Oncostatin-M functionalized cryogel microspheres for promoting diabetic bone defects regeneration.

BACKGROUND/OBJECTIVE: Bone defects, especially those associated with diabetes, pose a significant challenge due to impaired healing capabilities. In situ bone tissue engineering harnesses the body's innate self-repair capabilities instead of introducing exogenous cells, and the development of biomaterials with well-designed biophysical and biochemical properties is pivotal for this strategy. Oncostatin M (OSM), a pleiotropic cytokine belonging to the IL-6 family, is responsible for recruiting endogenous cells and bone regeneration. This study focuses on the role of OSM in osteogenesis, angiogenesis, and immunoregulation, as well as developing OSM functionalized cryogel microspheres (OSM/MS) to enhance bone regeneration in diabetic conditions. METHODS: We systematically investigated the in vitro bioactivities of OSM on bone marrow mesenchymal stromal cells (BMSCs), human umbilical vein endothelial cells (HUVEC), and macrophages (RAW264.7). Subsequently, we fabricated OSM-loaded porous GelMA cryogel microspheres (OSM/MS) via the combination of emulsification and gradient freeze-crosslinking techniques. The biocompatibility, osteogenic and angiogenic potentials, and immunomodulatory effects of OSM/MS were evaluated in vitro. The in vivo efficacy of OSM/MS was assessed in an inflammatory diabetic rat calvarial defect model. RESULTS: 50 ng/ml OSM can enhance migration and osteogenic differentiation of BMSCs, and angiogenesis in vitro without inciting an inflammatory response. OSM/MS, with an average diameter of ∼80 μm and an average pore size of about ∼10 μm, demonstrated excellent biocompatibility and significantly promoted the migration and osteogenic differentiation of BMSCs, as well as the angiogenic potential of HUVEC. Moreover, OSM/MS effectively regulated macrophage polarization towards an anti-inflammatory M2 phenotype. In vivo studies revealed that OSM/MS reduced osteoclast differentiation and promoted bone regeneration in diabetic rats. CONCLUSION: The multifunctional properties of OSM/MS, including stem cell recruitment, osteogenesis, immunomodulation, and angiogenic induction, make it an effective approach for promoting bone regeneration in challenging diabetic conditions. This research not only lay the groundwork for the clinical utilization of OSM, but also presents a novel bioactive microsphere-based strategy for the management of diabetic bone defects. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: The ability of OSM/MS to promote endogenous stem cell recruitment, modulate the immune-osteogenesis microenvironment, and induce angiogenesis makes it a potent candidate for diabetic bone defects. The injectable and porous nature of OSM/MS facilitates minimally invasive delivery and integration with the irregular bone defect site. In particular, OSM/MS face fewer regulatory hurdles compared with traditional tissue engineering strategy due to the lack of cellular components. Given the significant unmet clinical need and the promising in vivo results, OSM/MS holds great potential for transforming the treatment paradigm for bone defects in diabetic patients.