A Cultured Autologous Dermo-epidermal Skin Substitute for Full-Thickness Skin Defects: A Phase I, Open, Prospective Clinical Trial in Children

Abstract

BACKGROUND: The management of deep partial-thickness and full-thickness skin defects remains a significant challenge. Particularly with massive defects, the current standard treatment, splitthickness skin grafting, is fraught with donor-site limitations and unsatisfactory long-term outcomes. A novel, autologous, bioengineered skin substitute was developed to address this problem. METHODS: To determine whether this skin substitute could safely provide permanent defect coverage, a phase I clinical trial was performed at the University Children's Hospital Zurich. Ten pediatric patients with acute or elective deep partial-or full-thickness skin defects were included. Skin grafts of 49 cm were bioengineered using autologous keratinocytes and fibroblasts isolated from a patient's small skin biopsy specimen (4 cm), incorporated in a collagen hydrogel. RESULTS: Graft take, epithelialization, infection, adverse events, skin quality, and histology were analyzed. Median graft take at 21 days postoperatively was 78 percent (range, 0 to 100 percent). Healed skin substitutes were stable and skin quality was nearly normal. There were four cases of hematoma leading to partial graft loss. Histology at 3 months revealed a wellstratified epidermis and a dermal compartment comparable to native skin. Mean follow-up duration was 15 months. CONCLUSIONS: In the first clinical application of this novel skin substitute, safe coverage of skin defects was achieved. Safety and efficacy phase II trials comparing the novel skin substitute to split-thickness skin grafts are ongoing. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

A Concise Review on Tissue Engineered Artificial Skin Grafts for Chronic Wound Treatment: Can We Reconstruct Functional Skin Tissue In Vitro?

“…Nevertheless, it is known that cell lines may reveal a completely different gene expression compared to primary cells [65,66], and thus primary cultures should be preferentially used for both skin graft production and biocompatibility testing of new biomaterial-based skin substitutes. Indeed, most cellular artificial skins were developed using either isolated primary fibroblasts and/or keratinocytes [67][68][69][70] or primary culture of skin cells purchased from the cell culture bank [71,72]. The main disadvantage of the use of isolated primary cells is their low proliferation potential, making it difficult to obtain a sufficient number of cells for cellular skin graft production [49].…”

“…The main limitation of artificial skin grafts is their ability to generate only the epidermal, dermal, and hypodermal layers of the skin. Dermis and epidermis are usually reconstructed using biomaterials seeded with fibroblasts and keratinocytes [67,71], whereas the hypodermis is formed by incorporation of ADSCs within the biomaterial structure [75]. Most of the developed artificial skin substitutes fail to reconstruct nerves and skin appendages, like hair follicles, sweat glands, and sebaceous glands.…”

A simplified fabrication technique for cellularized high-collagen dermal equivalents

“…Over the last few decades, various scaffold biomaterials have been established for creating dermal equivalents of bioengineered skin [3,[7][8][9], and are currently being applied in clinical practice [10][11][12][13][14][15]. In the present study, we focused on the use of natural biomaterials, namely collagen, due to successful outcomes in clinical settings [5,11]. In skin substitutes, the scaffolds mimic the extracellular matrix (ECM) and provide mechanical stability to the graft, which is essential for convenient surgical handling.…”

“…To achieve high mechanical stability, collagen hydrogel is compacted using external pressure by displacing water and increasing the final collagen density. Braziulis et al [16] have improved this technique and used dermal scaffolds in clinical applications [5].…”

Fabrication of Bioengineered Skin by Injection Molding: A Feasibility Study on Automation

“…12,13 Transplantation of skin grafts has been successfully performed in humans in Switzerland, Canada, and the United States. [14][15][16][17] The demand for skin equivalents is increasing in all fields. Because of the current, predominantly manual, fabrication techniques, however, the quality and quantity of skin equivalents produced are largely dependent on the expertise of the technicians producing the tissues.…”