Polyethylene oxide (PEO) is an important biomaterial because it is non-adsorptive toward biopolymers, and is non-thrombogenic, i.e, it does not adsorb proteins of the intrinsic clotting system nor of the platelet membrane. However, when PEO is combined with other molecules at the surface, thrombogenicity may be enhanced. Okkema, J. Biomat. Sci. 1:43-62 (1989). Thus, it is essential that no other molecular entity besides PEO be accessible to proteins. It has been widely studied as a blood-contacting biomaterial in various forms: in segmented polyurethanes, in block copolymers with styrene or siloxane blocks, end-linked into junctions through isocyanate reactions, as side-chains on acrylate polymers and as hydrogels cross-linked from PEO solutions.
PEO is naturally soluble in water and certain organic solvents. Therefore, in order to render PEO insoluble it must be cross-linked, or end-linked to a support. The manner in which this is accomplished often affects physical and chemical properties of PEO.
Chemical cross-linking of PEO can be employed, but the chemical cross-linking agent (e.g., a polyfunctional isocyanate) may be incorporated into the PEO. If exposed at the ultimate surface, such a chemical moiety can cause adverse biopolymer reactions, including non-specific binding of proteins and platelet adhesion.
Physically cross-linked PEO produced from polyethylene oxide-polystyrene multiblock polymers or from polyether-urethanes suffers from the presence of the non-PEO materials at the surface. Adverse biological reactions caused by the non-PEO material may often be avoided if the molecular weight of the PEO is made higher than about 5,000. However, such material tends to swell excessively in water and is fragile.
End-linking PEO to supports by various means, so as to leave an available hydroxyl groups for attachment of an affinity ligand, for example, is not easily carried out if the molecular weight of the PEO is more than about 1,000. Furthermore, complete coverage of a surface by end-linking PEO is very difficult, unless the molecular weight is relatively high (several thousand).
Various forms of PEO have also been widely used as a molecular leash for affinity ligands and enzymes. Golander et al., Int. Chem. Congress of Pacific Basin Societies, Abstract No. 253, Honolulu, Hi., Dec. 17-22, 1989, Harris, J. Macromolecular Sci. C25:325-373 (1985); Holmberg, Int. Chem. Congress of Pacific Basin Societies, Abstract No. 255, Honolulu, Hi., Dec. 17-22, 1989. Typically, PEO has terminal hydroxyl groups which can be activated for attachment to biopolymers. Most processes for forming PEO biomaterials, however, reduce the hydroxyl content to very low values or zero. In order to produce a cross-linked PEO having a significant concentration of terminal hydroxyls, low molecular weight PEO (2,000 to 10,000) are required but often result in fragile materials. Alternatively, using short PEO side chains on macromonomers like polyethylene glycol methacrylate may result in exposure of the methacrylate residues at the surface, and these short PEO side chains are almost invariably methyl terminated, so that no hydroxyl exists for subsequent attachment of ligands.
Thus, a need exists for a method of immobilizing PEO to a support surface without detracting from its physical properties and biological compatibility. In addition, it would be desirable to provide a material having a high concentration of hydroxyl groups for attachment to biopolymers.
USPTO Backgrounds
USPTO Backgrounds