CAREER: Bottom-up Approach to Engineer Liquid-Liquid Phase Separation and Mechanical Heterogeneity in Microstructured Hydrogels

About This Grant

Non-Technical Summary A hydrogel is a three-dimensional, sponge-like material that can hold a large amount of water. Hydrogels with complex microstructures have become a promising type of material because they offer unique advantages compared to traditional, uniform hydrogels. However, making these advanced hydrogels often requires complicated and time-consuming steps, such as creating and packaging tiny gel particles using methods like microfluidics or water-and-oil mixtures. These techniques can be unsuitable for biological applications and often require additional cleaning processes. This NSF CAREER project aims to develop a simpler and more efficient way to create structured hydrogels using a sugar-based material system and a natural process called liquid-liquid phase separation (LLPS) – a phenomenon similar to how oil and vinegar separate in salad dressing. This novel approach uses chemical modifications to design hydrogels with customizable microstructures that vary in shape, size, and stiffness, enabling scientists to better understand how these material structures affect mechanical properties and cell behavior. Advanced tools like chemical analytical equipment and powerful microscopes will help reveal how the gel’s structure affects its strength and interactions with cells. Unlike current methods, this new process avoids harmful chemicals, simplifies production, and supports the creation of more complex hydrogel designs. Additionally, this research includes educational efforts to teach and train students and researchers how to combine principles of chemical engineering and bioengineering to develop innovative materials for applications such as medicine and tissue repair. Technical Summary Microstructured hydrogels have emerged as a promising class of biomaterials due to their distinct advantages over conventional bulk hydrogels. However, current methods for producing microparticle hydrogels often involve complex, multi-step processes, such as microgel formulation and encapsulation, using techniques like microfluidics and bulk emulsions that rely on water/oil emulsions. This NSF CAREER proposal aims to develop an innovative bottom-up approach to engineer liquid-liquid phase separation (LLPS) in a polysaccharide-based biocomposite material system. This approach leverages versatile chemical crosslinking reactions to produce a library of hydrogels with tunable microstructural morphologies and mechanical heterogeneity, enabling the investigation of their impact on cellular behavior. Analytical chemistry, multiscale mechanical analysis, and confocal microscopic characterizations are employed to elucidate fundamental relationships between hydrogel network structure, material properties, and cellular interactions. The proposed de novo engineered LLPS technique offers a simplified process that eliminates the need for organic solvent while enhancing structural complexity. This work strives to provide a fundamental and generalizable understanding of structural-property-performance relationships in hydrogels. Finally, the educational plan capitalizes on the interdisciplinary nature of the research by providing comprehensive demonstrations and training, fostering the integration of chemical engineering and bioengineering principles in biomaterials design. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.