Abstract
Chronic wounds represent a major global health problem, causing staggering economic and social burdens. The pursuit of effective wound healing strategies demands a multidisciplinary approach, and advances in material sciences and bioengineering have paved the way for the development of novel wound healing biomaterials and technologies. In this Review, we provide an overview of the history and challenges of wound management and highlight the current state-of-the-art in wound healing biomaterials alongside the emerging technologies poised to transform the landscape of chronic wound treatment and monitoring. Moreover, we discuss the clinical and commercial considerations associated with wound healing strategies, including the regulatory pathways and key steps in the translational process. Furthermore, we highlight existing translational gaps, and offer a nuanced understanding of the challenges that persist in translating innovative concepts into mainstream clinical practices. Continued innovations and interdisciplinary collaboration will pave the way for better wound care outcomes and potentially dramatically improved quality of life for a steadily increasing and aging population.
ToC blurb:
Chronic wounds, a global health crisis, demand innovative approaches for healing and monitoring. This review explores the progression of wound care, highlighting advanced biomaterials, emerging technologies, and the intricate process of transforming laboratory breakthroughs into clinically applied solutions.
Introduction
Wound healing is an intricate and dynamic process crucial for preserving the integrity and functionality of the skin and the adjacent tissues. Acting as a protective barrier, the skin’s efficient healing is essential in preventing infections and maintaining homeostasis. Being categorized into acute and chronic, wounds present considerable challenges to the healthcare system. Acute wounds typically follow a predictable sequence of inflammation, proliferation or repair, and remodeling. Conversely, chronic wounds, often associated with conditions such as diabetes, vascular diseases, or pressure injuries, frequently linger in the inflammatory stage, leading to prolonged healing times, heightened infection risks, increased morbidity, and even mortality (Fig. 1)1–3.
Figure 1. Chronic wound healing and management process.
Schematic illustrates the process of healing process in chronic wounds. Chronic wounds exhibit a complex and protracted healing trajectory, marked by the occurrence of various healing phases in a non-linear and unpredictable fashion. Addressing the distinct challenges posed by each phase within the same wound necessitates diverse therapeutic approaches tailored to specific areas. Wound healing is facilitated by physiological activities such as angiogenesis and phagocytosis, which are driven by positive intracellular and intercellular communication involving growth factors and cytokines. Conversely, pathological conditions, including chronic inflammation, fibroblast aging, and oxidative stress, arise from disrupted signaling mechanisms. These conditions are often worsened by elements like matrix metalloproteinases (MMPs), damage-associated molecular patterns (DAMPs), and bacterial toxins, leading to wounds that do not heal. Therefore, therapeutic efforts should aim to modulate these biochemical pathways and signals to promote a shift towards healing by addressing the specific challenges that impede recovery in pathological wound healing scenarios. Advanced smart technologies and materials have been innovatively designed to tackle this complexity and provide a personalized and dynamic strategy for optimal wound management. ROS, reactive oxygen species; RNS, reactive nitrogen species.
The burden of wounds on healthcare systems is substantial, affecting millions annually with associated costs estimated to be over USD 28 billion4, 5. A recent update suggests 40–60 million people worldwide are affected by diabetic foot ulcers (DFUs), with prevalence rates fluctuating due to variations in surveillance methods, definitions, and access to care. DFU prevalence in North America is 13% and lower in Europe (5.1%), with a global average of 6.4%. Increasing rates have been reported in Africa and South America (15%), with males and patients with Type 2 Diabetes more frequently affected4, 6. Surgical wounds, pressure injuries, and burns contribute extensively to this burden, underscoring the need for effective wound management strategies. The current standard of care involves preparing a viable wound bed through practices such as debridement, irrigation, and closure techniques. However, continuous innovation is evident in wound care, ranging from advanced wound dressings to technologies targeting specific pathophysiological factors7.
It is noteworthy that chronic wounds pose a mortality risk greater than commonly appreciated. For instance, the five-year mortality rates among individuals contending with diverse forms of chronic wounds, such as diabetic chronic ulcers, stand at a considerable 70%. This statistic notably exceeds the five-year mortality rates observed in patients with conditions like colorectal, breast, and prostate cancers. Unlike cancer treatments, there exists a conspicuous gap in education and awareness about wound care among both healthcare professionals, patients, and the general population. Strengthening community engagement and patient advocacy efforts is crucial for addressing such educational gap and promoting preventive measures for more effective wound management.
Commercial wound care products are not limited to passive biomaterial-based wound dressings, and Smart wound dressings capable of real-time monitoring and active intervention have also been developed. Chronic wounds often involve bacterial infections, excessive inflammation, poor perfusion, and vascularization. The limitations of conventional wound dressings in providing real-time information on the complex wound microenvironment impede the attainment of optimal wound healing. A promising solution to overcome this constraint lies in the integration of wearable sensors into smart wound dressings. Furthermore, the advent of smart bioelectronic systems presents great potential for personalized wound care, owing to their advantages such as wearability, cost-effectiveness, and rapid and simple application8–16.
Although numerous wound care products have been developed, each follows a distinct clinical and regulatory pathway, and only a limited number of them have received clinical approval, with many failing during the translation process. According to the United States Food and Drug Administration (USFDA) guidelines, a fundamental understanding of the pathophysiological processes driving injury is crucial for developing targeted therapies. Multidisciplinary collaboration efforts and early engagement with clinicians are imperative for identifying unmet clinical needs and creating evidence-based target product profiles. Additionally, preclinical models that accurately represent human tissue responses are also critical for successful translation from bench to bedside7. The notable increase in wound care technologies since 2017 reflects the result of a convergence of factors that have collectively accelerated advancements in this field (Fig. 2). This surge can be largely attributed to the fusion of multidisciplinary technologies, including biotechnology, nanotechnology, and digital health, which have paved the way for the development of innovative wound care solutions such as smart dressings and bioactive materials. Additionally, there has been a marked increase in funding for wound care research from both governmental and private sources. This uptick in investment is motivated by a growing awareness of the challenges posed by chronic wounds and the expanding wound care market, which was valued at $US 20.18 billion in 2022 and is expected to reach $US 30.52 billion by the end of 203017–20. Advancements in material science have introduced novel biomaterials that enhance wound healing more effectively. The introduction of wearable technologies has transformed wound monitoring and management by enabling real-time data analysis. Furthermore, regulatory bodies have optimized their approval processes for medical devices and therapeutic products, accelerating the commercialization of new innovations. Additionally, global collaborations between researchers, clinicians, and industry stakeholders have improved the distribution and adoption of these advanced technologies. This multifaceted progression underscores the dynamic evolution of wound care methodologies, marking a leap in therapeutic approaches and product development in recent years.
Figure 2. A timeline of technology development in chronic wound management.
The history of wound care devices, encompassing the United States Food and Drug Administration (USFDA)-approved innovations and those currently undergoing pre-clinical or clinical research. The history of wound care products spans from cellular level topical ointment, sophisticated therapy, to cutting-edge biosensors and portable diagnostic devices, illustrating the forward-moving trajectory of key advancements in wound management technologies. Adapted/Reproduced with permission from Refs. 11, 95, 96, Alliqua BioMedical, Inc., DARCO International, Klinik Inocare, Organogenesis Inc., Aesthetique Skin & Body and MolecuLight.
In this Rview, we present the design principles for wound care technologies tailored to specific clinical applications, aiming to bridge the gap between applied research and translational outcomes. Our assessment of wound care encompasses various aspects of material design principles derived from diverse fields, such as tissue regeneration, wound dressing, smart bandages, and cell or drug delivery in the context of wound care applications. We then delve into recent advances in chronic wound management, emphasizing the importance of a multidisciplinary approach and capitalizing on breakthroughs in material science and bioengineering to enable personalized chronic wound assessment. The integration of novel materials facilitates controllable and sustainable delivery of therapeutic agents to the wound site while preserving physiological microenvironments. Furthermore, we explore recent strides in diagnostic medical devices, particularly wearable biosensors, which empower non-invasive, real-time monitoring and analysis of the wound condition to enable timely intervention and enhance patient compliance. The imperative development of such materials and technologies has become evident to address the unmet needs of chronic wound care. Additionally, we will describe the translational process and regulatory pathways indispensable for the effective development of wound management strategies. Last but not least, we provide an illustrative overview of the various classifications of wound care products, offering a comprehensive perspective on the evolving landscape of wound care technologies.
Emerging materials for advanced wound management
The evolution of wound management has witnessed the integration of a diverse array of materials designed to modulate the wound microenvironment, thereby orchestrating essential facets of the healing process. These materials play pivotal roles in fostering fibroblast growth, re-epithelization, vascularization, collagen deposition, immunomodulation, and mitigating complications such as infection, pain, bleeding, and tissue scar formation. Tailored materials and methodologies are crucial across the four stages of wound healing (Fig. 1), although their linear sequence may not correspond with the healing process of chronic wounds. Initially, hydrogels and chitosan contribute to clotting and offer antimicrobial benefits. As healing progresses, smart dressings facilitate the release of anti-inflammatory agents during the inflammation phase. In the proliferative phase, biodegradable scaffolds, such as collagen, foster new tissue formation. During the remodeling phase, the focus shifts towards minimizing scarring, with silicone sheets and biomimetic materials being preferred options. Given that chronic wounds may deviate from this orderly progression, the selected materials must be adaptable, capable of simultaneously addressing various aspects of healing to effectively manage the intricate dynamics of chronic wound care.
Rational material and technology design for clinical applications
Achieving effective wound care necessitates the strategic development of materials and technologies tailored specifically to the nuanced requirements of clinical applications. The rational design of biomaterials for wound healing entails meticulous considerations to uphold the physiological microenvironment and therapeutic functionality (Fig. 3a, b)9, 21, 22.
Figure 3. Translational materials for wound treatment.
a, Various material types employed for chronic wound treatment, including nano/micro particles, bioscaffolds, bioelectronic materials and stimuli responsive materials. b, Physical properties including mechanical stability, adhesion, wettability, moisture control, transparency, and breathability, as well as biochemical properties such as anti-FBR, biodegradability and hemostasis. These characteristics can control a range of cellular functions and therapeutic efficiency. FBR, foreign body response. c, The materials designed to realized functionalities such as fibroblast growth stimulation, re-epithelization, vascularization, collagen deposition, scar prevention, immunomodulation, and infection prevention. d, Currently, available therapeutic approaches could be categorized as material-based therapy, extra stimuli therapy as well as material-device combinational therapy.
Mechanical properties
The mechanical properties of materials play a pivotal role in minimizing secondary damage and promoting the healing process. Human epidermis’s maximum strain rate, approximately 15%, underscores the importance of proper elasticity to ensure adherence and prevent damage to both tissue and device23. The strength, elasticity, and adaptability of materials not only safeguard wounds but also exert a profound influence on cellular behaviors. The mechanical attributes of wound dressings and scaffolds can severely impact tissue regeneration, inflammation, and even scar formation. For instance, a substrate stiffness of 10 kPa and a dressing length of 7–9 cm to promote force transmission proves ideal for fibroblast proliferation, closely mirroring the mechanical environment of cutaneous tissues24, 25. Materials endowed with adjustable mechanical properties have shown promise in the context of chronic wounds, demonstrating improved healing by offering controlled and sustained contraction on moist wound surfaces26.
Porosity, breathability, and transparency
The scaffold’s porosity plays a critical role in governing cellular infiltration and supporting the vascularization, as interconnected pore networks enhance the transport of elements such as nutrients, oxygen, and waste products27. Beyond porosity, the breathability of wound dressing is crucial, allowing the penetration of oxygen towards the wound while simultaneously serving as an effective barrier against bacterial contamination28, 29. Additionally, material transparency proves invaluable, facilitating real-time monitoring and visualization of the wound’s healing progress. When employing transparent wound devices, integrating layers that shield against ultraviolet (UV) radiation is crucial. This measure prevents possible changes in skin pigmentation and ensures both the material durability and sustained functionality of its embedded components.
Wettability
The wettability of wound dressings greatly influences the behavior of biofluids in the proximity of wounds. Although a moisture-retentive feature is essential, an excess of biofluids at wound sites can lead to infections and impede the healing process30. To address this, self-pumping dressings are ingeniously designed to drain excess biofluids from their hydrophobic side to their hydrophilic side, effectively preventing the wound from becoming excessively wet31. Achieving a delicate balance between retaining moisture and facilitating evaporation is key to avoiding fluid buildup, which can cause maceration and infection. The water vapor transmission rate (WVTR) is an important metric that varies with the type and stage of the wound; for instance, normal skin has a WVTR range of 204 to 278 g m−2 day−1, whereas 1st-degree burns and granulating wounds exhibit a substantially higher rate of 5138 ± 202 g m−2 day−1 32. A dressing is considered to have adequate moisture-retentive properties if its WVTR is less than 840 g m−2 day−1 33. Dressings with high water vapor permeability may dry out the wound too quickly, leading to scarring, whereas those with low permeability may cause exudate accumulation, slowing the healing process and increasing infection risk.
Adhesion
Adhesive dressings are gaining prominence in wound care due to their direct application, eliminating the need for cutting and attaching surgical tapes. This ensures not only secured wound coverage but also maintains a stable interface between the wound and the dressing material34. However, it is crucial to note that excessive adherence to the wound can lead to removal of substantial layers of the stratum corneum, either from the newly formed epithelium or from the healthy skin surrounding the wound.
Hemostasis
Retaining wound hemostatic constituents on the dressing material is paramount, as they can contribute to hemostasis and provide a scaffold for incoming cells and growth factors. This retention potential holds promise for enhancing wound regeneration35, 36. For example, the application of Laponites, a synthetic nanoclay with inherent hemostasis capacity, can improve shear-thinning properties, making it a widely-utilized material for the 3D printing of wound dressing37, 38.
Biochemical properties
The biochemical properties of wound biomaterials encompass critical factors such as biocompatibility, the interaction between biomaterials and the wound microenvironment, scaffold degradation, and the release of entrapped therapeutic agents. Following application, dressings and devices will quickly accumulate a layer of adsorbed proteins, triggering the immune system recognition and dictating the foreign body response (FBR) process. Anti-FBR properties become imperative to mitigate inflammation and complications, optimize device performance, and enhance overall functionality. The degradation of biomaterials is intricately linked to the local microenvironment. For example, chronic wounds are characterized by a high level of proteases, which can accelerate the degradation of peptide-derived matrix39. Conversely, the release of signaling ions from biomaterials can positively alter the local microenvironment. For example, calcium ions released from alginate can serve as both hemostatic and fibroblast proliferation signals40.
The implementation of therapeutic strategies in wound management can be intricately customized to align with the distinct characteristics and demands of diverse wound types. Essential to this approach is a profound understanding of the underlying causes of the wound, such as pressure, diabetes, venous insufficiency, or arterial disease, as this knowledge is crucial to judiciously select appropriate materials. For instance, addressing venous leg ulcers typically involves the application of compression bandages to enhance circulation, whereas the treatment of diabetic foot ulcers often prioritizes meticulous debridement and safeguarding the wound from further injury41. Moreover, individual patient considerations, such as pain levels, can influence dressing selection, the frequency of dressing changes, and may necessitate the incorporation of pain management interventions. Additionally, the selection of a wound care strategy is shaped not only by clinical considerations but also by economic factors and the availability of qualified care providers. These factors underscore the paramount importance of adopting a holistic and adaptable approach to wound care that not only caters to the specific needs of the wound but also addresses the broader context of patient well-being.
Advanced materials for wound treatment
Cutting-edge materials play a pivotal role in supporting the healing process and mitigating complications associated with wounds. Acting as protective shields, they redistribute pressure and shield against external contaminants. In situations demanding wound stabilization, immobilization, or precise pressure distribution, medical devices incorporating rigid materials present specialized solutions such as negative pressure therapy, orthotic device for wound prediction and prognosis, and casts for fractures. These tailored devices contribute to optimal wound recovery by addressing individual patient needs.
Nevertheless, conventional materials, even though they provide essential support, often fall short in conforming to the body’s contours and lack breathability. These factors can result in discomfort, potential skin complications, and the need for frequent adjustments during the healing process. There is a growing interest in developing novel materials that are more adaptable, comfortable, and conducive to the overall healing trajectory.
Emerging materials-based treatments have shown great potential in wound healing applications42. Unlike conventional rigid materials that offer passive wound support, many of these materials are flexible and wearable, enhancing user comfort and enabling responsive, personalized treatment for faster tissue regeneration and reduced infection risks (Fig 3c). Leveraging materials such as hydrocolloids, hydrogels, nanofibers, and other functionalized materials, these treatments exhibit promising biocompatibility and the ability to maintain and modulate the physiological microenvironment of the wound21, 35, 43, 44. Various technologies for wound healing, including targeted and controlled drug delivery45, 46, bioelectronics stimulation11, photodynamic therapy47, 48, negative pressure wound therapy (NPWT)49, hyperbaric oxygen therapy50, and gene and cell therapy51 have witness substantial progress, facilitated by these novel materials. The integration of these innovative material-based therapies has the potential to revolutionize wound management, improving healing outcomes and reducing healthcare costs. The focus on patient-centric care is evident in the drive to enhance patient comfort, minimize the risk of complications, and improve overall treatment outcomes in wound care (Fig. 3d).
Micro- and nanoparticles
Micro- and nanoparticles possess immense potential for direct treatments and functioning as carriers for delivering therapeutic agents due to their tailorable characteristics, including a high surface area, tunable properties, and the ability to encapsulate therapeutic agents. Micro- and nanoparticles, including metallic, ceramic, polymeric, self-assembling, composite, and hydrogel-embedded nanoparticles, have versatile functionality, rendering them invaluable tools for advancing wound healing processes. To mitigate skin irritation and multisystemic complications, as well as to maintain their functional integrity, nanoparticles can be stabilized using materials like metal shells, polymers, or surfactants, and coated with low-sensitization substances52.
Micro- and nanoparticles can directly influence cellular behavior and physiological balance. For example, zinc oxide (ZnO) nanoparticles impact inflammatory responses, enhance epithelialization, and facilitate the restoration of skin hemostasis. Nanoparticles can influence the wound healing process by modulating the activity of various cells engaged in regeneration and immune response. Notably, wounds treated with microporous annealed particle (MAP) revealed a de novo regenerated appearance, enhanced myeloid cell recruitment, improved tissue architecture, and increased vascularization, indicating a return to a healthier, more normal state of the skin43.
Metal-based nanoparticles, including metallic and metal oxide varieties, as well as quantum dots, offer substantial advantages for antimicrobial activity and reactive oxidative species (ROS) scavenging, particularly against multidrug-resistant organisms53–55. Among these, silver nanoparticles are increasingly incorporated into commercial wound dressings, playing a crucial role in preventing and combating infections in wound care56. Certain nanoparticles can be externally controlled for drug releases with responsiveness to wound features such as the levels of pH or metabolites, offering utility in precisely directing them to a wound site or for remote activation.
Micro- and nanoparticles are extensively employed for target delivery of drugs directly to the wound site in a controlled manner. Various therapeutic agents, ranging from antibiotics and anti-inflammatory drugs, to growth factors and genetic material such as DNA or RNA, can be incorporated into these particles for efficient delivery. The sustained release capability of these particles proves crucial for prolonged therapeutic effects, particularly in wound healing scenarios where a consistent drug supply maintains the optimal healing environment. Additionally, the encapsulation of therapeutic agents in micro- or nanoparticles can protect drugs from premature degradation caused by the enzymatic and pH conditions in the wound environment. However, utilizing micro-nanoparticles in wound healing and monitoring presents several challenges that must be addressed. One primary concern is the risk of cytotoxicity, as certain materials used in nanoparticles such as metals and metal oxides can elicit adverse cellular responses, potentially compromising the healing process. Another challenge lies in the precise control of particle delivery and retention at the wound site, as inadequate localization may reduce therapeutic efficacy and increase the risk of off-target effects. Furthermore, the complex wound microenvironment, characterized by varying pH levels, enzymes, and fluid exudates, can affect the stability and functionality of nanoparticles, necessitating robust particle design and surface modification strategies. Addressing these challenges requires comprehensive preclinical testing and the development of innovative engineering solutions to fully exploit the capabilities of micro- and nanoparticles in advancing wound care.
Bioelectronic materials
The discovery that cutaneous cells can generate and respond to bioelectrical signals has sparked a wave of innovation in techniques aimed at electrically assessing and modulating wounds. Specifically, the pursuit of refined ways to augment the bioelectrical signal at the wound site has led to the evolution of materials and methodologies that seamlessly integrate electronics into wound care and tissue repair processes.
Electroactive materials, possessing the ability to generate or respond to electrical signals, introduce a dynamic dimension to wound management strategies. Made from conductive matrices or by encapsulating conductive components, these materials exhibit excellent electron-ion interconversion efficiency, which is independent of voltage and frequency. Their notable capacitive characteristics and their ability to operate effectively across a broad frequency range, all the while maintaining their electrical conductivity, strength, flexibility, and biocompatibility, are attributes crucial for achieving optimal performance57. For instance, low frequency (<10 Hz) monophasic pulsed microcurrents lead to enhanced fibroblast proliferation and migration whereas high-frequency (>1 kHz) therapy is used for pain reduction and antibacterial treatment58–61. Electric field generated by nanogenerators are also employed to facilitate healing progress21, 62.
The integration of electronic conductors, such carbon nanotubes (CNTs), metal nanoparticles, and graphene oxides, into biomaterials could enable better electrical signal transmission63. Challenges, however, arise from the uneven dispersion of the conductive materials, leading to interruptions or irregularities in the electrical signals transmitted through it. In addition, these materials’ long-term safety needs to be assessed due to concerns about their potential toxicity. Alternatives such as conductive organic polymers, notably polyaniline, polypyrrole, and poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS), have shown promise in creating stretchable electrodes capable of accommodating the movement of wound tissues64–66.
Ion-conductive hydrogels, characterized by their high water content and malleability, are ideal candidates for direct application to wound sites. Despite appearing solid at the macroscopic level, these hydrogels exhibit liquid-like properties at the microscopic scale, facilitating ion migration and contributing to the charge conversion between ion-conductive hydrogels and tissues. They can serve multiple purposes, including maintaining wound moisture and aiding electric field-driven healing processes67–69. Ion-conductive hydrogels, although exhibiting lower electrical conductivity and electrochemical properties than their conductive nanomaterial-infused hydrogels or conducting polymers counterparts, still offer great potential for wound healing applications. In therapeutic settings, particularly where the objective is to apply low-level electrical stimulation to facilitate healing, the safety and biocompatibility of ion-conductive hydrogels take precedence over achieving the highest possible conductivity.
Harnessing electrical cues, bioelectronics materials can facilitate cell migration, enhance tissue regeneration, and modulate inflammation. Furthermore, electroactive materials have the potential for controllable drug delivery, real-time monitoring of wound healing progress, and the creation of electrically stimulated environments that expedite the overall healing process. Employing electroactive materials in wound care requires meticulous consideration of several key factors: biocompatibility, precise adjustment of electrical characteristics, and a careful balance of mechanical durability and appropriate degradation rates. Moreover, incorporating electroactive materials into current medical devices and ensuring their scalability for clinical applications poses significant engineering challenges. Overcoming these challenges necessitates a multidisciplinary approach to ensure these materials are safe, effective, and compatible with bodily dynamics and existing medical technologies.
Natural and synthetic bioscaffolds
Bioscaffolds, inspired by the natural extracellular matrix, offer a platform that fosters the body’s intrinsic healing processes, redefining the realm of wound management. Natural bioscaffolds, such as collagen, chitosan, silk, and alginate, closely emulate the body’s own extracellular matrix, creating a conducive environment for tissue regeneration70–73. In addition to their high biocompatibility, these natural scaffolds provide receptors essential for cell migration and proliferation, neo-angiogenesis support, and scar-free healing.74 Multiple studies and clinical trials have explored products from xenogenous sources (such as porcine and bovine) and human tissues as scaffolds for wound dressing7, with some of these products also containing growth factors from the donor75, 76. However, the inherent variability in composition of natural bioscaffolds, stemming from differences in their biological sources, can result in inconsistent properties that may influence the healing outcomes. Furthermore, these natural scaffolds pose a risk of immunogenic reactions or disease transmission, requiring stringent purification procedures to ensure their safety and effectiveness.
Conversely, synthetic bioscaffolds such as polyethylene glycol (PEG), poly(lactic-co-glycolic acid) (PLGA), and polycaprolactone (PCL) offer precise control over properties like porosity, degradation rate, and mechanical strength77–79. This versatility enables the customization of the scaffold to meet specific wound care requirements. By providing mechanical support, promoting cell attachment, and modulating biochemical cues, these scaffolds accelerate wound healing while minimizing scar formation. Additionally, these scaffolds can also be finely tuned to realize controllable release of bioactive molecules and therapeutic drugs entrapped inside. For example, polyacrylamide hydrogels can be designed with varying stiffness, ranging from 0.1 to 25 kPa, with the stiffness crucially influencing stem cell differentiation80. However, their biocompatibility and bioactivity might not rival those of natural scaffolds, possibly requiring surface modifications such as their coating with cell adhesin molecules (CAM) to enhance cell interactions81, 82.
Stimuli-responsive materials
Stimuli-responsive materials, also known as smart materials, have garnered a lot of interest for wound healing due to their ability to respond to internal changes within the wound microenvironment (such as temperature, pH, metabolites, and enzymes) or external stimuli fields (such as force, electrical, magnetic, and ultrasound fields).
Responsive wound care products can be devised by harnessing the physical properties of materials, such as a low critical solution temperature, strategically aligning with the pathological conditions typically observed in wound environments. For example, drugs can be evenly dispersed throughout a liquid-state hydrogel, while its solidification transition under body temperature prevents the rapid release of the drug, thereby ensuring the prolonged delivery. Additionally, these materials can dynamically adjust their size in response to temperature changes and provide contractile force, which accelerates the healing process. Alternatively, responsive materials can be engineered using scaffold and crosslinkers that are susceptible to digestion by biochemicals present in the wound for therapeutic agent release83, 84. For example, a DNA crosslinked hydrogel was designed to degrade in response to deoxyribonuclease (DNase) secreted by pathogens and release neutrophils85.
Nanogenerators, capable of converting mechanical energy from body movements or external pressure into electrical energy, present an innovative approach for wound care62, 66, 86. For example, piezoelectric materials produce electrical signals in response to mechanical stress, which can be harnessed to stimulate cellular processes vital for tissue repair and regeneration. This property is particularly useful in dynamic wound dressings designed to provide continuous electrical stimulation directly to the wound site, thus promoting healing in an active, non-invasive manner.
Photodynamic therapy is a strategy that has been used to achieve antibacterial properties, in which light is used to locally elevate temperature, inducing bacteria mortality. This method is effective against antibiotics-resistant bacteria while minimizing side effects87–90. Employing stimuli fields to control scaffold degradation is a prevalent approach to realize drug or cell therapy. For example, by incorporating magnetic particles in wound dressing scaffolds, magneto-induced dynamic mechanical stimulation can enable controlled drugs and cutaneous cell release, accelerating the healing process91, 92. Despite these strides, challenges, including the longevity of these materials, ensuring the precision in controlled drug release dosages, and maintaining consistent therapeutic effectiveness over time, persist.
Direct applications of stimuli fields have also been leveraged for wound treatment. For instance, applying ultrasound to induce cavitation, leading to the breakdown and erosion of devitalized tissue93, shows promise for debriding wounds, a process of removing dead, damaged, or infected tissue to improve the healing potential of the remaining healthy tissue. This can be a critical step in the management of chronic wounds, particularly those with necrotic tissue.
Emerging technologies for wound monitoring
Traditional methods of wound assessment, primarily relying on visual inspection and subjective evaluation, are undergoing a transformation as sophisticated technologies emerge to provide objective, real-time, and precise data. These advances are shaping a new paradigm where wound care becomes increasingly predictive, personalized, and efficient. The integration of wearables and imaging tools is at the convergence of engineering and clinical practice, paving the way for a future in which wounds can be monitored and managed with unprecedented precision. This approach not only reduces complications but also accelerates the healing process, marking a significant leap forward in the field of wound care. Advanced wound care monitoring technologies cater to various wound conditions and multiplexed biomarkers through signal transduction techniques and system integration, providing a comprehensive platform for the development and application of smart wound management (Fig. 4).
Figure 4. Materials and technologies for wound analyzing and monitoring.
The schematic represents an overview of the integrated components and processes involved in advanced wound monitoring systems. This includes a holistic representation of key elements such as wound conditions, biomarkers, signal transduction, performance-enhancing materials, system integration, and strategies for wound fluid sampling and target recognition. CRISPR, clustered regularly interspaced short palindromic repeats; NFC, near field communication.
Biomarkers for wound healing
Emerging biosensors and imaging devices have shown promising capabilities to characterize wound features and monitor versatile biomolecules including metabolites (such as glucose, uric acid, and lactate), electrolytes (such as pH, Na+, Ca2+, and NH4+), nutrients (such as vitamins, amino acids, and fatty acids), proteins (such as cytokines and C-reactive protein), and therapeutic drugs (such as growth factors, plasmids, and antibiotics)85, 94–100. These biomarkers are associated with physiological and pathological conditions, such as infection and inflammation101–103. Notably, analytes of interest can be detected directly at the wound site, eliminating the need for blood tests or invasive tissue biopsies. Blood tests typically reflect systemic conditions that may differ from the local wound environment, whereas tissue biopsies, being invasive, can exacerbate wound damage and typically require weeks to produce results. Additionally, certain crucial wound biomarkers, such as ROS and reactive nitrogen species (RNS), exhibit high reactivity and short half-lives. In situ monitoring addresses these challenges by providing real-time analysis, yielding results that are otherwise unattainable with current approaches104–106.
The detection of crucial proteins plays a pivotal role in assessing the healing process and guiding treatment. These proteins include growth factors and cytokines like platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-β), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and interleukins, which regulate cell functions essential for repair. Matrix metalloproteinases (MMPs) like MMP-2 and MMP-9 are involved in extracellular matrix remodeling, with elevated levels indicating chronic wounds. Structural proteins such as collagen, elastin, and fibronectin, contribute significantly to tissue formation and integrity. Inflammatory markers, including C-reactive protein (CRP) and procalcitonin, signal inflammation stages.
Monitoring these biomarkers provides a comprehensive view of wound healing phases and potential complications. For instance, the presence of virulence factors such as pyocyanin and bacteria DNA fragment could serve as early sign of infection. Timely treatment based on such insights could enhance therapeutic efficacy. These wound monitoring devices not only contribute to our understanding of the wound environment, classifications, and healing process but could also assist in drug screening and prognosis prediction107, 108.
Wound sampling
Efficient and precise sampling of wound exudate is crucial in wound care research and management, given that wound exudate is a valuable source of biomarkers. Ensuring the precision and relevance of data derived from biomarkers necessitates the careful collection of samples where fresh and old wound exudate must be separated. Old exudate, potentially laden with degraded substances, may not accurately convey the wound’s current condition, contrarily to fresh exudate, which provides immediate insights into the wound’s state. The ability to efficiently collect and promptly transfer fresh exudate to analysis modules is crucial for reliable wound assessment. Adopting continuous and effective in situ sampling techniques, aimed at isolating fresh exudate through a singular extraction process, offers a promising avenue. However, the practical implementation and success of such a strategy remain areas for future demonstration and refinement.
Dressings with enhanced exudate absorption capacity and a self-pumping feature were developed for efficient exudate sampling31. However, there are challenges associated with this approach, such as potential contamination from the biomaterials and difficulties in extracting fluid from the dressing scaffolds without losing critical information. Alternatively, NPWT and microneedles are capable of extracting fluid from deeper tissue layers, providing a more comprehensive overview of the wound environment. However, this approach may not solely represent surface conditions. The methods used for measuring wound exudate can yield disparate results. A comparative study of 14 patients revealed significant differences in exudate collection between methods: 0.17–0.21 g cm−2 day−1 with dressing and 1.3 g cm−2 day−1 with NPWT109. The inconsistencies in wound analysis methods and sample collection pose a crucial challenge, hindering accurate characterization of the wound healing process and impeding effective results comparison across studies. To address these challenges, microfluidic-based sampling has been introduced for on-site intermittent storage and precise management of wound exudate. This approach effectively reduces the likelihood of dilution, mixing, or cross-contamination96, 110. However, one main challenge of such microfluidic sampling is the limited volume of collected wound extrudate, typically 0.05–0.4 g/cm2 per day111. Despite numerous reports on microfluidics for wound sampling, none have demonstrated direct wound exudate collection from animals or patients. The limited volume of wound exudate, coupled with its high content of solid components (such as proteins, dead cells, and debris), reduces the available liquid portion for analysis. Furthermore, the drainage rate also varies across patients with different chronic wound types, depths, positions, circulations, and other underlying health issues. For example, a cross-sectional study of 41 patients with pressure ulcers exhibited a mean exudate volume of 6 ml per day with a wide range of 0.0–47.0 ml per day112. These variations underscore the complexity of wound exudate dynamics, emphasizing the need for standardized and efficient sampling methods to advance our understanding of wound healing processes.
Sensors
Sensors are devices capable of translating biomarker levels into measurable signals. The real-time insights into specific biomarkers obtained by wearable sensors have the potential to address the critical demand for personalized monitoring and timely intervention in various medical conditions. Achieving selective biomarker detection in the wound environment often require the integration of specific target-recognition materials or receptors such as ionophores, enzymes, antibodies, aptamers, and molecularly imprinted polymers. In the realm of wound care, many reported sensors rely on either electrochemical or optical principles for their signal transduction mechanisms.
Electric and electrochemical sensors
Electric sensors typically utilize impedimetry to detect variations in electrical signals prompted by changes in physical parameters such as temperature and skin impedance, providing crucial indicators of infection, hydration, and inflammation. Conversely, electrochemical sensors leverage techniques including amperometry, potentiometry, and voltammetry, to precisely quantify alterations in electrical signals at the sensor interface, facilitating detailed analysis of chemical and biological processes. For ions (such as Na+, Ca2+, and NH4+) and pH monitoring, potentiometry is primarily employed, utilizing ion-selective electrodes (ISEs) modified with ionophores (such as valinomycin) that selectively and reversibly bind to ions or ion-sensitive materials (such as polyaniline for pH sensing)113, 114. The measured voltage difference between the ISE and the reference electrode shows a log-linear relationship with the analyte concentration. The detection of metabolites such as glucose, uric acid, and lactate can be achieved using amperometric enzymatic electrodes immobilized with a specific enzyme (such as glucose oxidase, uricase, and lactate oxidase) to catalyze the oxidation of the target analyte. Redox mediators such as Prussian blue are often used to enable low-potential and efficient signal transduction with mitigated interferences from other electroactive molecules95. The measured current signals in this case are linearly correlated with the concentration of the target analyte. The detection of protein-based wound healing biomarkers, such as TGF-β and interleukins, often necessitates the use of antibody or aptamer receptors coupled with tagged electrochemical redox probes or field-effect transistors. Continuous monitoring of these biomarkers remains challenging due to their low concentration and difficulties in in situ sensor regeneration96, 115. When selecting biomarker measurement methods, it’s essential to consider their physiological concentration ranges. For instance, glucose levels in wound exudate can range into the tens of mM, whereas uric acid concentrations might hover around 100 μM95. The presence and concentration of specific biomarkers are influenced by the wound healing stage and the type of wound. For example, as wounds advance towards the proliferative and remodeling phases, the pH level typically decreases. Animal studies have shown that lactate concentration, a crucial indicator of cellular metabolism and hypoxia, peaks within the first three days post-injury. In diabetic wounds, lactate levels can surpass the 5–15 mM range typical for non-diabetic wounds, indicating the distinct metabolic challenges in diabetic wound healing116. Techniques like square wave voltammetry (SWV) and differential pulse voltammetry (DPV) offer greater sensitivity compared to linear sweep voltammetry (LSV), particularly due to their sampling methodology that effectively reduces the charging current associated with non-faradaic processes117. This greater sensitivity makes SWV and DPV particularly effective for detecting biomarkers within their precise concentration ranges in the wound environment, leading to more accurate and dependable readings. Additionally, the choice of recognition mechanism between receptors and targets can substantially influence the sensitivity range. For example, some aptamer or antibody-based biosensors can detect concentrations down to pM level, whereas enzyme-based sensors are typically utilized for identifying biomarkers at μM levels or above, showcasing the importance of sensing method selection and specific wound context to ensure accurate and effective wound monitoring16, 118.
Optical sensors
Optical sensors function by leveraging chemical or biological reactions that induce changes in optical signals of specific molecules or materials. These changes manifest as shifts in light absorbance (exemplified by color alterations), or as modifications in light emission (exemplified by changes in fluorescence or luminescence). Notably, these alterations are directly associated with the levels of analyte molecules.
In the realm of wound care, optical sensors, predominantly colorimetric ones, have been developed to monitor crucial parameters including temperature, pH and small molecules such as oxygen and amino acids119. The benefits of employing colorimetric sensors in wound care include direct visual detection, design simplicity, cost effectiveness, and ease of operation. Nevertheless, when compared to electrochemical sensors, colorimetric sensors exhibit a slower response time and require an external readout system to achieve quantitative measurements. Their dependence on visual color transformations resulting from chemical reactions requires a duration to gather observable alterations, which must subsequently be quantified by an external system. This stands in contrast to electrochemical sensors, which provide a more rapid, real-time electronic conversion of data. These characteristics pose challenges, particularly in scenarios requiring high-frequency continuous data collection. Additionally, the sensitivity and selectivity of this method can be influenced by environmental factors such as ambient light conditions and the optical properties of the wound matrix.
Imaging sensors
Various imaging modalities can provide visual and quantitative insights into critical wound characteristics such as size, depth, volume, and tissue composition. Conventional digital photography is commonly used for surface visualization of wounds, facilitating the monitoring of changes in size and appearance over time.
Infrared thermography is a powerful technique for mapping wound temperature, with elevated temperatures serving as reliable markers of inflammation, which is a predictive risk of ulceration, infection, and potential amputation. Conversely, decreased temperatures may indicate insufficient blood supply, signaling potential ischemia120.
Fluorescence imaging devices, strategically deployed at the point-of-care, enable real-time, non-contact visualization of tissue and bacterial fluorescence within wounds. Tissues typically emit green fluorescence, whereas bacteria exhibit red or cyan fluorescence under violet excitation light. Red fluorescence indicates the presence of porphyrins (by-products of bacterial heme production), whereas cyan signals the presence of pyoverdines, particularly in Pseudomonas aeruginosa121–123. These distinct fluorescence signals, derived from natural bacterial processes, aid in the early identification and treatment of wound infections. Clinical trials of MolecuLight i:X (MolecuLight Inc.), a portable, point-of-care device for bacteria imaging, have demonstrated a 100% positive predictive value for the detection of bacteria in wounds, highlighting its effectiveness in identifying wound pathogens124, 125.
Ultrasound imaging surpasses superficial wound assessment by effectively measuring wound depth and volume, key factors in ascertaining the severity and healing stage. It also aids in detecting underlying structures, such as bone involvement or sinus tracts, essential for devising appropriate and targeted treatment plans126.
Materials for enhanced in situ wound monitoring
Advanced materials play a crucial role in the development of sensors for enhanced in situ wound biomarker analysis. Metals, carbon nanomaterials, hydrogels, or polymers are commonly chosen in the sensor matrix owing to their unique properties, including high conductibility, biocompatibility, electrochemical stability, and the ability to host biorecognition and signal transduction elements.
Given that wound healing biomarkers are often present at extremely low concentrations, achieving the desired sensitivity requires in situ signal amplification strategies. Nanomaterials or porous structures are frequently employed to increase the sensor surface area, thereby enhancing the functionalization of recognition elements and facilitating electron transfer. Emerging materials such as quantum dots and pyranine offer advantages such as intense brightness and high resistance to photobleaching compared to traditional fluorescent dyes127, 128.
The intricate interactions between the wound environment and electrodes present challenges such as biofouling, impacting sensor longevity and performance. To address this, antifouling coatings, such as polyethylene glycol (PEG), hydrogels, Nafion, and chitosan are commonly utilized129–132. These protective coatings introduce desired surface hydrophilicity, charge, or porosity to minimize protein adsorption and cell adhesion, ensuring the sensors’ functionality in complex wound fluids. Additionally, filtration membranes made from materials like polyvinylidene fluoride (PVDF) or polytetrafluoroethylene (PTFE) are employed to selectively permit the passage of target analytes while excluding larger interfering substances86, 133. The stability of receptors, such as antibodies or enzymes, is often addressed through receptor stabilization coatings such as silica-based materials and polyvinyl alcohol (PVA), and cross-linking agents like glutaraldehyde or carbodiimide that protect these sensitive elements from the harsh conditions of the wound environment118, 134, 135. Furthermore, coatings, including hydrogel-based coatings for adjustable permeability, regulate the rate at which analytes reach the sensor, ensuring consistent and controlled detection136. These coating elements are integral to developing advanced wound sensors, providing reliable and precise data for effective wound management and treatment.
For reliable in situ biomarker monitoring with conformal sensor-skin contact, stretchable biosensors can be developed. This typically involves incorporating metallic or carbon-based nanomaterials into elastomers, such as polydimethylsiloxane (PDMS) or styrene–butadiene–styrene (SBS)137, 138. This approach enhances flexibility and adaptability, allowing the sensors to maintain optimal performance even in dynamic and challenging wound environments.
In summary, the judicious selection and integration of advanced materials, coupled with the implementation of signal amplification and antifouling strategies, contribute to the development of sensors that meet the demands of in situ wound biomarker analysis. These advancements pave the way for improved accuracy, longevity, and reliability in monitoring wound healing processes.
System integration and data processing
The emergence of advanced wound monitoring technologies and the integration of telemedicine into wound care are revolutionizing chronic wound management. The development of wireless smart bandages marks a significant milestone, signaling the beginning of a new era in closed-loop wound monitoring and treatment. These advanced bandages incorporate pivotal components such as data collection systems on wound conditions, advanced data processing capabilities, adjustable therapeutic delivery systems, and modules for both wireless communication and energy supply11, 95, 139–141. The incorporation of state-of-the-art data processing techniques, including artificial neural network (ANN), instance-based algorithms, and decision tree algorithms142, further enhances the functionality of these technologies. For example, decision tree algorithms can provide clear logical decision-making paths for therapeutic actions based on real-time wound status, enabling decisions like when to intensify antimicrobial therapy. Additionally, the application of AI in image processing stands out for wound classification and assessment, where traditional assessments largely rely on the subjective experience and visual evaluations of clinicians143, 144. Machine learning algorithms, in particular, have shown great promise for processing wound images and signals, identifying wound features, interpreting pathological signals, and predicting healing trajectory. The ability to analyze and interpret medical images with high precision introduces a level of objectivity and consistency that can substantially improve the efficiency of wound clinics, surpassing the limitations of manual examinations. Nevertheless, as AI-driven tools for wound assessment gain prevalence in clinical settings, their accuracy must be meticulously validated. Ensuring that these tools provide precise wound evaluations is crucial for supporting clinicians in delivering informed, evidence-based care145. This technological advancement promises to transform wound care practices by providing data-driven insights that support more informed clinical decisions.
Despite its immense potential, the development of consistent and reliable AI-driven wound care systems requires the creation of extensive training datasets and their validation against a wide range of diverse and complex clinical scenarios. Moreover, ensuring the privacy and security of patient data presents a formidable challenge due to the digital nature of data transmission and storage. Equally important is the task of training healthcare professionals to adeptly use and interpret the data generated by these advanced systems, which continues to be an area requiring focused effort and resources.
Wearable closed-looped systems present possibilities for telemedicine, enabling the analysis of wound condition and delivery of healthcare services remotely146–148. The ascent of telemedicine has empowered patients with chronic wounds to receive continuous, quality care without frequent hospital visits. This is especially beneficial for patients in rural areas or those facing mobility issues, as it improves the accessibility to specialized wound care services and provides real-time and monitoring consultations for patients with chronic wounds. These applications gain momentum due to the convenience they offer to both healthcare providers and patients, thereby boosting the therapeutic efficacy and improving patient adherence149–151.
The integration of wireless smart bandages with telemedicine platforms allows healthcare providers to remotely monitor the wound progress and make informed decisions about treatment adjustments, ultimately enhancing the overall efficiency of wound management.
Regulatory and commercialization considerations
The development of new wound healing technologies and biomaterials is a multifaceted journey demanding substantial investments in research and development152. Beyond scientific and technical challenges, navigating the regulatory and commercialization landscape is equally crucial153. There are several pivotal steps in the translational process and regulatory pathways pertinent to wound management strategies. Clinical and commercial considerations intrinsic to wound healing strategies are also critical.
Regulatory and communication path
In addressing the translational process of wound management strategies, it’s crucial to consider both universal and locale-specific clinical practices and regulatory frameworks. Globally, a common thread includes the need for ensuring safety, efficacy, and quality in wound care products, while locally, strategies must adapt to the varying regulatory criteria. This global-to-local spectrum underscores the diversity in regulatory paths and communication necessary for the successful worldwide application of advanced wound healing strategies. This section will focus on the specifics within the regulatory process, offering insights that are applicable both within and outside the U.S. context.
Wound care dressings and devices are classified according to the risk associated with the wound, ranging from Class I to III in the U.S., China, and Australia, Class I, IIa, IIb, III in the European Union, and Class I to IV in Canada. Class I representing low-risk categories, which only require minimal regulatory standards for approval. For example, in regulated markets such as the U.S., Europe, and China, wound dressings are typically classified as Class I medical devices, with the onus on manufacturers to maintain safety and quality post-approval. However, in emerging markets, classifications can be less clearly defined, leading to a reliance on established approvals from the U.S. and Europe as benchmarks for quality and safety, thus avoiding additional approval processes154, 155.
The USFDA approval process for wound care products is extensive and involves multiple submissions before initiating clinical trials. These processes are designed to evaluate the physical and chemical properties of these wound dressings and therapeutic products. Wound care products undergo classification by the USFDA into categories such as drugs, devices, biological products, or combination products. Despite the critical importance of advancing wound care, the clinical translation of these products encounters various challenges, including a complex wound healing process in different wound types, outdated tools and standards for wound categorization and evaluation, an overcrowded and inefficient market flooded with similar products, constraints tied to USFDA-acceptable outcome for wound closure, and a dearth of standard care practices with reproducible data collection. The 510(k)-approval process, although intended to streamline product entry into the market, has inadvertently contributed to a crowded landscape marked by overlapping and redundant wound healing products. Rectifying this situation requires collaborative efforts among key decision-makers and legislators to formulate a comprehensive strategic plan for optimizing and developing a more effective wound care ecosystem.
Medical devices are categorized into Class I, II, or III based on risk levels, accompanied by specific regulatory controls ensuring safety and effectiveness (Table 1 and Box 1). Class I devices, posing minimal risk, are subject to general controls, and exempt from premarket notification 510(k). Examples of Class I device include non-resorbable gauzes and sponges for external use, hydrophilic wound dressings, occlusive wound dressings, hydrogel wound dressings, and burn dressings. Wound care products that surpass Class I risk levels may fall into Class II category, necessitating a substantial equivalence review and specific controls, often evaluated through a premarket notification 510(k) submission. Notable examples of Class II devices encompass wound dressing with animal-derived material, absorbable synthetic wound dressings, wound therapy bioelectronic devices (NPWT and hyperbaric oxygen therapy), and wound biosensors. Class III devices, carrying higher risks or life-supporting functions, generally involve innovative compositions and clinical applications, requiring a premarket approval (PMA) application. PMA is a rigorous USFDA process designed for high-risk medical devices that supports or sustains human life or presents a potential, unreasonable risk of illness or injury. It requires proof of safety and effectiveness, often including results from clinical trials. On the other hand, the 510(k) process is for devices that are substantially equivalent to a legally marketed device that is not subject to PMA, allowing a more streamlined process. The Center for Devices and Radiological Health (CDRH) oversees a range of wound care devices across all classes, which vary in classification based on their intended use and technology. Notably, wound dressings combined with drugs, such as antimicrobial-containing wound dressings, fall under the unclassified product code FRO and are generally regulated through 510(k) pathway, while interactive wound and burn dressings promoting wound healing are classified as Class III devices156, 157.
Table 1.
Translational process and regulatory pathways for advancing wound management strategies.
| Class I (low risk) | Class II (intermediate risk) | Class III (high risk) | Unclassified | |
|---|---|---|---|---|
| Categories | Non-resorbable gauze/sponge for external use Hydrophilic wound dressings Occlusive wound dressings Hydrogel wound dressings and burn dressings |
Wound dressings with animal-derived material Absorbable synthetic wound dressings Wound therapy bioelectronics (NPWT, ultrasound and HBOT) Wound biosensors |
Interactive wound and burn dressings that promote or accelerate wound healing Product code MGR |
Antimicrobial-containing wound dressings |
| Regulatory pathway | Most are exempt from premarket notification 510(k) Should not contain drugs, biologics or animal-derived material |
510(k) pathway under the KGN product code Substantial equivalence Special controls |
Premarket approval and effectiveness Intended for wound treatment Intended to be a skin substitute Life-supporting or life-sustaining |
Product code FRO (dressing, wound and drug) No classification regulation 510(k) pathway |
| Examples | WOUND FREE; Comfeel Plus; Dynarex Xeroform; Persys Woundstop Care Fibracol Plus; GraftJacket; DermACELL; EpiFix (HCT/Ps); TheraSkin (HCT/Ps) | Talymed; Oasis; Promogran; Algisite; Tegaren; Hyalomatrix; SonicOne Ultrasonic Wound Care System; 3M Prevena Therapy | Integra; Apligraf; Dermagraft | AMNIOFIX; Titan SGS; Omeza Collagen Matrix; Promogran Prisma Matrix |
Class I includes low-risk items such as gauze and hydrogel dressings; class II covers intermediate-risk items such as animal-derived materials and biosensors; class III encompasses high-risk devices such as interactive dressings that promote healing. Antimicrobial-containing dressings are noted as unclassified device. HBOT, hyperbaric oxygen therapy; HCT/P, human cells, tissues and cellular and tissue-based product; NPWT, negative pressure wound therapy.
Box 1. Overview of FDA regulatory approval processes for wound care products.
Navigating the regulatory landscape is a critical step in bringing new wound care products to market. Each FDA approval pathway is designed to ensure patient safety and product efficacy, with different requirements based on the novelty and risk level of the device. Here is an overview of the main pathways for market authorization.
510(k) Clearance: Targeted at Class I and II devices similar to existing market products, the 510(k) process, taking around 90 days, is a quick pathway to market. It mandates the submission of evidence demonstrating that the new device is as safe and effective as an already legally marketed device. Examples include various wound dressings and over-the-counter products like Band-Aid® and Tegaderm®.
Premarket Approval (PMA): The PMA is a rigorous scientific and regulatory review to evaluate the safety and effectiveness of Class III medical devices, which represent the highest risk category and typically involve more than 180 days to process. PMA devices often bring innovative therapies to market and include examples such as Dermagraft® for diabetic foot ulcers and RECELL® for burns.
De Novo pathway: This process provides a route to classify novel devices of low to moderate risk that do not have a legally marketed predicate device. It involves a variable timeframe and allows the FDA to grant marketing authorization with special controls to ensure safety and efficacy. The De Novo pathway can include more sophisticated care systems, like the SNaP® Wound Care System. It is designed as a portable and lightweight option for NPWT, using mechanical power to create the necessary vacuum for wound healing without the need for batteries.
Each pathway plays a critical role in the introduction of safe and effective wound care products. The 510(k) route is ideal for products that can be compared to an existing one, while the PMA and De Novo pathways cater to novel or higher-risk devices. These regulatory frameworks help ensure that new wound care products are rigorously tested and meet high standards, providing healthcare professionals and patients with confidence in the treatments used.
The De Novo process provides a pathway for the classification of novel devices into Class I or II. Recent examples include NPWT devices, extracorporeal shock wave devices for hard-to-heal wounds, bacterial protease activity detectors, pressure ulcer management tools, and wound autofluorescence imaging devices. This dynamic classification process accommodates emerging technologies and fosters innovation in the realm of wound care.
Clinical data may be requested in premarket submissions when non-clinical testing is insufficient to establish substantial equivalence. Such information should be provided through Investigational Device Exemption (IDE) studies, literature reviews, real-world evidence (RWE), or other valid scientific evidence. Developers are strongly encouraged to submit pre-submissions (Q-Submissions) for feedback, especially for innovative devices featuring novel materials or indications for use. CDRH supports a collaborative approach in the development of innovative wound care devices, offering programs like the breakthrough devices program and guidance on utilizing real-world evidence for regulatory decision-making. Interested parties are urged to explore these pathways and engage with the USFDA to foster innovation in wound care7.
In 2018, the USFDA announced plans to modernize the 510(k) program, emphasizing that new medical devices under this pathway should reflect technological advances or demonstrate compliance with modern safety and performance criteria. The goal was to encourage competition for adopting contemporary features that improve patient care. The USFDA aimed to retire outdated predicates (>10 years old) and consider releasing an online list of cleared devices substantially equivalent to predicates older than a decade. The initial steps toward modernization included the release of updated draft guidance in 2019, primarily focusing on premarket performance criteria and testing methodologies for certain devices, excluding tissue engineering products158, 159.
Various complexities in wound healing regulation demand careful attention. These include: ensuring the sterility of the wound healing product; addressing combinations of wound healing products, with evolving regulatory flexibility for multiple-agent therapy based on established synergistic interactions and safety profiles from preclinical studies; establishing standards for clinical care or optimal basic wound care within clinical trials; and determining product jurisdiction based on the primary mode of action160.
In conclusion, ongoing reforms at the regulated markets aim to speed up the regulatory process and increase the review consistency. Nevertheless, the most efficient pathway for a sponsor to attain product approval continues to center on solid foundational, preclinical, and clinical science.
Challenges and opportunities beyond clinical translation
Wound healing is a dynamic and intricate process that extends beyond the boundaries of traditional clinical care, presenting several challenges and opportunities. Preclinical investigations play a pivotal role in bridging the gap between innovation and effective wound care therapies, ultimately enhancing the overall quality of wound management practices. Initially, during the concept and feasibility phase, preclinical investigations help in understanding the basic biology related to the device’s intended function, which informs design and development. Before entering clinical trials, researchers must complete rigorous preclinical testing to satisfy regulatory requirements and submit substantial evidence to the FDA, typically in the form of an Investigational Device Exemption (IDE). These studies serve as foundational steps in the rigorous evaluation of wound care interventions, focusing on safety, efficacy, and feasibility. Detailing the type and scope of preclinical evidence required by the FDA is essential for ensuring compliance and facilitating a smoother approval process. For medical devices, these investigations encompass an array of essential elements, including biocompatibility testing, biomechanical analysis, and in vivo evaluations using animal models that simulate human wound healing processes. For drugs, clarifying the extent and specificity of preclinical data required by the FDA, such as toxicity profiles and pharmacokinetics, is essential. As the FDA no longer requires animal tests for the approval of new medicines161, alternative approaches such as organ-on-chip technology could be used to study the efficacy of proposed wound care products162. Innovative preclinical research approaches, such as organ-on-a-chip models, advanced imaging techniques, and multi-omics profiling, could enhance the predictive value of preclinical studies and accelerate the development of clinically relevant wound care interventions
The journey to commercialize wound care products extends well beyond obtaining regulatory approval and clinical validation, encompassing a multifaceted strategy and detailed planning. Market acceptance is contingent upon proving cost-effectiveness, seamless integration with current healthcare protocols, and congruence with the priorities of payers and providers. Scaling up production necessitates careful planning to confirm that manufacturing capabilities can satisfy market demand without sacrificing product quality. Moreover, the success of commercialization relies heavily on engaging patients effectively and implementing comprehensive education programs to enhance awareness, encourage adoption, and ensure correct usage of new wound care technologies. Such efforts are pivotal in ensuring that advancements in wound management smoothly transition from clinical validation to becoming integral components of routine healthcare, thereby enhancing patient outcomes on a widespread level.
Additionally, incorporating companion diagnostic strategies is crucial for guiding therapy initiation and conclusion, as well as for its optimization. Particularly in the post-pandemic world, technologies that can assist in measuring and managing care remotely at home are essential.
With the development of telemedicine, considerations related to data privacy and security are paramount163, 164. These encompass environmental factors such as ensuring private spaces for telehealth to protect patient confidentiality, technological aspects such as securing data and enhancing digital literacy to prevent unauthorized access, and operational challenges such as navigating telehealth reimbursement policies and providing adequate training for healthcare providers. Addressing these multifaceted concerns is essential for building trust in remote wound care technologies and promoting their effective use.
Wound healing transcends the confines of traditional clinical care, with preclinical investigations playing a key role not only in meeting regulatory mandates but also in deepening the understanding of wound biology. This foundational knowledge is critical for innovation and the advancement of wound care therapies. Beyond regulatory compliance, the path to commercialization entails addressing market acceptance, scalability of production, and active engagement with patients and healthcare providers to educate and ensure the effective adoption of new treatments in the wider healthcare ecosystem.
Conclusions and perspectives
This Review highlights major advances in the realm of wound healing biomaterials and technologies. These innovations not only show promise for the effective treatment of chronic wounds, but also have the potential to revolutionize the landscape of clinical wound management. Our exploration has extended to considerations vital for regulatory approval and commercialization, underscoring the imperative role of translational processes and the incorporation of both preclinical and clinical studies in the developmental phase. This holistic approach is key to bridging the gap between pioneering research and practical clinical applications.
Looking forward, the field of wound management is poised for further exploration and innovation. The ongoing development of new biomaterials, bioengineering approaches, and telemedicine technologies presents a compelling opportunity to enhance patient outcomes and alleviate the burden associated with chronic wounds. The frontiers of regenerative medicine and tissue engineering, including stem cell therapy and 3D bioprinting, hold transformative potential for regenerating damaged tissues and organs165–169. Advanced manufacturing technologies offer new opportunities for the development of multifunctional personalized wound care devices, which are crucial due to the intricate and diverse nature of complex wound structures and types12, 170–172. For instance, 3D bioprinting could be used to create custom-fitted wound care devices, such as dressings and skin grafts, that conform precisely to the unique topography of a patient’s wound. This approach not only improves physical fit and user comfort but also enhances the therapeutic efficacy and monitoring signals by ensuring proper contact and integration with the wound bed. Furthermore, 3D printing allows for the incorporation of various materials and living agents, such as antibacterial agents, growth factors, or stem cells, into a single platform. The integration of different functionalities within a personalized device aims to enhance healing outcomes by providing a cohesive solution that addresses multiple aspects of wound management concurrently.
Moreover, the integration of artificial intelligence and machine learning into wound care emerges as a powerful tool for predicting wound healing trajectories, ushering in a new era of precision and personalized wound management173–177. As we embrace these innovative approaches, the synergy between the state-of-the-art technologies and conventional wound care practices is poised to redefine the standards of patient care and elevate therapeutic efficacy.
Addressing global disparities in wound care is crucial. In developed regions such as North America and Europe, advanced wound management strategies and personalized therapy are the next frontier. Meanwhile, in developing regions like sub-Saharan Africa and parts of Asia, where healthcare resources are scarce and the prevalence of infectious diseases complicate chronic wound management, there is a dire need for cost-effective and scalable solutions. Such disparities underscore the necessity for innovative, affordable wound care solutions in resource-constrained environments and highlight the potential for international collaboration in research and training. For example, in low and middle-income countries, the unique needs for wound care management emphasize the necessity for materials and technologies that are accessible, affordable, and user-friendly, capable of addressing the local prevalence of diseases, including those with infectious complications. Essential practical considerations include the provision of training for healthcare workers, the adaptability of solutions to local climates and resources, and the reinforcement of community-based care. There is a significant focus on research into materials that can be locally produced or sourced to fulfill these requirements effectively. It is imperative for the wound care community to strive for an equitable distribution of advancements, ensuring that effective wound management is accessible across diverse global contexts and bridging the gap between varied economic and geographical landscapes.
Acknowledgements
This project was supported by the National Science Foundation grant 2145802, National Institutes of Health grant R01HL155815 and R21DK13266, Army Research Office grant W911NF-23-1-0041, American Cancer Society Research Scholar Grant RSG-21-181-01-CTPS, Office of Naval Research grants N00014-21-1-2483 and N00014-21-1-2845, and Heritage Medical Research Institute.
Footnotes
Competing interests
The authors declare no competing interests.
Related links
XXX: https://url
References
- 1.Gurtner GC, Werner S, Barrandon Y & Longaker MT Wound repair and regeneration. Nature 453, 314–321 (2008). [DOI] [PubMed] [Google Scholar]
- 2.Eriksson E et al. Chronic wounds: Treatment consensus. Wound Repair Regen 30, 156–171 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Armstrong DG & Gurtner GC A histologically hostile environment made more hospitable? Nature reviews. Endocrinology 14, 511–512 (2018). [DOI] [PubMed] [Google Scholar]
- 4.Sen CK Human Wounds and Its Burden: An Updated Compendium of Estimates. Adv Wound Care (New Rochelle) 8, 39–48 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Nussbaum SR et al. An Economic Evaluation of the Impact, Cost, and Medicare Policy Implications of Chronic Nonhealing Wounds. Value in Health 21, 27–32 (2018). [DOI] [PubMed] [Google Scholar]
- 6.McDermott K, Fang M, Boulton AJ, Selvin E & Hicks CW Etiology, epidemiology, and disparities in the burden of diabetic foot ulcers. Diabetes Care 46, 209–221 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Sharma A, Sharma D & Zhao F Updates on Recent Clinical Assessment of Commercial Chronic Wound Care Products. Advanced Healthcare Materials 12, 2300556 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Kalidasan V et al. Wirelessly operated bioelectronic sutures for the monitoring of deep surgical wounds. Nature Biomedical Engineering 5, 1217–1227 (2021). [DOI] [PubMed] [Google Scholar]
- 9.Wang C, Shirzaei Sani E & Gao W Wearable Bioelectronics for Chronic Wound Management. Advanced Functional Materials 32, 2111022 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Derakhshandeh H, Kashaf SS, Aghabaglou F, Ghanavati IO & Tamayol A Smart Bandages: The Future of Wound Care. Trends Biotechnol 36, 1259–1274 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Jiang Y et al. Wireless, closed-loop, smart bandage with integrated sensors and stimulators for advanced wound care and accelerated healing. Nature Biotechnology 41, 652–662 (2023). [DOI] [PubMed] [Google Scholar]
- 12.Farahani M & Shafiee A Wound Healing: From Passive to Smart Dressings. Advanced Healthcare Materials 10, 2100477 (2021). [DOI] [PubMed] [Google Scholar]
- 13.Ray TR et al. Bio-Integrated Wearable Systems: A Comprehensive Review. Chemical Reviews 119, 5461–5533 (2019). [DOI] [PubMed] [Google Scholar]
- 14.Nan K et al. Mucosa-interfacing electronics. Nature Reviews Materials 7, 908–925 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Shubham P et al. Wearable electronics for skin wound monitoring and healing. Soft Science 2, 9 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Yang Y & Gao W Wearable and flexible electronics for continuous molecular monitoring. Chemical Society Reviews 48, 1465–1491 (2019). [DOI] [PubMed] [Google Scholar]
- 17.Global Wound Care Market by Product (Dressings [Foam, Hydrocolloid, Collagen], Devices [NPWT, Debridement]), Biological Skin Substitutes, Sutures, Staplers), Wounds (Traumatic, Surgical, Burns), End User (Hospitals, Clinics), and Region - Global Forecast to 2028. Markets and Markets (2023). [Google Scholar]
- 18.Medicare severe wound care. United States Government Accountability Office (2021). [Google Scholar]
- 19.Baquerizo Nole KL et al. Wound research funding from alternative sources of federal funds in 2012. Wound Repair Regen 22, 295–300 (2014). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Sen CK Human Wound and Its Burden: Updated 2022 Compendium of Estimates. Adv Wound Care (New Rochelle) 12, 657–670 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Yuk H, Wu J & Zhao X Hydrogel interfaces for merging humans and machines. Nature Reviews Materials 7, 935–952 (2022). [Google Scholar]
- 22.Brown MS, Ashley B & Koh A Wearable Technology for Chronic Wound Monitoring: Current Dressings, Advancements, and Future Prospects. Frontiers in Bioengineering and Biotechnology 6 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Liu Y, Pharr M & Salvatore GA Lab-on-Skin: A Review of Flexible and Stretchable Electronics for Wearable Health Monitoring. ACS Nano 11, 9614–9635 (2017). [DOI] [PubMed] [Google Scholar]
- 24.Discher DE, Janmey P & Wang Y -l. Tissue Cells Feel and Respond to the Stiffness of Their Substrate. Science 310, 1139–1143 (2005). [DOI] [PubMed] [Google Scholar]
- 25.McElvain K, Klister J, Ebben A, Gopalakrishnan S & Dabagh M Impact of Wound Dressing on Mechanotransduction within Tissues of Chronic Wounds. Biomedicines 10 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Theocharidis G et al. A strain-programmed patch for the healing of diabetic wounds. Nature Biomedical Engineering 6, 1118–1133 (2022). [DOI] [PubMed] [Google Scholar]
- 27.Griffin DR, Weaver WM, Scumpia PO, Di Carlo D & Segura T Accelerated wound healing by injectable microporous gel scaffolds assembled from annealed building blocks. Nature materials 14, 737–744 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Miyamoto A et al. Inflammation-free, gas-permeable, lightweight, stretchable on-skin electronics with nanomeshes. Nature Nanotechnology 12, 907–913 (2017). [DOI] [PubMed] [Google Scholar]
- 29.Jiang S et al. Breathable, antifreezing, mechanically skin-like hydrogel textile wound dressings with dual antibacterial mechanisms. Bioactive Materials 21, 313–323 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Langer V, Bhandari PS, Rajagopalan S & Mukherjee MK Negative pressure wound therapy as an adjunct in healing of chronic wounds. International Wound Journal 12, 436–442 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Shi L, Liu X, Wang W, Jiang L & Wang S A Self-Pumping Dressing for Draining Excessive Biofluid around Wounds. Advanced Materials 31, 1804187 (2019). [DOI] [PubMed] [Google Scholar]
- 32.Negut I, Dorcioman G & Grumezescu V Scaffolds for Wound Healing Applications. Polymers (Basel) 12 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.S S, A SK, Nair PD & Thomas LV A nonadherent chitosan-polyvinyl alcohol absorbent wound dressing prepared via controlled freeze-dry technology. International journal of biological macromolecules 150, 129–140 (2020). [DOI] [PubMed] [Google Scholar]
- 34.Wu J et al. An off-the-shelf bioadhesive patch for sutureless repair of gastrointestinal defects. Science translational medicine 14, eabh2857. [DOI] [PubMed] [Google Scholar]
- 35.Guo B, Dong R, Liang Y & Li M Haemostatic materials for wound healing applications. Nature Reviews Chemistry 5, 773–791 (2021). [DOI] [PubMed] [Google Scholar]
- 36.Yuk H et al. Rapid and coagulation-independent haemostatic sealing by a paste inspired by barnacle glue. Nature Biomedical Engineering 5, 1131–1142 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Gaharwar AK et al. Shear-thinning nanocomposite hydrogels for the treatment of hemorrhage. ACS Nano 8, 9833–9842 (2014). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Zhao X et al. Polysaccharide-Based Adhesive Antibacterial and Self-Healing Hydrogel for Sealing Hemostasis. Biomacromolecules 23, 5106–5115 (2022). [DOI] [PubMed] [Google Scholar]
- 39.Briquez PS, Clegg LE, Martino MM, Gabhann FM & Hubbell JA Design principles for therapeutic angiogenic materials. Nature Reviews Materials 1, 15006 (2016). [Google Scholar]
- 40.Preman NK et al. Bioresponsive supramolecular hydrogels for hemostasis, infection control and accelerated dermal wound healing. J Mater Chem B 8, 8585–8598 (2020). [DOI] [PubMed] [Google Scholar]
- 41.Falanga V et al. Chronic wounds. Nature Reviews Disease Primers 8, 50 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Latif A et al. Microparticles Decorated with Cell-Instructive Surface Chemistries Actively Promote Wound Healing. Advanced Materials n/a, 2208364 (2022). [DOI] [PubMed] [Google Scholar]
- 43.Griffin DR et al. Activating an adaptive immune response from a hydrogel scaffold imparts regenerative wound healing. Nature Materials 20, 560–569 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Tu Z et al. Design of therapeutic biomaterials to control inflammation. Nature Reviews Materials 7, 557–574 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Johnson J et al. First-in-human clinical trial of allogeneic, platelet-derived extracellular vesicles as a potential therapeutic for delayed wound healing. Journal of extracellular vesicles 12, e12332 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Yao G et al. A programmable and skin temperature–activated electromechanical synergistic dressing for effective wound healing. Science Advances 8, eabl8379. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Brown S Clinical antimicrobial photodynamic therapy: phase II studies in chronic wounds. Journal of the National Comprehensive Cancer Network: JNCCN 10 Suppl 2, S80–83 (2012). [DOI] [PubMed] [Google Scholar]
- 48.Lee SY et al. Combinatorial wound healing therapy using adhesive nanofibrous membrane equipped with wearable LED patches for photobiomodulation. Science Advances 8, eabn1646. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Armstrong DG & Lavery LA Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomised controlled trial. The Lancet 366, 1704–1710 (2005). [DOI] [PubMed] [Google Scholar]
- 50.Pasek J, Szajkowski S & Cieślar G Application of Topical Hyperbaric Oxygen Therapy and Medical Active Dressings in the Treatment of Arterial Leg Ulcers-A Pilot Study. Sensors (Basel) 23 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Stone RC et al. A bioengineered living cell construct activates an acute wound healing response in venous leg ulcers. Science translational medicine 9 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Kang H et al. Stabilization of Silver and Gold Nanoparticles: Preservation and Improvement of Plasmonic Functionalities. Chem Rev 119, 664–699 (2019). [DOI] [PubMed] [Google Scholar]
- 53.Liu Y & Shi J Antioxidative nanomaterials and biomedical applications. Nano Today 27, 146–177 (2019). [Google Scholar]
- 54.Huang T et al. Glucose oxidase and Fe(3)O(4)/TiO(2)/Ag(3)PO(4) co-embedded biomimetic mineralization hydrogels as controllable ROS generators for accelerating diabetic wound healing. J Mater Chem B 9, 6190–6200 (2021). [DOI] [PubMed] [Google Scholar]
- 55.Chen J et al. Tailored Hydrogel Delivering Niobium Carbide Boosts ROS-Scavenging and Antimicrobial Activities for Diabetic Wound Healing. Small 18, 2201300 (2022). [DOI] [PubMed] [Google Scholar]
- 56.Hartmann CA, Rode H & Kramer B Acticoat™ stimulates inflammation, but does not delay healing, in acute full-thickness excisional wounds. Int Wound J 13, 1344–1348 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Yao B et al. Ultrastrong, highly conductive and capacitive hydrogel electrode for electron-ion transduction. Matter 5, 4407–4424 (2022). [Google Scholar]
- 58.Yoshikawa Y et al. Monophasic Pulsed Microcurrent of 1–8 Hz Increases the Number of Human Dermal Fibroblasts. Progress in rehabilitation medicine 1, 20160005 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Magnoni C et al. Electrical stimulation as adjuvant treatment for chronic leg ulcers of different aetiology: an RCT. Journal of Wound Care 22, 525–533 (2013). [DOI] [PubMed] [Google Scholar]
- 60.Rabbani M, Rahman E, Powner MB & Triantis IF Making Sense of Electrical Stimulation: A Meta-analysis for Wound Healing. Annals of biomedical engineering (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Wang C et al. Flexible patch with printable and antibacterial conductive hydrogel electrodes for accelerated wound healing. Biomaterials 285, 121479 (2022). [DOI] [PubMed] [Google Scholar]
- 62.Long Y et al. Effective Wound Healing Enabled by Discrete Alternative Electric Fields from Wearable Nanogenerators. ACS Nano 12, 12533–12540 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63.Chen X et al. MiR-21 regulating PVT1/PTEN/IL-17 axis towards the treatment of infectious diabetic wound healing by modified GO-derived biomaterial in mouse models. Journal of nanobiotechnology 20, 309 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64.Li Y, Zhou X, Sarkar B, Gagnon-Lafrenais N & Cicoira F Recent Progress on Self-Healable Conducting Polymers. Advanced materials (Deerfield Beach, Fla.) 34, e2108932 (2022). [DOI] [PubMed] [Google Scholar]
- 65.Kai H, Suda W, Yoshida S & Nishizawa M Organic electrochromic timer for enzymatic skin patches. Biosensors & bioelectronics 123, 108–113 (2019). [DOI] [PubMed] [Google Scholar]
- 66.Luo B et al. Nonadjacent Wireless Electrotherapy for Tissue Repair by a 3D-Printed Bioresorbable Fully Soft Triboelectric Nanogenerator. Nano Lett 23, 2927–2937 (2023). [DOI] [PubMed] [Google Scholar]
- 67.Jia M & Rolandi M Soft and Ion-Conducting Materials in Bioelectronics: From Conducting Polymers to Hydrogels. Advanced Healthcare Materials 9, 1901372 (2020). [DOI] [PubMed] [Google Scholar]
- 68.Li S, Wang L, Zheng W, Yang G & Jiang X Rapid Fabrication of Self-Healing, Conductive, and Injectable Gel as Dressings for Healing Wounds in Stretchable Parts of the Body. Advanced Functional Materials 30, 2002370 (2020). [Google Scholar]
- 69.Liang Y, Qiao L, Qiao B & Guo B Conductive hydrogels for tissue repair. Chemical science 14, 3091–3116 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70.Rafiq A et al. Biosynthesis of silver nanoparticles from novel Bischofia javanica plant loaded chitosan hydrogel: as antimicrobial and wound healing agent. Biomass Conversion and Biorefinery, 1–11 (2022). [Google Scholar]
- 71.Morena AG, Pérez-Rafael S & Tzanov T Lignin-Based Nanoparticles as Both Structural and Active Elements in Self-Assembling and Self-Healing Multifunctional Hydrogels for Chronic Wound Management. Pharmaceutics 14 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72.Ruszczak Z Effect of collagen matrices on dermal wound healing. Advanced Drug Delivery Reviews 55, 1595–1611 (2003). [DOI] [PubMed] [Google Scholar]
- 73.Farokhi M, Mottaghitalab F, Fatahi Y, Khademhosseini A & Kaplan DL Overview of Silk Fibroin Use in Wound Dressings. Trends Biotechnol 36, 907–922 (2018). [DOI] [PubMed] [Google Scholar]
- 74.Angele P et al. Influence of different collagen species on physico-chemical properties of crosslinked collagen matrices. Biomaterials 25, 2831–2841 (2004). [DOI] [PubMed] [Google Scholar]
- 75.Serena TE et al. A randomized controlled clinical trial of a hypothermically stored amniotic membrane for use in diabetic foot ulcers. Journal of comparative effectiveness research 9, 23–34 (2020). [DOI] [PubMed] [Google Scholar]
- 76.McDevitt CA, Wildey GM & Cutrone RM Transforming growth factor-beta1 in a sterilized tissue derived from the pig small intestine submucosa. Journal of biomedical materials research. Part A 67, 637–640 (2003). [DOI] [PubMed] [Google Scholar]
- 77.Zhang Y et al. Exosome/metformin-loaded self-healing conductive hydrogel rescues microvascular dysfunction and promotes chronic diabetic wound healing by inhibiting mitochondrial fission. Bioact Mater 26, 323–336 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78.Wang H et al. Extracellular Matrix-Mimetic Immunomodulatory Hydrogel for Accelerating Wound Healing. Adv Healthc Mater 12, e2301264 (2023). [DOI] [PubMed] [Google Scholar]
- 79.Peng Y et al. Electrospun PLGA/SF/artemisinin composite nanofibrous membranes for wound dressing. International journal of biological macromolecules 183, 68–78 (2021). [DOI] [PubMed] [Google Scholar]
- 80.Engler AJ, Sen S, Sweeney HL & Discher DE Matrix Elasticity Directs Stem Cell Lineage Specification. Cell 126, 677–689 (2006). [DOI] [PubMed] [Google Scholar]
- 81.Stevens AJ et al. Programming multicellular assembly with synthetic cell adhesion molecules. Nature 614, 144–152 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 82.Zhu J Bioactive modification of poly(ethylene glycol) hydrogels for tissue engineering. Biomaterials 31, 4639–4656 (2010). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 83.Ouyang J et al. In situ sprayed NIR-responsive, analgesic black phosphorus-based gel for diabetic ulcer treatment. Proceedings of the National Academy of Sciences 117, 28667–28677 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 84.Feng C et al. Germanene-Based Theranostic Materials for Surgical Adjuvant Treatment: Inhibiting Tumor Recurrence and Wound Infection. Matter 3, 127–144 (2020). [Google Scholar]
- 85.Xiong Z et al. A wireless and battery-free wound infection sensor based on DNA hydrogel. Science Advances 7, eabj1617. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 86.Han Y et al. Fish Gelatin Based Triboelectric Nanogenerator for Harvesting Biomechanical Energy and Self-Powered Sensing of Human Physiological Signals. ACS Appl Mater Interfaces 12, 16442–16450 (2020). [DOI] [PubMed] [Google Scholar]
- 87.Shanmugapriya K & Kang HW Engineering pharmaceutical nanocarriers for photodynamic therapy on wound healing: Review. Materials science & engineering. C, Materials for biological applications 105, 110110 (2019). [DOI] [PubMed] [Google Scholar]
- 88.Buzzá HH et al. Porphyrin nanoemulsion for antimicrobial photodynamic therapy: effective delivery to inactivate biofilm-related infections. Proceedings of the National Academy of Sciences 119, e2216239119 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 89.Yang C et al. Niobium Carbide MXene Augmented Medical Implant Elicits Bacterial Infection Elimination and Tissue Regeneration. ACS Nano 15, 1086–1099 (2021). [DOI] [PubMed] [Google Scholar]
- 90.Barman SR et al. A self-powered multifunctional dressing for active infection prevention and accelerated wound healing. Science Advances 9, eadc8758. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 91.Shou Y et al. Mechano-Activated Cell Therapy for Accelerated Diabetic Wound Healing. Advanced Materials n/a, 2304638 (2023). [DOI] [PubMed] [Google Scholar]
- 92.Chung CW et al. Magnetic Responsive Release of Nitric Oxide from an MOF-Derived Fe(3)O(4)@PLGA Microsphere for the Treatment of Bacteria-Infected Cutaneous Wound. ACS Appl Mater Interfaces 14, 6343–6357 (2022). [DOI] [PubMed] [Google Scholar]
- 93.Ennis WJ, Valdes W, Gainer M & Meneses P Evaluation of Clinical Effectiveness of MIST Ultrasound Therapy for the Healing of Chronic Wounds. Advances in Skin & Wound Care 19 (2006). [DOI] [PubMed] [Google Scholar]
- 94.Kimball AS et al. The Histone Methyltransferase Setdb2 Modulates Macrophage Phenotype and Uric Acid Production in Diabetic Wound Repair. Immunity 51, 258–271.e255 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 95.Shirzaei Sani E et al. A stretchable wireless wearable bioelectronic system for multiplexed monitoring and combination treatment of infected chronic wounds. Science Advances 9, eadf7388. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 96.Gao Y et al. A flexible multiplexed immunosensor for point-of-care in situ wound monitoring. Science Advances 7, eabg9614. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 97.Tu J, Torrente-Rodríguez RM, Wang M & Gao W The Era of Digital Health: A Review of Portable and Wearable Affinity Biosensors. Advanced Functional Materials 30, 1906713 (2020). [Google Scholar]
- 98.Tu J et al. A wireless patch for the monitoring of C-reactive protein in sweat. Nature Biomedical Engineering (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 99.Saiko G et al. Hyperspectral imaging in wound care: A systematic review. International Wound Journal 17, 1840–1856 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 100.Wang M et al. A wearable electrochemical biosensor for the monitoring of metabolites and nutrients. Nature Biomedical Engineering 6, 1225–1235 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 101.Rebling J, Ben-Yehuda Greenwald M, Wietecha M, Werner S & Razansky D Long-Term Imaging of Wound Angiogenesis with Large Scale Optoacoustic Microscopy. Advanced Science 8, 2004226 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 102.Brasier N et al. A three-level model for therapeutic drug monitoring of antimicrobials at the site of infection. The Lancet Infectious Diseases (2023). [DOI] [PubMed] [Google Scholar]
- 103.Armstrong DG, Tan T-W, Boulton AJM & Bus SA Diabetic Foot Ulcers: A Review. Jama 330, 62–75 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 104.Brown MD & Schoenfisch MH Electrochemical Nitric Oxide Sensors: Principles of Design and Characterization. Chemical Reviews 119, 11551–11575 (2019). [DOI] [PubMed] [Google Scholar]
- 105.Carlström M Nitric oxide signalling in kidney regulation and cardiometabolic health. Nature Reviews Nephrology 17, 575–590 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 106.Ottolini M et al. Local Peroxynitrite Impairs Endothelial Transient Receptor Potential Vanilloid 4 Channels and Elevates Blood Pressure in Obesity. Circulation 141, 1318–1333 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 107.Singh N, Armstrong DG & Lipsky BA Preventing Foot Ulcers in Patients With Diabetes. Jama 293, 217–228 (2005). [DOI] [PubMed] [Google Scholar]
- 108.Cortes-Penfield NW et al. Evaluation and Management of Diabetes-related Foot Infections. Clinical Infectious Diseases (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 109.Dealey C, Cameron J & Arrowsmith M A study comparing two objective methods of quantifying the production of wound exudate. Journal of Wound Care 15, 149–153 (2006). [DOI] [PubMed] [Google Scholar]
- 110.Ge Z et al. Wireless and Closed-Loop Smart Dressing for Exudate Management and On-Demand Treatment of Chronic Wounds. Advanced Materials n/a, 2304005 (2023). [DOI] [PubMed] [Google Scholar]
- 111.Wound exudate: effective assessment and management. (Wounds International, World Union of Wound Healing Societies (WUWHS) Consensus Document.; 2019).
- 112.Iizaka S et al. Quantitative estimation of exudate volume for full-thickness pressure ulcers: the ESTimation method. J Wound Care 20, 453–454, 458–463 (2011). [DOI] [PubMed] [Google Scholar]
- 113.Gao W et al. Fully integrated wearable sensor arrays for multiplexed in situ perspiration analysis. Nature 529, 509–514 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 114.Nyein HYY et al. A Wearable Electrochemical Platform for Noninvasive Simultaneous Monitoring of Ca2+ and pH. ACS Nano 10, 7216–7224 (2016). [DOI] [PubMed] [Google Scholar]
- 115.Arroyo-Currás N et al. Real-time measurement of small molecules directly in awake, ambulatory animals. Proceedings of the National Academy of Sciences 114, 645 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 116.Garland NT et al. A Miniaturized, Battery-Free, Wireless Wound Monitor That Predicts Wound Closure Rate Early. Advanced Healthcare Materials 12, 2301280 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 117.Hussain G & Silvester DS Comparison of Voltammetric Techniques for Ammonia Sensing in Ionic Liquids. Electroanalysis 30, 75–83 (2018). [Google Scholar]
- 118.Ye C et al. A wearable aptamer nanobiosensor for non-invasive female hormone monitoring. Nature Nanotechnology (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 119.Wang L, Zhou M, Xu T & Zhang X Multifunctional hydrogel as wound dressing for intelligent wound monitoring. Chemical Engineering Journal 433, 134625 (2022). [Google Scholar]
- 120.Ramirez-GarciaLuna JL, Bartlett R, Arriaga-Caballero JE, Fraser RDJ & Saiko G Infrared Thermography in Wound Care, Surgery, and Sports Medicine: A Review. Frontiers in physiology 13, 838528 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 121.Rennie M, Lindvere-Teene L, Tapang K & Linden R Point-of-care fluorescence imaging predicts the presence of pathogenic bacteria in wounds: a clinical study. Journal of Wound Care 26, 452–460 (2017). [DOI] [PubMed] [Google Scholar]
- 122.Ottolino-Perry K et al. Improved detection of clinically relevant wound bacteria using autofluorescence image-guided sampling in diabetic foot ulcers. International wound journal 14, 833–841 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 123.Rennie MY et al. Understanding real-time fluorescence signals from bacteria and wound tissues observed with the MolecuLight i: XTM. Diagnostics 9, 22 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 124.Cole W & Coe S Use of a bacterial fluorescence imaging system to target wound debridement and accelerate healing: A pilot study. Journal of Wound Care 29, S44–S52 (2020). [DOI] [PubMed] [Google Scholar]
- 125.Serena TE, Harrell K, Serena L & Yaakov RA Real-time bacterial fluorescence imaging accurately identifies wounds with moderate-to-heavy bacterial burden. Journal of Wound Care 28, 346–357 (2019). [DOI] [PubMed] [Google Scholar]
- 126.Mantri Y et al. Point-of-Care Ultrasound as a Tool to Assess Wound Size and Tissue Regeneration after Skin Grafting. Ultrasound in medicine & biology 47, 2550–2559 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 127.Yang P et al. Orange-Emissive Carbon Quantum Dots: Toward Application in Wound pH Monitoring Based on Colorimetric and Fluorescent Changing. Small 15, e1902823 (2019). [DOI] [PubMed] [Google Scholar]
- 128.Marks H et al. A paintable phosphorescent bandage for postoperative tissue oxygen assessment in DIEP flap reconstruction. Science Advances 6, eabd1061 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 129.Wei X et al. A cell-based electrochemical sensor for assessing immunomodulatory effects by atrazine and its metabolites. Biosensors & bioelectronics 203, 114015 (2022). [DOI] [PubMed] [Google Scholar]
- 130.Al-Belushi MA et al. ZnO nanorod-chitosan composite coatings with enhanced antifouling properties. International journal of biological macromolecules 162, 1743–1751 (2020). [DOI] [PubMed] [Google Scholar]
- 131.Zhang J et al. Antibacterial and Antifouling Hybrid Ionic-Covalent Hydrogels with Tunable Mechanical Properties. ACS Appl Mater Interfaces 11, 31594–31604 (2019). [DOI] [PubMed] [Google Scholar]
- 132.Chen Q et al. Impact of Antifouling PEG Layer on the Performance of Functional Peptides in Regulating Cell Behaviors. J Am Chem Soc 141, 16772–16780 (2019). [DOI] [PubMed] [Google Scholar]
- 133.Li L et al. Electrospun Core-Sheath PVDF Piezoelectric Fiber for Sensing Application. ACS Appl Mater Interfaces 15, 15938–15945 (2023). [DOI] [PubMed] [Google Scholar]
- 134.Huang Z et al. An ultrasensitive aptamer-antibody sandwich cortisol sensor for the noninvasive monitoring of stress state. Biosensors & bioelectronics 190, 113451 (2021). [DOI] [PubMed] [Google Scholar]
- 135.Heredia Rivera U et al. Printed Low-Cost PEDOT:PSS/PVA Polymer Composite for Radiation Sterilization Monitoring. ACS Sens 7, 960–971 (2022). [DOI] [PubMed] [Google Scholar]
- 136.Yu J et al. Diffusion-modulated colorimetric sensor for continuous gas detection. IEEE sensors journal 23, 11404–11411 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 137.Zheng XT et al. Carbon Dot-Doped Hydrogel Sensor Array for Multiplexed Colorimetric Detection of Wound Healing. ACS Appl Mater Interfaces 15, 17675–17687 (2023). [DOI] [PubMed] [Google Scholar]
- 138.Sharifuzzaman M et al. Smart bandage with integrated multifunctional sensors based on MXene-functionalized porous graphene scaffold for chronic wound care management. Biosensors & bioelectronics 169, 112637 (2020). [DOI] [PubMed] [Google Scholar]
- 139.Mostafalu P et al. Smart Bandage for Monitoring and Treatment of Chronic Wounds. Small, e1703509 (2018). [DOI] [PubMed] [Google Scholar]
- 140.Xu G et al. Battery-Free and Wireless Smart Wound Dressing for Wound Infection Monitoring and Electrically Controlled On-Demand Drug Delivery. Advanced Functional Materials n/a, 2100852. [Google Scholar]
- 141.Song JW et al. Bioresorbable, wireless, and battery-free system for electrotherapy and impedance sensing at wound sites. Science Advances 9, eade4687. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 142.Luz CF et al. Machine learning in infection management using routine electronic health records: tools, techniques, and reporting of future technologies. Clinical Microbiology and Infection 26, 1291–1299 (2020). [DOI] [PubMed] [Google Scholar]
- 143.Reifs D, Casanova-Lozano L, Reig-Bolaño R & Grau-Carrion S Clinical validation of computer vision and artificial intelligence algorithms for wound measurement and tissue classification in wound care. Informatics in Medicine Unlocked 37, 101185 (2023). [Google Scholar]
- 144.Anisuzzaman DM et al. Multi-modal wound classification using wound image and location by deep neural network. Scientific Reports 12, 20057 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 145.Howell RS et al. Development of a Method for Clinical Evaluation of Artificial Intelligence–Based Digital Wound Assessment Tools. JAMA Network Open 4, e217234–e217234 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 146.Zheng XT et al. Battery-free and AI-enabled multiplexed sensor patches for wound monitoring. Science Advances 9, eadg6670. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 147.Anisuzzaman DM et al. Image-Based Artificial Intelligence in Wound Assessment: A Systematic Review. Adv Wound Care (New Rochelle) 11, 687–709 (2022). [DOI] [PubMed] [Google Scholar]
- 148.He X, Yang S, Liu C, Xu T & Zhang X Integrated Wound Recognition in Bandages for Intelligent Treatment. Advanced Healthcare Materials 9, 2000941 (2020). [DOI] [PubMed] [Google Scholar]
- 149.Armstrong DG, Boulton AJM & Bus SA Diabetic Foot Ulcers and Their Recurrence. New England Journal of Medicine 376, 2367–2375 (2017). [DOI] [PubMed] [Google Scholar]
- 150.Baughman DJ et al. Comparison of Quality Performance Measures for Patients Receiving In-Person vs Telemedicine Primary Care in a Large Integrated Health System. JAMA Network Open 5, e2233267–e2233267 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 151.McLean KA et al. Evaluation of remote digital postoperative wound monitoring in routine surgical practice. npj Digital Medicine 6, 85 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 152.Taboada GM et al. Overcoming the translational barriers of tissue adhesives. Nature Reviews Materials 5, 310–329 (2020). [Google Scholar]
- 153.Li J, Liang JY, Laken SJ, Langer R & Traverso G Clinical Opportunities for Continuous Biosensing and Closed-Loop Therapies. Trends in Chemistry 2, 319–340 (2020). [Google Scholar]
- 154.Yadav V, Bansal P, Mittal A & Singh S Global regulatory aspects of wound care and burn dressings. Asian Journal of Pharmaceutical and Clinical Research 11, 516 (2018). [Google Scholar]
- 155.Guidance Documents (Medical Devices and Radiation-Emitting Products). U.S. Food and Drug Administration (2024).
- 156.Maderal AD, Vivas AC, Eaglstein WH & Kirsner RS The FDA and designing clinical trials for chronic cutaneous ulcers. Seminars in Cell & Developmental Biology 23, 993–999 (2012). [DOI] [PubMed] [Google Scholar]
- 157.Groupa, F.D.A.W.H.C.F. Guidance for industry: Chronic cutaneous ulcer and burn wounds—developing products for treatment. Wound Repair and Regeneration 9, 258–268 (2001). [DOI] [PubMed] [Google Scholar]
- 158.Driver VR et al. Identification and content validation of wound therapy clinical endpoints relevant to clinical practice and patient values for FDA approval. Part 1. Survey of the wound care community. Wound Repair and Regeneration 25, 454–465 (2017). [DOI] [PubMed] [Google Scholar]
- 159.Robson MC & Barbul A Guidelines for the best care of chronic wounds. Wound Repair Regen 14, 647–648 (2006). [DOI] [PubMed] [Google Scholar]
- 160.Murphy PS & Evans GR Advances in wound healing: a review of current wound healing products. Plastic surgery international 2012, 190436 (2012). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 161.Wadman M FDA no longer has to require animal testing for new drugs. Science 379, 127–128 (2023). [DOI] [PubMed] [Google Scholar]
- 162.Flynn K, Mahmoud NN, Sharifi S, Gould LJ & Mahmoudi M Chronic Wound Healing Models. ACS Pharmacology & Translational Science 6, 783–801 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 163.Bassan S Data privacy considerations for telehealth consumers amid COVID-19. Journal of law and the biosciences 7, lsaa075 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 164.Shachar C, Engel J & Elwyn G Implications for Telehealth in a Postpandemic Future: Regulatory and Privacy Issues. Jama 323, 2375–2376 (2020). [DOI] [PubMed] [Google Scholar]
- 165.Huerta CT et al. Novel Gene-Modified Mesenchymal Stem Cell Therapy Reverses Impaired Wound Healing in Ischemic Limbs. Annals of surgery 278, 383–395 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 166.Wu X, Huang D, Xu Y, Chen G & Zhao Y Microfluidic Templated Stem Cell Spheroid Microneedles for Diabetic Wound Treatment. Advanced materials (Deerfield Beach, Fla.) 35, e2301064 (2023). [DOI] [PubMed] [Google Scholar]
- 167.Chen P et al. Single-Cell and Spatial Transcriptomics Decodes Wharton’s Jelly-Derived Mesenchymal Stem Cells Heterogeneity and a Subpopulation with Wound Repair Signatures. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 10, e2204786 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 168.Wang Z, Liang X, Wang G, Wang X & Chen Y Emerging Bioprinting for Wound Healing. Advanced materials (Deerfield Beach, Fla.), e2304738 (2023). [DOI] [PubMed] [Google Scholar]
- 169.Kim SH et al. 3D bioprinted silk fibroin hydrogels for tissue engineering. Nat Protoc 16, 5484–5532 (2021). [DOI] [PubMed] [Google Scholar]
- 170.Tabriz AG & Douroumis D Recent advances in 3D printing for wound healing: A systematic review. Journal of Drug Delivery Science and Technology 74, 103564 (2022). [Google Scholar]
- 171.Tay RY, Song Y, Yao DR & Gao W Direct-ink-writing 3D-printed bioelectronics. Materials Today 71, 135–151 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 172.Song Y et al. 3D-printed epifluidic electronic skin for machine learning–powered multimodal health surveillance. Science Advances 9, eadi6492. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 173.Tulloch J, Zamani R & Akrami M Machine Learning in the Prevention, Diagnosis and Management of Diabetic Foot Ulcers: A Systematic Review. IEEE Access 8, 198977–199000 (2020). [Google Scholar]
- 174.Sempionatto JR, Lasalde-Ramírez JA, Mahato K, Wang J & Gao W Wearable chemical sensors for biomarker discovery in the omics era. Nature Reviews Chemistry 6, 899–915 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 175.Xu C, Solomon SA & Gao W Artificial intelligence-powered electronic skin. Nature Machine Intelligence 5, 1344–1355 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 176.Xue Y et al. Artificial Intelligence-Assisted Bioinformatics, Microneedle, and Diabetic Wound Healing: A “New Deal” of an Old Drug. ACS Appl Mater Interfaces 14, 37396–37409 (2022). [DOI] [PubMed] [Google Scholar]
- 177.Howell RS et al. Development of a Method for Clinical Evaluation of Artificial Intelligence-Based Digital Wound Assessment Tools. JAMA Netw Open 4, e217234 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]