Injectable bone-replacement mixture
An injectable mixture for substituting bone tissue in situ comprises: A) a two-component powder/liquid bone cement which upon mixing forms a self-hardening cement paste; and B) a third component consisting of a liquid which essentially is non-miscible with the cement paste and which is suitable to be washed out after hardening of said mixture in situ, resulting in a porous bone substituting material; and C) an X-ray contrast agent which is an organic substance. The injectable bone substitute material for bone augmentation has adaptable mechanical properties, an optimal radio-opacity without any inorganic X-ray contrast agent and therefore good biocompatibility.
1 . An injectable mixture for substituting bone tissue in situ, said mixture comprising:
(a) a two-component powder/liquid bone cement which upon mixing forms a self-hardening cement paste;
(b) a third component comprising a liquid which essentially is non-miscible with the cement paste and which is suitable to be washed out after hardening of said mixture in situ, resulting in a porous bone substituting material; and
(c) an X-ray contrast agent which is an organic substance.
2 . The injectable mixture of claim 1 , wherein the X-ray contrast agent is a liquid substance or a solid substance dissolved in a liquid solvent.
3 . The injectable mixture of claim 1 , wherein the X-ray contrast agent is based on iodine and is iopromidum, iopamidol, aminotrizoate acid, iotroxin acid, iopodin acid, iomeprol, iodamid, ioxithalamate, iothalamate, ioxaglin acid, or Lipiodol® (iodised ethyl ester of the fatty acids of poppy-seed oil).
4 . The injectable mixture of claim 3 , wherein the iodine-based X-ray contrast agent is used in an aqueous solution in a concentration of 30 to 80 weight %.
5 . The injectable mixture of claim 1 , wherein the injectable mixture comprises at least 5 weight % of said X-ray contrast agent.
6 . The injectable mixture of claim 1 , wherein the viscosity of said third component is less than 200,000 centipoise.
7 . The injectable mixture of claim 1 , wherein the viscosity of said third component is less than 100,000 centipoise.
8 . The injectable mixture of claim 1 , wherein the viscosity of said third component is between 1,000 and 100,000 centipoise.
9 . The injectable mixture of claim 1 , wherein the viscosity of the injectable mixture measured 4 minutes after mixing all of the components is in the range of 200,000 to 300,000 centipoise.
10 . The injectable mixture of claim 1 , wherein the two-component powder/liquid bone cement is based on a polyacrylic cement or a calcium phosphate cement.
11 . The injectable mixture of claim 1 , wherein the two-component powder/liquid bone cement is a powder/liquid system based on polymethylmethacrylate (PMMA) powder and monomethylmethacrylate (MMA) liquid with a polymerization catalyst and a polymerization accelerator.
12 . The injectable mixture of claim 1 , wherein the third component comprises water.
13 . The injectable mixture of claim 1 , wherein the third component comprises discrete particles of a water-soluble solid substance.
14 . The injectable mixture of claim 13 , wherein the water-soluble solid substance is gelatin or collagen.
15 . The injectable mixture of claim 13 , wherein the water-soluble solid substance is a polysaccharide.
16 . The injectable mixture of claim 15 , wherein the polysaccharide is chondroitin sulfate, carboxymethyl cellulose, hydroxyethylmethylcellulose, fucan, carregeenan, dextran, heparin, heparan sulfate, hydroxyethlycellulose (HEC), hydroxypropylmethyl cellulose, sodium alginate, chitosan or a hyaluronate.
17 . The injectable mixture of claim 1 , wherein the third component is an aqueous hyaluronate solution.
18 . The injectable mixture of claim 17 , wherein the aqueous hyaluronate solution has a concentration in the range of 0.1% to 5.0%.
19 . The injectable mixture of claim 17 , wherein the aqueous hyaluronate solution comprises hyaluronate having a molecular weight of at least 500,000 Daltons.
20 . The injectable mixture of claim 17 , wherein the aqueous hyaluronate solution comprises hyaluronate having a molecular weight of below 5,000,000 Daltons.
21 . The injectable mixture of claim 1 , wherein the third component is a hydrophobic liquid.
22 . The injectable mixture of claim 21 , wherein the hydrophobic liquid is ricinoleic acid (C 17 H 33 OCOOH), linoleic acid (C 17 H 31 COOH), palmitic acid (C 15 H 31 COOH), palmitoleic acid (C 15 H 29 COOH), stearic acid (C 17 H 35 COOH), linolenic acid (C 17 H 29 COOH), arachidic acid (C 19 H 39 COOH), myristic acid (C 13 H 27 COOH), lauric acid (C 11 H 23 COOH), capric acid (C 9 H 19 OH), caproic acid (C 5 H 11 COOH), oleic acid (C 17 H 33 COOH), caprylic acid (C 7 H 15 COOH), erucic acid (C 21 H 41 COOH), butyric acid (C 3 H 7 COOH), ethyl myristate (C 13 H 27 COOC 2 H 5 ), ethyl oleate (C 17 H 33 COOC 2 H 5 ), ethyl palmitate (C 15 H 31 COOC 2 H 5 ), ethyl linoleate (C 17 H 31 COOC 2 H 5 ), ethyl laurate (C 11 H 23 COOC 2 H 5 ), ethyl linolenate, (C 17 H 29 COOC 2 H 5 ), ethyl stearate (C 17 H 35 COOC 2 H 5 ), ethyl arachidate (C 19 H 39 COOC 2 H 5 ), ethyl caprilate (C 7 H 5 COOC 2 H 5 ), ethyl caprate (C 9 H 19 COOC 2 H 5 ), ethyl caproate (C 5 H 11 COOC 2 H 5 ), ethyl butyrate (C 3 H 7 COOC 2 H 5 ), triacetin (C 9 H 14 O 6 ), alpha tocopherol (C 29 H 5 OO 2 ), beta tocopherol (C 28 H 48 O 2 ), delta tocopherol (C 27 H 46 O 2 ), gamma tocopherol (C 28 H 48 O 2 ), benzyl alcohol (C 7 H 80 ), benzyl benzoate (C 14 H 12 O 2 ), methylphenol (C 7 H 80 ), di-n-butyl sebacate (C 18 H 34 O 4 ), diethylphthalate (C 12 H 14 O 4 ), glyceryl monooleate (C 21 H 40 O 4 ), lecithin, medium chain triglycerides, mineral oil, petrolatum, or liquid paraffines.
23 . The injectable mixture of claim 1 , wherein the mixture is divided into a powder component and a liquid component, whereby
(a) said powder component of the mixture comprises the powder component of said two-component bone cement and a polysaccharide in powder form; and
(b) said liquid component of the mixture comprises the liquid component of said two-component bone cement and an aqueous solution of said X-ray contrast agent.
24 . The injectable mixture of claim 1 , wherein the third component is a freshly mixed calcium phosphate cement paste.
25 . The injectable mixture of claim 1 , wherein the size of all powder particles of the mixture are smaller than 300 micrometers.
26 . The injectable mixture of claim 1 , wherein the size of at least 80% of all powder particles is in the range of 50 to 300 micrometers.
27 . The injectable mixture of claim 1 which hardens within 7 to 10 minutes after mixing of its components.
28 . The injectable mixture of claim 1 which has a Young's modulus of elasticity in the range of 10 to 2800 MPa.
29 . The injectable mixture of claim 1 , wherein the third component further comprises an osteoinductive substance.
30 . The injectable mixture of claim 29 , wherein the osteoinductive substance is
(a) bone morphogenetic proteins, preferably BMP2, BMP4 or BMP7;
(b) TGFb-3 (transforming growth factor) or IGF-1 (insulin-like growth factor);
(c) plateled-derived growth factor (PDGF);
(d) parathyroid hormone (PHT) and parathyroid hormone-related protein (PTHrP);
(e) sexual hormones, in particular estrogen; or
(f) prostaglandin.
31 . The injectable mixture of claim 1 , wherein the third component further comprises an antiresorptive substance.
32 . The injectable mixture of claim 31 , wherein the antiresorptive substance is a bisphosphonate.
33 . The injectable mixture of claim 1 , further comprising an anabolic substance, a parathyroid hormone (PTH) or an estrogene.
34 . The injectable mixture of claim 1 , further comprising a hydrogen pump inhibitor.
35 . A method for preparing the injectable mixture of claim 1 , comprising the following steps:
(a) mixing the power and liquid components to obtain a bone cement mixture; and subsequently
(b) dispersing the bone cement mixture in the third component.
36 . A method for preparing the injectable mixture of claim 1 , comprising the following steps:
(a) mixing the powder and liquid components to obtain a bone cement mixture; and subsequently
(b) dispersing the third component in the bone cement mixture.
37 . A method for preparing the injectable mixture of claim 1 , comprising the following steps:
(a) mixing separately a two-component powder/liquid bone cement;
(b) mixing separately a two-component calcium phosphate cement to form the third component;
(c) adding the separately mixed and still pasty two-component calcium phosphate cement to said separately mixed and still pasty two-component bone cement.
38 . The method of claim 36 , wherein the third component is dispersed into the two-component bone cement in such a way that the mean diameter of droplets of the third component dispersed in the two-component bone cement is less than 1 mm.
39 . The method of claim 37 , further comprising dispersing the third component into the two-component bone cement in such a way that the mean diameter of droplets of the third component dispersed in the two-component bone cement is less than 1 mm.