Designing Fibrin Microthread Scaffolds for Skeletal Muscle Regeneration

Summary

Principal Investigator: Jonathan M Grasman
Abstract: DESCRIPTION (provided by applicant): Skeletal muscle trauma to the head or neck can not only be debilitating, but can result in severe psychological impairment. While skeletal muscle has an innate repair mechanism directed by growth factors and mediated by satellite cells, this mechanism cannot compensate for large, volumetric muscle loss as a result of trauma related events such as car accidents or cancer resection. Clinical strategies to treat these defects consist of autologous tissue transfer techniques, requiring large donor sites and extensive surgical procedures that can result in donor site morbidity and limited functional recovery. As such, there is a clinical need for an off-the-shelf, bioactive scaffold that directs patient's cell to align and differentiate into muscle tissue in situ. Our laboratory recently developed fibrin microthreads, a tissue construct that resembles the morphologic structure of a muscle fiber and can align cells longitudinally along the fiber length. In the wound site, fibrin degrades quickly i the presence of numerous proteinases such as plasmin. We recently developed a crosslinking strategy to modify fibrin microthreads to increase their resistance to enzymatic degradation. The overall goal of this project is to use these microthreads to design a novel biomimetic scaffold that will utilize the endogenous skeletal muscle regeneration pathway to regenerate volumetric muscle loss. We hypothesize that fibrin microthreads, with precisely tuned degradation properties and conjugated with wound healing growth factors such as hepatocyte growth factor (HGF) and insulin-like growth factor (IGF)-I, will enhance skeletal muscle regeneration of a large muscle defect via endogenous pathways. To systematically test this hypothesis, we will analyze the effects of synthetic and natural crosslinking agents on the structural and biochemical properties of fibrin microthreads. We will analyze the dose-dependent responses of satellite cells to growth factors on fibrin microthreads that contribute to the skeletal muscle regeneration pathway and determine how these factors affect cell phenotype through immunohistochemical assays. We will assess the contribution of fibrin microthreads to regeneration using a murine muscle excision model to analyze the recovery of mechanical function and collagen deposition within the wound site over time. Our ultimate goal is to develop a scaffold that will persist in siu throughout the peak time of skeletal muscle regeneration, 2-4 weeks, with clinically relevant growth factor concentrations to direct mechanically functional tissue regeneration in vivo through the study of the following Specific Aims: (1) To develop microthreads with structural and biochemical properties similar to native skeletal muscle, and (2) assess microthreads'enhancement of skeletal muscle regeneration in vivo. Through the combination of finely tuned structural and mechanical properties, and the conjugation of growth factors designed to promote and mimic skeletal muscle regeneration, we will create a biomimetic scaffold to regenerate large skeletal muscle defects in vivo.
Funding Period: 2013-05-01 - 2015-04-30
more information: NIH RePORT

Detail Information

Research Grants30

  1. Mechanisms of Adaptation to Exercise in Health and COPD
    Peter D Wagner; Fiscal Year: 2013
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  2. Cardiac Regeneration through Growth Factor Eluting Microrod Scaffolds
    Paul H Goldspink; Fiscal Year: 2013
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  3. A temporospatial analysis of epithelial integrity following vocal fold injury
    Ciara Leydon; Fiscal Year: 2013
    ....
  4. Skin Regeneration with Stem Cells and Scaffolds
    SUSAN RENEE OPALENIK; Fiscal Year: 2013
    ..abstract_text> ..
  5. A Rational Approach to Stimulating Peripheral Nerve Regeneration Across Criticall
    Ravi V Bellamkonda; Fiscal Year: 2013
    ..abstract_text> ..
  6. Rebuilding the Failing Heart
    Piero Anversa; Fiscal Year: 2013
    ..abstract_text> ..
  7. Neural Mechanisms of Itch
    ROBERT H LA MOTTE; Fiscal Year: 2013
    ..abstract_text> ..
  8. Synaptic Function: Effects of the Nerve Injury, Repair, and Altered Activity
    Timothy C Cope; Fiscal Year: 2013
    ..The Resume and Summary of Discussion above summarizes the final outcome of the group discussion. OVERALL PROGRAM EVALUATION ..
  9. MicroRNA Regulation of Macrophage Polarization in Muscle Regeneration
    Paula K Shireman; Fiscal Year: 2013
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  10. Engineering fibrin polymers for enhanced angiogenesis
    THOMAS HARRISON BARKER; Fiscal Year: 2013
    ..This project will have direct relevance to wound healing and regenerative medicine by establishing new methods to manipulate fibrin for specific clinical outcomes. ..
  11. Molecular and Cellular Therapies for Muscular Dystrophy
    Stanley C Froehner; Fiscal Year: 2013
    ..The mechanism of NPC1 phenotype amelioration and its applicability to LGMDs will be studied. Two core facilities will serve the participating laboratories. ..
  12. Biomimetic Scaffold Anisotropy and Biomolecule Conjugation to Direct Tendon
    Brendan A Harley; Fiscal Year: 2013
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  13. Fabrication of 3D Cardiac Patches for Myocardial Recovery
    RAVI KUMAR BIRLA; Fiscal Year: 2013
    ..abstract_text> ..
  14. Osteocyte Regulation of Bone/Muscle with Age
    Lynda F Bonewald; Fiscal Year: 2013
    ..The results of these experiments should lead to novel therapeutics for the prevention and treatment of both osteoporosis and sarcopenia. ..
  15. An Enabling Technology for Improving Engraftment of Implanted Materials and Cells
    Michael J Yost; Fiscal Year: 2013
    ..It is our aim to develop an enabling technology that promotes scar-free healing after surgery of implanted biological and synthetic materials in the human body. ..
  16. Modulation of Muscle Regenerationby Growth Factors
    Elisabeth R Barton; Fiscal Year: 2013
    ..The mechanisms underlying their actions are essential to understand so that repair-enhancing therapies based on their functions can be developed. ..
  17. A Novel Approach for Biomaterials Assisted Regeneration of Pulp-Dentin Complex
    Satish Alapati; Fiscal Year: 2013
    ....
  18. Core Center for Musculoskeletal Disorders
    Louis J Soslowsky; Fiscal Year: 2013
    ..abstract_text> ..
  19. The University of Rochester Core Center for Musculoskeletal Biology and Medicine
    Edward M Schwarz; Fiscal Year: 2013
    ..abstract_text> ..
  20. A tissue specific approach to enhance tendon repair
    James H C Wang; Fiscal Year: 2013
    ..Moreover, we will use the proven tendon injury mode in this study as a "stepping-stone" for further studying healing problems of other tendon types, including flexor and rotator cuff tendons. ..