GB2395713A - A synthetic bone material - Google Patents

A synthetic bone material Download PDF

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Publication number
GB2395713A
GB2395713A GB0226469A GB0226469A GB2395713A GB 2395713 A GB2395713 A GB 2395713A GB 0226469 A GB0226469 A GB 0226469A GB 0226469 A GB0226469 A GB 0226469A GB 2395713 A GB2395713 A GB 2395713A
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Prior art keywords
silicon
process
synthetic
calcium
bone
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GB0226469D0 (en
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William Bonfield
Serena Best
Mamoru Aizawa
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Cambridge University Technical Services Ltd (CUTS)
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Cambridge University Technical Services Ltd (CUTS)
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02Inorganic materials
    • A61L27/12Phosphorus-containing materials, e.g. apatite
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/02Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
    • CCHEMISTRY; METALLURGY
    • C30CRYSTAL GROWTH
    • C30BSINGLE-CRYSTAL-GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
    • C30B29/00Single crystals or homogeneous polycrystalline material with defined structure characterised by the material or by their shape
    • C30B29/10Inorganic compounds or compositions
    • C30B29/14Phosphates
    • CCHEMISTRY; METALLURGY
    • C30CRYSTAL GROWTH
    • C30BSINGLE-CRYSTAL-GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
    • C30B7/00Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2430/00Materials or treatment for tissue regeneration
    • A61L2430/02Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Abstract

A synthetic silicon-containing apatite single crystal, for example a silicon-substituted apatite single crystal. The single crystal may be in the form of a fibre having a long-axis length in excess of 5 žm. The single crysal may be used in a synthetic bone material.

Description

- 1 - A synthetic bone material The present invention relates to the field

of

synthetic bone materials for biomedical applications 5 and, in particular, to silicon-substituted apatite and hydroxyapatite single crystal fibers and a process for their preparation.

The apatite group of minerals are based on 10 calcium phosphate, with naturally occurring apatite having a molar ratio of approximately Ca/P of 1.67.

Hydroxyapatite, which has the chemical formula CalO (P04) 6 (OH) 2, iS a biomedical ceramic which resembles 15 the mineral component of bone. This similarity has led to the development of the material for biomedical applications, and hydroxyapatite and hydroxyapatite-

glass composites have been used as skeletal reconstitution materials.

It has been observed that bone will bond directly to hydroxyapatite in the human body (a property referred to as bioactivity) through a bone- like apatite layer formed in the body environment.

Although the composition of synthetic hydroxyapatite is similar to the mineral component of bone, there are a number of distinct differences between the two materials in terms of their trace 30 element content. In this regard, it is known that the bioactivity of hydroxyapatite can be enhanced by the substitution of suitable elements into the crystal lattice. For example, substitution of low levels of silicon into the lattice has been found to improve the

rate at which bone bonding occurs with implant materials. PCT/GB97/02325 describes a process for the 5 preparation of an essentially phase pure silicon-

substituted hydroxyapatite material.

JP 2691593 and JP 2849686 describe carbonate-

containing hydroxyapatite fibers and a process for 10 their preparation. The synthesis process relies on homogeneous precipitation under either normal or hydrothermal conditions.

In an alternative process described in Nihon 15 kagaku-kaishi, 1988, 1565 (1988), hydroxyapatite whiskers are synthesized from a calcium phosphate slurry by a hydrothermal crystallization method. The whiskers produced by this process have a long-axis dimension of less than 5 m.

In another alternative process described in JP 57-117621, JP 61-75817 and JP 61-106166, apatite-like fibers are prepared by spinning melts/slurry using a nozzle. The apatite-like fibers produced by this 25 process are polycrystalline and have inferior mechanical properties compared with single crystal fibers. In a first aspect, the present invention provides 30 a synthetic silicon-containing apatite single crystal.

Apatite as used herein means one of the apatite group of minerals, for example hydroxyapatite. Thus, the present invention is intended to encompass a silicon-

containing hyroxyapatite single crystal.

- 3 - Advantageously, at least some of the silicon in the single crystal is substituted therein. Thus, the present invention also provides a synthetic silicon-

substituted apatite single crystal.

By the term silicon-substituted is meant that silicon is substituted into the apatite crystal lattice, rather than being added interstitially into the crystal structure. It is believed that silicon 10 substitutes on or primarily on the phosphate site.

The silicon is thought to exist and/or substitute in the crystal lattice as a silicon ion or as a silicate Ion. 15 The single crystal will typically be in the form of a fibre, which preferably has a long-axis length of > 5 um, more preferably > 7,um, still more preferably 10 um. Advantageously, the long-axis length is in the range of from 5 to 500 um, typically from 10 to 20 300 Am, more typically from 20 to 200 um. The single crystal typically has a short-axis length of < 5 m, more typically from 0.1 to 5 Em, still more typically from 0.5 to 3,um.

25 The aspect ratio of the fibre will typically be from 1 to 5000, more typically from 3 to 600.

With regard to the crystallographic growth direction, the fibre has a preferred orientation to 30 the c-axis direction and develops the a-plane in the apatite hexagonal crystal structure.

The term fibre as used herein is intended to encompass any needle-like, thread-like, filament-like

4 - or acicular three dimensional form of crystal.

The synthetic silicon-containing apatite single crystal will typically comprise up to 5% by weight of 5 silicon, more typically up to 3% by weight. The single crystal will generally comprise at least 0.1 % by weight of silicon. Advantageously, the single crystal comprises from 0.4 to 2.4 % by weight of silicon, more preferably from 0.5 to 1.6%, still more 10 preferably from 0.5 to 1%.

The Ca:(P+Si) molar ratio in the single crystal is preferably from 1:1.4 to 1:2, more preferably from 1:1.6 to 1:1.8, still more preferably from 1:1.65 to 15 1:1.75. The most preferred molar ratio is approximately 1:1. 67.

The synthetic silicon-containing apatite single crystal may be phase pure (or at least essentially 20 phase-pure), containing substantially no other calcium phosphate forms or phases, such as octacalcium phosphate, calcium hydrogen phosphate, calcium oxide, tricalcium phosphate and tetracalcium phosphate.

Thus, the present invention also provides a single 25 phase (or essentially single phase) silicon-containing apatite single crystal. In this connection, the phase purity, as measured by x-ray diffraction, may be at least 98%, preferably at least 99%, more preferably approximately 100%.

The silicon-containing apatite single crystal as herein described may, however, contain carbonate ions depending on the method of synthesis. At least some of the carbonate ions (CO32-) are believed to

- 5 - substitute in the PO4 and/or OH sites in the crystal lattice. The present invention also provides a synthetic 5 bone material (which term is intended to encompass dental materials) comprising one or more synthetic silicon-containing apatite single crystal(s) as herein described. 10 The present invention also provides a composition which comprises a synthetic bone material as herein described, together with a pharmaceutically acceptable carrier. 15 The present invention also provides a bone implant, bone graft, bone scaffold, hydroxyapatite polymer composite material, filler, coating (for a metallic implant for example) or cement which comprises a synthetic bone material as herein 20 described or a composition as herein described. The bone implant, graft, scaffold, composite material, filler, coating or cement may be porous.

The present invention also provides a synthetic 25 bone material, bone implant, bone graft, bone scaffold, hydroxyapatite-polymer composite material, filler or cement comprising a plurality of synthetic siliconcontaining apatite single crystals as herein described in a biocompatible matrix (for example a 30 polymer matrix such as PLLA, PGA or copolymer thereof). In this case, at least some of said single crystals are aligned in said matrix in substantially the same direction.

- 6 - The present invention also provides for the use of synthetic silicon-containing apatite single crystals as herein described as a fibre reinforcement in a synthetic bone material, bone implant, bone 5 graft, bone scaffold, hydroxyapatite-polymer composite material, filler or cement.

In a further aspect, the present invention provides a process for the preparation of silicon 10 containing apatite single crystals as herein described, which process comprises: (i) reacting a calcium source with a phosphorus source to form a precipitate comprising octacalcium phosphate and/or calcium hydrogen phosphate; and 15 (ii) heating said precipitate in the presence of a silicon source to form one or more silicon- containing apatite single crystals.

The single crystals produced by this process are 20 advantageously in the form of fibers, which preferably have a long-axis length in excess of 5 um, more preferably in excess of 10 Am. For example, the average longaxis length may be in the range of from 20 to 200 um. In this case, the precipitate formed in 25 step (i) will also typically be in the form of single crystal fibers, which preferably have a long-axis length in excess of 5 m, more preferably in excess of 10 Em. The average long-axis length of the precipitate fibers will typically be in the range of 30 from 100 to 300 m.

The calcium source preferably comprises a calcium salt and may be selected, for example, from one or more of calcium nitrate, a calcium carboxylate (for

- 7 example calcium acetate), a calcium halide (for example calcium chloride), and a calcium alkoxide.

The phosphorus source preferably comprises 5 phosphoric acid or a salt thereof and may be selected, for example, from one or more of ammoniumdihydrogen phosphate, diammonium hydrogen phosphate, phosphoric acid and an organic phosphate such as trimethyl phosphate. The silicon source preferably comprises a silicate and may be selected, for example, from one or more of a silicon carboxylate (for example silicon acetate), a silicon halide (for example silicon 15 chloride), tetraethyl orthosilicate and tetramethyl orthosilicate. Step (i) of the process typically involves forming a solution comprising the calcium source and 20 the phosphorus source. The solution may also comprise the silicon source. In this case, the silicon source is present in both steps (i) and (ii).

The solution will typically comprise a polar 25 solvent, for example water.

Advantageously, the solution further comprises a pH regulator, for example urea.

30Advantageously, the solution further comprises an acid, for example nitric acid or hydrochloric acid.

A preferred solution comprises water, calcium nitrate, diammonium hydrogen phosphate, tetraethyl

8 - orthosilicate (TEOS), urea and nitric acid.

The reaction to form the precipitate in step (i) is preferably carried out at a temperature T1, where 5 T1 is in the range of from 50 to 90 C, preferably from 70 to 90 C, more preferably from 75 to 85 C, still more preferably approximately 80 C. Heating in step (ii) is preferably carried out at a temperature T2, where T2 > T1. T2 will typically be in the range of 10 from 90 to 150 C, preferably from 95 to 130 C.

The concentration of calcium ions is preferably from 0.0167 to 1.67 moldm3, more preferably 0.08 to 0.25 moldm3, still more preferably approximately 15 0.167 moldm3.

The concentration of phosphorous-containing ions is preferably from 0.01 to 1.00 moldm3, more preferably 0.05 to 0.14 moldm3, still more preferably 20 approximately 0.09547 moldm3.

The Ca/P molar ratio is preferably from 1:1.4 to 1:2, more preferably from 1:1.6 to 1:1.8, still more preferably from 1:1.65 to 1:1.75.

Similarly, the Ca/(P+Si) molar ratio is preferably from 1:1.4 to 1:2, more preferably from 1:1.6 to 1:1.8, still more preferably from 1:1.65 to 1:1.75. The most preferred molar ratio is 30 approximately 1:1.67.

The pH of the reaction mixture during heating (step (ii)) is preferably maintained substantially at a pH of from 7 to 10, although the pH of the starting

9 - solution prior to heating is typically from 1 to 3.

The single crystals produced by the process according to the present invention are preferably free 5 or essentially free of any of the (precursor) precipitate material. The single crystals may be phase pure, or at least essentially phase pure.

The process is preferably a homogeneous 10 precipitation process, which may be conducted under hydrothermal conditions if desired. The process involves forming a precursor precipitate for the silicon-containing apatite single crystals. The precipitate is believed to comprise octacalcium 15 phosphate. The precipitate may be formed by heating the starting solution at a temperature typically in the range of from 70 to 90 C for from 12 to 24 h. In the early stages of heating, after typically about 2 h, a white compound is formed on the walls of the 20 glass reaction flask. This compound is believed to be calcium hydrogen phosphate (CaHPO4). Nucleation is believed to occur on the surface of the calcium hydrogen phosphate and octacalcium phosphate (CaH2(PO4)6.xH2O) single crystal fibers grow with an 25 average long-axis size of typically 100 to 300,um (after 24 h heating). Thus, the (precursor) crystal fibers are formed by a process of nucleation and growth. A pH regulator is preferably present (for example urea) to control the pH in the reaction 30 system. The resulting octacalcium phosphate crystal fibers are transformed into silicon-containing apatite crystal fibers in a further heating step in the presence of the silicon source. Under normal conditions (i.e. non-hydrothermal conditions), the

- 10 further heating step is preferably conducted at a temperature of from 90 to 98 C, typically for from 96 to 290 h. Under hydrothermal conditions, the further heating step is preferably conducted at a temperature 5 of from 100 to 150 C, typically for from 6 to 48 h. During the further heating step, the long-axis dimension of the octacalcium phosphate fibers tends to decrease. The hydrothermal treatment is typically performed at a pressure of from 2 to 4 bar, more 10 typically from 2.5 to 3.5 bar. The Si content in the final fibers will typically be up to 3 weight % (up to 5 weight % in the case of the hydrothermal treatment) and may be controlled by adjusting the concentration of silicate.

In a further aspect, the present invention provides a process for the preparation of silicon containing apatite single crystals as herein described, which process comprises heating a 20 precipitate comprising octacalcium phosphate and/or calcium hydrogen phosphate in the presence of a silicon source to form one or more silicon-containing apatite single crystals.

25 As will be appreciated, the features described herein in relation to the first mentioned process are applicable either singularly or in combination to this further aspect of the present invention.

30 In a yet a further aspect, the present invention provides a process for the preparation of silicon containing apatite single crystals as herein described, which process comprises: (a) providing a solution comprising a calcium source

selected from one or more of calcium nitrate, calcium acetate and calcium chloride, a phosphorus source selected from one or more of ammoniumdihydrogen phosphate, diammonium hydrogen phosphate and 5 phosphoric acid, and a silicon source selected from one or more of a silicon carboxylate, silicon chloride, tetraethyl orthosilicate and tetramethyl orthosilicate, wherein the concentration of calcium ions is from 0.0167 to 1.67 moldm3, the concentration 10 of phosphorous-containing ions is from 0.01 to 1.00 moldm3, and the Ca/(P+Si) molar ratio is from 1:1.6 to 1:1.8; and (b) heating the solution at a temperature in the range of from 50 to 90 C to form a precursor 15 precipitate comprising calcium and phosphorous, followed by further heating at a temperature in the range of from 90 to 150 C to form one or more silicon containing apatite single crystals.

20 Again, the features described herein in relation to the first mentioned process are applicable either singularly or in combination to this further aspect of the present invention.

25 As will be appreciated, the thus produced single crystals may be heated to effect drying, calcination and/or wintering.

As will also be appreciated, the processes may 30 further comprise collecting the silicon-containing apatite single crystals and forming a synthetic bone material, bone implant, bone graft, bone scaffold, hydroxyapatite-polymer composite, filler or cement comprising a plurality of the single crystals, for

12 example at least 5 to 10 crystals. This may involve aligning at least some of the crystals in substantially the same direction. The single crystals may be intertwined and a woven-like material may also 5 be formed from the single crystals. A sinter step may be performed after forming the desired product.

A preferred process for producing silicon containing apatite single crystals fibers according to 10 the present invention will now be described further by way of example.

The process generally relies on homogeneous precipitation (in an aqueous medium) of a precursor 15 precipitate, which is subsequently transformed into the desired silicon-containing apatite single crystal.

The homogeneous precipitation may be carried out under normal conditions or under hydrothermal conditions.

20 Homogeneous Precipitation Single crystal fibers may produced by: 1) forming a starting solution; 2) carrying out a first heating step to precipitate a precursor (for example 25 octacalcium phosphate, ca6H2(po4) 65H2O) of the silicon substituted hydroxyapatite; and 3) carrying out a second heating step for conversion of the precursor precipitate into the silicon-containing apatite single crystal fibre.

The starting solution may be prepared using a calcium salt, a phosphate, a silicate, a pH regulator (for example urea, (NH2)2CO) and an acid (for example nitric acid, HNO3). The calcium salt may be selected

from calcium nitrate tetrahydrate (Ca(NO3)24H2O), calcium acetate (Ca(CH3COO) 2) and calcium chloride (CaCl2), including mixtures of two or more thereof.

The preferred calcium salt is calcium nitrate 5 tetrahydrate. The phosphate may be selected from ammonium dihydrogen phosphate (NH4H2PO4), diammonium hydrogen phosphate ((NH4)2HPO4) and phosphoric acid (H3PO4), including mixtures of two or more thereof.

The preferred phosphate is diammonium hydrogen ! To phosphate. The silicate may be selected from both inorganic and organic silicon compounds, for example, silicon acetate (Si(CH3COO)4), silicon chloride (SiCl4), tetraethyl orthosilicate (TEDS) (Si(OC2Hs)4) and tetramethyl orthosilicate (TMOS) (Si(OCH3)), 15 including mixtures of two or more thereof. The preferred silicate is TEOS owing to its hydrolysis reaction rate.

The concentrations of Ca2+ and PO43 ions in the 20 starting solution are preferably in the ranges of from 0.0167 to 1.67 moldm3 and 0.01 to 1.00 moldm3, respectively. The Ca/(P+Si) molar ratio is preferably fixed at approximately 1.67. The concentration of urea is preferably from 0.05 to 5.00 moldm3. The 25 most preferred concentrations in the starting solution are approximately: 0.167 moldm3 Ca2+ ions, 0.09547 moldm3 PO43 ions, 4.57 x 10-3 moldm3 of SiO44- ions and 0.50 moldm3 of urea (in the case of the addition of 0.8 weight % Si as a nominal composition).

The process involves forming a precursor precipitate for the siliconcontaining apatite fiber.

The precipitate is believed to comprise or consist of octacalcium phosphate. The precipitate is formed by

- 14 heating the starting solution at a temperature typically in the range of from 70 to 90 C for from 12 to 24 h. The preferred heating conditions are approximately 80 C for 24 h. In the early stages of 5 heating (after about 2 h), a white compound is formed on the wall of the glass reaction flask. On the basis of XRD analysis, this compound is believed to be calcium hydrogen phosphate (CaHPO4). Nucleation is believed to occur on the surface of the calcium 10 hydrogen phosphate and octacalcium phosphate single crystal fibers grow with a long-axis size of typically 100 to 300,um (after 24 h heating). Thus, the crystal fibers are formed by process of nucleation and growth.

The urea in the starting solution controls the pH in 15 the reaction system.

The resulting octacalcium phosphate crystal fibers are transformed into silicon-containing apatite single crystal fibers by heating at a temperature in 20 the range of from 90 to 98 C for from 96 h to 240 h in the presence of the silicon source (which has always been in solution). The preferred heating conditions are approximately 95 C for 144 h. The long-axis dimension of the fibre will generally decrease during 25 the second heating stage and so the resulting single crystal fibers typically have an average long-axis dimension of 30 to 200,um.

The Si content in the final single crystal fibers 30 will typically be up to 3 weight % and may be controlled by adjusting the concentration of silicate.

However, the actual Si content in the final product tends to be lower than the nominal composition of starting solution.

- 15 Homoqeneous Precipitation Under Hydrothermal Conditions 5 The octacalcium phosphate fibers prepared in the manner described above are hydrothermally transformed into silicon-containing apatite fibers by heating at a temperature in the range of from 100 to 150 C for from 6 to 48 h in the presence of the silicon source (which 10 has always been in solution). The preferred heating conditions are approximately 120 C for 24 h. The long-axis dimension of the fibers tend to decrease during the hydrothermal treatment and so the resulting silicon-containing apatite single crystal fibers have 15 a long-axis dimension of typically 10 to 200 um. The Si content in the final single crystal fibers will typically be up to 5 weight % and may be controlled by adjusting the concentration of silicate. The hydrothermal treatment is preferably performed at a 20 pressure of from 2 to 4 bar, more preferably from 2.5 to 3.5 bar, still more preferably approximately 3 bar.

The present invention will now be described further, by way of example, with reference to the 25 following drawings in which: Figure 1 shows XRD patterns of silicon-containing hydroxyapatite single crystal fibers synthesized by a homogeneous precipitation method according to the 30 present invention ((a) Run #6 and (b) Run #8); Figure 2 shows IR spectra of silicon-containing hydroxyapatite single crystal fibers synthesized by a

- 16 homogeneous precipitation method according to the present invention ((a) Run #6 and (b) Run #8)i Figure 3 shows SEM micrographs of silicon 5 containing hydroxyapatite single crystal fibers synthesized by a homogeneous precipitation method according to the present invention ((a) Run #6 and (b) Run #8)i 10 Figure 4 shows XRD patterns of siliconcontaining hydroxyapatite single crystal fibers synthesized by a hydrothermal homogeneous precipitation method according to the present invention ((a) Run #11 and (b) Run #13-5) Figure 5 shows IR spectra of silicon-containing hydroxyapatite single crystal fibers synthesized by a hydrothermal homogeneous precipitation method according to the present invention ((a) Run #11 and 20 (b) Run #13-5)i and Figure 6 shows SEM micrographs of silicon-

containing hydroxyapatite single crystal fibers synthesized by a hydrothermal homogeneous 25 precipitation method according to the present invention ((a) Run #11 and (b) Run #13-5).

Examples

30 The following experiments are provided by way of example and were performed to synthesize silicon containing apatite single crystal fibers with an essentially single apatite phase and a controlled silicon content. The experiments are classified into

- 17 two categories: (1) The effect of Si content on the synthesis of fibers by homogeneous precipitation; and (2) The effect of hydrothermal conditions and the Si content on the synthesis of fibers by homogeneous 5 precipitation (under hydrothermal conditions).

(1) The effect of Si content on the synthesis of fibers bY homogeneous precipitation 10 Synthesis of fibers was carried out using a starting solution based on a Ca(NO3) 2 - (NH4)2HPOq TEOS - (NH2)2CO - HNO3 system. In order to obtain single phase apatite, the conditions (in the second heating stage) were fixed at approximately 95 C for 15 144 h. Five starting solutions were prepared with various Si contents. The preparation conditions are shown in Table 1, together with the phase composition 20 and morphology of the resultant products. The starting solution included 0.50 moldm3 (NH2)2CO and 0.1 moldm3 HNO3.

The starting solutions were first heated at 25 approximately 80 C for 24 h and then at approximately 95 C for 144 h to form the single crystal fibers.

Table 1

Sample Ca source P source S1 source S1 content Phase Morph (moldm3) (moldm3) (moldm3) (expected formula) (HAP%I') ology 30 Run Y6 Ca(NO3) 2 (NH4)2HPO' si free 0 mass% HAP Flber (0.167) (0.100) (---) Ca0(PO,) 6 (OH) ? ( 100%) Run #7 Ca(NO3) ? (NH4)2HPO' TEDS 0.4 mass% HAP Flber (0. 167) (0.0977) (2.30 x 10-3) Ca'0(PO,)s 85(51O')o,'3(OH)r 3s7 (100%) Run #8 Ca(NO3) ? (NH4)2HPO, TEOS 0.8 mass% HAP Flber (0.167) (0.09543) (4.57 x 10-3) Ca0(PO,)s,,5(510,)o 2ss( H) 7s (100%) Run #9 Ca(NO3) 2 (NH4) 2HPO' TEOS 1 6mass% HAP Flber (0.167) (0.09071) (9.29 x 10-3) CaO(PO)s 33(510)o s67(OH)r 33 (100%) Run #10 Ca(NO3) ? (NH4)2HPOl TEOS 2.4 mass% HAP Flber (0.167) (0.0861) (13.9 x 10-3) Ca0(PO)s 56(51O')o 844 (OH) 156 (100%)

- 18 1) Determined using XRD results of the crushed fibers.

Conversion of OCP into HAP (%) - IHAP(211) / (IHAP(211) + IOCP(OlOi) X 100 The XRD patterns of the products (Runs #7 to #9) prepared from the starting solutions with TEOS showed that the (100), (200) and (300) reflections of the apatite fibers were more intense than those of a typical 10 hydroxyapatite as listed in the JCPDS card (#9-432), as well as the XRD pattern of the fibers without TEOS (Run #6). The results of IR spectroscopy showed that the fibers were composed of a carbonatecontaining apatite.

The CO32- group is believed to substitute on both the PO4 15 and OH sites in the lattice structure (Type A + B). The formation of a carbonatecontaining apatite may be due to the generation of CO2 through the hydrolysis of the urea: 20 (NH2)2CO + 2H2O --> 2NH3 + CO2

SEM observations showed that the final product was composed of fibershaped crystals with long-axis sizes of from about 30 to about 200,um. The presence of 25 silicon in the individual fibers was evidenced by EDX analysis. Results for the fibers derived from Run #6 and Run #8 are shown in Figure 1 (XRD), Figure 2 (JR) and Figure 30 3 (SEM).

Table 2 shows the XRF results of the fibers derived from Run #6 and Run #8. The actual Si content in the fibers is lower than that in the nominal composition.

- 19 Table 2

Run#6 Run#8 (Si 0 mass%) (Si 0.8 mass%) Na2O < 0.1 % < 0.1 % 5 MgO 0.1 % < 0.1 % Al2O3 < 0.1 % < 0.1 % SiO2 < 0.1 % 0.27 % P2Os 39.38 % 38.75 % K2O < 0.1 % < 0.1 %

10 CaO 53.46 % 53.15 % TiO2 < 0.1 % < 0.1 % Mn3O4 < 0.1 % < 0.1 % V2Os < 0.1 % < 0.1 % Cr2O3 < 0.1 % < 0.1 % 15 Fe2O3 < 0.1 % < 0.1 % BaO < 0.1 % < 0.1 % ZrO2 < 0.1 % < 0.1 % ZnO < 0.1 % < 0.1 % SrO < 0.1 % < 0.1 % 20 Si content 0.13 % Ca/P 1.718 1.736 Ca/(P+Si) 1.718 1.722 (2) The effect of hydrothermal conditions and the Si 25 content on the synthesis of fibers by homogeneous precipitation While single crystal fibers can be synthesized using homogeneous precipitation at 95 C for 144 h, 30 longer heating periods may be required to obtain a single apatite phase. The following experiments rely on homogeneous precipitation under hydrothermal conditions to more rapidly synthesize the single crystal fibers.

The second heating stage is carried out at approximately 35 120 C for from 2 to 24 h. Five starting solutions were prepared with various Si contents. The preparation conditions are shown in Table 3, together with the phase composition and

- 20 morphology of the resultant products. The starting solution included 0.50 moldm3 (NH2)2CO and 0.1 moldm3 HNO3. 5 Table 3

Sample Ca So S1 Hydrothermal Phases %HAPI Morph (Run) source source source content Conditions ology (molded) (moldm3) (moldm3) (mass%) #11 Ca(NO3)2 (NH)2HPO' S1 free 120 C, 24 h HAP 100% Fiber (0.167) (0.100) (---) _

1 0 #12 Ca(NO3) 2 (NH4)2H2O' TEOS 0.4 120 C, 24 h HAP 10013 Plber (0.167) (0.0977) (2.30 x lo-3) _ #13-1 Ca(NO3)2 (NH,):HPO, TEOS 0.8 80 C, 24 h OCP >> < 5 % Flber (0.167) (0.09543) (4.57 x 10-3) HAP, CaHPO' #13- 2 Ca(NO3)2 (NH)2HPO' TEOS 0.8 120 C, 2 h OCP 42% Fiber (0.167) (0.09543) (4.57 x 10-3) >HAP #13-3 Ca(NO3) 2 (NH4)2HPO, TEOS 0. 8 120 C, 6 h HAP > 68% Flber (0.167) (0.09543) (4.57 x 103) OCP #13-4 Ca(NO3) 2 (NH,)tHPO, TEOS 0. 8 120 C, 12 h HAP >> 99.593 Flber (0.167) _ (0.09543) (4.57 x 10- 3) OCP 15 113-5 Ca(NO3} 2 (NH)2HPO, TEOS 0.8 120 C, 24 h HAP 100% Flber (0.167) (0.09543) (4.57 x 10-3) _ #14 Ca(NO3) 2 (NH4)zHPO' TEOS 1. 6 120 C, 24 hHAP 100% Flber (0.167) (0.09071) (9.29 x 10-3) #15 Ca(NO3) 2 (NH4) zHPO' TEOS 2.4 120 C, 24 h HAP 100% Flber (0.167) (0.0861) (13.9 x 10-3) 1) Determined using XRD results of the crushed fibers.

20 Conversion of OCP into HAP (%) IHAP(211) / ( I HAp(2ll) + ocP(o0)) x 100 The Ca/(P+Si) ratio in the starting solution was fixed at approximately 1.67. The starting solutions 25 were first heated at approximately 80 C for 24 h and then at approximately 120 C for 2 to 24 h to form the single crystal fibers.

Five experiments (Runs #13-1 to #13-5) were 30 performed in order to determine the hydrothermal period required to obtain an apatite single phase. Large amounts of octacalcium phosphate and trace amounts of hydroxyapatite and calcium hydrogen phosphate were present in the product in the case of Run #13-1 before

the hydrothermal treatment. The octacalcium phosphate was transformed into hydroxyapatite with increasing hydrothermal treatment period. A single apatite phase was obtained after a 24 h hydrothermal treatment. The 5 products derived from Runs #13-1 to #13-5 were composed of fiber- shaped crystals. The long-axis dimension decreased with increasing hydrothermal treatment period.

The effect of the Si content on the synthesis of 10 single crystal fibers was assessed under hydrothermal conditions fixed at approximately 120 C for 24 h. These experiments correspond to Runs #11, #12, #13-5, #14 and #15. 15 The XRD patterns of the products (Runs #12, #13-5, #14, #15) prepared from the starting solutions comprising TEDS showed that the (100) , (200) and (300) reflections of the apatite fibers were more intense than those of a typical hydroxyapatite listed in the JCPDS 20 card (#9- 432), as well as the XRD pattern of the fibers without silicon (Run#11). The results from the IR spectra indicated that the fibers were composed of a carbonate-containing apatite (Type A + B) similar to that produced by the homogeneous precipitation process.

25 SEM observations showed that the final product was composed of fibershaped crystals with long-axis sizes of from about 30 to about 200,um. The presence of silicon in the individual fibers was evidenced by EDX analysis. The long-axis size of the fibers decreased 30 with increasing Si content in the starting solution.

The results for the single crystal fibers derived from Run #11 and Run #13-5 are shown in Figure 4 (XRD), Figure 5 (JR) and Figure 6 (SEM).

Table 4 shows the XRF results in respect of the single crystal fibers derived from Run #11 and Run #13-

5. The actual Si content in the fibers agrees with that in the nominal composition.

Table 4

Run#11 Run#13-5 (Si 0 mass%) (Si 0.8 masse) Na2O < 0.1 % < 0.1 % 10 MgO < 0.1 % < 0.1 % Al203 < 0.1 % < 0.1 % SiO2 < 0.1 % 1.62 % P2Os 39.32 % 39. 10 % K2O < 0.1 % < 0.1 %

15 CaO 53.44 % 52.08 % TiO2 < 0.1 % < 0.1 % Mn3O4 < 0.1 % < 0.1 % V2Os < 0.1 % < 0.1 % Cr2O3 < 0.1 % < 0.1 % 20 Fe203 < 0.1 % < 0.1 % BaO < 0.1 % < 0.1 % ZrO2 < 0.1 % < 0.1 % ZnO < 0.1 % < 0.1 % SrO < 0.1 % < 0.1 % 25 Si content 0.76 % Ca/P 1.720 1.686 Ca/(P+Si) 1.720 1.607 The present invention provides a silicon-containing 30 apatite ceramic material (for example silicon-containing hydroxyapatite) having enhanced bioactivity compared with pure hydroxyapatite. At least some of the silicon is preferably substituted in the apatite crystal lattice. Moreover, the provision of the material in the 35 form of single crystal fibers results in enhanced mechanical properties over polycrystalline equivalents.

The single crystal fibers may be used, for example, in the production of fibre-reinforced biomedical composite materials for bone grafts and scaffolds.

Claims (43)

  1. - 23 CLAIMS:
    A synthetic silicon-containing apatite single crystal.
  2. 2. A synthetic silicon-containing apatite single crystal as claimed in claim 1 which is a silicon-
    substituted apatite.
    10
  3. 3. A synthetic silicon-containing apatite single crystal as claimed in claim 1 or claim 2 which is in the form of a fibre.
  4. 4. A synthetic silicon-containing apatite single 15 crystal as claimed in claim 3 which has a long-axis length in excess of 5 Sum, preferably > 10 Sum.
  5. 5. A synthetic silicon-containing apatite single crystal as claimed in claim 4 having a long-axis 20 dimension in the range of from 5 to 500 Sum, preferably from 10 to 300 Am.
  6. 6. A synthetic silicon-containing apatite single crystal as claimed in any one of the preceding claims 25 comprising up to 5% by weight of silicon.
  7. 7. A synthetic silicon-containing apatite single crystal as claimed in claim 6 comprising from 0.4 to 2.4 % by weight of silicon.
  8. 8. A synthetic silicon-containing apatite single crystal as claimed in any one of the preceding claims, wherein the Ca:(P+Si) molar ratio is from 1:1.4 to 1:2.
    - 24
  9. 9. A synthetic silicon-containing apatite single crystal as claimed in any one of the preceding claims which is essentially phase-pure having substantially no impurity phases of calcium oxide, tricalcium phosphate, 5 octacalcium phosphate and/or calcium hydrogen phosphate.
  10. 10. A synthetic silicon-containing apatite single crystal as claimed in claim 9 having a phase purity, as measured by x-ray diffraction, of at least 98%.
  11. 11. A synthetic silicon-containing apatite single crystal as claimed in any one of the preceding claims which is also a carbonate-containing and/or carbonate-
    substituted crystal.
  12. 12. A synthetic bone material comprising one or more synthetic siliconcontaining apatite single crystal(s) as defined in any one of the preceding claims.
  13. 13. A composition which comprises a synthetic bone material as defined in claim 12 together with a pharmaceutically acceptable carrier: 25
  14. 14. A bone implant, bone graft, bone scaffold, filler or cement which comprises a synthetic bone material as defined in claim 12 or a composition as defined in claim 13.
    30
  15. 15. A hydroxyapatite-polymer composite material comprising a synthetic bone material as defined in claim 12 or a composition as defined in claim 13.
  16. 16. A synthetic bone material, bone implant,
    - 25 bone graft, bone scaffold, filler or cement comprising a plurality of synthetic silicon-containing apatite single crystals as defined in any one of claims 1 to 11 in a biocompatible matrix.
  17. 17. A synthetic bone material, bone implant, bone graft, bone scaffold, filler or cement as claimed in claim 16, wherein at least some of said single crystals are aligned in said matrix in substantially the 10 same direction.
  18. 18. Use of synthetic silicon-containing apatite single crystals as defined in any one of claims 1 to 11 as a fibre reinforcement in a synthetic bone material, 15 bone implant, bone graft, bone scaffold, filler or cement.
  19. 19. A process for the preparation of silicon-
    containing apatite single crystals as defined in any one 20 of claims 1 to 11, which process comprises: (il reacting a calcium source with a phosphorus source to form a precipitate comprising octacalcium phosphate and/or calcium hydrogen phosphate; and (ii) heating said precipitate in the presence of a 25 silicon source to form one or more siliconcontaining apatite single crystals.
  20. 20. A process as claimed in claim 19, wherein the calcium source is selected from one or more of calcium 30 nitrate, calcium acetate, calcium chloride and calcium alkoxide.
  21. 21. A process as claimed in claim 19 or claim 20, wherein the phosphorus source is selected from one or
    - 26 more of ammonium-dihydrogen phosphate, diammonium hydrogen phosphate, phosphoric acid and trimethyl phosphate. 5
  22. 22. A process as claimed in any one of claims 19 to 21, wherein the silicon source is selected from one or more of a silicon acetate, silicon chloride, tetraethyl orthosilicate and tetramethyl orthosilicate.
    10
  23. 23. A process as claimed in any one of claims 19 to 22, wherein step (i) involves forming a solution comprising the calcium source and the phosphorus source.
  24. 24. A process as claimed in claim 23, wherein said 15 solution also comprises the silicon source.
  25. 25. A process as claimed in claim 23 or claim 24, wherein said solution comprises water.
    20
  26. 26. A process as claimed in any one of claims 23 to 25, wherein said solution further comprises a pH regulator of urea.
  27. 27. A process as claimed in any one of claims 23 25 to 26, wherein said solution further comprises nitric acid or hydrochloric acid.
  28. 28. A process as claimed in any one of claims 19 to 27, wherein the reaction to form said precipitate in 30 step (i) is carried out at a temperature T1, where T1 is in the range of from 70 to 90 C.
  29. 29. A process as claimed in claim 28, wherein heating of said precipitate in step (ii) is carried out
    - 27 at a temperature T2, where T2 > T1.
  30. 30. A process as claimed in claim 29, wherein T2 is in the range of from 90 to 150 C.
  31. 31. A process as claimed in any one of claims 19 to 30, wherein the concentration of calcium ions is from 0.0167 to 1.67 moldm3.
  32. 1032. A process as claimed in any one of claims 19 to 30, wherein the concentration of phosphorous containing ions is from 0.01 to 1.00 moldm3.
  33. 33. A process as claimed in any one of claims 19 15to 32, wherein the Ca/(P+Si) molar ratio is from 1:1.6 to 1:1.8.
  34. 34. A process as claimed in any one of claims 19 to 33, wherein the pH of the reaction mixture during 20 heating step (ii) is maintained substantially in the range of from 7 to 11.
  35. 35. A process for the preparation of silicon-
    containing apatite single crystals as defined in any one 25 of claims 1 to 11, which process comprises heating a precipitate comprising octacalcium phosphate and/or calcium hydrogen phosphate in the presence of a silicon source to form one or more silicon-containing apatite single crystals.
  36. 36. A process for the preparation of silicon-
    containing apatite single crystals as defined in any one of claims 1 to 11, which process comprises: (a) providing a solution comprising a calcium source
    - 28 selected from one or more of calcium nitrate, calcium acetate and calcium chloride, a phosphorus source selected from one or more of ammonium-dihydrogen phosphate, diammonium hydrogen phosphate and phosphoric 5 acid, and a silicon source selected from one or more of a silicon carboxylate, silicon chloride, ethyl silicate and methyl silicate, wherein the concentration of calcium ions is from 0.0167 to 1.67 moldm3, the concentration of phosphorous-containing ions is from 10 0.01 to 1.00 moldm-3, and the Ca/(P+Si) molar ratio is from 1:1.6 to 1:1.8; (b) heating the solution at a temperature in the range of from 50 to 90 C to form a precursor precipitate comprising calcium and phosphorous, followed by further 15 heating at a temperature in the range of from 90 to 150 C to form one or more silicon-containing apatite single crystals.
  37. 37. A process as claimed in any one of claims 19 20 to 36, wherein the precipitate is in the form of one or more crystal fibers having an average long-axis length in the range of from 5 to 500 am, preferably from 100 to 300 am.
    l 25
  38. 38. A process as claimed in any one claims 19 to 37, wherein the silicon-containing apatite single crystals are free or essentially free of said precipitate material.
    30
  39. 39. A process as claimed in any one of claims 19 to 38, wherein the silicon-containing apatite single crystals are heated to effect drying, calcination and/or sistering.
    - 29
  40. 40. A process as claimed in claim 39, wherein said single crystals are heated at a temperature of from 50 to 500 C.
    5
  41. 41. A process according to any one of claims 19 to 40 further comprising collecting the silicon-containing apatite single crystals and forming a synthetic bone material, bone implant, bone graft, bone scaffold, filler or cement comprising said single crystals.
  42. 42. A synthetic silicon-containing apatite single crystal as claimed in any one of claims 1 to 11, or a synthetic bone material as claimed in claim 12, or a composition as claimed in claim 13, or a bone implant, 15 bone graft, bone scaffold, filler or cement as claimed in claim 14 for use in a method of treatment of the human or animal body by surgery or therapy.
  43. 43. A synthetic silicon-containing apatite single 20 crystal substantially as hereinbefore described with reference to any one of the examples.
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ITMI20051966A1 (en) 2005-10-18 2007-04-19 C N R Consiglio Naz Delle Ri C A plurisostituita hydroxyapatite and its composite with a natural and or synthetic polymer their preparation and uses
FR2904553A1 (en) * 2006-08-03 2008-02-08 Isthmes Group Res And Innovati Biocompatible material fabricating method for e.g. percutaneous vertebroplasty, involves activating nucleating agent to develop mixed pseudo-crystalline lattice in condensate for obtaining crystallized biocompatible material
TWI407979B (en) * 2010-05-04 2013-09-11 Nat Univ Chung Hsing Preparation of Microspheres with Hydroxyapatite and Gelatin
CN102908663A (en) * 2012-10-25 2013-02-06 无锡市三力胶带厂 Silicon-atom and apatite doped composite high-polymer material and preparation method thereof

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US8758500B2 (en) 2007-04-11 2014-06-24 University Court Of The University Of Aberdeen Biomedical materials
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