Immunomodulatory biomaterials for skeletal muscle repair

Abstract

Though skeletal muscle possesses robust potential for healing after injury, large volumetric wounds that occur during combat, accidents or surgical resection often do not heal completely, resulting in fibrotic scarring and limited range of motion. Current standard of care involves the autologous transfer of tissue but exhibits limited success and complications at both the donor and injury site. Repair of injured skeletal muscle requires the coordinated activities of innate and adaptive immune cells that orchestrate the progression of inflammation and guide healing outcome. The overall objective of this work is to improve understanding of the roles that immune cells subsets play in the regeneration of volumetric muscle defect injuries, and to engineer biomaterial therapies that tune their recruitment and function. Towards this goal, we identified non-classical monocytes as biased progenitors of CD206+ alternatively-activated macrophages. Subsequently, we demonstrated for the first time that non-classical monocytes are directly recruited to volumetric muscle injury and that their recruitment can be increased by local delivery of the immunomodulatory molecule FTY720. Enrichment of non-classical monocytes within muscle injury coincided with increased CD206+ alternatively-activated macrophages in peri-defect tissue and improved muscle healing, along with decreased fibrotic tissue deposition. We then further explored how incorporating FTY720 into an electrospun nanofiber scaffold would impact parenchymal and immune cell behavior in a non-healing volumetric muscle defect. We found that FTY720 delivery from a nanoscale fiber scaffold (FTY720-NF) resulted in acute lymphopenia and decreased lymphocytes in the muscle tissue, and subsequently, increases in muscle stem cell (satellite cell), non-classical monocyte, and alternatively-activated macrophage numbers. Regenerated muscle fibers exposed to FTY720 cues displayed higher diameter and notably, increased alignment to the pre-injury fiber axis. These findings represent an improved understand of the role that pro-regenerative subsets of immune cells play in promoting endogenous mechanisms of tissue repair after traumatic muscle injuries.