It is well appreciated that extracellular cues stemming from the matrix dictate a multitude of cellular functions, from motility to stem cell differentiation. Yet, the extracellular environment is inherently complex and thus hinders our full understanding of specific matrix-based contributions to cellular behavior. Our work focuses specifically on the context of age-related matrix remodeling and engineering materials capable of recapitulating matrix properties in vitro at both the micro and nano length scales. This talk will highlight some of our material approaches to control cell-matrix interactions in the context of cardiac aging and mechanobiology. In the first, we describe methods for developing tunable stiffness gradient polyacrylamide (PA) hydrogels using a two-step polymerization method. These platforms are capable of spanning the diverse physiological and pathological mechanical landscapes present in the heart, allowing us to understand the regulation of mechanosensitive processes on cardiac function. Our second material strategy is a hybrid hydrogel-decellularized cardiac tissue platform that maintains age-specific matrix composition and organization independent of matrix stiffness. Subsequent culture of cardiac fibroblasts (young and aged) show that the matrix ‘age’ can outweigh matrix mechanics in driving fibroblast activation. In our third approach, we mimic ligand presentation at the nanoscale using Block Copolymer Micelle Nanolithography (BCMN), in which highly ordered gold nanoparticle arrays are deposited onto surfaces with defined interparticle spacing. These particles are subsequently functionalized with peptides and we find that cardiac cell adhesion and mechanomarker expression are enhanced at 35 vs. 50 nm interparticle spacing. Our strategies ultimately aim to interrogate the cell-matrix interface using highly defined biomaterial systems at different length scales that can inform future matrix-based treatment strategies.

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