Regulation of Inflammatory Response and Osteogenesis to Citrate‐Based Biomaterials through Incorporation of Alkaline Fragments

A proper pH microenvironment is crucial to mobilizing regeneration function of biomaterials. Neutralizing the acidity in bone defects with alkaline substances is a promising strategy to create favorable environments for cell proliferation and bone repair. In this study, to neutralize the acidity and reduce the inflammation caused by the rapid release of citric acid, a novel citrate-based biodegradable elastomeric poly(citric acid-1,8-octanediol-1,4-bis(2-hydroxyethyl)piperazine (BHEp)) (POPC) is synthesized with the introduction of the alkaline fragment BHEp, and then POPC/β-tricalcium phosphate (β-TCP) porous scaffolds are fabricated by 3D printing technique. The results reveal that the alkaline fragment BHEp effectively corrects the acid environment and improves the biocompatibility, cells affinity and promoted cell adhesion, and proliferation of POPC. Furthermore, the improved pH of POPC15/β-TCP (PTCP15) enhances the adhesion and the proliferation of rabbit bone marrow mesenchymal stem cells, and the expression of osteogenesis-related genes. Moreover, PTCP15 scaffolds relieve inflammatory response and switch RAW 264.7 toward a prohealing extreme. The rat femoral defect model further demonstrates good biocompatibility and enhanced bone regeneration of PTCP15. In conclusion, the results offer a promising approach for biodegradable polymers to address the degradation acidity issue. Meanwhile, a positive regulation strategy is provided for biopolymer to enhance cell proliferation, osteogenic differentiation, and bone repair.