Title:

Engineering Macromolecular Hydrophobicity to Induce Phase Separation and Microstructure in Biomaterials

The compositional heterogeneity and structural diversity of native extracellular matrix (ECM) are essential in regulating cell behavior and promoting tissue regeneration. Synthetic hydrogels with engineered microstructures offer substantial opportunities in tissue engineering applications, owing to the increased matrix complexity that better recapitulates tissue microenvironment to promote cellular behavior. Here we employed versatile chemical routes to induce reversible phase-separation in polysaccharide macromers and developed protocols to form hydrogels with defined microstructures. Conjugating hydrophobic moieties to hydrophilic polysaccharide backbone yielded a continuous increase in macromolecular hydrophobicity that triggers a reversible phase separation whose lower critical solution temperature (LCST) can be systematically modulated via variations in polysaccharide concentration, molecular weight, degree of methacrylation, ionic strength, denaturing agents and Hofmeister salt series, as indicated via UV-vis spectroscopy and dynamic light scattering. Photo-initiated radical polymerization permits facile chemical crosslinking and was utilized for on-demand hydrogel formation to capture microstructures during phase-separation. The resulting phase-separated hydrogels exhibited well-defined yet tunable micro-domains within hydrogel matrix and supported cell attachment with enhanced focal adhesion features. Therefore, developing heterogeneous hydrogels with controlled microstructures will find applications in drug delivery, biosensing, mechanobiology and tissue repair.

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