Chronic wounds, characterized by prolonged healing times and high complication rates, present significant challenges to healthcare systems. This randomized, double-blind, placebo-controlled clinical trial evaluated the adjunctive effect of 904 nm gallium arsenide (GaAs) laser therapy in the treatment of chronic venous and diabetic ulcers. The study adhered to the CONSORT 2025 guidelines to ensure transparency and quality in reporting. Seventy patients were randomly assigned to two groups: active laser (AL) group (laser + standard care) and placebo laser group (PL) (simulated laser + standard care). All participants were followed twice a week until complete wound healing or a maximum of 15 sessions. Outcomes assessed included wound area reduction, microbial load and histological analysis. Results showed that the AL group had a 53% reduction in wound area, while the PL group had a 9% reduction (p < 0.001), with complete closure observed in two AL patients. Laser therapy also significantly reduced bacterial colonization, particularly, of Pseudomonas aeruginosa, Escherichia coli and Proteus mirabilis (p ≤ 0.007). Histological analysis demonstrated enhanced angiogenesis, reduced inflammatory infiltrate and improved collagen organization at the wound edges in the AL group (p ≤ 0.042). These findings demonstrate that 904 nm GaAs laser therapy accelerates healing, reduces microbial burden and promotes favourable tissue remodelling. The integrative approach, combining clinical, microbiological and histological assessments, underscores its potential as a safe and effective adjunct in chronic wound management, offering a promising strategy to improve outcomes and reduce healthcare burdens.

Severe burns present significant challenges in military and civilian settings, especially in austere environments where care may be delayed. This study presents a multifunctional, deployable hydrogel dressing composed of agarose and minocycline (8 mg/mL) designed to prevent burn progression, control infection and promote healing. Agarose hydrogel formulations containing between 0.5% and 1.25% agarose were characterised by rheology, and their drug-release kinetics were measured. Based on rheological characterisation (Pa · s) and minocycline release rates, hydrogels containing 1% agarose were used in subsequent studies. In vitro studies measured the rate of minocycline diffusion through burnt porcine skin (1.5 μg/h), and the minocycline hydrogel effectively inhibited growth of S. aureus, P. aeruginosa and A. baumannii in wound tissue, as measured by colony-forming units (CFU). In porcine deep partial-thickness burns, the minocycline hydrogel reduced inflammation compared to silver sulfadiazine (SSD) and gauze controls, as indicated by lower levels of interleukin (IL)-1β and IL-6 (pg/ml) in wound tissue, and mitigated burn progression, resulting in significantly shallower burns by Day 4 compared with blank hydrogel, SSD and gauze controls. By Day 14, re-epithelialization reached 70% ± 12% for burns treated with the minocycline hydrogel, compared to 51%-58% for controls. Bacterial load was significantly reduced in infected burns treated with the minocycline hydrogel compared with blank hydrogel on Day 4, compared with all control groups on Day 7, and compared with blank hydrogel on Day 14. These results demonstrate that minocycline agarose hydrogel provides mitigation of burn wound progression, and effective infection control, representing a promising strategy for burn care, particularly in settings with limited or delayed access to specialised treatment.

Chronic wound healing depends on local wound-edge perfusion, which is not fully characterised by conventional vascular assessments. We evaluated whether quantitative periwound ring enhancement on indocyanine green angiography could predict 12-week wound healing. This retrospective cohort study included 71 patients with diabetic foot ulcers or pressure sores who underwent baseline indocyanine green angiography. Relative fluorescence intensity, time to peak, perfusion slope and ring continuity were quantified and integrated into an exploratory 0-8-point Perfusion Success Index. Forty-two patients achieved complete healing within 12 weeks and 29 did not. Healers showed higher relative fluorescence intensity, shorter time to peak, steeper perfusion slope, greater ring continuity and a higher Perfusion Success Index than non-healers (5.83 ± 1.45 vs. 3.24 ± 1.38, p < 0.001). The Perfusion Success Index demonstrated the highest overall discrimination for 12-week healing (area under the curve, 0.894; 95% confidence interval, 0.823-0.965); a cut-off of ≥ 5 yielded 83.3% sensitivity and 82.8% specificity. A clinical model including wound type, wound area, wound depth, infection and serum albumin had an area under the curve of 0.777, which increased to 0.908 after addition of the Perfusion Success Index (absolute increase in area under the curve, 0.131; p = 0.012). After bootstrap internal validation, the clinical-plus-index model retained favourable discrimination with an optimism-corrected area under the curve of approximately 0.87. Quantitative periwound ring enhancement on indocyanine green angiography may provide complementary prognostic information regarding wound-edge healing potential beyond conventional clinical assessment.

Healing after split-skin grafting remains difficult to anticipate in small-area burns, particularly when wounds show no clinically diagnosed infection. We tested whether the burn wound microbiome before grafting captures early wound states linked to subsequent healing. Twenty-six adults with mid-dermal to full-thickness burns involving < 10% total body surface area underwent longitudinal sampling at surgery, graft check and clinic review. At surgery, swabs were collected from the burn wound before grafting, the split-skin donor site and anatomically matched uninjured control skin. Across 170 infection-free samples, microbiome profiling showed that pre-grafting burn wounds already had reduced microbial diversity and distinct community structure compared with matched control skin. This baseline dysbiosis included depletion of commensal-associated anaerobes, including Finegoldia and Anaerococcus and enrichment of opportunistic burn-associated taxa, including Pseudomonas and Acinetobacter. Donor sites acquired a related wound-like microbiome and remodelled in parallel with burn wounds during healing, but post-grafting burn microbiota were not preferentially similar to matched donor sites, arguing against a donor-to-burn microbial transfer. The clearest clinical signal was present before grafting: lower burn wound diversity at surgery was associated with delayed healing, and baseline community structure differed in wounds that later required regrafting. These findings suggest that the pre-grafting burn wound microbiome may provide an early, infection-independent marker of healing trajectory and should be tested as a predictive biomarker in larger prospective cohorts.

Lactoferrin (LF) is a natural glycoprotein. Its diverse biological roles include immune modulation and osteogenesis. Evidence shows that LF promotes collagen synthesis and fibroblast activity, thereby accelerating wound healing. This study investigates the role LF plays in wound healing and potential future applications. A systematic review was conducted in accordance with PRISMA guidelines. Articles were sourced from MEDLINE, Embase, Web of Science, and the Cochrane Central Register. Studies published before September 2025 were eligible. The primary outcome of interest was wound healing rate, while secondary outcomes included collagen synthesis and fibroblast migration associated with LF exposure. An NIH quality assessment was performed to score the quality of the papers. Comparative analyses and descriptive statistics were performed to synthesise the findings. Of the 261 screened articles, 17 studies met the inclusion criteria. Twelve studies reported that LF accelerated wound healing compared to controls, 12 demonstrated increased collagen synthesis, and 9 showed enhanced fibroblast migration. All included studies were preclinical, comprising human in vitro or animal models. Most originated from Japan (n = 6), followed by China (n = 3) and Russia (n = 2), and were published within the last 20 years. This review highlights consistent preclinical evidence linking LF to enhanced wound healing. These findings provide a strong rationale for future clinical trials investigating LF as a therapeutic agent for wound healing. To date, no human studies have directly evaluated LF in wound repair, further emphasising the need for well-designed clinical trials.

After full-thickness injuries, foetal skin regenerates, while adult skin heals with scarring. Upon injury, mesenchymal stromal cells (MSCs) produce extracellular matrix (ECM) that shapes the wound microenvironment by providing structure, regulating the availability of soluble factors and directing cell behaviour. Therefore, the ECM secreted by MSCs likely guides the healing outcome towards either scarless or scar prone healing. We analysed the ECM produced by primary human MSCs from foetal skin (hfS-MSCs; regenerative/healthy), adult dermis (hD-MSCs; scarring/healthy) and burn eschar tissue (hBE-MSCs; scarring/wounded). We first optimised ECM production across MSC populations, then quantified total ECM deposition, collagen and total protein content and analysed ECM-related genes. Finally, we assessed collagen maturity in foetal versus adult skin. Standard medium containing 10 μg/mL of magnesium ascorbyl phosphate stimulated ECM deposition in all MSC populations, while minimising ECM area reduction and contraction. Total protein, collagen gene and protein expressions were higher in hfS-MSC-derived ECM, while ECMs derived from hBE-MSCs and hD-MSCs showed an increased proportion of non-collagenous proteins. Collagen I:V gene ratio was decreased in hfS-MSCs, while collagen I:III gene ratio was increased in hBE-MSCs compared to hD-MSCs. Both hfS-MSCs and hBE-MSCs showed increased ECM deposition and collagen insolubility. Moreover, hBE-MSCs showed higher ECM contraction, as well as PLOD2 and fibronectin gene expression. Foetal skin exhibited higher immature collagen, whereas adult skin exhibited higher mature collagen. We revealed intrinsic differences in ECM amount, composition and ECM-related gene expression between MSC populations and their tissues of origin, suggesting potential ECM-related biomarkers underlying regeneration or repair.

Chronic wounds associated with diabetes remain a major challenge due to impaired angiogenesis, reduced fibroblast activity and dysfunction of regenerative cells. Adipose-derived mesenchymal stromal cells (ASCs) represent a promising therapeutic option; however, their regenerative potential is limited under hyperglycaemic conditions. This study investigated whether metformin could enhance ASC function and improve their therapeutic potential for tissue regeneration. Transcriptomic analysis of wound tissue identified pathways associated with angiogenesis, inflammation, extracellular matrix remodelling and cell survival, including PI3K-AKT, JAK-STAT and AGE-RAGE signalling. Functionally, metformin increased ASC proliferation in a concentration-dependent manner and promoted sustained cell expansion over time. Metformin-treated ASCs also enhanced fibroblast migration in a co-culture system, indicating improved paracrine pro-reparative signalling. Metformin further increased the secretion of angiogenic factors, including vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), supporting a pro-angiogenic secretory profile. Metformin enhanced CD31 expression and tube formation capacity of ASCs under normoglycemic conditions, particularly in combination with VEGF; however, these effects were attenuated under high-glucose conditions. Additionally, metformin improved ASC adhesion to small intestinal submucosa (SIS) scaffolds and supported endothelial marker expression in a three-dimensional biomaterial environment. Collectively, these findings demonstrate that metformin promotes a pro-regenerative ASC phenotype characterized by enhanced proliferation, paracrine signalling, endothelial-associated responses and scaffold integration. However, hyperglycaemic conditions partially impair these effects, highlighting the influence of metabolic stress on regenerative responses. Overall, metformin preconditioning represents a promising strategy to enhance ASC-based therapies for chronic and diabetic wound healing.

Surgical wound dehiscence (SWD) is a serious postoperative complication associated with significant morbidity, mortality and healthcare costs. Traditional management, including negative pressure wound therapy (NPWT), relies on secondary intention healing, which can be prolonged. This study evaluates a strategy of aggressive surgical debridement followed by primary wound closure (ASDC) to convert surgical wounds to primary intention healing. In this retrospective cohort study, we compared outcomes between ASDC and NPWT in 106 SWD patients (2013-2023). The ASDC group (n = 62) underwent radical debridement and early closure, while the NPWT group (n = 44) received standard debridement and NPWT until complete epithelialization. Healing time, hospital stay, costs and complications were analyzed. Non-parametric tests and Kaplan-Meier analysis with log-rank test were used for comparisons. The ASDC group had a significantly shorter median healing time (21.0 vs. 47.5 days, p < 0.001) and median hospital stay (14.0 vs. 19.0 days, p = 0.004). Total treatment costs were lower in the ASDC group (36,897 ± 14,188 vs. 57,457 ± 28,791 RMB, p < 0.001). Complication rates (infection, bleeding, reoperation) showed no statistically significant difference between groups. Sensitivity analysis of patients treated during the overlapping protocol period (2015-2017) yielded consistent results. In this retrospective analysis, ASDC was associated with significantly accelerated wound healing, shorter hospitalization and lower costs compared to NPWT for SWD management, without an increase in detected complications. This suggests ASDC may be an efficient alternative strategy, though prospective studies are needed to control for selection bias and confirm these findings.

Hypertrophic scar (HS) is characterised by excessive fibroblast proliferation and abnormal differentiation; however, the underlying molecular mechanisms remain incompletely understood. Here, we identify the collagen receptor discoidin domain receptor 1 (DDR1) as a key regulator of fibroblast activation during HS formation. We observed markedly increased expression and phosphorylation of DDR1 in human HS tissues compared with adjacent normal skin. To investigate the functional role of DDR1, primary fibroblasts derived from human HS tissues were stimulated with collagen III to induce DDR1 activation in vitro. DDR1 activation significantly enhanced fibroblast proliferation and promoted myofibroblast differentiation, as evidenced by increased collagen III and α-smooth muscle actin (α-SMA) expression. Concomitantly, DDR1 activation suppressed the expression of the tumour suppressor phosphatase and tensin homologue (PTEN) and promoted nuclear translocation of NF-κB p65, a known inhibitor of PTEN transcription. Consistent with these findings, HS tissues exhibited elevated DDR1 expression and reduced PTEN levels relative to adjacent normal skin. The pathological role of DDR1 in HS was further validated in a rabbit ear model, in which local administration of a selective DDR1 inhibitor significantly attenuated scar formation. Together, these findings delineated a collagen III-DDR1-PTEN signalling axis that drives fibroblast proliferation and activation in hypertrophic scarring, highlighting DDR1 as a promising therapeutic target for the prevention and treatment of HS.

Complex extremity wounds from burns or trauma often involve exposed tendon or bone, making direct skin grafting unreliable and increasing the likelihood of flap reconstruction. This review evaluated whether early dermal scaffold application reduces subsequent surgical requirements. PubMed, Embase, the Cochrane Library and clinical trial registries were searched for studies published between 2016 and 2026. Of 409 records screened, 10 studies comprising 415 scaffold-treated wounds in 414 patients were included. Outcomes were synthesised descriptively and stratified by aetiology; meta-analysis was precluded by heterogeneity. Across nine non-randomised studies (393 patients), 38 (9.7%) healed without grafting and 352 (89.6%) were grafted. Graft avoidance differed markedly by aetiology: 32 of 192 trauma patients (16.7%) versus 0 of 190 burn patients (0%). All trauma events arose from three studies of small, highly selected defects, whereas three further trauma cohorts using immediate or staged grafting reported none. In the single randomised trial, scaffold take succeeded in 5 of 22 patients (22.7%) and all were grafted, whereas the graft-only comparator achieved complete coverage success, although scar quality was better with the scaffold (Vancouver Scar Scale 2.40 vs. 7.45, p < 0.001). No study contained a flap comparator, and certainty of evidence was very low for five of seven outcomes and low for two. Current evidence suggests early dermal scaffold application may reduce reconstructive burden in selected trauma wounds, whereas in burns scaffolds appear to enable staged grafting rather than replace it. Reconstructive downstaging is presented as an exploratory framework, not a validated outcome.

Pyoderma gangrenosum (PG) is a rare, painful ulcerative dermatosis associated with significant functional impairment. Complete w closure is the standard endpoint in wound clinical trials, including PG, but clinically meaningful improvement may occur before total epithelization is achieved. No disease-specific minimal important difference exists for patient-reported physical function in PG. We evaluated whether partial healing is associated with differences in physical function and estimated such a threshold using the Skindex-Mini. This retrospective cohort study included adults with PG receiving dermatologic care at a single academic referral centre between August 2024 and November 2025. Clinical data and patient-reported outcome measures were obtained from a prospectively maintained PG registry and electronic health records. Healing stage at each visit was categorized as healed, partially healed (≥ 50% reduction in ulcer area) or not healed, and Skindex-Mini Physical Function scores (0-100 scale, higher scores indicating worse function) were compared using linear mixed-effects models. The cohort included 80 adults with PG contributing 385 clinical encounters. Physical function scores differed significantly across healing stages (χ[2] = 39.0; p < 0.001). Compared with unhealed patients, partially healed patients reported better physical function (approximately 17 points lower) and were closer to fully healed patients. A 1-point improvement in patient global assessment corresponded to an adjusted 20.8-point improvement in physical function (95% CI, 14.5-27.2; p < 0.001), consistent with distribution-based estimates. Partially healed patients reported substantially better physical function than unhealed patients, supporting incorporation of patient-reported physical function and intermediate healing states alongside complete wound closure in PG outcome assessment.

Chronic wounds result from combined defects in vascular perfusion, inflammatory resolution, and epithelial repair. The skin's non-neuronal cholinergic system (NNCS), formed by keratinocytes, endothelial cells, fibroblasts, and immune cells that synthesise and respond to acetylcholine (ACh), helps coordinate these processes through muscarinic and nicotinic receptors. Inhibition of acetylcholinesterase (AChE) increases local ACh concentrations and may engage two key pathways supported by preclinical data: M3 muscarinic receptor (M3 mAChR)-endothelial nitric oxide synthase (eNOS)-nitric oxide (NO)-mediated vasodilation, and α7 nicotinic acetylcholine receptor (α7-nAChR)-mediated suppression of pro-inflammatory cytokines. Donepezil is a reversible, selective AChE inhibitor with physicochemical properties compatible with dermal administration. Low-dose or microneedle dermal delivery has produced dermal exposure with limited systemic uptake in animal and ex vivo skin studies. In preclinical diabetic wound models, nicotinic receptor activation accelerated healing, reduced inflammatory signalling, and improved control of bacterial burden. We hypothesise that topical donepezil formulated for localised dermal delivery could restore cholinergic signalling within the wound microenvironment by increasing local ACh concentrations. This approach may complement metabolic therapies that support arginine-NO coupling and redox balance. Controlled pilot studies should assess local cutaneous pharmacodynamics, perfusion responses, and wound-closure outcomes.

Deep partial-thickness and full-thickness thermal burns require timely eschar removal, but surgical excision can sacrifice viable dermis, cause blood loss, and consume operating-room resources. Anacaulase-bcdb is a standardised pineapple stem-derived proteolytic biologic approved for enzymatic eschar removal in eligible adult and paediatric thermal burns. This Drug Evaluation reviews the product's biological origin, composition, mechanism of action, regulatory status, administration, clinical efficacy, safety and place in therapy. A targeted review of peer-reviewed and regulatory evidence was undertaken, prioritising the phase 3 DETECT trial, the randomised paediatric CIDS trial, systematic reviews, consensus guidance, prescribing information, and postmarketing studies. Anacaulase-bcdb provides rapid eschar removal, reduces surgical excision and debridement-related blood loss, and preserves subsequent options for conservative healing or grafting. Procedural pain, hypersensitivity, strict eligibility criteria, and specialist-team requirements remain important limitations. Anacaulase-bcdb is a clinically meaningful, tissue-sparing adjunct rather than a replacement for burn surgery. Its greatest value is likely in eligible deep partial-thickness and selected full-thickness thermal burns treated within protocolized burn-center pathways. Future adoption will depend on comparative effectiveness, cost-effectiveness, real-world safety, optimal patient selection and evidence that reduced operative burden translates into improved clinical and health-system outcomes.

Deep burn injuries in mammals typically heal with fibrosis and scar formation. Although the Japanese fire-bellied newt (Cynops pyrrhogaster) exhibits scarless skin regeneration after injury, whether this capacity is maintained after third-degree burn remains unclear. A third-degree burn model was established in adult newts, and the regenerative process was analysed over 1 year using macroscopic, histological, ultrastructural and molecular approaches. Blood cell dynamics and proliferative cells were evaluated by Wright-Giemsa staining and PCNA immunohistochemistry. Burn wounds were completely re-epithelialised by post-burn day (PBD) 8 despite persistence of damaged tissue. The wound subsequently underwent progressive tissue remodelling and closely resembled normal skin macroscopically by PBD 365 without evidence of contracture. Histological and ultrastructural analyses demonstrated restoration of organised dermal collagen architecture and muscle sarcomere structures without fibrotic scar formation. Erythrocytes transiently accumulated within damaged tissues and peaked on PBD 12, whereas neutrophils peaked earlier and declined after re-epithelialisation. PCNA-positive proliferative cells in the dermis and subcutaneous tissue peaked on PBD 30. Semi-quantitative RT-PCR suggested temporal changes in inflammatory marker expression during the regenerative process. Adult newts achieve scarless regeneration following third-degree burns. These findings establish a useful experimental model and provide a comprehensive characterisation of scarless regeneration following third-degree burns, providing a foundation for future mechanistic studies.

Chronic and complex wounds are a major burden worldwide, and a considerable number remain unresponsive to traditional therapy. Cord blood-derived platelet gel (CBPG) is a novel allogeneic wound therapy providing a fibrin-based scaffold enriched with neonatal platelet-derived growth factors, including high concentrations of VEGF, HGF and FGF, directly into the wound bed, without the need for blood collection from the patient. This narrative review provides an overview of the biological features of CBPG, discusses clinical evidence across different wound indications, and assesses ethical, regulatory, and translational issues important to its development. CBPG has been studied in clinical trials in recessive dystrophic epidermolysis bullosa, cutaneous and oral chronic graft versus host disease after allogeneic haematopoietic stem cell transplantation, partial thickness burns, neonatal pressure injuries and diabetic foot ulcers. Across these conditions, CBPG has shown a consistent safety profile and promising signals of benefit, but evidence is restricted by small sample sizes, diverse methods and short follow-up. CBPG offers a biologically rational alternative to complex wound management in fragile patient populations. To move toward validated clinical application, manufacturing standardisation, regulatory classification, multicentre randomised trials with embedded health-economic endpoints, and transparent governance of cord blood allocation are needed.