# Aligned and electrically conductive collagen scaffolds for guiding innervated muscle-tendon junction repair of volumetric muscle loss injuries

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2021 · $382,939

## Abstract

ABSTRACT
Volumetric muscle loss (VML) injuries are debilitating traumas that result in permanent loss of muscle function.
Moreover, VML injuries are often compounded by damage to multiple tissues including connective and nervous
tissue. Peripheral nervous system damage can result in denervation that limits force generation while the
disruption of muscle fibers at the musculotendinous junction (MTJ), where most muscle injuries occur, can further
ablate the transfer of muscle-generated force to the skeletal system. Unfortunately, many therapeutic
approaches for VML solely focus on skeletal muscle, neglecting neighboring tissues that are essential for
function. Despite this clear clinical need, therapies to treat combined VML/MTJ injuries are lacking. Therefore,
the central objective of this proposal is to apply a tissue engineering scaffold mimicking MTJ structure to promote
innervated functional regeneration of VML/MTJ injuries. We will take an innovative biomaterials-based approach
that builds on our team’s recent development of a 3D aligned and electrically conductive collagen-
glycosaminoglycan (CG) scaffold that recapitulates both the anisotropic extracellular matrix (ECM) organization
and electrical excitability of native skeletal muscle. We hypothesize that an engineered biomaterial with spatially-
defined microenvironmental cues paired with bioreactor preconditioning of myogenic and neuronal cells will
enable regeneration of clinically relevant VML/MTJ injuries. We will test this hypothesis through two aims: 1)
Determine the combined ability of 3D scaffold alignment and electrical conductivity to drive in vitro myogenesis
of muscle-derived cell (MDC) and neural stem cell (NSC) co-cultures, and 2) Determine the ability of 3D multi-
compartment scaffolds with co-cultured MDCs and NSCs to guide repair of MTJ VML injuries. We will first build
on recent work demonstrating the utility of co-culturing neural and muscle progenitor cells to improve in vitro
myogenesis by determining if biomimetic scaffold cues, including 3D structural alignment and electrical
conductivity, can further amplify this process. We will evaluate MDC and NSC viability, proliferation, cytoskeletal
organization, and myotube and neuromuscular junction (NMJ) formation within scaffolds both with and without
electrical and/or mechanical stimulation. Anisotropic CG scaffolds with spatially-defined electrical conductivity
and mechanics to recapitulate the biophysical properties of the MTJ interface will then be implanted, with or
without bioreactor preconditioned MDCs and NSCs, in rat tibialis anterior VML/MTJ defects. Repair metrics will
include immunohistochemistry, quantification of force generation, and analysis of gait biomechanics over 24
weeks. Our proposal directly addresses the treatment of challenging and clinically relevant VML injuries while
answering previously intractable biological questions, including understanding of how scaffold structural and
electrical signals ...

## Key facts

- **NIH application ID:** 10183865
- **Project number:** 1R01AR078866-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Steven Caliari
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $382,939
- **Award type:** 1
- **Project period:** 2021-05-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10183865

## Citation

> US National Institutes of Health, RePORTER application 10183865, Aligned and electrically conductive collagen scaffolds for guiding innervated muscle-tendon junction repair of volumetric muscle loss injuries (1R01AR078866-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10183865. Licensed CC0.

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