Stretchable wireless optoelectronic synergistic patches for effective wound healing | npj Flexible Electronics

npj Flexible Electronics volume 8, Article number: 64 (2024) Cite this article

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Physiotherapies play a crucial role in noninvasive tissue engineering for wound healing. However, challenges such as the implementation of complex interventions and unsatisfactory treatment outcomes impede widespread application. Here, we proposed a stretchable and wirelessly-powered optoelectronic synergistic patch with a dual-layer serpentine wireless receiver circuit to drive the optoelectronic modulation component. Optimized structure and impedance matching enable the patch to seamlessly attach to irregular skin surfaces and operate robustly over a 30% tensile strain range. Based on Sprague-Dawley rat wound model. The wound closure rate of the optoelectronic synergistic group significantly outperformed both monointervention and blank control groups. Mechanistically, optoelectronic synergistic intervention enhances the secretion of vascular endothelial marker proteins and growth factors, and stabilizes mitochondrial function during oxidative stress. Overall, the scalable amalgamation of flexible electronics, wireless transmission, and synergistic interventions promise to improve wound care.

Skin wounds resulting from acute external injuries or chronic illnesses plague over 305 million people worldwide, causing significant suffering and imposing a substantial global medical burden1,2,3,4. Addressing this critical public health issue and aiming for rapid and organized wound closure, the primary goal in skin wound treatment, clinical therapeutic strategies predominantly encompass pharmacological and nonpharmacological modalities5. Although pharmacological therapies, such as antibiotics or growth factors, may reduce inflammation and accelerate wound closure, concerns related to drug abuse, inadequate absorptivity, immune rejection, and healing disorders necessitate thorough investigation and assessment6,7. Nonpharmacological therapies, including electrostimulation(ES), photomodulation(PM), hyperthermia, ultrasound therapy, etc.8,9, emerge as promising noninvasive physical strategies in the clinic and have received approval from the U.S. Food and Drug Administration for tissue injury engineering7,10. However, clinically available medical resources often feature large-sized and complex equipment that requires skilled clinicians for operation, leading to frequent clinic visits and intricate intervention implementation11. As an urgent challenge facing clinical medicine, noninvasive, effective, and convenient therapeutic strategies are desired for skin wound management12,13. Flexible bioelectronics (FBEs), leveraging the flexible electronic advantages in biomedical applications, stand out for their inherent lightweight and deformable features, offering a promising platform for in situ tissue engineering and noninvasive wound healing14,15,16. Contemporary advanced nonpharmacological FBEs, providing electrostimulation or photomodulation, have been meticulously designed and demonstrated remarkable effectiveness in wound repair7,13,17,18,19,20,21,22.

ES enhances the endogenous electric field (EF) in the wound and promotes epithelial cell migration, proliferation, and differentiation for wound re-epithelialization, however, the oxidative stress state of the wound impairs this cellular repair process5,23,24,25,26,27. Notably PM could enhance mitochondrial activity, promote adenosine triphosphate (ATP) production, and enhance cellular energy supply, which would help reduce inflammatory mediators and improve the persistent oxidative stress state thus remodeling the cellular wound repair process17,19,28,29.

Due to the complexity of the wound environment, a mono physical field therapy is no longer sufficient to meet the existing challenges. Therefore, multi-physical field therapy of wounds has become a new research direction, combining multiple physical therapy mechanisms to synergistically improve wound healing30,31. Overall the therapeutic effect of combining ES and PM demonstrates a great potential in wound repair. Meanwhile, stretchability and miniaturization play a crucial role in evaluating the wearing comfort of FBEs32. Meanwhile, stretchability and miniaturization play a crucial role in evaluating the wearing comfort of FBEs. Convenient power design, noninvasive/stretchable/miniaturized optoelectronic component integration, therapeutic efficacy assessment, and mechanism exploration will be the basis and challenges for developing optoelectronic wound management systems based on FEBs.

Here, we presented a stretchable and wireless-powered optoelectronic synergistic patch (OESP) designed to expedite effective and ordered wound healing. The OESP integrates a circular interdigital electrode-based electrostimulation (ES) and a light-emitting diode (LED, 620 nm)-enabled photomodulation (PM), both exclusively driven by a double-layered serpentine wireless receiver circuit and encased with biocompatible polydimethylsiloxane (PDMS) encapsulation layers, which the double-layer serpentine structure design endows the OESP with miniaturization and stretchability. Through optimization of structural geometry and impedance matching, the OESP demonstrates robust operation within a 30% tensile strain, allowing seamless attachment to irregular, non-developable surfaces across various application scenarios. For validation, Sprague-Dawley rats were randomly divided into four groups to establish a full-thickness circular skin wound model and assess OESP effectiveness. Within an 8-day intervention, the optoelectronic synergistic intervention group achieved a wound closure rate exceeding 94%, statistically surpassing the ES (~81%), PM (~79%), and blank control (~65%) groups. Mechanistic investigations revealed that the OESP intervention synergistically enhanced the secretion of vascular endothelial marker protein and key growth factors, including platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31), epidermal growth factor (EGF), transforming growth factor-β (TGF-β), and vascular endothelial growth factor (VEGF). This synergistic modulation influenced metabolic-related angiogenesis and reepithelization, contributing to effective wound healing5,20,33,34. In addition we further explored and found that OESP-integrated PM could protect cellular mitochondrial function in oxidative stress environments, thereby enhancing cellular metabolism and modulating inflammatory responses.

This work introduced an efficient and noninvasive wound healing strategy within a wireless-powered, optoelectronic synergistic paradigm, holding promise for remote personalized health management.

The proposed stretchable and wireless-powered OESP for effective wound healing was designed following the principle depicted in Fig. 1a. In the exploded schematic (Fig. 1a, right), the OESP consisted of seven layers: two protective PDMS encapsulation layers were positioned on the outer and inner surfaces, followed by a double-layered serpentine wireless receiver circuit beneath the top PDMS encapsulation layer. Within this circuit, a PDMS interlayer film served as the intermediate medium, separating two serpentine-geometry polyimide/copper (PI/Cu) films. A circular interdigital electrode for ES, supported by a PDMS layer, was situated above the underlying PDMS encapsulation layer. The PM (LED, 620 nm) and ES components were successively installed onto the wireless transmission and electrode layers, connected to the double-layered wireless circuit through a micro rectifier. For the wireless transmission system of the OESP, both PI/Cu transmitter and double-layer receiver units were fabricated through laser-cutting patterning technology, modulating the working frequency to 13.56 MHz through impedance matching. The double-layered and serpentine structural design endowed the OESP with miniaturization, stretchability, and robustness. Firstly, the overall dimensions of the OESP in the initial state were ~20 × 20 × 1.58 (L × W × T) mm3 (Fig. 1b), falling within the dimension range of commercially available band-aids for human wear. Secondly, its stretchable feature rendered the OESP robust operating when subjected to considerable deformation, such as stretching and twisting (Fig. 1c). Additionally, Fig. 1d illustrated the device’s wearing mode on a human hand, showcasing its seamless attachment to irregular skin surfaces. The feature positions the OESP as a noninvasive and scalable platform for in situ wound healing manipulation (Supplementary Movie 1).

a Schematics illustrating the overall OESP structure and an enlarged view of the device components, essential materials, and multilayer structures. b Optical image of the initial state of the OESP. c Optical images of the stretched state (top) and twisted state (bottom) of the OESP. d Demonstration of the OESP applied to the back of the hand. e A three-dimensional microscope image depicting the multilayer structures. f Height profile along the red line indicating the height of multilayer components. g Finite Element Analysis (FEA) and experimental (EXP) mechanical results of a double-layer serpentine wireless receiver circuit under initial and horizontal tensile strain. h Fluorescence images of fibroblasts cultured on a cell culture dish (top) and a PDMS-encapsulated OESP (bottom) surface. i Measurement of the relative cell viability of fibroblasts cultured in packaging materials for three days (n = 3). The control is the 96-well cell culture plate.

Comprehensive and systematic evaluations of the as-prepared OESP were conducted to assess its practicality in various application scenarios, focusing on multilayer configuration, stretchable adaptability, and biocompatibility. A microscope-captured three-dimensional (3D) image revealed uniform surface topography across all layers. A height profile along one scanning line quantified the cross-sectional height information of OESP components (Fig. 1e). The quantitative thickness of the top PDMS encapsulation layer, top PI/Cu wireless transmission layer, PDMS intermediate medium layer, bottom PI/Cu wireless transmission layer, PDMS supporting layer, interdigital PI/Cu electrode layer, and bottom PDMS encapsulation layer were 118 μm, 61 μm, 1030 μm, 60 μm, 129 μm, 59 μm, and 120 μm, respectively (Fig. 1f). The thickness of the PDMS intermediate medium layer, crucial for operating at the target frequency (13.56 MHz), was set to 1030 μm. Finite element analysis (FEA) and experimental uniaxial tensile modalities were utilized to assess the stretchable adaptability and mechanical robustness. FEA simulation consistently displayed even strain distribution on the serpentine lines under a series of tensile deformations (0–30%). Both FEA and experimental results demonstrated similar deformation behaviors. Under 30% deformation, the subjected strain (≤0.3%) consistently remained smaller than its failure strain (~5%), indicating excellent stretchable adaptability (Fig. 1g and Supplementary Fig. 1). Additionally, the OESP withstood repeated stretching (deformation from 0 to 30%) without structural damage, underscoring its superb mechanical robustness. To verify biocompatibility in a biological environment, mouse fibroblasts were cultured on the encapsulated OESP and a reference culture dish for three days. Fluorescence staining images revealed normal cell morphology and structure, with similar densities and equivalent morphologies in both media (Fig. 1h).

Non-cytotoxicity and biocompatibility were confirmed by Cell Counting Kit-8 (CCK8) assay. No significant difference in the relative proliferation and viability of cells between the OESP group and the control group was observed over three days (Fig. 1i). Together, these results confirmed that OESP was non-cytotoxic. To verify the biosafety of the in vivo application, OESP was implanted subcutaneously in SD rats, and vital organs were harvested for H&E staining analysis 2 weeks later. The results suggested that OESP implantation did not cause damage to vital organs, consistent with the blank group (Supplementary Fig. 2). This result further demonstrated the in vivo biosafety of OESP.

The detailed fabrication procedure of the OESP is displayed in Fig. 2a, including nanosecond laser patterning, transfer printing, double-layer folding, component integration, and device encapsulation. The initial step involves nanosecond laser (Laser power approx. 2 W) cutting the serpentine structure into a PI/Cu film (20 × 20 mm2) affixed on the water-soluble tape. Then, the patterned PI/Cu film was adhered to the PDMS substrate by a transfer printing technique. After removing the water-soluble tape, the PI/Cu film undergoes a double-layer folding process guided by alignment marks. Subsequently, the rectifier unit, LED, and circular interdigital electrode are successively soldered onto the circuit, which was then encapsulated with PDMS. The micro rectifier, model M24LR04E-R, operating at 13.56 MHz ± 7 kHz, with an internal capacitance of 27.5 pF. To validate the design rationality, an electromagnetic field simulation of the double-layer circuit was conducted (Supplementary Fig. 3). The simulation illustrated the reversal of the electric current direction before folding and the alignment of the electric current direction in the double-layer post-in-plane folding, demonstrating mutual reinforcement as per Lorentz’s left-hand rule. Figure 2b (top) detailed the serpentine geometry of the double-layered serpentine wireless receiver circuit, with the linewidth, arc angle, and radius set at 200 μm, 120°, and 300 μm, respectively. The circular interdigital electrodes’ linewidth and spacing were 200 μm, and the ring number was designed to be 6 with an overall electrode diameter of ~12 mm to align with the full-thickness circular skin wound size (Fig. 2b, bottom).

a The fabrication procedure of the OESP. b Serpentine geometries of the double-layered serpentine wireless receiver circuit and circular interdigital electrodes. c HFSS simulation of the double-layered receiver circuit with different PDMS interlayer film thicknesses. d HFSS simulation of designed transmitters for various (C1, C2) settings. e Experimental S11 measurements of the OESP driven by the designed transmitter.

Determining the double-layer design and the basic parameters of the serpentine line, the thickness of the intermediate medium within the double-layered receiver circuit becomes critical for modulating wireless transmission properties. High-frequency structure simulator (HFSS) simulations were executed within specific PDMS interlayer film thickness ranges. As shown in Fig. 2c, the resonant frequency points exhibited a monotonic increase with thickness, reaching 11.69 MHz, 12.37 MHz, 12.85 MHz, 13.39 MHz, and 13.76 MHz for thicknesses of 0.1 mm, 0.25 mm, 0.5 mm, 1 mm, and 1.5 mm, respectively. In particular, the absolute return loss remained nearly constant at around 40 dB, indicating that the medium thickness primarily affects the resonant frequency point rather than the return loss. Considering the comprehensive performance, a PDMS thickness of 1 mm was selected to seamlessly align with commercial and medical near-field communication standards (13.56 MHz). A spiral transmitter, designed with an inner radius of 30 mm and an outer radius of 40 mm, was devised to match the OESP (Supplementary Fig. 4). The (resonant frequency point, absolute return loss) values were (12.33 MHz, 10.18 dB), (13.27 MHz, 25.04 dB), (14.48 MHz, 27.48 dB), and (16.53 MHz, 15.02 dB) for various (C1, C2) settings (Fig. 2d). To integrate with the OESP, (C1 = 16 pF, C2 = 82 pF) was chosen, as corroborated by experimental S11 measurements demonstrating regular operation under 13.76 MHz with a bandwidth of 0.62 MHz (13.45 MHz–14.07 MHz) (Fig. 2e).

In order to clarify the relationship between the output voltage of the wireless receiver circuit and the load impedance, different capacitors were attached to the circuit for output testing. Among them, the 27 pF capacitor has the highest output voltage of Vpp = 6.0 v, which is the matched capacitance in the L-C resonant circuit (Supplementary Fig. 5a). In addition, the output voltage of the antenna was negatively correlated with the distance from the transmitter (Supplementary Fig. 5b). The wireless heating performance and repeatability of the OESP are critical to the wearability of the device. We examined the wireless heating performance of the OESP with infrared thermography. The heating performance of the OESP was stable without passing the batch, with average maximum, minimum, and mean temperatures of 33.52, 30.27, and 32.37 °C, respectively (Supplementary Fig. 6a). Importantly the operating temperature of the OESP was stable, which ensured safety and comfort when worn on the skin surface (Supplementary Fig. 6b, c).

We implemented effectiveness verification of the OESP on six-week-old Sprague-Dawley rats with a circular skin wound model to systematically investigate its healing effect. As depicted in Fig. 3a (left), rats were randomly divided into four groups (n = 4) and maintained under identical conditions. After grouping and acclimatizing the rats, full-thickness circular skin wounds (approximately 1 cm in diameter) were created on the dorsal regions of the rats to simulate wounds (Supplementary Fig. 7).

a Schematics of patches applied to the circular wound in the OESP, ES, PM and Con groups (left). Images of the circular wound area over time of the OESP, ES, PM and Con groups (n = 4, right). b Circular wound closure rate over time of the wound area from OESP, ES, PM and Con groups. c Final circular wound closure rate for OESP, ES, PM, and Con groups on day 8. d Images of circular wound tissues with H&E staining on day 8. e Images of circular wound tissues with Masson’s trichrome staining on day 8. f Circular wound closure rate of the OESP compared to the reported results by the electrostimulation and photomodulation. n.s., non-significant (P > 0.05); *P < 0.05.

Notably, to ensure the breathability of the OESP patches, we modified the OESP patches used for wound experiments using the sodium chloride template method35. Porous PDMS was obtained by adding 10 w% sodium chloride particles to the PDMS precursor solution and dissolving the sodium chloride in deionized water after the PDMS was cured. The modified OESP patches had an average water vapor transmission rate (WVTR) of 117.1 ± 17.1 g/(m2-h), which is sufficient to satisfy the requirement of OESP as a wound dressing for breathability (Supplementary Fig. 8)36. OESP patches are seamlessly applied to wounds using medical surgical glue(Supplementary Fig. 9). The rats wore OESP for 7 consecutive days and then underwent skin histologic examinations including H&E and Masson staining. The staining results showed that the epidermis and dermis were structurally intact and clear, and the cells were organized and densely packed (Supplementary Fig. 10). Importantly, no pathologic changes were observed. These results confirm the safety of long-term OESP wear.

Rats in the OESP group were stimulated with OESP. In comparison, rats in the ES and PM groups received interventions solely through circular interdigital electrode-based electrostimulation and LED (620 nm)-provided photomodulation, respectively. Additionally, rats without external intervention (only PDMS films) constituted the blank control (Con) group. All groups underwent the same surgical procedure and were housed in individual cages. Wounds were recorded and assessed every 2 days after surgery and before euthanasia, with continuous intervention in the OESP, ES, and PM groups. Minor soft tissue trauma and the use of flexible patches did not affect the daily activity of rats in this wound-healing model (Supplementary Movie 2).

We assessed the mental state of SD rats wearing OESP and blank rats through an open field test (OFT) to ensure that the optoelectronic treatment generated by OESP was gentle and painless. The OFT test showed that there was no significant difference in the number of grids worn, the number of standing and climbing times, and the total distance moved between the OESP group and the blank group (Supplementary Fig. 11), which suggests that OESP did not produce painful stimuli and thus produced nervousness and anxiety during the working period of rats.

Figure 3a (right) and Supplementary Fig. 12 displayed images in four groups on day 0, day 2, day 4, day 6, and day 8. Images indicated that OESP intervention promoted circular wound healing more effectively compared to the ES and PM groups, while the Con group exhibited delayed healing. Specifically, the OESP and PM groups formed a smaller amount of scab than the ES and Con groups throughout the 8-day monitoring period, suggesting that photomodulation might alleviate inflammation and facilitate healing metabolism. The wound closure rate was defined as the equation: wound closure rate (%) = (Wx - W0) / W0 × 100, where W is the wound closure area, and x is the day after stimulation. The quantified wound closure rate over time demonstrated that the OESP and ES groups had higher closure rates than the PM and Con groups on day 2 (Fig. 3b), with no significant difference between the OESP and ES groups (similar to PM and Con groups). From day 2 to day 6, the OESP and ES groups maintained higher closure rates than the other two groups, and the closure rate gap between the OESP group and ES group gradually widened. On day 8, the OESP group almost completed wound healing, marked by blurring the wound area and scab. In contrast, delayed healing was observed in the ES and PM groups, with closure rates being similar and higher than that of the Con group. The final wound closure rates for different groups were shown in Fig. 3c. The average values measured after 8 days revealed that the closure rate of the OESP group was 94.12 ± 3.399%, significantly higher than those of other groups (81.57 ± 2.381% for ES, 79.47 ± 3.073% for PM, and 65.25 ± 6.782% for Con).

The skin from the circular wound site in the different groups was collected on day 8 post-intervention for histological examination using H&E staining (Fig. 3d and Supplementary Fig. 12). The histological analysis provides a clearer view of the cell structure and tissue layer37,38,39. H&E staining revealed that the wound center in the OESP group achieved reepithelialization, exhibiting a completely new epidermis closely connected to the underlying granulation tissue. The connection between the new epidermis and granulation tissue in ES and PM groups was loose, indicating relatively weak healing. In contrast, the Con group had no epidermis at all. Masson’s trichrome staining was also performed, as shown in Fig. 3e and Supplementary Fig. 12, primarily to identify collagen fibers and muscle fibers to illustrate skin tissue regeneration and matrix remodeling40. Numerous hair follicles and sebaceous glands appeared on the wound tissues of the OESP group, indicating that wound healing in this group progressed into the advanced phase, with good tissue regeneration and restoration of the function of skin accessory organs. A large amount of orderly precipitated collagen fibers in skin tissue demonstrated excellent wound healing and remodeling in the OESP group. In contrast, fewer collagen fibers and inflammatory cell infiltration were observed in the other groups. In Fig. 3f, we compared OESP intervention with electrostimulation (voltage, electric field) and photomodulation (LED, NIR) reported in literatures8,19,21,41,42. Our optoelectronic synergistic system achieved a closure rate of over 94.12% and a superb reepithelialization effect within 8 days, surpassing other reported electrostimulation and photomodulation approaches based on similar rat models.

Wound healing is a dynamic process encompassing three overlapping but distinct crucial phases: the inflammatory phase, tissue formation phase, and remodeling phase (Fig. 4a). Following tissue damage, the inflammatory phase involves the recruitment of immune cells and the secretion of cytokines to prevent infection43,44,45. Subsequently, in the tissue formation phase, the migration and proliferation of fibroblasts, epithelial cells, and endothelial cells lead to the creation of new tissue components such as epithelium, granulation tissue, and blood vessels. Finally, the remodeling phase is marked by the reorganization of disorganized collagen, facilitated by migrated fibroblasts within the epithelialized wound site. To comprehend the mechanism of accelerated wound healing influenced by the OESP, we investigated and evaluated key vascular endothelial marker protein/multiple growth factors involved in wound repair, including CD31, EGF, TGF-β, and VEGF. Wound tissues from different animal groups at injury sites were collected and analyzed using immunohistochemistry (IHC) and immunofluorescence (IFC) at the end of the OESP intervention. IHC staining quantitatively analyzed the microangiogenesis in the wound tissues of each group, with the dark brown color indicating the vascular endothelial marker protein CD31. IFC staining further quantitatively detected EGF, TGF-β, and VEGF expression levels in wound tissues. The average optical density (IntDen/Area) of CD31 and corresponding growth factors (EGF, TGF-β, and VEGF) in the epithelium and mesenchyma were calculated using ImageJ V 1.8.0 and Profile plug-in software, defining them as IHC/IFC expressions. CD31, a highly glycosylated immunoglobulin-like membrane receptor expressed by white blood cells, platelets, and endothelial cells, served as a crucial marker for vascular endothelium46,47. It marked newly formed microvessels (green arrow, Fig. 4b and Supplementary Fig. 13) and exhibited high expression in the wound tissue of the OESP group (49.7), surpassing the ES group (26.28), PM group (31.62), and the Con group (16.45, Fig. 4c). These findings confirm that OESP intervention enhances angiogenesis, restores blood supply, and promotes skin tissue regeneration.

a Three classic stages of wound healing: inflammation, tissue formation, and remodeling. b IHC staining images of circular wound tissues with CD 31 among different groups on day 8. c IHC expression of the CD 31 in different groups (n = 4). d IFC staining images of EGF, TGF-β and VEGF in wound tissues among different groups on day 8. The nucleus was stained with 4, 6-diamidino-2-phenylindole (DAPI, blue). e IFC analysis of EGF, TGF-β and VEGF in wound tissues among different groups on day 8 (n = 4). * vs Con P < 0.05, # vs PM P < 0.05, @ vs ES P < 0.05, & vs OESP P < 0.05.

For multiple growth factors, EGF plays a direct role in promoting epidermal growth48, TGF-β induces the formation of extracellular matrix49, and VEGF effectively stimulates the regeneration of blood vessels50. On day 8, skin from various groups were collected and subjected to IFC expression analysis to assess the distribution of these essential growth factors (Fig. 4d and Supplementary Fig. 13). In general, the IFC expression results revealed a significant enhancement in the secretion of EGF, TGF-β, and VEGF in the OESP group compared to the ES, PM, and Con groups (Fig. 4e). The overall level of VEGF secretion was particularly higher than that of other growth factors. The average fluorescence expression in the OESP group was 35.19, 28.15, and 37.92 for EGF, TGF-β, and VEGF, respectively, exceeding the levels in the ES group (19.29, 10.19, and 27.43), PM group (21.28, 15.85, and 25.32), and Con group (10.35, 4.46, and 12.22). The expressions of EGF, TGF-β, and VEGF growth factors in the OESP, ES, and PM groups surpassed those in the Con group. Furthermore, the ES and PM groups exhibited similar effects on EGF and VEGF expression, suggesting the potential to accelerate cell proliferation, differentiation, vascular regeneration, and epidermal regeneration. Overall, the OESP patch combined with electrostimulation and photomodulation can elevate the expression of CD31, EGF, TGF-β, and VEGF, accelerate cascade healing metabolism, and promote reepithelization.

Reactive oxygen species (ROS) are a class of highly reactive molecules that include superoxide (O2--), hydroperoxide (H2O2), and hydroxyl radicals (-OH)51. ROS are products of mitochondrial metabolism, and an excess of ROS causes oxidative stress, which exacerbates the persistent inflammatory state of wounds and leads to delayed healing26. ROS production is closely related to mitochondrial function, and oxidative stress in wounds can lead to mitochondrial dysfunction and excessive ROS production that impairs wound healing27.

Infrared and near-infrared light can affect mitochondrial function through light-sensitive pigments such as cytochrome coxidase. Adenosine triphosphate (ATP) is produced by Cox enzymes and is a component of the electron transport chain in mitochondria. It catalyzes the transfer of electrons from the cytochrome c complex to molecular oxygen. So these lights increase the mitochondrial membrane potential (Δψm, mmp) (decreased MMP i.e., mitochondrial depolarization represents mitochondrial dysfunction) and enhance the transfer of electrons leading to ATP synthesis52,53. This process promotes mitochondrial energy production, which enhances overall cellular function, and this process reduces ROS production and promotes the transition of the wound from the inflammatory phase to the proliferative phase, thereby accelerating wound healing as shown in Fig. 5a54.

a Illustrative diagram of the mechanisms of PM intervention in wound healing. b, c Mitochondrial membrane potential analysis of L929 cells co-cultured with H2O2 was intervened with PM by Fluro microscope. n = 3, *p < 0.05, **p < 0.01, Scale bar, 100 μm. d Mitochondrial membrane potential analysis of L929 cells co-cultured with H2O2 using PM intervention with FCM.

We constructed an H2O2-induced oxidative stress model of mouse fibroblasts (L929) to simulate wound inflammation. Subsequently, the protective effect of photomodulation (PM) on mitochondria was evaluated using the JC-1 staining system. Immunofluorescence staining and flow cytometry were performed to quantify MMP. When MMP was decreased, green fluorescence intensity increased and red fluorescence intensity decreased. We found that the green/red ratio in the H2O2-induced group was obviously higher than that in the control group, which was significantly reversed by the intervention of PM (Fig. 5b, c). This indicated that PM could inhibit the H2O2-induced decrease of MMP. And the flow cytometry (FCM) assay verified the results even further (Fig. 5d).

These results suggest that PM can protect mitochondrial function and enhance energy metabolism in the oxidative stress state of wound. This will reduce the generation of ROS to mitigate the damage to cells within the wound. Meanwhile, healthy mitochondria can provide sufficient energy support for cells to enhance the proliferation, migration and differentiation of cells within the wound to accelerate wound healing.

In summary, we present a stretchable and flexible wireless-powered optoelectronic patch for the synergistic intervention of wound healing. This system comprises a double-layered serpentine receiver transmission circuit, a rectifier unit, an electrostimulation layer, and a photomodulation layer. Through meticulous optimization of structural geometry and impedance matching within the OESP, the device can accommodate ~30% tensile strain, ensuring seamless adherence to the irregular skin surface. Validation of the full-thickness circular wound model, utilizing the stretchable and wireless-powered OESP, was conducted in Sprague-Dawley rats. Within an 8-day intervention, the wound closure rate for the OESP group reached 94%, significantly surpassing the rates observed in the ES (~81%), PM (~79%), and Con (~65%) groups. H&E and Masson’s trichrome staining analyses demonstrated that optoelectronic synergistic stimulation effectively expedites wound healing. Mechanistic investigations unveiled that OESP intervention synergistically enhances the secretion of key protein/factors, including CD31, EGF, TGF-β, and VEGF. This modulation of the wound microenvironment, coupled with metabolic-related angiogenesis and reepithelization, accelerates cascade healing metabolism, contributing to effective wound healing.

In addition we found that PM intervention protects cellular mitochondrial function in oxidative stress environments. This not only safeguards cellular energy metabolism and supports the repair behaviors of cell proliferation, migration and differentiation, but also attenuates ROS generation within the wound, thereby modulating the level of wound inflammation. Notably, patients in coma, Alzheimer’s disease, spinal cord injury or stroke often develop pressure-damaging wounds due to prolonged bed rest, which can cause life-threatening systemic infections in severe cases55,56. For these patients, setting up a transmission antenna at the hospital bed, applying the OESP to the wound and wirelessly powering the antenna to drive and regulate the treatment parameters can avoid the need for lengthy wires and provide comfortable and precise treatment, thus enhancing the level of treatment. In general, sophisticated optoelectronic synergistic design establishes a pivotal foundation for advancing intelligent and personalized wound management systems.

The mechanical properties of the OESP were assessed using ABAQUS software. Young’s modulus and Poisson’s ratio of copper (Cu) were specified as 119 GPa and 0.35, respectively, while Young’s modulus and Poisson’s ratio of polyimide were set to 2.5 GPa and 0.34. Subsequently, the strain distribution of OESP grids was analyzed for varying tensile lengths, ranging from 0 to 30%.

Mouse fibroblasts were cultured on both PDMS and reference dishes for a duration of 3 days, following identical procedures and incubation conditions. The samples underwent fixation with 2 to 4% formaldehyde for 15 min and were rinsed thrice with prewarmed phosphate-buffered saline. Staining was performed using Texas Red-X Phalloidin (100 nM) and Hoechst (50 nM) at 37 °C for 30 min. Following staining, the cells were washed three times with prewarmed buffer and subjected to imaging using a Nikon A1RS confocal microscope.

Cell proliferation was assessed after culturing fibroblasts for 1, 2, and 3 days using the CCK8 kit (US Everbright). Briefly, cells were digested and seeded into 96-well plates and custom devices at an initial density of 2 × 103 cells/well. After a 2-h incubation with CCK8 working solution, the solution was transferred to another 96-well plate, and absorbance was measured at a wavelength of 450 nm using a BioTek microplate reader. All experiments were conducted in triplicate, and the results were expressed as the percentage increase in CCK8 absorbance, with the absorbance of control cells set at 100%.

Sprague-Dawley rats were purchased from Dossy Animal Limited Company (Chengdu, China) for use in this study. Sixteen 6-week-young male rats (180 ± 20 g) were included in the circular wound surgery experiment. All rats were housed under controlled temperature (25 °C) conditions and fed with standard food and water. All animal experiments were performed following the standard protocol approved by the University of Electronic Science and Technology of China (1061420210617002).

Anesthesia induction was initiated by administering 2 to 5% isoflurane, followed by maintaining anesthesia with 2% isoflurane. Under anesthesia conditions, rats were positioned in a supine orientation. The dorsal area of Sprague-Dawley rats earmarked for the experiment was prepared by shaving the hair using an electric clipper, followed by the uniform application of hair removal cream. After a 5-minute interval, the back was cleansed with a PBS solution. Preceding the surgery, the rat’s back underwent scrubbing with iodine solution and alcohol. Subsequently, a circular wound (1 cm in diameter) was excised along the full layer of the wound on the rat’s back.

Skin samples were obtained from the backs of rats following OESP, ES, and PM treatments. Control skin from untreated areas on the rat’s back was collected simultaneously. The collected tissues were fixed using 4% formaldehyde, and 3 μm slices were prepared for H&E staining. In the staining process, the slices underwent sequential treatment with xylene, anhydrous ethanol, gradient alcohol, and a final wash with water. Subsequently, the slices were immersed in the hematoxylin dye tank, washed, and differentiated in ethanol hydrochloride. Finally, the slices were placed into anhydrous ethanol and xylene in succession, undergoing dehydration, transparency, neutralization, rubber sealing, and drying in the oven. H&E slides were observed directly using an inverted optical microscope.

First, the sections were dewaxed to water following a process similar to H&E staining. Subsequently, staining was carried out using Weigert’s iron hematoxylin from the staining kit. Ethanol differentiation with hydrochloric acid was performed, and the blue color was restored after washing. Following this, an acid fuchsin solution of Lichence red was employed for staining, followed by treatment with a phosphomolybdic acid solution, restaining with aniline blue, glacial acetic acid treatment, and, finally, the sections underwent dehydration, sealing, and microscopic examination.

paraffin sections underwent dewaxing and hydration through a series of steps: immersion in xylene, gradient ethanol, and a final wash in distilled water. Antigenic repair followed, involving soaking the slices in 3% H2O2, placing them in a microwave container with citric acid buffer, and heating to boiling. Afterward, the sections were cooled naturally, and the slides were washed with PBS. The next step involved serum blocking, where BSA was evenly applied to cover the tissue. The process was carried out at room temperature, followed by the addition of primary and secondary antibodies, with color displayed by DAB. Finally, cell nuclei were restained using Harris hematoxylin for approximately 3 min. Further steps included hydrochloric alcohol differentiation, dehydration, transparency, sealing, and microscopic examination.

The procedure involved dewaxing to water, antigen repair, and sealing, following similar steps outlined in the abovementioned IHC process. Subsequently, primary antibody application, fluorescent secondary antibody addition, DAPI restaining of nuclei, and plate sealing were carried out. The stained sections were then imaged using a Nikon A1 Confocal Microscope, and analysis was performed using Image J software.

L929 cells in logarithmic growth phase were taken and inoculated in 6-well plates. The cells were grouped and intervened for 1 hour; after that, the cells were collected and stained with JC-1 staining solution, and then added to a flow cytometer to analyze the results of JC-1 staining with CytExpert software. As before, after 1 hour of intervention, each group of cells was added with prepared JC-1 staining solution, incubated for 20 minutes, rinsed with PBS, added with culture medium, photographed under a fluorescence microscope, and analyzed by Image J Pro software.

The results were expressed as mean ± standard deviation. The comparison between multiple groups for the final wound closure rate in circular wounds was assessed through Ordinary one-way ANOVA analysis. Kruskal-Wallis test was performed to determine the differences between the OESP, ES, PM, and Con groups in immunohistochemistry and immunofluorescence staining. Statistical analyses were conducted using GraphPad Prism 8 (GraphPad Software lnc, La Jolla, CA, USA). n.s., non-significant (P > 0.05); *P < 0.05, **P < 0.01, ***P < 0.001.

The data that support the findings of this work are available from the corresponding author upon reasonable request.

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This work was supported by the National Natural Science Foundation of China under grant Nos. 61825102 (Y.L.), U21A20460 (Y.L.), 62371115 (G.Y.), and 52021001 (Y.L.); Science and Technology Major Project of Tibetan Autonomous Region of China under grant No. XZ202201ZD0001G (G.Y.); Science and Technology Department of Sichuan Province under grant No. 24NSFSC1553 (G.Y.); and the Medico-Engineering Cooperation Funds, Fundamental Research Funds for the Central Universities, UESTC under grant Nos. ZYGX2020ZB041 (G.Y.) and ZYGX2021YGLH002 (Y.L.).

School of Materials and Energy, University of Electronic Science and Technology of China, Chengdu, Sichuan, China

Qian Wang, Guang Yao, Wenhao Lou, Maowen Xie, Xingyi Gan, Chenzheng Zhou, Taisong Pan, Min Gao & Yuan Lin

Department of Plastic Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China

Siyuan Cai, Liyuan Zhang, Youxin Chen, Qingqing Li & Zhen Cai

Department of Plastic and Cosmetic Surgery, Xinqiao Hospital, Army Medical University, Chongqing, China

Siyuan Cai

State Key Laboratory of Electronic Thin Films and Integrated Devices, University of Electronic Science and Technology of China, Chengdu, Sichuan, China

Guang Yao & Yuan Lin

Shenzhen Institute for Advanced Study, University of Electronic Science and Technology of China, Shenzhen, Guangdong, China

Guang Yao

State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, International School of Materials Science and Engineering, Wuhan University of Technology, Wuhan, Hubei, China

Kangning Zhao

Medico-Engineering Cooperation on Applied Medicine Research Center, University of Electronic Science and Technology of China, Chengdu, Sichuan, China

Yuan Lin

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G.Y. conceived the concept. G.Y., Z.C., and Y.L. discussed, finalized the project plan, and supervised the research. Y.L. and Z.C. provided lab assistance. Q.W., S.C., L.Z., W.L., Y.C., Q.L., M.X., X.G., and C.Z. performed the experiments and generated data in all figures. Q.W., G. Y., T.P., M.G., K.Z., Z.C., and Y.L. analyzed the data. Q.W., Z.C., G.Y., and Y.L. wrote the manuscript. All authors reviewed and provided constructive feedback on the manuscript.

Correspondence to Guang Yao, Zhen Cai or Yuan Lin.

The authors declare no competing interest.

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Wang, Q., Cai, S., Yao, G. et al. Stretchable wireless optoelectronic synergistic patches for effective wound healing. npj Flex Electron 8, 64 (2024). https://doi.org/10.1038/s41528-024-00351-x

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Received: 27 February 2024

Accepted: 24 September 2024

Published: 08 October 2024

DOI: https://doi.org/10.1038/s41528-024-00351-x

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