Metabolically activated energetic materials mediate cellular anabolism for bone regeneration

Poly(3-hydroxybutyrate-co-4-hydroxybutyrate) [P(3HB-co-4HB)] is biosynthesized by engineered Halomonas bluephagenesis TD01.3-Hydroxybutyrate (3HB) enhances cellular anabolism, thereby promoting osteogenesis of human bone marrow-derived mesenchymal stem cells (hBMSCs).3HB administration significantly increased bone mass in rats with ovariectomy (OVX).The P(3HB-co-4HB) scaffold substantially enhances long-term vascularized bone regeneration in rat models with critical-sized defects. The understanding of cellular energy metabolism activation by engineered scaffolds remains limited, posing challenges for therapeutic applications in tissue regeneration. This study presents biosynthesized poly(3-hydroxybutyrate-co-4-hydroxybutyrate) [P(3HB-co-4HB)] and its major degradation product, 3-hydroxybutyrate (3HB), as endogenous bioenergetic fuels that augment cellular anabolism, thereby facilitating the progression of human bone marrow-derived mesenchymal stem cells (hBMSCs) towards osteoblastogenesis. Our research demonstrated that 3HB markedly boosts in vitro ATP production, elevating mitochondrial membrane potential and capillary-like tube formation. Additionally, it raises citrate levels in the tricarboxylic acid (TCA) cycle, facilitating the synthesis of citrate-containing apatite during hBMSCs osteogenesis. Furthermore, 3HB administration significantly increased bone mass in rats with osteoporosis induced by ovariectomy. The findings also showed that P(3HB-co-4HB) scaffold substantially enhances long-term vascularized bone regeneration in rat cranial defect models. These findings reveal a previously unknown role of 3HB in promoting osteogenesis of hBMSCs and highlight the metabolic activation of P(3HB-co-4HB) scaffold for bone regeneration. [Display omitted] The gradual release of 3-hydroxybutyrate (3HB) from the degradation of biosynthesized poly(3-hydroxybutyrate-co-4-hydroxybutyrate) [P(3HB-co-4HB)] implants creates a metabolic microenvironment that promotes cellular anabolism by facilitating ATP production and stimulating the formation of citrate-containing apatite. These effects enhance osteogenesis in human bone marrow-derived mesenchymal stem cells (hBMSCs), leading to osteoblast differentiation and ultimately supporting bone regeneration. Engineered scaffolds not only provide essential support for tissue regeneration but also significantly influence the outcome of functional tissue regeneration by mediating the metabolic microenvironment. The current unde