Featured Studies #1: The Cullen Laboratory
STUDY TITLE: BIO-FABRICATED NERVE-MUSCLE COMPLEXES TO AUGMENT REGENERATION AND FACILITATE REINNERVATION FOLLOWING VOLUMETRIC MUSCLE LOSS
STUDY OVERVIEW:
Rodents with traumatic muscle loss had artificially grown tissue (InTEM) implanted. After three weeks, rodents with implanted tissue had increased muscle volume and cell function compared to traditional therapeutic interventions. This success in rodents provides initial evidence artificial tissue therapies could enhance recovery and function within humans.
STUDY PURPOSE:
Volumetric muscle loss (VML) is characterized by traumatic or surgical loss of skeletal muscle tissue beyond the inherent regenerative capacity of the body. Musculo-skeletal injuries leading to VML account for the majority of the trauma sustained by our warfighters, often leaving them debilitated with chronic functional deficiencies. Appropriate motor innervations remain one of the biggest challenges for an autologous muscle graft as well as tissue engineered muscle. However, the concept of promoting integration of an engineered muscle graft with the host nervous system remains largely unexplored.
GOALS/OBJECTIVE
The purpose of this study is to investigate the efficacy of pre-innervated tissue engineered muscle in augmenting functional regeneration following clinically relevant VML. They aim to fabricate long aligned fibrils of “pre-Innervated Tissue Engineered Muscle (InTEM)” using a co-culture of human myocytes and spinal motor neurons (each separately derived from adult stem cells) to assess the effect of neurons in situ on the growth and morphology of skeletal muscle fibers. These InTEM constructs will then be implanted in an athymic rat model of VML and functional regeneration of injured muscle will be monitored at acute and chronic time points. The InTEM constructs developed herein may serve as a “personalized” neuromuscular construct that can potentially be implanted to accelerate functional recovery of injured muscle.
STUDY RESULTS:
In a recently published study, our group fabricated InTEMs using mouse skeletal myocytes and rat spinal motor neurons grown on aligned nanofiber sheets. These InTEMs were implanted in a rodent VML model and observed for up to three weeks. The pre-innervated bioscaffolds (InTEMs) significantly increased satellite cell density, neuromuscular junction maintenance, graft revascularization, and muscle volume over 3 weeks as compared to myocyte-only constructs and nanofiber scaffolds alone. These pro-regenerative effects may enhance neuromuscular regeneration following VML, thereby improving the levels of functional recovery following these devastating injuries.
NEXT STEPS
Working towards fabricating InTEMs with adult human stem cell derived motor neurons and myocytes.
Acute and chronic efficacy studies with human InTEMs in rodent VML model.
Fabrication of thicker multilayered InTEMs for application in a large animal model of VML.
HOW DOES THIS STUDY IMPACT VETERANS?
Veterans who suffer from volumetric muscle loss (VML) could have increased recovery and muscle functioning if implanted InTEMs are found to show similar effectiveness in humans.
Read more about the Cullen Laboratory’s VML research at https://bioengineeringcommunity.nature.com/posts/pre-innervated-bioscaffolds-to-repair-volumetric-muscle-loss
This research is supported by the Congressionally Directed Medical Research Programs (CDMRP):
W81XWH-19-1-0867 (PI: DK Cullen) '
U.S. DoD / CDMRP-PRORP
