An Enabling Technology for Improving Engraftment of Implanted Materials and Cells

Summary

Principal Investigator: Michael J Yost
Abstract: DESCRIPTION (provided by applicant): The foreign body response to medical devices and materials implanted in the human body, including scarring, fibrous encapsulation and potential rejection, is a longstanding and serious clinical issue. There are no widely acceptable or safe therapies for ameliorating the foreign body response. Clinical complications resulting from the response include disfigurement of silicone prostheses and loss of function of devices such as implanted pacemakers, stents, and shunts. Cellularized implants and stem cells placed in the body are also subject to the foreign body response with the added issue that the regenerative repair intended to be prompted by the graft may be inhibited. Beneficial modification of the body's reaction to implanted materials, medical devices, engineered constructs or stem cells would be a fundamentally important therapeutic advance. We have recently reported the use of a peptide based on the Cx43 carboxyl terminus (CT) that reduces inflammation, scarring and myofibroblast differentiation associated with cutaneous wounds and sub-dermal placement of a silicone implant in rodent and porcine models. Our data are consistent with growing evidence for key roles of the gap junction protein Cx43 in wound response and tissue repair processes (Rhett et al., 2008). In this application it is our hypothesis that disruption of the function of Cx43 reduces scarring and improves regenerative integration of implanted materials, including cellularized constructs via Cx43-mediated effects on TGF-beta signaling. We will test this hypothesis in 3 aims: First, by determining the mode of action of the Cx43 CT peptide in reducing scarring and promoting tissue regeneration and comparing its mechanism and actions to another Cx43-function-targeting approach based on Cx43 shRNA. Second, by determining and comparing the efficacies of the Cx43 CT peptide and Cx43 shRNA in ameliorating the foreign body response to sub-dermal placement of a simple silicone implant and a collagen-based 3D implant containing progenitor cells designed to regenerate skeletal muscle. And third, the efficacy of the two Cx43 targeting approaches in enabling regenerative repair of muscle by the device in the mechanically active muscles of the abdomen. It is our objective to characterize and establish the usefulness of targeting Cx43 function as a strategy for improving the biocompatibility of medical implants. PUBLIC HEALTH RELEVANCE: This proposal addresses a need of fundamental significance to surgery. 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.
Funding Period: 2010-06-20 - 2015-04-30
more information: NIH RePORT

Top Publications

  1. pmc A peptide mimetic of the connexin43 carboxyl terminus reduces gap junction remodeling and induced arrhythmia following ventricular injury
    Michael P O'Quinn
    Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, USA
    Circ Res 108:704-15. 2011
  2. pmc Scaffold-free tissue engineering: organization of the tissue cytoskeleton and its effects on tissue shape
    Caitlin A Czajka
    Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, BSB 626, MSC 508, Charleston, SC, 29425, USA
    Ann Biomed Eng 42:1049-61. 2014
  3. pmc Fibroblast-myocyte electrotonic coupling: does it occur in native cardiac tissue?
    Peter Kohl
    Imperial College, National Heart and Lung Institute, Harefield Hospital, UB6 9JH, UK Electronic address
    J Mol Cell Cardiol 70:37-46. 2014
  4. ncbi A model system for primary abdominal closures
    Michael J Yost
    Department of General Surgery, Medical University of South Carolina, Charleston, SC, USA
    Methods Mol Biol 1037:165-73. 2013
  5. pmc Cx43 associates with Na(v)1.5 in the cardiomyocyte perinexus
    J Matthew Rhett
    Department of Regenerative Medicine, Medical University of South Carolina, 173 Ashley Ave, CRI Room 616, Charleston, SC 29425, USA
    J Membr Biol 245:411-22. 2012
  6. pmc The connexin43 carboxyl terminus and cardiac gap junction organization
    Joseph A Palatinus
    Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA
    Biochim Biophys Acta 1818:1831-43. 2012
  7. pmc Enhanced PKCĪµ mediated phosphorylation of connexin43 at serine 368 by a carboxyl-terminal mimetic peptide is dependent on injury
    Joseph A Palatinus
    Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA
    Channels (Austin) 5:236-40. 2011
  8. pmc Connexin 43 connexon to gap junction transition is regulated by zonula occludens-1
    J Matthew Rhett
    Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
    Mol Biol Cell 22:1516-28. 2011
  9. ncbi Intercellular electrical communication in the heart: a new, active role for the intercalated disk
    Rengasayee Veeraraghavan
    Center for Cardiovascular and Regenerative Biology, Virginia Tech Carilion Research Institute, Roanoke, VA, USA
    Cell Commun Adhes 21:161-7. 2014

Detail Information

Publications10

  1. pmc A peptide mimetic of the connexin43 carboxyl terminus reduces gap junction remodeling and induced arrhythmia following ventricular injury
    Michael P O'Quinn
    Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, USA
    Circ Res 108:704-15. 2011
    ..Remodeling of connexin (Cx)43 gap junctions (GJs) is linked to ventricular arrhythmia...
  2. pmc Scaffold-free tissue engineering: organization of the tissue cytoskeleton and its effects on tissue shape
    Caitlin A Czajka
    Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, BSB 626, MSC 508, Charleston, SC, 29425, USA
    Ann Biomed Eng 42:1049-61. 2014
    ..Our studies suggest that the deformation of scaffold-free tissues due to tensions mediated via the tissue cortical cytoskeleton represents a major and underappreciated challenge to modular tissue engineering. ..
  3. pmc Fibroblast-myocyte electrotonic coupling: does it occur in native cardiac tissue?
    Peter Kohl
    Imperial College, National Heart and Lung Institute, Harefield Hospital, UB6 9JH, UK Electronic address
    J Mol Cell Cardiol 70:37-46. 2014
    ..This article is part of a Special Issue entitled "Myocyte-Fibroblast Signalling in Myocardium." ..
  4. ncbi A model system for primary abdominal closures
    Michael J Yost
    Department of General Surgery, Medical University of South Carolina, Charleston, SC, USA
    Methods Mol Biol 1037:165-73. 2013
    ....
  5. pmc Cx43 associates with Na(v)1.5 in the cardiomyocyte perinexus
    J Matthew Rhett
    Department of Regenerative Medicine, Medical University of South Carolina, 173 Ashley Ave, CRI Room 616, Charleston, SC 29425, USA
    J Membr Biol 245:411-22. 2012
    ..This work provides a detailed characterization of the structure of the perinexus at the GJ edge and indicates that one of its potential functions in the heart may be in facilitating conduction of action potential...
  6. pmc The connexin43 carboxyl terminus and cardiac gap junction organization
    Joseph A Palatinus
    Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA
    Biochim Biophys Acta 1818:1831-43. 2012
    ..This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics...
  7. pmc Enhanced PKCĪµ mediated phosphorylation of connexin43 at serine 368 by a carboxyl-terminal mimetic peptide is dependent on injury
    Joseph A Palatinus
    Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA
    Channels (Austin) 5:236-40. 2011
    ..These results suggest that peptide-enhanced phosphorylation of the Cx43 carboxyl-terminus is dependent on injury-mediated cellular responses...
  8. pmc Connexin 43 connexon to gap junction transition is regulated by zonula occludens-1
    J Matthew Rhett
    Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
    Mol Biol Cell 22:1516-28. 2011
    ..It is concluded that ZO-1 regulates the rate of undocked connexon aggregation into GJs, enabling dynamic partitioning of Cx43 channel function between junctional and proximal nonjunctional domains of plasma membrane...
  9. ncbi Intercellular electrical communication in the heart: a new, active role for the intercalated disk
    Rengasayee Veeraraghavan
    Center for Cardiovascular and Regenerative Biology, Virginia Tech Carilion Research Institute, Roanoke, VA, USA
    Cell Commun Adhes 21:161-7. 2014
    ..This review will discuss the role of the ID in the context of the canonical, electrotonic view of conduction and highlight new, emerging possibilities of its playing a more active role in ephaptic coupling between cardiac myocytes...

Research Grants30

  1. MicroRNA Regulation of Macrophage Polarization in Muscle Regeneration
    Paula K Shireman; Fiscal Year: 2013
    ....
  2. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  3. Early Metazoan Nano-collagens for Promotion of Wound Healing
    Angel Anne Yanagihara; Fiscal Year: 2013
    ....
  4. Biomimetic Tissue Adhesive with Mechanically Tough Hydrogel Support
    Bruce P Lee; Fiscal Year: 2013
    ..This AREA award will provide the PI with resources to train undergraduate and graduate students, obtain data for future NIH funding, and build a nationally-recognized graduate program. ..
  5. Regenerative Integration of Percutaneous Implants
    PHIL GORDON CAMPBELL; Fiscal Year: 2013
    ..Furthermore, the knowledge gained from this proposed research will elucidate the emerging role of monocytes and macrophages in tissue repair and regeneration. ..
  6. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  7. Development of Adult Pluripotent Very Small Embryonic Like (VSEL) Stem Cells to T
    DENIS OVEREND RODGERSON; Fiscal Year: 2013
    ....
  8. Infection resistant surface for ventricular assist device (VAD) transcutaneous dr
    PATRICK THOMAS CAHALAN; Fiscal Year: 2013
    ..Successful completion of the Fast Track project plan will result in a surface ready for qualification testing, regulatory approval, and subsequent commercialization. ..
  9. 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. ..