Glow discharge plasma treatment of polyethylene tubing with tetraglyme results in ultralow fibrinogen adsorption and greatly reduced platelet adhesion Lan Cao, 1 Sivaprasad Sukavaneshvar, 2 Buddy D. Ratner, 1,3 Thomas A. Horbett 1,3 1 Department of Chemical Engineering, University of Washington, Seattle, Washington 98195 2 Utah Artificial Heart Institute, Salt Lake City, Utah 84103 3 Department of Bioengineering, University of Washington, Seattle, Washington 98195 Received 20 December 2005; revised 13 April 2006; accepted 28 April 2006 Published online 1 August 2006 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jbm.a.30908 Abstract: Previous studies from our lab have shown that fibrinogen adsorption (G Fg ) must be reduced below 10 ng/cm 2 to significantly reduce platelet adhesion, and that radio fre- quency glow discharge (RFGD) treatment of polymeric films in the presence of tetraethylene glycol dimethyl ether (tetra- glyme) can reduce G Fg to the desired ultralow value. In this report, the effects of RFGD coatings of tetraglyme on the lumenal surface of PE tubing on G Fg and on blood interac- tions both in vitro and ex vivo are described. G Fg on the tetra- glyme-coated PE tubing was reduced to the desired ultra- low level (<10 ng/cm 2 ), and we also observed a significant decrease in adsorption of von Willebrand’s factor. In vitro platelet adhesion from washed platelet suspensions, platelet rich plasma, or whole blood to tetraglyme-coated PE tubing was decreased compared to PE, polyurethane, or silicone rubber tubes. In addition, thrombin generation by platelets adherent to tetraglyme-coated PE was also much less than by platelets adherent to PE. When inserted in an ex vivo ca- rotid artery-carotid artery shunt in sheep, the RFGD tetra- glyme-coated PE exhibited a very low number of adherent platelets compared to heparin-coated, chromic acid-etched, or plain PE. The RFGD tetraglyme-coated PE tubes exhib- ited high protein and platelet resistance in vitro, and high platelet resistance ex vivo. The improved hemocompatibility is attributed to the unique chemical structure of RFGD tetra- glyme that makes it highly protein resistant. Ó 2006 Wiley Periodicals, Inc. J Biomed Mater Res 79A: 788–803, 2006 Key words: hemocompatibility; glow discharge plasma deposition; protein adsorption; platelet adhesion; tetraglyme INTRODUCTION Thrombosis and thromboembolization are major problems for medical devices used in contact with blood. 1–4 Thus, anticoagulants are always given to patients with implants that contact blood, but bleed- ing and other complications, for example thrombocy- topenia, can occur. 5–8 Coupling heparin to the surface of the device physically, covalently, or ionically im- proves resistance to clotting, but still does not prevent all clotting on devices. Therefore, biomaterials that would have intrinsically low reactivity with blood and reduce the need for surface or bulk hepariniza- tion are still desired. Surface modification is a commonly used strategy to reduce adverse reactions of blood with biomateri- als. 9 In recent years, much research has focused on nonfouling surfaces to reduce plasma protein adsorp- tion and subsequent blood cell attachment and activa- tion. 4,9 Many approaches to making the surface more ‘nonfouling’ have been taken, including chemical covalent bonding, spin coating, electrical vapor spray, surface modifying additives, and plasma deposi- tion. 10–15 Many of these surface modifications exhibit improved protein or platelet repellency in vitro. 12,16–23 However, materials that are protein-resistant and pla- telets-resistant in vitro sometimes fail to perform equally well in vivo. 4,15,16,24 The discrepancy between in vitro and in vivo results for nonfouling materials may be partly explained by more recent studies of protein adsorption that have provided evidence for a need for ultralow protein ad- sorption. Since protein adsorption on biomaterial sur- faces occurs prior to platelet interaction, and is known to mediate subsequent platelet adhesion and activa- tion, 25,26 protein adsorption is considered to be a key Correspondence to: T. A. Horbett; e-mail: Horbett@cheme. washington.edu Contract grant sponsor: NIH; contract grant number: HL RO1 67923 Contract grant sponsor: NIBIB; contract grant number: EB-002027 ' 2006 Wiley Periodicals, Inc.