Pharmacological Mitigation of Fibrosis in a Porcine Model of Volumetric Muscle Loss Injury

Volumetric muscle loss (VML) increases fibrotic tissue leading to deficits in function by interfering with a number of connections including neural, vascular and mechanical that complicate implementing regenerative therapeutics. In this paper, Corona et al. investigate muscle architecture and function after VML in Yorkshire Cross pigs to elucidate whether antifibrotic measures can lessen the accumulation of fibrosis and thus mitigate function deficits. Pigs (n = 10) were Randomly assigned to a sham or ~20% VML injury, then once again randomized to either nintedanib (anti-fibrotic agent) or no treatment for 30 days. In-vivo functional measurements of the anterior compartment, including maximum isometric torque, were made over the course of 30 days using Aurora’s 890A large animal apparatus in addition to tracking compartment volume and muscle stiffness. Further histological and molecular measurements of the muscle tissue were made following euthanizing of the animals. After 4-weeks following the VML injury, nontreated muscles showed a significant (23%) maximal torque deficit in contrast to sham. The affected area of the muscle was significantly stiffer (7-fold) in the VML-nontreated leg compared to the nintedanib treated legs. In addition, there was shown to be roughly 40% greater level of hydroxyproline per mg of muscle than the treated muscles. When taken together, the results show VML causes increased fibrosis and stiffness of the affected tissue. These resultant affects post VML can be lessened following antifibrotic treatment.

Long-Term Evaluation of Functional Outcomes Following Rat Volumetric Muscle Loss Injury and Repair

Tissue-engineered muscle repair (TEMR) technology is used to facilitate the regeneration of muscle by providing a favorable microenvironment for regenerative growth. This is done by seeding muscle progenitor cells (MPCs) onto a porcine bladder acellular matrix (BAM), which is then implanted into the animal. Although tissue-engineered constructs are a good restorative option for volumetric muscle loss (VML) injuries, the variability between different muscles poses a challenge in creating fully compatible constructs. This study focuses on improving the matching geometry of TEMR to the TA muscle, specifically, in the rat animal model. Using Aurora’s 1305A 3-in-1 Whole Animal System, an in vivo analysis of peak isometric torque was conducted. At 6 months post VML injury, 67% of TEMR-implanted rats showed significantly greater peak isometric torque compared to other treatment groups. Moreover, 38% of TEMR responders reached approximately 90% of the maximum force production, thus demonstrating near full recovery. In addition to functional assessment, the authors conducted histological and immunofluorescence analyses. Fiber cross sectional area (FCSA) was quantified in both the experimental and control TA muscles of maximum responder rats. It was found that the median FCSA was lower in the experimental TA muscles than in the TA muscles of the control leg. Vascularization and macrophage counts were also assessed, although no significant differences were found. This study highlights the importance of adapting and improving existing tissue engineering technology to allow for optimal treatment of VML injuries in various muscles.

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