Aortic valve stenosis (AVS) is one of the most common and most progressive valve disease problems. AVS involves a transformation of valvular interstitial cells (VICs) from fibroblast phenotype to a myofibroblast phenotype and eventually an osteoblast phenotype with calcification. My research focuses on utilizing synthetic biomaterials to elucidate how mechanical and chemical cues in the extracellular microenvironment affect VICs behaviors, especially phenotypic change.
Motivated by the fact that collagen fibers loose alignment and become disorganized during wound healing and disease progression, my first project focus on investigating the effect of subcellular matrix mechanics organization change on VICs activation. We utilized a hydrogel platform with photo-cleavable crosslinkers and created subcellular patterns of matrix mechanics by a photomask with lithographic patterns. The patterns on the hydrogel substrates were validated by AFM and we further cultured VICs on the substrates with different patterns. We found out that VICs can not only sense the magnitude of underlying matrix stiffness in a narrow range but also can differentiate the change of subcellular mechanics organizations. A randomized pattern would lead to less mature of focal adhesion, which correlates with a lower Yes-associated protein (YAP) activation as well as fewer α-smooth muscle actin (α-SMA) stress fiber formation. We published a paper with this project on Biomaterials: https://www.sciencedirect.com/science/article/pii/S0142961217301977
I also have two on-going projects, the first one aims to create a dual protein patterning platform with orthogonal click chemistry and further use the platform to probe synergistic proteins (e.g. TGF-β, FGF, BMP-2) effects on VICs performance. Another on-going project is focused on creating an in vitro drug screening and selection system for reversing VICs activation and fibrosis in the early stage. We identify a viscoelastic platform in which VICs spread and align with each other within 24 hrs. We are currently characterizing VICs behaviors in this system as well as preliminarily screening potential drugs to reverse VICs phenotypic change to myofibroblast and osteoblast.