title: Enhanced biocompatibility of CD47-functionalized vascular stents.
abstract: The effectiveness of endovascular stents is hindered by in-stent restenosis (ISR), a secondary re-obstruction of treated arteries due to unresolved inflammation and activation of smooth muscle cells in the arterial wall. We previously demonstrated that immobilized CD47, a ubiquitously expressed transmembrane protein with an established role in immune evasion, can confer biocompatibility when appended to polymeric surfaces. In present studies, we test the hypothesis that CD47 immobilized onto metallic surfaces of stents can effectively inhibit the inflammatory response thus mitigating ISR. Recombinant CD47 (recCD47) or a peptide sequence corresponding to the Ig domain of CD47 (pepCD47), were attached to the surfaces of both 316L-grade stainless steel foils and stents using bisphosphonate coordination chemistry and thiol-based conjugation reactions to assess the anti-inflammatory properties of CD47-functionalized surfaces. Initial in vitro and ex vivo analysis demonstrated that both recCD47 and pepCD47 significantly reduced inflammatory cell attachment to steel surfaces without impeding on endothelial cell retention and expansion. Using a rat carotid stent model, we showed that pepCD47-functionalized stents prevented fibrin and platelet thrombus deposition, inhibited inflammatory cell attachment, and reduced restenosis by 30%. It is concluded that CD47-modified stent surfaces mitigate platelet and inflammatory cell attachment, thereby disrupting ISR pathophysiology.
authors.affiliation: Division of Cardiology, Department of Pediatrics, The Children's Hospital of Philadelphia, USA; Perelman School of Medicine, The University of Pennsylvania, USA.
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Slee
authors.affiliation: Division of Cardiology, Department of Pediatrics, The Children's Hospital of Philadelphia, USA; Perelman School of Medicine, The University of Pennsylvania, USA.
authors.forename: Ivan S
authors.initials: IS
authors.lastname: Alferiev
authors.affiliation: Department of Cell and Developmental Biology, Perelman School of Medicine, The University of Pennsylvania, USA.
authors.forename: Chandrasekaran
authors.initials: C
authors.lastname: Nagaswami
authors.affiliation: Department of Cell and Developmental Biology, Perelman School of Medicine, The University of Pennsylvania, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Weisel
authors.affiliation: Division of Cardiology, Department of Pediatrics, The Children's Hospital of Philadelphia, USA; Perelman School of Medicine, The University of Pennsylvania, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Levy
authors.affiliation: Division of Cardiology, Department of Pediatrics, The Children's Hospital of Philadelphia, USA; Perelman School of Medicine, The University of Pennsylvania, USA. Electronic address: fishbein@email.chop.edu.
authors.forename: Ilia
authors.initials: I
authors.lastname: Fishbein
authors.affiliation: Division of Cardiology, Department of Pediatrics, The Children's Hospital of Philadelphia, USA; Perelman School of Medicine, The University of Pennsylvania, USA. Electronic address: stachelek@email.chop.edu.
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Stachelek
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000627:therapeutic use*; D001792:Blood Platelets / Q000187:drug effects; D051928:CD47 Antigen / Q000737:chemistry / Q000627:therapeutic use*; D002339:Carotid Arteries / Q000601:surgery; D002460:Cell Line; D020099:Coated Materials, Biocompatible / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D055767:Immobilized Proteins / Q000737:chemistry / Q000627:therapeutic use*; D007249:Inflammation / Q000209:etiology / Q000517:prevention & control*; D051381:Rats; D013193:Stainless Steel / Q000737:chemistry*; D015607:Stents / Q000009:adverse effects*; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control*
chemical_list: D000893:Anti-Inflammatory Agents; D051928:CD47 Antigen; D020099:Coated Materials, Biocompatible; D055767:Immobilized Proteins; D013193:Stainless Steel
keywords: Bare metal stents; Bioactive surface coating; Inflammation; Platelets; Restenosis; Signal regulatory protein alpha