title: Polymeric stent materials dysregulate macrophage and endothelial cell functions: implications for coronary artery stent.
abstract: BACKGROUND
  Biodegradable polymers have been applied as bulk or coating materials for coronary artery stents. The degradation of polymers, however, could induce endothelial dysfunction and aggravate neointimal formation. Here we use polymeric microparticles to simulate and demonstrate the effects of degraded stent materials on phagocytic activity, cell death and dysfunction of macrophages and endothelial cells.
  
  
  METHODS
  Microparticles made of low molecular weight polyesters were incubated with human macrophages and coronary artery endothelial cells (ECs). Microparticle-induced phagocytosis, cytotoxicity, apoptosis, cytokine release and surface marker expression were determined by immunostaining or ELISA. Elastase expression was analyzed by ELISA and the elastase-mediated polymer degradation was assessed by mass spectrometry.
  
  
  RESULTS
  We demonstrated that poly(D,L-lactic acid) (PLLA) and polycaprolactone (PCL) microparticles induced cytotoxicity in macrophages and ECs, partially through cell apoptosis. The particle treatment alleviated EC phagocytosis, as opposed to macrophages, but enhanced the expression of vascular cell adhesion molecule (VCAM)-1 along with decreased nitric oxide production, indicating that ECs were activated and lost their capacity to maintain homeostasis. The activation of both cell types induced the release of elastase or elastase-like protease, which further accelerated polymer degradation.
  
  
  CONCLUSIONS
  This study revealed that low molecule weight PLLA and PCL microparticles increased cytotoxicity and dysregulated endothelial cell function, which in turn enhanced elastase release and polymer degradation. These indicate that polymer or polymer-coated stents impose a risk of endothelial dysfunction after deployment which can potentially lead to delayed endothelialization, neointimal hyperplasia and late thrombosis.
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, United States.
authors.forename: Xintong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, United States.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Zachman
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, United States.
authors.forename: Young Wook
authors.initials: YW
authors.lastname: Chun
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, United States.
authors.forename: Fang-Wen
authors.initials: FW
authors.lastname: Shen
authors.affiliation: Department of Maxillofacial Biomedical Engineering, Kyung Hee University, Seoul, South Korea.
authors.forename: Yu-Shik
authors.initials: YS
authors.lastname: Hwang
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, United States; Department of Maxillofacial Biomedical Engineering, Kyung Hee University, Seoul, South Korea. Electronic address: hak-joon.sung@vanderbilt.edu.
authors.forename: Hak-Joon
authors.initials: HJ
authors.lastname: Sung
mesh_terms: D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D011108:Polymers / Q000008:administration & dosage* / Q000009:adverse effects; D015607:Stents / Q000009:adverse effects
chemical_list: D011108:Polymers
keywords: Dysfunction; Elastase; Endothelial cell; Poly(L-lactic acid); Polycaprolactone; Stent