Abstract
Volumetric muscle loss (VML) is the traumatic or surgical loss of skeletal muscle beyond the inherent regenerative capacity of the body, generally leading to severe functional deficit. Formation of appropriate somato-motor innervations remains one of the biggest challenges for both autologous grafts as well as tissue-engineered muscle constructs. We aim to address this challenge by developing pre-innervated tissue-engineered muscle comprised of long aligned networks of spinal motor neurons and skeletal myocytes on aligned nanofibrous scaffolds. Motor neurons led to enhanced differentiation and maturation of skeletal myocytes in vitro. These pre-innervated tissue-engineered muscle constructs when implanted in a rat VML model significantly increased satellite cell density, neuromuscular junction maintenance, graft revascularization, and muscle volume over three weeks as compared to myocyte-only constructs and nanofiber scaffolds alone. These pro-regenerative effects may enhance functional neuromuscular regeneration following VML, thereby improving the levels of functional recovery following these devastating injuries.
Highlights
Volumetric muscle loss (VML) is the traumatic or surgical loss of skeletal muscle beyond the inherent regenerative capacity of the body, generally leading to severe functional deficit
Skeletal myocytes and spinal motor neurons were further confirmed by staining for Myosin Heavy Chain (MHC) protein (Fig. 2d) and Choline Acetyltransferase (ChAT) motor neuron marker, respectively (Supplementary Fig 1a)
Severe musculoskeletal trauma like VML is accompanied by progressive motor axotomy over several weeks, leading to denervation of the injured muscle thereby severely limiting functional recovery[37]
Summary
Volumetric muscle loss (VML) is the traumatic or surgical loss of skeletal muscle beyond the inherent regenerative capacity of the body, generally leading to severe functional deficit. Motor neurons led to enhanced differentiation and maturation of skeletal myocytes in vitro These pre-innervated tissue-engineered muscle constructs when implanted in a rat VML model significantly increased satellite cell density, neuromuscular junction maintenance, graft revascularization, and muscle volume over three weeks as compared to myocyte-only constructs and nanofiber scaffolds alone. These pro-regenerative effects may enhance functional neuromuscular regeneration following VML, thereby improving the levels of functional recovery following these devastating injuries. It is imperative that tissue engineering strategies for muscle replacement should consider innervation as an essential component of the biofabrication process itself to facilitate maturation of myofibers in vitro as well as promote reinnervation of damaged host muscle in vivo following implantation in severe musculoskeletal injuries
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