Negative pressure wound therapy improves bone regeneration by promoting osteogenic differentiation via AMPK/ULK1/autophagy axis

A substantial proportion of trauma patients suffer bone defects that urges for development of novel therapies. In this study, we applied negative pressure wound therapy (NPWT) and showed significantly improved bone healing in a rat calvarial defect model. We found that NPWT promoted bone regeneration by inducing osteoblastogenesis in vivo and its effect on osteoblast differentiation was mimicked and confirmed in vitro in rat mesenchymal stem cell culture. A mechanistic study based on transcriptomic analysis demonstrated that negative pressure caused autophagy by activating AMPK/ULK1 signaling. Pharmaceutical intervention or inhibition of the AMPK/ULK1/autophagy axis dampened the effect of negative pressure. In consistent, clinical samples from patients with nonunion of bone exhibited impaired AMPK/ULK1/autophagy axis. More importantly, a combined therapy of mesenchymal stem cells in hydrogels with negative pressure on rat critical-size calvarial defects significantly improved bone regeneration. Thus, our study identifies a novel AMPK/ULK1/autophagy axis by which negative pressure promotes osteoblast differentiation of mesenchymal stem cells and bone regeneration. NPWT treatment can potentially be adopted for therapy of bone defects.