In Silico and In Vivo Studies Detect Functional Repair Mechanisms in a Volumetric Muscle Loss Injury

In this study, we report the development of a biologically relevant animal model for evaluation of tissue engineering approaches for repair of volumetric muscle loss (VML) injuries to craniofacial muscles (e.g., cleft lip). We also show that the application of in silico methods provides key mechanistic insights for improved understanding of functional regeneration in complex biological systems. Briefly, implantation of a tissue-engineered muscle repair (TEMR) construct into a surgically created VML injury to the rat latissimus dorsi produced significantly greater contractile force recovery than implantation of bladder acellular matrix (BAM) or no repair (NR). Robust de novo muscle regeneration was observed with TEMR, but not NR or BAM. Furthermore, TEMR implantation modified the passive tissue properties of the remodeled implant area. A novel finite-element model suggests that, at optimal muscle fiber length, most of the force recovery is attributed to the passive mechanical properties of tissue in the TEMR-implanted region, which despite significant muscle regeneration is still largely attributable to the greater volume reconstitution promoted by the TEMR implant compared with BAM implant. However, at shorter muscle fiber lengths as well as in larger injury sizes, the presence of active (i.e., regenerated) tissue is required to achieve consistent force recovery.