Biomacromolecules 2001, 2, 588-596
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In Vitro Studies on the Effect of Physical Cross-Linking on the Biological Performance of Aliphatic Poly(urethane urea) for Blood Contact Applications Vinoy Thomas,† T. V. Kumari,‡ and Muthu Jayabalan*,† Sree Chitra Tirunal Institute for Medical Sciences and Technology, Polymer Division, Division of Implant Biology, Biomedical Technology Wing, Thiruvananthapuram 695 012, Kerala, India Received March 1, 2001
The effect of physical cross-linking in candidate cycloaliphatic and hydrophobic poly(urethane urea) (4,4′methylenebis(cyclohexylisocyanate), H12MDI/hydroxy-terminated polybutadiene, HTPBD/hexamethylenediamine, HDA) and poly(ether urethane urea)s (H12MDI/HTPBD-PTMG/HDA) on the in vitro calcification and blood-material interaction was studied. All the candidate poly(urethane urea)s and poly(ether urethane urea)s elicit acceptable hemolytic activity, cytocompatibility, calcification, and blood compatibility in vitro. The studies on blood-material interaction reveal that the present poly(urethane urea)s are superior to polystyrene microtiter plates which were used for the studies on blood-material interaction. The present investigation reveals the influence of physical cross-link density on biological interaction differently with poly(urethane urea) and poly(ether urethane urea)s. The higher the physical cross-link density in the poly(urethane urea)s, the higher the calcification and consumption of WBC in whole blood. On the other hand, the higher the physical cross-link density in the poly(ether urethane urea)s, the lesser the calcification and consumption of WBC in whole blood. However a reverse of the above trend has been observed with the platelet consumption in the poly(urethane urea)s and poly(ether urethane urea)s. 1. Introduction Poly(ether urethane) elastomers, viz., pellethane, have been used for various biomedical applications, viz., cardiovascular devices, in comparison to the other elastomers due to appreciable physical and mechanical properties and biocompatibility.1,2 But poly(ether urethane)s that have been used for biomedical devices in the previous decade are no longer commercially available as biomedical grade raw material. Moreover the last generation poly(ether urethane)s are also not suitable for blood compatible devices intended for longterm blood contact applications because of the lack of biodurability in highly flexing biomechanical environments. Biocompatibility and biodurability are the mandatory requirements for cardiac devices, viz., membranes of blood pumps3 and flexible leaflets of artificial trileaflet heart valves,4,5 etc. The polymer used in these devices has to undergo repeated loading and unloading cycles during the functioning of these devices. The nonexistence of these clinical devices for patient care in the present health care market is due to the catastrophic fatigue failure of poly(ether urethane) material that is attributed to the biodegradation in vivo. Though pellethane has been used in the development of a cardiac pacemaker, failure of pellethane-coated pacing leads has been reported during long-term use.6,7 Several mechanisms have been proposed for biodegradation of poly(ether urethane) materials in vivo such as * To whom correspondence may be addressed. E-mail: jaybalan@ sctimst.ker.nic.in. † Polymer Division. ‡ Division of Implant Biology.
hydrolysis, oxidation, calcification, and environmental stress corrosion cracking.6-10 Polyether polyol based polyurethanes demonstrated surface degradation in vivo due to oxidation of ether linkage6,11 and environmental stress cracking.6,7 Wang et al.12 have reported that hard segment content and ability of polyurethane to form hard segment domains have a significant impact on the biodegradation of poly(ester urea urethane) by cholesterol esterase. They investigated a series of polyurethanes differing in their hard segment content only and proposed a relationship between hard segment domain formation and hydrolysis of urea/urethane groups. Physically cross-linked poly(urethane urea)s are more promising elastomers for long-term applications. Takahara et al.13 have synthesized aromatic poly(urethane urea)s using aliphatic diamine chain extenders. As part of the development of high flex life biostable and biocompatible polyurethane for cardiovascular devices, we have synthesized and evaluated hydrophobic and aliphatic poly(urethane urea)s based on cycloaliphatic diisocyanate (H12MDI) and hydroxyterminated polybutadiene (HTPBD).14-16 The urea groups in a poly(urethane urea) are potential sites for intermolecular hydrogen bonding leading to a physically cross-linked structure and are responsible for the high flex life. Calcification is also one of the major causes for the catastrophic failure of polyurethane cardiac-assist devices.1-2,17,18 The calcification can be defined as the deposition of calcium compounds as either calcium phosphate minerals consisting of hydroxy apatite or calcium salts. The calcification results in the loss of the flexibility of polyurethane, thereby causing their mechanical failure and degrada-
10.1021/bm010044f CCC: $20.00 © 2001 American Chemical Society Published on Web 04/26/2001
Biomacromolecules, Vol. 2, No. 2, 2001 589
Effects of Physical Cross-Linking Table 1. In Vitro Calcification of Aliphatic Physically Cross-Linked Poly(urethane urea)s composition (%) polymer HFL9-PU1 HFL13-PU2 HFL16-PU3 HFL17-PU4 Tecoflex 85Aa
hard segment HDA 57.50 67.90 57.50 67.90
soft segment HTPBD:PTMG 42.50:0 32.10:0 21.25:21.25 16.05:16.05
cross-link density (mol/cm3) (×104) 1.8520 6.7813 2.260 3.090
amount deposited (mg/g)
calcium
inorganic phosphorus
total (ratio of calcium to phosphorus)
0.0733 ( 0.02b 0.3433 ( 0.10b 0.4238 ( 0.13b 0.2446 ( 0.08c 0.2382 ( 0.10
0.0384 ( 0.01c 0.1996 ( 0.02b 0.0417 ( 0.01c 0.0919 ( 0.02b 0.0546 ( 0.01
0.1117 (1.9) 0.5429 (1.7) 0.4655 (10.2) 0.3365 (2.7) 0.2928 (4.4)
a Tecoflex 85A is linear segmented polyurethane containing H MDI, PTMG, and 1,4-butanediol. b p values
