(150l) Engineering Macromolecular Hydrophobicity to Induce Phase Separation and Control Microstructure in Biomaterials to Enhance Cellular Function

The compositional heterogeneity and structural diversity of native extracellular matrix (ECM) are essential in regulating cell behavior and promoting tissue regeneration. Thermoresponsive polysaccharide-based materials with tunable transition temperatures and phase-separated microstructure offer substantial opportunities in tissue engineering, drug delivery and wound healing applications. To develop novel synthetic thermoresponsive polysaccharides, we employed versatile chemical routes to attach intrinsically hydrophobic adducts to the backbone of hydrophilic dextran and developed protocols to form hydrogels with defined microstructures. Systematically conjugating methacrylate moieties to the dextran backbone yielded a continuous increase in macromolecular hydrophobicity that induced a reversible phase transition whose lower critical solution temperature can be systematically modulated via variations in polysaccharides concentration, molecular weight, degree of methacrylation, ionic strengths and Hofmeister salts. Photo-initiated radical polymerization permits facile chemical crosslinking and enables the formation of phase-separated hydrogels with controlled microstructure. The resulting heterogeneous hydrogels exhibited well-defined yet tunable microdomains that promote enhanced cell adhesion in 2D and cell migration in 3D. Engineering macromolecular hydrophobicity with temperature triggered phase separation of conventional hydrophilic, non-phase separating polysaccharides to generate heterogeneous hydrogels with controlled microstructures will find potential applications in drug delivery, cancer therapy, biosensing, mechanobiology and tissue repair.