Engineering the immune and fibrotic response in VML

Volumetric muscle loss (VML) provides a significant challenge for regeneration, despite current treatments with free functional muscle transfer. VML injury overwhelms the native process of wound healing, leading to a dysregulated immune response and eventually fibrosis. Tissue engineered muscle grafts are a promising method of treatment without donor site morbidity. Tissue engineered muscle grafts not only provide structural support, but also address the myogenic deficit by transplanting satellite cells and myoblasts to supplement those lost as a result of injury and secrete additional stimuli to create a more pro-regenerative microenvironment. However, adequate treatment of VML also requires immune modulation and limiting fibrotic deposition. To address this, some approaches have targeted other cells involved in the injury response such as macrophages, regulatory T cells, fibroadipogenic progenitor, and myofibroblasts. Treatments that supplement myogenic cells at the same time as co-delivering either immune or fibrotic modulatory signals have demonstrated increased success. One limitation is that many of these treatments are being tested in models that exhibit limited fibrosis, and the observed benefits of treatment may not be seen in more clinically relevant scenarios. Future studies may also address the incomplete understanding of the cellular signalling responses that ameliorate fibrosis. We provide a summation of recent strategies employed for this purpose, as well as predictions about new strategies yet to be utilized in VML.