Preclinical Evaluation of Laminin-111 and Electrical Stimulation Therapies for Muscle Regeneration and Rehabilitation Following Volumetric Muscle Loss
Abstract
This investigator-initiated peer-reviewed orthopedic applied research award application is in response to the Department of Defense fiscal year 2017-2018 funding opportunity number W18XWH-17-PRORP-ARA and addresses the limited availability of techniques to regenerate functional, innervated muscle units in the treatment of volumetric muscle loss (VML). The proposed preclinical work will utilize a novel laminin-111=based biomaterial therapy combined with electrical stimulation as an innovative rehabilitation technique for the regeneration of functional muscle tissue following VML injury. Trauma care ranks second in total U.S. health care spending. Traumatic injuries cost upwards of $400 billion per year in medical expenses, lost wages, and productivity worldwide. Muscle trauma accounts for 50% to 70% of total military injuries. Injuries involving muscle trauma result in approximately 80% of delayed amputations. Traumatic skeletal muscle injuries rank among the top 10 most frequent unfitting conditions that prevent return to work. Skeletal muscle possesses a remarkable ability to repair and regenerate following moderately severe injuries (e.g., tears, sprains, etc.). However, when considering the frank loss of muscle tissue (>20%) termed as a VML, the muscle tissue is unable to repair and regenerate itself. VML injuries result in muscle weakness, pain, loss of limb function, and increased risk of amputation, as well as contribute to long-term disability. Currently, there is no definitive therapy for VML that regenerates or restores the frank loss of muscle mass. Clinical treatment for VML injuries often involves the transfer of autologous muscle tissue to the injury region. However, this approach is limited by the inadequate availability of donor muscle and potential donor-site injury. Existing tissue engineering therapies have failed to appreciably regenerate muscle tissue and often result in scar tissue deposition. Physical therapy is highly recommended for rehabilitation of muscle injuries. However, pain and muscle weakness due to VML limits patient participation. Laminin is a crucial component of the native skeletal muscle matrix. Injection of laminin in injured, diseased, or aged muscle tissues has shown remarkable improvements in regeneration and force production. We have created laminin-enriched gels that are capable of enhancing muscle stem cell activity. These gels can be directly injected into the wound site or pre-made to fit the geometry of the wound. Electrical stimulation uses electrical pulses to elicit involuntary muscle contractions and can serve as a strength training tool for injured patients. We have also optimized an electrical stimulation protocol in rodents to improve stem cell quantity and strength in uninjured muscles. We propose implanting laminin-enriched gels at the site of VML injury and using electrical stimulation as a rehabilitation strategy to improve muscle regeneration, innervation, and force production by increasing stem cell quantity and pro-regenerative factor secretion in the VML-injured muscle. The objective of the studies outlined in this proposal is to develop and optimize novel laminin- and electrical stimulation-based therapeutic approaches to regenerate and rehabilitate VML-injured skeletal muscle. We will use a well-established rat model of VML injury in these projects. In Aim 1, hydrogels enriched with laminin in varying concentrations will be implanted in the VML defect region. Muscle regeneration, innervation, and strength gains will be assessed using established methodology. The concentration of laminin resulting in maximal strength benefits will be used in Aim 2 in combination with electrical stimulation training. The additive effect of electrical stimulation and laminin treatment is expected to maximize the functional gains in the injured muscle further. The proposed experiments will take place over 3 years. The overall impact of thi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810251
Entities
People
- Koyal Garg
Organizations
- Saint Louis University
- United States Army