Phosphonated polyurethanes that resist calcification

Abstract

Cardiovascular implant mineralization involving bioprosthetic materials, such as glutaraldehyde cross linked porcine aortic valves or synthetic materials such as polyurethanes, is an important problem that frequently leads to clinical failure of bioprosthetic heart valves, and complicates long‐term experimental artificial heart device implants. Novel, proprietary, calcification resistant polyetherurethanes (PEU) as an alternative to bioprosthetic materials were the subject of these investigations. A series of PEU was derivatized through a proprietary reaction mechanism to achieve covalent binding of 100 to 500 nM/mg of bisphosphonate (2‐hydroxyethane bisphosphonic acid, HEBP). The stability of HEBP (physically dispersed or covalently bound) verified by studying the release kinetics in physiological buffer (pH 7.4) at 37°C, demonstrated the covalent binding reaction to be stable, efficient, and permanent. Surface (FTIR‐ATR, ESCA, SEM/EDX) and bulk (solubility, GPC) properties demonstrated that the covalent binding of HEBP occurs in the soft segment of the PEU, reduces surface degradation, and does not affect the original material properties of the PEU (prior to derivatization). In vitro calcium diffusion of the derivatized PEU showed a decrease in calcium permeation as the concentration of HEBP covalent binding was increased. In vivo properties of underivatized and derivatized PEU (containing 100 nM of covalently bound HEBP) were studied with rat subdermal implants for 60 days. Explants demonstrated calcification resistance due to the covalently bound HEBP without any side effects. It is concluded that a PEU containing HEBP might serve as a calcification resistant candidate material for the fabrication of a heart valve prosthesis and other implantable devices. © 1994 John Wiley & Sons, Inc.

Localized gene delivery using antibody tethered adenovirus from polyurethane heart valve cusps and intra-aortic implants

“…[11][12][13][14][15] Our polyurethane bisphosphonate derivatization studies demonstrated that covalent attachment of bisphosphonates effectively inhibited polyurethane mineralization, and had essentially no effect on the biomechanical properties of the polyurethane heart valve leaflets. 9,10,16 In the present studies, we utilized polyurethane films in order to investigate two unique surfaces for use in gene delivery studies: (1) Attaching a collagen coating to the surface of polyurethane films, with subsequent derivatization of the collagen coating with thiol-based attachment of anti-adenovirus antibodies, and (2) using alkyl-thiol-activated polyurethane films to directly attach anti-adenovirus antibodies to the surface of polyurethane surfaces. These thiol-reactive sites were then further reacted in each instance to attach antiadenovirus antibodies for vector tethering.…”

Calcification resistance of polyisobutylene and polyisobutylene‐based materials

“…28,29 Similarly, PDMS-based PUs (Elast-Eon, Angioflex, etc) that also contain surface ─O─ atoms (─Si(Me) 2 ─O─Si(Me) 2 ─) are also prone to calcification. 22,28,29 The objectives of our investigations were to assess the calcification resistance of PIB, PIB-based PUs, SIBS, and similar PIB-containing materials containing a reinforcing agent and, further, to compare their calcification resistance with a widely used relatively calcification resistant PDMS-based PU, Elast-Eon (we were unable to obtain Angioflex, another PDMS-based PU developed for calcification resistance, for these studies).…”

“…Conventional polyether‐based PUs (ie, PUs whose continuous soft segment is of polytetramethylene oxide, such as pellethane, tecothane, etc) that contain ether oxygen atoms (─CH 2 ─O─CH 2 ─) at their surfaces are prone to calcification . Similarly, PDMS‐based PUs (Elast‐Eon, Angioflex, etc) that also contain surface ─O─ atoms (─Si(Me) 2 ─O─Si(Me) 2 ─) are also prone to calcification …”

“…18 Conventional non-PIB-based PUs, including special grades, such as polydimethylsiloxane (PDMS)-based PUs (eg, Elast-Eon and Angioflex), are inferior in this respect. [19][20][21][22] Various approaches have been studied to reduce the calcification tendency of polymeric surfaces including the use of metal salts, detergents, biphosphonate pretreatment, and covalent attachment of anticalcification agents. [23][24][25][26][27] Biphosphonate modification did not improve the calcification resistance of PUs, and biphosphonated Angioflex heart valves showed no calcification resistance improvement over unmodified Angioflex.…”

Polymeric nanobiocomposites for biomedical applications

“…Addition of the anti-calcification agents [i.e., polyetherurethanes (PEU) 213 and polyhedral oligomeric silsesquioxane-poly(carbonateurea)urethane (POSS-PCU) 214 ] into polymer matrix significantly reduces calcification without hindering its mechanical properties. The second factor that needs to keep in mind while designing a cardiovascular implant is the thrombosis and intimal hyperplasia.…”