MCC950-loaded silk microgel-hydrogel composite scaffolds effectively modulate inflammation for improving tissue interaction and remodeling

This study developed silk fibroin microgel-hydrogel composite scaffolds loaded with MCC950, a selective NLRP3 inflammasome inhibitor, to address the poor tissue integration and fibrotic encapsulation commonly seen with bulk hydrogels in soft tissue engineering. The authors first optimized horseradish peroxidase-crosslinked silk hydrogels for MCC950 encapsulation, showing that 4% silk formulations formed stable drug-loaded hydrogels with mechanical properties in the soft-tissue range and sustained release behaviour. These hydrogels were then mechanically fragmented into silk microgels and embedded within a softer silk hydrogel filler to create a microporous composite scaffold. In vitro, drug eluted from the constructs retained bioactivity against THP-1 macrophage-like cells, preserving cell viability and selectively suppressing IL-1β while leaving TNF-α signaling comparatively intact. In a 2-week subcutaneous mouse implantation model, the microgel-hydrogel architecture increased cell infiltration relative to bulk hydrogels, and MCC950 loading further reduced fibrous capsule thickness and enhanced infiltration. Mechanistic analysis linked these effects to reduced NLRP3 expression around the implant, reduced M1-like macrophage presence near the scaffold, and increased M2-like macrophages within the scaffold. Overall, the study demonstrates that combining microporous scaffold architecture with localized NLRP3 inhibition creates a more pro-regenerative immune microenvironment that improves tissue interaction and remodeling.