The pathophysiology associated with endovascular stent usage is well documented and is observed in up to 50% of all patients receiving the medical device. Unfortunately there has been a paucity of innovative solutions to prevent the untoward effects, such as in-stent restenosis and neointimal formation, of cardiovascular stent deployment. Biofunctionalizing the blood-contacting surface of medical devices, with bioactive therapeutic molecules, would hypothetically attenuate the aberrant hemocompatibility issues that are observed in stent usage. CD47 has been identified as a ligand for the immune inhibitory receptor SIRP? and has been shown to confer "self" status on xenotransplanted red blood cells and synthetic nanoparticles. Dr. Stanley J. Stachelek, one of this project's co-Principle Investigator (PI) and an expert on developing strategies to address the inflammatory response to cardiovascular biomaterials, has recently described a platform technology to reduce the inflammatory response to a range of biomaterials such as polyvinyl chloride (PVC) and polyurethane (PU), by covalently linking a ubiquitously expressed cell surface protein, CD47, to the polymers'surface. Complementing Dr. Stachelek's expertise, Dr. Ilia Fishbein, M.D., Ph.D., the other co-PI on the project, has published extensively on developing new and innovative strategies to enhance endovascular stent biocompatibility. Drawing from the expertise of these two investigators, this proposal will test the hypothesis that recombinant CD47 can be immobilized onto the surface of endovascular stents to decrease the pro-thrombotic and pro-inflammatory events that are observed after stent deployment. The proposal will have two Specific Aims. In the first aim, the investigators will optimize the attachment of recombinant CD47 to stainless steel surfaces. Additional studies will be performed to characterize, using in vitro and ex vivo methodologies, the anti-inflammatory properties of CD47 functionalized metal surfaces. Lead formulations of CD47 modified metal surfaces will then be used in the second and final Specific Aim where a rat model of stenting angioplasty will be used to assess the efficacy of CD47 modified stents in enhancing hemocompatibility and reducing neointimal formation and in-stent restenosis. This proposal, which blends expertise and concepts from cardiology, synthetic chemistry, immunology, and materials science will contribute to developing a novel and innovative therapeutic strategy to address the aberrant effects of cardiovascular stent usage.

Public Health Relevance

The pathophysiology associated with endovascular stent usage is well known. At present, addressing this problem remains an unmet need in the field of biomaterials. This proposal will investigate a novel approach for addressing the inflammatory response to endovascular stent deployment by immobilizing a naturally expressed protein marker of self, CD47, to the metallic stent surface.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21EB015612-01A1
Application #
8512290
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Hunziker, Rosemarie
Project Start
2013-04-15
Project End
2015-03-31
Budget Start
2013-04-15
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$209,375
Indirect Cost
$84,375
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104