Cardiac Matrix-Derived Granular Hydrogel Enhances Cell Function in 3D Culture

Hydrogels derived from decellularized porcine myocardial matrix have demonstrated significant potential as therapeutic delivery platforms for promoting cardiac repair after injury. Our previous study developed a fibrin-enriched cardiac matrix hydrogel to enhance its angiogenic capacities. However, the bulk hydrogel structure may limit their full potential in cell delivery. Recently, granular hydrogels have emerged as a promising class of biomaterials, offering unique features such as a highly interconnected porous structure that facilitates nutrient diffusion and enhances cell viability. Several techniques have been developed for fabricating various types of granular hydrogels, among which extrusion fragmentation is particularly appealing due to its adaptability to many types of hydrogels, low cost, and high scalability. In this study, we first confirmed the effects of the bulk cardiac matrix hydrogel on the viability of encapsulated human umbilical vein endothelial cells and human mesenchymal stem cells. We then tested the feasibility of producing granular hydrogels from both cardiac matrix and fibrin-enriched cardiac matrix through cellular cross-linking of microgels fabricated by extrusion fragmentation. Afterward, we examined the roles of the produced granular hydrogels in the embedded cells and cell spheroids. Our <i>in vitro</i> data demonstrate that cardiac matrix-derived granular hydrogels support optimal viability of encapsulated cells and promote sprouting of human mesenchymal stem cell spheroids. Additionally, granular hydrogel derived from fibrin-enriched cardiac matrix accelerates angiogenic sprouting of embedded human mesenchymal stem cell spheroids. The results obtained from this study lay an important foundation for the future exploration of using cardiac matrix-derived granular hydrogels for cardiac cell therapy.