Elsevier

Biomaterials

Volume 29, Issue 2, January 2008, Pages 150-160
Biomaterials

The haemocompatibility of polyurethane–hyaluronic acid copolymers

https://doi.org/10.1016/j.biomaterials.2007.09.028Get rights and content

Abstract

Despite decades of research into haemocompatible biomaterials, there remain surprisingly few materials that can be used in blood-contacting applications. We have synthesized copolymers of polyurethane (PU) with hyaluronic acid (HA) with the goal of creating materials that incorporate an inherently non-thrombogenic, biological component into the bulk polymer structure. HA was incorporated into the polymer backbone as a chain extender during PU synthesis, and the physical and biological properties of the resulting copolymer were directly controlled by the HA content. Increases in HA content led to a linear increase in hydrophilicity (R2=0.993) and corresponding increase in surface energy compared to PU controls. Elastic modulus also increased with HA content (p<0.001), while surface roughness did not significantly differ from PU controls for most PU–HA formulations. Incorporation of HA resulted in negligible platelet adhesion to the PU–HA (p<0.001), representing a 20-fold decrease in platelet adhesion compared to PU. Red blood cell adhesion also decreased with increasing HA content (p<0.001). The PU–HA materials were cytocompatible and supported endothelial cell adhesion and viability. Thus, we have demonstrated the synthesis of a copolymer whose physical and biological properties are easily tailored, and whose potent anti-thrombogenic properties demonstrate its great promise for use in vascular applications.

Introduction

Materials that are resistant to platelet adhesion are needed for a wide range of applications, including vascular grafts, stents, heart valve replacements, pacemaker leads, hemodialysis tubing, and catheters. Moreover, as cardiovascular disease remains the leading cause of death in the US (41.4% of all deaths), there is a high demand for cardiovascular materials and blood-contacting devices, in the range of millions of devices per year in the US [1], [2], [3]. Yet, after several decades of research into haemocompatible biomaterials, there remain surprisingly few materials that can be used in blood-contacting applications without administering anticoagulant therapy to the patient [4], [5], [6]. Even materials viewed as haemocompatible have significant shortcomings—while Dacron and Teflon are the most widely used synthetic vascular graft materials, their failure due to thrombosis is almost immediate when used in small-diameter (<6 mm) applications, and 5-year patency rates are less than 50% even in large-diameter applications [7], [8].

Regarding the performance of small diameter vascular grafts, it was recently noted that “The poor blood-compatibility of an artificial vascular graft is not simply because of its coagulation-stimulating or platelet-activating properties, but more due to its inability to actively participate in the prevention of blood coagulation and platelet deposition” [9] (emphasis added). To this end, efforts to improve the haemocompatibility of various materials have often concentrated on designing systems to elute anticoagulants, such as heparin [10], [11]. Heparin is a naturally occurring glycosaminoglycan (GAG) with anti-thrombotic properties. Unfortunately, release of heparin from a biomaterial represents a relatively short-term solution to inhibiting thrombosis, as the delivery duration will be finite. Furthermore, the recent and significant troubles with some drug-eluting stents have illustrated risks of the strategy of non-covalently adding a non-thrombogenic coating to an existing surface [12], [13]. Thus, a safer, alternative strategy to imparting anti-thrombotic activity upon a material would be to make the core material itself inherently non-thrombogenic. In this manner, the availability of the anti-thrombotic agent would not be transient, as the agent would be physically part of the material.

Polyurethane (PU) block copolymers have been widely used for numerous biomedical applications due to their excellent mechanical properties and biocompatibility [14]. In contrast to other materials used in vascular applications (Dacron, Teflon), PU-based materials support the growth of endothelial cells and possess mechanical properties that match that of the native vasculature [15]. Both of these characteristics are particularly important for applications such as vascular grafts, where the relatively rigid mechanics of Dacron and Teflon and their inability to support endothelialization are major contributors to the failure of these materials in small-diameter applications [8]. Their significant mechanical mismatch with adjacent arterial tissue (<0.4 MPa tensile modulus of elasticity for native artery vs. 500 MPa for Teflon) leads to significant problems at the graft anastomoses such as thrombosis and hyperplasia induced by migration and growth of fibroblasts and smooth muscle cells. Another advantage of PUs is the relative ease of modifying their structures; surface and/or bulk modification of PU via attachment of biologically active species is possible due to reactive groups which are part of the PU structure, and such modifications may be designed to control or mediate host responses [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33]. Finally, PUs may be fabricated via a myriad of processing technologies, including casting, electrostatic and wet spinning of fibers and monofilaments, extrusion, dip coating, or spraying [14].

Despite the numerous favorable properties of PUs regarding their use in vascular applications, their marginal haemocompatibility has been a significant problem. As noted earlier, native GAGs such as heparin possess anti-coagulant characteristics, and there have been numerous successful efforts to covalently modify PU surfaces with heparin in order to improve haemocompatibility [16], [17], [18], [21], [23], [26], [27], [30], [32], [33]. While not as widely incorporated into vascular materials or devices as heparin, other native GAGs, such as hyaluronic acid (HA), similarly possess anti-thrombotic properties. HA is a particularly intriguing biomolecule for use in vascular applications, as it is not only non-immunogenic, but it also stimulates the proliferation of endothelial cells [34], [35].

In this report, we describe the synthesis and characterization of new haemocompatible materials consisting of PU–HA copolymers. Our rationale in combining PU with HA was to: (1) take advantage of the beneficial properties of PU, such as its good mechanics and processibility, and (2) take advantage of the natural anti-thrombotic properties of HA, in order to (3) create biomaterials that are inherently non-thrombogenic and actively participate in the inhibition of platelet adhesion.

Section snippets

Materials and methods

All chemicals were obtained from Sigma-Aldrich (St. Louis, MO) unless otherwise noted.

Synthesis and FTIR

Synthesis of PU–HA ranging from 0.33 to 5.4 wt% HA resulted in a rubbery, yellowish solid that was macroscopically indistinguishable from the PU formulation that did not contain HA. Product recovery was approximately 100% for all syntheses. The PU and PU–HA copolymers dissolved readily in DMF, and thin films cast from these materials were transparent in appearance. Analysis of the copolymers via FTIR (Fig. 2) revealed the characteristic bands for urethane carbonyl bonds in all materials at 1730 cm

Discussion

In this publication, we report the synthesis and characterization of haemocompatible biomaterials comprised of PU copolymerized with HA. These materials have numerous intriguing and promising properties, which can be exploited to promote the use of PU–HA in various applications. First, the excellent linear correlation between material hydrophilicity and HA content allows for control and predictability with respect to tailoring the physical properties of these materials. The hydrophilicity and

Conclusions

As demonstrated in this communication, we have synthesized non-thrombogenic polyurethane–hyaluronan copolymers whose physical and biological properties can be easily tailored. This work is significant because of the manner in which the HA modification was performed (to the bulk polymer structure, as opposed to the PU surface), the use of HA (as opposed to heparin) as the anti-thrombotic agent, the range and relative predictability of PU–HA physical characteristics, the excellent

Acknowledgments

This work was funded in part by a Translational Research Partnership grant from the W.H. Coulter Foundation (to K.S.M.). The authors would also like to thank Ms. Claire Flanagan for her technical support.

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