Keloid disease is characterized by the formation of benign hyperproliferative lesions that develop in response to cutaneous injury. Surgical treatment of keloids is challenging, and patients suffer from high reoccurrence rates. These masses can lead to decreased quality of life as they can be cosmetically disfiguring, pruritic, and painful. Clinically, keloids have been noted to form in areas of high tissue tension, including the chest, shoulder, and back, suggesting a mechanobiology component to the pathological condition. These observations are supported by basic scientific research in which keloid fibroblasts have increased growth factor and matrix molecule expression when exposed to static stretch in two dimensional cultures. Furthermore, although keloid disease was initially thought to be the result of abnormal dermal fibroblast activity, altered epidermal signaling and vascular growth have also been reported in diseased tissue. It is therefore important to replicate the interactions of cutaneous tissues, in addition to mechanical stretch, when modeling the condition. Basic research and development of advanced therapies for keloid disease suffers from a lack of animal models or advanced in vitro models, as keloid disease presents itself only in humans. Microfluidic organ models are particularly well suited for the study of keloid disease as they result in high content research with small amounts of human cells. Typically comprised of polydimethylsiloxane (PDMS) microfluidic chambers, these multi-layered biomimetic microsystems combine advanced techniques in microfluidics, biology, and tissue engineering to investigate how microenvironmental cues influence pathophysiological responses. Therefore, the objective of the proposed research is to first develop a skin-on-a-chip model, with an epidermal component cultured at an air interface atop a vascularized dermal component. This complex, three-dimensional microfluidic skin model will then be used to study the mechanoresponsiveness of keloid cells in response to dynamic stretch, aiming to replicate the pathological condition. Mechanically regulated pathways and nuclear translocation of gene expression regulating complexes (Hippo [YAP/TAZ] and TGF-? [Smad2/3]) with dynamic culture will be compared (normal vs. keloid). Finally, these pathways will be targeted with small molecules to determine if strain induced pathology can be mitigated, thus providing targets for clinical treatment of lesion formation. Completion of the proposed aims will result in the contribution of a versatile microfluidic organ model to the skin community in addition to enhancing the understanding of the mechanobiology of keloid disease.
Keloid disease is characterized by the formation of benign dermal pseudo-tumors in response to injury, which typically develop in areas of high tissue tension, suggesting a mechanobiology component to the disease. Basic research and development of advanced therapies suffers from a lack of animal models as keloid disease presents itself only in humans. The aim of this proposal is to develop a microfluidic organ model of the skin, or skin-on-a-chip, to investigate the role of, and subsequently target, mechanosensitive pathways (Smad2/3, YAP/TAZ) in keloid progression.
