Autologous minced muscle grafts improve endogenous fracture healing and muscle strength after musculoskeletal trauma

Abstract

The deleterious impact of concomitant muscle injury on fracture healing and limb function is commonly considered part of the natural sequela of orthopedic trauma. Recent reports suggest that heightened inflammation in the surrounding traumatized musculature is a primary determinant of fracture healing. Relatedly, there are emerging potential therapeutic approaches for severe muscle trauma (e.g., volumetric muscle loss [VML] injury), such as autologous minced muscle grafts (1 mm3 pieces of muscle; GRAFT), that can partially prevent chronic functional deficits and appear to have an immunomodulatory effect within VML injured muscle. The primary goal of this study was to determine if repair of VML injury with GRAFT rescues impaired fracture healing and improves the strength of the traumatized muscle in a male Lewis rat model of tibia open fracture. The most salient findings of the study were: (1) tibialis anterior (TA) muscle repair with GRAFT improved endogenous healing of fractured tibia and improved the functional outcome of muscle regeneration; (2) GRAFT repair attenuated the monocyte/macrophage (CD45+ CDllb+) and T lymphocyte (CD3+) response to VML injury; (3) TA muscle protein concentrations of MCP1, IL‐10, and IGF‐1 were augmented in a proregenerative manner by GRAFT repair; (4) VML injury concomitant with osteotomy induced a heightened systemic presence of alarmins (e.g., soluble RAGE) and leukocytes (e.g., monocytes), and depressed IGF‐1 concentration, which GRAFT repair ameliorated. Collectively, these data indicate that repair of VML injury with a regenerative therapy can modulate the inflammatory and regenerative phenotype of the treated muscle and in association improve musculoskeletal healing.

RAGE Signaling in Skeletal Biology

“…Consistent with the decreased femoral cancellous bone accrual and altered architecture detected in the 4-month-old RAGE KO mice, the expression of several osteoblast-associated genes, ALP, Cola1, Runx2, and Osterix was decreased in femurs from these mice [58]. Further, global RAGE deficiency suppresses PPARα and its co-factor PGC1α, which leads to a pro-inflammatory phenotype in bones and osteoblasts from RAGE KO compared to control mice [61]. It should be noted that the meaning of the "pro-inflammatory phenotype" was not clearly described in the Biswas study, making it hard to draw conclusions about the osteoblastic effects of RAGE deficiency.…”

Multiscale analysis of a regenerative therapy for treatment of volumetric muscle loss injury

“…The fairly extensive number of regenerative therapies that have been tested for VML repair have proceeded to date without a comprehensive understanding of the pathophysiology of the injury response. Animal models of VML injury have described 15 , 16 a dysregulated immune response that coincides with aberrant or muted muscle fiber regeneration and fibrosis, although the temporal coordination of these events and drivers of this response trajectory have not been elucidated. Without determination of a clearly effective therapy and lack of knowledge of the molecular phenomenology-mediating injury repair, further advancement of the field depends on understanding and mitigation of the host pathobiological response.…”

Biomimetic sponges improve muscle structure and function following volumetric muscle loss

“…At the same time, monocyte recruitment, myoblast proliferation, and myofiber growth are diminished [57]. In a study by Hurtgen et al, implantation of minced muscle autografts resulted in enhanced presence of CD3 + , CD4 + , and CD8 + T cells in a VML model [58]. The increased presence of these cell types over 14 days postinjury did not hinder muscle regeneration, as evidenced by newly regenerating myofibers and improved functional recovery.…”