Project Grant R41AG080953

INNOVATIVE MEDICAL DEVICE TO TREAT NONUNION FRACTURE FOR OLDER ADULTS - ABSTRACT 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 THE RAPID GROWTH OF ELDERLY POPULATION IN THE US, IT IMPOSES A SUBSTANTIAL COST BURDEN ON THE HEALTH CARE SYSTEM TO TREAT FRACTURE. ALTHOUGH SIGNIFICANT ADVANCES HAVE BEEN MADE IN DEVELOPING THERAPEUTIC 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 FRACTURE NON-UNION, ESPECIALLY FOR ELDERLY PATIENTS. TO FULFILL THIS EFFORT, WE HAVE FOCUSED ON ANGIOGENESIS, WHICH HAS LONG BEEN CONSIDERED AS A KEY INITIAL 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 ELDERLY PATIENTS, CHRONIC INFLAMMATION ADVERSELY AFFECTS ANGIOGENESIS, AND IN TURN RESULTS IN THE FAILURE OF BONY CALLUS FORMATION AND DEVELOPS DELAYED UNION OR NON-UNION. IN THIS REGARD, WE PROVIDE EVIDENCE THAT SYSTEMIC INFLAMMATION RESULTS IN IMPAIRED ANGIOGENESIS AND FRACTURE NON-UNION IN MICE. MECHANISTICALLY, ANGIOGENESIS DEFECT MEDIATED BY INFLAMMATION IS AT LEAST PARTIALLY DUE TO DOWN-REGULATION OF CXCL12 (C-X-C MOTIF CHEMOKINE LIGAND 12) AND EXOGENOUS CXCL12 CAN RESTORE ANGIOGENESIS CAPACITY IN VITRO. IN ORDER TO APPLY CXCL12 TO LOCAL FRACTURE TREATMENT WHILE AVOIDING EXCESSIVE ANGIOGENESIS OR OTHER SIDE EFFECTS IN OTHER TISSUES, WE DESIGN TO DELIVER CXCL12 LOCALLY BY FDA APPROVED PCL MATERIAL. THE PCL/CXCL12 MATERIAL DISPLAY SIMILAR BIOMECHANICAL PROPERTIES COMPARED TO PERIOSTEUM AND A CONTROLLED SLOW-RELEASE PATTERN OF CXCL12. MORE IMPORTANTLY, LOCAL DELIVERY OF CXCL12 SHOWS A ROBUST ANGIOGENESIS PROCESS AND A RESTORATION OF FRACTURE UNION IN MICE UNDER SYSTEMIC INFLAMMATION CONDITIONS. THE OVERARCHING GOAL OF THIS STTR PROPOSAL IS TO PURSUE THE COMMERCIALIZATION OF THIS BIODEGRADABLE AND RELEASE CONTROLLABLE PCL/CXCL12 MATERIAL AS A POTENTIAL THERAPEUTIC TREATMENT TO PROMOTE FRACTURE HEALING, ESPECIALLY IN ELDERLY PATIENTS.