Immune regulation enhances osteogenesis and angiogenesis using an injectable thiolated hyaluronic acid hydrogel with lithium-doped nano-hydroxyapatite (Li-nHA) delivery for osteonecrosis

Osteonecrosis is a devastating orthopedic disease in clinic that generally occurs in the femoral head associating with corticosteroid use up to 49 % in patients. In particular, glucocorticoids induced osteonecrosis of the femoral head is closely related to the local immune response that characterized by abnormal macrophage activation and inflammatory cell infiltration at the necrotic site, forming a pro-inflammatory microenvironment dominated by M1 macrophages, and thus leads to failure of bone repair and regeneration. Here, we report a bone regeneration strategy that constructs an immune regulatory biomaterial platform using an injectable thiolated hyaluronic acid hydrogel with lithium-doped nano-hydroxyapatite (Li-nHA@Gel) delivery for osteonecrosis treatment. LinHA@Gel achieved a sustain and longterm release of Li ions, which might enhance M2 macrophage polarization through the activation of the JAK1/STAT6/STAT3 signaling pathway, and the following induced pro-repair immune microenvironment mediated the enhancement of the osteogenic and angiogenic differentiation. Moreover, both in vitro and in vivo studies indicated that Li-nHA@Gel enhanced M2 macrophage polarization, osteogenesis, and angiogenesis, and thus promoted the bone and blood vessel formation. Taken together, this novel bone immunomodulatory biomaterial platform that promotes bone regeneration by enhancing M2 macrophage polarization, osteogenesis, and angiogenesis could be a promising strategy for osteonecrosis treatment.