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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DE019355-03
Application #
8246417
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Lumelsky, Nadya L
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2012
Total Cost
Indirect Cost
Name
University of South Carolina at Columbia
Department
Surgery
Type
Schools of Medicine
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
Rhett, J Matthew; Fann, Stephen A; Yost, Michael J (2014) Purinergic signaling in early inflammatory events of the foreign body response: modulating extracellular ATP as an enabling technology for engineered implants and tissues. Tissue Eng Part B Rev 20:392-402
Kohl, Peter; Gourdie, Robert G (2014) Fibroblast-myocyte electrotonic coupling: does it occur in native cardiac tissue? J Mol Cell Cardiol 70:37-46
Veeraraghavan, Rengasayee; Poelzing, Steven; Gourdie, Robert G (2014) Intercellular electrical communication in the heart: a new, active role for the intercalated disk. Cell Commun Adhes 21:161-7
Veeraraghavan, Rengasayee; Gourdie, Robert G; Poelzing, Steven (2014) Mechanisms of cardiac conduction: a history of revisions. Am J Physiol Heart Circ Physiol 306:H619-27
Czajka, Caitlin A; Mehesz, Agnes Nagy; Trusk, Thomas C et al. (2014) Scaffold-free tissue engineering: organization of the tissue cytoskeleton and its effects on tissue shape. Ann Biomed Eng 42:1049-61
Yost, Michael J; Morales, Mary O; Rodriguez-Rivera, Veronica et al. (2013) A model system for primary abdominal closures. Methods Mol Biol 1037:165-73
Rhett, Joshua Matthew; Gourdie, Robert G (2012) The perinexus: a new feature of Cx43 gap junction organization. Heart Rhythm 9:619-23
Rhett, J Matthew; Jourdan, Jane; Gourdie, Robert G (2011) Connexin 43 connexon to gap junction transition is regulated by zonula occludens-1. Mol Biol Cell 22:1516-28
Palatinus, Joseph A; Rhett, Joshua M; Gourdie, Robert G (2011) Enhanced PKC? mediated phosphorylation of connexin43 at serine 368 by a carboxyl-terminal mimetic peptide is dependent on injury. Channels (Austin) 5:236-40