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Improving blood-compatibility of polymeric surfaces.

Biocompatibility has been defined by consensus, but not blood-compatibility. The interactions between blood and a surface depend on the blood composition, the blood flow and the surface of the material defined by its physicochemical features. Blood response is sensitive to surface features such as surface area, crystallinity, hydrophobicity/hydrophilicity, outermost structure and surface chemistry. Material surfaces are not blood-compatible, resulting in triggering of the non-specific self-protection mechanisms of blood. Improving blood-compatibility of polymeric surfaces requires that the surfaces are able to delay, or to control locally the biochemical events implied in these responses. Strategies such as the "repelling brush" or the heparinised and heparin-like surfaces are currently developed to improve blood-compatibility of polymeric surfaces.

INTRODUCTION

Biocompatibility has been defined as the ability of a material to perform with an appropriate host response in a specific application (1). There is presently no consensus definition of blood-compatibility. In 1856, Virchow noticed that the interactions between blood and a blood vessel depended on the blood composition, the flow and the surface of the vessel. Concerning materials in contact with blood, the role of the surface of the vessel could be played by the surface of the material defined by its physicochemical features. As the other parameters remain similar, it results that the reactions of blood at the interface with a material depend not only on the material, but also on local conditions of flow and blood composition. Thus a tentative definition of a blood-compatible surface could be "a surface able to keep under control coagulation and inflammation processes at its interface with normal blood, in given haemodynamic conditions", as a healthy endothelium does it.

Polymeric materials in contact with blood

Many polymeric materials have already been used in devices in contact with blood, as constituents of blood bags, catheters, large vascular grafts, artificial heart, oxygenators, renal dialysers, and microparticles for therapeutic embolisation and nanoparticles for drug delivery. None of these are intrinsically blood-compatible and they induce many reactions which can be linked for instance to the presence of leachables or surface contaminants of diverse origins, in addition to the reactions linked to the polymer itself. But even in that case, the reactions of blood at the interface are apparently different, leading to different ultimate fates for the material.

Events occurring after contact between blood and a material surface

Blood can be considered as a flowing suspension of different kinds of cells in an aqueous solution of small solutes and proteins. From a kinetic point of view, the contact of blood with a material surface can be schematized by the "first come, first served" principle. In other words, the initial reactions are kinetically controlled by diffusion. After very fast exchanges of water and hydrated ions, including calcium and magnesium, the most diffusible and abundant proteins are adsorbed on the surface. The initial stage is followed by affinity-dependent processes in which some reversibly adsorbed proteins are displaced by others, i.e. The Vroman effect. With time, adsorption can become irreversible, associated with changes of conformation and possible binding of reactive species. At this stage, the non-specific mechanisms of self-protection have been triggered, leading to activation of the coagulation and complement systems. Then the initial processes are amplified through efficient cooperations between proteins present on the surface and bearing enzymatic activities, and activated blood cells.

Effects linked to physico-chemical surface features

The response of blood to contact with a material depends on physico-chemical features such as surface area, crystallinity and hydrophobicity/hydrophilicity of the surface. The response depends directly on the contacted surface area. As shown by Carreno et al. (2), activation of complement was either negligible, or visible, or high, in the presence of the same weight of Sephadex, depending whether Sephadex beads were large, small or crushed, i.e. endowed with an increasing specific surface area, and increased linearly with the amount of material in contact with human serum.

Concerning crystallinity, some blood proteins are very sensitive to ordered surfaces. Nylons are known to induce complement C3 activation and thermal treatments increasing crystallinity increase also complement C1 activation (3).

After contact with hydrophobic surfaces, protein adsorption becomes irreversible with changes of conformation adapting the protein with its new hydrophobic environment. For instance, adsorption of C3 on a polystyrene surface results in a change towards an activated conformation, which triggers complement activation through a non-physiologic way (4). Protein adsorption on hydrophilic surfaces is usually more reversible. But the reactions following such a contact depend both on the chemical nature of the hydrophilic groups and on the outermost surface structure. Concerning the latter, Jeon et al. (5) have modelised the interactions between proteins and poly (ethylene oxide) (PEO)-bearing surfaces and shown that they depend both on the density and on the length of the terminally attached PEO. Validity of such models have been experimentally tested with nanoparticulate systems by several authors, e.g. Vittaz et al. (6), who have shown that complement activation could turn dramatically from negligible to high when the density of the PEO "brush" on the surface was decreased.

Effects linked to surface chemistry of natural and artificial surfaces

It is now a piece of evidence that the non-thrombogenicity of the blood vessels is linked to their internal lining by healthy endothelial cells, which are able to control locally thrombogenic events occurring in their vicinity owing to the presence of different entities on the surface. Similarly, the surface of our healthy cells in permanent contact with blood is able to control locally the random non-specific recognition by our own complement system. Some pathogens are also able to avoid this recognition by closely related mechanisms (7). As the role of surface chemistry to control locally coagulation and inflammation is prominent, many attempts have been made to endow polymeric surfaces with such properties. The most popular approach has been the binding of heparin on surfaces (8). Heparin is a mixture of glycosaminoglycans of animal origin used for many years as anticoagulant. Its powerful activity is linked to the presence of a pentasaccharidic sequence which catalyses the activity of circulating inhibitors of the procoagulant enzymatic sites generated during the activation of the coagulation system, resulting for instance in a fast neutralization of thrombin. As the heparin molecule is highly negatively charged, it can be ionically bound to cationic surfaces. The modified surface is antithrobogenic for a duration, which depends on the amount of bound heparin and on its release rate. Heparinised catheters are commercially available. Heparin has also been bound to polymer surfaces by covalent binding. As the activity of heparin is link to its catalytic activity, its surface binding at least decreases the accessibility of the catalytic site to the rather large circulating inhibitors. Depending on the type of binding, the heparin anticoagulant activity can be variable, but well below its activity in solution.

Heparin has also been shown to possess an inhibitory activity against complement activation and this activity does not depend on the presence of the anticoagulant site, but depends on the presence of sulfate groups and on the type of binding when linked to a surface. Mollnes et al. (9) have shown that end-attachment of heparin on the surface of nanoparticles, Passirani et al. (10) have shown that such systems were long-circulating, i.e. able to escape recognition by the complement system and macrophages.

The effects induced by the presence of different chemical groups on coagulation and complement has been extensively studied. It has been shown that modification of polymeric surfaces by introducing sulfate, sulfonate, or some sulfonamide groups can improve their blood-compatibility by endowing them with heparin-like activity. The molecular mechanisms involved in such activities have not been completely understood yet but a recent review on this topic has been published by Jozefowicz and Jozefonvicz (11).

CONCLUSION

Polymeric surfaces are not blood-compatible. Presently, polymers are used in large devices in contact with blood in conditions in which blood coagulation is controlled either by anticoagulants, and/or by a high flow rate. Injected nanoparticulate systems are taken up by macrophages, mainly Kupffer cells, after recognition by the complement system. To be able to use polymers in other conditions in contact with blood, their surface has to be modified either by endowing it by a repelling outermost structure, or by mimicking the surface activity of our own cells, or by combining both strategies. Some tracks have been open, but a lot of work has still to be done both for fundamental understanding of the mechanisms and for technological development.

REFERENCES

(1.) Williams D.F., Definitions in Biomaterials, Progress in Biomedical Engineering 4, Elsevier, Amsterdam, 1987.

(2.) Carreno M.P., Labarre D., Jozefowicz, Kazatchkine M.D., The ability of Sephadex to activate human complement is suppressed in specifically substituted functional Sephadex derivatives, Mol. Immunol., 25, 165-171, 1988.

(3.) Niinobe M., Matsuda T., Iwata H., Molecular mechanism of complement activation on polymer surfaces: contact activation of reconstituted first component (CI) of classical pathway, in Advances in Biomaterials, eds. C. De Putter, G.I. De Groot, J.C. Lee, Vol 8, 181-186, Elsevier, Amsterdam, 1988.

(4.) Nilsson U.R., Strom K.E., Elwing H., Nilsson B., Conformational epitope of C3 reflecting its mode of binding to an artificial polymer surface, Mol. Immunol., 30, 211-219, 1993.

(5.) Jeon S.I., Lee J.H., Andrade J.D., De Gennes P.G., Protein-surface interactions in the presence of polyethylene oxide, I Simplified theory, J. Colloid Interface Sci., 142, 149-158, 1991.

(6.) Vittaz M., Bazile D., Spenlehauer G., Verrecchia, T., Veillard M., Piusieux F., Labarre D., Effect of PEO surface density on long-circulating nanoparticles which are low complement activators, Biomaterials, 17, 1575 -1581, 1996.

(7.) Cooper N.R., Complement evasion strategies of microorganisms, Immunology Today, 12, 327-331, 1991.

(8.) Labarre D., Heparin-like polymer surfaces: control of coagulation and complement activation by insoluble functionalised polymers, Int. J. Artif. Organs, 13, 651-657, 1990.

(9.) Mollnes T.E., Riesenfeld J., Garred P., Nordstrom E., Hogasen K., Fosse E., Gotze O., Harboe M., A new model for evaluation of biocompatibility: combined determination of neoepitopes in blood and on artificial surfaces demonstrates reduced complement activation by immobilization of heparin, Artif. Organs, 19, 909-917, 1995.

(10.) Passirani C., Barratt G., Devissaguet J.P., Labarre D., Long-circulating nanoparticles bearing heparin or dextran covalently bound to poly (methyl methacrylate), Pharm. Res., 15, 1046-1050, 1998.

(11.) Jozefowicz M., Jozefonvicz, J., Randomness and biospecificity: random copolymers are capable of biospecific molecular recognition in living systems, Biomaterials, 18, 1633-1644, 1997.

Denis Labarre

Biomateriaux et Polymeres, UMR CNRS 8612, Universite Paris-Sud, Chatenay-Malabry, France
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Author:Labarre, Denis
Publication:Trends in Biomaterials and Artificial Organs
Geographic Code:4EUFR
Date:Jul 1, 2001
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