Chronic Diabetic Wounds and Their Treatment with Skin Substitutes.
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ABSTRACT:
SUBMITTER: Holl J
PROVIDER: S-EPMC8001234 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC8485225 | biostudies-literature
Project description:Skin wound healing is a crucial process for regenerating healthy skin and avoiding the undesired consequences associated with open skin wounds. For epidermolysis bullosa (EB), a debilitating group of fragile skin disorders currently without a cure, skin blistering can often be severe and heal poorly, increasing susceptibility to life-threatening complications. To prevent these, investigational therapies have been exploring the use of tissue-engineered skin substitutes (TESSs) aimed at replacing damaged skin and promoting long-term wound closure. These products have either been developed in house or commercially sourced and are composed of allogeneic or autologous human skin cells, often with some form of bioscaffolding. They can be broadly classified based on their cellular composition: keratinocytes (epidermal substitutes), fibroblasts (dermal substitutes) or a combination of both (composite substitutes). Encouraging long-term wound healing has been achieved with epidermal substitutes. However, these substitutes have not demonstrated the same efficacy for all patients, which may be due to the molecular heterogeneity observed between EB subtypes. Autologous composite TESSs, which more closely resemble native human skin, are therefore being investigated and may hold promise for treating an extended range of patients. Additionally, future TESSs for EB are focused on using gene-corrected patient skin cells, which have already demonstrated remarkable long-term wound healing capabilities. In this review, we provide an overview of the different TESSs that have been investigated in clinical studies to treat patients with EB, as well as their long-term wound healing results. Where available, we describe the methods used to develop these products to inform future efforts in this field.
| S-EPMC9626425 | biostudies-literature
Project description:Clinical application of skin substitute is typically a two-stage procedure with application of skin substitute matrix to the wound followed by engraftment of a split-thickness skin graft (STSG). This two-stage procedure requires multiple interventions, increasing the time until the wound is epithelialised. In this study, the feasibility of a one-stage procedure by combining bioengineered collagen-chondroitin-6-sulfate (DS1) or decellularised fetal bovine skin substitute (DS2) with autologous skin cell suspension (ASCS) in a porcine full-thickness wound healing model was evaluated. Twelve full-thickness excisional wounds on the backs of pigs received one of six different treatments: empty; ASCS; DS1 with or without ASCS; DS2 with or without ASCS. The ASCS was prepared using a point-of-care device and was seeded onto the bottom side of DS1, DS2, and empty wounds at 80 000 cells/cm2 . Wound measurements and photographs were taken on days 0, 9, 14, 21, 28, 35, and 42 post-wounding. Histological analysis was performed on samples obtained on days 9, 14, 28, and 42. Wounds in the empty group or with ASCS alone showed increased wound contraction, fibrosis, and myofibroblast density compared with other treatment groups. The addition of ASCS to DS1 or DS2 resulted in a marked increase in re-epithelialisation of wounds at 14 days, from 15 ± 11% to 71 ± 20% (DS1 vs DS1 + ASCS) or 28 ± 14% to 77 ± 26 (DS2 vs DS2 + ASCS) despite different mechanisms of tissue regeneration employed by the DS used. These results suggest that this approach may be a viable one-stage treatment in clinical practice.
| S-EPMC8684857 | biostudies-literature
Project description:DNA methyltransferase inhibitor zebularine was proven to induce regeneration in the ear pinna in mice. We utilized a dorsal skin wound model to further evaluate this epigenetic inhibitor in wound healing. Full-thickness excisional wounds were made on the dorsum of 2 and 10-month-old healthy BALB/c and 3 and 8-month-old diabetic (db/db) mice, followed by topical or intraperitoneal zebularine delivery. Depending on the strain, age, dose, and delivery, the zebularine treatments either had no effect or accelerated or delayed wound closure. In principle, zebularine applied topically moderately promoted wound closure in the healthy but markedly delayed in the diabetic mice, which was in line with decreased viability of cultured keratinocytes from diabetic patients exposed to zebularine. The histological analysis revealed an improvement in the architecture of restored skin in zebularine-treated mice, manifested as a distinct layered pattern resembling panniculus carnosus. The finding corresponds with the zebularine-mediated activation of the Wnt5a gene, an essential regulator of Wnt signaling, the pathway involved in hair follicle development, the process which in turn is connected with regenerative skin healing. Although zebularine did not remarkably accelerate wound healing, zebularine and other epigenetic inhibitors deserve further testing as potential drugs to improve the quality of restored skin.
| S-EPMC10099879 | biostudies-literature
Project description:The formation of severe scars still represents the result of the closure process of extended and deep skin wounds. To address this issue, different bioengineered skin substitutes have been developed but a general consensus regarding their effectiveness has not been achieved yet. It will be shown that bioengineered skin substitutes, although representing a valid alternative to autografting, induce skin cells in repairing the wound rather than guiding a regeneration process. Repaired skin differs from regenerated skin, showing high contracture, loss of sensitivity, impaired pigmentation and absence of cutaneous adnexa (i.e., hair follicles and sweat glands). This leads to significant mobility and aesthetic concerns, making the development of more effective bioengineered skin models a current need. The objective of this review is to determine the limitations of either commercially available or investigational bioengineered skin substitutes and how advanced skin tissue engineering strategies can be improved in order to completely restore skin functions after severe wounds.
| S-EPMC6947552 | biostudies-literature
Project description:Wound healing is a complex physiological process including overlapping phases (hemostatic/inflammatory, proliferating and remodeling phases). Every alteration in this mechanism might lead to pathological conditions of different medical relevance. Treatments for chronic non-healing wounds are expensive because reiterative treatments are needed. Regenerative medicine and in particular mesenchymal stem cells approach is emerging as new potential clinical application in wound healing. In the past decades, advance in the understanding of molecular mechanisms underlying wound healing process has led to extensive topical administration of growth factors as part of wound care. Currently, no definitive treatment is available and the research on optimal wound care depends upon the efficacy and cost-benefit of emerging therapies. Here we provide an overview on the novel approaches through stem cell therapy to improve cutaneous wound healing, with a focus on diabetic wounds and Systemic Sclerosis-associated ulcers, which are particularly challenging. Current and future treatment approaches are discussed with an emphasis on recent advances.
| S-EPMC4879897 | biostudies-literature
Project description:Diabetic chronic wound is one of the most serious complications of diabetes, imposing enormous socioeconomic burdens on diabetic patients, their families, and society due to its refractory nature. MicroRNAs (miRNAs) have emerged as important regulators of various physiological and pathological processes. Abnormalities arise in the regulatory functions of miRNAs in chronic diabetic wounds. Therefore, the modification of miRNAs expression in diabetic wounds is an important channel for the improvement of wound healing. The clinical translation of miRNA-based therapy may become a prospective direction of diabetic wound healing. However, miRNA-based therapy is still in its early stage of development, and actual translation into clinical application will take a long time. Herein, we summarized the latest research findings on miRNAs in diabetic chronic wounds healing.
| S-EPMC10408961 | biostudies-literature
Project description:Engineered skin substitutes (ESS), prepared using primary human fibroblasts and keratinocytes with a biopolymer scaffold, were shown to provide stable closure of excised burns, but relatively little is known about innervation of ESS after grafting. This study investigated innervation of ESS and, specifically, whether Merkel cells are present in healed grafts. Merkel cells are specialized neuroendocrine cells required for fine touch sensation in skin. We discovered cells positive for keratin 20 (KRT20), a general marker for Merkel cells, in the basal epidermis of ESS after transplantation to mice, suggesting the presence of Merkel cells. Cells expressing KRT20 were not observed in ESS in vitro. However, widely separated KRT20-positive cells were observed in basal epidermis of ESS by 2 weeks after grafting. By 4 weeks, these cells increased in number and expressed keratins 18 and 19, additional Merkel cells markers. Putative Merkel cell numbers increased further between weeks 6 and 14; their densities varied widely and no specific pattern of organization was observed, similar to Merkel cell localization in human skin. KRT20-positive cells co-expressed epidermal markers E-cadherin and keratin 15, suggesting derivation from the epidermal lineage, and neuroendocrine markers synaptophysin and chromogranin A, consistent with their identification as Merkel cells. By 4 weeks after grafting, some Merkel cells in engineered skin were associated with immature afferents expressing neurofilament-medium. By 8 weeks, Merkel cells were complexed with more mature neurons expressing neurofilament-heavy. Positive staining for human leukocyte antigen demonstrated that the Merkel cells in ESS were derived from grafted human cells. The results identify, for the first time, Merkel cell-neurite complexes in engineered skin in vivo. This suggests that fine touch sensation may be restored in ESS after grafting, although this must be confirmed with future functional studies.
| S-EPMC6400390 | biostudies-literature
Project description:Owing to the persistent inflammatory microenvironment and unsubstantial dermal tissues, chronic diabetic wounds do not heal easily and their recurrence rate is high. Therefore, a dermal substitute that can induce rapid tissue regeneration and inhibit scar formation is urgently required to address this concern. In this study, we established biologically active dermal substitutes (BADS) by combining novel animal tissue-derived collagen dermal-replacement scaffolds (CDRS) and bone marrow mesenchymal stem cells (BMSCs) for the healing and recurrence treatments of chronic diabetic wounds. The collagen scaffolds derived from bovine skin (CBS) displayed good physicochemical properties and superior biocompatibility. CBS loaded with BMSCs (CBS-MCSs) could inhibit M1 macrophage polarization in vitro. Decreased MMP-9 and increased Col3 at the protein level were detected in CBS-MSCs-treated M1 macrophages, which may be attributed to the suppression of the TNF-α/NF-κB signaling pathway (downregulating phospho-IKKα/β/total IKKα/β, phospho-IκB/total IκB, and phospho-NFκB/total NFκB) in M1 macrophages. Moreover, CBS-MSCs could benefit the transformation of M1 (downregulating iNOS) to M2 (upregulating CD206) macrophages. Wound-healing evaluations demonstrated that CBS-MSCs regulated the polarization of macrophages and the balance of inflammatory factors (pro-inflammatory: IL-1β, TNF-α, and MMP-9; anti-inflammatory: IL-10 and TGF-β3) in db/db mice. Furthermore, CBS-MSCs facilitated the noncontractile and re-epithelialized processes, granulation tissue regeneration, and neovascularization of chronic diabetic wounds. Thus, CBS-MSCs have a potential value for clinical application in promoting the healing of chronic diabetic wounds and preventing the recurrence of ulcers.
| S-EPMC10189465 | biostudies-literature
Project description:Diabetic wounds are characterized by persistent accumulation of proinflammatory monocytes (Mo)/macrophages (MΦ) and impaired healing. However, the mechanisms underlying the persistent accumulation of Mo/MΦ remain poorly understood. In this study, we report that Ly6C+F4/80lo/- Mo/MΦ proliferate at higher rates in wounds of diabetic mice compared with nondiabetic mice, leading to greater accumulation of these cells. Unbiased single cell RNA sequencing analysis of combined nondiabetic and diabetic wound Mo/MΦ revealed a cluster, populated primarily by cells from diabetic wounds, for which genes associated with the cell cycle were enriched. In a screen of potential regulators, CCL2 levels were increased in wounds of diabetic mice, and subsequent experiments showed that local CCL2 treatment increased Ly6C+F4/80lo/- Mo/MΦ proliferation. Importantly, adoptive transfer of mixtures of CCR2-/- and CCR2+/+ Ly6Chi Mo indicated that CCL2/CCR2 signaling is required for their proliferation in the wound environment. Together, these data demonstrate a novel role for the CCL2/CCR2 signaling pathway in promoting skin Mo/MΦ proliferation, contributing to persistent accumulation of Mo/MΦ and impaired healing in diabetic mice.
| S-EPMC7927918 | biostudies-literature