the research findings, a wireless thermoelectric hydrogel embedded with therapeutic exosomes (HFN-RGE) exhibits a maximum tensile strain surpassing 200% and a maximum compressive strain of around 81% in Figure 5F, G, allowing it to adapt proficiently to the deformations of the human body surface. Moreover, under a 25% tensile or compressive strain, its Young’s modulus measures 68.10 KPa and 129.55 KPa, respectively. Figure 5H, I shows that even following 20 cycles of 50% tensile or compressive strain, the hydrogel is capable of completely reverting to its initial state, with the hysteresis ratio consistently maintaining at a relatively low value below 0.1. These inherent characteristics empower the device to adapt with flexibility to diverse movements and deformations of the skin during its practical application^[62]. This research provides a guiding example for the future treatment of diabetic ulcers.

In wound-healing research, beyond hydrogels, the emergence of TE devices fabricated from conventional TE materials represents a promising alternative for accelerating wound recovery. These devices utilize temperature gradients to generate electrical energy, delivering microcurrent stimulation to wounds that promotes cell proliferation and migration. Furthermore, their unique material and structural designs offer advantages in adapting to the body’s complex physiological environment. For instance, Zhang et al.^[56] engineered a circular TE device, thereby ushering in a novel breakthrough in the realm of wound-healing treatment. Figure 5K demonstrates TE structures deposited on a flexible polyimide (PI) substrate via magnetron sputtering. These structures utilize the natural temperature difference between the skin and the environment (6–30 K achievable in daily life) to spontaneously generate electrical energy, and deliver an output voltage of 10 mV under a temperature difference of 10 K, without the need for an external power supply. The left panel shows the circular-shaped multi-leg TE device, consisting of 6 pairs of n-type Bi₂Te₃ and p-type Bi_0.5Sb_1.5Te₃ rectangular thin layers, is sealed by a flexible PI layer. The black and red arrows mark the TE materials and Cu electrode, respectively. The right panel illustrates that this device is extraordinarily flexible, and it can be folded manually. As shown in Figure 5E, under a bending radius of 12 mm, following 400 bending cycles, its internal resistance experiences a negligible decrease. This phenomenon attests to its stable performance postrepeated bending and implies a protracted service life, endowing it with the ability to accommodate the deformation of the skin during locomotion. In terms of its structural configuration, the implementation of a circular design enables it to conform intimately to the skin surface and adapt to wounds located on diverse body regions, thus exemplifying commendable flexibility and tensile capabilities^[56].

Although progress has been made in the TE wound therapy devices, significant challenges must be overcome to achieve widespread clinical adoption and market penetration. At the structural design level, current devices lack adequate thinness and fit, necessitating innovative breakthroughs to develop thinner, lighter, and better-fitting device configurations. Through the use of advanced manufacturing technologies such as 3D printing and personalized customization based on the shape, size, and location of different wounds, it is possible to achieve a close fit between the device and the wound, which significantly improves the therapeutic effect^[66]. At the same time, the development of stretchable and foldable structures is the key to adapting the device to the movements and deformations of various parts of the body. Ensuring that the device can cope with complex scenarios, such as joint wound treatment, without affecting its TE properties will ensure that the device continues to work stably^[67]. Wu et al.’s study demonstrated that Ag₂Te_1-XS_X (0.3≤ X ≤0.6) achieves an ultrahigh elongation of up to 10150% via the mechanism of “anionic sublattice amorphization and Ag⁺ ion diffusion.” Notably, it can trigger plastic strain with only low stress without structural collapse. Meanwhile, its intrinsic superionic conductivity and plasticity exhibit a synergistic effect: during deformation, the rigid anionic sublattice transforms into a metastable amorphous phase while maintaining local bonding integrity^[68]. Their results directly confirm that the designed TE material can conform to irregular wounds, accommodate limb movements, and retain stable TE performance without degradation during deformation. This provides strong support for the selection and design of ideal TE material systems for wound therapy. In terms of clinical application, the safety and efficacy of the device in the treatment of different types of wounds have not yet been adequately studied. In the future, more clinical trials need to be conducted to explore the effectiveness of the device in various wound types and treatment scenarios, and to obtain sufficient clinical data to support and accelerate the product’s approval by the regulatory authorities^[69]. In addition, reducing the manufacturing cost of the device and improving the production efficiency are equally important directions to promote the large-scale clinical application and market promotion of the device.

3.2 Biocompatibility for thermoelectric wound dressing

Presented in Table 2, TE materials demonstrate unique advantages in wound healing, offering novel therapeutic directions. Ensuring treatment safety and efficacy necessitates an in-depth investigation of TE material-biological tissue interfacial interactions^[77]. Biocompatibility, a critical safety criterion for clinical implantation, holds particular significance for these materials, encompassing immediate cell/tissue responses, long-term stability, immune responses, and body fluid compatibility^[78].

Comprehensive assessments elucidate the biodegradation behavior of TE materials in vivo, including metabolic pathways and effects on cells, tissues, and organs, as characterized in Figure 6E^[83,84]. This, in turn, provides a key basis for its rational design and optimization. In the evaluation process, in vitro and in vivo test methods should strictly follow internationally recognized standards and norms, such as the ISO 10,993 series of standards^[85].

A systematic biocompatibility assessment is therefore essential to ensure the safe and effective use of TE materials in biological systems. Gao et al.^[24], conducted a comprehensive in vitro and in vivo biocompatibility assessment of 12 typical sulfur compound TE materials, and determined that Ag₂Se, Bi₂Se₃, and Bi₂Te₃ have good biocompatibility, which provides an important basis for their application in the biomedical field. In contrast, materials containing high concentrations of tellurium (Te) ions, such as Te, GeTe, SnTe, MnTe, Bi_0.5Sb_1.5Te₃, and Sb₂Te₃, which have a concentration of Te ions higher than 7.2 ppm, high concentrations of Te trigger irreversible oxidative stress, disrupting intracellular tissues and energy homeostasis, and exhibit significant cytotoxicity^[24].

Bi₂Te₃-based composite TE materials are known for their very high room-temperature stability, ease of deposition, high electrical conductivity, and low thermal conductivity^[86]. The highest known TE ZT value at room temperature (ZT = 1.86 at 300 K)^[87]. Therefore, Bi₂Te₃-based materials have been widely used in biomedical applications. Gao et al.^[24] made disc-shaped samples of Bi₂Te₃ (10 mm in diameter and 1 mm in thickness) and implanted them subcutaneously in male Sprague-Dawley (SD) rats. Blood samples and tissue samples from vital organs, including liver, kidney, and heart, as well as those near the implantation site, were collected at 3, 7, and 30 days after implantation for a comprehensive study of in vivo biocompatibility. The results of hematological analysis showed that the key blood parameters of the rats, such as red blood cells, white blood cells, and hemoglobin, were all within the normal range, with no significant difference compared with the titanium alloy control group, which indicated that it has less impact on the blood system, suggesting that it has less impact on the organism and has relatively good biocompatibility. Hematoxylin–eosin (H&E) staining of the collected heart, liver, spleen, subcutaneous tissues, and other important organs showed that these organs did not show obvious pathological changes, and the tissue structure remained intact, indicating that the tissues have a relatively good compatibility between Bi₂Te₃ and the surrounding biological tissues^[24]. In addition, Ma et al.^[80] investigated the biocompatibility of Bi₂Te₃ nanoparticles based on cytotoxicity and hemolysis experiments, and Figure 6B showed that the cell viability of Bi₂Te₃ nanoparticles at different concentrations did not show any significant decrease after 24 hours of incubation in 96-well plates with 4T1 breast cancer cells, which suggests that the composites do not have toxicity effects on cells and have good biocompatibility. This indicates that the composite material does not have toxic effects on cells and has good biocompatibility. Different concentrations (0.125, 0.25, 0.5, 1, and 2 mg/mL) of Bi₂Te₃ nanoparticles were dispersed in PBS, and 0.3 mL of blood was taken and mixed with 1.2 mL of the sample dispersion and incubated for 4 hours at room temperature. The results showed that the hemolysis rate was at a low level, which further proved that the nanoparticles had good biocompatibility and would not cause damage to the blood system, providing stronger support for their application in biomedical fields^[80]. Considering the high toxicity of Te elements, when TE devices are in direct contact with the human body, their potential hazards cannot be ignored. Therefore, it is crucial to effectively prevent these harmful substances from coming into contact with the human body. In this case, PI plays an important role, which is the most common flexible substrate material in the field of TE devices, and the staining of the living dead cells in Figure 6A shows that PI is more biocompatible than latex rubber, which avoids any toxicity to the organ^[79]. Zhang et al.^[56] developed a TE device utilizing Bi₂Te₃-based compounds as the core material. The device demonstrated superior TE performance near room temperature and exhibited robust stability under various environmental conditions. To prevent the possible toxicity of the Te element in the material to living organisms, the device is completely sealed with PI for the entire TE device. This avoids direct contact between the TE material and human tissue and guarantees the biocompatibility of the device at the material level and in the package design^[56].

Nevertheless, Te is scarce, expensive in the Earth’s crust, and furthermore exhibits potential toxicity, rendering it unsuitable for devices requiring long-term human contact^[88]. Moreover, they are also more toxic and not suitable for the preparation of devices that are in long-term contact with the human body. Consequently, developing novel Te-free TE materials has attracted extensive research interest. Ag₂Se, a narrow bandgap n-type semiconductor, exists as a stable orthorhombic phase (β-Ag₂Se) at room temperature (298 K). Its crystalline structure transforms from orthorhombic to cubic (α-Ag₂Se) at approximately 407 K. Notably, β-Ag₂Se exhibits remarkable TE properties at room temperature, with ZT ranging from 0.32 to 1.2^{[89–90–91–92–93–94–95]}. Ag₂Se exhibits significantly low toxicity and cost, and its room-temperature TE performance has garnered considerable attention. Gao et al.^[24] implanted Ag₂Se subcutaneously into SD rats and monitored at different time intervals for a comprehensive study of its in vivo biocompatibility. H&E staining of the collected organ tissues showed that the heart, liver, spleen, lungs, kidneys, and brain showed no significant pathological changes, and the tissue structure remained intact. This showed that the tissues were well adapted to Ag₂Se, and the material had some compatibility and tissue integration with the surrounding biological tissues. H&E staining and Masson trichrome staining of the subcutaneous tissue at the implantation site showed no signs of macroscopic rupture, infection, necrosis, or edema, reflecting the biocompatibility of the material with the surrounding biological tissues^[24]. In addition, Ren et al.^[82] synthesized Bio-Ag₂Se nanoparticles as antimicrobial agents from the yeast strain R. mucilaginous PA-1 and evaluated their safety on human and plant cells by cytotoxicity assays. In humans, 293T cells (epithelioid cells) and Jurkat cells (immortalized T-lymphocyte cell line) were selected, and the cells were treated with medium containing 1.08 μg/mL and 2.16 μg/mL of Bio-Ag₂Se nanoparticles, respectively. The assay was performed using cell counting kit-8 reagent, and the relative cell viability was calculated. Figure 6D shows that the relative viability of 293T cells treated for 24 hours was (96.6 ± 8.3)% and (81.2 ± 8.2)% at the concentrations of 1.08 and 2.16 μg/mL, respectively, which was not significantly (P < 0.05) different from that of the untreated control group (with a viability of [100 ± 19.0]%). The difference was not significant (P < 0.05). The relative viability of Jurkat cells was (115.3 ± 6.9)% and (94.8 ± 3.0)% after 24 h of treatment at the same concentration, respectively, and there was no significant cell death compared with untreated control (viability of [115.3 ± 6.9]%) (P < 0.05), and the exposure to Bio-Ag₂Se nanoparticles Jurkat cells respiratory activity slightly increased after exposure to Bio-Ag₂Se nanoparticles^[82]. The experimental results show that Bio-Ag₂Se nanoparticles have excellent biocompatibility with human cells and have potential applications in biomedical fields. Quantitative biomarkers are significant for disease diagnosis, health monitoring, and drug development^{[96–97–98]}.

Organic TEs (e.g., PEDOT:PSS) exhibit lower conversion efficiency than inorganic counterparts but offer critical advantages in reduced cytotoxicity and enhanced biocompatibility^[99]. PEDOT:PSS shows promise in soft bioelectronics due to its high conductivity and ability to electrically couple with tissues for sensing/stimulation. Yang et al.^[100] developed a highly conductive PEDOT:PSS hydrogel demonstrating good biocompatibility with PC12 cells through cytotoxicity testing, live/dead staining, and proliferation experiments, confirming its suitability for in situ cellular sensing. As a biocompatible electrical conductor, its intrinsic conductivity enables stimulation of cultured cells/tissues^[101,102]. Mostafa Yazdimamaghani et al.^[81] fabricated conductive bone scaffolds incorporating PEDOT:PSS, where Figure 6C shows enhanced cell viability peaking at 0.3%(w/w) concentration. Cells on these scaffolds exhibited extended morphology with filamentous pseudopods connecting to the surface, demonstrating effective adhesion/spreading and forming denser monolayers after 14-day culture, indicating improved scaffold conductivity and biocompatibility^[81]. Thus, with controlled concentration and surface modification, PEDOT:PSS is promising for TE therapy applications.

Although numerous strategies^{[103–104–105–106]} can enhance the biocompatibility of TE materials, establishing a comprehensive biosafety assessment system remains imperative. This requires unified standards and test methodologies to ensure material/device safety and efficacy. Concurrently, strengthening monitoring and research on the long-term biological effects is essential to generate reliable translational data, thus advancing TE materials’ widespread biomedical applications^[107].

3.3 Strategies for enhancing thermoelectric antimicrobial therapy

Bacterial infections, exacerbated by widespread misuse of antibiotics and multidrug resistance, pose an increasingly serious threat to individual and public health, and cases of failure of conventional antibiotic therapy are commonplace^[108]. In this context, the development of antimicrobial drugs with both efficacy and biocompatibility has become an urgent need to deal with drug-resistant bacteria^[109,110]. With the exploration of new strategies for infection control, the anti-infective effect of TE materials has been well demonstrated through a series of in vitro antimicrobial tests and in vivo anti-infection modeling studies. Here, we discuss ways to enhance the anti-infective ability of TE materials based on their therapeutic examples.

An effective and simple TE catalytic therapeutic strategy is the controlled release design of antimicrobials. By doping the TE materials with antimicrobial substances, the TE materials are endowed with active bacterial inhibition to solve the problem of traumatic infection while maintaining their TE properties. For example, Gao et al.^[16] doped the constructed TE hydrogel with tannic acid (TA) with antibacterial and anti-inflammatory properties in Figure 7E, which has the ability to disrupt the integrity of bacterial cell membranes and interfere with bacterial energy metabolism, thus inhibiting bacterial growth. In Figure 7A–C, the antibacterial properties against methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli were significantly enhanced with the increase of TA content in the hydrogel. This is because TA can interact with proteins and lipids on the bacterial cell membrane, disrupting the structure and function of the cell membrane and leading to leakage of bacterial contents, as well as interfering with the bacterial energy-producing process so that the bacteria are unable to grow and multiply normally. Meanwhile, excessive ROS at the wound will hinder wound healing. Figure 7D demonstrated that TA has a strong antioxidant capacity, which can effectively scavenge excessive ROS, reduce ROS-induced lipid peroxidation and DNA damage, and protect the tissues and cells from oxidative stress. TA is released into the wound environment, which can react with ROS and convert them into harmless substances, reduce the damage of oxidative stress on tissues and cells, and promote wound healing^[16]. Furthermore, Alipuly et al.^[111] constructed a hydrogel system of PANI using phytic acid and tested for antimicrobial activity. Since phytic acid is a multivalent acid, it contains several phosphate groups. These phosphate groups can interact with metal ions and proteins on the surface of bacterial cells and interfere with the normal physiological metabolic processes of bacteria. The phosphate group can bind with metal ions on the bacterial cell membrane, destroying the integrity of the cell membrane and leading to the leakage of intracellular substances, thus inhibiting bacterial growth and reproduction; it may also interfere with enzyme activities in the body of the bacteria, affecting processes such as energy metabolism and substance synthesis of the bacteria, and thus exerting an antimicrobial effect. Therefore, as shown in Figure 7F, the hydrogel containing phytic acid showed a certain inhibitory effect on both Gram-positive bacteria (S. aureus ATTC12600) and Gram-negative bacteria (E. coli ATTC25922)^[111].

Inflammatory reaction at the wound slows down the healing process^[113], and multimodal treatment with TE materials can effectively modulate inflammation. Electrical stimulation has been demonstrated to suppress bacterial proliferation by perturbing bacterial cell membrane potential and disrupting intracellular metabolic pathways^[114]. An illustrative example of this strategy is found in the work of Barman, whose design features a synergistic inhibition of bacterial growth and promotion of wound healing based on both thermal catalysis and electrical stimulation, consisting of TE-catalyzed analytical Bi₂Te₃ nanoplates (Bi₂Te₃ nanoparticles) acting on carbon fiber fabric electrodes. Figure 7G demonstrates that the Bi₂Te₃ material nanoplates (Bi₂Te₃NPs) have excellent ROS generation capability. The generated H₂O₂ has an antibacterial effect and is capable of destroying the cell membrane and intracellular biomolecules of bacteria, thus effectively inhibiting the growth of bacteria against E.coli and S. aureus. By connecting the integrated electrodes to a wearable friction nanogenerator (triboelectric nanogenerator [TENG]), the internal friction electric layer contacts and separates when subjected to external mechanical forces, resulting in charge transfer and the generation of electrical energy. The electrical stimulation generated by the TENG activates growth factors that promote cell proliferation, migration, and angiogenesis^[112]. This hybrid treatment not only acts as an antimicrobial agent but also accelerates wound healing. In addition, photothermolysis has a significant inhibitory and killing effect on bacteria, showing great potential in the antimicrobial field, while, as an effective antimicrobial treatment, the use of the near-infrared (NIR) region^[115]. Wang et al.^[70], focusing on bacterial infection wound treatment, reduced graphene oxide modified Bi₂Te₃ nanosheets (rGO-Bi₂Te₃) based on reduced graphene oxide were developed, which were experimentally demonstrated to be highly effective antibacterial against both S. aureus and MRSA in vitro and in vivo. The rGO-Bi₂Te₃ nanosheets were integrated into polyurethane fibers to make an electrostatically spun film, and the antimicrobial therapy was achieved by using near-infrared light irradiation. Figure 7H demonstrated a photothermal electrocatalytic mechanism based on the fact that under NIR light irradiation, the Bi₂Te₃ excitation produces photogenerated electrons and hot carriers, and the electrons migrate from the Bi₂Te₃ to the rGO, which efficiently separates the electron-cavity pairs to produce a large number of ROS with strong oxidizing property can destroy the bacterial cell membrane and internal proteins to inhibit bacterial growth. At the same time, the good photothermal performance of rGO-Bi₂Te₃ increases the temperature, and the thermal effect synergizes with ROS to accelerate bacterial death. In addition, rGO provides additional carrier transport channels to enhance the TE properties and promote charge transfer and separation, further enhancing the antibacterial effect^[70]. Combination with other substances or materials can activate or amplify the therapeutic effect, and combined with biocompatibility assessment, suggests that TE materials hold significant promise for antimicrobial therapy.

4.1 Electrical transmission performance optimization

The TE property enhancement of TE materials is mainly achieved by optimizing the ZT, which requires the synergistic regulation of the electrical transport properties (Seebeck coefficient S, electrical conductivity σ) and thermal transport properties (thermal conductivity κ). The core objective of the electrical transport properties optimization is to enhance the PF of the material, to increase the S and σ at the same time. Since there is a natural trade-off between S and σ, where high carrier concentration decreases S and vice versa, this limitation needs to be addressed by the following strategy:

4.1.1 Carrier concentration optimization

Optimization of the TE ZT can be achieved through meticulous control of the doping level. Such high-efficiency doping strategies enable precise engineering of carrier concentration, thereby allowing for fine-tuned manipulation of the Fermi level during material synthesis^[120]. Therefore, the carrier concentration can be regulated by doping to be at or near the optimal concentration^[121]. Doping has been widely used to activate additional electrons (n-type doping) or holes (p-type doping) to regulate the carrier concentration of a subject^[122]. Cheng et al.^[123] TE properties of β-FeSi₂ were optimized with phosphorus (P) doping at 850 K, FeSi_1.96P_0.04has the highest TE optimum ZT of about 0.12, which is much higher than the results of previous studies (the highest ZT is only 0.03 at 673 K). Meanwhile, the carrier concentration of P-doped β-FeSi₂ was changed, the highest was about10²⁰ cm^–3[123]. Meanwhile, Hou et al.^[124] investigated the effects of indium (In) doping and copper (Cu) dynamic doping on the TE properties of n-type PbS. It acted as a donor atom, replacing the Pb site to introduce free electrons into PbS, and when the indium doping concentration x = 0.0015, in Figure 8A, the carrier concentration was enhanced from 1.7 × 10¹⁶ to 3 × 10²⁰/cm³, which synergistically improves the conductivity and Seebeck coefficient, resulting in a room temperature PF of 12.3 μW/cm/K² for the PbS sample with a ZT value of 0.7. After that, Cu atoms are introduced to realize the dynamic doping, which optimizes the carrier concentration in the high-temperature region and enlarges the effective mass of the carriers, and further improves the PF in a wide temperature domain. Figure 8B shows the Pb_0.995In_0.005S + 3% Cu sample, the PF reaches a peak of 21.7 μW/cm/K² at 573 K, and the average PF reaches 18.8 μW/cm/K² at 423–823 K, and the average ZT value is improved from 0.4 to 0.8^[124]. Carrier concentration optimization has significant advantages in enhancing TE properties, but it also has certain limitations. It faces problems such as low solubility of dopant elements, difficulty in precise control, and mutual constraints of each parameter in practical applications, which are yet to be further investigated.

4.2 Thermal conductivity reduction strategies

The central aim of optimizing thermal transport properties is to reduce the thermal conductivity (κ) of materials, which consists of 2 components: electronic thermal conductivity (κₑ) and lattice thermal conductivity (κ₁). Electronic thermal conductivity adheres to the Wiedemann-Franz law,

where L represents the Lorenz number. Evidently, κₑ exhibits a direct proportionality to electrical conductivity (σ). In contrast, lattice thermal conductivity can be tuned relatively independently, rendering its reduction an effective strategy for enhancing thermal transport performance^{[142–143–144–145–146]}. Since lattice thermal conductivity is governed by phonon propagation, suppressing heat conduction through enhanced phonon scattering becomes crucial. High-symmetry cubic structured materials (e.g., PbTe, SnTe) require special properties such as phonon nesting and avoiding crossing to induce strong anharmonicity, thereby reducing κ₁. Low-symmetry structured materials (e.g., SnSe and Ag₈SnSe₆) can enhance phonon scattering via multiple mechanisms, including lone-pair electrons, weak interlayer interactions, vacancies, and ion diffusion, inherently possessing low κ₁. Defect engineering (e.g., doping and vacancy introduction) and nanostructure self-assembly (e.g., the superlattice of AgSbTe₂) are effective approaches to regulating phonon properties^[147]. When the grain size of CoSb₃ is reduced from the microscale to the nanoscale, both lattice thermal conductivity and the overall thermal conductivity of the TE material decrease significantly. Specifically, reducing the grain size from 1 μm to 100 nm lowers the thermal conductivity at room temperature from 10.67 to 3.84 W/m/K, and further decreasing it to 50 nm reduces the conductivity to 1.44 W/m/K. This trend underscores that a lower lattice thermal conductivity is advantageous for improving TE performance. The underlying mechanism lies in the nanostructuring of the CoSb₃ compound: as the grain size diminishes, the mean free path (d₁) of phonons shortens. Concurrently, the increased surface-to-volume ratio of the material amplifies phonon scattering at interfaces, thereby reducing both d₁ and the average phonon velocity (v₁). According to the formula for lattice thermal conductivity,

these reductions in d₁ and v₁ lead to a substantial decline in κ₁^[148].

Topological insulators (TIs) are quantum materials with unique electronic structures, featuring insulating bulk states and topologically protected conducting states on their surfaces or edges. Studies have shown that TIs can exhibit extremely low lattice thermal conductivity^{[144,149,150]}, and their distinctive surface conductivity holds promise to break through the limitations of semiconductor-based TE materials, achieving dual optimization of electrical and thermal properties. TIs inherently possess low κ₁ due to strong spin-orbit coupling induced by heavy atoms. Additionally, their unique band inversion drives the generation of non-parabolic warping in conduction bands/valence bands, and this warping effect can enhance weighted mobility by reducing the electrical conductivity effective mass and increasing the Seebeck effective mass^[151]. These 2 effects synergistically optimize the balance among electrical conductivity, Seebeck coefficient, and thermal conductivity. The influence of their surface states on TE performance is regulated by the surface-to-volume ratio, temperature (with a significant effect at temperatures below 200 K), and Fermi level: the higher the surface-to-volume ratio, the greater the contribution of surface states; as temperature increases, bulk states become dominant; and the Fermi level regulates the contribution ratio between surface and bulk states. The offsetting effect of surface states can be weakened through targeted regulation. The core strategies for enhancing their bulk TE performance include 3 categories: Mechanical strain and external pressure enhance the strength of band inversion by strengthening atomic orbital interactions^[152], alloying regulates lattice parameters and orbital interactions through chemical pressure or elemental substitution^[151], topological phase transitions optimize carrier transport near the critical composition by forming alloys of conventional insulators and TIs^[153]. All 3 strategies achieve performance enhancement by focusing on strengthening band inversion and optimizing band structure^[154].

However, a single regulatory approach is often difficult to break through the performance bottleneck. Ma’s group adopted a multidimensional synergistic strategy encompassing “single crystal growth, composition regulation, crystal structure and band engineering, and bipolar conduction suppression,” simultaneously achieving the enhancement of electrical transport efficiency and precise inhibition of thermal conduction^[155]. First, Mg₃Bi₂-based single crystals were precisely synthesized via a slow cooling method, which effectively eliminates grain boundaries and various defects commonly present in polycrystalline materials, reduces scattering losses during carrier transport, significantly enhances carrier mobility, and thereby lowers the electrical resistivity of the material, laying a solid foundation for optimizing electrical transport performance^[156,157]. Second, through a composition regulation scheme involving Sb substitution for Bi^[158], trace Te doping, and Mg excess design, the carrier concentration was accurately fine-tuned to the optimal range while optimizing carrier transport characteristics. This avoids a significant drop in the Seebeck coefficient under the premise of ensuring high electrical conductivity, realizing an efficient improvement in the PF. Third, leveraging the unique anti-La₂O₃-type layered structure and 3D atomic bonding network of Mg₃Bi₂-based single crystals, near-isotropic charge transport channels were constructed. The electrical conductivity effective mass exhibits minimal difference between the ab-plane (0.24m₀) and c-plane (0.21m₀), which not only guarantees carrier transport efficiency in all directions but also enhances phonon scattering through structural distortion and atomic size differences. This effectively reduces the lattice thermal conductivity (κ₁), achieving a dynamic balance between electrical transport and thermal conduction^[159,160]. Fourth, the bipolar conduction effect was suppressed by optimizing the band structure, avoiding the attenuation of the Seebeck coefficient and increase in thermal conductivity caused by the simultaneous participation of electrons and holes in transport—addressing the critical issue of performance degradation in traditional Bi₂(Te, Se)₃ materials at elevated temperatures^[161]. Under the synergistic effect of the multidimensional strategy, the Mg₃Bi_1.497Sb_0.5Te_0.003 single crystal ultimately achieved a ZT value of 1.05 at 300 K and 0.87 at 250 K^[162], which is significantly superior to commercial n-type Bi₂(Te, Se)₃ materials. Moreover, it maintains high performance above 350 K, successfully expanding the temperature application range for high ZT values. This fully confirms the core logic that the improvement of TE performance requires the synergistic efforts of multiple approaches.

5.1 Challenges in thermoelectric materials for wound healing

Despite the promising potential, the clinical translation of TE materials for wound healing faces several formidable challenges. First, a significant hurdle lies in the biosafety-performance paradox. Most inorganic TE materials with high ZT values (e.g., Bi₂Te₃) raise biosafety concerns due to the potential leaching of toxic ions (e.g., Te⁴⁻) upon long-term implantation, necessitating complex encapsulation strategies^[56] that may compromise flexibility and performance. Conversely, organic TE materials (e.g., PEDOT:PSS, PANI) offer superior biocompatibility and flexibility but generally exhibit inferior TE properties (lower σ and S)^[38] that require substantial optimization to generate therapeutic electrical signals efficiently.

Another challenge in the use of TE materials in wound therapy is optimizing the TE properties of TE materials at room temperature. The optimal TE properties of some TE materials act at higher temperatures than room temperature^[163]. More precise strategies, such as elemental doping, surface modification, and interfacial engineering, are needed to address this problem. In addition, wound dressing matrices require innovative design in materials and devices to provide safe, stable, and effective TE therapy and to maximize the temperature gradient in wound care.

Beyond the aforementioned issues, there is currently no unified good manufacturing practice (GMP) standard for TE hydrogels/devices, thus hindering the acquisition of regulatory approval^[164]. Furthermore, divergent classification criteria for TE hydrogels/devices across different countries/regions, coupled with variations in GMP requirements for TE materials, further exacerbate certification complexity.

5.2 Prospects in thermoelectric materials for wound healing

In recent years, many research works have focused on TE materials, and the results have fully demonstrated the promising development of these materials in the field of wound healing. As research continues, the development of TE materials with excellent antimicrobial efficacy, biocompatibility, intelligence, and multifunctional properties has become a promising research direction. Based on this, we systematically analyze and propose several cutting-edge strategies for the design and preparation of TE materials, aiming to provide more efficient, safer, and more precise therapeutic solutions for wound healing, with a view to promoting technological innovation and clinical translation in this field.

1. Multimodal synergistic therapy: Combining TE material-based antimicrobial drug therapy with other mechanisms to promote wound healing^[165]. Through the design of composite functions, a combination of drug sustained-release systems, antibacterial coatings, piezoelectric materials, and photocatalytic materials is integrated to develop multifunctional devices, such as smart temperature sensors, thermal sensors, TE modules, and trigger circuits^[166]. These multifunctional devices can realize synergistic therapy in applications such as low-grade thermal energy harvesting, temperature sensing, and self-powered electronic devices, thereby enhancing the therapeutic effect. Furthermore, we can draw on the ideas of synergistic design between energy storage facilities and energy systems, as well as multi-energy complementarity, to enhance energy supply stability^[167], thereby achieving a long-term stable energy supply for chronic wounds.

2. Material design: The development of Te-free inorganic materials (e.g., Ag₂Se) and the hybridization of high-performance inorganic fillers within biocompatible organic matrices (e.g., hydrogels, polymers) represent a promising path to break the biosafety-performance trade-off. Concurrently, advancing the molecular design of organic semiconductors and nanostructuring techniques is crucial to enhance the electrical conductivity and Seebeck coefficient of flexible organic TE materials^[168]. In addition, to avoid insufficient temperature difference resulting from excessively high ambient temperature, diurnal cooling technology can be integrated with the cold side of the TE wound dressing to maintain an optimal temperature difference^[169].

3. Advancing clinical translation and standardization: Bridging the gap between laboratory research and clinical practice is paramount. This requires establishing standardized protocols for evaluating the long-term biosafety, stability, and efficacy of TE devices in biologically relevant environments. Large-scale animal studies and eventual pilot clinical trials on various wound types (e.g., diabetic ulcers^[170,171], burns) are essential to validate therapeutic outcomes. Moreover, efforts should be directed toward scalable manufacturing processes (e.g., 3D printing, roll-to-roll processing) and cost reduction to facilitate future commercialization and widespread accessibility^[172].

4. Cooperation between universities and GMP-certified enterprises should be pursued to develop specialized guidelines for TE materials as medical devices, clarify product classification and testing standards, and shorten the approval cycle. Meanwhile, TE raw material suppliers should collaborate with GMP-certified chemical enterprises to establish a standardized raw material production system. Additionally, equipment manufacturers are encouraged to partner with medical device companies to modify specialized equipment to meet GMP requirements.

These innovations will not only promote the upgrading of treatment modalities but also help expand clinical applications. Through standardization and cost optimization, TE materials will play a greater role in chronic wound repair and postoperative rehabilitation, fundamentally revolutionizing the concept and practice of wound treatment and bringing patients a more efficient and better treatment experience.