Designing cell-instructive hydrogels to understand and exploit mechanobiology

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ABSTRACT Anchorage-dependent cells sense the mechanics of their surroundings by pulling and pushing on the extracellular matrix (ECM), and in response, generate intracellular signals in a process known as mechanotransduction. Matrix mechanical properties regulate a range of cell behaviors such as traction force generation, cytoskeletal organization, proliferation, migration, and differentiation, necessitating the development of in vitro model systems to investigate and understand these cellular phenomena. My lab is at the forefront of designing hydrogels as in vitro models that move away from static, monolithic constructs and toward dynamic, interactive, and responsive materials that capture the complexity of native cellular milieus. The proposed research program will address a critical bottleneck in the field of understanding and exploiting mechanistic knowledge of cellular mechanotransduction toward addressing health challenges in disease and tissue regeneration. Theme 1: How Do Time-Dependent Mechanics Affect Cellular Mechanotransduction? While nearly all synthetic biomaterials present an elastic mechanical environment to cells, most natural ECM materials are viscoelastic and exhibit complex time-dependent mechanical behavior. There is still an unmet need for cell culture platforms that permit the design flexibility of synthetic materials (e.g., spatiotemporal tuning of ligand presentation and stiffness) while also displaying viscoelastic mechanical properties. This research theme will build on burgeoning efforts from my group to develop viscoelastic hydrogels in order to test the hypothesis that in 3D cultures viscoelasticity, not stiffness-based signaling, is the overriding factor required for active mechanotransduction in fibroblast activation and mesenchymal stromal cell (MSC) differentiation. Theme 2: How Do Mechanics Regulate Growth Factor Signal Transduction? While recent integral studies have explored the influence of stiffness, ligand presentation, and degradation on stem cell proliferation and differentiation, little is known about how these properties contribute to transforming growth factor-β (TGF-β) signal transduction. By investigating the combined influence of substrate biophysical and biochemical properties, this theme will elucidate design rules for how cellular microenvironments influence the mechanobiology of growth factor signal transduction, thus providing a framework for the design of biomaterials that permit more efficient presentation of growth factors. Theme 3: Can We Engineer Thermoresponsive Biomaterials for Stem Cell Maintenance and Expansion? The ability to efficiently generate large numbers of specific, well-defined cell types is critical to the treatment of numerous diseases and disorders. This theme will focus on the creation of thermoresponsive tunable biomaterials to optimize the expansion, maintenance, and mechanical priming of MSCs, while also enabling facile cell harvesting and validation. Multiple levels of stimuli-responsiveness will be engineered (e.g., through inclusion of liquid crystalline domains) to permit both mechanical actuation during culture and subsequent cell release for use in downstream applications.