title: Covalent modification of pericardial patches for sustained rapamycin delivery inhibits venous neointimal hyperplasia.
abstract: Prosthetic grafts and patches are commonly used in cardiovascular surgery, however neointimal hyperplasia remains a significant concern, especially under low flow conditions. We hypothesized that delivery of rapamycin from nanoparticles (NP) covalently attached to patches allows sustained site-specific delivery of therapeutic agents targeted to inhibit localized neointimal hyperplasia. NP were covalently linked to pericardial patches using EDC/NHS chemistry and could deliver at least 360 ng rapamycin per patch without detectable rapamycin in serum; nanoparticles were detectable in the liver, kidney and spleen but no other sites within 24 hours. In a rat venous patch angioplasty model, control patches developed robust neointimal hyperplasia on the patch luminal surface characterized by Eph-B4-positive endothelium and underlying SMC and infiltrating cells such as macrophages and leukocytes. Patches delivering rapamycin developed less neointimal hyperplasia, less smooth muscle cell proliferation, and had fewer infiltrating cells but retained endothelialization. NP covalently linked to pericardial patches are a novel composite delivery system that allows sustained site-specific delivery of therapeutics; NP delivering rapamycin inhibit patch neointimal hyperplasia. NP linked to patches may represent a next generation of tissue engineered cardiovascular implants.
authors.affiliation: The Vascular Biology and Therapeutics Program and the Department of Surgery, Yale University School of Medicine, New Haven, CT, 06520, USA.|Basic Medical College of Zhengzhou University, Henan, China.|Department of Vascular Surgery, First Affiliated Hospital of Zhengzhou University, Henan, China.
authors.forename: Hualong
authors.initials: H
authors.lastname: Bai
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT, 06520, USA.
authors.forename: Jung Seok
authors.initials: JS
authors.lastname: Lee
authors.affiliation: The Vascular Biology and Therapeutics Program and the Department of Surgery, Yale University School of Medicine, New Haven, CT, 06520, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Chen
authors.affiliation: The Vascular Biology and Therapeutics Program and the Department of Surgery, Yale University School of Medicine, New Haven, CT, 06520, USA.
authors.forename: Mo
authors.initials: M
authors.lastname: Wang
authors.affiliation: Basic Medical College of Zhengzhou University, Henan, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT, 06520, USA.|Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06520, USA.
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Fahmy
authors.affiliation: The Vascular Biology and Therapeutics Program and the Department of Surgery, Yale University School of Medicine, New Haven, CT, 06520, USA.|Department of Surgery, VA Connecticut Healthcare System, West Haven, CT 06515, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Dardik
mesh_terms: D017130:Angioplasty / Q000379:methods*; D000818:Animals; D004337:Drug Carriers / Q000008:administration & dosage; D006131:Growth Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006651:Histocytochemistry; D006965:Hyperplasia / Q000473:pathology / Q000517:prevention & control*; D053758:Nanoparticles / Q000008:administration & dosage*; D058426:Neointima / Q000473:pathology*; D051381:Rats; D020123:Sirolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019737:Transplants / Q000601:surgery*; D016896:Treatment Outcome
chemical_list: D004337:Drug Carriers; D006131:Growth Inhibitors; D020123:Sirolimus