# US 8,465,772 B2 · Methods and compositions for treating tissue using silk proteins

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- Number: US 8,465,772 B2
- Document ID: US8465772B2
- Status: Granted
- Kind: B2
- Application number: 13/472,324
- Filed: 2012-05-15
- Published: 2012-09-06
- Granted: 2013-06-18
- Earliest claimed: 2006-12-04
- Assignees: Abbott Cardiovascular Systems Inc.
- Applicants: Syed Hossainy; Michael Ngo; Mikael Trollsas; John Stankus; Gene Michal
- Inventors: Syed Hossainy; Michael Ngo; Mikael Trollsas; John Stankus; Gene Michal
- Web page: https://patentgrep.com/patent/US8465772B2

## CPC

- A61K 47/42: Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein (oligopeptides having up to five amino acids {A61K47/183}; polyamino acids A61K47/34)
- 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 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence)
- A61L 27/3804: {characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells}
- A61L 27/3839: {characterised by the site of application in the body (materials for artificial blood vessels A61L27/507; materials for use in artificial skin A61L27/60)}
- A61L 27/3895: {using specific culture conditions, e.g. stimulating differentiation of stem cells, pulsatile flow conditions}
- A61L 27/48: with macromolecular fillers
- A61L 27/52: Hydrogels or hydrocolloids
- A61P 9/00: Drugs for disorders of the cardiovascular system
- 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 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- Y10S 530/812: Peptides or proteins is immobilized on, or in, an organic carrier
- Y10S 530/815: Carrier is a synthetic polymer
- 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
- Y10S: TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS

## Abstract

Compositions for forming a self-reinforcing composite biomatrix, methods of manufacture and use therefore are herein disclosed. Kits including delivery devices suitable for delivering the compositions are also disclosed. In some embodiments, the composition can include at least three components. In one embodiment, a first component can include a first functionalized polymer, a second component can include a second functionalized polymer and a third component can include silk protein or constituents thereof. In some embodiments, the composition can include at least one cell type and/or at least one growth factor. In some embodiments, the composition can include a biologic encapsulated, suspended, disposed within or loaded into a biodegradable carrier. In some embodiments, the composition(s) of the present invention can be delivered by a dual lumen injection device to a treatment area in situ, in vivo, as well as ex vivo applications.

## Claims

### Claim 1

A composition comprising:
a first component of a two-component gelation system;
a second component of a two-component gelation system;
a block copolymer of silk protein conjugated with a glycosaminoglycan; and
at least one cell type, and
wherein the block copolymer of silk protein conjugated with a glycosaminoglycan and the at least one cell type are in an aqueous solution that form a self-reinforcing composite matrix in vivo when combined with the first component and the second component of the two-component gelation system.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the two-component gelation system is a fibrin glue system.

### Claim 3 (depends on 2)

The composition of claim 2, wherein the two-component gelation system is a fibrin glue system comprising fibrinogen or a derivative thereof as the first component and thrombin as the second component.

### Claim 4 (depends on 1)

The composition of claim 1, wherein the block copolymer of silk protein is synthetic.

### Claim 5 (depends on 1)

The composition of claim 1 wherein at least one of the first component and the second component is in a solid phase.

### Claim 6 (depends on 5)

The composition of claim 5, wherein the block copolymer of silk protein is up to 50 mass percent of the solid phase mixture.

### Claim 7 (depends on 1)

The composition of claim 1, wherein the at least one cell type is in the form of a suspension comprising between 0.5 million to 10 million cells.

### Claim 8 (depends on 1)

The composition of claim 1, wherein the at least one cell type is at least one of cardiomyocytes, chondrocytes or bone marrow mononuclear cells.

### Claim 9 (depends on 1)

The composition of claim 1, wherein the at least one cell type is at least one of adipose tissue derived stem cells, embryonic stem cells, umbilical-cord-blood-derived stem cells, smooth muscle cells or skeletal myoblasts.

### Claim 10 (depends on 1)

The composition of claim 1, wherein the first component and the second component is combined in a 1:1 ratio.

### Claim 11 (depends on 1)

The composition of claim 1, wherein the block copolymer of silk protein is in an aqueous solution and combined with a growth factor.

### Claim 12 (depends on 11)

The composition of claim 11, wherein the growth factor is selected from the group consisting of insulin-like growth factor 1, hepatocyte growth factor, vasoendothelial growth factor, beta-platelet derived growth factor, stem cell factor, granulocyte-colony stimulating factors, or platelet derived growth factor.

### Claim 13

A kit comprising:
a first syringe comprising precursors of a two-component gelation system;
a second syringe comprising a block copolymer of silk protein conjugated with a glycosaminoglycan and at least one cell type in an aqueous solution; and
a third syringe comprising a first aqueous buffer solution in a pH range from about 7.5 to about 9.0.

### Claim 14 (depends on 13)

The kit of claim 13, wherein the two-component gelation system is a fibrin glue system.

### Claim 15 (depends on 14)

The kit of claim 14, wherein the two-component gelation system is a fibrin glue system comprising fibrinogen or a derivative thereof as the first component and thrombin as the second component.

### Claim 16 (depends on 13)

The kit of claim 13, wherein the or block copolymer of silk protein is synthetic.

### Claim 17 (depends on 13)

The kit of claim 13, wherein the block copolymer of silk protein comprises about one-tenth mass of the precursors.

### Claim 18 (depends on 13)

The kit of claim 13, wherein the glycosaminoglycan is one of hyaluronic acid, heparin sulfate, chondroitin sulfate or keratin sulfate.

### Claim 19 (depends on 1)

The composition of claim 1, wherein the glycosaminoglycan is one of hyaluronic acid, heparin sulfate, chondroitin sulfate or keratin sulfate.

### Claim 20 (depends on 13)

The kit of claim 13, wherein the at least one cell type is in the form of a suspension comprising between 0.5 million to 10 million cells.

### Claim 21 (depends on 13)

The kit of claim 13, wherein the at least one cell type is at least one of cardiomyocytes, chondrocytes or bone marrow mononuclear cells.

### Claim 22 (depends on 13)

The kit of claim 13, wherein the at least one cell type is at least one of adipose tissue derived stem cells, embryonic stem cells, umbilical-cord-blood-derived stem cells, smooth muscle cells or skeletal myoblasts.

### Claim 23 (depends on 11)

The composition of claim 11, wherein the growth factor is encapsulated, suspended, disposed within or loaded into a biodegradable microfiber or microparticle.

### Claim 24 (depends on 13)

The kit of claim 13, wherein the aqueous solution within the second syringe further comprises a biologic encapsulated, suspended, disposed within or loaded into a biodegradable microfiber or microparticle.