Granular Nanofiber‐Hydrogel Composite‐Programmed Regenerative Inflammation and Adipose Tissue Formation

Abstract The interplay between biomaterials and host immune responses critically determines outcomes in tissue restoration. Recent studies suggest that physicochemical properties of materials can dictate pro‐regenerative versus pro‐fibrotic responses and have begun to define the key immune cell types and signals governing these divergent effects. This emerging understanding enables the engineering of regenerative biomaterials capable of functional restoration in situ. An injectable nanofiber‐hydrogel composite (NHC) microparticles are designed and constructed from cross–linked electrospun collagen nanofiber fragments surface‐bonded to the hyaluronic acid hydrogel network via covalent conjugation during the cross–linking process. The collagen nanofiber fragments, acting as the structural reinforcement component, increased the overall storage modulus of the NHC to a level comparable to native soft tissues while maintaining a sufficiently high degree of porosity of the hydrogel phase to allow host cell infiltration following subcutaneous injection of the NHC microparticles. More importantly, the NHC promoted macrophage/monocyte infiltration, migration, and spreading, sustained cell recruitment over time, and enhanced the proangiogenic effect and recruitment of PDGFRα + perivascular progenitor cells, leading to extensive adipose tissue remodeling. This study demonstrates the regenerative potential of the injectable NHC microgels as an off‐the‐shelf solution for devastating soft tissue losses.