Dynamic Macropore Formation via Dual-Degrading Injectable Microgels Enhances Host-Mediated Angiogenesis and Regeneration.

Hydrogels are widely employed in tissue engineering for their biomimetic microenvironments. However, the dense crosslink network of hydrogels with matching mechanical properties of soft tissues often restricts cell infiltration and tissue integration. While granular hydrogels enhance host integration through the formation of porous channels between particles, they self-anneal in vivo, thereby limiting porosity and interconnectivity. To address this, an injectable hyaluronic acid (HA) macroporous hydrogel mixture consisting of two microgels with differential degradation profiles (faster- and slower-degrading) is designed. The faster-degrading fraction gradually generates interconnected macropores, enhancing cell infiltration throughout the mixtures, whereas the slower-degrading counterpart preserves volumetric integrity. Computational simulations refined the microgel ratio, identifying that a 1:1 volume ratio of the two microgels achieves the highest degree of host cell infiltration. The faster-degrading HA exerts biostimulatory effects in rats, recruiting and programming macrophages to a pro-regenerative phenotype and amplifying pro-angiogenic responses that are absent in macrophage-depleted rats. The dual-degrading microgels simultaneously enable gradual pore formation while maintaining structural integrity through ECM deposition by infiltrating host cells. This study presents a programmable hydrogel design that leverages dynamic macroporous structure formation to modulate host cell infiltration and tissue integration, with potential applications in soft tissue regeneration.