Tacrolimus as an adjunct to autologous minced muscle grafts for the repair of a volumetric muscle loss injury

Abstract

BackgroundVolumetric muscle loss (VML) following extremity orthopaedic trauma or surgery results in chronic functional deficits and disability. A current translational approach to address the devastating functional limitations due to VML injury is the use of an autologous minced muscle graft (~1 mm3 pieces of muscle tissue) replacement into the injured defect area, although limitations related to donor site morbidity are still unaddressed. This study was designed to explore adjunct pharmacological immunomodulation to enhance graft efficacy and promote muscle function following VML injury, and thereby reduce the amount of donor tissue required.FindingsUsing a validated VML porcine injury model in which 20% of the muscle volume was surgically removed, this study examined muscle function over 3 months post-VML injury. In vivo isometric torque of the peroneus teritus (PT) muscle was not different before surgery among sham, non-repaired, non-repaired with tacrolimus, graft-repaired, and graft-repaired with tacrolimus VML groups. Bi-weekly torque analysis of the VML injured musculature presented a significant strength deficit of ~26% compared to pre-injury in the non-repaired, non-repaired with tacrolimus, and graft-repaired groups. Comparatively, the strength deficit in the graft-repair with systemic tacrolimus was marginally improved (~19%; p = 0.056). Both of the minced graft repaired groups presented a greater proportion of muscle tissue in full-thickness histology specimen.ConclusionsWe demonstrate that adjunctive use of tacrolimus with an ~50% minced muscle graft replacement resulted in modest improvements in muscle function 3 months after injury and repair, but the magnitude of improvement is not expected to elicit clinically meaningful functional improvements.

Robust inflammatory and fibrotic signaling following volumetric muscle loss: a barrier to muscle regeneration

“…Therapeutic modalities that incorporate immunomodulatory elements 13 may promote a more favorable environment for subsequent regenerative therapies, by removing debris and emitting soluble factors that recruit and support regenerative progenitors. For example, Corona et al 14 administered Tacrolimus, a calcineurin phosphatase inhibitor that reduces macrophage and dendritic cell activity and inhibits interleukin-2 (IL-2) mediated activation of T lymphocytes, in combination with MMGs. Administration of systemic Tacrolimus with MMGs reduced the functional deficit by about one third compared to MMGs alone.…”

Biomimetic sponges improve muscle structure and function following volumetric muscle loss

“…In a subsequent study, when FK-506 was injected i.p. and VML defect was treated with autologous minced muscle grafts in a porcine model, muscle regeneration and function was enhanced [24]. Taken together, these studies suggest that a combination of regenerative and immunomodulatory therapy is essential for functional muscle regeneration.…”

“…Dendritic cells have been detected as early as 24 hours after muscle injury [69,70]. While continuous administration of FK-506 has been done in VML models [23,24], others have reported that a single local application of FK-506 at the time of repair can support functional nerve regeneration 2-3 months after injury [71,72]. Future studies may investigate the impact of sustained-release FK-506 on VML injury to determine if a short-term administration is adequate.…”

Pre-Innervated Tissue Engineered Muscle Promotes a Pro-Regenerative Microenvironment Following Volumetric Muscle Loss

“…Hence, in addition to topographical guidance, tissue engineered scaffolds must be myo-conductive, promote angiogenesis through either pre-vascularization or incorporation of vasculogenic accelerant, have immunomodulatory effect as well as facilitate reinnervation to overcome the pathophysiology of VML and achieve functional restoration. Direct administration of anti-inflammatory agents can reduce fibrosis but has been shown to hinder muscle regeneration 25,26 . Acellular scaffolds cannot address such multidimensional challenges and reinforces the necessity of incorporating multiple cell types in a scaffold 18 .…”