Sandwich-structured PVDF/protein piezoelectric hydrogel regulates osteogenesis and adipogenesis through glycerophospholipid metabolism in osteoporotic inflammatory bone defects

Osteoporosis can occur when age-related ovarian dysfunction leads to estrogen deficiency. When bone mineral content decreases, fragile bones are susceptible to bone defects. This estrogen deficiency causes differentiation of mesenchymal cells to shift towards adipogenesis and reduced osteogenesis, which culminates in nonunion. With the potential to modulate cell differentiation, electrical stimulation is promising for osteoporosis defects complicated by an inflammatory environment. A sandwich-structured silk fibroin hydrogel (RSF) with three layers of polyvinylidene fluoride (PVDF) membrane with many β-crystalline phases and MXene for electrical conductance was fabricated, generating voltages up to 500 mV to leverage the implanted bone grafts for a sustainable source of electrical stimulation. Combined transcriptomic and metabolomic analyses revealed that piezoelectric stimulation promoted osteogenesis and suppressed glycerophospholipid metabolism by upregulating lipid degradation-related genes. Specifically, Pla2g4a was critical to the hydrolysis of phospholipids, as shown by Sudan black B staining in rBMSCs. Finally, we created femoral defects in osteoporotic rats and implanted MXene/PVDF/RSF hydrogel to promote osteogenesis and reduce adipogenesis, as shown by micro-CT and immunostaining. As a result, piezoelectric MXene/PVDF/RSF hydrogel effectively redirected bone-fat balance and overcame the inflammatory environment in osteoporotic bone defects, serving future clinical applications.