The haemocompatibility of polyurethane–hyaluronic acid copolymers
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.
References (54)
- et al.
Biomaterial-associated thrombosis: roles of coagulation factors, complement, platelets and leukocytes
Biomaterials
(2004) - et al.
Heparin immobilization reduces thrombogenicity of small-caliber expanded polytetrafluoroethylene grafts
J Vasc Surg
(2006) - et al.
Novel bioengineered small caliber vascular graft with excellent one-month patency
Ann Thorac Surg
(2007) - et al.
New prostheses for use in bypass grafts with special emphasis on polyurethanes
Cardiovasc Surg
(2002) - et al.
In vitro blood compatibility of surface-modified polyurethanes
Biomaterials
(1998) - et al.
A novel solvent system for blending of polyurethane and heparin
Biomaterials
(2003) - et al.
Preparation and characterization of hydrophobic polymeric films that are thromboresistant via nitric oxide release
Biomaterials
(2000) - et al.
Bacterial adhesion on PEG modified polyurethane surfaces
Biomaterials
(1998) - et al.
Preparation and characterization of polymeric coatings with combined nitric oxide release and immobilized active heparin
Biomaterials
(2005) - et al.
Monopolar surfaces
Adv Colloid Interface Sci
(1987)
The surface energy of various biomaterials coated with adhesion molecules used in cell culture
Colloids Surf B Biointerfaces
Determination of the components of the surface tension of some liquids from interfacial liquid-liquid tension measurements
J Colloid Interface Sci
FTIR studies of sodium hyaluronate and its oligomers in the amorphous solid phase and in aqueous solution
Carbohydr Res
Cell adhesion on solids and the role of surface forces
J Theor Biol
The guidance of human mesenchymal stem cell differentiation in vitro by controlled modifications to the cell substrate
Biomaterials
Activation of valvular interstitial cells is mediated by transforming growth factor-beta1 interactions with matrix molecules
Matrix Biol
Small-diameter artificial arteries engineered in vitro
Circ Res
Drug-eluting stents: cost versus clinical benefit
Circulation
Tissue engineered heart
Guidelines for the management of patients with valvular heart disease: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines
Circulation
What really is blood compatibility?
J Biomater Sci Polym Ed
Current status of prosthetic bypass grafts: a review
J Biomed Mater Res B: Appl Biomater
The mechanical behavior of vascular grafts: a review
J Biomater Appl
Endothelialization of small-diameter vascular prostheses
Arch Physiol Biochem
Development of coronary aneurysm after drug-eluting stent implantation
Ann Intern Med
Debating the risks of drug-eluting stents
N Engl J Med
Polyurethanes in biomedical applications
Cited by (52)
Evaluation of electrospun PCL diol-based elastomer fibers as a beneficial matrix for vascular tissue engineering
2022, Colloids and Surfaces B: BiointerfacesA scope at antifouling strategies to prevent catheter-associated infections
2020, Advances in Colloid and Interface ScienceCitation Excerpt :According to the results from a DNA assay, E. coli adhesion was only slightly reduced in the HA-coated PU-PEI surface compared to the bare film under static conditions, but the differences were not significant upon flow exposure. The authors attributed the weak antifouling effect on bacterial adhesion to the low HA surface density of the biomaterial, since it was previously shown that microbial colonization on HA-modified PUs depended upon HA content [149] while HA molecular weight regulated the bioactivity (hemocompatibility and endothelialization) of these materials [138,150]. Heparin (HEP) is another natural GAG of animal origin with a complex structure, made of repeating disaccharide units of N-acetyl-D-glucosamine and L-iduronic acid variably sulfated at the oxygen and/or nitrogen atoms.
Strategies to improve the hemocompatibility of biodegradable biomaterials
2018, Hemocompatibility of Biomaterials for Clinical Applications: Blood-Biomaterials InteractionsStrategies to improve the hemocompatibility of biodegradable biomaterials
2017, Hemocompatibility of Biomaterials for Clinical Applications: Blood-Biomaterials InteractionsInterfacial energetics approach for analysis of endothelial cell and segmental polyurethane interactions
2016, Colloids and Surfaces B: BiointerfacesAntimicrobial Polyurethanes for Intravascular Medical Devices
2016, Advances in Polyurethane Biomaterials