# US 2014/0194363 A1 · Compression-resistant collagen-based artificial bone repair material

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- Number: US 2014/0194363 A1
- Document ID: US20140194363A1
- Status: Published application
- Kind: A1
- Application number: 13/736,371
- Filed: 2013-01-08
- Published: 2014-07-10
- Earliest claimed: 2013-01-08
- Assignees: Beijing Allgens Medical and Technology Co, Ltd
- Inventors: Eric Gang Hu
- Web page: https://patentgrep.com/patent/US20140194363A1

## CPC

- A61K 38/39: Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
- A61K 33/06: Aluminium, calcium or magnesium; Compounds thereof {, e.g. clay}
- A61K 33/42: Phosphorus; Compounds thereof
- A61L 27/46: with phosphorus-containing inorganic fillers
- A61L 27/50: Materials characterised by their function or physical properties {, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials}
- A61L 2400/12: Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
- 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)

## Abstract

The present invention provides a compression-resistant collagen-based artificial bone repair material that could be used for bone defect repair at human load-bearing sites. Such material has a composition and structure of self-assembled nano-sized calcium phosphate salt and collagen molecules, thereby possessing a biomimetic mineralization structure similar to the natural bone. On the aspect of mechanical properties, such material has a similar mechanical strength to human cortical bone, which makes it suitable for repairing bone defects at human load-bearing sites. The present invention further provides preparation methods of such Compression-resistant collagen-based artificial bone repair material.

## Claims

### Claim 1

A compression-resistant collagen-based artificial bone repair material, characterized in that the material is a dense and homogeneous organic/inorganic composite material, wherein,
the organic phase contains collagen,
the inorganic phase contains nano-sized calcium phosphate salt, and
the weight ratio of the organic phase to the inorganic phase is 9/1˜4/6.

### Claim 2 (depends on 1)

A compression-resistant collagen-based artificial bone repair material according to claim 1, characterized in that the organic phase of the material further contains polyester, said polyester is one or more of poly (lactic acid), poly (glycolic acid), poly (lactic-co-glycolic acid), polycaprolactone and polydioxanone, the weight ratio of the organic phase to the inorganic phase is 9/1˜4/6, and the weight ratio of collagen to polyester is 9/1˜1/9.

### Claim 3 (depends on 1, 2)

A compression-resistant collagen-based artificial bone repair material according to claim 1 or 2, characterized in that the material possesses a compressive strength of 65˜150 MPa and a bending strength of 20˜100 MPa.

### Claim 4 (depends on 1, 2)

A compression-resistant collagen-based artificial bone repair material according to claim 1 or 2, characterized in that said nano-sized calcium phosphate salt possesses a particle size of 20˜200 nm, and a molar ratio of Ca/P=1/1˜2/1.

### Claim 5 (depends on 1, 2)

A compression-resistant collagen-based artificial bone repair material according to claim 1 or 2, characterized in that said nano-sized calcium phosphate salt is nano-sized hydroxyapatite with particle size of 20˜200 nm.

### Claim 6 (depends on 2)

A compression-resistant collagen-based artificial bone repair material according to claim 2, characterized in that said polyester possesses a molecular weight of 50,000˜500,000.

### Claim 7 (depends on 1)

A method for preparing compression-resistant collagen-based artificial bone repair material according to claim 1, characterized in that the method comprises following steps:
Step S1. Preparation of nano-Ca-P/collagen biomimetic composite powders, further comprising:
Step S1-1. Dissolve collagen in any one of hydrochloric acid, nitric acid or acetic acid to form an acidic collagen solution, wherein, the concentration of the collagen is 5.0×10−5˜5.0×10−3 g/mL;
Step S1-2. Keep stiffing the solution obtained by step S1-1 and add Ca2+ containing solution dropwise, wherein, the addition of Ca2+ is 0.01˜0.16 mol for 1 g of collagen;
Step S1-3. Keep stiffing the solution obtained by step S1-2 and add PO43− containing solution dropwise, wherein, the molar ratio of the added PO43− and the added Ca2+ in S1-2 is Ca/P=1/1˜2/1;
Step S1-4. Keep stirring the solution obtained by step S1-3 and add NaOH solution until the pH of the mixture system gets to 6˜8, wherein, precipitation appears when the pH of the mixture system gets to 5˜6, and white suspension will be obtained when the pH gets to 7;
Step S1-5. Stand the mixture system obtained by step S1-4 for 24˜120 hours, and then separate out the precipitation and wash it to remove impurity ions, followed by a freeze-drying, the composite powders will be obtained after gridding;
Step S2. Cold compression molding of the composite, further comprising:
Step S2-1. Weigh the composite powders obtained by step S1-5 and fill the powders into a cold compression dies;
Step S2-2. Compress the dies and make the pressure applied to the composite powders reaches 200˜1400 MPa;
Step S2-3. Keep the pressure for 30˜300 seconds, and then demould to obtain the Compression-resistant collagen-based artificial bone repair material.

### Claim 8 (depends on 2)

A method for preparing Compression-resistant collagen-based artificial bone repair material according to claim 2, characterized in that the method comprises following steps:
Step S1. Preparation of nano-Ca-P/collagen biomimetic composite powders, further comprising:
Step S1-1. Dissolve collagen in any one of hydrochloric acid, nitric acid or acetic acid to form an acidic collagen solution, wherein, the concentration of the collagen is 5.0×10−5˜5.0×10−3 g/mL;
Step S1-2. Keep stiffing the solution obtained by step S1-1 and add Ca2+ containing solution dropwise, wherein, the addition of Ca2+ is 0.01˜0.16 mol for 1 g of collagen;
Step S1-3. Keep stiffing the solution obtained by step S1-2 and add PO43− containing solution dropwise, wherein, the molar ratio of the added PO43− and the added Ca2+ in S1-2 is Ca/P=1/1˜2/1;
Step S1-4. Keep stirring the solution obtained by step S1-3 and add NaOH solution until the pH of the mixture system gets to 6˜8, wherein, precipitation appears when the pH of the mixture system gets to 5˜6, and white suspension will be obtained when the pH gets to 7;
Step S1-5. Stand the mixture system obtained by step S1-4 for 24˜120 hours, and then separate out the precipitation and wash it to remove impurity ions, followed by a freeze-drying, the composite powders will be obtained after gridding;
Step S2. Preparation of collagen/nano-Ca-P/polyester composite, further comprising:
Step S2-1. Preparation polyester solution with a concentration of 0.02˜0.15 g/mL by dissolving polyester with molecular weight of 50,000˜200,000 into any one of 1,4-dioxane, dichloromethane, chloroform or dimethyl sulfoxide at 40˜70° C., said polyester is one or more of poly (lactic acid), poly (glycolic acid), poly (lactic-co-glycolic acid), polycaprolactone and polydioxanone;
Step S2-2. Add the composite powders obtained by step S1-5 into the polyester solution obtained by step S2-1 to form a collagen/nano-Ca-P/polyester mixture suspension system, wherein, the weight ratio of the composite powders to the polyester within the polyester solution is 1/2˜3/2;
Step S2-3. Put the mixture suspension system obtained by step S2-2 into an environment of −20˜4° C. to thoroughly freeze, and then freeze-dry for 24˜72 hours, followed by transferring to a vacuum drying oven to dry for 72˜120 hours, thus obtaining a collagen/nano-Ca-P/polyester composite;
Step S2-4. Smash the composite obtained by step S2-3 and sieve to screen out composite powders with particle size of 100˜600 μm;
Step S3. Cold compression molding of the composite, further comprising:
Step S3-1. Weigh the composite powders obtained by step S2-4 and fill the powders into a cold compression dies;
Step S3-2. Compress the dies and make the pressure applied to the composite powders reaches 200˜1400 MPa;
Step S3-3. Keep the pressure for 30˜300 seconds, and then demould to obtain the Compression-resistant collagen-based artificial bone repair material.

### Claim 9 (depends on 8)

A method for preparing compression-resistant collagen-based artificial bone repair material according to claim 8, characterized in that in step S2-3, put the mixture suspension system obtained by step S2-2 into an environment of −20˜4° C. to thoroughly freeze, and then into liquid nitrogen to deep freeze, followed by freeze-dry for 24˜72 hours and vacuum dry for 72˜120 hours, thus obtaining said collagen/nano-Ca-P/polyester composite.

### Claim 10

A compression-resistant collagen-based artificial bone repair material, characterized in that the material is a dense-porous bi-layer organic/inorganic composite, wherein,
said organic phase contains both collagen and polyester, said polyester is one or more of poly (lactic acid), poly (glycolic acid), poly (lactic-co-glycolic acid), polycaprolactone and polydioxanone,
the inorganic phase contains nano-sized calcium phosphate salt,
the weight ratio of the organic phase to the inorganic phase is 9/1˜2/8, and
the weight ratio of collagen to poly (lactic acid) is 9/1˜1/9;
said bi-layer structure contains:
a dense layer as the lower layer, with a thickness of 0.5˜5 mm, a compressive strength of 65˜150 MPa and a bending strength of 20˜100 MPa, and
a porous layer as the upper layer, with a thickness of 0.5˜5 mm and a porosity of 50%˜80%.

### Claim 11 (depends on 9)

A compression-resistant collagen-based artificial bone repair material according to claim 9, characterized in that said nano-sized calcium phosphate salt possesses a particle size of 20˜200 nm, and a molar ratio of Ca/P=1/1˜2/1.

### Claim 12 (depends on 9)

A compression-resistant collagen-based artificial bone repair material according to claim 9, characterized in that said nano-sized calcium phosphate salt is nano-sized hydroxyapatite with particle size of 20˜200 nm.

### Claim 13 (depends on 9)

A compression-resistant collagen-based artificial bone repair material according to claim 9, characterized in that said polyester possesses a molecular weight of 50,000˜500,000.

### Claim 14 (depends on 10, 11, 12, 13)

A method for preparing compression-resistant collagen-based artificial bone repair material according to any one of claims 10-13, the method comprises following steps:
Step S1. Preparation of nano-Ca-P/collagen biomimetic composite powders, further comprising:
Step S1-1. Dissolve collagen in any one of hydrochloric acid, nitric acid or acetic acid to form an acidic collagen solution, wherein, the concentration of the collagen is 5.0×10−5˜5.0×10−3 g/mL;
Step S1-2. Keep stiffing the solution obtained by step S1-1 and add Ca2+ containing solution dropwise, wherein, the addition of Ca2+ is 0.01˜0.16 mol for 1 g of collagen;
Step S1-3. Keep stiffing the solution obtained by step S1-2 and add PO43− containing solution dropwise, wherein, the molar ratio of the added PO43− and the added Ca2+ in S1-2 is Ca/P=1/1˜2/1;
Step S1-4. Keep stirring the solution obtained by step S1-3 and add NaOH solution until the pH of the mixture system gets to 6˜8, wherein, precipitation appears when the pH of the mixture system gets to 5˜6, and white suspension will be obtained when the pH gets to 7;
Step S1-5. Stand the mixture system obtained by step S1-4 for 24˜120 hours, and then separate out the precipitation and wash it to remove impurity ions, followed by a freeze-drying, the composite powders will be obtained after gridding;
Step S2. Preparation of collagen/nano-Ca-P/polyester composite, further comprising:
Step S2-1. Preparation polyester solution with a concentration of 0.02˜0.15 g/mL by dissolving polyester with molecular weight of 50,000˜200,000 into any one of 1,4-dioxane, dichloromethane, chloroform or dimethyl sulfoxide at 40˜70° C., said polyester is one or more of poly (lactic acid), poly (glycolic acid), poly (lactic-co-glycolic acid), polycaprolactone and polydioxanone;
Step S2-2. Add the composite powders obtained by step S1-5 into the polyester solution obtained by step S2-1 to form a collagen/nano-Ca-P/polyester mixture suspension system, wherein, the weight ratio of the composite powders to the polyester within the polyester solution is 1/2˜3/2;
Step S2-3. Put the mixture suspension system obtained by step S2-2 into an environment of −20˜4° C. to thoroughly freeze, and then freeze-dry for 24˜72 hours, followed by transferring to a vacuum drying oven to dry for 72˜120 hours, thus obtaining a collagen/nano-Ca-P/polyester composite;
Step S2-4. Smash the composite obtained by step S2-3 and sieve to screen out composite powders with particle size of 100˜600 μm;
Step S3. Cold compression molding of the composite, further comprising:
Step S3-1. Weigh the composite powders obtained by step S2-4 and fill the powders into a cold compression dies;
Step S3-2. Compress the dies and make the pressure applied to the composite powders reaches 200˜1400 MPa;
Step S3-3. Keep the pressure for 30˜300 seconds, and then demould to obtain said dense layer;
Step S4. Fabrication of porous layer on the dense layer, further comprising:
Step S4-1. Use the dense layer obtained by step S3-3 as the substrate, and repeat steps S1-1˜S2-2 to cover a collagen/nano-Ca-P/polyester mixture suspension obtained by step S2-2 on such substrate, then standing for 2˜15 min, meanwhile slight solvation occurs on the substrate upper surface;
Step S4-2. Put the dense and the covered mixture suspension obtained by step S4-1 into a low-temperature environment of −20˜−10° C. to achieve quick-freezing, freeze-dry them for 24˜72 hours, and then transfer to a vacuum drying oven to dry for 72˜120 hours, thus finally obtain said dense-porous bi-layer Compression-resistant collagen-based artificial bone repair material.

### Claim 15 (depends on 14)

A method for preparing compression-resistant collagen-based artificial bone repair material according to claim 14, characterized in that in step S2-3, put the mixture suspension system obtained by step S2-2 into an environment of −20˜4° C. to thoroughly freeze, and then into liquid nitrogen to deep freeze, followed by freeze-dry for 24˜72 hours and vacuum dry for 72˜120 hours, thus obtaining said collagen/nano-Ca-P/polyester composite.