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.
Highlights
Cuteanous wound healing is a natural, complex response to tissue injury and normally results in a scar
The hypertrophic scar (HTscar) model was validated with therapeutics generally used in the clinic for scar treatment (5-fluorouracil and a triamcinolone (Kenacort®-A40)) (Mustoe et al, 2002; Wang et al, 2009) and a therapeutic known to be unsuccessful in scar reduction (1,25-dihydroxy vitamin D3)
Rete ridges are almost absent in HTscar and occur to a lesser extent in normotrophic scar (NTscar) compared to Nskin (Ehrlich et al, 1994) (Fig. 1A)
Summary
Cuteanous wound healing is a natural, complex response to tissue injury and normally results in a scar. The most desirable scar is thin and flat and is mostly seen after superficial injury. This type is called a normotrophic scar (NTscar). Deep burns, and sometimes even standard surgery, can result in wound closure with an adverse scar formation which is red, firm, raised, itchy, and painful. This adverse scar is known as a hypertrophic scar (HTscar) (Bayat et al, 2003). The quality of life of patients with HTscars can be severely affected due to loss of joint mobility, contractures, and disfigurements which lead to accompanying psychological problems (like depression and social avoidance) (Bayat et al, 2003)
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