# US 2019/0167852 A1 · Systems and methods of radioprotection of allografts

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- Number: US 2019/0167852 A1
- Document ID: US20190167852A1
- Status: Published application
- Kind: A1
- Application number: 16/093,540
- Filed: 2017-04-17
- Published: 2019-06-06
- Earliest claimed: 2016-04-15
- Assignees: The General Hospital Corporation
- Applicants: The General Hospital Corporation
- Inventors: Ebru ORAL; Jeremy SUHARDI; Orhun MURATOGLU
- Web page: https://patentgrep.com/patent/US20190167852A1

## CPC

- A61L 27/54: Biologically active materials, e.g. therapeutic substances {(A61L27/227 takes precedence)}
- A61K 35/32: Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
- A61L 27/3608: {Bone, e.g. demineralised bone matrix [DBM], bone powder}
- A61L 27/3683: {subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment}
- A61L 27/3687: {characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents}
- A61L 27/3691: {characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation}
- A61L 27/3821: {Bone-forming cells, e.g. osteoblasts, osteocytes, osteoprogenitor cells}
- A61L 2300/428: Vitamins, e.g. tocopherol, riboflavin
- A61L 2430/02: for reconstruction of bones; weight-bearing implants
- 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)

## Abstract

Systems and methods of protecting allograft against radiation damage are disclosed. Systems and methods of incorporating additives such as radioprotectants into allograft tissue are also disclosed. The systems and methods comprise providing an allograft; cleaning the allograft; contacting the allograft with at least one radioprotectant, thereby obtaining a radioprotectant-doped allograft; contacting the radioprotectant-doped allograft with a supercritical fluid, thereby obtaining a radioprotectant doped and homogenized allograft.

## Claims

### Claim 1

A method of incorporating a radioprotectant into an allograft, the method comprising:
a. providing an allograft;
b. cleaning the allograft;
c. contacting the allograft with at least one radioprotectant, thereby obtaining a radioprotectant-doped allograft; and
d. contacting the radioprotectant-doped allograft with a supercritical fluid thereby obtaining a radioprotectant doped and homogenized allograft.

### Claim 2

A method of making a radiation sterilized allograft, the method comprising:
a. providing an allograft;
b. cleaning the allograft;
c. contacting the allograft with at least one radioprotectant(s), thereby obtaining a radioprotectant-doped allograft;
d. contacting the radioprotectant-doped allograft with a supercritical fluid; thereby obtaining a radioprotectant doped and homogenized allograft; and
e. irradiating the radioprotectant doped and homogenized allograft, thereby obtaining a radiation sterilized allograft.

### Claim 3 (depends on 2)

The method according to claim 2, wherein the allograft is a bone allograft.

### Claim 4 (depends on 3)

The method according to claim 3, wherein the bone allograft is cancellous or cortical.

### Claim 5 (depends on 3)

The method according to claim 3, wherein the bone allograft is crushed, machined or whole.

### Claim 6 (depends on 2)

The method according to claim 2, wherein the allograft is a cartilaginous allograft selected from the group consisting of a tendon, a ligament, an articular cartilage, an auricular cartilage, and a meniscus allograft.

### Claim 7 (depends on 6)

The method according to claim 6, wherein the cartilaginous graft is processed, machined or whole.

### Claim 8 (depends on 1, 2, 3, 4, 5, 6, 7)

The method according to any of claims 1 to 7, wherein the provided allograft is irradiated.

### Claim 9 (depends on 2)

The method according to claim 2, wherein the radioprotectant is vitamin E.

### Claim 10 (depends on 2)

The method according to claim 2, wherein the radioprotectant is a mixture containing vitamin E.

### Claim 11 (depends on 2)

The method according to claim 2, wherein the radioprotectant is selected from the group consisting of pure, in solution, and in an emulsion.

### Claim 12 (depends on 2)

The method according to claim 2, wherein the allograft is contacted with radioprotectant at about room temperature.

### Claim 13 (depends on 2)

The method according to claim 2, wherein the allograft is contacted with the radioprotectant at a temperature between room temperature and 60° C.

### Claim 14 (depends on 2)

The method according to claim 2, wherein the supercritical fluid is carbon dioxide.

### Claim 15 (depends on 2)

The method according to claim 2, wherein the radioprotectant-doped allograft is contacted with the supercritical fluid at a temperature between room temperature and 100° C.

### Claim 16 (depends on 2)

The method according to claim 2, wherein the radioprotectant-doped allograft is contacted with the supercritical fluid for a time between 4 and 24 hours.

### Claim 17 (depends on 2)

The method according to claim 2, wherein a terminal irradiation dose is below 30 kGy.

### Claim 18 (depends on 2)

The method according to claim 2, wherein a terminal irradiation dose is between 30 and 50 kGy.

### Claim 19 (depends on 2)

A method according to claim 2, wherein a terminal irradiation dose is above 50 kGy.

### Claim 20

A method of making a medical implant, the method comprising:
a. providing an allograft;
b. cleaning the allograft;
c. contacting the allograft with radioprotectant(s), thereby obtaining a radioprotectant-doped allograft;
d. contacting the radioprotectant-doped allograft with a supercritical fluid thereby obtaining a radioprotectant doped and homogenized allograft; and
e. irradiating the radioprotectant doped and homogenized allograft.

### Claim 21

A method of incorporating radioprotectant into allografts, the method comprising:
a. providing a allograft;
b. cleaning allograft;
c. contacting allograft with radioprotectant(s) and at least one more additive, thereby obtaining a radioprotectant-doped allograft; and
d. contacting the radioprotectant-doped allograft with a supercritical fluid thereby obtaining a radioprotectant doped and homogenized allograft.

### Claim 22

A method of making a radiation sterilized allograft, the method comprising:
a. providing an allograft;
b. cleaning allograft;
c. contacting allograft with radioprotectant(s) and at least one more additive, thereby obtaining a radioprotectant-doped allograft;
d. contacting the radioprotectant-doped allograft with a supercritical fluid thereby obtaining a radioprotectant doped and homogenized allograft; and
e. irradiating the radioprotectant doped and homogenized allograft.

### Claim 23

A method of making a medical implant, the method comprising:
a. providing an allograft;
b. cleaning allograft;
c. contacting allograft with radioprotectant(s) and at least one more additive, thereby obtaining a radioprotectant-doped allograft;
d. contacting the radioprotectant-doped allograft with a supercritical fluid thereby obtaining a radioprotectant doped and homogenized allograft; and
e. irradiating radioprotectant doped and homogenized allograft.

### Claim 24 (depends on 20, 21, 22, 23)

The method according to any of claims 20 to 23, wherein the allograft is a bone allograft.

### Claim 25 (depends on 25)

The method according to claim 25, wherein the bone allograft is cancellous or cortical.

### Claim 26 (depends on 25)

The method according to claim 25, wherein the bone allograft is crushed, machined or whole.

### Claim 27 (depends on 20, 21, 22, 23)

The method according to any of claims 20 to 23, wherein the allograft is a cartilaginous allograft from the group consisting of a tendon, ligament, articular cartilage, auricular cartilage, and meniscus allograft.

### Claim 28 (depends on 27)

The method according to claim 27, wherein the cartilaginous graft is processed, machined or whole.

### Claim 29 (depends on 20, 21, 22, 23)

The method according to any of claims 20 to 23, wherein the provided allograft is irradiated.

### Claim 30 (depends on 20, 21, 22, 23)

The method according to any of claims 20 to 23, wherein the radioprotectant is vitamin E.

### Claim 31 (depends on 20, 21, 22, 23)

The method according to any of claims 20 to 23, wherein the radioprotectant is a mixture containing vitamin E.

### Claim 32 (depends on 20, 21, 22, 23)

The method according to any of claims 20 to 23, wherein the radioprotectant is pure, in solution or in an emulsion.

### Claim 33 (depends on 20, 21, 22, 23)

The method according to any of claims 20 to 23, wherein the allograft is contacted with radioprotectant at about room temperature.

### Claim 34 (depends on 20, 21, 22, 23)

The method according to any of claims 20 to 23, wherein the allograft is contacted with radioprotectant at a temperature between room temperature and 60° C.

### Claim 35 (depends on 20, 21, 22, 23)

The method according to any of claims 20 to 23, wherein the supercritical fluid is carbon dioxide.

### Claim 36 (depends on 20, 21, 22, 23)

The method according to any of claims 20 to 23, wherein the radioprotectant-doped allograft is contacted with supercritical fluid at a temperature between room temperature and 100° C.

### Claim 37 (depends on 20, 21, 22, 23)

The method according to any of claims 20 to 23, wherein the radioprotectant-doped allograft is contacted with supercritical fluid for a time between 4 and 24 hours.

### Claim 38 (depends on 20, 22, 23)

The method according to any of claims 20, 22 or 23, wherein a terminal irradiation dose is below 30 kGy.

### Claim 39 (depends on 20, 22, 23)

The method according to any of claims 20, 22 or 23, wherein a terminal irradiation dose is between 30 and 50 kGy.

### Claim 40 (depends on 20, 22, 23)

The method according to any of claims 20, 22 or 23, wherein a terminal irradiation dose is above 50 kGy.

### Claim 41 (depends on 21, 22, 23)

The method according to any of claims 21 to 23, wherein the at least one additive is an antibiotic.

### Claim 42 (depends on 41)

The method according to claim 41, wherein the antibiotic is vancomycin.

### Claim 43 (depends on 41)

The method according to claim 41, wherein the antibiotic is gentamicin.

### Claim 44 (depends on 21, 22, 23)

The method according to any of claims 21 to 23, wherein the at least one additive is an anti-inflammatory agent.

### Claim 45 (depends on 21, 22, 23)

The method according to any of claims 21 to 23, wherein the at least one additive is an analgesic.

### Claim 46

A method of protecting collagen cross-links in a radiation sterilized allograft, the method comprising:
a. providing an allograft;
b. cleaning the allograft;
c. contacting the allograft with at least one radioprotectant thereby creating a radioprotectant-doped allograft;
d. contacting the radioprotectant-doped allograft with a supercritical fluid thereby obtaining a radioprotectant doped and homogenized allograft; and
e. irradiating the radioprotectant doped and homogenized allograft.

### Claim 47

A method of making a medical implant with preserved collagen cross-linking, the method comprising:
a. providing an allograft;
b. cleaning the allograft;
c. contacting the allograft with radioprotectant(s);
d. contacting the radioprotectant-doped allograft with a supercritical fluid thereby obtaining a radioprotectant doped and homogenized allograft; and
e. irradiating the radioprotectant doped and homogenized allograft.

### Claim 48 (depends on 1)

A material for the repair of a bone defect, the material comprising: a radioprotectant-doped allograft created by the method of claim 1.

### Claim 49 (depends on 48)

The material of claim 48, wherein the allograft is a bone allograft.

### Claim 50 (depends on 49)

The material of claim 49, wherein the bone allograft is cancellous or cortical.

### Claim 51 (depends on 49)

The material of claim 49, wherein the bone allograft is crushed, machined or whole.

### Claim 52 (depends on 48)

The material of claim 48, wherein the allograft is a cartilaginous allograft selected from the group consisting of a tendon, ligament, articular cartilage, auricular cartilage, and meniscus allograft.

### Claim 53 (depends on 52)

The material of claim 52, wherein the cartilaginous allograft is processed, machined or whole.

### Claim 54

A prosthetic system for implantation in a subject, the prosthetic system comprising:
radioprotectant-doped allograft(s).

### Claim 55 (depends on 54)

The prosthetic system of claim 54, wherein the radioprotectant-doped allograft is created by contacting an allograft with at least one radioprotectant and contacting with a supercritical fluid.

### Claim 56 (depends on 54)

The prosthetic system of claim 54, wherein the radioprotectant-doped allograft is contacted by a supercritical fluid and is irradiated.

### Claim 57 (depends on 54)

The prosthetic system of claim 54, wherein the prosthetic system is configured to replace a defect in a joint of a subject.

### Claim 58 (depends on 57)

The prosthetic system of claim 57, wherein the joint is selected from the group consisting of an ankle, a knee, a hip, a wrist, an elbow, a shoulder, a finger, and a toe.

### Claim 59 (depends on 54)

The prosthetic system of claim 54, wherein the prosthetic system is configured to replace a defect in a spine.

### Claim 60 (depends on 1)

The method according to claim 1, wherein the allograft is comprised of different tissues.

### Claim 61 (depends on 1)

The method according to claim 1, wherein the allograft is comprised of bone and tendon.

### Claim 62

A method of making an allograft with improved integration to host tissue, the method comprising:
a. providing an allograft;
b. cleaning the allograft;
c. contacting the allograft with at least one radioprotectant, thereby obtaining a radioprotectant-doped allograft; and
d. contacting the radioprotectant-doped allograft with a supercritical fluid thereby obtaining a radioprotectant doped and homogenized allograft; and
e. Irradiating the radioprotectant doped and homogenized allograft.

### Claim 63

An allograft with improved integration to host tissue made by a method comprising:
a. providing an allograft;
b. cleaning the allograft;
c. contacting the allograft with at least one radioprotectant and optionally other additive(s), thereby obtaining a radioprotectant-doped allograft; and
d. contacting the radioprotectant-doped allograft with a supercritical fluid optionally in the presence of other additive(s); thereby obtaining a radioprotectant doped and homogenized allograft; and
e. irradiating the radioprotectant doped and homogenized allograft.

### Claim 64

A method of making an allograft with improved integration to host tissue, the method comprising:
a. providing an allograft;
b. cleaning the allograft;
c. contacting the allograft with at least one radioprotectant and optionally other additive(s), thereby obtaining a radioprotectant-doped allograft; and
d. contacting the radioprotectant-doped allograft with a supercritical fluid optionally in the presence of other additive(s); thereby obtaining a radioprotectant doped and homogenized allograft; and
e. irradiating the radioprotectant doped and homogenized allograft.

### Claim 65

A method of making an allograft with improved integration to host tissue, the method comprising:
a. providing an allograft;
b. cleaning the allograft;
c. contacting the allograft with at least one radioprotectant and at least one antibiotic, thereby obtaining a radioprotectant and antibiotic-doped allograft; and
d. contacting the radioprotectant-doped allograft with a supercritical fluid; thereby obtaining a radioprotectant and antibiotic-doped and homogenized allograft; and
e. irradiating the radioprotectant and antibiotic-doped and homogenized allograft.

### Claim 66

A method according to any of the claims, wherein the doping is done at room temperature.

### Claim 67

A method according to any of the claims, wherein the doping is done between room temperature and 60° C.

### Claim 68

A method according to any of the claims, wherein the homogenization is done at about 40° C.

### Claim 69

A method according to any of the claims, wherein the doping is done under inert atmosphere.

### Claim 70

A method according to any of the claims wherein the homogenization in supercritical carbon dioxide is done at about 85 bar.

### Claim 71

A method according to any of the claims, wherein the doping is done for about 6 hours.

### Claim 72

A method according to any of the claims, wherein the doping is done for less than 6 hours.

### Claim 73

A method according to any of the claims, wherein the homogenization in supercritical fluid is done for about 24 hours.

### Claim 74

A method according to any of the claims, wherein the homogenization in supercritical carbon dioxide is done for less than 24 hours.