The exact incidence of volumetric muscle loss (VML) following combat trauma is unknown and has not been rigorously assessed. Estimates from civilian trauma indicate that ~250,000 open fractures occur per year in the US, and these commonly involve a component of VML injury. In the military, a study of battlefield injuries in 14,500 Service members evacuated from OEF/OIF from 2001-2013 suggests high VML incidence. Approximately 77% had musculoskeletal injuries and many had open soft tissue extremity wounds. Roughly 8% of all medically evacuated patients received a disability rating specifically for VML injury. The estimated life-time disability cost per patient is $340,000-440,000 in addition to medical costs and lost wages.
Recovery is uniformly poor, leading to significant long term disability, and leading to increased rates of delayed amputation of technically salvageable, but functionally deficient limbs. There is no agreed upon standard of care for this condition, and no clinically available therapy that can address the loss of function for this condition. The current standard of care for VML involves the use of free muscle transfer (i.e., muscle flaps) for bone coverage followed by extensive physical rehabilitation. However, most muscle flap procedures are not intended to restore muscle function except in limited circumstances. Functional muscle transfer, including vasculature and innervation, has been shown to improve strength to an injured muscle group. However, such procedures require a level of surgical expertise available only in limited, specialized centers.
It is unlikely that there will be a single solution for VML repair. Interventions will likely be required along the continuum of care, beginning close to the point of injury or during initial damage control surgery. In the course of market research, multiple products have been identified which may potentially prevent additional muscle loss and stimulate a repair response early in the course of injury. Such products may be highly valuable in a prolonged field care situation. Such interventions may offer significant improvements over currently limited treatment options.
The focus of this MTEC program is to develop an advanced off-the-shelf prototype capable of preventing, mitigating or treating traumatic large-VML injuries along the continuum of care. The prototype must be able to repair injured muscle tissue to a degree suitable for extremity repair and reconstruction. This program specifically sought projects focused on repurposing products already commercially available or in clinical development for related indications, such as critical limb ischemia, iatrogenic muscle injuries, Duchene’s muscular dystrophy, compartment syndrome, and severe sports medicine injuries. Products capable of regenerating or repairing multiple tissue types or creating a therapeutic wound environment were also considered.
The goal of the MTEC awards is to develop a prototype through proof-of-concept for VML treatment (first in a rodent model, then in a large animal model), with an option to continue product development to relevant supplemental FDA marketing approval/licensure. Support included subject matter expertise, consultation and funding to develop regulatory strategy, conduct animal bridging studies, clinical trials and/or improve efficiency and reproducibility of the manufacturing process at scale to support the desired military indication.
The research project award recipients were selected from the Offerors who responded to MTEC’s Request for Project Proposals (19-03-VML).
Title of Project: Cardiosphere-Derived Cells for the Regeneration of Skeletal Muscle Following Traumatic Volumetric Muscle Loss
Project Team: Smidt Heart Institute, Cedars-Sinai Medical Center
Award Amount: $1,930,033
Project Duration: 2 years
Project Objectives: Traumatic volumetric muscle loss (VML) injuries are exceptionally complex and result in chronic loss of muscle strength, range of motion, and ultimately permanent disability. Skeletal muscle naturally possesses extensive ability to self-repair and regenerate from less destructive forms of muscle injury. Critical components to effective muscle repair include satellite cells and the basal lamina, which must remain intact. When these components are ablated by trauma such as VML, the remaining musculature does not suffice to orchestrate regeneration of the damaged tissue, resulting in the loss of contractile skeletal muscle tissue and extensive fibrosis that ultimately impairs muscle function beyond the frank loss of muscle mass.
There are currently no biological therapies that sufficiently generate de novo muscle, nerve, and vascular tissue following VML. Here, we plan to test the efficacy of clinical grade cardiac stromal cells, called cardiosphere-derived cells (CDCs) to stimulate muscle repair in preclinical models of VML. CDCs have been shown to ameliorate muscle fibrosis and promote endogenous regeneration of dystrophin-deficient muscle in the mdx mouse, a model of Duchenne muscular dystrophy (DMD). In the HOPE clinical trial, CDCs also improved skeletal muscle function in DMD patients. Preliminary data have shown that CDCs coax defective muscle stem cells (called satellite cells) to form new muscle tissue in mdx mice, leading to regeneration of significant amounts of skeletal muscle tissue. Such a fundamental principle of therapeutic action is highly relevant to VML.
The specific aims of this project are designed to answer five inter-connected questions:
- 1. What delivery method and how many cells (and doses) result in the most effective regeneration?
- 2. How long after the injury can CDCs be given before diminution of regenerative potential?
- 3. Can CDCs promote degradation of scar mass and induce muscle regeneration after a mature scar has formed?
- 4. Will the pro-regenerative effects of CDCs be effective at repairing injury to multiple muscles of a single muscle group?
- 5. Can the results obtained from a rodent model of VML be reproduced in a large animal model of VML?
Year 1 accomplishments
We developed a mouse model of VML to test muscle regeneration and recovery of muscle function. Initial testing of CDCs in mice with VML injury have been completed, including:
- a) Determination of the optimal delivery method
- b) Determination of the effective dose ranges
- c) Determination of the efficacy of multiple doses.
We are continuing to study optimal treatment strategies for VML. These data will inform on upcoming IND-enabling studies for the use of cardiosphere-derived cells to drive muscle regeneration and improve functional recovery after VML injury.
Title of Project: Enhanced Biologic Scaffold for Volumetric Muscle Loss
Project Team (including major subs): University of Pittsburgh
Award Amount: $1,839,921 (with additional cost share of $140,786)
Project Duration: 2 years
Project Objective: Surgical mesh materials composed of extracellular matrix (ECM) can promote functional tissue remodeling by mechanisms that include stem cell maturation and differentiation and modulation of the host immune response toward a regulatory, pro-healing phenotype. From 2011 to 2015, we conducted a thirteen-patient human cohort study in which ECM surgical meshes (including XenMatrix™) were used to treat volumetric muscle loss. Results showed significant restoration of vascularized, innervated, and functional skeletal muscle with a marked improvement in the quality of life for all patients (ClinicalTrails.gov, identifier NCT01292876).
In this MTEC-funded project, the team will:
- • Determine efficacy of an antibiotic-coated biologic scaffold (XenMatrix™ AB) for the promotion of muscle regeneration in human patients. XenMatrix™ AB is an antibiotic (minocycline plus rifampin)-coated version of the same product (XenMatrix™) used in the previously reported thirteen patient cohort study.
- • Develop and test in a rodent model an alternative antibiotic coating that has the added benefit of enhancing the strength of soft tissue repair. Preliminary work in our laboratory showed that wounds treated with doxycycline-coated ECM mesh produce remodeled tissue with 33% greater strength as compared to minocycline, the current FDA-approved antibiotic coating. Therefore, this aim focuses on the development of an enhanced version of the antibiotic-coated biologic scaffold that substitutes doxycycline for minocycline. This enhanced version of XenMatrix™ AB will be evaluated in a preclinical rodent model.
Figure. A bioscaffold/surgical mesh composed of porcine dermal ECM (XenMatrix™) was implanted at a site of volumetric muscle loss and can be visualized by MRI. The dark area in the left image represents the appearance of the mesh one month after surgery. The image on the right shows the MRI signal to be almost indistinguishable from adjacent normal muscle.