# US 7,744,912 B1 · Biomaterials formed by nucleophilic addition reaction to conjugated unsaturated groups

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- Number: US 7,744,912 B1
- Document ID: US7744912B1
- Status: Granted
- Kind: B1
- Application number: 09/496,231
- Filed: 2000-02-01
- Granted: 2010-06-29
- Earliest claimed: 1999-02-01
- Assignees: Eidgenossische Technische Hochschule Zurich; UniversitäT ZüRich
- Inventors: Jeffrey A. Hubbell; Donald Elbert; Matthias Lütolf; Alison Pratt; Ronald Schoenmakers; Nicola Tirelli; Brent Vernon
- Web page: https://patentgrep.com/patent/US7744912B1

## CPC

- A61K 9/0024: {Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue (compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L)}
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 47/6903: {the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel}
- A61L 24/0031: {Hydrogels or hydrocolloids}
- A61L 24/043: {Mixtures of macromolecular materials}
- A61L 26/0052: {Mixtures of macromolecular compounds}
- A61L 26/008: {Hydrogels or hydrocolloids}
- A61L 27/26: Mixtures of macromolecular compounds
- A61L 27/52: Hydrogels or hydrocolloids
- A61L 31/041: {Mixtures of macromolecular compounds}
- A61L 31/145: {Hydrogels or hydrocolloids}
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 41/00: Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C08G 81/00: Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers (involving only carbon-to-carbon unsaturated bond reactions C08F299/00 {; polyester-amides C08G69/44; polyester-imides C08G73/16; polyamides-imides C08G73/14; block- or graft polymers containing polysiloxane sequences C08G77/42})
- Y10S 524/916: Hydrogel compositions
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- Y10S: TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS

## Abstract

The invention features polymeric biomaterials formed by nucleophilic addition reactions to conjugated unsaturated groups. These biomaterials may be used for medical treatments.

## Claims

### Claim 1

A method for making a biomaterial, said method comprising combining two or more precursor components of said biomaterial under conditions that allow polymerization of the components, wherein said polymerization occurs through self selective reaction between a strong nucleophile and a conjugated unsaturated bond or a conjugated unsaturated group, by nucleophilic addition, wherein each of said precursor components comprises at least two strong nucleophiles or at least two conjugated unsaturated bonds or conjugated unsaturated groups, wherein one of said components comprises at least three strong nucleophiles or at least three conjugated unsaturated bonds or at least three conjugated unsaturated groups, and wherein said biomaterial does not comprise albumin in its natural state, and said unsaturated bonds or groups are not maleimide or a vinyl sulfone, thereby making said biomaterial.

### Claim 2 (depends on 1)

The method of claim 1, wherein said components are selected from the group consisting of oligomers, polymers, biosynthetic proteins or peptides, naturally occurring peptides or proteins, processed naturally occurring peptides or proteins, and polysaccharides.

### Claim 3 (depends on 1)

The method of claim 1, wherein said strong nucleophile is selected from the group consisting of a thiol or a group containing a thiol.

### Claim 4

A method for making a biomaterial, said method comprising combining two or more precursor components of said biomaterial under conditions that allow polymerization of the components, wherein said polymerization occurs through self selective reaction between an amine and a conjugated unsaturated bond or a conjugated unsaturated group, by nucleophilic addition, wherein each of said precursor components comprises at least two amines or at least two conjugated unsaturated bonds or conjugated unsaturated groups, and wherein said biomaterial does not comprise albumin in its natural state, and said unsaturated bonds or groups are not maleimide or a vinyl sulfone, thereby making said biomaterial.

### Claim 5 (depends on 1)

The method of claim 1, wherein said conjugated unsaturated group is an acrylate, an acrylamide, a quinone, or 2- or 4-vinylpyridinium.

### Claim 6 (depends on 2)

The method of claim 2, wherein said polymer is selected from the group consisting of poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(ethylene-co-vinyl alcohol), poly(acrylic acid), poly(ethylene-co-acrylic acid), poly(ethyloxazoline), poly(vinyl pyrrolidone), poly(ethylene-co-vinyl pyrrolidone), poly(maleic acid), poly(ethylene-co-maleic acid), poly(acrylamide), and poly(ethylene oxide)-co-poly(propylene oxide) block copolymers.

### Claim 7 (depends on 2)

The method of claim 2, wherein said peptide comprises an adhesion site, growth factor binding site, or protease binding site.

### Claim 8 (depends on 1)

The method of claim 1, further comprising combining said precursor components with a molecule that comprises an adhesion site, a growth factor binding site, or a heparin binding site and also comprises either a strong nucleophile or a conjugated unsaturated bond or a conjugated unsaturated group.

### Claim 9 (depends on 8)

The method of claim 8, wherein said strong nucleophile is a thiol or said conjugated unsaturated bond or conjugated unsaturated group is an acrylate, an acrylamide, a quinone, or a vinyl pyridinium.

### Claim 10 (depends on 1)

The method of claim 1, wherein said biomaterial is a hydrogel.

### Claim 11 (depends on 1)

The method of claim 1, wherein said biomaterial is degradable in vivo.

### Claim 12 (depends on 1)

The method of claim 1, wherein said biomaterial is made in the presence of cells or tissues.

### Claim 13 (depends on 1)

The method of claim 1, wherein said biomaterial is made within or upon the body of an animal.

### Claim 14 (depends on 1)

The method of claim 1, further comprising combining said precursor components with an accelerator prior to polymerization.

### Claim 15 (depends on 1)

The method of claim 1, further comprising mixing said precursor components with a component that comprises at least one conjugated unsaturated bond or conjugated unsaturated group and at least one amine reactive group.

### Claim 16 (depends on 12)

The method of claim 12, further comprising applying an additional component to the cell or tissue surface, the additional component comprising at least one conjugated unsaturated bond or conjugated unsaturated group and at least one amine reactive group.

### Claim 17 (depends on 1)

The method of claim 1, wherein said strong nucleophile is a thiol and said conjugated unsaturated group is an acrylate.

### Claim 18 (depends on 1)

The method of claim 1, wherein said at least two components comprise poly(ethylene glycol).

### Claim 19 (depends on 1)

The method of claim 1, wherein one of said components comprises poly(ethylene glycol) and one of said components does not comprise poly(ethylene glycol).

### Claim 20 (depends on 1)

The method of claim 1, wherein said components are poly(ethylene glycol) dithiol and poly(ethylene glycol) tetraacrylate.

### Claim 21 (depends on 1)

The method of claim 1, wherein one of said components comprises pentaerythritol.

### Claim 22 (depends on 1)

The method of claim 1, wherein one of said components is poly(ethylene glycol) dithiol with a molecular weight of 3400 Da.