Bony fracture is one of the most challenging musculoskeletal injuries in the elderly population.In clinic, a significant decline in bone healing potential, accompanying with mental and life-threatening complications, is commonly observed in elderly who are 65 years or older. With therapid growth of elderly population in the US, it imposes a substantial cost burden on the healthcare system to treat fracture. Although significant advances have been made in developingtherapeutic approaches (bone graft materials, growth factors and stem cells) for fracture repair,there is still unmet clinical need for new approaches to treat delayed fracture healing or fracturenon-union, especially for elderly patients.To fulfill this effort, we have focused on angiogenesis, which has long been considered as a keyinitial step during fracture healing to re-establish blood supply for delivery of oxygen, nutrients,and cells. Particularly, recent studies have illustrated that due to the inflammaging in elderlypatients, chronic inflammation adversely affects angiogenesis, and in turn results in the failure ofbony callus formation and develops delayed union or non-union. In this regard, we provideevidence that systemic inflammation results in impaired angiogenesis and fracture non-union inmice. Mechanistically, angiogenesis defect mediated by inflammation is at least partially due todown-regulation of CXCL12 (C-X-C Motif Chemokine Ligand 12) and exogenous CXCL12 canrestore angiogenesis capacity in vitro. In order to apply CXCL12 to local fracture treatmentwhile avoiding excessive angiogenesis or other side effects in other tissues, we design todeliver CXCL12 locally by FDA approved PCL material. The PCL/CXCL12 material displaysimilar biomechanical properties compared to periosteum and a controlled slow-release patternof CXCL12. More importantly, local delivery of CXCL12 shows a robust angiogenesis processand a restoration of fracture union in mice under systemic inflammation conditions. Theoverarching goal of this STTR proposal is to pursue the commercialization of this biodegradableand release controllable PCL/CXCL12 material as a potential therapeutic treatment to promotefracture healing, especially in elderly patients.
Public Health Relevance Statement: Delayed union and non-union are frequently observed in the aging population. The goal of the
study is to develop a device that can promote fracture healing to improve the health of older
adults.
Project Terms: |
| | | | | | | |
