# US 10,478,284 B2 · Methods for tissue passivation

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- Number: US 10,478,284 B2
- Document ID: US10478284B2
- Status: Granted
- Kind: B2
- Application number: 14/601,023
- Filed: 2015-01-20
- Published: 2015-05-14
- Granted: 2019-11-19
- Earliest claimed: 2012-07-20
- Assignees: The General Hospital Corporation
- Applicants: The General Hospital Corporation
- Inventors: William G. Austen, Jr.; Michael McCormack; Robert W. Redmond; Irene E. Kochevar
- Web page: https://patentgrep.com/patent/US10478284B2

## CPC

- A61F 2/06: Blood vessels
- A01N 1/142: Apparatus
- A01N 1/168: using electromagnetic fields or radiation; using acoustic waves or corpuscular radiation
- A61F 2/062: {Apparatus for the production of blood vessels made from natural tissue or with layers of living cells}
- A61K 41/0057: {Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent}
- A61L 27/3604: {characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel}
- A61L 27/3633: {Extracellular matrix [ECM]}
- A61L 27/50: Materials characterised by their function or physical properties {, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials}
- A61L 27/505: {Stabilizers}
- A61L 27/54: Biologically active materials, e.g. therapeutic substances {(A61L27/227 takes precedence)}
- A61L 31/005: {Ingredients of undetermined constitution or reaction products thereof}
- A61L 31/14: Materials characterised by their function or physical properties {, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials}
- A61L 31/16: Biologically active materials, e.g. therapeutic substances {(A61L31/047 takes precedence)}
- A61N 5/0601: {Apparatus for use inside the body}
- A61N 5/062: {Photodynamic therapy, i.e. excitation of an agent}
- A61L 2300/418: Agents promoting blood coagulation, blood-clotting agents, embolising agents
- A61L 2300/424: Anti-adhesion agents
- A61L 2300/442: Colorants, dyes
- A61L 2400/18: Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
- A61L 2430/04: for mammary reconstruction
- A61L 2430/22: for reconstruction of hollow organs, e.g. bladder, esophagus, urether, uterus
- A61L 2430/34: for soft tissue reconstruction
- A61M 1/3655: {Arterio-venous shunts or fistulae}
- A61N 5/0603: {for treatment of body cavities}
- A61N 5/0624: {for eliminating microbes, germs, bacteria on or in the body}
- A61F: FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS (dental prosthetics A61C)
- A01N: PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF (preservation of food or foodstuff A23); BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES (preparations for medical, dental or toiletry purposes which kill or prevent the growth or proliferation of unwanted organisms A61K); PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- 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)
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)
- A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)}

## Abstract

Methods of tissue passivation are described herein for use in preserving normal tissue architecture, reducing post-surgical inflammation, and reducing or preventing the development of pathogenic collagen bundles and adhesions following surgical procedures. Passivated tissues prepared in accordance with these methods are useful in a variety of therapies including, e.g., cardiac bypass surgery, hemodialysis, etc.

## Claims

### Claim 1

A method of preventing or decreasing intimal hyperplasia within a human blood vessel, the method comprising exposing an intact, non-proliferative, exterior surface of the human blood vessel to a cross-linking tissue structure stabilizing agent (“TSSA”) that does not penetrate beyond an external layer of collagen in the exterior surface under conditions sufficient to promote cross-linking of proteins within the exterior vascular surface while preserving normal tissue architecture of regions of the human blood vessel beyond the external layer of collagen, thereby preventing or decreasing intimal hyperplasia within the human blood vessel.

### Claim 2 (depends on 1)

The method of claim 1, wherein the exterior vascular surface has an area selected from the group consisting of: about 20 cm2, 25 cm2, 50 cm2, 100 cm2, 500 cm2, and about 1000 cm2.

### Claim 3 (depends on 1)

The method of claim 1, wherein the TSSA is a photoactive agent or a chemical cross-linking compound.

### Claim 4 (depends on 3)

The method of claim 3, wherein the TSSA is a photoactive agent.

### Claim 5 (depends on 1)

The method of claim 1, further comprising the step of irradiating the exterior vascular surface at an irradiance of less than about 1 W/cm2.

### Claim 6 (depends on 4)

The method of claim 4, wherein the photoactive agent is Rose Bengal (“RB”).

### Claim 7 (depends on 5)

The method of claim 5, wherein the irradiance is provided for a period of about 1 minute to about 30 minutes.

### Claim 8 (depends on 7)

The method of claim 7, wherein the irradiance is provided for less than about 5 minutes.

### Claim 9 (depends on 3)

The method of claim 3, wherein the TSSA is a chemical cross-linking compound.

### Claim 10

A method of preventing or decreasing scarring, fibrotic response, or contracture within a dissected cavity in a human subject, the method comprising: topically applying a cross-linking tissue structure stabilizing agent (“TSSA”) to at least a non-proliferative, uninjured internal connective tissue surface of a dissected abdominal, thoracic, or chest cavity under conditions sufficient to promote cross-linking of proteins within the non-proliferative, uninjured internal connective tissue surface of the dissected abdominal, thoracic, or chest cavity, thereby preventing or decreasing scarring, fibrotic response, or contracture while otherwise preserving normal tissue architecture within the dissected abdominal, thoracic, or chest cavity.

### Claim 11 (depends on 10)

The method of claim 10, wherein the contracture comprises scar contracture or capsular contracture.

### Claim 12 (depends on 10)

The method of claim 10, wherein the TSSA is a photoactive agent or a chemical cross-linking compound.

### Claim 13 (depends on 1)

The method of claim 1, wherein the exterior surface is continuous.

### Claim 14 (depends on 1)

The method of claim 1, wherein the exterior surface is uninjured.

### Claim 15 (depends on 1)

The method of claim 1, wherein the exterior surface is whole.

### Claim 16 (depends on 10)

The method of claim 10, wherein the TSSA is a photoactive agent.

### Claim 17 (depends on 16)

The method of claim 16, wherein the dissected cavity is a breast implant pocket and the method further comprises:
irradiating the TSSA under conditions sufficient to promote cross-linking of proteins within the internal connective tissue surface of the dissected cavity while otherwise preserving normal tissue architecture, thereby preparing a non-adhesive internal connective tissue surface;
implanting a breast implant within the dissected cavity; and
closing the dissected cavity.

### Claim 18 (depends on 6)

The method of claim 6, wherein the TSSA does not penetrate more than about 100 μm into connective tissue of the exterior vascular surface.

### Claim 19 (depends on 1)

The method of claim 1, wherein the exposing step otherwise preserves existing tissue architecture of the exterior surface.

### Claim 20 (depends on 1)

The method of claim 1, wherein:
the human blood vessel is a vein; and
the method further comprises coupling the vein to an artery after the exposing step to form an arterio-venous fistula.

### Claim 21 (depends on 16)

The method of claim 16, wherein the photoactive agent is selected from the group consisting of xanthenes, flavins, thiazines, porphyrins, expanded porphyrins, chlorophylls, phenothiazines, cyanines, mono azo dyes, azine mono azo dyes, rhodamine dyes, benzophenoxazine dyes, oxazines, and anthroquinone dyes.

### Claim 22 (depends on 16)

The method of claim 16, wherein the photoactive agent is selected from the group consisting of Rose Bengal (“RB”), erythrosine, riboflavin, methylene blue (MB), Toluidine Blue, Methyl Red, Janus Green B, Rhodamine B base, Nile Blue A, Nile Red, Celestine Blue, Remazol Brilliant Blue R, riboflavin-5-phosphate (R—S—P), N-hydroxypyridine-2-(I H)-thione (N-HTP) and photoactive derivatives thereof.

### Claim 23 (depends on 16)

The method of claim 16, wherein the photoactive agent is Rose Bengal (“RB”).

### Claim 24 (depends on 23)

The method of claim 23, wherein the TSSA does not penetrate more than about 100 μm into connective tissue.

### Claim 25 (depends on 10)

The method of claim 10, wherein the intact, non-proliferative, internal tissue surface is continuous.

### Claim 26 (depends on 10)

The method of claim 10, wherein the intact, non-proliferative, internal tissue surface is uninjured.

### Claim 27 (depends on 10)

The method of claim 10, wherein the intact, non-proliferative, internal tissue surface is whole.

### Claim 28 (depends on 10)

The method of claim 10, wherein the internal connective tissue surface has an area selected from the group consisting of: about 20 cm2, 25 cm2, 50 cm2, 100 cm2, 500 cm2, and about 1000 cm2.

### Claim 29

A method of preventing or decreasing tissue adhesion and/or contracture within a dissected cavity in a human subject, the method comprising:
topically applying a photoactive cross-linking tissue structure stabilizing agent (“TSSA”) to at least a non-proliferative, uninjured internal connective tissue surface of a dissected cavity;
irradiating the photoactive cross-linking TSSA under conditions sufficient to promote cross-linking of proteins within the internal connective tissue surface of the dissected cavity while otherwise preserving normal tissue architecture, thereby preparing a non-adhesive internal connective tissue surface;
implanting natural or synthetic materials within the dissected cavity; and
closing the dissected cavity.