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

Abstract

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.

Keywords: bioreactors; bottom-up tissue engineering; dermal substitutes; extracellular matrix; scar tissue.; skin substitutes; tissue engineering; vascularization; wound healing.

Figure 1

Main components of the human skin. (Image source: brgfx/Freepik).

Figure 2

The main steps of a two-step procedure to treat deep and partial wounds with the application of a DRT. (A) Healthy skin and wound bed after debridement. (B) Application of a DRT possessing an artificial silicone epidermis and covered with gauze. (C) Removal of the silicone epidermis and application of the STSG. (D) Long-term appearance of the repaired dermis. (E) Cellular end extracellular dynamics occurring during the wound healing process after the application of a DRT. W = week; M = month. DRT, dermal regeneration templates; STSG, split thickness skin graft; ECM, extracellular matrix.

Figure 3

The main steps for the production of a DRT composed of fibroblast-assembled/pre-vascularized human dermis substitutes, and its morphological features before and after implantation in a nude mice model. (A) From left to right: production of Dermal-μTissues; their molding and assembly in a maturation chamber that is kept under dynamic culture conditions; formation of a continuum of fibroblasts embedded in their own dermal extracellular matrix; epithelization and vascularization of the endogenous human dermis. (B) Fabrication of large pieces of endogenous human dermis (major dimension 20 cm). (C) Histology of the endogenous human dermis supporting the differentiation of epidermis with the formation of spontaneous rete ridge profile. (D) Vascularized endogenous human dermis: cell nuclei in green and capillary network in red. (E) Vascularized endogenous human dermis: fibroblast-assembled collagen bundles observed under label-free multiphoton microscopy in gray; capillary network in red. (F) Top: fibroblast-assembled hyaluronic acid in green, cell nuclei in blue; Bottom: fibroblast-assembled elastin network in yellow, cell nuclei in blue. (G) Implantation of a piece of the pre-vascularized endogenous human dermis. (H) Connection between engineered capillary network (green) and recipient capillary network (red); fibroblast-assembled collagen in gray. Figure 3B, 3D, 3E, 3G, and 3H are from reference [34] “Mazio, C. et al. Pre-vascularized dermis model for fast and functional anastomosis with host vasculature. Biomat. 192, 159–170 (2019)”. Authors obtained permision from Elsevier: License Number 4681910194044.