title: Water-soluble argatroban for antithrombogenic surface coating of tissue-engineered cardiovascular tissues.
abstract: Argatroban is a powerful synthetic anticoagulant, but due to its water-insoluble nature, it is unsuitable for use as a coating material to reduce the thrombogenic potential of natural or tissue-engineered blood-contacting cardiovascular tissues. On the other hand, anionic compounds could adsorb firmly onto connective tissues. Therefore, in this study, an anionic form of argatroban was prepared by neutralization from its alkaline solution, dialysis, and freeze-drying. The subsequently obtained argatroban derivative could be easily dissolved in water. Analysis of the surface chemical composition showed that the water-soluble argatroban (WSA) could be adsorbed on the entire surface of tissue-engineered connective tissue sheets composed mainly of collagen. Adsorption was achieved on immersion of the tissue-engineered connective tissue sheet in a saline/WSA solution for only 30 s without any change in the mechanical properties of the tissue-engineered sheets. Complete surface adsorption (ca., 1 mg/cm(2) ) was obtained at WSA concentrations of over 5 mg/mL. WSA adsorption was maintained for at least 7 days with rinsing. Blood coagulation was significantly prevented on the WSA-adsorbed surfaces in acute in vitro experiments. The coating was applied to in vivo tissue-engineered vascular grafts (biotubes) or tri-leaflet tissues (biovalves) under development, ensuring a high likelihood of nonthrombogenicity of their blood-contacting surfaces with high patency, at least in the subchronic phase. It appears that WSA satisfies the initial requirements for a biocompatible aqueous coating material for use in natural or tissue-engineered tissues.
authors.affiliation: Division of Medical Engineering and Materials, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan. nakayama@ri.ncvc.go.jp
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Nakayama
authors.forename: Saori
authors.initials: S
authors.lastname: Yamaoka
authors.forename: Masashi
authors.initials: M
authors.lastname: Yamanami
authors.forename: Megumi
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Masami
authors.initials: M
authors.lastname: Uechi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Takamizawa
authors.forename: Hatsue
authors.initials: H
authors.lastname: Ishibashi-Ueda
authors.forename: Marie
authors.initials: M
authors.lastname: Nakamichi
authors.forename: Kingo
authors.initials: K
authors.lastname: Uchida
authors.forename: Taiji
authors.initials: T
authors.lastname: Watanabe
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kanda
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yaku
mesh_terms: D000327:Adsorption; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives; D001807:Blood Vessel Prosthesis; D020099:Coated Materials, Biocompatible / Q000737:chemistry; D004396:Coloring Agents / Q000737:chemistry / Q000494:pharmacology; D003238:Connective Tissue / Q000473:pathology; D004285:Dogs; D005260:Female; D006350:Heart Valve Prosthesis; D006801:Humans; D007477:Ions; D008422:Materials Testing; D008956:Models, Chemical; D010875:Pipecolic Acids / Q000737:chemistry*; D012995:Solubility; D013449:Sulfonamides; D013499:Surface Properties; D023822:Tissue Engineering / Q000379:methods*; D014867:Water / Q000737:chemistry*
chemical_list: D020099:Coated Materials, Biocompatible; D004396:Coloring Agents; D007477:Ions; D010875:Pipecolic Acids; D013449:Sulfonamides; D014867:Water; D001120:Arginine; C031942:argatroban