Functional Skin Grafts: Where Biomaterials Meet Stem Cells

Abstract

Skin tissue engineering has attained several clinical milestones making remarkable progress over the past decades. Skin is inhabited by a plethora of cells spatiotemporally arranged in a 3-dimensional (3D) matrix, creating a complex microenvironment of cell-matrix interactions. This complexity makes it difficult to mimic the native skin structure using conventional tissue engineering approaches. With the advent of newer fabrication strategies, the field is evolving rapidly. However, there is still a long way before an artificial skin substitute can fully mimic the functions and anatomical hierarchy of native human skin. The current focus of skin tissue engineers is primarily to develop a 3D construct that maintains the functionality of cultured cells in a guided manner over a period of time. While several natural and synthetic biopolymers have been translated, only partial clinical success is attained so far. Key challenges include the hierarchical complexity of skin anatomy; compositional mismatch in terms of material properties (stiffness, roughness, wettability) and degradation rate; biological complications like varied cell numbers, cell types, matrix gradients in each layer, varied immune responses, and varied methods of fabrication. In addition, with newer biomaterials being adopted for fabricating patient-specific skin substitutes, issues related to escalating processing costs, scalability, and stability of the constructs under in vivo conditions have raised some concerns. This review provides an overview of the field of skin regenerative medicine, existing clinical therapies, and limitations of the current techniques. We have further elaborated on the upcoming tissue engineering strategies that may serve as promising alternatives for generating functional skin substitutes, the pros and cons associated with each technique, and scope of their translational potential in the treatment of chronic skin ailments.

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

“…When the biomaterials are pre-seeded or have cells incorporated within their matrix, they are classified as cellular artificial skin grafts, whereas biomaterials without or deprived of cells are defined as acellular artificial skin grafts [2,46]. Depending on their anatomical structure, similarly to autologous skin transplants, artificial skin substitutes may be categorized as epidermal, dermal, or dermo-epidermal ( Figure 3) [2,49,50]. Epidermis is non-vascular tissue; thus, the primary role of epidermal skin constructs is to promote re-epithelialization and cover the wound bed, protecting the wound against dehydration and infections.…”

“…For instance, Paggiaro et al [51] used glycerolated human amniotic membrane for the fabrication of cellular epidermal graft seeded with keratinocytes. Nevertheless, it usually takes as long as 2-3 weeks to generate autologous epidermal graft, which is the main disadvantage of cellular epidermal substitutes [49,50]. However, it has been shown that the application of natural biopolymers as membranes for cell cultivation, like fibrin, chitosan or hyaluronic acid (HA), significantly reduces the time needed for the production of cellular epidermal skin grafts, since these biomaterials are known to promote the migration and proliferation of cultured keratinocyes [49].…”

Application of 3D Bioprinting Technologies to the Management and Treatment of Diabetic Foot Ulcers

“…Bioengineered human skin equivalent (HSE) products are also used for grafting, and they eliminate the issue of non-healing secondary wounds [ 83 , 84 , 85 ]. Bioengineered skin substitutes are broadly categorized into epidermal-, dermal- and bilayered-constructs, depending on the cellular composition and thickness of the constructs [ 86 ]. Cultured epithelial autografts typically comprise 6-8 stratified layers of autologous keratinocytes grown on irradiated murine fibroblasts.…”

Self-assembly of progenitor cells under the aegis of platelet factors facilitates human skin organoid formation and vascularized wound healing

“…Successful tissue regeneration is strongly dependent on effective vascularization of injured organs, rapidly supporting the tissue with oxygen and nutrients 8 . Extending previous experience with robust human vasculogenesis induction by combining ECFCs with stromal cells 11 , co-transplantation of ECFCs significantly increased dermal vessel formation compared to keratinocyte/fibroblast transplants devoid of ECFCs, despite adding hPL in both conditions (Fig.…”

“…The current gold standard for extended area epidermal replacement is transplantation of ex vivo engineered epidermal sheets 6,7 . Improved dermal restoration and vascularization strategies are prerequisite for providing an oxygen-rich environment that promotes extended skin tissue regeneration 8 . In vitro generated dermis equivalents with pre-formed vessels showed enhanced full-thickness skin wound repair in rats 9 .…”