# US 10,245,351 B2 · Malleable hydrogel hybrids made of self-assembled peptides and biocompatible polymers and uses thereof

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- Number: US 10,245,351 B2
- Document ID: US10245351B2
- Status: Granted
- Kind: B2
- Application number: 15/463,089
- Filed: 2017-03-20
- Published: 2017-07-06
- Granted: 2019-04-02
- Earliest claimed: 2010-06-03
- Assignees: Technology Innovation Momentum Fund (Israel) Limited Partnership
- Applicants: Technology Innovation Momentum Fund (Israel) Limited Partnership
- Inventors: Moran Aviv; Ludmila Buzhansky; Shmuel Einav; Zvi Nevo; Ehud Gazit; Lihi Adler-Abramovich
- Web page: https://patentgrep.com/patent/US10245351B2

## CPC

- A61L 27/52: Hydrogels or hydrocolloids
- A61K 8/042: {Gels}
- A61K 8/64: Proteins; Peptides; Derivatives or degradation products thereof
- A61K 8/735: {Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof}
- A61K 8/736: {Chitin; Chitosan; Derivatives thereof}
- A61K 38/05: Dipeptides
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61L 27/20: Polysaccharides
- A61L 27/227: {Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24}
- A61L 27/26: Mixtures of macromolecular compounds
- A61L 27/50: Materials characterised by their function or physical properties {, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials}
- A61L 27/54: Biologically active materials, e.g. therapeutic substances {(A61L27/227 takes precedence)}
- A61Q 19/00: Preparations for care of the skin
- C08L 89/00: Compositions of proteins; Compositions of derivatives thereof
- A61K 9/1694: {resulting in granules or microspheres of the matrix type containing more than 5% of excipient}
- A61K 2800/10: General cosmetic use
- A61L 2300/25: Peptides having up to 20 amino acids in a defined sequence
- A61L 2400/06: Flowable or injectable implant compositions
- 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)
- 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)
- A61Q: SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)

## Abstract

Hybrid hydrogels formed of a plurality of peptides that are capable of self-assembling into a hydrogel in an aqueous solution and a biocompatible polymer that is characterized by high swelling capability, high elasticity and low mechanical strength are disclosed, with exemplary hybrid hydrogels being formed of a plurality of aromatic dipeptides and hyaluronic acid. The hybrid hydrogels are characterized by controllable mechanical and biological properties which can be adjusted by controlling the concentration ratio of the peptides and the polymer, and which average the mechanical and biological properties of the peptides and the polymer. Processes of preparing the hydrogels and uses thereof in pharmaceutical, cosmetic or cosmeceutic applications such as tissue engineering and/or regeneration are further disclosed.

## Claims

### Claim 1

A hydrogel comprising a fibrous network of a plurality of peptides and at least one biocompatible polymer, wherein said peptides are capable of self-assembling in an aqueous solution so as to form a hydrogel, wherein each peptide in said plurality of peptides comprises an amino acid sequence not exceeding 6 amino acids in length, said amino acid sequence comprising at least one aromatic amino acid residue, and wherein said biocompatible polymer features at least one characteristic selected from the group consisting of:
(i) a storage modulus G′ lower than 500 Pa at 10 Hz frequency and at 25° C.;
(ii) a swelling ratio (Q) higher than 500;
(iii) a viscosity at 0.1 Sec−1 shear rate and at 25° C., lower than 300 Pa·s; and
(iv) a viscosity recovery after shear of at least 95%.

### Claim 2 (depends on 1)

The hydrogel of claim 1, wherein said biocompatible polymer is a polysaccharide.

### Claim 3 (depends on 2)

The hydrogel of claim 2, wherein said biocompatible polymer is hyaluronic acid.

### Claim 4 (depends on 2)

The hydrogel of claim 2, wherein said biocompatible polymer is a chitosan.

### Claim 5 (depends on 1)

The hydrogel of claim 1, wherein at least one peptide in said plurality of peptides consists essentially of aromatic amino acid residues.

### Claim 6 (depends on 1)

The hydrogel of claim 1, wherein at least one peptide in said plurality of peptides is a dipeptide.

### Claim 7 (depends on 6)

The hydrogel of claim 6, wherein at least one of said dipeptides is a homodipeptide.

### Claim 8 (depends on 1)

The hydrogel of claim 1, wherein at least one peptide in said plurality of peptides is an end-capping modified peptide.

### Claim 9 (depends on 8)

The hydrogel of claim 8, wherein said end capping modified peptide comprises at least one end capping moiety, said end capping moiety being selected from the group consisting of an aromatic end capping moiety and a non-aromatic end-capping moiety.

### Claim 10 (depends on 3)

The hydrogel of claim 3, wherein each peptide in said plurality of peptides is a homodipeptide.

### Claim 11 (depends on 10)

The hydrogel of claim 10, wherein said homodipeptide is phenylalanine-phenylalanine dipeptide.

### Claim 12 (depends on 11)

The hydrogel of claim 11, wherein each dipeptide in said plurality of dipeptides is an end-capping modified peptide.

### Claim 13 (depends on 12)

The hydrogel of claim 12, wherein each of said end-capping modified dipeptides comprises an aromatic end-capping moiety.

### Claim 14 (depends on 1)

The hydrogel of claim 1, wherein a total concentration of said plurality of peptides and said polymer ranges from 0.1 weight percent to 5 weight percents of the total weight of the gel.

### Claim 15 (depends on 1)

The hydrogel of claim 1, wherein a weight ratio of said plurality of peptides and said polymer ranges from 10:1 to 1:10.

### Claim 16 (depends on 1)

The hydrogel of claim 1, wherein said fibrous network comprises a plurality of fibrils, whereas an average diameter of said fibrils ranges from about 10 nm to about 100 nm.

### Claim 17 (depends on 1)

The hydrogel of claim 1, characterized by at least one of:
a storage modulus G′ to loss modulus G″ ratio that is greater than 4;
a storage modulus G′ higher than 1,000 Pa at 10 Hz frequency and at 25° C.; and
a storage modulus G′ lower than 100,000 Pa at 10 Hz frequency and at 25° C.

### Claim 18 (depends on 1)

The hydrogel of claim 1, characterized by:
a viscosity that ranges from 200 to 2000 Pa·s at 0.1 Sec−1 shear rate, at 25° C.;
a viscosity recovery after shear of at least 50%, at 0.1 sec−1; and
a swelling ratio (Q) that ranges from 100 to 500.

### Claim 19 (depends on 1)

A composition-of-matter comprising the hydrogel of claim 1 and at least one agent being incorporated therein or thereon.

### Claim 20 (depends on 1)

A process of preparing the hydrogel of claim 1, the process comprising contacting said plurality of peptides and said biocompatible polymer in an aqueous solution.

### Claim 21 (depends on 20)

The process of claim 20, wherein said contacting is effected ex-vivo.

### Claim 22 (depends on 20)

The process of claim 20, wherein said contacting is effected in-vivo.

### Claim 23 (depends on 1)

A pharmaceutical, cosmetic or cosmeceutical composition comprising the hydrogel of claim 1.

### Claim 24 (depends on 19)

A pharmaceutical, cosmetic or cosmeceutical composition comprising the composition-of-matter of claim 19.

### Claim 25 (depends on 1)

An article-of-manufacture comprising the hydrogel of claim 1.

### Claim 26 (depends on 19)

An article-of-manufacture comprising the composition-of-matter of claim 19.

### Claim 27 (depends on 1)

A kit for forming the hydrogel of claim 1, the kit comprising said plurality of peptides and said biocompatible polymer.

### Claim 28 (depends on 27)

The kit of claim 27, further comprising instructions for forming the hydrogel by contacting said peptides and said biocompatible polymer with an aqueous solution.

### Claim 29 (depends on 27)

The kit of claim 27, further comprising an aqueous solution, wherein said peptides and said aqueous solution are individually packaged within the kit.

### Claim 30 (depends on 19)

A kit of for forming the composition-of-matter of claim 19, the kit comprising said plurality of peptides, said biocompatible polymer and said active agent.

### Claim 31 (depends on 30)

The kit of claim 30, further comprising instructions for forming the hydrogel by contacting said plurality of peptides, said biocompatible polymer and said active agent with an aqueous solution.

### Claim 32 (depends on 31)

The kit of claim 31, further comprising an aqueous solution, wherein said plurality of peptides and said aqueous solution are individually packaged within the kit.

### Claim 33 (depends on 1)

A method of repairing a damaged tissue, the method comprising contacting the damaged tissue with the hydrogel of claim 1.

### Claim 34 (depends on 19)

A method of repairing a damaged tissue, the method comprising contacting the damaged tissue with the composition-of-matter of claim 19.