Development, validation and testing of a human tissue engineered hypertrophic scar model

Abstract

Adverse hypertrophic scars can form after healing of full-thickness skin wounds. Currently, reliable animal and in vitro models to identify and test novel scar reducing therapeutics are scarce. Here we describe the development and validation of a tissue-engineered human hypertrophic scar (HTscar) model based on reconstructed epidermis on a dermal matrix containing adipose derived mesenchymal stem cells (ASC). Although obtained from normal, healthy skin, ASC, in contrast to dermal mesenchymal cells, were found to facilitate HTscar formation. Quantifiable HTscar parameters were identified: contraction; thickness of dermis, collagen-1 secretion, epidermal outgrowth, epidermal thickness, and cytokine secretion (IL-6, CXCL8). The model was validated with therapeutics currently used for treating scars (5-fluorouracil, triamcinolon) and a therapeutic known to be unsuccessful in scar reduction (1,25-dihydroxyvitamin-D₃). Furthermore, it was shown that atorvastatin, but not retinoic-acid, may provide a suitable alternative for scar treatment. Each therapeutic selectively affected a different combination of parameters, suggesting combined therapy may be most beneficial. This animal-free hypertrophic scar model may provide an alternative model for mechanistic studies as well as a novel in vitro means to test anti-scar therapeutics, thereby reducing the use of animals.