Combined regenerative rehabilitation improves recovery following volumetric muscle loss injury in a rat model.

Volumetric muscle loss (VML) injury causes irreversible deficits in muscle mass and function, often resulting in permanent disability. The current standard of care is physical therapy, but it is limited in mitigating functional deficits. We have previously optimized a rehabilitation technique using electrically stimulated eccentric contraction training (EST) that improved muscle mass, strength, and size in VML-injured rats. A biosponge scaffold composed of extracellular matrix proteins has previously enhanced muscle function postVML. This study aimed to determine whether combining a regenerative therapy (i.e., biosponge) with a novel rehabilitation technique (i.e., EST) could enhance recovery in a rat model of VML. A VML defect was created by removing ~20% of muscle mass from the tibialis anterior muscle in adult male Lewis rats. Experimental groups included VML-injured rats treated with biosponge with EST or biosponge alone (n = 6/group). EST was implemented 2 weeks postinjury at 150 Hz and was continued for 4 weeks. A linear increase in eccentric torque over 4 weeks showed the adaptability of the VML-injured muscle to EST. Combining biosponge with EST improved peak isometric torque by ~52% compared with biosponge treatment alone at 6 weeks postinjury. Application of EST increased MyoD gene expression and the percentage of large (>2000 µm2) type 2B myofibers but reduced fibrotic tissue deposition in VML-injured muscles. Together, these changes may provide the basis for improved torque production. This study demonstrates the potential for combined regenerative and rehabilitative therapy to improve muscle recovery following VML.

Combined application of biosponges and an antifibrotic agent for the treatment of volumetric muscle loss.

Volumetric muscle loss (VML) causes irrecoverable loss of muscle mass and strength and results in permanent disability. VML injury shows extensive fibrosis, which impedes functional tissue regeneration. Our lab has created a biosponge scaffold composed of extracellular matrix (ECM) proteins (i.e., biosponge) that can enhance muscle regeneration and function following VML. In this work, a potent small molecule inhibitor of alpha v-subunit containing integrins known as IDL-2965 was incorporated into the biosponges for localized suppression of fibrosis post-VML. Our results demonstrate that local delivery of IDL-2965 via the biosponges attenuated the deposition of fibrotic tissue preceded by a downregulation of profibrotic genes in VML-injured muscles. The reduction in fibrotic tissue had no detrimental effects on muscle mass, function, size, or vascularity. Overall, these findings suggest that the codelivery of biosponges and IDL-2965 is a safe and effective strategy for the mitigation of fibrotic tissue deposition in VML-injured muscles.