¹Arizona College of Osteopathic Medicine, Glendale, AZ, USA

²California Health Sciences University College of Osteopathic Medicine, USA

³New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY, USA

⁴Department of Dermatology, Northwell Health, New Hyde Park, NY, USA

⁵California Health Sciences University College of Osteopathic Medicine, USA

⁶Philadelphia College of Osteopathic Medicine, PA, USA

⁷School of Medicine, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, USA

⁸College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia

*Corresponding author: Kelly Frasier, DO, MS, Department of Dermatology, Northwell Health, New Hyde Park, NY, USA, Phone: 3105956882, Email: [email protected]

Received Date: April 03, 2025

Publication Date: April 26, 2025

Citation: Rizzo D, et al. (2025). Advancing Wound Healing Using Cutaneous Bioelectronic Interfaces for Real-Time Monitoring and Electrical Stimulation. Dermis. 5(2):36.

Copyright: Rizzo D, et al. © (2025).

ABSTRACT

Advances in bioelectronic technologies have opened new frontiers in wound healing, providing innovative solutions for real-time monitoring and therapeutic intervention. Wound healing is a complex physiological process involving hemostasis, inflammation, proliferation, and remodeling, often hindered by chronic conditions, infections, or impaired vascularization. Traditional wound care approaches are limited in their ability to adapt dynamically to the wound environment. This review explores the emerging role of cutaneous bioelectronic interfaces, which integrate real-time monitoring and electrical stimulation, to address these challenges and improve healing outcomes. Bioelectronic interfaces incorporate flexible, biocompatible materials and advanced sensors to track critical wound parameters such as pH, temperature, oxygenation, and infection biomarkers. The real-time feedback enables precision medicine by allowing timely and targeted interventions. In parallel, electrical stimulation has demonstrated significant benefits in enhancing cellular migration, angiogenesis, and tissue regeneration through mechanisms that leverage electrochemical gradients and cellular signaling pathways. The synergy between monitoring and stimulation, supported by closed-loop systems, offers a novel paradigm for adaptive wound care. Despite significant progress, the translation of these systems into clinical practice is hindered by technological, regulatory, and ethical challenges. Issues such as device durability, power management, data privacy, and standardization require further attention. Future directions emphasize the integration of artificial intelligence, advanced biomaterials, and personalized medicine approaches to enhance the utility and accessibility of bioelectronic systems. This review highlights the transformative potential of cutaneous bioelectronic interfaces in wound healing, presenting a pathway toward improved clinical outcomes and setting the stage for interdisciplinary innovation in regenerative medicine.

Keywords: Bioelectronic Technologies, Bioelectronic Medicine, Pathology, Electromagnetic Fields, Cells, Diabetic Wounds

ABBREVIATIONS

AI: Artificial Intelligence; CPs: Conductive Polymers; NIRS: Near-Infrared Spectroscopy; CRP: C-Reactive Protein; MMPs: Matrix Metalloproteinases; ML: Machine Learning; ANNs: Artificial Neural Networks; VEGF: Vascular Endothelial Growth Factor; EBC: Enzymatic Biofuel Cell; EFs: Electric Fields; DC: Direct Current; PC: Pulsed Current; EMF: Electromagnetic Fields; HVPC: High-Voltage Pulsed Current; PEMF: Pulsed Electromagnetic Fields; FGF-2: Fibroblast Growth Factor-2; bFGF: basic Fibroblast Growth Factor; NAC: N-Acetylcysteine; LTP: Low-Temperature Plasma; MSCs: Mesenchymal Stem Cells; FBEs: Flexible Bioelectronics; BISS: Bio-Integrated Systems; EEG: Electroencephalography; ECG: Electrocardiography.

INTRODUCTION

Effective wound healing is critical for maintaining tissue integrity and preventing complications, and recent advancements in bioelectronic technologies offer new opportunities for improving therapeutics and their related outcomes. Wounds are classified based on their healing process. Primary healing, such as surgical wounds, progresses smoothly. However, secondary healing, often in cases with complications like infections, involves granulation tissue formation and epithelialization. Wounds, especially chronic ones, are a global health issue, with around 15% of wounds failing to heal within a year, leading to physical, emotional, and economic burdens [1]. This suggests that a better understanding of wound healing and its underlying pathophysiology has the potential to significantly improve treatment and prevent severe outcomes, like amputation or death.

Effective wound healing is a natural, complex process requiring the coordinated action of various cells, growth factors, and cytokines, including platelets, neutrophils, macrophages, fibroblasts, keratinocytes, endothelial cells, and T-lymphocytes. It involves three major phases: inflammation, proliferation, and remodeling [2]. The process begins with vasoconstriction and platelet aggregation to stop bleeding, followed by an influx of inflammatory cells, particularly neutrophils. These cells release mediators that promote angiogenesis, thrombosis, and re-epithelialization. Additionally, fibroblasts contribute by forming extracellular scaffolding. This is followed by the inflammatory phase, which lasts a few days and involves hemostasis, chemotaxis, and increased vascular permeability to limit damage, close the wound, and promote cell migration. Consequently, the proliferative phase, lasting several weeks, includes granulation tissue formation, re-epithelialization, and new blood vessel growth. The final maturation and remodeling phase involves strengthening the wound as it fully heals [2]. These three phases often overlap, and this disruption can cause abnormal bleeding, poor healing, and other severe complications [3].

Both acute and chronic wound infections are significant global health issues, leading to high rates of morbidity and mortality. In particular, chronic wounds, such as diabetic foot ulcers, venous leg ulcers, and pressure ulcers, present significant challenges for patients, wound care professionals, and healthcare systems. They complicate healing due to factors like aging, diabetes, and immune system dysfunction. Additionally, despite improvements in wound care, managing these infections remains difficult due to challenges like biofilm formation, delayed healing, and drug resistance. A review by Ding et al. explored the microorganisms commonly found in wound infections and examined the difficulties in diagnosis and treatment, including non-surgical and surgical methods. They described that recent innovations such as antimicrobial peptides, phages, controlled drug delivery, wound dressing materials, and herbal treatments offer promising solutions [4]. Although antibiotics and topical treatments are commonly used, the persistence of infections due to biofilm formation and antibiotic resistance highlights the need for alternative therapies [4]. Thus, managing chronic wounds involves addressing factors that impede healing while selecting appropriate therapies. However, evidence-based guidance for treatment remains limited [5]. Future advancements in wound care will depend on a deeper understanding of the molecular and cellular differences among chronic wound types, leading to improved treatment strategies and more effective therapies. Collectively, better diagnostics, combined therapies, and regulation of the skin’s microbiome could enhance wound infection management.

Bioelectronic medicine is an emerging field that utilizes bioelectronic devices to modulate the central and peripheral nervous systems, aiming to restore homeostasis, treat diseases, and enhance wound healing through inflammation regulation. Recent advancements have demonstrated how the nervous system regulates immune function and inflammation, challenging the traditional view that these systems operate independently. One notable approach, vagus nerve stimulation, has shown potential in treating chronic inflammatory conditions such as rheumatoid arthritis and inflammatory bowel disease by controlling immune responses. This was approved for drug-resistant epilepsy in 1997 and treatment-resistant depression in 2005, marking significant milestones in the field. The FDA’s approval for these conditions confirmed its safety and effectiveness [6,7]. These findings fueled the development of bioelectronic therapies for a wide range of disorders, including autoimmune diseases, cardiovascular issues, neurodegenerative diseases, and spinal cord injuries [8].

Beyond inflammatory regulation, bioelectronic medicine offers tremendous promise across various biomedical fields, including oncology, tissue healing, and aging research. This market is rapidly growing, expected to increase from $20 billion to $60 billion by 2029, highlighting its expanding role, particularly in cancer detection and treatment [6]. By modulating the bioelectric properties of cells and, in turn, the body’s innate electrical communication networks, these devices can regulate cellular functions such as regeneration and differentiation, potentially influencing the progression of cancer on a cellular level [6]. Thus, bioelectronic medicine is rapidly advancing, leveraging bioelectronic devices to regulate nervous system activity for therapeutic purposes. However, challenges remain, including the need for personalized treatment approaches in light of the potential adverse effects.

The development of flexible, wearable, and implantable bioelectronic devices has further expanded the field, offering an alternative to traditional rigid electronic devices. These soft, ultrathin, and biocompatible devices seamlessly integrate into various tissues and organs, enabling continuous health monitoring, human-machine interfaces, and therapeutic interventions. They track physical, chemical, and electrophysiological information using piezoresistive, capacitive, and piezoelectric principles [9]. Recent breakthroughs in this field have led to the development of multifunctional nanomaterials and sensor technologies, impacting their practical applications in bioelectronics through innovative materials and processing methods, impacting research and practical applications. A special issue on wearable and implantable bioelectronics highlights these advancements, covering functional nanomaterials, sensor principles, and therapeutic strategies [9]. As research progresses, bioelectronic medicine holds immense potential for revolutionizing treatments across multiple medical specialties.

Electrical stimulation is a promising treatment for chronic wounds, which often requires surgical intervention, but the need for external devices limits its clinical use to power electrical stimulation-based dressings. To address the growing clinical challenge of chronic non-healing wounds, researchers have developed a new wearable bioelectronic system that wirelessly monitors wound bed conditions using a custom electrochemical biosensor array. This system provides noninvasive combination therapy, delivering controlled anti-inflammatory and antimicrobial treatment alongside electrically stimulated tissue regeneration [10]. The flexible, stretchable, and biocompatible patch adheres to the wound throughout healing. Preclinical studies demonstrated its efficacy in accelerating wound healing in a rodent model based on monitoring a variety of metabolic and inflammatory biomarkers [10].

Similarly, to address the challenges of diabetic wound care, a new sandwich-structured photovoltaic microcurrent hydrogel dressing (PMH) was developed. The PMH dressing combines flexible organic photovoltaic cells, a micro-electro-mechanical systems electrode, and a multifunctional hydrogel to deliver electrical stimulation when exposed to light, mimicking the body's natural injury currents [11]. In vitro testing confirmed its biocompatibility and antibacterial properties, while in vivo studies showed that the dressing significantly accelerated wound healing in diabetic mice by promoting extracellular matrix regeneration, reducing bacteria, regulating inflammation, and enhancing vascular functions [11]. These findings highlight the PMH dressing as a promising, effective, and wireless solution for diabetic wounds.

Further innovations in physiotherapy-based wound healing include a wireless, stretchable optoelectronic patch. This device features a dual-layer serpentine wireless receiver circuit, allowing it to conform to irregular skin surfaces and function effectively under a 30% tensile strain. Preclinical studies in a Sprague-Dawley rat wound model found that the optoelectronic patch significantly improved wound closure by enhancing growth factor secretion and stabilizing mitochondrial function compared to other treatments [12]. Thus, the integration of bioelectronic technologies into wound care represents a significant advancement in medical treatment, combining real-time monitoring, controlled therapy, and wireless power solutions to enhance wound healing outcomes. Innovations such as wearable bioelectronic patches, photovoltaic microcurrent hydrogel dressings, and wirelessly powered optoelectronic devices offer noninvasive and biocompatible approaches that enhance wound healing through electrical stimulation, anti-inflammatory therapy, and biomarker tracking. As research continues to refine these technologies, their potential to revolutionize wound management and broader clinical applications becomes increasingly evident, as will be discussed.

MECHANISMS OF WOUND HEALING AND CHALLENGES

Wound healing is a complex clinical challenge that requires efficient management for both acute and chronic wounds. The healing process involves various cell types, the extracellular matrix, and soluble mediators such as growth factors and cytokines. It is typically divided into four phases: coagulation and hemostasis, inflammation, proliferation, and wound remodeling with scar tissue formation [13]. Therefore, understanding the intricacies of wound healing will translate to better wound management, significantly impacting healing outcomes.

A key factor in understanding wound healing is the cellular diversity and plasticity involved. Emerging wound models provide valuable insights into the molecular and cellular mechanisms of wound repair, and integrating these models with advanced tissue, cell, and molecular technologies can significantly enhance our understanding of wound pathology. This progress holds great potential for developing innovative therapeutic strategies for advanced wound care [14]. Specifically, advances in single-cell technologies have revealed functional and phenotypic diversity within various cell types, uncovering rare stem cell subsets in the skin that become multipotent after injury [15]. Understanding these cells' roles and interactions is crucial for comprehending standard wound closure mechanisms and the factors that contribute to wound healing disruptions. Changes in the wound microenvironment, such as mechanical forces, oxygen levels, and growth factor alterations, can impair healing, leading to chronic wounds. These wounds present a significant socioeconomic burden due to their high prevalence and recurrence. Therefore, understanding wound repair's biological and clinical mechanisms is crucial [14]. Single-cell technologies can help detect these cellular changes in chronic wounds and hypertrophic scarring, offering insights into more effective therapies [15]. Advances in wound models, single-cell technologies, and molecular approaches offer promising avenues for enhancing our ability to diagnose, manage, and treat complex wounds more effectively.

As significant progress has been made in understanding the cellular and molecular mechanisms of acute wound healing through animal models, research is now shifting its focus to the causes of chronic wounds and their healing. While acute wounds typically heal quickly (through coordinated cell migration, inflammation, and angiogenesis), chronic wounds, which fail to heal within three months, present significant therapeutic challenges. The growing prevalence of chronic wounds is closely associated with aging populations and the increasing incidence of diabetes, obesity, and vascular diseases [16]. Notably, delayed wound healing is a significant issue, especially for aging individuals and those with comorbidities like diabetes, cardiovascular disease, and cancer. These comorbidities increase the risk of infection and can lead to chronic, non-healing ulcers, such as diabetic foot ulcers and pressure sores, which are difficult to treat [16]. A key factor contributing to chronic wound formation is sustained immune activation and inflammation, often driven by bacterial biofilms. These biofilms protect bacteria from the immune system and antibiotics, impairing tissue repair and promoting persistent inflammation [17]. Thus, it is important to understand that effective chronic wound management should target bacterial biofilms in addition to addressing the underlying immune dysfunction that contributes to delayed healing.

Recent research has questioned the necessity of excessive capillary growth in wound healing, particularly in tissues that heal quickly with minimal scarring, like fetal skin and oral mucosa, which have fewer but more mature vessels [18]. During wound healing, there is a rapid increase in capillary growth to supply nutrients, oxygen, and immune cells. However, most new capillaries eventually regress, leaving a vascular density similar to normal skin. This has led to the idea that controlling inflammation and angiogenesis may improve wound healing outcomes by reducing the formation of dense, poorly oxygenated capillary beds, ultimately enhancing wound resolution and reducing scarring [18].

Biofilms, which are communities of microorganisms encased in a self-produced protective matrix, play a significant role in persistent infections and antimicrobial resistance. These biofilms can form on both inanimate surfaces and living tissue, complicating wound healing and contributing to chronic wounds [17]. Bacteria within biofilms communicate through quorum sensing, which coordinates gene expression crucial for virulence factors, including biofilm formation [19]. Traditional treatments for chronic wounds focus on reducing microbial colonization, but the emergence of multi-drug resistant microorganisms complicates management. In vitro models, such as the Lubbock chronic wound biofilm (LCWB) model, have been developed to replicate the chronic wound environment and study polymicrobial biofilms. This model plays a vital role in evaluating the efficacy of novel antimicrobial compounds and improving treatment strategies for chronic wounds [20]. Despite extensive research into anti-biofilm and antimicrobial treatments, there remains a lack of standardized clinical guidelines for biofilm management in wound care. Studies show that biofilms are prevalent in a significant percentage of chronic wounds, ranging from 20% to 100% in prevalence [21]. Understanding the interplay between immune dysfunction, bacterial biofilms, and delayed healing is essential for developing more effective treatments.

Furthermore, the virulence and pathogenicity of biofilms, rather than the biofilm itself, play a critical role in delayed wound healing. Biofilms interfere with fibroblast function, inflammatory responses, and antimicrobial efficacy, making wound management challenging [22]. However, the exact role of biofilms in wound healing remains an area of ongoing debate. Clinicians must consider the composition, microbial number, and host immune response when assessing the impact of biofilms on wound healing. Identifying and targeting pathogenic biofilms could lead to more effective treatment strategies in the future [22]. Nevertheless, a deeper understanding of biofilm composition, host interaction, and collective impact on wound healing could lead to more effective clinical strategies, including silver nanoformulations that contain nanoparticles or nanocomposites. For these agents to be successful, they must possess strong wound-healing properties that improve the various stages of the healing process [23].

Wound assessment is crucial for selecting appropriate treatments and monitoring progress. While biofilms and quorum sensing contribute to persistent infections, emerging AI-powered assessment tools present innovative solutions. In addition to biomedical advancements, digital health technologies are becoming an essential component of wound care. Wound assessment apps and artificial intelligence (AI) tools have the potential to enhance wound monitoring and predict healing outcomes. However, current apps lack sufficient evidence-based reliability, highlighting the necessity for a systematic assessment. A study by Kabir et al. evaluated 170 apps from Google Play and Apple App stores, selecting 10 based on specific criteria. Their findings revealed that most apps did not meet clinical standards for effective wound monitoring. ImitoWound scored the highest among the reviewed apps but still lacked some essential features [24]. Other studies across different regions have shown that AI can improve wound care, but challenges remain in its implementation [25]. This highlights the need for further improvements in AI-driven wound assessment tools to address current limitations and enhance accuracy and clinical utility before integrating these technologies into clinical practice for better patient care.

BIOELECTRONIC INTERFACES: OVERVIEW AND APPLICATIONS

Bioelectronic interfaces are revolutionizing the way we interact with biological tissues, with applications ranging from neural engineering and cardiac monitoring to tissue regeneration. These systems rely on three key components: sensors, actuators, and biocompatible materials, each playing a crucial role in bridging the gap between electronics and the human body. Sensors serve as the system’s eyes and ears, detecting and measuring physiological signals in real time, such as neural activity and biochemical markers. Many of these sensors rely on conductive polymers (CPs) because of their unique ability to conduct both electronic and ionic signals while remaining soft and flexible—making them particularly well-suited for neural recording and stimulation [26].

While sensors capture data, actuators enable interaction with biological tissues by delivering precise electrical, mechanical, or chemical stimuli. These actuators power technologies like neural stimulation, cardiac pacing, and targeted drug delivery, helping restore function or modulate biological processes. Materials like conductive hydrogels and nanomaterials are commonly used for their flexibility and biocompatibility, allowing them to integrate seamlessly with living tissue [27]. At the core of every bioelectronic interface is biocompatibility, ensuring that these systems can function in harmony with the body without triggering harmful immune responses. Advanced materials, including biodegradable polymers, hydrogels, and thin-film encapsulations, are being developed to enhance the durability and flexibility of these devices [28]. Innovations in materials chemistry continue to make bioelectronic devices softer, stretchier, and more adaptable, enabling them to conform naturally to the body’s contours for seamless, long-term integration.

A key advantage of bioelectronic interfaces is their ability to provide continuous real-time physiological monitoring. By tracking parameters such as skin impedance, temperature, and pH, these devices allow for the early detection of infection, inflammation, or delayed healing [29]. This continuous monitoring represents a shift from traditional periodic wound assessments to proactive data-driven intervention, significantly improving clinical outcomes by ensuring that complications are addressed at their earliest stages. Beyond passive monitoring, bioelectronic devices facilitate active treatment by delivering precise, localized treatments. For example, they can release anti-inflammatory and antimicrobial agents directly to the wound site, reducing the need for systemic medications and their associated side effects [10]. This targeted approach not only enhances therapeutic efficacy but also minimizes toxicity and the risk of drug resistance associated with prolonged systemic antibiotic use.

In addition to monitoring and direct treatment, bioelectronic interfaces improve patient comfort and wound management. Traditional wound dressings require frequent application and removal, which can disrupt tissue regeneration, cause discomfort, and prolong healing. In contrast, bioelectronic interfaces incorporate on-demand adhesion and detachment technologies, allowing them to adhere securely when needed and release without causing secondary tissue damage or pain [30]. This feature is particularly valuable for fragile or sensitive wound sites, where repeated dressing changes can exacerbate tissue injury. By integrating monitoring, diagnosis, and treatment into a single multifunctional platform, bioelectronic interfaces streamline wound care, enhance patient autonomy, and improve overall healing outcomes.

The evolution of bioelectronic interfaces in dermatology has significantly advanced wound healing, particularly through wearable and implantable systems. These technologies bridge the gap between biomedical engineering and dermatological care. A breakthrough in this field is the emergence of “skintronics” (skin-interfaced electronics) – ultra-thin, flexible, and biocompatible electronic systems that conform seamlessly to the skin [31]. Unlike rigid electronic devices, “skintronics” mimic the skin’s natural elasticity and stretchability, minimizing discomfort and reducing the risk of irritation or damage to the wound site. Innovations in multifunctional nanostructured skin patches have further expanded their capabilities by integrating stretchable sensors with self-powered electronics, eliminating the need for external power sources and making these systems more practical for real-world, long-term use [32]. Additionally, the emergence of soft bioelectronics has further improved device longevity and stability, addressing one of the key challenges in bioelectronic dermatology [33]. These next-generation devices are engineered from biodegradable and biocompatible materials, allowing for extended use without causing inflammation or adverse reactions, addressing many of the common challenges related to device longevity.

Beyond wound healing, bioelectronic interfaces have shown success in cardiovascular, neural, and orthopedic applications, providing a strong foundation for expansion to wound healing. In the cardiovascular field, bioelectronic devices have been widely used for electrophysiological monitoring and therapy. These advanced systems seamlessly integrate with cardiac tissue, enabling real-time electrophysiological mapping and feedback-driven electrical stimulation [34]. The development of flexible and stretchable electronics has provided continuous monitoring and targeted interventions, significantly improving arrhythmia management and post-cardiac event recovery. Similarly, bioelectronic interfaces play a critical role in neurology, where they decode neural signals to provide neurostimulation to treat disorders such as epilepsy and Parkinson’s disease [27]. These devices interpret complex neural activity and deliver precisely timed electrical impulses, helping to restore neural function and mitigate disease symptoms. Additionally, in orthopedics, bioelectronic technologies enhance bone fracture healing and musculoskeletal regeneration. A notable advancement in this field is the use of piezoelectric material-based bioelectronics, which generate electrical stimulation in response to body movement, accelerating bone regeneration and improving mechanical stability [35]. As bioelectronic technologies continue to evolve, their cross-disciplinary integration is paving the way for next-generation wound care solutions, further enhancing their clinical impact through patient-centered wound care strategies.

REAL-TIME MONITORING IN WOUND HEALING

Real-time monitoring plays a role in wound healing by providing continuous assessment of key biomarkers, such as pH, temperature, oxygenation, and biochemical indicators, which offer valuable insights into the healing process. The pH of a wound is a critical marker of its healing trajectory, typically shifting from an alkaline state in chronic wounds to a more acidic environment as healing progresses. A lower pH is associated with enhanced fibroblast activity, improved collagen synthesis, and reduced bacterial burden, all of which contribute to more favorable wound conditions [36]. Temperature fluctuations also serve as important indicators, as localized increases in temperature often signify inflammation or infection, while a gradual decrease in temperature suggests successful healing. Infrared thermometry enables non-invasive temperature assessments, allowing for real-time detection of inflammatory changes that may necessitate early intervention [37].

Oxygenation is another essential biomarker, as it supports cellular metabolism, angiogenesis, and infection resistance. Tissue oxygen levels can be evaluated through transcutaneous oxygen measurement (TcPO₂) and near-infrared spectroscopy (NIRS), both of which provide insights into tissue perfusion and oxygen delivery to the wound bed. Impaired oxygenation is often correlated with delayed healing, making continuous monitoring an important aspect of wound management [38]. Additionally, biochemical markers such as C-reactive protein (CRP) reflect systemic inflammation and may indicate an underlying infection [39]. Matrix metalloproteinases (MMPs), particularly MMP-9, are upregulated in chronic wounds and gradually decrease as healing progresses, while increased levels of neutrophil elastase are associated with prolonged inflammation, excessive tissue degradation, and impaired wound closure [36]. Continuous monitoring of these physiological and biochemical biomarkers through bioelectronic interfaces enables early detection of complications and timely intervention, reducing the risk of complications and ultimately improving wound healing outcomes.

Recent advancements in wearable and wireless bioelectronic technologies have significantly improved real-time wound monitoring by providing continuous, non-invasive tracking while simultaneously enabling active therapeutic interventions. Flexible and stretchable sensors can detect fluctuations in temperature, pH, and infection-related biomarkers while seamlessly conforming to the wound site due to their biocompatible materials and design, ensuring uninterrupted data collection. For instance, Jiang et al. developed a wireless, closed-loop smart bandage incorporating integrated sensors and stimulators to monitor skin impedance and temperature while delivering therapeutic electrical stimulation to accelerate healing [40]. Similarly, Shirzaei Sani et al. introduced a stretchable, wireless bioelectronic system capable of multiplexed monitoring and combination therapy for infected chronic wounds, demonstrating remarkable accuracy and stability in preclinical models [10]. By integrating real-time data collection with targeted treatments, these innovations reduce the need for frequent manual assessments and allow for more personalized, responsive care.

Beyond wearable sensors, advancements in wireless and battery-free systems have further improved the practicality of real-time monitoring and the usability of these technologies by eliminating the need for bulky power sources and wired connections. Xiong et al. reported a wireless, battery-free wound infection sensor utilizing a DNA hydrogel that detects pathogenic bacteria and wirelessly transmits data to a smartphone, enabling remote infection monitoring and early intervention [41]. Additionally, Garland et al. developed a miniaturized, battery-free wireless wound monitor capable of measuring lactate levels to predict wound closure rates [42]. These technological innovations not only highlight the critical role of metabolic markers in wound healing but also demonstrate the potential of bioelectronic systems to guide clinical decision-making in real time.

Artificial intelligence (AI) and machine learning (ML) have further revolutionized wound monitoring by enabling advanced data analysis into real-time wound monitoring, personalizing wound care management. AI-driven algorithms process vast amounts of data collected from bioelectronic sensors to assess wound healing in real time, enabling continuous, non-invasive assessment of key healing parameters (i.e., pH, temperature, moisture levels, and biochemical markers), early detection of complications, and data-driven treatment recommendations. One of the most promising applications of AI in wound management is the use of deep artificial neural networks (ANNs) to predict tissue regeneration based on sensor data. Intelligent wearable sensors integrated with advanced wound dressing bandages, such as the FLEX-AI wearable system, utilize ANNs to analyze wound healing progression with high accuracy through contactless measurements [43]. This allows for more objective, quantitative assessments of wound status, minimizing reliance on subjective clinical evaluations. Digital twin technology has also emerged as a novel approach, creating a virtual model of a patient’s wound that continuously updates based on real-time sensor data. This allows healthcare providers to simulate healing trajectories and optimize treatment strategies accordingly [44]. Additionally, ML-based algorithms analyzing sub-epidermal moisture levels have been developed to detect deep tissue injuries before visible ulceration occurs, offering a proactive strategy for preventing hospital-acquired pressure ulcers [45]. Additionally, AI-powered wearable sensors enhance the precision and reliability of real-time wound monitoring, allowing for more personalized and data-driven interventions [46]. Thus, the integration of AI and ML into bioelectronic wound monitoring systems reduces the risk of chronic wound complications and creates personalized treatment plans based on real-time data trends.

The impact of real-time monitoring technologies extends beyond early detection and assessment, as they have also demonstrated the ability to enhance wound healing through sensor-based monitoring, therapeutic stimulation, and responsible drug delivery. Wireless, closed-loop smart bandages, for example, continuously monitor skin impedance and temperature while delivering electrical stimulation in response to real-time changes in the wound environment. Preclinical models have demonstrated that this technology accelerates wound healing by approximately 25% and improves dermal remodeling by 50% compared to standard wound care methods [40]. Another innovative approach is the self-healing multifunctional dressing, which integrates antibacterial properties with real-time monitoring capabilities to track critical wound parameters (i.e., temperature, pH, and glucose levels), providing timely insights into wound progression. In vivo studies revealed that these dressings facilitated wound closure by promoting organized collagen deposition and improved the structural integrity of newly formed tissue [47]. The integration of stretchable wireless wearable bioelectronic systems has further advanced chronic wound management by enabling localized drug delivery and electrical stimulation, which have been shown to significantly accelerate wound healing in preclinical studies in rodent models [10]. Additionally, flexible wound healing systems incorporating temperature monitoring and infection early-warning capabilities have been tested in pig skin wound models, identifying infection risks and allowing for timely therapeutic adjustments to prevent delayed healing and wound deterioration [37].

These advancements highlight the transformative potential of real-time wound monitoring technologies. By continuously providing accurate physiological data, facilitating proactive interventions, and integrating AI-driven analytics, bioelectronic systems hold promise for revolutionizing wound care. Their ability to enhance clinical decision-making, improve healing efficiency, and reduce complications represents a significant step forward in personalized medicine, ultimately improving patient quality of life and outcomes.

ELECTRICAL STIMULATION FOR ENHANCED WOUND HEALING

Real-time monitoring in wound healing influences several key biological processes, including cell migration, angiogenesis, inflammation modulation, electrochemical gradients, and tissue regeneration. By integrating continuous real-time monitoring with bioelectronic therapies, these technologies optimize the wound environment, accelerating tissue repair. One critical mechanism involves regulating cell migration, particularly during the re-epithelialization phase of wound healing. Bioresorbable electrotherapy devices enhance keratinocyte migration by delivering targeted electrical stimulation, guiding these cells toward the wound center, accelerating epithelial coverage, and restoring the skin barrier more efficiently [48]. Similarly, angiogenesis is crucial for sustained tissue repair as newly formed blood vessels provide oxygen and nutrients essential for regeneration. Smart dressings incorporating vascular endothelial growth factor (VEGF) -infused hydrogels have been shown to enhance neovascularization, ensuring proper tissue perfusion and improving wound healing outcomes [49]. In addition to promoting cell migration and angiogenesis, real-time monitoring systems can modulate inflammation, a process that, when prolonged, can impair wound healing. Continuous tracking of wound parameters such as temperature, pH, and moisture enables dynamic therapeutic adjustments to control excessive inflammation, improving recovery rates.

One innovative approach is the glucose-responsive enzymatic biofuel cell (EBC) skin patch, which simultaneously monitors glucose levels and delivers bioelectric stimulation to regulate inflammatory responses [50]. Another innovative strategy involves replicating and enhancing the body’s endogenous electric fields (EFs). These naturally occurring electric fields play a pivotal role in guiding cell migration, coordinating immune responses, and accelerating tissue repair. Bioelectronic interfaces equipped with controlled electrical stimulation mimic these physiological endogenous signals, reinforcing wound healing mechanisms by directly cellular activity and modulating inflammation [51]. Beyond modulating cellular and molecular responses, advanced wound care systems that integrate real-time monitoring with therapeutic interventions have demonstrated significant potential in accelerating tissue regeneration. Wireless, closed-loop smart bandages exemplify this approach by continuously assessing wound parameters and delivering targeted electrical stimulation. These systems have been shown to activate pro-regenerative gene expression within monocytes and macrophages, thereby enhancing dermal remodeling and tissue restoration [40].

Electrical stimulation therapies can be categorized into three primary modalities: direct current (DC), pulsed current (PC), and electromagnetic fields (EMF). Each modality exerts distinct physiological effects and varies in its effectiveness in wound healing acceleration by influencing cellular activity, angiogenesis, and tissue regeneration. DC therapy, which involves a continuous unidirectional flow of electricity, stabilizes the electrochemical environment within the wound bed. Studies suggest that DC stimulation enhances angiogenesis by promoting endothelial cell proliferation and the release of VEGF, particularly in ischemic diabetic foot ulcers. Additionally, DCs have been linked to improved fibroblast migration and collagen deposition, both critical for wound closure and tissue regeneration [52]. However, despite promising findings, clinical studies remain limited, making it difficult to determine optimal treatment parameters and long-term use.

Among the different electrical stimulation modalities, high-voltage pulsed current (HVPC) has demonstrated the greatest efficacy in accelerating wound healing. HVPC delivers short bursts of high-voltage pulses that stimulate cellular migration, increase protein synthesis, and significantly reduce wound size. It has been particularly effective in treating pressure ulcers, improving circulation within the wound bed, and promoting faster healing while minimizing discomfort or skin irritation [53]. Due to its superior safety profile, effectiveness, and patient compliance, HVPC is widely regarded as the preferred electrical stimulation method in clinical wound care.

In contrast, EMF-based approaches such as pulsed electromagnetic fields (PEMF) provide an alternative strategy by inducing electrical currents in tissues without direct electrode contact, unlike DC and PC. It induces electrical currents within tissues through electromagnetic induction. PEMF has been shown to enhance fibroblast proliferation, stimulate angiogenesis, and increase growth factors such as fibroblast growth factor-2 (FGF-2). Studies indicate that PEMF significantly improves wound closure rates in both normal and diabetic conditions, making it a valuable option for patients with impaired healing responses [54]. While each ES modality offers distinct advantages, HVPC appears to be the most effective modality, particularly for pressure ulcers, due to its ability to accelerate healing with minimal risks. DC and EMF-based approaches also show promise, particularly for ischemic wounds and chronic ulcers [55]. However, further research is necessary to refine treatment parameters and explore their potential integration with bioelectronic monitoring systems.

The impact of real-time monitoring technologies extends beyond electronic stimulation, significantly improving clinical outcomes for chronic wounds, burns, and hard-to-heal injuries. By enabling continuous assessment and personalized data-driven therapeutic interventions, these systems allow for early detection of complications, precise treatment adjustments, and improved patient care. One innovative approach involves κ-carrageenan-C-phycocyanin-based injectable hydrogels, which enable real-time wound monitoring through in vivo fluorescence imaging while simultaneously accelerating wound recovery. These hydrogels possess antimicrobial, antioxidant, and anti-inflammatory properties, collectively enhancing tissue repair and reducing the risk of infection-related complications. In experimental models, bioactive hydrogels have demonstrated superior wound healing, facilitating re-epithelialization, collagen deposition, and improved granulation tissue formation [56]. Additionally, digital wound monitoring tools have improved healing outcomes and healthcare efficiency. A comparative study of digital monitoring applications versus traditional manual assessments revealed that digital tracking significantly reduced healing times and the number of required clinic visits [57]. These findings support the growing potential of technology-driven wound management.

Incorporating combination therapies into wound care further enhances healing by integrating multiple therapeutic modalities, such as bioresponsive drug delivery systems, biomaterials, and cellular therapies. These strategies optimize the wound microenvironment, promote faster recovery, and mitigate complications like infection and excessive inflammation. One promising approach involves bioresponsive hydrogels that dynamically release therapeutic agents in response to wound conditions. For instance, a hydrogel system incorporating basic fibroblast growth factor (bFGF) and N-acetylcysteine (NAC) has been developed for diabetic wound healing. This hydrogel responds to oxidative stress by sequentially releasing NAC to reduce oxidative damage, followed by the controlled release of bFGF to stimulate tissue regeneration. This controlled mechanism enhances re-epithelialization, collagen deposition, and neovascularization [58]. Notably, this effectively counteracts the delayed healing often observed in diabetic wounds.

Beyond hydrogel-based therapies, multimodal therapeutic approaches have emerged to address complex wound environments. A particularly effective approach combines low-temperature plasma (LTP), negative pressure wound therapy (NPWT), and bone marrow mesenchymal stem cells (MSCs). LTP acts as a non-thermal antimicrobial agent that sterilizes the wound site, while NPWT improves tissue perfusion and mechanical debridement. When combined with MSCs, which release growth factors such as VEGF, this therapy significantly enhances wound closure and epithelial regeneration, demonstrating superior wound healing outcomes compared to individual therapies alone [59]. In addition to biological interventions, advanced biomaterial-based systems have been explored to improve wound healing and repair. One innovative example is the integration of electrospun nanofibers with microneedle arrays, which allows for precise and sustained drug delivery. This approach mimics the extracellular matrix, providing a scaffold for cellular attachment and proliferation, which accelerates tissue regeneration while minimizing systemic side effects [60]. Furthermore, coaxial nanofiber membranes co-delivering ciprofloxacin and tetracycline hydrochloride have been designed for infected wounds. These membranes offer controlled antibiotic release, providing strong antibacterial activity while maintaining excellent biocompatibility, making them particularly effective for wounds at high risk of bacterial colonization [61]. By optimizing cellular responses, enhancing drug delivery, and integrating continuous assessment, these technologies hold immense potential for improving healing outcomes, particularly for chronic wounds.

INTEGRATED CUTANEOUS BIOELECTRONIC SYSTEMS

Innovative flexible bioelectronics (FBEs) transform medical care by enabling non-invasive health monitoring, disease diagnosis, and treatment, including cancer therapy. Unlike traditional rigid electronics, FBEs offer a more adaptable, intimate connection with the human body, allowing for stable signal capture and precise therapeutic interventions. However, key challenges in FBE development include miniaturization, multifunctionality, and enhancing intelligence remain [62]. The future of FBEs holds significant potential, with ongoing advancements in materials and fabrication techniques aimed at addressing these challenges, expanding FBEs’ capabilities in healthcare.

Medical technology has advanced significantly with innovations like robotic surgery and gene editing. Still, recent attention has shifted to leveraging the body's innate electrical systems, or "biological circuits," for therapeutic purposes. Bioelectronics, which reset, stimulate, or block electrical pathways, bridge the gap between drug treatments and medical devices, facilitating homeostasis and continuous monitoring. Current research focuses on developing flexible, stretchable, and miniaturized bioelectronics that conform to tissues while minimizing toxicity and immune reactions. These advancements are particularly relevant in skin bioelectronics, biosensors, and neural implants [63]. Yet, challenges in creating these devices remain, ranging from choosing appropriate materials and fabrication techniques to ensuring reliable signal transmission.

Bioelectronic-enabled bio-integrated systems (BISS) are emerging as up-and-coming technologies driven by integrating AI and ML. These systems offer intelligent sensing and data processing capabilities, enabling accurate physiological and somatosensory recognition. Recent advancements in BISS combine flexible bioelectronic sensors with algorithmic support, leading to innovations in implantable, skin-mounted, and wearable applications. Each of these categories requires unique materials, fabrication methods, and algorithms, but collectively, they pave the way for personalized healthcare and advanced human-machine interfaces [64]. Flexible inorganic bioelectronics, in particular, are rapidly advancing, offering high-quality, continuous monitoring of bioelectrical signals such as electroencephalography (EEG) and electrocardiography (ECG), as well as biophysical and biochemical markers like temperature, pressure, and glucose levels [65]. Thus, the rapid advancements in flexible bioelectronics are revolutionizing healthcare by enabling seamless, non-invasive monitoring, precise diagnostics, and innovative therapeutic interventions.

Bioelectronic devices offer real-time control of biological processes by tracking biological responses through sensors. Yet, challenges such as system stability and managing the complexity of controlling biological systems indirectly remain. One solution is using bioelectronic controllers to regulate wound pH in a target area, accelerating healing while preventing chronic inflammation. This closed-loop system adapts to different biological conditions or systems, demonstrating the potential for automating bioengineering therapies [66]. Similarly, bio-inspired soft robots, modeled after vertebrate motor and sensory functions, are emerging in medical applications. These robots integrate sensors and actuators to interact safely with tissues and organs, advancing diagnostics and treatments. Examples include robotic implants for bladder control, blood pressure measurement, and drug delivery, which enhance precision in medical interventions [67]. However, challenges remain in creating materials and manufacturing technologies that meet such devices' mechanical, biocompatibility, and functional requirements, impacting their widespread adoption.

The growing use of sensors and algorithms in medical devices enables the automation of therapies, improving outcomes, reducing side effects, and easing the burden on patients and clinicians. However, the automaticity of these systems introduces new risks, necessitating careful regulation. Existing regulations and frameworks for automated systems, such as incubators and syringe pumps, offer guidance for designing bioelectronic systems, including implantable devices. Historical examples like cardiac pacemakers, artificial pancreas, and neuromodulators provide insights into automated systems' design choices and risk mitigations. A notable example is a brain-computer interface for treating essential tremors, which integrates automaticity and feedback into a unified bioelectronic system, offering a template for future device design and risk management [68]. Furthermore, integrating digitalization and intelligence with advanced health monitoring sensors has transformed healthcare, particularly in personal health and elderly care. While challenges such as signal noise, data overload, and insufficient feedback persist, AI-driven analytics improve data analysis, leading to more efficient health monitoring and predictive diagnostics. The fusion of AI and sensors is expected to lead to more intelligent healthcare solutions in the future [69]. Thus, integrating bioelectronic devices, bio-inspired soft robotics, and AI-enhanced health monitoring systems transforms medical technology by enabling real-time monitoring, precise control, and automated therapies.

Real-time monitoring and treatment of soft wound tissues are critical in biomedical research and clinical care. However, conventional devices, like thermometers and thermocouples, lack sufficient spatial resolution for effective wound management. A study by Liu et al. introduced a flexible, silicon-based temperature sensor array combined with a drug-loaded hydrogel to improve wound healing. This system enables precise, submillimeter temperature mapping with high sensitivity (0.1°C) to detect localized inflammation, triggering drug delivery using infrared light-emitting diodes [70]. Tested on both animal models and human subjects, this system demonstrates closed-loop monitoring and treatment capabilities, offering significant potential for clinical wound care and advanced therapies [69]. In parallel, biosensor devices are gaining significant traction for disease diagnosis, monitoring, treatment, and health management. Most skin-integrated and implanted biosensors utilize a flexible polymer layer combined with functional materials to generate and process signals [71]. Bioelectronic implantable devices are key to continuous health monitoring and early disease detection, providing valuable insights into the physiological conditions of various organs while also offering therapeutic benefits, such as neuromodulation for medical conditions. A review by Oh et al. highlighted advancements in closed-loop systems that adjust treatments based on real-time physiological feedback, leveraging AI and edge computing to enhance diagnostic and therapeutic precision [72]. These innovations demonstrate the growing role of bioelectronic devices in transforming healthcare.

Expanding beyond healthcare, bioelectronic systems are also advancing sensory restoration and human-machine interfaces. A study by Kim et al. introduced a skin-compatible interface that simulates heat and touch sensations through thermo-haptic stimulation. This technology enhances virtual and augmented reality experiences while also offering medical applications for amputees and individuals with impaired sensory functions [73]. The wireless interface precisely controls thermal and mechanical receptors on the skin across large areas, enabling fast, power-efficient, and high-resolution stimulation. The platform delivers programmable vibration and thermal stimulation patterns, supporting real-time control mechanisms. It has been tested in controlling robotic prosthetics and interacting with pressure/temperature-sensitive touch displays, demonstrating its effectiveness in transmitting thermal and physical information [73]. Additionally, wearable and implantable bioelectronics are emerging as promising alternatives to traditional healthcare by offering patient-friendly, efficient, and continuous monitoring outside of hospital or clinical settings. To develop next-generation healthcare systems, bioelectronic devices must be tailored to specific biological targets while ensuring long-term biocompatibility and sustainability, ensuring they are eco-friendly for long-term use [74].

Skin-integrated electronics further move the boundaries of bioelectronic applications, offering real-time physiological signal sensing and healthcare monitoring with flexibility and comfort. These devices conform comfortably to the skin without irritation, allowing for multifunctional sensing of health-related signals, body movements, and artificial sensory inputs, including visual, auditory, and tactile sensations. Future advancements will require interdisciplinary collaborations across materials science, engineering, and biomedical fields to enhance performance and durability. Innovations such as e-eyes, e-ears, and e-skin rely on these future advancements, bridging medical technology with human enhancements [75]. Developing skin-compatible bioelectronic systems, including thermo-haptic interfaces and wearable sensors, holds significant potential for transforming healthcare, virtual reality experiences, and sensory restoration for individuals with impaired functions.

CURRENT LIMITATIONS AND CHALLENGES

The development of cutaneous bioelectronic interfaces for wound healing faces significant technological barriers, particularly concerning power supply, durability, scalability, and biocompatibility. A reliable and continuous power source is essential for these devices, yet conventional batteries and wired power connections restrict mobility, making them impractical for long-term wear. Emerging alternatives such as flexible batteries, biofuel cells, and supercapacitors offer potential solutions, but integrating them into soft, stretchable, and biocompatible materials without compromising energy efficiency remains a major challenge [76]. Wireless energy transfer, including inductive and radiofrequency-based systems, presents another avenue, yet these methods often suffer from energy losses, limited power output, and potential interference with surrounding tissues [77].

Durability is another critical concern, as bioelectronic interfaces must withstand the constant mechanical stress caused by skin movement, stretching, and compression. The wound environment further complicates this issue, as moisture, secretions, and the risk of biofouling can degrade electronic components over time, necessitating materials that are not only flexible but also resistant to corrosion and degradation [76]. Biocompatibility is a crucial factor, as the materials used in these devices must not trigger adverse immune responses, cause irritation, or disrupt the delicate wound healing process. Many bioelectronic devices rely on conductive materials such as metal-based electrodes, which can pose risks of cytotoxicity or inflammatory reactions if not properly coated or modified [78]. The integration of bioelectronic systems into dynamic, irregularly shaped wounds is another major challenge. Achieving seamless adherence without impeding natural healing processes requires advanced fabrication techniques, such as nanostructured conductive polymers and stretchable hybrid electronics, that can conform to tissue surfaces while maintaining electrical functionality. Additionally, scalability remains a major hurdle, as fabricating bioelectronic devices with advanced energy storage solutions at a clinically viable scale is both costly and complex [79]. Ensuring consistency in device performance while maintaining cost-effectiveness requires innovations in material science and manufacturing techniques. Without addressing these challenges, the widespread clinical adoption of bioelectronic wound healing technologies will remain limited, preventing their full potential in accelerating tissue regeneration and improving patient outcomes.

The integration of cutaneous bioelectronic interfaces for wound healing into clinical practice faces significant regulatory and standardization challenges. Given the diverse nature of wounds, ranging from chronic ulcers to surgical incisions, establishing standardized protocols for the application, calibration, and maintenance of bioelectronic interfaces is essential to ensure consistent therapeutic outcomes across different patient populations. Ensuring these devices do not pose risks to patients can mitigate delayed approval timelines and deflate development costs [79]. Additionally, a lack of uniformity in the regulatory framework governing bioelectronic devices across different regions complicates the global commercialization of these technologies, limiting their accessibility in international healthcare markets. The absence of well-defined guidelines for the implementation of real-time monitoring and stimulation systems further hinders seamless integration into existing wound care workflows, necessitating additional clinical studies to validate their efficacy and safety under diverse clinical conditions [80].

Beyond regulatory and standardization concerns, economic considerations remain a substantial barrier to the widespread adoption of bioelectronic wound healing technologies. The high costs associated with research and development, coupled with the need for specialized materials and manufacturing processes, can make these devices prohibitively expensive, particularly for healthcare systems in resource-limited settings. Ensuring affordability without compromising efficacy and quality requires innovation in material science, scalable manufacturing techniques, and strategic cost-reduction initiatives. Furthermore, reimbursement policies for bioelectronic therapies remain underdeveloped, with insurance providers often hesitant to cover emerging technologies without robust long-term clinical data demonstrating cost-effectiveness compared to conventional wound care treatments [79]. Overcoming these economic barriers will require close collaboration between academic researchers, industry leaders, regulatory agencies, and healthcare providers to develop sustainable reimbursement models and financial incentives that support the adoption of bioelectronic systems. Additionally, public-private partnerships and government-backed funding initiatives may play a crucial role in accelerating clinical translation and ensuring that these advanced technologies become accessible to a broader patient population.

The integration of cutaneous bioelectric interfaces in wound healing presents significant ethical and privacy considerations, particularly concerning data security in real-time monitoring and the balance between technological innovation and patient rights. These devices, which manipulate the electrochemical environment of wounds to promote healing, often collect and transmit sensitive physiological data. Ensuring the confidentiality and integrity of this data is paramount, as unauthorized access could lead to misuse or breaches of patient privacy [81]. Robust cybersecurity measures should be implemented to protect against potential threats, ensuring that patient information remains secure throughout the data lifecycle. Moreover, the rapid advancement of bioelectronic medicine necessitates a careful balance between embracing innovative treatments and upholding patient autonomy and informed consent. Patients should be thoroughly educated about the functionalities of these devices, the nature of the data collected, and the purposes for which it will be used. Transparent communication fosters trust and allows patients to make informed decisions regarding their care [82]. These ethical considerations may also extend to the equitable distribution of such advanced therapies, ensuring that access is not limited by socioeconomic status, thereby promoting social justice in healthcare [81]. As the field progresses, continuous ethical evaluations are essential to navigate the complex interplay between technological innovation and the safeguarding of patient rights.

Research on cutaneous bioelectric interfaces for wound healing has shown promising potential, but significant gaps remain, particularly regarding long-term studies and clinical trials. While some studies have demonstrated that cutaneous bioelectric interfaces can enhance tissue regeneration, reduce inflammation, and promote faster wound closure, most of these studies are short-term and conducted in controlled laboratory settings [83]. This leaves questions regarding the long-term efficacy, safety, and biocompatibility of these interfaces in real-world clinical scenarios. For instance, there is a lack of data on the durability of the therapeutic effects over extended periods and whether any adverse effects may arise over time, such as skin irritation or tissue damage. Furthermore, the gap between preclinical success and clinical translation is underscored by the limited number of clinical trials evaluating cutaneous bioelectric interfaces in humans [84]. These trials are essential not only for confirming the safety and efficacy of cutaneous bioelectric interfaces but also for understanding how they interact with diverse patient populations, particularly those with chronic wounds. To bridge these gaps, interdisciplinary collaboration is crucial, bringing together bioengineers, clinicians, material scientists, and regulatory experts [84]. Such collaboration can foster the development of optimized, patient-specific devices and help address regulatory hurdles, ultimately advancing cutaneous bioelectric interfaces from experimental treatments to mainstream therapeutic options.

FUTURE DIRECTIONS AND INNOVATIONS

Recent advancements in nanotechnology and biomaterials are advancing the future of cutaneous bioelectronic interfaces for wound healing. Nanomaterials, including graphene-based sensors and bioresorbable conductive polymers, could offer enhanced biocompatibility and flexibility. Graphene-based materials, like graphene oxide, show great potential in wound healing by promoting angiogenesis, enhancing antibacterial properties, and supporting cell growth [85]. When combined with natural polymers like chitosan and collagen, these materials create frameworks that accelerate wound closure, improve mechanical properties, and provide controlled drug release. This would allow graphene-based materials to mimic natural tissue, improving wound closure and overall healing speed, especially in complex or chronic wounds [86]. While promising, further research on their safety, interactions with bacterial biofilms, and clinical application is needed before they can be used widely in wound care.

Alongside graphene, hydrogels offer another promising solution for wound healing. These materials maintain a moist environment, absorb exudates, and promote re-epithelialization through their biocompatibility, biodegradability, and flexibility [87]. Hydrogels could be instrumental in accelerating healing, reducing infection risk, and improving patient outcomes. In the future, “smart” and sprayable versions of hydrogels could be developed to adapt to wound conditions and improve healing efficiency, further revolutionizing wound care for chronic and acute wounds.

Artificial intelligence is also playing an increasing role in predictive modeling for wound healing. ML algorithms can analyze vast amounts of patient data, identifying patterns that predict wound healing trajectories and complications [88]. It can be used to assist with diagnosis, therapy selection, disease stratification, and reducing medical errors. A study by Barakat-Johnson et al. found that AI could effectively be used for wound healing by showing that 101 out of 132 wounds improved after AI intervention [89]. However, there are still challenges, like limited data availability, slow image collection, and the lack of efficient data analysis systems, that limit AI’s ability to be used practically. One of the primary concerns with AI is that data privacy concerns limit the ability for essential data to be shared to improve the training models [90]. To effectively use AI to improve wound healing, mechanisms must be created to share this vital data while preserving patient privacy. As AI continues to evolve, it is expected to enhance wound care by providing personalized and high-quality treatment options. However, further development and standardization are needed to ensure reliable and consistent clinical applications.

Personalized medicine is a key factor in the future of bioelectronic wound healing technologies. Customizable bioelectronic devices, tailored to individual patient needs, offer a more targeted and efficient therapeutic approach. Innovations such as 3D-printed biosensors allow for the development of patient-specific devices that conform to unique wound geometries and improve healing rates [91]. These materials create highly customizable wound healing treatments that can be tailored to the size, shape, and needs of the wound, enhancing healing speed, reducing infection risks, and improving overall treatment efficacy. Another crucial aspect of personalization is the development of adaptive bioelectronic systems capable of responding to real-time physiological changes. For example, a study by Shirzaei Sani et al. developed a flexible, wearable bioelectronic system that enabled real-time monitoring and combination therapy, which accelerated healing in chronic wounds [10]. This customization enhances therapeutic precision, ensuring that the treatment is optimized for each patient’s specific condition. Smart bandages with biofeedback mechanisms can dynamically modify electrical stimulation based on wound healing progression. This technology has been successfully used in mouse models to continuously monitor skin physiological signals while delivering targeted electrical cues to close wounds faster, increase blood vessel formation, and improve dermal healing [92]. These advancements reduce the risk of over- or under-stimulation, which can either inhibit healing or cause unnecessary tissue damage.

The successful implementation of bioelectronic wound healing solutions needs collaboration across multiple scientific disciplines. Early collaboration between engineers, scientists, and healthcare professionals historically has led to several innovative wound care products. For example, the Tegaderm and the Vacuum Assisted Closure products were both enhanced after gaining input from those with hands-on clinical experience [93]. This cross-field collaboration not only drove technological advancement but also ensured that the products were tailored to meet real-world needs. Due to its complex nature, developing modern cutaneous bioelectronic interfaces requires integrating multiple advanced technologies, such as materials science, electronics, signal processing, and biology, to create systems that are both biocompatible and highly functional [94]. These tasks cannot be accomplished by any single discipline alone. By leveraging expertise from diverse fields, researchers can develop efficient, biocompatible, and flexible bioelectronic devices that align with therapeutic goals in wound healing.

The integration of bioelectronic interfaces into wound care represents a transformative shift in medical technology. These systems have the potential to revolutionize not only wound healing but also broader applications in regenerative medicine. Future bioelectronic platforms may incorporate wireless connectivity, allowing remote patient monitoring and telemedicine integration [40,95]. Such advancements could significantly reduce healthcare costs while improving accessibility to high-quality wound care, particularly in remote or underserved regions. The principles underlying cutaneous bioelectronic interfaces could extend to other medical applications, such as neural regeneration, musculoskeletal repair, and chronic disease management [7,96,97]. As technology advances, these systems may become integral parts of personalized healthcare, enhancing patient recovery and quality of life. The future of wound healing lies at the convergence of bioelectronics, AI, nanotechnology, and personalized medicine [98]. To ensure the successful implementation of these technologies in medical treatments, sustained investment in research and development, coupled with regulatory frameworks that ensure safety and efficacy, will be crucial.

CONCLUSION

Cutaneous bioelectronic interfaces represent a transformative advancement in wound healing, offering the dual benefits of real-time monitoring and targeted therapeutic intervention. By continuously tracking critical biomarkers such as pH, temperature, oxygen saturation, and early signs of infection, these devices enable timely clinical decisions that help prevent complications and optimize wound management. This continuous monitoring provides dynamic insights into the wound microenvironment, allowing for early detection of infection, inflammation, or impaired healing. Additionally, controlled electrical stimulation enhances key biological processes like cell migration, angiogenesis, and collagen synthesis, accelerating tissue repair and promoting more effective healing. This stimulation activates cellular pathways that promote fibroblast proliferation, keratinocyte migration, and improved blood flow, all of which are essential for efficient tissue regeneration. Clinically, these technologies have the potential to significantly improve patient care by reducing recovery times, minimizing infection risks, and enhancing the management of chronic or non-healing wounds, such as diabetic ulcers, venous leg ulcers, and pressure injuries. However, widespread adoption faces challenges, including ensuring long-term biocompatibility, device durability in diverse environments, safety over extended use, and cost-effectiveness for broader healthcare applications. Future research should address these limitations through innovative design improvements, the integration of artificial intelligence for smarter diagnostics and personalized treatments, and the development of scalable, patient-centered solutions that can be effectively implemented in both hospital and home-care settings.

Ultimately, the successful integration of bioelectronic systems into wound care will rely on collaborative efforts among healthcare professionals, biomedical researchers, and engineers. By working together, they can advance the technology by ensuring that bioelectronic systems become an integral part of wound management and significantly enhance the quality of life for patients. The future of wound healing lies in the continued convergence of bioelectronics, AI, and personalized medicine, offering new avenues for faster, more effective healing and better patient outcomes.

ACKNOWLEDGEMENTS

None.

CONFLICTS OF INTEREST

The author declares that there are no conflicts of interest.

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