Immunomodulatory ECM-like Microspheres for Accelerated Bone Regeneration in Diabetes Mellitus

Bone repair and regeneration process is markedly impaired in diabetes mellitus (DM) that affects hundreds of millions of people worldwide. As a chronic inflammatory disease, DM creates a proinflammatory micro-environment in defective sites. Most of the studies on DM, associated bone regeneration, however', neglect the importance-of immunomodulation under the DM condition and adopt the same approaches to normal bone healing, leading to limited bone healing. In this study, we developed a unique bioinspired injectable microsphere as an osteoimmunomodulatory big material that modulates macrophages to create a prohealing microenvironment under the DM condition. The microsphere was self-assembled with heparin-Modified gelatin nanofibers, and interleukin 4 (IL4) was incorporated into the nanofibrous heparin modified gelatin microsphere (NHG-MS). IL4 has binding domains with heparin, and the binding of 11,4 to heparin stabilizes this cytokine, protects it from denaturation and degradation, and subsequently prolongs its sustained release to modulate macrophage polarization. The IL4-loaded NH-MS switched the proinflammatory M1 macrophage into a prohealing phenotype, recovered the M2/M1 ratio to a normal level, efficiently resolved-the inflammation, and ultimately enhanced osteoblastic differentiation; and bone regeneration. The development of osteoimmunomodulatory biomaterials that harness, the power of macrophages for immunomodulation, therefore, is a novel and promising strategy to enhance bone regeneration under DM condition.