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)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE019355-05
Application #
8461465
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Lumelsky, Nadya L
Project Start
2010-06-20
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$346,655
Indirect Cost
$63,910
Name
Medical University of South Carolina
Department
Surgery
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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Rodriguez-Rivera, Veronica; Weidner, John W; Yost, Michael J (2016) Three-dimensional Biomimetic Technology: Novel Biorubber Creates Defined Micro- and Macro-scale Architectures in Collagen Hydrogels. J Vis Exp :53578
Veeraraghavan, Rengasayee; Lin, Joyce; Hoeker, Gregory S et al. (2015) Sodium channels in the Cx43 gap junction perinexus may constitute a cardiac ephapse: an experimental and modeling study. Pflugers Arch 467:2093-105
George, Sharon A; Sciuto, Katherine J; Lin, Joyce et al. (2015) Extracellular sodium and potassium levels modulate cardiac conduction in mice heterozygous null for the Connexin43 gene. Pflugers Arch 467:2287-97
Chen, Cheng-Hung; Mayo, Jamie N; Gourdie, Robert G et al. (2015) The connexin 43/ZO-1 complex regulates cerebral endothelial F-actin architecture and migration. Am J Physiol Cell Physiol 309:C600-7
Calder, Bennett W; Matthew Rhett, Joshua; Bainbridge, Heather et al. (2015) Inhibition of connexin 43 hemichannel-mediated ATP release attenuates early inflammation during the foreign body response. Tissue Eng Part A 21:1752-62
Czajka, Caitlin A; Calder, Bennet W; Yost, Michael J et al. (2015) Implanted scaffold-free prevascularized constructs promote tissue repair. Ann Plast Surg 74:371-5
Dennis, Sarah Grace; Trusk, Thomas; Richards, Dylan et al. (2015) Viability of Bioprinted Cellular Constructs Using a Three Dispenser Cartesian Printer. J Vis Exp :
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

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