Battlefield casualty and trauma often results in major injury to the extremities, one example of this is Volumetric Muscle Loss (VML) injuries. While advances in prolonged field care have saved many warfighters lives, those with VML injures are left with long-term functional complications. Unlike more simple muscle injuries, VML injuries are not capable of undergoing significant self-repair. Furthermore, simple muscle injuries have known, validated, and highly reproducible rehabilitation protocols that return those injured to full function, while there are no current evidence based rehabilitation protocols to improve function following VML injuries.
Our central hypothesis is that to improve function (i.e., strength, power, endurance) following VML injury, optimal evidence-based rehabilitation needs to be developed; treatment of physiologic limitations needs to occur in conjunction with rehabilitation; and long-term impacts of both injury and treatment need to be understood across the neuromusculoskeletal system (e.g., bone and muscle) to support long-term health of those injured. Our overall goals are to optimize regenerative rehabilitation solutions to skeletal muscle and bone pathology following limb trauma that will improve warfighter performance and quality of life.
There are currently no short- or long-term guidelines for the restoration of tissue function following Volumetric Muscle Loss (VML) injury and concomitant bone polytrauma. We believe that evidence-based approaches for VML rehabilitation and regenerative rehabilitation are limited by a predominant focus in the field on engineering strategies that neglects the physiology of the tissue and overwhelmingly fails to include clinically relevant outcomes measurements. The proposed research represents a substantive departure from this status quo by leveraging our insight into the VML pathophysiology to correct the dysfunction and resistant plasticity to improve short- and long-term physiologically relevant outcome measurements of muscle and bone function. Our central hypothesis is that to improve function (i.e., increases in muscle power, strength, oxidative capacity, and fatigue resistance) following VML injury, optimal evidence-based rehabilitation needs to be developed; treatment of physiologic limitations needs to occur in conjunction with rehabilitation; and long-term impacts of both injury and treatment need to be understood across the neuromuskulosketal system (e.g., bone) to support long-term health of those injured.
We previously developed a multi-muscle VML injury model to the posterior compartment of the mouse, which will be used in this proposal. The injury encompasses the gastrocnemius, plantaris, and soleus muscles, and the posterior compartment injury is a useful model for chronic evaluations because the muscle group is highly active (with adjacent bone) playing a role in normal ambulation and weight bearing for the animals. Our clinically relevant outcome measurements will include skeletal muscle power, fatigue resistance, oxidative capacity, joint range of motion, and bone ultimate load and morphology (e.g., cross-sectional moment of inertia). These outcomes will be evaluated across three specific aims:
Specific aim 1: Identification of multi-modal rehabilitation parameters to improve lower limb functionality. We have validated muscle electrical stimulation, voluntary wheel running, and whole body vibration as tools to enhance muscle contractile function and passive ankle movements as a tool to improve joint range of motion following VML injury. We propose a combination of approaches that will adjust treatment intensity (low/high).
Specific aim 2: Regenerative rehabilitation solutions to maximize lower limb functionality. Our ongoing work indicates full restorative function with rehabilitation is limited by dysregulated muscle signaling and extensive pathologic fibrotic tissue deposition. We propose a regenerative rehabilitation approach that will use technologies we have identified to address the underlying muscle pathophysiology in combination with our validated rehabilitation strategies and any multi-modal strategies identified. Technologies include fibrosis inhibitors, oxidative capacity stimulators, and muscle atrophy suppressors.
Specific aim 3: Addressing muscle-bone interactions following VML injury. Our strong preliminary data show bone function and quality declines after VML injury and may be resistant to adaptation. Bones will be collected and analyzed for function and quality as part of the studies in both aims 1 and 2. However, additional research is required to better understand the unique muscle-bone interaction and challenges with VML. To address this concern, we will evaluate a regenerative rehabilitation approach to address a muscle-bone polytrauma and evaluate a micro-bone defect model combined with 2-photon microscopy that will enable us identify confounding factors to bone remodeling in the presence of a VML injury.
Current rehabilitation strategies do little for the recovery of muscle function and may in fact be detrimental. This presents a frustrating clinical problem for the VML injured patient and clinical care team. This work will advance the efficacy of regenerative rehabilitation approaches and can impact a range of military service members from those acutely injured in current and forthcoming conflicts to those that have already transitioned to the VA health care system and are confronting the chronic devastating outcomes of VML injury.