Bioengineered Skin Substitutes Research Articles

Bioengineered Skin for Diabetic Foot Ulcers: A Scoping Review.

Diabetic foot ulcers (DFUs) pose a significant threat to individuals with diabetes mellitus (DM), such as lower limb amputation and severe morbidity. Bioengineered skin substitutes (BSS) are alternatives to traditional interventions for treating DFUs, but their efficacy compared to standard wound care (SWC) or other treatment types, such as allografts, remains unknown. A scoping review of human studies was conducted to identify current approaches in the treatment of DFUs using BSS as compared with other treatment options. Systematic searches in PubMed, Cochrane Library, and Web of Science were conducted to identify comparative studies that enrolled 10 or more patients and evaluated wound healing outcomes (closure, time-to-healing, and area reduction). Database searches isolated articles published from 1 December 2012 to 1 December 2022 and were conducted in accordance with PRISMA-ScR guidelines. The literature search yielded 1312 articles, 24 of which were included for the qualitative analysis. Findings in these studies demonstrated that BSS outperformed SWC in all measured outcomes, suggesting that BSS may be a superior treatment for DFUs. Of the 24 articles, 8 articles compared human amniotic membrane allografts (hAMA) to BSS. Conflicting evidence was observed when comparing BSS and hAMA treatments, highlighting the need for future research.

Bioengineered Skin Substitutes: the Role of Extracellular Matrix and Vascularization in the Healing of Deep Wounds.

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.

Critical Issues in Successful Production of Skin Substitutes for Wound Healing

Novel findings on fabrication techniques for bioactive materials, discovering further basic knowledge about wound healing process, and availability of stem cells as alternative candidate for differentiated cells have highly encouraged scientists for developing new bioengineered skin substitutes (BSS) that offer an effective remedy for a specific wound type. However, technical, clinical, legislative and economic reasons hamper wide-spread commercialization and clinical translation of BSS. Among the various types of strategies that target skin repair and regeneration, tissue engineering with stem cells is most promising route. Tissue engineering by cooperation of several disciplines forms a context on which the commercial development of BSS is possible to provide benefits for patients who currently have limited or no cure options. The principles of tissue engineering are to initiate cell cultures in vitro, grow them in monolayer or on porous scaffolds and transplant the composite into a patient with a specific wound indication in vivo. The potential for creating of custom-designed biomaterials and availability of stem cells from either autologous or allogenic sources have helped to produce novel innovative BSS. Currently, wide range of skin substitutes are already being fabricated for clinical use in different wound indications but not yet definitively established. Therefore, many novel engineered constructs might be fabricated in the future. In this review, we describe the progress that has been made to date in the field of skin substitutes and the critical issues that are still hindering successful production and bench to bedside translation of BSS and restricting the availability of these innovative therapeutic constructs. Integrity of the science and technology, interdisciplinary expertise collaborations, and early interaction with regulatory entities such as Food and Drug Administration (FDA) and European Medicines Agency (EMA), together with other critical determinants, is vital to the successful commercialization of tissue engineering products into the marketplace/clinic.

A Surgical Device to Study the Efficacy of Bioengineered Skin Substitutes in Mice Wound Healing Models.

Due to the poor regenerative capacity of adult mammalian skin, there is a need to develop effective skin substitutes for promoting skin regeneration after a severe wound. However, the complexity of skin biology has made it difficult to enable perfect regeneration of skin. Thus, animal models are being used to test potential skin substitutes. Murine models are valuable but their healing process involves dermal contraction. We have developed a device called a dome that is able to eliminate the contraction effect of rodent skin while simultaneously housing a bioengineered skin graft. The dome comes in two models, which enables researchers to evaluate the cells that contribute in wound healing from neighboring intact tissue during skin healing/regeneration. This protocol simplifies grafting of skin substitutes, eliminates the contraction effect of surrounding skin, and summarizes a simple method for animal surgery for wound healing and skin regeneration studies.

Critical Issues in Successful Production of Skin Substitutes for Wound Healing

Novel findings on fabrication techniques for bioactive materials, discovering further basic knowledge about wound healing process, and availability of stem cells as alternative candidate for differentiated cells have highly encouraged scientists for developing new bioengineered skin substitutes (BSS) that offer an effective remedy for a specific wound type. However, technical, clinical, legislative and economic reasons hamper wide-spread commercialization and clinical translation of BSS. Among the various types of strategies that target skin repair and regeneration, tissue engineering with stem cells is most promising route. Tissue engineering by cooperation of several disciplines forms a context on which the commercial development of BSS is possible to provide benefits for patients who currently have limited or no cure options. The principles of tissue engineering are to initiate cell cultures in vitro, grow them in monolayer or on porous scaffolds and transplant the composite into a patient with a specific wound indication in vivo. The potential for creating of custom-designed biomaterials and availability of stem cells from either autologous or allogenic sources have helped to produce novel innovative BSS. Currently, wide range of skin substitutes are already being fabricated for clinical use in different wound indications but not yet definitively established. Therefore, many novel engineered constructs might be fabricated in the future. In this review, we describe the progress that has been made to date in the field of skin substitutes and the critical issues that are still hindering successful production and bench to bedside translation of BSS and restricting the availability of these innovative therapeutic constructs. Integrity of the science and technology, interdisciplinary expertise collaborations, and early interaction with regulatory entities such as Food and Drug Administration (FDA) and European Medicines Agency (EMA), together with other critical determinants, is vital to the successful commercialization of tissue engineering products into the marketplace/clinic.

Dermal matrices and bioengineered skin substitutes: a critical review of current options.

Background:Over recent decades, scientists and surgeons have collaborated to develop various bioengineered and synthetic products as an alternative to skin grafts. Despite the numerous articles and reviews written about dermal skin substitutes, there is no general consensus.Methods:This article reviews dermal skin scaffolds used in clinical applications and experimental settings. For scaffold evaluation, we focused on clinical and/or histological results, and conclusions are listed. Explanations for general trends were sought based on existing knowledge about tissue engineering principles and wound healing mechanisms.Results:Decellularized dermis seems to remain the best option with no other acellular scaffold being clinically proven to gain better results yet. In general, chemically cross-linked products were seen to be less effective in skin tissue engineering. Biocompatibility could be enhanced by preseeding substitutes with fibroblasts to allow some natural scaffold remodeling before product application.Conclusions:Skin substitutes are a useful tool in plastic and reconstructive surgery practices as an alternative to skin grafts. In the choice of substitute, the general plastic surgery principle of replacing like tissue with like tissue seems to be still standing, and products most resembling the natural dermal extracellular matrix should be preferred.

Bioengineered Skin Substitute Considerations in the Diabetic Foot Ulcer

Diabetes constitutes a global emergency with case numbers increasing exponentially every year. Diabetic foot ulcers are the leading cause of nontraumatic lower limb amputations. A complex background of pathophysiologic events has been identified with advances in molecular biology such that newer interventions are possible. Bioengineered skin substitutes currently play an important role in the diabetic foot ulcer, particularly in the "stalled" wounds that fail to show progress in their healing trajectory. However, newer designs and scaffold incorporation may herald a new generation of products with more focused targeting of these pathophysiologic events. The major background impairment is that of vasculogenesis brought about as a direct result of hyperglycemia, advanced glycation end product/methylglyoxal generation, and its direct effect on endothelial progenitor cell production and attraction to the wound site. At the same time, glycation end products affect immunity and inflammation, increasing the susceptibility to infection. Thus, reactive oxygen species scavengers, methylglyoxal scavengers, vascular endothelial growth factor stimulators as well as various lipids and neuropeptides are all potential agents that could be incorporated into such templates. The logical sequence of events and possible interventions is detailed. In this manner, intrinsic healing is encouraged in preference to our current attempts at adding unknown quantities of specialized cellular and growth factor components which seem to provide very temporary advantages.

Wound‐healing Gene Family Expression Differences Between Fetal and Foreskin Cells Used for Bioengineered Skin Substitutes

For tissue engineering, several cell types and tissues have been proposed as starting material. Allogenic skin products available for therapeutic usage are mostly developed with cell culture and with foreskin tissue of young individuals. Fetal skin cells offer a valuable solution for effective and safe tissue engineering for wounds due to their rapid growth and simple cell culture. By selecting families of genes that have been reported to be implicated in wound repair and particularly for scarless fetal wound healing including transforming growth factor-beta (TGF-beta) superfamily, extracellular matrix, and nerve/angiogenesis growth factors, we have analyzed differences in their expression between fetal skin and foreskin cells, and the same passages. Of the five TGF-beta superfamily genes analyzed by real-time reverse transcription-polymerase chain reaction, three were found to be significantly different with sixfold up-regulated for TGF-beta2, and 3.8-fold for BMP-6 in fetal cells, whereas GDF-10 was 11.8-fold down-regulated. For nerve growth factors, midkine was 36-fold down-regulated in fetal cells, and pleiotrophin was 4.76-fold up-regulated. We propose that fetal cells present technical and therapeutic advantages compared to foreskin cells for effective cell-based therapy for wound management, and overall differences in gene expression could contribute to the degree of efficiency seen in clinical use with these cells.

Nonoperative Management of Venous Ulcers and the Emerging Role of Bioengineered Skin Substitutes

Chronic venous ulcers are a common medical problem that have a dramatic medical, economic, and psychosocial impact on patients. Nonoperative therapy has been proven to be effective in controlling the symproms of chronic venous insufficiency and promoting healing of chronic venous leg ulcers. The mainstays of nonoperative treatment continue to be leg elevation and compression therapy. Recently, bioengineered skin substitutes, ranging from an epidermal or dermal layer to a bilayered living skin construct, have been developed to aid in local wound healing and represent an added nonoperative treatment option for venous ulcers.

Nonoperative Management of Venous Ulcers and the Emerging Role of Bioengineered Skin Substitutes

-Chronic venous ulcers are a common medical problem that have a dramatic medical, economic, and psychosocial impact on patients. Nonoperative therapy has been proven to be effective in controlling the symproms of chronic venous insufficiency and promoting healing of chronic venous leg ulcers. The mainstays of nonoperative treatment continue to be leg elevation and compression therapy. Recently, bioengineered skin substitutes, ranging from an epidermal or dermal layer to a bilayered living skin construct, have been developed to aid in local wound healing and represent an added nonoperative treatment option for venous ulcers.