title: A biologically active surface enzyme assembly that attenuates thrombus formation.
abstract: Activation of hemostatic pathways by blood-contacting materials remains a major hurdle in the development of clinically durable artificial organs and implantable devices. We postulate that surface-induced thrombosis may be attenuated by the reconstitution onto blood contacting surfaces of bioactive enzymes that regulate the production of thrombin, a central mediator of both clotting and platelet activation cascades. Thrombomodulin (TM), a transmembrane protein expressed by endothelial cells, is an established negative regulator of thrombin generation in the circulatory system. Traditional techniques to covalently immobilize enzymes on solid supports may modify residues contained within or near the catalytic site, thus reducing the bioactivity of surface enzyme assemblies. In this report, we present a molecular engineering and bioorthogonal chemistry approach to site-specifically immobilize a biologically active recombinant human TM fragment onto the luminal surface of small diameter prosthetic vascular grafts. Bioactivity and biostability of TM modified grafts is confirmedin vitroand the capacity of modified grafts to reduce platelet activation is demonstrated using a non-human primate model. These studies indicate that molecularly engineered interfaces that display TM actively limit surface-induced thrombus formation.
authors.affiliation: Departments of Biomedical Engineering and Surgery, Georgia Institute of Technology and Emory University Atlanta, GA 30322 (USA).
authors.forename: Zheng
authors.initials: Z
authors.lastname: Qu
authors.forename: Sharmila
authors.initials: S
authors.lastname: Muthukrishnan
authors.forename: Murali K
authors.initials: MK
authors.lastname: Urlam
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Haller
authors.forename: Sumanas W
authors.initials: SW
authors.lastname: Jordan
authors.forename: Vivek A
authors.initials: VA
authors.lastname: Kumar
authors.forename: Ulla M
authors.initials: UM
authors.lastname: Marzec
authors.forename: Yaseen
authors.initials: Y
authors.lastname: Elkasabi
authors.forename: Joerg
authors.initials: J
authors.lastname: Lahann
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Hanson
authors.forename: Elliot L
authors.initials: EL
authors.lastname: Chaikof
keywords: Biomedical applications; Staudinger Ligation; blood compatibility; thrombosis; vascular graft