Minced muscle grafts reduce the proinflammatory immune response and partially restore musculoskeletal healing

Abstract

Abstract The immune response plays a key role in healing of bone and muscle injuries. An unrestrained proinflammatory response generally results in impaired healing. Extremity fracture is often complicated by traumatic volumetric muscle loss (VML), which can lead to delayed or non-union of the fracture (i.e., impaired healing). In a rat model, we recently showed that the VML injury of the tibialis anterior muscle prevented healing of the adjacent tibia fracture and induced a robust proinflammatory response in the musculature early post-injury that was not observed with the fracture alone. In the current studies, we show that a fracture treated with rhBMP-2, a highly osteoinductive protein, was impaired by the VML injury and corresponded with a heightened proinflammatory response. We utilized an autologous minced muscle graft (MMG) to repair the VML which, interestingly, reduced the proinflammatory response. Gene transcript analysis of the muscle injury indicates that MMG repair results in decreased gene expression of proinflammatory mediators including ITGAM, IL18, and CCL12, compared to non-repaired muscle. In the bone defect, MMG repair also induced a modest proinflammatory response with lower expression of IFNG and TNF than the non-repaired group. The restrained proinflammatory response corresponded with restored healing of the bone fracture and, remarkably, partial restoration of muscle function which does not normally occur clinically. Altogether, data suggest that MMG repair controls the proinflammatory response in a manner conducive to improved healing responses in both muscle and bone. These data reveal that immunomodulation to dampen proinflammatory responses could provide an effective therapy for musculoskeletal trauma.