Stock material or miscellaneous articles – Composite – Of polyamide
Reexamination Certificate
2000-12-05
2003-01-21
Hampton-Hightower, P. (Department: 1711)
Stock material or miscellaneous articles
Composite
Of polyamide
C428S411100, C428S423500, C427S002100, C427S322000, C427S331000, C128SDIG008, C523S112000, C525S050000, C525S054100, C525S054200, C525S054220
Reexamination Certificate
active
06509104
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to an article having a non-thrombogenic surface and a process for making the article. More particularly, this invention relates to an article formed by (i) coating a polymeric substrate with a crosslinked chemical combination of a polymer having at least two amino substituted side chains, a crosslinking agent containing at least two crosslinking functional groups which react with amino groups on the polymer, and a linking agent containing a first functional group which reacts with a third functional group of the crosslinking agent, and (ii) contacting the coating on the substrate with an antithrombogenic agent, such as heparin, which covalently bonds to a second functional group of the linking agent.
2. Description of the Related Art
It is well known that when blood comes into contact with a surface other than the natural wall of a blood vessel, the activation of certain circulating substances results in the coagulation of the blood. If thrombi are formed on portions of the surface which contact blood flow, there is a risk that the thrombi will be released and cause serious blood circulation disturbances called thrombosis. As a result, extensive investigations have been undertaken over many years to find materials having a reduced tendency to form thrombosis. This area of research has become increasingly important with the development of various objects and articles which can be in contact with blood, such as artificial organs, vascular grafts, probes, cannulas, catheters and the like.
Synthetic polymeric materials have come to the fore as preferred materials for such articles. However, these polymeric materials have the major drawback of being thrombogenic. Accordingly, numerous procedures for rendering a polymeric surface non-thrombogenic have been proposed. (As used herein, “non-thrombogenic” and “antithrombogenic” refer to any material which inhibits thrombus formation on a surface.) One well known approach for counteracting thrombogenicity of a polymeric surface has been the use of antithrombogenic agents or anticoagulants such as heparin. Heparin is a highly sulfated dextrorotatory mucopolysaccharide composed of D-glucosamine and D-glucuronic acid residues, and is known to prolong the clotting time of blood.
Various general methods for the attachment of heparin to otherwise thrombogenic polymeric surfaces are known. In one general method, heparin is ionically bound to a surface. Heparin is an anionic compound which easily forms ion complexes with cationic compounds. As a result, it has been proposed to attach a cationic substance to a surface and thereafter ionically bind heparin to the cationic substance. For example, U.S. Pat. No. 3,617,344 discloses a method in which a polymeric surface is chemically modified to include a chloromethyl group, the chloromethyl group is aminated to provide a quaternary ammonium halide, and the halide is reacted with sodium heparin to ionically bond heparin to the surface. One disadvantage with ionically bound systems is that the heparin can leach off the surface when contacted with blood or other fluids.
Because of the leachability of ionically bound heparin, another general method for the attachment of heparin to otherwise thrombogenic polymeric surfaces has been developed wherein heparin is covalently bound to a surface. Immobilization of heparin to artificial blood-contacting materials through covalent bonding has proven to be a successful approach for achieving a non-thrombogenic surface suitable for use in medical applications. Previous efforts to covalently immobilize heparin include: (1) the formation of an amide linkage derived from the —CO
2
H of heparin and a polymer carrying an NH
2
-side-chain by coupling with a water-soluble carbodiimide (see, for example, U.S. Pat. No.
4,521,564);
(2) the formation of an ether group by reaction of the —OH group of the sugar ring with an epoxidized support; and (3) the linking of heparin at its reducing end to an —NH
2
containing solid matrix by reductive amination (see U.S. Pat. No. 4,810,784). According to the last approach, a polyethylene substrate was modified by (i) brief treatment with KMnO
4
in concentrated sulfuric acid to generate anionic (—CO
2
H/SO
3
H) sites, (ii) incubation with 0.01%. polyethylenimine, and (iii) coupling of the resulting NH
2
-rich surface with heparin by reductive amination (NaBH
3
CN in buffer at pH 3.5). Apart from the advantage of its long-term stability (reportedly up to several months), the heparin incorporated this way (the so-called “end-point attachment”) mimics its natural configuration, allowing maximal retention of its antithrombogenic properties.
It has been established further, that the end-point attachment technique can be successfully extended to polymeric carriers bearing surface hydrazide groups (See D. J. O'Shannessy and M. Milcheck,
Anal. Biochem.
191, 1-8, 1990). Hydrazide is much more active over —NH
2
as a nucleophile in reaction with aldehydes (including all reducing sugars), while possessing lower basicity in comparison to amines (pK for hydrazides: ~3, for primary amines: ~7). Notable advantages of using a hydrazide matrix for immobilization of reducing sugars, including heparin, are: (1) a faster reaction (about 30-fold for simple saccharides) than using the —NH
2
supports (See Y. Ito, Y. Yamasaki, N. Seno, and I. Matsumoto,
J. Biochem. Tokyo,
99, 1267-1272, 1986); (2) the reaction of hydrazide with —CHO is an irreversible process and therefore, the need for further stabilization by NaBH
3
CN reduction can be partly avoided or totally eliminated; and (3) unlike primary amines, hydrazides remain unprotonated at slightly acidic pH levels (as low as 3-4.7). Reaction under these conditions will help to minimize the possible by-products originating from the —NH
2
groups in the substrate and coating materials.
A number of solid supports (mostly in the form of polysaccharide beads) containing hydrazide groups are presently commercially available for use as adsorbents in affinity chromatography. These hydrazide supports may be prepared by: (1) diimide coupling of polymeric amines with p-hydrazinobenzoic acid; (2) direct condensation of an epoxy-containing polymer with a dihydrazide like adipic dihydrazide; and (3) coupling of polymeric active esters with hydrazine. The preparation of hydrazide supports and their application in affinity chromatography of oligosaccharides, polysaccharides, glycoproteins, and enzymes carrying sugar units is described in a number of patents (See, for example, U.S. Pat. Nos. 4,217,338, 4,419,444, 4,874,813, 4,948,836, 5,104,931, 5,316,912, and Japanese Patent Publication No. 59015401.) Immobilization is carried out by reaction of the hydrazide reagent with the reducing terminus of the target molecule. Alternatively, the hydrazide coupling is preceded by a periodate-oxidation (to split the vicinal diols of sugar unit and provide newly generated —CHO groups) and finally completed by NaBH
3
CN reduction.
The preparation of hydrazide matrices has been reported in the technical literature. For example, (1) the preparation of modified polysaccharide matrices (cellulose, Sephadex, and Sepharose) through NalO
4
-oxidation and subsequent reaction with adipic dihydrazide is described by E. Junowicz, and S. E. Charm at
Biochim. Biophys. Acta
428, 157-165, 1976; (2) the preparation of polyacrylhydrazide-agarose by periodate oxidation of agarose followed by reaction with polyacrylhydrazide is described by T. Miron and M. Wilchek at
J. Chromatogr.
215, 55-63, 1981; (3) the preparation of polyacrylamide-polyhydrazides from the corresponding N-hydroxysuccinimide-ester and hydrazine and use in the analysis of glycoproteins is described by U. Heimgartner, B. Kozulic, and K. Mosbach at
Anal Biochem.
181, 182-189, 1989; and (4) the preparation of hydrazide-derivatized Eupergit C beads from Eupergit C [a poly(methyl methacrylamide) bearing epoxide group] and adipic dihydrazide is described by G. Fleminger, E. Hadas, T. Wolf, a
Huang Zhi Heng
McDonald William F.
Taylor Andrew C.
Wright Stacy C.
Hampton-Hightower P.
Michigan Biotechnology Institute
Quarles & Brady LLP
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