Vascularization of the Dermal Support Enhances Wound Re-Epithelialization by In Situ Delivery of Epidermal Keratinocytes

Abstract

Despite significant advances in management of severe wounds such as burns and chronic ulcers, autologous split-thickness skin grafts are still the gold standard of care. The main problems with this approach include pain and discomfort associated with harvesting autologous tissue, limited availability of donor sites, and the need for multiple surgeries. Although tissue engineering has great potential to provide alternative approaches for tissue regeneration, several problems have hampered progress in translating technological advances to clinical reality. Specifically, engineering of skin substitutes requires long culture times and delayed vascularization after implantation compromises graft survival. To address these issues we developed a novel two-prong strategy for tissue regeneration in vivo: (1) vascularization of acellular dermal scaffolds by infiltration of angiogenic factors; and (2) generation of stratified epidermis by in situ delivery of epidermal keratinocytes onto the prevascularized dermal support. Using athymic mouse as a model system, we found that incorporation of angiogenic factors within acellular human dermis enhanced the density and diameter of infiltrating host blood vessels. Increased vascularization correlated with enhanced proliferation and stratification of the neoepidermis originating from the fibrin-keratinocyte cell suspension. This strategy promoted tissue regeneration in vivo with no need for engineering skin substitutes; therefore, it may be useful for treatment of major wounds when skin donor sites are scarce and rapid wound coverage is required.

Biomaterials to Prevascularize Engineered Tissues

“…Fibrin has been widely used to create vascularized tissue constructs for skin [62,63], adipose tissue [63][64][65][66], bone [67][68][69], cartilage [70], skeletal muscle [71], retina [72], liver [73], and cardiovascular [74,75] applications. The wide use of fibrin in vascularized tissues is due to its excellent pro-angiogenic properties.…”

Novel bilayer wound dressing composed of silicone rubber with particular micropores enhanced wound re-epithelialization and contraction

“…For example, Integra™, which was designed to rebuild the dermal substrate [11,12]. However, the main component of Integra was still the collagen/chondroitin-6-sulfate composite [13,14], the silicone sheet was just used to protect the collagen-based scaffold.…”

Microenvironment-induced myofibroblast-like conversion of engrafted keratinocytes

“…It has been reported that keratinocytes, when placed in a suitable microenvironment, are able to regenerate multi-lineage skin in mice [7]. Moreover, the transplanted keratinocytes facilitate the formation of blood vessels [8]. In addition, skin grafting has been used for the treatment of burns and chronic leg ulcers, which can promote faster re-epithelialization of partial thickness wounds [9][10][11][12].…”