Abstract
Vascularization of reconstructed tissues is one of the remaining hurdles to be considered to improve both the functionality and viability of skin grafts and the relevance of in vitro applications. Our study, therefore, sought to develop a perfusable vascularized full-thickness skin equivalent that comprises a more complex blood vasculature compared to existing models. We combined molding, auto-assembly and microfluidics techniques in order to create a vascularized skin equivalent representing (a) a differentiated epidermis with a physiological organization and correctly expressing K14, K10, Involucrin, TGM1 and Filaggrin, (b) three perfusable vascular channels with angiogenic sprouts stained with VE-Caderin and Collagen IV, (c) an adjacent microvascular network created via vasculogenesis and connected to the sprouting macrovessels. Histological analysis and immunostaining of CD31, Collagen IV, Perlecan and Laminin proved the integrity of vascular constructs. In order to validate the vascularized skin potential of topical and systemic applications, caffeine and minoxidil, two compounds with different chemical properties, were topically applied to measure skin permeability and benzo[a]pyrene pollutant was systemically applied to evaluate systemic delivery. Our results demonstrated that perfusion of skin reconstructs and the presence of a complex vascular plexus resulted in a more predictive and reliable model to assess respectively topical and systemic applications. This model is therefore aimed at furthering drug discovery and improving clinical translation in dermatology.
Highlights
Tissue engineering and regenerative medicine hold high promises for organ replacement and development of novel therapies
By combining molding and autoassembly techniques as well as microfluidics, we developed for the first time a fully vascularized perfusable reconstructed skin that comprises a differentiated epidermis containing all the layers of the in vivo structure, perfusable macrovessels with angiogenic sprouts, and a microvascular network with capillaries organized by vasculogenesis in the dermis part
Development of a full-thickness skin equivalent with three vascular channels and angiogenic sprouts This study was aimed at creating a full-thickness skin equivalent model with a complex perfusable vascular network as well as a mature epidermal layer
Summary
Tissue engineering and regenerative medicine hold high promises for organ replacement and development of novel therapies. More advanced and complex skin substitutes were published by the integration of hair follicles [10], mature adipocytes in a three-layered skin equivalent [11], sebocytes organoids derived from human induced pluripotent stem cells (hIPS) [12], IPS derived sensory neurons, and Schwann cells with endothelial cells in an innervated engineered skin sponge model [13], etc. Recent interest has focused on transferring various micro-physiological organ models, including skin, onto microfluidic platforms [14,15,16,17,18] These skin-on-a-chip models enable physiologically relevant transport of nutrients and exogenous substances to the skin tissue, better control over physical and chemical factors in the cell microenvironment [19], and more reliable evaluation of drug candidates in terms of toxicity, efficacy, and delivery compared to static conditions [20]
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