Discoveries in our laboratory have led to the synthesis of novel polyurethanes derivatized through an epoxy bonding mechanism with covalent linking of either the calcification inhibitor ethanehydroxydiphosphonate (EHDP), or heparin. These epoxy derivatized polyurethanes have been used by our group in pilot animal model studies with results revealing the EHDP derivatized polyurethane resists calcification both in the rat subdermal model (using calciphylaxis), as well as in mitral valve replacements in sheep. Heparin derivatized polyurethane also resisted calcification in subdermal implants in rats(calciphylaxis). Furthermore, heparin derivatized polyurethanes also demonstrated thrombo-resistance. Thus far our derivatized polyurethanes are the only calcification resistant polyurethanes synthesized by any group. These new polyurethanes will be used to investigate hypotheses concerning the mechanism and inhibition of polyurethane calcification in the circulation. Specifically, we will investigate a three component hypothesis: 1) We hypothesize that polyurethane calcification is due in part to the propensity of this material to provide an appropriate nucleating and crystal growth surface for calcium phosphates; 2) We hypothesize that the predominantly surface oriented polyurethane calcification is due to adsorption of biologic components consisting of cells, cell debris, lipids, and proteins; and 3) We hypothesize that in the blood stream, the observed thrombus oriented calcification also contributes to the overall mechanism of polyurethane mineralization. The three component hypothesis will be investigated using appropriate in vitro, ex vivo, and animal mod systems. An in vitro model of calcium phosphate formation on polyurethane surfaces will be investigated in collaboration with Professor George Nancollas of the State University of Buffalo, using a dual constant composition approach (calcium and phosphorous). Coagulation will be investigated in collaboration with Drs. Robert Bartlett and Stuart Cooper through studies of our polyurethanes with an in vitro fibrometer assay, as well as an ex vivo circulatory loop to assess thrombogenicity. Thrombus and calcification orientation in sheep mitral valve replacements will also be of interest in these studies. The biologic adsorption hypothesis will be assessed (with collaborators, Dr. A. Veis, H. Kruth, and C. Webb) in sheep mitral valve replacements and by using a rat subdermal model of polyurethane calcification, using dihydrotachysterol induced calciphylaxis to cause an aggravated and accelerated calcification. We will examine the relationship of the adsorption of the mineralization-related proteins, alkaline phosphatase and osteopontin, to the calcification mechanism. Similarly, lipid adsorption and cellular/cell debris deposition will also be studied.

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National Heart, Lung, and Blood Institute (NHLBI)
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Surgery and Bioengineering Study Section (SB)
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Children's Hospital of Philadelphia
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Stachelek, Stanley J; Alferiev, Ivan; Fulmer, James et al. (2007) Biological stability of polyurethane modified with covalent attachment of di-tert-butyl-phenol. J Biomed Mater Res A 82:1004-11
Alferiev, Ivan S; Connolly, Jeanne M; Stachelek, Stanley J et al. (2006) Surface heparinization of polyurethane via bromoalkylation of hard segment nitrogens. Biomacromolecules 7:317-22
Stachelek, Stanley J; Alferiev, Ivan; Connolly, Jeanne M et al. (2006) Cholesterol-modified polyurethane valve cusps demonstrate blood outgrowth endothelial cell adhesion post-seeding in vitro and in vivo. Ann Thorac Surg 81:47-55
Stachelek, Stanley J; Alferiev, Ivan; Choi, Hoon et al. (2006) Prevention of oxidative degradation of polyurethane by covalent attachment of di-tert-butylphenol residues. J Biomed Mater Res A 78:653-61
Stachelek, Stanley J; Alferiev, Ivan; Choi, Hoon et al. (2005) Cholesterol-derivatized polyurethane: characterization and endothelial cell adhesion. J Biomed Mater Res A 72:200-12
Fishbein, Ilia; Stachelek, Stanley J; Connolly, Jeanne M et al. (2005) Site specific gene delivery in the cardiovascular system. J Control Release 109:37-48
Stachelek, S J; Song, C; Alferiev, I et al. (2004) Localized gene delivery using antibody tethered adenovirus from polyurethane heart valve cusps and intra-aortic implants. Gene Ther 11:15-24
Alferiev, Ivan; Stachelek, Stanley J; Lu, Zhibin et al. (2003) Prevention of polyurethane valve cusp calcification with covalently attached bisphosphonate diethylamino moieties. J Biomed Mater Res A 66:385-95
Alferiev, I; Vyavahare, N; Song, C et al. (2001) Bisphosphonate derivatized polyurethanes resist calcification. Biomaterials 22:2683-93
Alferiev, I S; Hinson, J T; Ogle, M et al. (2001) High reactivity of alkyl sulfides towards epoxides under conditions of collagen fixation--a convenient approach to 2-amino-4-butyrolactones. Biomaterials 22:2501-6