Neurocentric Enhancement of Skeletal Muscle Function for the Treatment of Volumetric Muscle Loss
Abstract
Objectives and Rationale: Severe musculoskeletal trauma is pervasive among battlefield injuries and results in substantial medical cost and long-term functional disability. Volumetric muscle loss (VML) occurs when there is significant traumatic orthopaedic injury or surgical removal of skeletal muscle, a common outcome of these severe musculoskeletal traumas. A lack of understanding currently exists regarding VML injuries? inherent disruption of a portion of neuromuscular junctions (NMJs) within the traumatized muscle, resulting in fiber denervation and presumptive motor unit (motoneuron and muscle fiber unit) dysfunction. This proposal will characterize and understand the degree of neural dysfunction, specifically at the terminal axons of the intramuscular nerves and NMJs, following VML injury. Notably, acute and chronic consequences of neuromuscular disruption inherent to VML injury are likely to include secondary loss of function and impairment of therapies. That is to say, a limitation and limited efficacy of any current rehabilitative and regenerative therapies may be impaired by neural dysfunction and inability to reinnervate muscle fibers. We are investigating how VML injury impairs the neuro aspect of the neuromuscular system. We will test two specific aims: (1) to understand and characterize the loss in innervation and the neurocentric pathophysiologic response acutely post-VML injury, we will examine the disruption of the motor unit at various times post-injury and (2) to exploit neurotrophic signaling for the enhancement of skeletal muscle function following VML injury. Research Applicability: By studying and investigating the neuromuscular system and specifically the effects of VML injury on the innervation of the muscle fibers, we hope to be able to test targeted treatments to improve healing of the muscle following injury. Additionally, we hope to elevate the wounded Service member?s long-term quality of life. The proposed work directly addresses current Regenerative Medicine Capability Gaps: ?Lack of understanding and control of physiological interactions for regenerative medicine optimization? and ?Inadequate ability to regenerate and integrate functional muscle units.? Clinical and Patient Alignment and Timelines: This proposal will examine and advise future clinical care guidelines following extremity trauma. Advances in military medicine have made extremity wounds the most common survivable injury in modern military conflicts. Approximately 14,500 Service members were evacuated from war between 2001 and 2013, and about 77% had some musculoskeletal injuries. Of injuries that limit Service members from returning to duty, ~83% are orthopaedic and many have a component of VML. Extremity combat casualties cost the Department of Defense $42.4 billion in initial costs and contribute to the $108.8 billion in lifetime disability benefit cost to injured Service members and require the longest hospitalization and rehabilitation times. Using the Army Physical Evaluation Board, it has been shown that disability ratings following VML-related injuries do not improve over time, even with additional recovery time. This work is crucial to determine clinically appropriate treatment strategies that could be initiated in immediate and long-term clinical care plans for VML, for both the military and civilian populations. This work addresses the most significant extremity injury among Service members evacuated from the battlefield. Our approach of using off-label use of a U.S. Food and Drug Administration (FDA)-approved drug will accelerate potential successful findings to clinical testing. We hope that the research outcomes can be used to test this neurocentric treatment strategy in large animal models of VML injury. If successful, we plan to collaborate with our clinical colleagues to test these approaches in the clinic and ultimately inform clinical care guidelines. Service Member Benefit: This p
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 05, 2019
- Source ID
- W81XWH1910075XX0
Entities
People
- Sarah M Greising
Organizations
- United States Army
- University of Minnesota