To determine whether cellular matrix (CM) products result in better healing rates than acellular matrix (ACM) products for nonhealing diabetic foot ulcers.

The Dermagraft and Oasis Longitudinal Comparative Efficacy Study (DOLCE) was a randomized, single-blinded, three-arm controlled trial. Patients (aged ≥18 years) with a full-thickness nonhealing diabetic foot ulcer who met inclusion/exclusion criteria were enrolled.

Of 169 eligible patients, 138 were enrolled and 117 randomly assigned. For 12 weeks, patients received standard of care (SOC), CM, or ACM. The primary outcome was the percentage of wounds healed by 12 weeks. Of the 117 participants, 41 were in the CM group, 48 in the ACM group, and 28 in the SOC group. There were 21 withdrawals, but seven had reached the first primary end point. Complete re-epithelialization of the ulcer by 12 weeks occurred in 59% of the 117 total participants: 49% in the CM group, 69% in the ACM group, and 57% in the SOC group (P = 0.16 by χ2 test). At 28 weeks, 25 participants (61%) in the CM group, 27 (56%) in the ACM group, and 18 (64%) in the SOC group had healed (P = 0.78). No differences were found in wound recidivism or adverse event occurrence between groups.

No difference in efficacy was found between SOC, ACM, and CM, suggesting that SOC can reduce the economic burden of diabetic foot ulcer treatment.

Acute wounds present a significant clinical challenge due to delayed healing, which is often exacerbated by elevated levels of reactive oxygen species (ROS). These high ROS concentrations hinder the natural healing process, leading to prolonged recovery and increased risk of complications. W-GA nanodots, synthesized via a simple coordination method, have emerged as promising solutions, demonstrating multifunctional enzymatic activity that effectively scavenges ROS. To explore the underlying mechanisms of ROS-induced oxidative stress, we conducted RNA sequencing on macrophages exposed to H2O2. The results revealed significant regulation of key stress response pathways, including substantial upregulation of the "p53 signaling pathway" and the "HIF-1 signaling pathway," both of which are essential for cellular adaptation to oxidative stress. By alleviating oxidative stress, W-GA nanodots not only accelerate wound repair but also improve overall healing outcomes. Notably, RNA sequencing of animal tissue samples revealed that W-GA nanodots activate the "Wnt signaling pathway," further promoting wound healing. These findings underscore the potential of W-GA nanodots as a novel therapeutic strategy for enhancing wound healing and treating oxidative stress-related conditions, positioning them as promising candidates for future clinical applications in wound care and inflammatory diseases.

Diabetic foot ulcers (DFUs) are a devastating complication of diabetes mellitus (DM) that affect millions of people worldwide every year. They have a long-term impact on patients' quality of life and pose a significant challenge for both patients and clinicians, alongside negative economic implications on affected individuals. The current therapeutic approaches are costly and, in many cases, ineffective, highlighting the urgent need to develop novel, affordable, more efficient, and personalized treatments. Recent advances in high-throughput omics technologies, including proteomics, bulk RNA sequencing (bulk RNA-seq), single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics in both preclinical animal and human clinical studies, have enhanced our understanding of the molecular function and mechanisms of DFUs, thereby offering potential for targeted therapies. Additionally, these technologies provide valuable insights behind the mechanism of action of novel wound dressings and treatments. In this review, we outline the latest application of omics technologies in DFU preclinical animal and human clinical research on diabetic wound healing, and spotlight recent findings.A graphical abstract is available with this article.

Chronic wounds remain in a state of disrupted healing, impeding neurite outgrowth from injured nerves and poor development of new blood vessels by angiogenesis. Current therapeutic approaches primarily focus on the restoration of vascularization and overlook the need of nerve regeneration for complete healing. Vascular endothelial growth factor (VEGF) is a critical growth factor supporting angiogenesis in wound healing, promoting vascularization and has also demonstrated neuro-protective capabilities in both central and peripheral nervous system. While the delivery of pro-regenerative recombinant growth factors has shown promise, gene delivery offers greater stability, reduced off-target side effects, diminished cytotoxicity, and lower production costs. In this context, the overarching goal of this study was to develop a VEGF-activated scaffold with the potential to provide a multifaceted response that enhances both angiogenesis and nerve repair in wound healing through the localized delivery of plasmid encoding VEGF (pVEGF) encapsulated within the GET peptide system. Initially, delivery of pVEGF/GET nanoparticles to dermal fibroblasts led to higher VEGF protein expression without a compromise in cell viability. Transfection of dermal fibroblasts and endothelial cells on the VEGF-activated scaffolds resulted in enhanced VEGF expression, improved endothelial cell migration and organization into vascular-like structures. Finally, the VEGF-activated scaffolds consistently displayed enhanced neurogenic ability through improved neurite outgrowth from neural cells in in vitro and ex vivo models. Taken together, the VEGF-activated scaffold demonstrates multifaceted outcomes through the induction of pro-angiogenic and neurogenic responses from dermal, vascular and neural cells, illustrating the potential of this platform for the healing of chronic wounds.

The field of three-dimensional (3D) bio/printing, known as additive manufacturing (AM), heavily relies on bioinks possessing suitable mechanical properties and compatibility with living cells. Among the array of potential hydrogel precursor materials, chitosan (CS) has garnered significant attention due to its remarkable physicochemical and biological attributes. These attributes include biodegradability, nontoxicity, antimicrobial properties, wound healing promotion, and immune system activation, making CS a highly appealing hydrogel-based bioink candidate. This review explores the transformative potential of CS-based bioink for enhancing dermal wound healing therapies. We highlight CS's unique qualities that make it an optimal choice for bioink development. Advancements in 3D bio/printing technology for tissue engineering (TE) are discussed, followed by an examination of strategies for CS-based bioink formulation and their impacts on wound healing. To address the progress in translating advanced wound healing from lab to clinic, we highlight the current and ongoing research in CS-based bioink for 3D bio/printing in skin wound healing applications. Finally, we explore current evidence, commercialization prospects, emerging innovations like 4D printing, and the challenges and future directions in this promising field.

The high incidence and prevalence of diabetic foot ulcers (DFUs) present a substantial clinical and economic burden, necessitating innovative therapeutic approaches. Fibroblasts, characterized by their intrinsic cellular plasticity and multifunctional capabilities, play key roles in the pathophysiological processes underlying DFUs. Hyperglycemic conditions lead to a cascade of biochemical alterations that culminate in the dysregulation of fibroblast phenotype and function, which is the primary cause of impaired wound healing in DFUs. Biomaterials, particularly those engineered at the nanoscale, hold significant promise for enhancing DFU treatment outcomes. Electrospun nanofiber scaffolds, with their structural and compositional similarities to the natural extracellular matrix, serve as an effective substrate for fibroblast adhesion, proliferation, and migration. This review comprehensively summarizes the biological behavior of fibroblasts in DFUs and the mechanism mediating wound healing. At the same time, the mechanism of biological materials, especially electrospun nanofiber scaffolds, to improve the therapeutic effect by regulating the activity of fibroblasts was also discussed. By highlighting the latest advancements and clinical applications, we aim to provide a clear perspective on the future direction of DFU treatment strategies centered on fibroblast-targeted therapies.

Chronic wounds, defined by their prolonged healing process, significantly impair patients' quality of life and impose a hefty financial burden on healthcare systems worldwide. Sex- and gender-specific mechanisms regulate inflammation and infection, angiogenesis, matrix synthesis and cell recruitment. All of these processes contribute to cutaneous wound healing but remain largely understudied. This review aims to spotlight the innovative realm of bioengineering and nanomedicine, which is at the helm of revolutionizing complex chronic wound care. It underscores the significance of integrating patient sex into the development and (pre)clinical testing of these avant-garde treatment modalities, in order to enhance healing prospects for all patients regardless of sex. Moreover, we explore the representation of male and female patients in clinical trials of bioengineered and nanomedicine products. Finally, we examine the primary reasons for the historical neglect in translating sex-specific wound healing research into clinical practice and propose strategic solutions. By tackling these issues, the article advocates advanced treatment frameworks that could significantly improve healing outcomes for individuals of all sexes, thereby optimizing both efficacy and inclusivity in chronic wound management.

Impaired wound healing is a significant concern for humans in space, where the unique microgravity environment poses challenges to the natural healing processes of the body. Similar to chronic wounds on earth, such as diabetic foot ulcers and venous leg ulcers, wounds inflicted in space exhibit delayed or impaired healing responses. These wounds share common features, including dysregulated cellular signaling, altered cytokine profiles, and impaired tissue regeneration. Little is known about the mechanisms underlying wound healing under microgravity. In this review, we focused on exploring the parallels between wound healing in space and chronic wounds on earth as a fundamental approach for developing effective countermeasures to promote healing and mitigate associated health risks during long-space missions.

Our objective was to evaluate risk factors for re-infection in patients after treatment for diabetic foot osteomyelitis (OM). We used pooled patient level data from two RTCs that evaluated patients with diabetic foot infections. We evaluated 171 patients with OM. OM was confirmed with bone culture or histopathology. Data from the 12-month follow-up were used to determine clinical outcomes. Re-infection occurred in 47 (27.5%) patients. Risk factors for re-infection were Toe Brachial Index <0.40 (25.7% vs. 9.8%, p = 0.02), skin perfusion pressure <40 mmHg (6.3% vs. 5.9%, p = 0.04), wound healing (55.3% vs. 75.0%, p = 0.01), time to heal (156.0, 69.5-365 vs. 91.5, 38.8-365, p = 0.001), and history of MI (14.9% vs. 3.2%, p = 0.005). During 12-month follow-up, patients with re-infections were 198.8 times more likely to require a foot related hospitalisation (81.8% vs. 0.0%, p = 0.001), 10.4 times more likely have an all-cause hospitalisation (70.2% vs. 18.5%, p = 0.001) and 9.4 times more likely to need an amputation (36.2% vs. 5.6%, p = 0.001). Patients with re-infection had a significantly longer median length of hospitalisation (20.0, 13.5-34.5 vs. 14.0, 10.0-22.0, p = 0.003) and median length of antibiotic duration (55.0, 35.0-87.0 vs. 46.0, 22.8-68.0, p = 0.03). Patients with re-infection are less likely to heal and have more foot-related hospitalizations and amputations.

This meta-analysis aimed to systematically assess and synthesise healing rates within a 12- to 24-week treatment period among patients with diabetic foot ulcers receiving standard-of-care interventions in randomised controlled trials. This meta-analysis included 32 randomised controlled trials conducted between 1996 and 2023, with sample sizes ranging from 9 to 169 patients. A random-effects model was applied to estimate pooled healing and infection rates. Heterogeneity was quantified using the I2 statistic, and publication bias was assessed using Egger's test. The results revealed a pooled healing rate of 33.15% with a 95% confidence interval (CI) of 31.18%-35.11% and an average healing time of approximately 50.14 days (standard deviation: 31.10 days). The infection proportion was determined to be 17.4% (95% CI: 12.2%-22.5%). Subgroup analysis indicated marginally higher healing rates in the 'Saline Gauze' group compared to the 'Alginate' group, although the latter exhibited a reduced infection proportion. Sensitivity analysis affirmed the robustness of these findings whereas Egger's test suggested the presence of potential publication bias concerning the healing outcomes. The standard-of-care interventions for diabetic foot ulcers demonstrate limited effectiveness, with only about one-third of patients achieving wound closure. The significant heterogeneity and publication bias observed necessitate a cautious interpretation of these results. The findings highlight the need for advanced wound care strategies and personalised treatment plans to improve outcomes in diabetic foot ulcers management. Future research should focus on conducting high-quality, well-reported randomised controlled trials to better understand effective treatments for DFUs.

To assess the effects of several adjuvant therapies (AT) commonly used in the treatment of diabetic foot ulcers (DFU). The present meta-analysis was designed to support the development of the Italian Guidelines for the Treatment of Diabetic Foot Syndrome.

A Medline and Embase search were performed up to May 20th, 2024 collecting all RCTs including diabetic patients or reporting subgroup analyses on diabetic patients with DFU comparing AT with placebo/standard of care (SoC), with a duration of at least 12 weeks. Prespecified endpoints were: ulcer healing (principal), time-to-healing, major and minor amputation, serious adverse events (SAE), and all-cause mortality. AT assessed were: growth factors (GF), Platelet-rich plasma and fibrin (PRP/F), skin substitutes (SS), negative pressure wound therapy (NPWT), and hyperbaric oxygen therapy (HBOT). Mantel-Haenzel Odds ratios and 95% confidence intervals (MH-OR, 95% CIs) were either calculated or extracted directly from the publications. Weighted mean differences and 95% CIs were calculated for continuous variables.

Fifty-one studies fulfilled all inclusion criteria (3, 5, 27, 8, and 8 with GF, PRP/F, SS, NPWT, and HBOT, respectively). Participants treated with any of the explored AT had a significantly higher ulcer healing rate (MH-OR ranging from 2.17 to 4.18) and shorter time-to-healing in comparison with SoC/placebo. Only PRP/F and HBOT showed a significantly lower risk of major amputation (MH-OR: 0.32(0.11;0,93; p = 0.04 and 0.28(0.10;0,79; p = 0.02, respectively), despite a higher risk of SAE. No other significant effects on the above-reported prespecified endpoints were observed. For the primary endpoint, the quality of evidence was rated as "high" for all the AT, except for NPWT ("moderate").

In conclusion, AT can actively promote wound healing and shorten time-to-healing in patients with DFU. HBOT and PRP/F also showed a reduction of the risk of major amputation, despite a higher rate of SAE.

To compare the incidence of infection, wound closure and time to wound closure in patients treated with cryopreserved (CPUT) and lyopreserved umbilical tissue (LPUT) in complex diabetic surgical wounds. This single-blinded 12-week randomized clinical trial compared cryopreserved and lyopreserved amniotic cord tissue to treat complex diabetic foot wounds. LPUT or CRAT was applied at baseline and again after four weeks. We enrolled subjects with UT2A-D and 3A-D wounds (depth to tendon, muscle, or bone with infection and/or PAD) and excluded subjects with ABI < 0.5 or TBI < 0.3, untreated osteomyelitis, and autoimmune diseases. We used a 3-D camera to evaluate wound area and volume. The mean baseline wound areas were 12.9 ± 10.7 cm2 for CPUT and 11.7 ± 7.0 cm2 for LPUT. The mean baseline wound volume was 7.5 ± 8.1 for CPUT and 9.2 ± 10.2 cm3 for LPUT. There was no difference between CPUT and LPUT in wound closure (36.8% vs 19.0%, P = .21) or infection (10.5% vs 4.8%, P = .60). There was no difference in mean wound area reduction between CPUT and LPUT (75.9 ± 32.3% vs 65.5 ± 38.4%, P = .41), nor in mean volume reduction (85.0 ± 30.8% vs 79.9 ± 31.9%, P = .61). In addition, there was no difference in wound closure trajectories for changes in area (P = .75) or volume (P = .43). Cryopreserved and lyopreserved amniotic tissue provided similar results in patients with complex diabetic foot wounds.

Hemorrhage affects human health, and severe bleeding remains a leading contributor to trauma-related mortality. The speed and effectiveness of the application of hemostatic materials are critical. Conventional hemostatic dressings such as bandages and gauze are gradually being replaced by new types of hemostatic dressings due to their poor hemostatic and antibacterial properties. Chitosan, a biopolymer, is biodegradable and nontoxic and possesses hemostatic and antibacterial properties. Chitosan induces hemostasis through direct contact with red corpuscles and platelets, independent of the coagulation pathways of the host, rendering it an optimal hemostatic dressing. It is widely used in wound care, particularly to stop bleeding, promote wound healing, and provide antimicrobial properties. This article reviews the recent research and development of chitosan-based hemostatic dressings, focusing on trauma hemostasis, burn hemostasis, diabetic skin ulcer hemostasis and other aspects. It also emphasizes the significance of chitosan dressings in wound hemostasis and healing, identifies their research opportunities in hemostasis and wound healing, and explores new research directions.

Significance: This Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant review focuses on the efficacy of cellular, acellular, and matrix-like products (CAMPs) in the management of diabetic foot ulcers (DFUs) based on published randomized controlled trials (RCTs). Recent Advances: Although CAMPs have been incorporated into the clinical algorithm for chronic wounds, evidence is lacking to comparatively evaluate the efficacy of these products. Critical Issues: Level 1 RCT studies are the gold standard to evaluate the efficacy of different treatment approaches; however, due to differences in surgical techniques, patient demographics, and compliance, standard-of-care (SOC) outcomes in the wound care space can vary significantly between different RCTs, making it difficult to compare them against each other. Future Directions: To mitigate variability between different RCTs, wound closure outcomes can be reported as risk ratios (RRs). This review of all the currently published RCTs (with a similar trial design) in patients with DFU and RRs confirms that CAMPs adjunct to SOC result in statistically superior wound closure outcomes in DFUs, when compared with SOC alone, with a RR of 1.72 [1.56, 1.90], p < 0.00001. Enough evidence is still lacking to determine a statistical difference between broad categories of cellular/acellular and amniotic/nonamniotic CAMPs, and hence, decision makers should consider published head-to-head comparative studies, real-world evidence, and cost-effectiveness evidence between individual CAMPs to decide on which to use in practice.

Diabetic wounds are usually entangled in a disorganized and self-perpetuating microenvironment and accompanied by a prolonged delay in tissue repair. Sustained and coordinated microenvironment regulation and tissue regeneration are key to the healing process of diabetic wounds, yet they continue to pose a formidable challenge. Here we report a rational double-layered dressing design based on chitosan and a degradable conjugated polymer polydiacetylene, poly(deca-4,6-diynedioic acid) (PDDA), that can meet this intricate requirement. With an alternating ene-yne backbone, PDDA degrades when reacting with various types of reactive oxygen species (ROS), and more importantly, generates proliferative succinic acid as a major degradant. Inheriting from PDDA, the developed PDDA-chitosan double layer dressing (PCD) can eliminate ROS in the microenvironment of diabetic wounds, alleviate inflammation, and downregulate gene expression of innate immune receptors. PCD degradation also triggers simultaneous release of succinic acid in a sustainable manner, enabling long-term promotion on tissue regeneration. We have validated the biocompatibility and excellent performance of PCD in expediting the wound healing on both diabetic mouse and porcine models, which underscores the significant translational potential of this microenvironment-modulating, growth-promoting wound dressing in diabetic wounds care.

Objective: New treatment options are emerging for chronic wounds, which represent a growing problem because of population ageing and increasing burden of chronic disease. While promising, the existing evidence for advanced modalities is commonly derived from small and/or poorly controlled studies and clear criteria for selecting patients, who are likely to benefit from these expensive options are lacking. In this study, we develop and validate a machine learning model to predict if a chronic wound, independent of etiology, is expected to heal within 12 weeks to identify cases in potential need of advanced treatment options. Approach: Retrospective analysis of electronic health record data from 2014 to 2018 covering 532 wound care clinics in the United States and 261,398 patients with 620,356 unique wounds. Prediction of 12-week healing trajectories with a machine learning model. Results: The best-performing model in a training dataset of a randomly drawn 75% subset of wounds contained variables for patient demographics, comorbidities, wound characteristics at initial presentation, and changes in wound dimensions over time, with the latter group being the most influential predictors. The final machine learning model had a high predictive accuracy with area under the receiver operating characteristic curves of 0.9 and 0.92 after 4 and 5 weeks of treatment, respectively. Innovation: A machine learning model can identify chronic wounds at risk of not healing by week 12 with high accuracy in the early weeks of treatment. Conclusions: If embedded in real-world care, the generated information could be able to guide effective and efficient treatment decisions.

Diabetic foot ulcer (DFU) is a common and highly morbid complication of diabetes with high unmet medical needs. AUP1602-C, a topical four-in-one gene therapy medicinal product (GTMP), consisting of a Lactococcus cremoris strain that produces fibroblast growth factor-2, interleukin-4, and colony-stimulating factor-1, is a promising novel treatment for DFU.

The aim of this first-in-human study was to investigate whether AUP1602-C is safe and effective in improving wound healing and quality of life (QoL) in patients with non-healing DFU (nhDFU), and to determine the recommended phase II dose.

Phase I, single-arm, open-label, uncontrolled, dose escalation study.

The study consisted of four cohorts of patients receiving AUP1602-C as a single dose of 2.5 × 105 colony-forming units (CFU)/cm2 ulcer size or as repeated doses between 2.5 × 106 and 2.5 × 108 CFU/cm2 administered 3 times per week for 6 weeks. Within each cohort, a 3 + 3 scheme for monitoring safety, tolerability, and efficacy was applied.

In total, 16 patients aged 53-80 years were included, 3 each in the safety and low dose, 4 in the medium dose, and 6 in the high-dose cohort. AUP1602-C demonstrated a favorable safety profile with almost 100% dosing compliance. The most frequently reported side effect related to treatment was skin maceration. No serious adverse reactions, systemic toxicity, deaths, or side effects suggestive of immunogenicity, hypersensitivity, allergic reaction, or dose-limiting toxicities related to treatment were reported. No biodistribution events were observed and shedding-related events were rare and did neither show accumulation nor dose dependency. The recommended phase II dose of 2.5 × 108 CFU/cm2 demonstrated complete healing in 83% of patients without recurrence of ulcers during follow-up.

AUP1602-C was safe and well tolerated and demonstrated dose-dependent efficacy in patients with nhDFU. Data supports further clinical development of AUP1602-C.

The study was registered in ClinicalTrials.gov (NCT04281992) and ClinicalTrialsRegister.eu (2018-003415-22).

Chronic wounds present a significant healthcare challenge marked by complexities such as persistent bleeding, inhibited cell proliferation, dysregulated inflammation, vulnerability to infection, and compromised tissue remodeling. Conventional wound dressings often prove inadequate in addressing the intricate requirements of chronic wound healing, leading to slow healing and heightened susceptibility to infections in patients with prolonged medical conditions. Bacterial biofilms in chronic wounds pose an additional challenge due to drug resistance. Advanced wound dressings have emerged as promising tools in expediting the healing process. Among these, pH-responsive polysaccharide-based hydrogels exhibit immense prospect by adapting their functions to dynamic wound conditions. Despite their potential, the current literature lacks a thorough review of these wound dressings. This review bridges this gap by meticulously examining factors related to chronic wounds, current strategies for healing, and the mechanisms and potential applications of pH-responsive hydrogel wound dressings as an emerging therapeutic solution. Special focus is given to their remarkable antibacterial properties and significant self-healing abilities. It further explores the pH-monitoring functions of these dressings, elucidating the associated pH indicators. This synthesis of knowledge aims to guide future research and development in the field of pH-responsive wound dressings, providing valuable insights into their potential applications in wound care.

To investigate risk factors for re-infection and compare the outcomes in people with diabetic foot infections. A retrospective chart review was conducted, and 294 hospitalised patients with moderate to severe diabetic foot infections (DFIs) were analysed for this study. The diagnosis and classification of the severity of infection was based on the International Working Group on the Diabetic Foot (IWGDF) infection guidelines. Skin and soft tissue infections were diagnosed based on clinical observations as per IWGDF classification in addition to ruling out any suspected osteomyelitis (OM) through negative bone culture, MRI or WBC SPECT CT. OM was confirmed by bone culture or histopathology. Clinical outcomes were based on a 12-month follow-up period. All dichotomous outcomes were compared using χ2 with an alpha of 0.05. The result of this study shows a 48% rate of re-infection in people admitted to our hospital with moderate and severe diabetic foot infections (DFI). Patients with osteomyelitis present during the index admission were 2.1 times more likely to experience a re-infection than patients with soft tissue infection (56.7% vs. 38.0% respectively). In the univariate analysis, risk factors for re-infection included osteomyelitis, non-healing wounds, prolonged wound healing, antidepressants and leukocytosis. In the regression analysis, the only risk factor for re-infection was wounds that were not healed >90 days (HR =2.0, CI: 1.5, 2.7, p = 0.001). Re-infection is very common in patients with moderate and severe diabetic foot infections. Risk factors include osteomyelitis, non-healing wound, prolonged wound healing, antidepressants and leukocytosis.

The treatment of diabetic foot ulcers remains a significant challenge, as their morbidity is increasing while current therapies are expensive and often ineffective. The dried mucus from the snail Achatina fulica promotes diabetic wound healing. Herein, to develop a more controllable and stable wound dressing for diabetic wound treatment, the AFG/StarPEG hydrogel mimicking snail mucus was prepared by covalently coupling of sulfated glycosaminoglycan from A. fulica (AFG) with star-shaped polyethylene glycol (StarPEG) amine. The AFG/StarPEG hydrogel reduced excessive inflammation in wound tissues by decreasing pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) and increasing anti-inflammatory cytokines (IL-4 and IL-10). Moreover, it promoted the polarization of macrophages to M2 anti-inflammatory type in diabetic wound. By improving transition of diabetic chronic wound from inflammatory phase to proliferative phase, it promoted angiogenesis, collagen deposition and re-epithelialization, and thus tissue regeneration for wound healing. This work provides a convenient and effective dressing for treating chronic diabetic wound.

Background/Objectives: The objective of this study was to assess the efficacy of a cell-containing wound dressing based on fibroblasts in hydroxyethylcellulose (HEC) gel for the local treatment of deep partial-thickness and/or full-thickness skin burns in an animal model. Methods: The rats (male Wistar, n = 100) were subjected to a full-thickness thermal burn (16 cm2). Radical necrectomy was performed one day after the burn. Three days later, the rats were randomly assigned to one of four groups: group 1 (no treatment), group 2 (chloramphenicol and methyluracil ointment, a routine clinical treatment), group 3 (a gel without cells, mock treatment), and group 4 (a dermal fibroblast-impregnated HEC gel). The treatment lasted for five days. The wound-healing process was evaluated by planimetric, cytologic, histologic, and immunohistochemical methods. Results: The differences in the rate of wound healing and the characteristics of wound cytology were identified. In the group 4, a regenerative type of cytogram was revealed, characterized by a significantly increased number of fibroblastic cells in comparison to samples from non-treated and mock-treated animals. Biopsy samples of burn wounds from animals in the group 4l demonstrated the presence of mature granulation tissue and a large number of microvessels. The repair process was stimulated, as evidenced by the increased thickness of newly formed granulation tissue and epidermis in the wound zone, elevated cellularity, and enhanced re-epithelialization activity. The number of Ki-67-positive proliferating cells was significantly higher in group 4 than in the control groups). A small number of non-proliferating donor fibroblasts was observed in the wound area 3 days after the end of treatment. Conclusions: The cell product is an effective agent for promoting wound healing during the regenerative phase. The experiments demonstrated that a gel populated by dermal fibroblasts can stimulate reparative regeneration processes in deep partial- and full-thickness burn wounds.

Objectives: To identify proteins that are prognostic for diabetic foot ulcer (DFU) healing and may serve as biomarkers for its management, serum samples were analyzed from diabetic mellitus (DM) patients. Approach: The serum specimens that were evaluated in this study were obtained from DM patients with DFU who participated in a prospective study and were seen biweekly until they healed their ulcer or the exit visit at 12 weeks. The group was divided into Healers (who healed their DFU during the study) and Non-Healers. Results: Interleukin (IL)-10, IL-4, IL-5, IL-6, and IL-13 and interferon-gamma were higher in the Healers while Fractalkine, IL-8, and TNFα were higher in the Non-Healers. The trajectory of IL-10 levels remained stable over time within and across groups, resulting in a strong prognostic ability for the prospective DFU healing course. Classification and Regression Tree analysis created an 11-node decision tree with healing status as the categorical response. Innovation: Consecutive measurements of proteins associated with wound healing can identify biomarkers that can predict DFU healing over a 12-week period. IL-10 was the strongest candidate for prediction. Conclusion: Measurement of serum proteins can serve as a successful strategy in guiding clinical management of DFU. The data also indicate likely superior performance of building a multiprotein biomarker score instead of relying on single biomarkers.

Diabetic foot ulcers often become infected, leading to treatment complications and increased risk of loss of limb. Therapeutics to manage infection and simultaneously promote healing are needed. Here we report on the development of a Janus liposozyme that treats infections and promotes wound closure and re-epithelialization. The Janus liposozyme consists of liposome-like selenoenzymes for reactive oxygen species (ROS) scavenging to restore tissue redox and immune homeostasis. The liposozymes are used to encapsulate photosensitizers for photodynamic therapy of infections. We demonstrate application in methicillin-resistant Staphylococcus aureus-infected diabetic wounds showing high ROS levels for antibacterial function from the photosensitizer and nanozyme ROS scavenging from the liposozyme to restore redox and immune homeostasis. We demonstrate that the liposozyme can directly regulate macrophage polarization and induce a pro-regenerative response. By employing single-cell RNA sequencing, T cell-deficient Rag1-/- mice and skin-infiltrated immune cell analysis, we further reveal that IL-17-producing γδ T cells are critical for mediating M1/M2 macrophage transition. Manipulating the local immune homeostasis using the liposozyme is shown to be effective for skin wound repair and tissue regeneration in mice and mini pigs.

Wound healing is a highly complex natural process, and its failure results in chronic wounds. The causes of delayed wound healing include patient-related and local wound factors. The main local impediments to delayed healing are the presence of nonviable tissue, excessive inflammation, infection, and moisture imbalance. For wounds that can be healed with adequate blood supply, a stepwise approach to identify and treat these barriers is termed wound bed preparation. Currently, a combination of patient-related and local factors, including wound debridement, specialty dressings, and advanced technologies, is available and successfully used to facilitate the healing process.

Diabetic foot ulcer (DFU) is a foremost cause of amputation in diabetic patients. Consequences of DFU include infections, decline in limb function, hospitalization, amputation, and in severe cases, death. Immune cells including macrophages, regulatory T cells, fibroblasts and other damage repair cells work in sync for effective healing and in establishment of a healthy skin barrier post-injury. Immune dysregulation during the healing of wounds can result in wound chronicity. Hyperglycemic conditions in diabetic patients influence the pathophysiology of wounds by disrupting the immune system as well as promoting neuropathy and ischemic conditions, making them difficult to heal. Chronic wound microenvironment is characterized by increased expression of matrix metalloproteinases, reactive oxygen species as well as pro-inflammatory cytokines, resulting in persistent inflammation and delayed healing. Novel treatment modalities including growth factor therapies, nano formulations, microRNA based treatments and skin grafting approaches have significantly augmented treatment efficiency, demonstrating creditable efficacy in clinical practices. Advancements in local treatments as well as invasive methodologies, for instance formulated wound dressings, stem cell applications and immunomodulatory therapies have been successful in targeting the complex pathophysiology of chronic wounds. This review focuses on elucidating the intricacies of emerging physical and non-physical therapeutic interventions, delving into the realm of advanced wound care and comprehensively summarizing efficacy of evidence-based therapies for DFU currently available.

Tissue engineering is a multidisciplinary field that merges engineering, material science, and medical biology in order to develop biological alternatives for repairing, replacing, maintaining, or boosting the functionality of tissues and organs. The ultimate goal of tissue engineering is to create biological alternatives for repairing, replacing, maintaining, or enhancing the functionality of tissues and organs. However, the current landscape of tissue engineering techniques presents several challenges, including a lack of suitable biomaterials, inadequate cell proliferation, limited methodologies for replicating desired physiological structures, and the unstable and insufficient production of growth factors, which are essential for facilitating cell communication and the appropriate cellular responses. Despite these challenges, there has been significant progress made in tissue engineering techniques in recent years. Nanoparticles hold a major role within the realm of nanotechnology due to their unique qualities that change with size. These particles, which provide potential solutions to the issues that are met in tissue engineering, have helped propel nanotechnology to its current state of prominence. Despite substantial breakthroughs in the utilization of nanoparticles over the past two decades, the full range of their potential in addressing the difficulties within tissue engineering remains largely untapped. This is due to the fact that these advancements have occurred in relatively isolated pockets. In the realm of tissue engineering, the purpose of this research is to conduct an in-depth investigation of the several ways in which various types of nanoparticles might be put to use. In addition to this, it sheds light on the challenges that need to be conquered in order to unlock the maximum potential of nanotechnology in this area.

Diabetic foot ulcers (DFUs) continue to challenge wound care practitioners. This prospective, multicentre, randomised controlled trial (RCT) evaluated the effectiveness of a dehydrated Amnion Chorion Membrane (dACM) (Organogenesis Inc., US) versus standard of care (SoC) alone in complex DFUs in a challenging patient population.

Subjects with a DFU extending into dermis, subcutaneous tissue, tendon, capsule, bone or joint were enrolled in a 12-week trial. They were allocated equally to two treatment groups: dACM (plus SoC); or SoC alone. The primary endpoint was frequency of wound closure determined by a Cox analysis that adjusted for duration and wound area. Kaplan-Meier analysis was used to determine median time to complete wound closure (CWC).

The cohort comprised 218 patients, and these were split equally between the two treatment groups with 109 patients in each. A Cox analysis showed that the estimated frequency of wound closure for the dACM plus SoC group was statistically superior to the SoC alone group at week 4 (12% versus 8%), week 6 (22% versus 11%), week 8 (31% versus 21%), week 10 (42% versus 27%) and week 12 (50% versus 35%), respectively (p=0.04). The computed hazard ratio (1.48 (confidence interval: 0.95, 2.29) showed a 48% greater probability of wound closure in favour of the dACM group. Median time to wound closure for dACM-treated ulcers was 84 days compared to 'not achieved' in the SoC-treated group (i.e., ≥50% of SoC-treated DFUs failed to heal by week 12; p=0.04).

In an adequately powered DFU RCT, dACM increased the frequency, decreased the median time, and improved the probability of CWC when compared with SoC alone. dACM demonstrated beneficial effects in DFUs in a complex patient population.

This study was funded by Organogenesis Inc., US. JC serves as a consultant and speaker for Organogenesis. RDD serves as a speaker for Organogenesis. OMA and MLS serve as consultants for Organogenesis. The authors have no other conflicts of interest to declare.

Diabetic wound healing is uniquely challenging to manage due to chronic inflammation and heightened microbial growth from elevated interstitial glucose. Carbon monoxide (CO), widely acknowledged as a toxic gas, is also known to provide unique therapeutic immune modulating effects. To facilitate delivery of CO, we have designed hyaluronic acid-based CO-gas-entrapping materials (CO-GEMs) for topical and prolonged gas delivery to the wound bed. We demonstrate that CO-GEMs promote the healing response in murine diabetic wound models (full-thickness wounds and pressure ulcers) compared to N2-GEMs and untreated controls.

Chronic wounds caused by diabetes or lower-extremity artery disease are intractable because the wound healing mechanism becomes ineffective due to the poor environment of the wound bed. Biosheets obtained using in-body tissue architecture (iBTA) are collagen-based membranous tissue created within the body and which autologously contain various growth factors and somatic stem cells including SSEA4-posituve cells. When applied to a wound, granulation formation can be promoted and epithelialization may even be achieved. Herein, we report our clinical treatment experience with seven cases of intractable diabetic foot ulcers.

Seven patients, from 46 to 93 years old, had large foot ulcers including in the heel area, which were failing to heal with standard wound treatment.

Two or four Biosheet-forming molds were embedded subcutaneously in the chest or abdomen, and after 3 to 6 weeks, the molds were removed. Biosheets that formed inside the mold were obtained and applied directly to the wound surface.

In all cases, there were no problems with the mold's embedding and removal procedures, and Biosheets were formed without any infection or inflammation during the embedding period. The Biosheets were simply applied to the wounds, and in all cases they adhered within one week, did not fall off, and became integrated with the wound surface. Complete wound closure was achieved within 8 weeks in two cases and within 5 months in two cases. One patient was lost due to infective endocarditis from septic colitis. One case required lower leg amputation due to wound recurrence, and one case achieved wound reduction and wound healing in approximately 9 months.

Biosheets obtained via iBTA promoted wound healing and were extremely useful for intractable diabetic foot ulcers involving the heel area.

Long-term diabetes often leads to chronic wounds refractory to treatment. Cell-based therapies are actively investigated to enhance cutaneous healing. Various cell types are available to produce biological dressings, such as adipose-derived stem/stromal cells (ASCs), an attractive cell source considering their abundancy, accessibility, and therapeutic secretome. In this study, we produced human ASC-based dressings under a serum-free culture system using the self-assembly approach of tissue engineering. The dressings were applied every 4 days to full-thickness 8-mm splinted skin wounds created on the back of polygenic diabetic NONcNZO10/LtJ mice and streptozotocin-induced diabetic K14-H2B-GFP mice. Global wound closure kinetics evaluated macroscopically showed accelerated wound closure in both murine models, especially for NONcNZO10/LtJ; the treated group reaching 98.7% ± 2.3% global closure compared to 76.4% ± 11.8% for the untreated group on day 20 (p=0.0002). Histological analyses revealed that treated wounds exhibited healed skin of better quality with a well-differentiated epidermis and a more organized, homogeneous, and 1.6-fold thicker granulation tissue. Neovascularization, assessed by CD31 labeling, was 2.5-fold higher for the NONcNZO10/LtJ treated wounds. We thus describe the beneficial impact on wound healing of biologically active ASC-based dressings produced under an entirely serum-free production system facilitating clinical translation.

To evaluate the efficacy of treatment of hard-to-heal wounds of patients with ischaemia of the lower extremities, and compare an omega-3 wound matrix product (Kerecis, Iceland) with a standard dressing.

A single-centre, prospective, randomised, controlled clinical trial of patients with hard-to-heal wounds following three weeks of standard care was undertaken. The ischaemic condition of the wound was confirmed as a decreased transcutaneous oxygen pressure (TcPO2) of <40mmHg. After randomising patients into either a case (omega-3 dressing) or a control group (standard dressing), the weekly decrease in wound area over 12 weeks and the number of patients that achieved complete wound closure were compared between the two groups. Patients with a TcPO2 of ≤32mmHg were taken for further analysis of their wound in a severe ischaemic context.

A total of 28 patients were assigned to the case group and 22 patients to the control group. Over the course of 12 weeks, the wound area decreased more rapidly in the case group than the control group. Complete wound healing occurred in 82% of patients in the case group and 45% in the control group. Even in patients with a severe ischaemic wound with a TcPO2 value of <32 mmHg, wound area decreased more rapidly in the case group than the control group. The proportions of re-epithelialised area in the case and control groups were 80.24% and 57.44%, respectively.

Considering the more rapid decrease in wound area and complete healing ratio in the case group, application of a fish skin-derived matrix for treating lower-extremity hard-to-heal wounds, especially with impaired vascularity, would appear to be a good treatment option.

Wound healing is an intricate process involving coordinated interactions among inflammatory cells, skin fibroblasts, keratinocytes, and endothelial cells. Successful tissue repair hinges on controlled inflammation, angiogenesis, and remodeling facilitated by the exchange of cytokines and growth factors. Comorbid conditions can disrupt this process, leading to significant morbidity and mortality. Stem cell therapy has emerged as a promising strategy for enhancing wound healing, utilizing cells from diverse sources such as endothelial progenitor cells, bone marrow, adipose tissue, dermal, and inducible pluripotent stem cells. In this systematic review, we comprehensively investigated stem cell therapies in chronic wounds, summarizing the clinical, translational, and primary literature. A systematic search across PubMed, Embase, Web of Science, Google Scholar, and Cochrane Library yielded 22,454 articles, reduced to 44 studies after rigorous screening. Notably, adipose tissue-derived mesenchymal stem cells (AD-MSCs) emerged as an optimal choice due to their abundant supply, easy isolation, ex vivo proliferative capacities, and pro-angiogenic factor secretion. AD-MSCs have shown efficacy in various conditions, including peripheral arterial disease, diabetic wounds, hypertensive ulcers, bullous diabeticorum, venous ulcers, and post-Mohs micrographic surgery wounds. Delivery methods varied, encompassing topical application, scaffold incorporation, combination with plasma-rich proteins, and atelocollagen administration. Integration with local wound care practices resulted in reduced pain, shorter healing times, and improved cosmesis. Stem cell transplantation represents a potential therapeutic avenue, as transplanted stem cells not only differentiate into diverse skin cell types but also release essential cytokines and growth factors, fostering increased angiogenesis. This approach holds promise for intractable wounds, particularly chronic lower-leg wounds, and as a post-Mohs micrographic surgery intervention for healing defects through secondary intention. The potential reduction in healthcare costs and enhancement of patient quality of life further underscore the attractiveness of stem cell applications in wound care. This systematic review explores the clinical utilization of stem cells and stem cell products, providing valuable insights into their role as ancillary methods in treating chronic wounds.

It is critical that interventions used to enhance the healing of chronic foot ulcers in diabetes are backed by high-quality evidence and cost-effectiveness. In previous years, the systematic review accompanying guidelines published by the International Working Group of the Diabetic Foot performed 4-yearly updates of previous searches, including trials of prospective, cross-sectional and case-control design.

Due to a need to re-evaluate older studies against newer standards of reporting and assessment of risk of bias, we performed a whole new search from conception, but limiting studies to randomised control trials only.

For this systematic review, we searched PubMed, Scopus and Web of Science databases for published studies on randomised control trials of interventions to enhance healing of diabetes-related foot ulcers. We only included trials comparing interventions to standard of care. Two independent reviewers selected articles for inclusion and assessed relevant outcomes as well as methodological quality.

The literature search identified 22,250 articles, of which 262 were selected for full text review across 10 categories of interventions. Overall, the certainty of evidence for a majority of wound healing interventions was low or very low, with moderate evidence existing for two interventions (sucrose-octasulfate and leucocyte, platelet and fibrin patch) and low quality evidence for a further four (hyperbaric oxygen, topical oxygen, placental derived products and negative pressure wound therapy). The majority of interventions had insufficient evidence.

Overall, the evidence to support any other intervention to enhance wound healing is lacking and further high-quality randomised control trials are encouraged.

This study considers the cost-effectiveness of commonly used cellular, acellular, and matrix‑like products (CAMPs) of human origin also known as human cell and tissue products (HCT/Ps) in the management of diabetic foot ulcers.

We developed a 1-year economic model assessing six CAMPs [cryopreserved placental membrane with viable cells (vCPM), bioengineered bilayered living cellular construct (BLCC), human fibroblast dermal substitute (hFDS), dehydrated human amnion chorion membrane (dHACM), hypothermically stored amniotic membrane (HSAM) and human amnion membrane allograft (HAMA) which had randomized controlled trial evidence compared with standard of care (SoC). CAMPs were compared indirectly and ranked in order of cost-effectiveness using SoC as the baseline, from a CMS/Medicare's perspective.

The mean cost, healed wounds (hw) and QALYs per patient for vCPM is $10,907 (0.914 hw, 0.783 QALYs), for HAMA $11,470 (0.903 hw, 0.780 QALYs), for dHACM $15,862 (0.828 hw, 0.764 QALYs), for BLCC $18,430 (0.816 hw, 0.763 QALYs), for hFDS $19,498 (0.775 hw, 0.757 QALYs), for SoC $19,862 (0.601 hw, 0.732 QALYs) and $24, 214 (0.829, 0.763 QALYs) for HSAM respectively. Over 1 year, vCPM results in cheaper costs overall and better clinical outcomes compared to other CAMPs. Following probabilistic sensitivity analysis, vCPM has a 60%, HAMA 40% probability of being cost-effective then dHACM, hFDS, BLCC, and lastly HSAM using a $100,000/healed wound or QALY threshold.

All CAMPs were shown to be cost-effective when compared to SoC in managing DFUs. However, vCPM appears to be the most cost-effective CAMP over the modelled 52 weeks followed by HAMA, dHACM, hFDS, BLCC, and HSAM. We urge caution in interpreting the results because we currently lack head-to-head evidence comparing all these CAMPs and therefore suggest that this analysis be updated when more direct evidence of CAMPs becomes available.

Principles of wound management, including debridement, wound bed preparation, and newer technologies involving alternation of wound physiology to facilitate healing, are of utmost importance when attempting to heal a chronic diabetes-related foot ulcer. However, the rising incidence and costs of diabetes-related foot ulcer management necessitate that interventions to enhance wound healing of chronic diabetes-related foot ulcers are supported by high-quality evidence of efficacy and cost effectiveness when used in conjunction with established aspects of gold-standard multidisciplinary care. This is the 2023 International Working Group on the Diabetic Foot (IWGDF) evidence-based guideline on wound healing interventions to promote healing of foot ulcers in persons with diabetes. It serves as an update of the 2019 IWGDF guideline.

We followed the GRADE approach by devising clinical questions and important outcomes in the Patient-Intervention-Control-Outcome (PICO) format, undertaking a systematic review, developing summary of judgements tables, and writing recommendations and rationale for each question. Each recommendation is based on the evidence found in the systematic review and, using the GRADE summary of judgement items, including desirable and undesirable effects, certainty of evidence, patient values, resources required, cost effectiveness, equity, feasibility, and acceptability, we formulated recommendations that were agreed by the authors and reviewed by independent experts and stakeholders.

From the results of the systematic review and evidence-to-decision making process, we were able to make 29 separate recommendations. We made a number of conditional supportive recommendations for the use of interventions to improve healing of foot ulcers in people with diabetes. These include the use of sucrose octasulfate dressings, the use of negative pressure wound therapies for post-operative wounds, the use of placental-derived products, the use of the autologous leucocyte/platelet/fibrin patch, the use of topical oxygen therapy, and the use of hyperbaric oxygen. Although in all cases it was stressed that these should be used where best standard of care was not able to heal the wound alone and where resources were available for the interventions.

These wound healing recommendations should support improved outcomes for people with diabetes and ulcers of the foot, and we hope that widescale implementation will follow. However, although the certainty of much of the evidence on which to base the recommendations is improving, it remains poor overall. We encourage not more, but better quality trials including those with a health economic analysis, into this area.

Diabetic wounds are a significant subset of chronic wounds characterized by elevated levels of inflammatory cytokines, matrix metalloproteinases (MMPs), and reactive oxygen species (ROS). They are also associated with impaired angiogenesis, persistent infection, and a high likelihood of hospitalization, leading to a substantial economic burden for patients. In severe cases, amputation or even mortality may occur. Diabetic foot ulcers (DFUs) are a common complication of diabetes, with up to 25% of diabetic patients being at risk of developing foot ulcers over their lifetime, and more than 70% ultimately requiring amputation. Electrospun scaffolds exhibit a structural similarity to the extracellular matrix (ECM), promoting the adhesion, growth, and migration of fibroblasts, thereby facilitating the formation of new skin tissue at the wound site. The composition and size of electrospun scaffolds can be easily adjusted, enabling controlled drug release through fiber structure modifications. The porous nature of these scaffolds facilitates gas exchange and the absorption of wound exudate. Furthermore, the fiber surface can be readily modified to impart specific functionalities, making electrospinning nanofiber scaffolds highly promising for the treatment of diabetic wounds. This article provides a concise overview of the healing process in normal wounds and the pathological mechanisms underlying diabetic wounds, including complications such as diabetic foot ulcers. It also explores the advantages of electrospinning nanofiber scaffolds in diabetic wound treatment. Additionally, it summarizes findings from various studies on the use of different types of nanofiber scaffolds for diabetic wounds and reviews methods of drug loading onto nanofiber scaffolds. These advancements broaden the horizon for effectively treating diabetic wounds.

The severe quality of life and economic burden imposed by non-healing skin wounds, infection risks, and treatment costs are affecting millions of patients worldwide. To mitigate these challenges, scientists are relentlessly seeking effective treatment measures. In recent years, extracellular vesicles (EVs) have emerged as a promising cell-free therapy strategy, attracting extensive attention from researchers. EVs mediate intercellular communication, possessing excellent biocompatibility and stability. These features make EVs a potential tool for treating a plethora of diseases, including those related to wound repair. However, there is a growing focus on the engineering of EVs to overcome inherent limitations such as low production, relatively fixed content, and targeting capabilities of natural EVs. This engineering could improve both the effectiveness and specificity of EVs in wound repair treatments. In light of this, the present review will introduce the latest progress in the design methods and experimental paradigms of engineered EVs applied in wound repair. Furthermore, it will comprehensively analyze the current clinical research status and prospects of engineered EVs within this field.

Significance: With the increasing diabetic population worldwide, diabetic foot ulcers (DFUs) are a significant concern. This study aimed to compare the efficacy of skin substitutes, biomaterials, and topical agents with standard care. Recent Advances: A meta-analysis was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, EMBASE, and Web of Science were searched using the following keywords: diabetes mellitus AND skin graft OR tissue replacement OR dressing OR drug. Two independent reviewers performed data collection and quality assessment of the eligible studies. The primary outcome was the 12- to 16-week healing rates and the secondary outcome was recurrence rates. Critical Issues: Thirty-eight randomized controlled trials, including 3,862 patients, were analyzed. The studies exhibited low heterogeneity (τ2 = 0.10) without significant asymmetry (Egger's test, p = 0.8852). After pooling direct and indirect estimates, placenta-based tissue products exhibited the best wound healing probability (p-score = 0.90), followed by skin substitutes with living cells (p-score = 0.70), acellular skin substitutes (p-score = 0.56), and advanced topical dressings (p-score = 0.34) compared with standard of care. The recurrence analysis showed significant improvement in the intervention group compared with the control group (11.21% vs. 15.15%). Future Directions: This network meta-analysis provides the relative effectiveness and rank of biomaterials and topical dressings in DFU healing. The results could help clinical decision making.