Abstract
Delayed repair caused by prolonged inflammatory response might lead to clinical nonunion and failed bone regeneration. The design of desirable biomaterials requires precise regulation of the initial osteoimmune responses and efficient osteoinductive capacity to facilitate later bone regeneration. Herein, a Dex-loaded blood clot-embedded BMP-2/CPC scaffold (Dex/blood/BMP-2/CPC) was fabricated for clinical bone regeneration with the sequential release of dexamethasone (Dex), a clinical immunosuppression drug, and BMP-2, a potent osteogenic growth factor. The introduction of Dex at a BMP-2/Dex ratio of 1/6 effectively facilitated M2 polarization of macrophages and exerted a synergetic effect on BMP-2-mediated osteogenic differentiation. The highest in vivo bone regenerative efficacy was achieved by Dex/blood/BMP-2/CPC scaffold with a 1/6 BMP-2/Dex dose, exhibiting significantly enhanced endochondral ossification and attenuated bone resorption in an ectopic model, as well as reduced fibrosis at the orthotopic defect site. Blood clot embedment further provides nutrition and cytokines for the endochondral ossification process. On these bases, a pilot clinical trial was carried out and the Dex/blood/BMP-2/CPC scaffold was demonstrated to accelerate fracture healing, improve therapeutic quality, and eliminate local inflammation compared to current bone regenerative treatment. Taken together, this work designed an immunoregulatory and osteoinductive Dex/blood/BMP-2/CPC scaffold, which might provide new insights for future biomaterial development (Trial registration: ChiCTR2100047693).