Development and Persistence of Tissue-Level Musculoskeletal Deformity Following Brachial Plexus Birth Injury

PROJECT SUMMARY Brachial plexus birth injury (BPBI) is a traumatic perinatal neuromuscular injury causing muscle paralysis and lifelong arm impairment. Muscle paralysis in these children also leads to bone and joint consequences, including deformed growth of the scapula and humerus. BPBI occurs during a critical period of rapid musculoskeletal growth, but the parallel postnatal interactions of muscle and bone that drive these persistent deformities are not understood. Clinical reports and preliminary work suggest that short, contracted muscles after injury can alter mechanical loading of the shoulder consistent with observed bone deformity at macro- and microstructural levels. Altered active limb function with reduced range of motion and load bearing is also present; disuse is known to alter tissue growth and maturation. Finally, nerve injury in other conditions also affects bone growth directly, and direct effects in the postnatal period are not clear. Identifying appropriate targets for future treatment requires understanding which factors associated with altered bone and muscle development are most critical for driving altered growth. Almost nothing is known about the timing and progression of changes in underlying bone and muscle structure or metabolism following nerve injury occurring at birth to provide a foundation for clinical decision-making. Our primary hypothesis is that the bone deformity following BPBI is driven primarily by the mechanical environment, derived from impaired longitudinal growth of paralyzed muscle and altered active functional loading beginning shortly after injury. We will apply our unique rodent and computational models of BPBI that probe the separate contributions of nerve injury and muscle contracture to perform complementary assessments of the relative contributions of nerve injury, passive muscle loading, and active functional loading following BPBI to bone deformity. We will do so using 1) previously validated rat neurectomy models of brachial plexus injury and our unique disarticulation model of altered loading and 2) an integrated computational model to determine which specific features of bone deformity following BPBI are driven primarily by each potential driver. This R01 project, conducted by a multidisciplinary team with expertise in orthopedic surgery and biomechanical engineering, has high potential to elucidate the role of denervation in the parallel development of bone and muscle that occurs postnatally. Our innovative study design permits us to isolate both direct neural effects and indirect effects from altered passive and active mechanical loading on bone development in a way that has not previously been possible. Ultimately, this work has the potential to shift current research and treatment paradigms from an isolated focus on muscle as a treatment target to an integrated muscle and bone approach based on driving factors of deformity and loss of function. We anticipate our results will provide new candidates for improved treatment of BPBI and other neuromuscular injuries.