Biopolymers modified with superoxide dismutase mimics

Abstract

This invention provides modified biopolymers comprising biopolymers attached to at least one non-proteinaceous catalyst capable of dismutating superoxide in the biological system or precursor ligand thereof. The invention further provides pharmaceutical compositions comprising the modified biopolymer and therapeutic methods comprising administering the modified biopolymer to a subject in need thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. Ser. No. 10 / 702,407, filed Nov. 5, 2003, which is a continuation of U.S. Ser. No. 09 / 580,007, filed May 26, 2000, which claims priority from provisional application No. 60 / 136,298 filed May 27, 1999, which are hereby incorporated by reference in their entirety for all purposes.BACKGROUND OF THE INVENTION [0002] The present invention relates to biomaterials modified with non-proteinaceous catalysts for the dismutation of superoxide, and processes for making such materials. This modification may be by covalent conjugation, copolymerization, or admixture of the non-proteinaceous catalysts with the biomaterial. The resulting modified biomaterials exhibit a marked decrease in inflammatory response and subsequent degradation when placed in contact with vertebrate biological systems. [0003]“Biomaterial” is a term given to a wide variety of materials which are generally considered appropriate for use i...

AI Technical Summary

Benefits of technology

[0013] Applicants have discovered that the modification of biomaterials with non-proteinaceous catalysts for the dismutation of superoxide greatly improves the biomaterial's resistance to degradation and reduces the inflammatory response. Thus, the present invention is directed to biomaterials which have been modified with non-proteinaceous catalysts for the dismutation of superoxide, or precursor ligands of non-proteinaceous catalysts for the dismutation of superoxide.

Problems solved by technology

However, they have inferior wear characteristics when compared with either cobalt-chromium-molybdenum alloys or 300 series stainless steel.

They also have the further disadvantage of being difficult to work.

These steels are, however, even less resistant to corrosion and hence more susceptible to corrosion fatigue.

However, as mentioned above, certain alloys corrode within the body and, as a result, dissolved metallic ions can produce adverse effects on the surrounding cells and can result in implant breakage.

But when used under the load of walking or the like, they may not remain fixed to the bone.

However, bioactive ceramics such as hydroxyapatite and tricalcium phosphate are relatively brittle and can fail under the loads in the human body.

However, polymers used in orthopedic devices such as hip and knee joints have a tendency for wear and build-up of fine debris, resulting in a painful inflammatory response.

For instance, thrombogenesis has posed a perennial problem for the use of biomaterials in hemodialysis membranes.

Although most biomaterials in current use are considered non-toxic, implanted biomaterial devices are seen as foreign bodies by the immune system, and so elicit a well characterized inflammatory response.

In addition, chemical modification has posed several difficulties.

Because of the unique chemical characteristics of each biomaterial and bioactive molecule, covalent linkage of the desired bioactive molecule to the biomaterial is not always possible.

Finally, the fact that many biologically active substances are heat liable has prevented their use with biomaterials that are molded or worked at high temperatures.

The impact of continual attempts by the organism to degrade biomaterial implants can lead to increased morbidity and device failure.

In the case of polyurethane pacemaker lead wire coatings, this results in polymer degradation and steady loss of function.

In the use of synthetic vascular grafts, this results in persistent thrombosis, improper healing, and restenosis.

As mentioned above, orthopedic devices such as hip and knee joints have a tendency for wear and build-up of fine debris resulting in a painful inflammatory response.

In addition, the surrounding tissue does not properly heal and integrate into the prosthetic device, leading to device loosening and opportunistic bacterial infections.

It has been proposed by many researchers that chronic inflammation at the site of implantation leads to the exhaustion of the macrophages and neutrophils, and an inability to fight off infection.

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