Mechanical Stimulation After Volumetric Muscle Loss Injury Improves Functional Recovery and Tissue Repair/Regeneration in a Large Animal Model

PURPOSE: Over 40,000 traumatic open fractures leading to volumetric muscle loss (VML) injuries are estimated to occur annually in the US (1,2). Even ~20% muscle loss causes disproportionate lasting strength deficits of 30 - 90% (3). The current gold standard, physical therapy, only achieves partial functional recovery of 17 - 58% (4, 5). Our prior murine model of VML showed that passive external mechanical stimulation (MS) improves muscular torque recovery (MMT +26%) and reduces fibrosis (-21%). Here, we hypothesize that MS has similar outcomes in a large animal model. METHODS: Left Peroneus Tertius muscle (PTM) VML injury was surgically induced in female (38-42 kg) Yucatan pigs; animals received no treatment (n=10) or MS of the PTM (n=8). Outcomes included post-injury day 35 (PID35) recovery of pre-injury MMT and baseline activity level (step count), PID35 strength in newton-centimeters per gram PTM (ncm/g), weekly gait assessments (Tarlov Score), PID 35 recovery of pre-injury fatigue resistance, PID35 Masson staining, and PID35 MRI for PTM inflammation/edema (T2) and fat fraction. RESULTS: MS significantly improved recovery of MMT (32±25% vs 12±6%; p=0.00019) and activity (110±75% vs 67±62%; p=0.028), increased PID35 PTM strength (3.3±3.1 ncm/g vs 1.5±1.4 ncm/g; p=0.0049), improved gait at PID 14 (4.9±0.7 vs 4.4±1.0; p=0.042) and 28 (5.0±0 vs 4.6±1.0; p=0.045), and insignificantly improved recovery of fatigue resistance (55±100% vs 26±31%; p=0.11). Histology and MRI showed reduced fibrosis (16±12% vs 24±16%; p=0.048) and reduced PID35 T2 signal (-27%) and fat fraction (-44%). CONCLUSIONS: In a translational large animal model, MS promotes strength recovery, reduces fibrosis, and reduces inflammation/fat fraction after VML injury. These results should be confirmed in a pilot clinical trial.