Muscle

Muscle

Multiple pathological conditions including traumatic injuries, congenital defects, post-operative damage, and degenerative myopathies can lead to volumetric loss of skeletal muscle tissue. Volumetric muscle loss (VML) is the loss of muscle tissue which exceeds the body’s capacity for self-repair, resulting in impaired muscle function, and in many cases, physical deformity. While many musculoskeletal traumas may be endogenously repaired over time through the myogenic potential of satellite cells, more severe cases of VML overwhelm this native repair mechanism, creating a need for surgical intervention. The primary treatment strategies involving muscle flap transposition or autologous tissue transfer are both limited by donor site morbidity and lack of available graft tissue. Thus, a demand exists for exogenous graft muscle tissue, prompting tissue-engineering approaches to be increasingly investigated as potential strategies for VML treatment. Therefore, the long-term goal of STEL laboratory has been to tissue-engineer a functional skeletal muscle unit (SMU) which has functional neuromuscular and myotendinous interfaces and when implanted allows for the rapid integration into the host and complete recovery of native muscle forces. Our current SMU exhibits significant advancement in phenotype towards that observed in adult skeletal muscle including uniaxially aligned muscle fibers encased in an extensive extra-cellular matrix, formation of an enthesis at the bone attachment, myotendinous interfaces, extensive vascularization, and innervation with concomitant formation of neuromuscular junctions. This exciting technology actually results in the addition of new muscle fibers to a VML repair area. Thus, our multiphasic composite tissue survives both implantation and the mechanical loads placed on it in vivo, and it develops the interfaces needed to advance the phenotype toward adult muscle structure and function.

Myotendinous Junction

Muscle Regeneration

Myofiber

Myosin heavy chains (shown in red) and Collagen 1 (green - larger image) shows the structure of the SMU muscle to tendon interface. The presence of paxillin (blue-in the insert) at this interface and its co-localization with the graft muscle fibers (red) demonstrate its similarity of this interface to a native myotendinous junction.

After 49 days in vivo as a VML repair graft, the SMU fibers had a cross-sectional area containing 18.2% native fibers. Area of muscle regeneration is shown in white circle.

Following 10 days of our new growth factor cocktail, we see advanced sarcomere formation and a 5-fold increase in force production. Scale bar = 600nm.