Cell-Derived Extracellular Matrix Fiber Scaffolds Improve Recovery from Volumetric Muscle Loss.

There are currently no surgical procedures that effectively address the treatment of volumetric muscle loss (VML) injuries that has motivated the development of implantable scaffolding. In this study, the effectiveness of an allogenic scaffold fabricated using fibers built from the extracellular matrix (ECM) collected from muscle fibroblast cells during growth in culture was explored using a hindlimb VML injury (tibialis anterior muscle) in a rat model. Recovery outcomes (8 weeks) were explored in comparison with unrepaired controls as well previously examined allogenic scaffolds prepared from decellularized skeletal muscle (DSM) tissue (n = 9/sample group). At 8-week follow-up, we found that the repair of VML injuries using ECM fiber scaffolds in combination with an autogenic mince muscle (MM) paste significantly improved the recovery of peak contractile torque (79% ± 13% of uninjured contralateral muscle) when compared with unrepaired VML controls (57% ± 13%). Similar significant improvements were measured for muscle mass restoration (93% ± 10%) in response to ECM fiber+MM repair when compared with unrepaired VML controls (73% ± 13%). Of note, mass and contractile strength recovery outcomes for ECM fiber scaffolds were not significantly different from DSM+MM repair controls. These in vivo findings support the further exploration of cell-derived ECM fiber scaffolds as a promising strategy for the repair of VML injury with recovery outcomes that compare favorably with current tissue-sourced ECM scaffolds. Furthermore, although the therapeutic potential of ECM fibers as a treatment strategy for muscle injury was explored in this study, they could be adapted for high-throughput fabrication methods developed and routinely used by the textile industry to create a broad range of woven implants (e.g., hernia meshes) for even greater clinical impact.

Local IL-10 delivery modulates the immune response and enhances repair of volumetric muscle loss muscle injury.

This study was designed to test the hypothesis that in addition to repairing the architectural and cellular cues via regenerative medicine, the delivery of immune cues (immunotherapy) may be needed to enhance regeneration following volumetric muscle loss (VML) injury. We identified IL-10 signaling as a promising immunotherapeutic target. To explore the impact of targeting IL-10 signaling, tibialis anterior (TA) VML injuries were created and then treated in rats using autologous minced muscle (MM). Animals received either recombinant rat IL-10 or phosphate buffered saline (PBS) controls injections at the site of VML repair beginning 7 days post injury (DPI) and continuing every other day (4 injections total) until 14 DPI. At 56 DPI (study endpoint), significant improvements to TA contractile torque (82% of uninjured values & 170% of PBS values), TA mass, and myofiber size in response to IL-10 treatment were detected. Whole transcriptome analysis at 14 DPI revealed activation of IL-10 signaling, muscle hypertrophy, and lymphocytes signaling pathways. Expression of ST2, a regulatory T (Treg) cell receptor, was dramatically increased at the VML repair site in response to IL-10 treatment when compared to PBS controls. The findings suggest that the positive effect of delayed IL-10 delivery might be due to immuno-suppressive Treg cell recruitment.