# US 8,465,582 B2 · Process for producing inorganic interconnected 3D open cell bone substitutes

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- Number: US 8,465,582 B2
- Document ID: US8465582B2
- Status: Granted
- Kind: B2
- Application number: 12/725,163
- Filed: 2010-03-16
- Published: 2011-09-22
- Granted: 2013-06-18
- Earliest claimed: 2010-03-16
- Assignees: Taipei Medical University
- Applicants: Jen-Chang Yang; Sheng-Yang Lee; Tsuimin Tsai; Hong-Da Wu; Hsin-Tai Hu; Yan-Cheng Yang; Chen-Feng Ma
- Inventors: Jen-Chang Yang; Sheng-Yang Lee; Tsuimin Tsai; Hong-Da Wu; Hsin-Tai Hu; Yan-Cheng Yang; Chen-Feng Ma
- Web page: https://patentgrep.com/patent/US8465582B2

## CPC

- A61K 35/32: Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
- A61K 35/28: Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
- A61K 38/1875: {Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor}
- A61K 38/39: Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
- A61L 27/10: Ceramics or glasses
- A61L 27/12: Phosphorus-containing materials, e.g. apatite
- A61L 27/18: obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
- A61L 27/20: Polysaccharides
- A61L 27/56: Porous materials, {e.g. foams or sponges}
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61L 2430/02: for reconstruction of bones; weight-bearing implants
- 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

## Abstract

The present invention relates to a process of using a heat responsive mixture to produce inorganic interconnected 3D open-cell bone substitutes which can be applied in the orthopedic or dental field for treatment of bone damage. The invention provides a simple and easily-controlled process of preparing porous inorganic bone substitute materials.

## Claims

### Claim 1

A method of using a heat responsive mixture to form an inorganic interconnected 3D open-pore bone substitute, wherein the heat responsive mixture comprises one or more polyelectrolytic complexes and one or more biomedical ceramic powders, comprising a first heating step of heating the mixture at a temperature ranging from 25° C. to 100° C., a second heating step of heating the resulting mixture to remove water and polyelectrolytic complexes contained therein and then cooling the mixture, resulting in an inorganic interconnected 3D open-pore bone substitute;
wherein after raising the temperature at the first heating step or the second heating step can further comprises a temperature-holding session for 0.25 to 10 hours;
wherein the polyelectrolytic complex is a gel form and formed by one or more positive charge polyelectrolyte and one or more negative charge polyelectrolyte;
wherein the positive charge polyelectrolyte is selected from the group consisting of polyarginine, polyornithine, DEAE dextran, polybrene, chitosan, polylysine, amino-cellulose, polyethyleneimine resin and mixture thereof and the negative charge polyelectrolyte is selected from the group consisting of: acetylcellulose, γ-polyglutamate (γ-PGA), hydroxypropyl methyl cellulose (HPMC), carboxy methyl cellulose (CMC), sodium polyphosphate, hyaluronan acid, sodium alginate and mixture thereof;
wherein the biomedical ceramic powder is selected from the group consisting of: calcium phosphate based ceramic powder, calcium sulfate based ceramic powder, oxide based ceramic powder, nitride based ceramic powder, carbide based ceramic powder, alumina-dispersed zirconia, titania-dispersed alumina and mixture thereof; and
wherein the weight percent (w/w, dry weight) of a polyelectrolyte complex and a biomedical ceramic material ranges from 2% to 20% and 15% to 50%, respectively, the remained composition is water.

### Claim 2 (depends on 1)

The method according to claim 1 wherein the calcium phosphate based ceramic powder is selected from the group consisting of hydroxyapatite (HA), β-tricalcium phosphate (β-TCP), amorphous calcium phosphate (ACP) and mixture thereof.

### Claim 3 (depends on 1)

The method according to claim 1 wherein the calcium sulfate based ceramic powder is selected from the group consisting of calcium sulfate dihydrate, calcium sulfate hemihydrate, and calcium sulfate anhydrate.

### Claim 4 (depends on 1)

The method according to claim 1 wherein oxide ceramic based powder is selected from the group consisting of alumina, zirconia and titania.

### Claim 5 (depends on 1)

The method according to claim 1 wherein the nitride based ceramic powder is selected from the group consisting of silicon nitride, titanium nitride and aluminum nitride.

### Claim 6 (depends on 1)

The method according to claim 1 wherein the carbide based ceramic powder is silicon carbide.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the temperature for heating the heat responsive mixture ranges from 55° C. to 100° C.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the temperature used in the second heating step is from 85° C. to 1500° C. and the heating can be completed with more than one stage.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the temperatures used in the second heating step are from 100° C. to 250° C., and then from 300° C. to 1300° C.

### Claim 10 (depends on 1)

The method according to claim 1, wherein the first heating step and the second heating step can be completed with more than one stage.

### Claim 11 (depends on 1)

The method according to claim 1, wherein the heating rate in the first heating step is 0.1 to 20° C./min.

### Claim 12 (depends on 1)

The method according to claim 1, the temperature-holding session is 1 to 8 hours.

### Claim 13 (depends on 1)

The method according to claim 1, wherein the bone substitute material has a macro-pore size range of 0.05 millimeter to 5 millimeter.

### Claim 14 (depends on 1)

The method according to claim 1, wherein the porosity of the bone substitute material is 50 to 95%.

### Claim 15 (depends on 1)

The method according to claim 1, which further comprises a step of attaching a polymer or a bioactive agent to the pores of the bone substitute material.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the agent is selected from the group consisting of demineralized bone matrix, growth factors, bone morphogenic proteins, antibiotic agents, vitamin, collagen, mesenchymal stem cells, antitumor agents, cellular attachment agents, immunosuppressant, clot activators and platelet-rich fibrin gel, and silk proteins.