Development of Calcium Phosphate Composite Cement Enabling Alkaline Microenvironment pH Regulation for Osteomyelitis Control and Bone Regeneration

Abstract Osteomyelitis, a chronic bone infection, poses significant challenges in clinical management due to the risks of severe bone necrosis and the increasing prevalence of antibiotic-resistant bacteria. Conventional therapeutic strategies, including surgical debridement and systemic antibiotic therapy, often fall short of achieving optimal outcomes due to antibiotic resistance and failure to achieve high-quality bone regeneration post-surgery. To address these clinical challenges, this study developed an alkaline calcium phosphate cement enabling sequential osteomyelitis control and bone regeneration. This cement was formed through a stepwise reaction between calcium hydroxide (Ca(OH)2) and sodium polyphosphate ((NaPO3)n) in an aqueous environment, enabling provisional defect filling as well as immediate generation of a hyperalkaline environment upon implantation to effectively inhibit both Gram-positive and Gram-negative bacteria. The pH value of bone cement extract gradually decreased from a hyperalkaline state (>11.5) to a mildly alkaline microenvironment (7.8-8.5) over time with the progression of the reaction between Ca(OH)2 and (NaPO3)n in situ, subsequently fostering a favorable microenvironment for bone regeneration. Meanwhile, a stable and effective rat osteomyelitis model was established to verify the sequential antibacterial and osteogenic performance of the material in vivo. In vitro cellular experiments demonstrated that bone cement enhances the proliferation and osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs). Moreover, an in vivo osteomyelitis rat model also revealed the absence of infectious reactions or tissue necrosis, as well as bone formation around the cement post-implantation, confirming the feasibility of this material in treating osteomyelitis. Collectively, these results indicated that the as-developed cement can serve as an active bone repair material adapted to dynamic microenvironment regulation needs, offering a promising approach for the treatment of osteomyelitis and the promotion of bone regeneration in a sequential manner.