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Increasing biocompatibility of stents via CD47 surface functionalization: Mechanistic and Preclinical studies

通过 CD47 表面功能化提高支架的生物相容性：机理和临床前研究

基本信息

批准号：
9565589
负责人：
Ilia Fishbein
金额：
$ 72万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9565589
关键词：
Address Adhesions Advocate Affect Amino Acids Anatomy Animal Model Animals Anti-inflammatory Antimitotic Agents Arteries Automobile Driving Biological Blood Blood Platelets Blood flow CD47 gene Carotid stent Cell Communication Cells Clinical Coronary Data Development Devices Disease Effectiveness Event Extracellular Protein Family suidae Functional disorder Future Goals Harvest Human Immobilization Immune response Immunologics Inflammation Inflammatory Inflammatory Response Integral Membrane Protein Laboratories Malignant Neoplasms Mediating Medical Device Medicine Metals Mission Modeling Modification Molecular Oryctolagus cuniculus Outcome Pathogenesis Pathology Patients Peptides Peripheral Pharmaceutical Preparations Physiology Polymers Process Property Public Health Rattus Receptor Signaling Recombinants Reperfusion Injury Research Risk SHPS-1 protein Signal Transduction Site Smooth Muscle Myocytes Solid Stents Sterilization Surface System Testing Therapeutic Therapeutic Studies Thrombosis Time Tissues United States National Institutes of Health Work aged biomaterial compatibility cell type clinically relevant design diabetic human model iliac artery implantation improved in vivo innovation interest metallicity monocyte neutrophil novel strategies paracrine pre-clinical preclinical study prevent programs protein aminoacid sequence protein biomarkers receptor binding recruit response restenosis therapeutic effectiveness translational impact validation studies

项目摘要

Abstract/Summary The pathophysiology associated with endovascular stent usage is well documented and is observed in up to 50% of all patients receiving the medical device. CD47 is a ubiquitously expressed transmembrane protein, that when bound to its cognate receptor Signal Regulatory Protein alpha (SIRP), inhibits the immune response. We have shown, both ex vivo and in a rat carotid stent model, that immobilized recombinant CD47, or a 21 amino acid peptide sequence (pepCD47) thereof, significantly inhibited restenosis and thrombosis. The overall objective of the proposed research is to investigate the anti-restenotic capacity of a pepCD47 functionalized endovascular stent in rabbit and porcine animal models. Three Specific Aims (SA) will test our central hypothesis that immobilized pepCD47 represents a pragmatic surface modification strategy that will control adverse immunological and hemocompatibility responses and thus significantly contribute to biocompatibility of endovascular stents. In SA 1 we will fabricate and perform efficacy and stability analysis on CD47 functionalized metal surface to test our working hypothesis that rabbit and pig CD47, immobilized on the bare metal surfaces, will confer a similar anti-platelet and anti-inflammatory activity as human CD47 and will be amenable to clinically relevant challenges. SA 2 will determine how immobilized CD47 affects cellular interactions at the blood/stent interface. Our working hypothesis is that immobilized CD47 confers a biocompatible microenvironment that inhibits inflammatory cell and platelet interactions and permits re- endothelialization. SA 3 will demonstrate in vivo efficacy of CD47 functionalized stents in the large animal models. Our working hypothesis is that CD47 modified stents would confer significantly greater biocompatibility, compared to commercially available bare metal stents and drug eluting stents (DES), which will be demonstrated by a significant reduction in ISR of the stented site. The rationale for the proposed research is that demonstration of pepCD47 mediated inhibition of ISR in a large animal model would provide necessary preclinical and usage data to advance the application of the CD47-functionalized stents into the clinical realm. The research is significant because it will demonstrate the broad translational importance of CD47 in regulating the cellular/molecular response to synthetic surfaces that are used in clinically relevant biomedical devices. The research proposed herein is innovative because it challenges and redirects current therapeutic strategies, such as DES, by identifying candidate molecular signaling mechanisms that actively regulate cellular interactions with solid synthetic surfaces, and then incorporating these concepts into the design and fabrication of metallic stents.

抽象/总结