title: Tacrolimus-Eluting Suture Inhibits Neointimal Hyperplasia: An Experimental In Vivo Study in Rats.
abstract: OBJECTIVE
  Neointimal hyperplasia (NIH) remains one of the leading causes of graft failure after vascular anastomoses. Cytotoxic drugs, such as rapamycin and tacrolimus, have been shown to inhibit the development of NIH. In this study, the aim was to test the impact of a sustained releasing tacrolimus-chitosan-eluting suture on the development of NIH in a rat model.
  
  
  METHODS
  After tacrolimus-chitosan coating of a 7/0 polyvinylidene difluoride (PVDF) Trofilen®suture, the tacrolimus concentration on the coated suture and in vitro release trials were performed spectrophotometrically. Twelve Wistar rats were included. After midline laparotomy, a 7-8 mm longitudinal aortotomy in the infrarenal aorta was made and then closed by a bare 7/0 PVDF (group C, n = 6) and a 7/0 tacrolimus-chitosan coated PVDF suture (0.65 μg/cm tacrolimus [0.9 wt%] + 1.82 μg/cm chitosan [2.28 wt%]) (group T, n = 6). After 1 month, rats were sacrificed and aortotomy sites were examined histologically by ratio of intimal area (including neointima) and immunohistochemically by α-smooth muscle actin (ASMA) and proliferating cell nuclear antigen (PCNA) immunostaining. The PCNA positive cells were indexed to total cell number and expressed as percentage.
  
  
  RESULTS
  In vitro tacrolimus release tests for a 7/0 tacrolimus-chitosan coated PVDF suture were confirmed for 1 month without an initial burst release. Endothelialisation over the aortotomy line occurred in both groups. The area of neointima was significantly reduced in group T compared with group C (ratio 0.22 ± 0.12 vs. 0.42 ± 0.11; p = .017) 1 month post-operatively. Likewise, the percentage of PCNA immunostaining significantly decreased in group C compared with group T (3.83 ± 2.85% vs. 11.17 ± 7.78%; p = .026). The cells constituting NIH were positive for ASMA immunostaining.
  
  
  CONCLUSIONS
  Tacrolimus-chitosan-eluting suture is shown to be an effective way to reduce NIH without interfering with normal endothelialisation.
authors.affiliation: Marmara University Faculty of Medicine, Department of Cardiovascular Surgery, Marmara Universitesi Pendik Egitim ve Arastırma Hastanesi, Ustkaynarca Pendik, Istanbul, Turkey; Eastern Mediterranean University, Faculty of Medicine, Gazimagusa, Cyprus. Electronic address: korayakmd@gmail.com.
authors.forename: K
authors.initials: K
authors.lastname: Ak
authors.affiliation: Faculty of Dentistry, Department of Basic Sciences, Histology and Embryology, Marmara Universitesi Pendik Egitim ve Arastırma Hastanesi, Ustkaynarca Pendik, Istanbul, Turkey.
authors.forename: E
authors.initials: E
authors.lastname: Ak
authors.affiliation: Marmara University Faculty of Medicine, Department of Cardiovascular Surgery, Marmara Universitesi Pendik Egitim ve Arastırma Hastanesi, Ustkaynarca Pendik, Istanbul, Turkey.
authors.forename: O
authors.initials: O
authors.lastname: Dericioglu
authors.affiliation: Faculty of Pharmacy, Department of Pharmaceutical Biotechnology and Marmara Universitesi Pendik Egitim ve Arastırma Hastanesi, Ustkaynarca Pendik, Istanbul, Turkey.
authors.forename: T
authors.initials: T
authors.lastname: Canak
authors.affiliation: Faculty of Pharmacy, Department of Pharmaceutical Biotechnology and Marmara Universitesi Pendik Egitim ve Arastırma Hastanesi, Ustkaynarca Pendik, Istanbul, Turkey.
authors.forename: J
authors.initials: J
authors.lastname: Akbuga
authors.affiliation: Vocational School of Health Services, Marmara Universitesi Pendik Egitim ve Arastırma Hastanesi, Ustkaynarca Pendik, Istanbul, Turkey.
authors.forename: N
authors.initials: N
authors.lastname: Ozkan
authors.affiliation: Faculty of Medicine, Department of Histology and Embryology, Marmara Universitesi Pendik Egitim ve Arastırma Hastanesi, Ustkaynarca Pendik, Istanbul, Turkey.
authors.forename: S
authors.initials: S
authors.lastname: Cetinel
authors.affiliation: Marmara University Faculty of Medicine, Department of Cardiovascular Surgery, Marmara Universitesi Pendik Egitim ve Arastırma Hastanesi, Ustkaynarca Pendik, Istanbul, Turkey.
authors.forename: S
authors.initials: S
authors.lastname: Isbir
authors.affiliation: Marmara University Faculty of Medicine, Department of Cardiovascular Surgery, Marmara Universitesi Pendik Egitim ve Arastırma Hastanesi, Ustkaynarca Pendik, Istanbul, Turkey.
authors.forename: S
authors.initials: S
authors.lastname: Arsan
authors.affiliation: Marmara University Faculty of Medicine, Department of Cardiovascular Surgery, Marmara Universitesi Pendik Egitim ve Arastırma Hastanesi, Ustkaynarca Pendik, Istanbul, Turkey.
authors.forename: A
authors.initials: A
authors.lastname: Cobanoglu
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D002317:Cardiovascular Agents / Q000008:administration & dosage*; D020099:Coated Materials, Biocompatible; D004867:Equipment Design; D006965:Hyperplasia; D008297:Male; D058426:Neointima; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D017208:Rats, Wistar; D012995:Solubility; D013536:Suture Techniques / Q000009:adverse effects / Q000295:instrumentation*; D013537:Sutures; D016559:Tacrolimus / Q000008:administration & dosage*; D013997:Time Factors
chemical_list: D000199:Actins; D002317:Cardiovascular Agents; D020099:Coated Materials, Biocompatible; D018809:Proliferating Cell Nuclear Antigen; D016559:Tacrolimus; C498862:Acta2 protein, rat
keywords: Eluting suture; Endothelialisation and anastomosis; Neointimal hyperplasia; Tacrolimus–chitosan