# Tissue Engineered Motor Units for Neuromuscular Modeling and Repair

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $552,303

## Abstract

PROJECT SUMMARY
Innervation plays a key role in muscle development, function, and regeneration. Therefore, tissue engineering
strategies to develop biomimetic skeletal muscle to study developmental mechanisms as well as for regenerative
medicine applications should consider the implications of neural inputs during the biofabrication process.
Moreover, tissue regeneration following severe musculoskeletal injuries like volumetric muscle loss (VML) is
hindered by a lack of appropriate motor innervations, which diminishes regenerative capacity and often results
in minimal functional recovery. Hence, there is an unmet clinical need for an intervention strategy that augments
reinnervation and promotes a pro-regenerative environment following severe musculoskeletal trauma. Over the
last several years, our group has shown that pre-innervated tissue engineered muscle scaffolds can effectively
enhance muscle regeneration, revascularization, and functional recovery following VML. Building on these
findings, the goal of the current program is to advance the first three-dimensional tissue engineered motor units
(3D-TEMUs) comprising dense bundles of centimeter-scale myofiber fascicles innervated by preformed axonal
networks projecting from discrete pools of motor and/or sensory neurons. The 3D-TEMUs will be validated as
an in vitro testbed to study the role of innervation in facilitating muscle development as well as a composite soft
tissue to augment functional regeneration following implantation in a rodent model of VML. Notably, 3D-TEMUs
will be generated using human induced pluripotent stem cell (iPSC) derived myocytes and motor/sensory
neurons to perform in-depth characterization using a clinically-relevant and potentially translatable biomass.
These efforts will be carried out across 3 Specific Aims. First, human 3D-TEMUs will be optimized to recapitulate
the native myofascicular architecture of skeletal muscle tissue in order to provide a biofidelic testbed to better
understand neuromuscular development and sensorimotor function in the context of myofiber formation and
maturation as well as to refine tissue engineering strategies for augmenting muscle regeneration (Aim 1). Next,
3D-TEMU neurons will be transduced to contain optogenetically controlled (i.e., light-activated) motor inputs that
allow for spatiotemporal control of muscle-fiber contraction to demonstrate refinement of motor units over time
and to measure sensorimotor function (Aim 2). Then, 3D-TEMUs will be implanted in a rat model of VML to
optimize acute graft cell survival (Aim 3A) followed by chronic studies assessing the ability of 3D-TEMUs in
facilitating bulk muscle replacement, reinnervation, revascularization, and overall functional restoration (Aim
3B). Successful execution of these studies will significantly advance the development of 3D-TEMUs as both an
in vitro testbed to study mechanisms of neuromuscular development as well as an implantable composite soft
tissue to enable fun...

## Key facts

- **NIH application ID:** 10776350
- **Project number:** 1R01AR083489-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Daniel Kacy Cullen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $552,303
- **Award type:** 1
- **Project period:** 2024-05-06 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10776350

## Citation

> US National Institutes of Health, RePORTER application 10776350, Tissue Engineered Motor Units for Neuromuscular Modeling and Repair (1R01AR083489-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10776350. Licensed CC0.

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