Objective: Evaluate quality of life (QoL) of patients with malignant wounds at baseline and through the course of management at a dedicated malignant wound care clinic. Methods: Retrospective review of patients with malignant wounds seen at a dedicated wound care clinic between January 2016 and April 2023 who completed the Skindex-16, a validated dermatologic QoL questionnaire. Clinical symptoms and management data were extracted from electronic medical records. Results: At baseline, patients reported high Skindex-16 scores across symptoms (mean = 64.2, standard deviation [SD] = 33.3), emotions (mean = 44.8, SD = 31.2), and functioning (mean = 67.7, SD = 29.7) domains. Overall Skindex-16 scores significantly improved over time, with a mean reduction of 4.9 points per visit (p = 0.002). Multimodal symptom management, including both topical and systemic treatments, and modern dressings were commonly utilized. Clinical Implications: Early referral to specialized wound care allows timely initiation of symptom-directed interventions to reduce pain, bleeding, odor, and infection risk. QoL improvements are often seen after the first follow-up visit, with the greatest benefit between the first and second visits. Access to structured wound care not only alleviates symptom burden but also supports continuation of oncologic treatment. Innovation: This study is the first to longitudinally assess malignant wound-related quality using a dermatology-specific instrument, the Skindex-16, in a real-world clinical setting. These findings highlight a model for integrating dermatologic wound care into supportive oncology and demonstrate that malignant wounds, often regarded as irreversible, can be meaningfully palliated with dedicated care. Conclusion: Dedicated wound care was associated with statistically significant improvements in QoL for patients with malignant wounds. Early referral to specialized wound clinics may enhance palliative care for these patients.
Diabetic foot ulcers (DFUs) remain a devastating complication of diabetes mellitus, with endothelial dysfunction playing a central role in their pathophysiology. Despite advances in wound care, current therapies often fail to address the complex molecular underpinnings of impaired healing. Diabetic foot ulcers (DFUs) remain a devastating complication of diabetes mellitus, with endothelial dysfunction playing a central role in their pathophysiology. Despite advances in wound care, current therapies often fail to address the complex molecular underpinnings of impaired healing. Using network pharmacology, molecular docking, in-vitro experiments, we identified 170 potential targets of Hy in DFU treatment. We found nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), serine/threonine protein kinase (AKT), and caspase-3 emerging as crucial hub proteins. Molecular docking revealed strong binding affinity (<-6.27 kcal/mol), particularly with Nrf2. In human endothelial cells exposed to a hyperglycemic microenvironment (HGM), Hy (5-10 μM) significantly restored cell viability while promoting Nrf2 nuclear translocation. This activation enhanced downstream antioxidant enzymes heme oxygenase-1, NAD(P)H quinone oxidoreductase 1, Catalase and suppressed oxidative stress markers p22phox, thioredoxin interacting protein. Hy inhibited NF-κB signaling and proinflammatory cytokines interleukin (IL)-6, IL-18 under hyperglycemic conditions. The compound also reversed HGM-induced suppression of angiogenic factors, vascular endothelial growth factor A, hypoxia-inducible factor 1-alpha, improving tube formation and migration in functional assays. Mechanistically, Hy restored AKT phosphorylation and modulated the Bcl-2 asscoiated X protein/B-cell lymphoma-2 (BAX/BCL2) ratio, protecting endothelial cells from apoptosis. Our findings highlight Hy's multifaceted action across redox, inflammatory, and survival pathways as a significant advantage over current single-target therapies. Although in vitro results are promising, animal models are needed to validate Hy's efficacy in the complex DFU microenvironment. Nevertheless, Hy's favorable absorption-distribution-metabolism-excretion profile and pleiotropic effects position it as an intriguing candidate for DFU management, potentially bridging preventive and regenerative approaches in diabetic wound healing.
Chronic wounds remain a major clinical and economic burden, affecting millions worldwide. Despite advances in wound care, many wounds fail to heal due to persistent tissue hypoxia, unresolved inflammation, lymphatic dysfunction, edema, and ischemia-reperfusion injury. These interrelated mechanisms are further compounded by comorbidities such as obesity, diabetes, and vascular disease, highlighting the need for therapeutic approaches that address multiple barriers to repair simultaneously. We review the pathophysiological drivers of wound chronicity-including the inflammation/edema/hypoxia cycle, endothelial dysfunction, and impaired lymphatic clearance-and summarize evidence on the roles of oxygen, nitric oxide, redox signaling, mechanotransduction, and specialized pro-resolving lipid mediators in tissue repair. We then evaluate two complementary, noninvasive interventions: topical oxygen therapy, which directly elevates wound tissue oxygen tension to support oxidative burst, angiogenesis, collagen synthesis, and specialized pro-resolving lipid mediator biosynthesis; and intermittent compression, which enhances lymphatic drainage, reduces edema, normalizes capillary gradients, and activates mechanosensitive repair pathways in endothelial cells, macrophages, fibroblasts, and keratinocytes. Chronic wound pathophysiology involves overlapping mechanisms of hypoxia, inflammation, edema, endothelial dysfunction, and reperfusion injury. Both topical oxygen therapy and intermittent compression independently improve oxygen delivery, perfusion, inflammation resolution, and tissue remodeling. When combined as intermittent topical oxygen therapy (ITOT), these modalities exert synergistic effects, amplifying oxygen bioavailability and potentiating anti-inflammatory, angiogenic, and reparative signaling. Clinical studies demonstrate that ITOT significantly increases healing rates, reduces healing time, lowers recurrence, and decreases hospitalizations and amputations in chronic wounds. Cost-effectiveness analyses further indicate improved quality-adjusted life years and reduced long-term expenditures. Chronic wounds persist due to a self-sustaining cycle of hypoxia, edema, and inflammation. By integrating oxygen delivery with cyclical compression, ITOT directly addresses the multifactorial barriers to repair, promoting durable healing and reducing complications. This multi-modality approach represents a promising therapeutic advance in the management of refractory lower extremity wounds, with broad implications for improving outcomes and quality of life and reducing health care costs.
Dressing changes after digit replantation can trigger pain, anxiety, and local wound cooling, yet the clinical impact of cleansing solution temperature remains unclear. This study evaluated whether warmed saline irrigation improves patient experience and physiological stability during wound care after digit replantation. In this single-center, parallel-group randomized controlled trial, 149 patients undergoing digit replantation were randomized to receive warmed or room-temperature saline irrigation during postoperative dressing changes. Primary outcomes were pain and digit temperature assessed before, during, and after dressing changes. Secondary outcomes included anxiety, comfort, complications, and digit survival. Analyses followed the intention-to-treat principle using linear mixed-effects models. Reporting adhered to CONSORT guidelines. Compared with room-temperature saline, warmed saline significantly reduced pain and anxiety and improved patient comfort over time (all p < 0.001). Warmed saline maintained peri-wound temperature during dressing changes, whereas room-temperature saline induced transient cooling. No between-group differences were observed in complication rates, C-reactive protein, or digit survival. Clinically meaningful improvements in pain, anxiety, and comfort were more frequent in the warmed-saline group. Exploratory analyses suggested greater benefit in younger patients and during colder seasons. This trial provides preliminary randomized evidence in a microsurgical population demonstrating that warmed saline irrigation, a simple and low-cost modification, can improve patient-reported outcomes without compromising safety. Warmed saline irrigation offers a safe and practical strategy to enhance comfort and reduce distress during wound care after digit replantation. These findings highlight thermal management as an underutilized, patient-centered component of postoperative care and support its integration into routine practice.
Objective: Wound closure is skin reepithelialization confirmed at two consecutive clinical visits 2 weeks apart. Our objective was to identify participant characteristics, including transepidermal water loss (TEWL), associated with complete wound closure of diabetic foot ulcers (DFUs) and reopening of a DFU within 2 weeks after initial closure in the National Institute of Diabetes and Digestive and Kidney Diseases-sponsored Diabetic Foot Consortium TEWL prospective observational cohort study of wound recurrence. At the site of wound closure, TEWL measures restoration of skin barrier function and functional wound closure. Approach: Four hundred and sixty-six eligible participants had physician-assessed wound closure at baseline. Of which, 418 (90%) had confirmed closure 2 weeks later and remained in the study, whereas 29 had their DFU reopen 2 weeks later and were not eligible for follow-up (i.e., screen failures). We compared baseline characteristics of 418 enrolled and 29 screen fail individuals using Wilcoxon rank sum and Fisher's exact tests p value for continuous and categorical outcomes, respectively. Results: There were no statistically significant differences in demographics, including age, sex, race, education, employment status, social support, or dressing change requirements between groups. The failure to maintain closure group had longer median duration of index DFU before initial closure (25.8 vs. 14 weeks, p = 0.003), higher frequency of prior total contact casting use (37% vs. 14%, p = 0.003), and a higher median initial TEWL measurement at the healed ulcer midpoint (27.1 vs. 21.0 g/m2/h, p = 0.006). Innovation: TEWL measurement at the site of wound closure can assess functional capacity of the skin in conjunction with current standards of wound closure end point in DFU and has significant potential to add quantitative measurement to assist in clinical assessment of healing wounds. Conclusion: Individuals with DFU who did not maintain wound closure had higher TEWL values at baseline, longer DFU wound duration, and more prior off-loading use. These findings are clinically relevant as a higher TEWL measurement demonstrates incomplete functional wound closure, supporting the use of TEWL to identify a healed DFU.
Chronic wounds remain a major global health burden and often stall despite guideline-based care because of persistent inflammation, oxidative stress, impaired perfusion, and dysregulated extracellular matrix remodeling. Protein-based nutrition is best positioned as an adjunct to, rather than a substitute for, standard wound care. Human studies, supported by mechanistic rationale, suggest that optimizing total protein intake (commonly ∼1.25 to 1.5 g/kg/day in appropriate patients) and, in selected settings, adding functional components such as arginine, glutamine, and β-hydroxy-β-methylbutyrate (HMB) may improve wound-area reduction and healing trajectories when integrated with standard care. Reported signals vary by etiology, including improved wound-area reduction and Pressure Ulcer Scale for Healing outcomes in pressure injuries, possible benefit in selected high-risk diabetic foot ulcer subgroups, and reduced venous ulcer area when supplementation is paired with consistent compression. Evidence remains heterogeneous across wound types and study designs, with inconsistent dosing, duration, endpoints, and patient-selection criteria that limit standardized implementation. Safety and feasibility are especially important in renal risk and diabetes, where renal function and glycemic control require monitoring. Clinical evidence was interpreted with attention to study design and reporting standards, including CONSORT, STROBE, or STARD, as applicable. This review translates current evidence into a clinician-oriented framework for patient selection, prescribing, monitoring, and treatment adjustment, emphasizing initiation triggers in stalled wounds and trajectory-based reassessment every 2-4 weeks. Future work should prioritize pragmatic, well-controlled trials comparing formulations and dosing windows by wound etiology, together with biomarker-informed stratification to improve personalization, safety, and real-world uptake.
Diabetic wounds are a devastating complication that cause chronic pain, recurrent infections, and limb amputations due to impaired healing. Despite advances in wound care, existing therapies often fail to address the underlying molecular dysregulation, highlighting the need for innovative and safe therapeutic approaches. Among these, D-amino acids such as D-tryptophan (D-Trp) have emerged as key regulators of cellular processes; however, their therapeutic potential in diabetic wounds remains largely unexplored. Here, we investigate the therapeutic potential of D-Trp in streptozotocin (STZ)-induced diabetic mice, comparing it with phosphate-buffered saline (PBS) controls and vascular endothelial growth factor (VEGF) as a positive control. Wound healing, inflammation, and histopathology were assessed. Protein and gene expression were analyzed via Western blot and RT-qPCR, respectively. Biolayer interferometry (BLI) measured the binding of D-Trp to hypoxia-inducible factor-1α (HIF-1α). D-Trp accelerated wound healing by modulating extracellular matrix (ECM) remodeling, signaling, and apoptosis. It upregulated matrix metalloproteinases (MMP1, MMP3, MMP-9), Janus kinase 2 (JAK2), and mitogen-activated protein kinase (MAPK) proteins while reducing pro-inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β], IL-6). D-Trp also suppressed caspase-3 and enhanced angiogenesis through HIF-1α activation. These findings suggest that D-Trp promotes healing by boosting ECM turnover, reducing inflammation, and activating MAPK/JAK pathways. Thus, D-Trp is a promising therapeutic for diabetic wounds.
Wound healing is an energetically demanding process that is easily disturbed by metabolic dysregulation. Metabolic dysregulation, induced by diabetes, obesity, insulin resistance, and various hormone imbalances, can disrupt each phase of wound repair, increasing the risk of post-operative complications, infection, wound dehiscence, and pathological scarring. We review the current evidence on the role of metabolic regulation in wound healing and highlight clinically relevant considerations for patient care. Animal and human studies have advanced our understanding of how metabolic pathways influence inflammation, angiogenesis, fibroblast function, and extracellular matrix remodeling during wound healing. These insights have led to the development of novel therapies, including hormone-based topical agents and dressings that both sense and modulate metabolites during wound healing. Despite growing recognition of the role of metabolic syndromes and hormonal regulation in wound healing, these factors are insufficiently integrated into clinical wound management. Bridging this gap requires a clear understanding of how metabolic syndromes and hormonal derangements influence healing. The continued development of treatments that modulate metabolic and hormonal pathways may enhance wound healing while minimizing systemic risk. Clinicians should also integrate local metabolic optimization with medical and lifestyle management to create the optimal wound healing environment for patients.
Artificial intelligence (AI) is rapidly transforming biomedical research and health care, offering new paradigms for discovery, diagnosis, and decision-making. This article provides a roadmap for researchers, clinicians, and reviewers seeking to understand and apply AI with rigor and relevance. It begins with a historical anchor: the birth of AI in health care at the University of Pittsburgh in the 1970s, where the INTERNIST-1 system pioneered diagnostic reasoning through symbolic logic, a milestone that laid the foundation for today's intelligent systems.Structured into three tiers-foundations, core techniques, and applications-the article addresses the full spectrum of biomedical AI. It introduces foundational concepts such as data engineering and preprocessing, knowledge representation and reasoning, and symbolic AI, which together enable structured, interpretable intelligence. Core techniques including expert systems, machine learning, deep learning, and explainable AI are presented with clinical examples, highlighting their role in wound care, image analysis, and predictive modeling. The applications tier showcases natural language processing, non-machine learning computer vision, robotics and automation, and distributed AI/multi-agent systems, demonstrating how AI integrates into real-world workflows. Ethical considerations and bias mitigation strategies are addressed with emphasis on Institutional Review Board oversight and fairness frameworks.Crucially, the article emphasizes that successful AI adoption begins not with technology, but with people. It outlines a systematic approach to building a biomedical AI workforce from within, empowering clinicians, researchers, and staff to become AI-literate contributors and leaders. With rigor checklists, practical guidance, and a vision for human-AI collaboration, this article invites readers to move beyond hype and toward responsible, transformative innovation in health care and biomedical science.
Pediatric pressure injuries (PIs) are a distinct and preventable clinical challenge, yet risk prediction models tailored to children remain underdeveloped. This systematic review critically evaluates existing pediatric PI prediction models to assess their methodological rigor, predictive performance, and clinical applicability. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, nine databases were searched to identify studies developing or validating PI risk prediction models for hospitalized patients younger than 18 years. Twelve models from nine studies were included. Risk of bias and applicability were assessed using the Prediction Model Risk Of Bias Assessment Tool (PROBAST) and PROBAST + AI tool. All models demonstrated acceptable discrimination (area under the curve [AUC] range: 0.612-0.978), with seven exceeding an AUC of 0.75. However, calibration was inconsistently reported, and only two models evaluated clinical utility-just one showed net benefit across a realistic threshold range. All models were rated as high risk of bias, and 10 had major concerns regarding applicability. Common methodological flaws included low events per variable <10, inappropriate categorization of continuous variables, poor handling of missing data, and lack of external validation. Most models were developed in single-center studies from China, limiting generalizability. Compared with adult PI models, pediatric models lacked age stratification, standardized outcome definitions, and robust validation. The first application of PROBAST + AI for evaluating machine learning prediction models highlighted algorithmic fairness and ethical risks within these models, but it showed insufficient interpretability regarding aspects such as the optimization process and the transparency of "black box" data leakage. To improve predictive accuracy and clinical relevance, future models should adopt the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis, PROBAST, and PROBAST + AI standards, use multicenter data, stratify by age and clinical setting, and focus on early-stage PIs. Incorporating objective measures and evaluating clinical utility will enhance model integration into practice. PROBAST + AI, in alignment with the advancements in information technology, requires widespread attention for its practical utility and ease of use to be further validated and optimized.[Figure: see text][Figure: see text]Conclusion:Current pediatric PI prediction models show promise but fall short in methodological rigor and clinical applicability. Addressing these gaps is essential to support early identification and targeted prevention in pediatric care.
Skin lipids are essential for various skin functions including maintaining barrier integrity, regulating hydration, and providing protection against microbes and inflammatory irritants. Along with skin health, the role of lipids in the etiology of macroangiopathic diseases, such as atherosclerosis of arteries, is well recognized. In diabetes, lipid dysregulation is evident and may contribute to the diverse complications of the disease. Diabetic vasculopathy primarily reflects the dysfunction and deterioration of existing blood vessels, as their preservation is key in preventing the progression of vascular disease and reducing the need for compensatory angiogenesis. In the peripheral diabetic skin of the limbs, diabetic vasculopathy runs alongside peripheral neuropathy. Although a causative link between the two is plausible, direct evidence in support of such claim is scanty. Diabetic skin is known to be compromised in many ways, including weakened barrier functionality and diabetes-induced alterations in the extracellular matrix, likely stemming from chronic inflammation, which may directly affect vascular integrity and nerve health. Both, in the compromised skin and within wounds, microbial pathogens and their enzymes may metabolize host lipids, driving inflammatory reactions and exacerbating the pathogenesis of diabetic vasculopathy and related neuropathy. This review focuses on lipid mediators such as sphingolipids, resolvins, oxidized low-density lipoproteins and their specific downstream signaling pathways to obtain a comprehensive understanding of diabetic complications relevant to wound healing. Through lipid-based strategies, this review hopes to inspire the development and utilization of individualized, precision-based approaches to manage diabetic vasculopathy and neuropathy.
Burn injuries affect over 11 million people annually, and methicillin-resistant Staphylococcus aureus (MRSA) infection significantly delays healing by sustaining inflammation and promoting scarring. This study evaluated N-benzyl benzenamine 4k-a novel dual-action compound with antibacterial and anti-inflammatory properties-in a murine model of MRSA-infected burn wounds. Skin safety of 4k was assessed through acute toxicity, sensitization, and irritation tests in BALB/c mice. A full-thickness burn model infected with MRSA2858 (1 × 108 CFU/mL) was treated topically with 4k, vancomycin (VAN), or vaseline. Outcomes included wound closure, bacterial load, histology, collagen organization, macrophage polarization markers (CD86/inducible nitric oxide synthase [iNOS] for M1; CD206/vascular endothelial growth factor [VEGF] for M2), cytokine levels, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway proteins. 4k demonstrated excellent dermal tolerability with no toxicity or irritation. Topical 4k reduced MRSA colonization and accelerated wound closure (residual wound area at day 15: 4k = 8.4 ± 2.2%, VAN = 17.8 ± 3.5%). Histology revealed organized collagen deposition and minimal scarring in the 4k group (scar score: 2.33 ± 0.58 vs. 13.33 ± 0.58 for vaseline). Mechanistically, 4k suppressed NF-κB activation, downregulated M1 markers (CD86, iNOS, tumor necrosis factor-alpha, and interleukin [IL]-6), and upregulated M2 markers (CD206, VEGF, transforming growth factor-beta 1, and IL-10), promoting a prohealing immune environment. This study introduces a dual-action topical therapy that combines potent antibacterial activity with immunomodulation, offering a promising strategy to overcome antibiotic resistance and improve burn wound outcomes. N-benzyl benzenamine 4k effectively eradicates MRSA, accelerates wound healing, and minimizes scarring through NF-κB inhibition and macrophage polarization, supporting its potential as a next-generation burn care agent.
Wound healing in pediatric patients is affected by physiology, growth, and development considerations unique from those in adults. In the following report, we review the primary literature on aging and wound healing and highlight clinical wound healing applications for the pediatric patient across age ranges from neonates and infants in the first year of life to adolescents (aged 10-19 years by World Health Organization definition). We characterize the differences in wound healing biology between infants, adolescents, and adults and discuss wound care strategies for pediatric surgical patients, highlighting evidence-based guidelines for wound management. We discuss relevant animal models and review the multidisciplinary aspects of providing wound care for children. Pediatric surgical patients have specialized wound care needs. Optimizing wound care outcomes for infants, children, and adolescents relies on an understanding of their wound-healing biology and unique physiological, psychological, and social considerations. Future directions in pediatric wound care will focus on validating and optimizing emerging technologies through pediatric-specific clinical trials, while also addressing key knowledge gaps in topical agent pharmacokinetics and advancing regenerative approaches like mesenchymal stem cell therapies tailored to the unique biology of infants and children.
Endogenous bioelectric signaling (including transepidermal potential [TEP] and the current of injury) plays a fundamental role in normal wound repair. Despite this, commonly used wound management frameworks do not consider this important driver of healing. The objectives of this review are to explore whether the patient characteristics/pathologies common in delayed healing are associated with weakened electrical properties of the skin and to consider whether compromised currents of injury are a barrier to healing that could be addressed with electrical stimulation therapy (EST) and incorporated into existing frameworks. This systematic review of PubMed was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and aimed to explore the impact of three characteristics associated with delayed healing (older age, diabetes, and chronic inflammation) on the electrical properties of skin/wounds. Twelve relevant studies were identified, revealing that TEP in older or diabetic people is significantly lower, and the current of injury is approximately half that of young, healthy controls. Lower currents of injury are associated with slower wound healing; therefore, the reduced current of injury/TEP identified here can be considered a barrier to healing. EST is designed to boost the weakened current of injury, back up to normal levels, stimulating a healing response. The incorporation of EST into existing wound management frameworks is therefore proposed. Endogenous bioelectrical signaling in the wound healing process appears to be compromised particularly in older people and those with diabetes. Patients may benefit from incorporating treatment with EST, which boosts bioelectrical signaling, into relevant wound treatment frameworks. [Figure: see text].
Chronic wounds represent a growing clinical and economic burden, affecting 1-2% of the global population, with prevalence expected to rise due to aging and increasing rates of diabetes, obesity, and vascular diseases. Wound persistence is often driven by infection and compounded by antimicrobial resistance (AMR), resulting in poor patient outcomes. High prevalence of microbial biofilms, which shield pathogens from immune clearance and promote AMR, further promotes the chronicity of infected wounds. Adoption of antimicrobial stewardship in wound care is increasing, emphasizing timely diagnosis of infection and pathogen identification to guide treatment and limit unnecessary AMR-driving antibiotic use. However, current diagnostic and therapeutic approaches remain only partially effective, particularly for biofilm-containing wounds. While many antimicrobials exist, their use is constrained by negative impacts on wound healing, limited antibiofilm activity, and insufficient evidence of improved clinical outcome. To address these gaps, recent advances in diagnostics and therapeutics aim to disrupt microbial communities, reduce AMR risk, and accelerate wound healing. The treatment of chronic wounds is challenged by AMR, biofilms, and the limited effectiveness of current therapies. Contemporary antimicrobials (e.g., broad-spectrum antibiotics and silver) are linked to AMR development, compounded by biofilms that shield pathogens, limit antimicrobial efficacy, and sustain infection. While alternative treatments with lower AMR risk and greater antibiofilm activity are under investigation, the lack of robust clinical data limits their adoption. Broader adoption of antimicrobial stewardship and biofilm-targeting sustainable wound care practices are key for combatting AMR and improving patient outcomes.
Barrier function of human skin maintains hydration by preventing excessive transepidermal water loss (TEWL), blocks the entry of pathogens and allergens, regulates thermal and chemical exchange with the environment, and sustains immune equilibrium. A wound arises when this barrier is breached, resulting in a loss of structural integrity and barrier function. An invisible wound represents a focal loss of human skin barrier function without any visible cut, ulcer, or defect. Despite appearing intact, the skin in these regions is functionally compromised. Current U.S. Food and Drug Administration (FDA) criteria define complete wound closure as full re-epithelialization without drainage or dressing needs, confirmed during two assessments at least 14 days apart. Wounds may satisfy this structural requirement for wound closure yet fail to restore barrier function. Recent studies demonstrate that wounds closed meeting FDA closure criteria but exhibiting elevated TEWL at the wound site (i.e., invisible wound) are more likely to recur, highlighting the clinical importance of achieving functional wound closure. Invisible wounds occur across the lifespan and arise from a wide range of everyday and high-risk exposures. They can result from age-related skin thinning, sunburn, and the routine use of cosmetic chemicals on vulnerable or sensitized skin. They may also develop after minor trauma that leaves no laceration, from mechanical stress imposed by prosthetic use, and from barotrauma or other subclinical mechanical forces commonly encountered by warfighters. Although outwardly undetectable, these silent disruptions weaken the skin's protective barrier, undermine systemic health, and contribute to chronic morbidity.
Objective: Patients with complex chronic wounds are at high risk for poor outcomes. This study assessed the relationship between nurse staffing and outcomes among patients with complex and noncomplex chronic wounds. [Figure: see text] Approach: This cross-sectional study linked three 2021 datasets: RN4CAST survey, Medicare Provider Analysis and Review claims, and American Hospital Association data. Nurse staffing was derived from the RN4CAST item asking nurses whether "there are enough nurses to get the work done." We calculated the hospital-level percentage of nurses who reported staffing inadequacy. Multilevel statistical modeling measured the association between staffing and in-hospital mortality and length of stay, adjusted for patient and hospital covariates and stratified among patients with complex and noncomplex chronic wounds. We followed STROBE criteria. Results: The sample included 19,027 patients with chronic wounds (66.7% complex) in 216 hospitals. Every 10% increase in nurses reporting staffing inadequacy was associated with 6% higher odds of in-hospital mortality among patients with complex wounds, with no significant relationship among patients with noncomplex wounds. Every 10% increase in staffing inadequacy was associated with longer lengths of stay, by a factor of 1.04, for patients with both complex and noncomplex wounds. Innovation: By linking nurse-reported staffing to outcomes for patients with chronic wounds, this study identifies a policy-relevant pathway to improve outcomes, particularly for those with complex wounds. Conclusion: Nurse staffing adequacy is consequential for patients with chronic wounds as it relates to length of stay and is particularly important in preventing in-hospital mortality among the highest-risk patients-those with complex wounds.
Wound healing is as much about opportunity (Gk. Karios) and sequence (Gk. Chronos). The sequential healing responses involve concerted responses of cells of various lineages along with both soluble (cytokines and growth factors) and insoluble (matrix composition and topology) that are precisely coordinated for ultimate healing. This motivated the current scoping review to examine the biological relevance and utility of current in vitro models of wound healing, focusing on specific cellular responses. We examined PubMed, Web of Science, and EBSCO of Science for the years 2020-2025, using keywords in vitro wound healing and individual cell type, namely epithelial cells, keratinocytes, fibroblasts, macrophages, platelets, and endothelial cells. This identified 126 relevant studies were selected and categorized by healing stage, cell types, and prototypical biological responses such as proliferation, migration, and lineage-specific functions. This analysis outlined the utility of a temporal framework to organize current in vitro models as acute-initial, early and late, and chronic-delayed. Existing two-dimensional and three-dimensional models focus on platelet function (hemostasis), neutrophil or macrophage chemotaxis and phagocytosis (inflammation), epithelium (closure), fibroblast (matrix synthesis, contraction), and endothelial (angiogenesis). While these models provide key insights into specific phases, cell functions, and molecular mechanisms, they do not fully replicate the integrated, multiorgan processes of wound healing observed in vivo. Sequential combinations of these models lend themselves to the advances in artificial intelligence, machine learning, and robotic automation that are integral to developing prognostic and therapeutic wound care agents.
Diabetic foot ulcers (DFUs) represent one of the most severe complications of diabetes mellitus, frequently leading to chronic infection, delayed wound healing, and lower-limb amputations. Despite advances in wound care, current therapeutic strategies largely rely on broad-spectrum antibiotics and mechanical interventions, which often fail to address the complex biological environment of non-healing wounds. Emerging evidence indicates that DFUs are strongly associated with alterations in the wound microbiome, including microbial dysbiosis, polymicrobial biofilm formation, and persistent inflammatory responses. These factors collectively contribute to impaired tissue regeneration and resistance to conventional therapies. Consequently, microbiome-targeted therapeutic strategies are gaining increasing attention as a promising approach for DFU management. Novel interventions such as bacteriophage therapy, probiotic and postbiotic-based wound dressings, and CRISPR-mediated genome editing provide precise tools for disrupting pathogenic biofilms, attenuating microbial virulence, and overcoming antimicrobial resistance while preserving beneficial microbial communities. In parallel, advances in rapid microbiome diagnostics, smart wound dressings, nanotechnology-based drug delivery systems, and data-driven personalized treatment platforms are enabling more adaptive and targeted wound management. By shifting the perspective from treating DFUs as simple infections to understanding them as complex microbial ecosystems, these emerging strategies offer new opportunities to enhance healing outcomes.
Chronic wounds such as diabetic foot ulcers, venous leg ulcers, and pressure ulcers are characterized by impaired healing and persistent inflammation. Cellular senescence, defined as irreversible growth arrest with a pro-inflammatory secretory phenotype (senescence-associated secretory phenotype), has emerged as a potential driver of these nonhealing states. While transient induction of senescence may aid acute repair, chronic accumulation of senescent cells is thought to disrupt tissue regeneration, promote extracellular matrix degradation, and sustain inflammation. Single-cell RNA sequencing and spatial transcriptomics have revealed diverse cell states in chronic wounds, including senescent subsets. Studies in diabetic, venous, and pressure ulcers implicate senescent fibroblasts and immune cells in impaired remodeling, often triggered by oxidative stress, hyperglycemia, or ischemia-reperfusion injury. Therapeutic strategies targeting senescent cells in delayed wound healing have demonstrated promise in preclinical models; however, interventions must be timed and targeted precisely. Despite emerging evidence, the identity, abundance, and location of senescent cells in chronic wounds remain poorly defined. Reliance on nonspecific markers such as p21 or SA-β-gal complicates interpretation. Senescence appears to play context-dependent roles, with beneficial effects during acute healing but harmful persistence in chronic wounds, presenting challenges for therapeutic targeting. More studies using single-cell RNA sequencing, spatial transcriptomics, and longitudinal profiling are needed to define senescent subpopulations, map their spatial distribution, and track dynamics during wound progression. These approaches will help distinguish transient from persistent senescence. A deeper understanding of interactions with immune, epithelial, and stromal components will guide precisely timed, cell type-specific interventions to improve outcomes.