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.
Impact Statement
Despite medical advances, volumetric muscle loss (VML) injuries to craniofacial muscles represent an unmet clinical need. We report an implantable tissue-engineered construct that leads to substantial tissue regeneration and functional recovery in a preclinical model of VML injury that is dimensionally relevant to unilateral cleft lip repair, and a series of corresponding computational models that provide biomechanical insight into mechanism(s) responsible for the VML-induced functional deficits and recovery following tissue-engineered muscle repair implantation. This unique combined approach represents a critical first step toward establishing a crucial biomechanical basis for the development of efficacious regenerative technologies, considering the spectrum of VML injuries.
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