Skin Substitutes Research Articles

Rethink Complex Wounds with Biodegradable Temporising Matrix (A Dermal Skin Substitute) - A Retrospective Analysis of Clinical Outcomes in 10 Patients

Rethink Complex Wounds with Biodegradable Temporising Matrix (A Dermal Skin Substitute) - A Retrospective Analysis of Clinical Outcomes in 10 Patients

Regenerative Medicine Approaches for Skin Wound Healing: from Allografts to Engineered Skin Substitutes

Abstract Purpose of the Review Recent advancements in tissue engineering and regenerative medicine have paved the way for innovative solutions in skin regeneration, particularly for extensive burns and full-thickness wounds where traditional approaches are limited. The purpose of the review is to explore the integration of bioactive materials, stem cell therapies, and tissue-engineered skin substitutes and their role in revolutionizing wound healing and skin transplantation. Recent Findings Studies leveraging natural and synthetic biomaterials as scaffolds, alongside the regenerative capabilities of mesenchymal stem cells (MSCs) and other cellular therapies, underscore the potential to enhance tissue repair, minimize scarring, and improve overall clinical outcomes. The development of multifunctional biomaterials and the advent of cutting-edge techniques such as 3D bioprinting and nanomedicine further propel the field, offering personalized and effective solutions. As these technologies evolve, they hold promise for more efficient, patient-specific skin grafting, reducing the need for systemic immunosuppression and enhancing graft survival. Summary The critical advancements in biomaterials, stem cell therapies, and tissue engineering, outline a course toward more effective and personalized skin regeneration therapies.

Engineered Skin Substitutes in Dermatologic Surgery: A Systematic Review.

Artificial skin substitutes are a flexible alternative to autografting in Mohs micrographic surgery (MMS), but the characteristics and clinical outcomes of skin substitutes are not well defined. Summarize clinical data of skin substitutes in MMS for cutaneous malignancy. A MEDLINE/Embase/Web of Science search was conducted. Articles with original data on outcomes after skin substitute use in MMS for cutaneous malignancy were included. Articles not in English or without original data were excluded. Bias was assessed using the Oxford CEBM Levels of Evidence Table. Outcomes were synthesized using weighted averages. This study was prospectively registered in PROSPERO. Of 1,007 articles, 40 met eligibility for inclusion. In total, 898 patients who underwent MMS and received a skin substitute were included. Xenografts were most commonly used ( n = 613). Semi-synthetic grafts (∼$<1/cm 2 ) and xenografts (∼$10/cm 2 ) are most affordable. Overall, outcomes were excellent for all skin substitutes, with a small proportion of patients experiencing correctable complications. Skin substitutes are highly effective in MMS, with enormous potential. While the data demonstrate positive outcomes, they predominately draw from small, retrospective studies or case reports. There is also a scarcity of data comparing skin substitutes with each other or controls. Prospective studies are recommended.

Functionalised Sodium-Carboxymethylcellulose-Collagen Bioactive Bilayer as an Acellular Skin Substitute for Future Use in Diabetic Wound Management: The Evaluation of Physicochemical, Cell Viability, and Antibacterial Effects.

The wound healing mechanism is dynamic and well-orchestrated; yet, it is a complicated process. The hallmark of wound healing is to promote wound regeneration in less time without invading skin pathogens at the injury site. This study developed a sodium-carboxymethylcellulose (Na-CMC) bilayer scaffold that was later integrated with silver nanoparticles/graphene quantum dot nanoparticles (AgNPs/GQDs) as an acellular skin substitute for future use in diabetic wounds. The bilayer scaffold was prepared by layering the Na-CMC gauze onto the ovine tendon collagen type 1 (OTC-1). The bilayer scaffold was post-crosslinked with 0.1% (w/v) genipin (GNP) as a natural crosslinking agent. The physical and chemical characteristics of the bilayer scaffold were evaluated. The results demonstrate that crosslinked (CL) groups exhibited a high-water absorption capacity (>1000%) and an ideal water vapour evaporation rate (2000 g/m2 h) with a lower biodegradation rate and good hydrophilicity, compression, resilience, and porosity than the non-crosslinked (NC) groups. The minimum inhibitory concentration (MIC) of AgNPs/GQDs presented some bactericidal effects against Gram-positive and Gram-negative bacteria. The cytotoxicity tests on bilayer scaffolds demonstrated good cell viability for human epidermal keratinocytes (HEKs) and human dermal fibroblasts (HDFs). Therefore, the Na-CMC bilayer scaffold could be a potential candidate for future diabetic wound care.

3D Bioprinting of Artificial Skin Substitute with Improved Mechanical Property and Regulated Cell Behavior through Integrating Patterned Nanofibrous Films.

Three-dimensional (3D) bioprinting has advantages for constructing artificial skin tissues in replicating the structures and functions of native skin. Although many studies have presented improved effect of printing skin substitutes in wound healing, using hydrogel inks to fabricate 3D bioprinting architectures with complicated structures, mimicking mechanical properties, and appropriate cellular environments is still challenging. Inspired by collagen nanofibers withstanding stress and regulating cell behavior, a patterned nanofibrous film was introduced to the printed hydrogel scaffold to fabricate a composite artificial skin substitute (CASS). The artificial dermis was printed using gelatin-hyaluronan hybrid hydrogels containing human dermal fibroblasts with gradient porosity and integrated with patterned nanofibrous films simultaneously, while the artificial epidermis was formed by seeding human keratinocytes upon the dermis. The collagen-mimicking nanofibrous film effectively improved the tensile strength and fracture resistance of the CASS, making it sewable for firm implantation into skin defects. Meanwhile, the patterned nanofibrous film also provided the biological cues to guide cell behavior. Consequently, CASS could effectively accelerate the regeneration of large-area skin defects in mouse and pig models by promoting re-epithelialization and collagen deposition. This research developed an effective strategy to prepare composite bioprinting architectures for enhancing mechanical property and regulating cell behavior, and CASS could be a promising skin substitute for treating large-area skin defects.

Factors Influencing Surgical Care and Outcome of Pediatric Burn Injuries and the Use of Synthetic Skin Substitutes

Abstract Burn trauma is one of the most common causes of inpatient treatment in children and is associated with severe physical and psychological consequences. Synthetic skin substitutes are designed to reduce the risk of infection, minimize wound pain, and reduce the frequency of dressing changes. However, data regarding premature detachment of these materials is scarce. The aim of this study was to identify factors associated with early detachment and subsequent consequences for surgical treatment. A retrospective analysis of 392 children with superficial and deep partial thickness burns undergoing inpatient treatment with the application of a skin substitute (Suprathel) was performed. Patient age, wound localization and progression, as well as burned total body surface area (TBSA%) were investigated as possible risk factors for early detachment of wound dressings and surgical intervention. Premature material detachment was significantly associated with burn localization (P &amp;lt; .001) and correlated with burn depth progression (r = 0.23, &amp;lt;0.001) and patient age (r = 0.22, &amp;lt;0.001). Surgical revision after material detachment was required in 13% of patients. Patient age and burn localization seem to increase the risk of premature material detachment. In addition, we observed increased premature detachment of Suprathel® in areas that elicited higher wound progression rates. Identifying these areas might prove pivotal in the improvement of pediatric burn trauma management.

715 Initial Use of PLA Skin Substitute at a Large Public Safety-Net Hospital

715 Initial Use of PLA Skin Substitute at a Large Public Safety-Net Hospital

534 Retrospective Study Comparing Acute Healing Outcomes of Two Epidermal Skin Substitutes in Paediatric Partial-Thickness Burns

534 Retrospective Study Comparing Acute Healing Outcomes of Two Epidermal Skin Substitutes in Paediatric Partial-Thickness Burns

Bioengineering Skin Substitutes for Wound Management-Perspectives and Challenges.

Non-healing wounds and skin losses constitute significant challenges for modern medicine and pharmacology. Conventional methods of wound treatment are effective in basic healthcare; however, they are insufficient in managing chronic wound and large skin defects, so novel, alternative methods of therapy are sought. Among the potentially innovative procedures, the use of skin substitutes may be a promising therapeutic method. Skin substitutes are a heterogeneous group of materials that are used to heal and close wounds and temporarily or permanently fulfill the functions of the skin. Classification can be based on the structure or type (biological and synthetic). Simple constructs (class I) have been widely researched over the years, and can be used in burns and ulcers. More complex substitutes (class II and III) are still studied, but these may be utilized in patients with deep skin defects. In addition, 3D bioprinting is a rapidly developing method used to create advanced skin constructs and their appendages. The aforementioned therapies represent an opportunity for treating patients with diabetic foot ulcers or deep skin burns. Despite these significant developments, further clinical trials are needed to allow the use skin substitutes in the personalized treatment of chronic wounds.

The Effects of Cellular Skin Substitutes on Diabetic Foot Ulcer Healing: A Systematic Review

Introduction: Diabetic foot ulcer (DFU) is one of the most common lower extremity diabetes-related complications. New therapies have been developed to increase the likelihood of wound healing and reduce complications, including biological and/or synthetic grafts that allow a temporary or permanent occlusion of wounds. Although their efficacy has been demonstrated, novel skin substitutes have been available, and few studies have described the head-to-head comparative effectiveness of those products. Therefore, this mini-review aims to analyze the available randomized clinical trials studying the impact of different cellular skin products on the healing of DFUs. Methods: The databases PubMed, EMBASE, Scopus, Scielo, and Lilacs were assessed from inception to July 30th, 2023, to identify randomized clinical trials on the effects of cellular skin substitutes on ulcer healing in adult patients aged 18 years or older with DFUs restricted to the skin and subcutaneous tissue, compared to standard of care or other skin substitutes. Results: Based on eligibility criteria, 22 articles were selected. These studies showed the efficacy and safety of cell skin substitutes compared to standard treatments, as demonstrated by the reduction in the total area of the ulcer and rates of complete wound healing. We identified a few studies with head-to-head comparisons among those products. Discussion: Cellular skin substitutes have shown promising results in healing DFUs as complementary therapies to the standard of care. Their incorporation into standard-of-care treatments could be discussed. Future studies should focus on head-to-head comparisons, cost-effective analysis, and long-term efficacy and safety.

Cancer Spheroids Embedded in Tissue-Engineered Skin Substitutes: A New Method to Study Tumorigenicity In Vivo.

Tumorigenic assays are used during a clinical translation to detect the transformation potential of cell-based therapies. One of these in vivo assays is based on the separate injection of each cell type to be used in the clinical trial. However, the injection method requires many animals and several months to obtain useful results. In previous studies, we showed the potential of tissue-engineered skin substitutes (TESs) as a model for normal skin in which cancer cells can be included in vitro. Herein, we showed a new method to study tumorigenicity, using cancer spheroids that were embedded in TESs (cTES) and grafted onto athymic mice, and compared it with the commonly used cell injection assay. Tumors developed in both models, cancer cell injection and cTES grafting, but metastases were not detected at the time of sacrifice. Interestingly, the rate of tumor development was faster in cTESs than with the injection method. In conclusion, grafting TESs is a sensitive method to detect tumor cell growth with and could be developed as an alternative test for tumorigenicity.

Alloplastic Epidermal Skin Substitute in the Treatment of Burns.

The goal of burn wound treatment is to ensure rapid epithelialization in superficial burns and the process of rebuilding the lost skin in deep burns. Topical treatment plays an important role. One of the innovations in the field of synthetic materials dedicated to the treatment of burns is epidermal skin substitutes. Since the introduction of Suprathel®, the alloplastic epidermal substitute, many research results have been published in which the authors investigated the properties and use of this substitute in the treatment of wounds of various origins, including burn wounds. Burn wounds cause both physical and psychological discomfort, which is why ensuring comfort during treatment is extremely important. Alloplastic epidermal substitute, due to its biodegradability, plasticity, no need to remove the dressing until healing, and the associated reduction in pain, is an alternative for treating burns, especially in children.

Perspectives on the Current State of Bioprinted Skin Substitutes for Wound Healing.

Human skin is particularly vulnerable to external damaging influences such as irradiation, extreme temperatures, chemical trauma, and certain systemic diseases, which reduce the skin's capacity for regeneration and restoration and can possibly lead to large-scale skin defects. To restore skin continuity in severe cases, surgical interventions such as the transplantation of autologous tissue are needed. Nevertheless, the coverage of larger skin defects caused by severe third-grade burns or extensive irradiation therapy is limited due to the depletion of uninjured autologous tissue. In such cases, many of the patient's epidermal cells can become available using biofabricated skin grafts, thereby restoring the skin's vital functions. Given the limited availability of autologous skin grafts for restoring integrity in large-scale defects, using bioprinted constructs as skin graft substitutes could offer an encouraging therapeutic alternative to conventional therapies for large-scale wounds, such as the transplantation of autologous tissue. Using layer-by-layer aggregation or volumetric bioprinting, inkjet bioprinting, laser-assisted bioprinting, or extrusion-based bioprinting, skin cells are deposited in a desired pattern. The resulting constructs may be used as skin graft substitutes to accelerate wound healing and reconstitute the physiological functions of the skin. In this review, we aimed to elucidate the current state of bioprinting within the context of skin tissue engineering and introduce and discuss different bioprinting techniques, possible approaches and materials, commonly used cell types, and strategies for graft vascularization for the production of bioprinted constructs for use as skin graft substitutes.

Human Acellular Amniotic Membrane as Skin Substitute and Biological Scaffold: A Review of Its Preparation, Preclinical Research, and Clinical Application.

Human acellular amniotic membrane (HAAM) has emerged as a promising tool in the field of regenerative medicine, particularly for wound healing and tissue regeneration. HAAM provides a natural biological scaffold with low immunogenicity and good anti-infective and anti-scarring results. Despite its potential, the clinic application of HAAM faces challenges, particularly with respect to the preparation methods and its low mechanical strength. This review provides a comprehensive overview of HAAM, covering its preparation, sterilization, preclinical research, and clinical applications. This review also discusses promising decellularization and sterilization methods, such as Supercritical Carbon Dioxide (SC-CO2), and the need for further research into the regenerative mechanisms of HAAM. In addition, we discuss the potential of HAAM as a skin dressing and cell delivery system in preclinical research and clinical applications. Both the safety and effectiveness of HAAM have been validated by extensive research, which provides a robust foundation for its clinical application.

Production of Tissue-Engineered Skin Substitutes for Clinical Applications: Elimination of Serum.

Tissue-engineered skin substitutes (TESs) are used as a treatment for severe burn injuries. Their production requires culturing both keratinocytes and fibroblasts. The methods to grow these cells have evolved over the years, but bovine serum is still commonly used in the culture medium. Because of the drawbacks associated with the use of serum, it would be advantageous to use serum-free media for the production of TESs. In a previous study, we developed a serum-free medium (Surge SFM) for the culture of keratinocytes. Herein, we tested the use of this medium, together with a commercially available serum-free medium for fibroblasts (Prime XV), to produce serum-free TESs. Our results show that serum-free TESs are macroscopically and histologically similar to skin substitutes produced with conventional serum-containing media. TESs produced with either culture media expressed keratin 14, Ki-67, transglutaminase 1, filaggrin, type I and IV collagen, and fibronectin comparably. Mechanical properties, such as contraction and tensile strength, were comparable between TESs cultured with and without serum. Serum-free TESs were also successfully grafted onto athymic mice for a six-month period. In conclusion, Surge SFM and Prime XV serum-free media could be used to produce high quality clinical-grade skin substitutes.

Updated Classification of Skin Substitutes.

Updated Classification of Skin Substitutes.

The Role of Skin Substitutes in Dermatologic Surgery: A Practical Review.

The number of skin substitutes (SS) available for wound care management has increased markedly in the last few decades. This presents a challenge as dermatologists attempt to determine the appropriate setting for a skin substitute use. This is a practical review of SS used in dermatologic surgery to assist clinicians in their selection of SS by providing information about the efficacy, risk, availability, shelf-life, and relative cost of the available options. Relevant data were identified through a search of PubMed, a manual search of relevant company websites, a manual search of the reference sections of relevant papers, and communicating with subject experts. SS can be divided into 7 categories based on composition: amnion, cultured epithelial autograft, acellular allograft, cellular allografts, xenografts, composites, and synthetics. These groups offer unique benefits and disadvantages that are outlined in the manuscript and tables. Considerations of the characteristics, settings of use, and efficacies of SS may allow more effective wound care and the potential for faster healing times. Additional studies are needed to evaluate and compare the healing benefits of these substitutes. Trials comparing the efficacy of each of the common SS vs each other and granulation are needed. J Drugs Dermatol. 2023;22(5): doi:10.36849/JDD.7132.

Multistage Reconstruction of a Large Upper Arm Defect Using a Keystone Type 1 Flap and a Synthetic Skin Substitute

Introduction: Reconstruction of large defects in the upper arm remains challenging due to insufficient tissue available, the tensions involved and anatomical limitations. Despite considerable donor site morbidity and technical difficulty, there are numerous techniques, including free and regional flaps, based on reliable and predictable anatomy. The introduction of perforator-based flaps has significantly led to reducing donor site morbidity. We aim to describe an approach combining a keystone type 1 flap and a synthetic skin substitute as a valid alternative for treating large upper arm defects. Materials and Methods: We report a case of a 67-year-old male who was adreessed to our department for melanoma wide excision on the posterior side of the upper left arm. Considering the significant size of the 14 x 8 cm defect and the good compliance of the patient, we decide to perform a multistage reconstruction. The first stage included a 1cm width safety margin surgical excision associated with axillary sentinel lymph node biopsy and a reconstruction based on the keystone type 1 flap with the temporary closure of the remaining tissue defect using a synthetic skin substitute. The second and third stages were performed one and two weeks later, respectively, and included removal of the temporary skin substitute and tension-free closure of the residual defect under local anaesthesia. Results: The recovery was uneventful with no surgical complications, and follow-up at 3-months postoperatively showed excellent aesthetic and functional outcomes. Conclusion: A combined approach based on keystone type 1 flap with a synthetic skin substitute can be used as a multistage procedure that allows reconstruction of large size defects of the upper arm. This is a viable option, especially for patients with good compliance. It provides optimal results while avoiding the donor site morbidity of other more challenging techniques.

Polycaprolactone nanofiber-alginate hydrogel interpenetrated skin substitute for regulation of wound-substitute interface

The management of the interface between the wound microenvironment and the skin substitute (SSS) is fundamental to wound repair and is an important factor in the regeneration of damaged tissue. Current biomaterials result in unideal repair effect of defective tissue due to limited management of early wound exudate and inability to respond positively to endogenous growth factors. Based on a refined electrospinning process, polycaprolactone fiber - alginate hydrogel interpenetrated network scaffold and subsequent multifunctional modifications serving as SSS was developed. The SSS exhibits excellent water absorption, water vapor permeability rate > 6000 g/m2/day and stretching properties. The amino-terminated hyperbranched polyamide enables the scaffold with both rapid antibacterial and reactive oxygen scavenging properties. Furthermore, fibroblast cells can be proliferated in the scaffold by 3D infiltration (>100 μm). Thus, the scaffolds are expected to be ideal candidates for the repair of different defective skin, especially those with excessive exudate.

The Fabrication of Gelatin-Elastin-Nanocellulose Composite Bioscaffold as a Potential Acellular Skin Substitute.

Gelatin usage in scaffold fabrication is limited due to its lack of enzymatic and thermal resistance, as well as its mechanical weakness. Hence, gelatin requires crosslinking and reinforcement with other materials. This study aimed to fabricate and characterise composite scaffolds composed of gelatin, elastin, and cellulose nanocrystals (CNC) and crosslinked with genipin. The scaffolds were fabricated using the freeze-drying method. The composite scaffolds were composed of different concentrations of CNC, whereas scaffolds made of pure gelatin and a gelatin-elastin mixture served as controls. The physicochemical and mechanical properties of the scaffolds, and their cellular biocompatibility with human dermal fibroblasts (HDF), were evaluated. The composite scaffolds demonstrated higher porosity and swelling capacity and improved enzymatic resistance compared to the controls. Although the group with 0.5% (w/v) CNC recorded the highest pore size homogeneity, the diameters of most of the pores in the composite scaffolds ranged from 100 to 200 μm, which is sufficient for cell migration. Tensile strength analysis revealed that increasing the CNC concentration reduced the scaffolds' stiffness. Chemical analyses revealed that despite chemical and structural alterations, both elastin and CNC were integrated into the gelatin scaffold. HDF cultured on the scaffolds expressed collagen type I and α-SMA proteins, indicating the scaffolds' biocompatibility with HDF. Overall, the addition of elastin and CNC improved the properties of gelatin-based scaffolds. The composite scaffolds are promising candidates for an acellular skin substitute.