Scalable High-Throughput Production of Modular Microgels for In Situ Assembly of Microporous Tissue Scaffolds

Hydrogel scaffolds that template the regeneration of tissue structures are widely explored; however, there is often a trade-off between material properties, such as stiffness and interconnected pore size, that may be equally important in supporting tissue growth. Microporous annealed particle scaffolds are introduced to address this trade-off while maintaining a flowable precursor; however, manufacturing throughput, reproducibility, and flexibility of hydrogel microparticle building blocks are limited, hindering widespread adoption. The scalable high-throughput production of bioactive microgels for the formation of microporous tissue scaffolds in situ is presented. Using a parallelized step emulsification device, scalable high-throughput generation of monodisperse microgels is achieved. Crosslinking is initiated downstream of droplet generation using pH modulation via proton acceptors dissolved in the oil phase. This approach enables continuous production of microgels for over 12 h while ensuring highly uniform physicochemical properties. Using this platform, the effects of local matrix stiffness on cell growth orthogonal to scaffold porosity are studied. Formation of injectable cell-laden mechanically heterogeneous microporous scaffolds is also demonstrated. This approach is particularly suited for the formation of modular, multimaterial scaffolds in situ, which could be applied to 3D bioprinting or to form more complex scaffolds to enhance regeneration of irregular wounds.