WO2013019099A1

WO2013019099A1 - Nanostructured carbonated hydroxy apatite and method and system for making the same

Info

Publication number: WO2013019099A1
Application number: PCT/MY2011/000203
Authority: WO
Inventors: Fauzi Mohd Noor Ahmad; Marliana Baba Ismail YANNY
Original assignee: Universiti Sains Malaysia
Priority date: 2011-08-03
Filing date: 2011-09-13
Publication date: 2013-02-07

Abstract

The present invention provides a method for preparing sintered nanostructured carbonated hydroxyapatite (CHA). The method comprises mixing of CHA powders with a sintering aid to form a mixture, dry pressing the mixture, sintering the mixture at a first predetermined temperature for a first predetermined time period in air atmosphere without provision of external C02 gas to form nanostructured CHA, cooling the nanostructured CHA to a second predetermined temperature, wherein the second predetermined temperature is lower than the first predetermined temperature, and refurbishing the nanostructured CHA with wet C02 gas for a second predetermined time period. The present invention also provides a sintered nanostructured carbonated hydroxyapatite (CHA). The present invention further provides a system for producing sintered nanostructured carbonated hydroxyapatite (CHA).

Description

NANOSTRUCTURED CARBONATED HYDROXY APATITE AND METHOD

AND SYSTEM FOR MAKING THE SAME

Field of the Invention

[0001] The present invention relates generally to carbonate hydroxyapatite (CHA), and more particularly to a nanostructured CHA and method and system for making the same. Background of the Invention

[0002] Bones are dynamic and highly vascularized tissues that continuously remodel themselves throughout the lifetime of an individual. Bones ensure that the skeleton has sufficient load-bearing capacity, and protect the delicate internal organs of a body. However, bones are prone to injury, defect and aging, resulting from many different causes. For example, trauma, infection, tumor or abnormal metabolism can cause bone injury; thus bone injury is a major public health problem. Dental and orthopaedics treatments also require adequate bone supplies and therefore the interest in bone regeneration is increasing. As a result, bone grafting or bone substitute has become critical in orthopaedics surgery.

[0003] Bone graft can be defined as implanted or transplanted bone from another part of a human body or mammal, or as any synthetic material to reconstruct bone defects. Bone graft should provide a good local and systematic compatibility, and the capability of being a substitute for bones and completely filling any defect. The sources of bone graft include another part of non-load bearing site of an individual's body (autograft), another human donor tissue (allograft), animal's tissue (xenograft), or synthetic biomaterials (artificial bones). However, autograft, allograft and xenograft are known to have serious drawbacks to patients. Among others, the drawbacks include the possibility of the patients being infected by diseases, inadequate supplies and severe pain to the graft donor.

[0004] Hydroxyapatite (HA) (CalO(PO)4(OH)2) is one of the most widely used bioceramic in bone graft substitute, bone tissue engineering and drug delivery system. This is possible due to its biocompatibility, bioactivity, osteoconductivity and non-toxicity properties. It is also greatly influenced by its similarity in chemical structure with the biological apatite that comprises of the mineral phase of calcified tissue in the enamel, dentin and bone. However, stoichiometric synthetic HA has been reported to have limited ability to form an interface and its resorption in vivo is too sluggish to induce a massive formation of a new bone tissue. In addition, stoichiometric synthetic HA does not degrade significantly but rather remains as a permanent fixture susceptible to long term failure.

[0005] One way to enhance the biological properties of HA implant is through chemical modification of HA. Recently, carbonated hydroxyapatite (CHA) has been reported to be superior to pure HA for being used as bioresorbable implants. This is because human and animal bone minerals have been shown to contain significant amounts of carbonate. Therefore, the biological apatite is referred as CHA. Generally, the amount of carbonate in biological bones is about 2-8 wt% of the calcified tissue and may vary depending on the age factor. Carbonate ion can substitute either in the hydroxyl groups (A-type) or the phosphate groups (B-type) or it can simultaneously substitute both hydroxyl and phosphate groups (AB-type). The presence of carbonate in the apatite lattice is known to increase the chemical reactivity of CHA and would therefore contribute to the ease of resorption in bony tissue. The incorporation of carbonate into HA would cause an increase in solubility, decrease in crystallinity, change in crystal morphology and better biological activity. With this, it is currently accepted that CHA is a prospective material for biological applications in order to mimic the composition of natural bones.

[0006] The mechanical properties of CHA are known to be less than that of the cortical bone even though CHA has excellent bioactivity, biocompatibility and osteoconductivity and has already attracted much attention in the field of tissue engineering as bioresorbable bone graft substitutes as well as for dental replacement and repair. Load bearing implant applications are hindered by the low strength and toughness of CHA, especially in wet environment, whereas applications of bulk CHA for nonstructural implants such as ossicles in ear have no particular difficulties.

[0007] Basically, the strength of carbonated hydroxyapatite (CHA) was found to be strongly dependent on the internal porosity of the compact and this can be controlled with proper sintering. Increasing the density by sintering will decrease the amount of porosity. However, the limited thermal stability of the CHA is a grave challenge to researchers. [0008] The presence of carbonate ions in apatite structure iafluence the decomposition and sinterability of CHA. Poor control of heat treatment of CHA would result in carbonate loss, leading to partial or total decomposition of the material and hence would affect the physical and mechanical properties of the synthetic material.

[0009] The attempts in the prior art to improve the mechanical properties of CHA included sintering of CHA in moist C0₂ atmosphere; it was claimed that sintering of CHA in moist C0₂ atmosphere could minimize the carbonate loss from the structure and at the same time promote densification. However, by flowing C0₂ gas, regardless it is dry or wet C0₂, throughout the sintering schedule which normally takes up 12-14 hours, could damage the furnace and increase the production cost. In addition, solid state sintering normally required high temperature, causing carbonate decomposition. The combination of high temperature and the use of C0 throughout the entire process in the furnace would cause the furnace to become brittle and prone to crack/break over longtime usage.

[0010] Therefore, the current process of making CHA needs to be improved.

Summary of the Invention

[0011] One aspect of the present invention provides a method for preparing sintered nanostructured carbonated hydroxyapatite (CHA). In one embodiment, the method comprises mixing of CHA powders with a sintering aid to form a mixture, dry pressing the mixture, sintering the mixture at a first predetermined temperature for a first predetermined time period in air atmosphere without provision of external CO₂ gas to form nanostructured CHA, cooling the sintered nanostructured CHA to a second predetermined temperature, wherein the second predetermined temperature is lower than the first predetermined temperature, and refurbishing the sintered nanostructured CHA with wet C0₂ gas for a second predetermined time period.

[0012] Another aspect of the present invention provides a sintered nanostructured carbonated hydroxyapatite (CHA).

[0013] Yet another aspect of the present invention provides a system for producing sintered nanostructured carbonated hydroxyapatite (CHA). In one embodiment, the system comprises a sintering module for sintering a CHA structure formed by pre-pressed CHA powders mixed with a sintering aid at a first predetermined temperature for a first predetermined period without supplying external C0₂ gas, and a carbonate refurbish module for refurbishing the sintered CHA at a second predetermined temperature for a second predetermined period, wherein the second predetermined temperature is lower than the first predetermined period, and the second predetermined period is longer than the first predetermined period; wherein the carbonate refurbish module comprises a wet C0₂ gas source, a high pressure tube with two ends, and a desiccator, where one end of the high pressure tube is conducively coupled with the wet C0₂ gas source and the other end of the high pressure tube with the desiccator, so that the wet C0₂ gas is channeled from the wet C0₂ gas source to the desiccator; and wherein the desiccator has a chamber in which the sintered CHA is refurbished with external carbonate.

[0014] The objectives and advantages of the invention will become apparent from the following detailed description of preferred embodiments thereof in connection with the accompanying drawings. Brief Description of the Drawings

[0015] Preferred embodiments according to the present invention will now be described with reference to the Figures, in which like reference numerals denote like elements.

[0016] FIG 1 shows a functional block diagram of the carbonate refurbish module in accordance with one embodiment of the present invention.

[0017] FIG 2 shows a flowchart of the method for preparing sintered nanostructured CHA in accordance with one embodiment of the present invention. Detailed Description of the Invention

[0018] The present invention may be understood more readily by reference to the following detailed description of certain embodiments of the invention.

[0019] Throughout this application, where publications are referenced, the disclosures of these publications are hereby incorporated by reference, in their entireties, into this application in order to more fully describe the state of art to which this invention pertains. [0020] Carbonated hydroxyapatite (CHA) is meant to refer to any structure made from CHA powders or granules, where the structure can be bones, dental fixtures or the like, and its configurations and dimensions are dependent upon specific applications. CHA powders or granules can be produced by any wet-chemical methods including precipitation in aqueous solution and nano-emulsion.

[0021] As discussed above, the wet-chemical process of sintering CHA is conducted in one step, sintering CHA at high temperature for a long period of time in the presence of C0₂ gas; the high temperature will cause carbonate decomposition, and the presence of C0₂ gas is intended to compensate the decomposed carbonate in the sintered CHA. However, the wet-chemical process has many problems including high production cost and damages to the furnace. The inventors of the present invention discovered that the addition of a sintering aid into CHA powders before sintering could lower the sintering temperature and shorten the sintering time period without compromising the mechanical properties of the sintered CHA and at the same time decrease the carbonate decomposition, making it possible that the sintering process is conducted without supplying external C0₂ gas. The inventors of the present invention also discovered that the carbonate loss of the sintered CHA could be refurbished at a temperature much lower than the sintering temperature. This two-step (sintering and refurbishing) process has many advantages over the wet-chemical ones. For example, no C0₂ gas supplied during sintering eliminates the furnace damages caused by C0₂ gas; the shortened sintering process at a lower temperature reduces the production cost.

[0022] The present invention provides a system for enabling the production of sintered nanostructured CHA in a two-step process. The system comprises a sintering module and a carbonate refurbish module, where the sintering module can be separate from or integrated with the carbonate refurbish module, depending upon the actual design. The sintering module sinters a CHA structure formed by pre-pressed CHA powders at a first predetermined temperature for a first predetermined period without supplying external C0₂ gas. In some embodiments, the first predetermined temperature is from 700-900°C, and the first predetermined period is about 1-3 hours, more preferably 2 hours. The sintering module can be any suitable furnace such as a Lenton tube furnace.

[0023] The carbonate refurbish module refurbishes the sintered CHA at a second predetermined temperature for a second predetermined period, where the second predetermined temperature is lower than the first predetermined period, and the second predetermined period is longer than the first predetermined period. FIG 1 shows a functional block diagram of the carbonate refurbish module in accordance with one embodiment of the present invention. The carbonate refurbish module 1 comprises a wet C0₂ gas source 10, a high pressure tube 20 with two ends, and a desiccator 30, where one end of the high pressure tube 20 is conducively coupled with the wet C0₂ gas source 10 and the other end of the high pressure tube 20 with the desiccator 30, so that the wet C0₂ gas is channeled from the wet C0₂ gas source to the desiccator 30. The means for controlling the flow of C0₂ gas is not shown, and it can be any suitable means such as valves. The desiccator 30 is preferably in a cylindrical configuration with integral ball- shaped top and bottom covers, forming a closed chamber. Within the chamber, a support 33 is provided for supporting a metal (e.g., alumina) crucible 31 on which the sintered CHA such as pellets is disposed. The bottom of the desiccator is filled with water 32 providing constant moisture to the closed chamber. The desiccator 30 is kept constant at ambient temperature throughout the process (before, during and after flowing of wet C0₂) so that the sintered samples could be cooled down gradually with time. The flow of wet C0₂ on the warm sintered samples helps the refurbishing process as the wet C0₂ is favorable to be adsorbed by the warm CHA due to strong affinity of C0₂ to Ca-based bioceramic compound. The water in the desiccator 30 is just to ensure that the atmosphere inside the desiccator 30 is kept moist throughout the entire process.

[0024] The present invention also provides a method for producing sintered nanostructured CHA in a two-step manner. In brief, the first step is sintering without supplying external C0₂ gas, and the second step is refurbishing the sintered CHA with carbonate at a lowered temperature.

[0025] Referring now to FIG 2, there is provided a flowchart of the method for preparing sintered nanostructured CHA in accordance with one embodiment of the present invention. The method 100 commences by providing CHA powders that are mixed with a sintering aid 110, where the addition of the sintering aid reduces the sintering temperature and thus minimizing the decomposition of CHA. In the development of bioceramic, it is important to ensure that the sintering aids are non- toxic or causing no side-effects. In one embodiment, the sintering aid is magnesium hydroxide (Mg(OH) ₂). During sintering, Mg(OH) 2 will then decompose to MgO that eventually forms Mg²⁺, while the residue H₂0 being removed as gaseous form. Mg²⁺ element also occurs naturally in the mineral phase of the human bones and plays a role in overall bioactivity. The introduction of Mg(OH) ₂ as sintering aid improve the sintering; thus higher densification and good mechanical properties were achieved at much lower sintering temperature while minimizing decomposition of CHA. Mg(OH) ₂ is usually used in the range of 5-10wt%. For making the samples analyzed in Table 1 below, Mg(OH) ₂ was used in 8wt%.

[0026] The mixture is then pressed into the desired configuration and dimensions

120.

[0027] The pressed mixture is then sintered in air atmosphere in a furnace 130. In one embodiment, the sintering is carried out at a first predetermined temperature from 700- 900°C for a first predetermined time period from 1 to 3 hours. With the Mg(OH) ₂ as the sintering aid, MgO during sintering reacts with CHA and forms a small amount of liquid phase between the particles or grains at the sintering temperature; this process is known as liquid-phase sintering. In one embodiment, the heating rate, soaking time and cooling rate for all the sintered materials were 10 /minute, 2 hours, and 10 /minutes, respectively.

[0028] The sintered CHA is then refurbished with external carbonate 140. In one embodiment, when the sintered CHA after sintering is cooling down to a temperature between 200-400 °C, it was taken out from the furnace and placed in a desiccator. Immediately, wet carbon dioxide (C0₂) gas was flowed into the desiccator for about 20 minutes with the flowing rate of 0.5L/min. The sintered CHA was then kept in the desiccator for 24 hours, where the disiccator was kept at atmospheric pressure.

[0029] From the results shown in Table 1, it is proved that this new method produced better synthetic CHA in terms of physical, mechanical and biological properties. It is also safer and economical for large scale production of synthetic CHA.

[0030] Table 1. Comparison of certain properties of CHA between prior arts and the present invention Properties Other Researchers In this study

Carbonate A-†ype CHA B-†ype CHA substitution [Teraoka et al., (1998)] (more (T= 900^°C) desirable)

CO2 gas usage From beginning- end During cooling

[Zyman & Tkachenko (2010)] stage

Amount of 7.8 (T= 700 °C) 6.85 (T= 700 carbonate retained (pump CO2 for entire process) °C)

(w†%) [Barralet et al., (2000)]

Vickers hardness 1.17 (T= 800 °C) 2.37 (T= 800 (GPa) [Murulithran & Ramesh (2000)] °C)

Relative density (%) 94% (T= 1000 °C) 94% (T= 800

°C) 14 (T= 800 °C)

Compressive strength 22.95 (T= 800 (MPa.m ^½) [Tkachenko & Zyman (2008)] °C)

[0031] While the present invention has been described with reference to particular embodiments, it will be understood that the embodiments are illustrative and that the invention scope is not so limited. Alternative embodiments of the present invention will become apparent to those having ordinary skill in the art to which the present invention pertains. Such alternate embodiments are considered to be encompassed within the scope of the present invention. Accordingly, the scope of the present invention is defined by the appended claims and is supported by the foregoing description.

[0032] References

[0033] Teraoka, K., Ito, A., Maekawa, K., Onuma, K., Tateishi, T., Tsutsumi, S.

(1998), Mechanical properties of hydroxyapatite and OH- carbonated hydroxyapatite single crystals, Journal of Dental Research 77: 1560-1568.

[0034] Zyman, Z. And Tkachenko, M. (2010), C0₂ gas-activated sintering of carbonated hydroxyapatites, Journal of European Ceramic Society 31: 241-248. [0035] Barralet, J.E., Best, S.M., Bonfield, W. (2000), Effect of sintering parameters on the density and microstructure of carbonated hydroxyapatite, Journal of Materials Science: Materials In Medicine 11 : 719-724.

[0036] Munilithran, G. and Ramesh, S. (2000), The effect of sintering temperature on the properties of hydroxyapatite, Ceramics International 25: 221-230.

[0037] Tkachenko, M.V., and Zyman, Z.Z. (2008), Effect of sintering conditions on physical properties of carbonated hydroxyapatite ceramics, Functional Materials 15: 574-578.

Claims

What is claimed is: 1. A method for preparing sintered nanostructured carbonated hydroxyapatite (CHA), said method comprising:

mixing of CHA powders with a sintering aid to form a mixture;

dry pressing the mixture;

sintering the mixture at a first predetermined temperature for a first predetermined time period in air atmosphere without provision of external C0₂ gas to form nanostructured CHA;

cooling the sintered nanostructured CHA to a second predetermined temperature, wherein the second predetermined temperature is lower than the first predetermined temperature; and

refurbishing the nanostructured CHA with wet C0₂ gas for a second predetermined time period.

2. The method of claim 1, wherein the sintering aid is magnesium hydroxide (Mg(OH)₂).

3. The method of claim 1, wherein the first predetermined temperature is 700-900°C, and the first predetermined time period is 1 to 3 hours.

4. The method of claim 1, wherein the second predetermined temperature is 200- 400°C.

5. The method of claim 1, wherein the second predetermined time period is 24 hours.

6. A sintered nanostructured carbonated hydroxyapatite (CHA) made by the method of claim 1.

7. The sintered nanostructured CHA of claim 6, wherein the sintering aid is magnesium hydroxide (Mg(OH) ₂).

8. The sintered nanostructured CHA of claim 6, wherein the first predetermined temperature is 700-900°C, and the first predetermined time period is 1 to 3 hours.

9. The sintered nanostructured CHA of claim 6, wherein the second predetermined temperature is 200-400T.

10. The sintered nanostructured CHA of claim 6, wherein the second predetermined time period is 24 hours.

11. A system for producing sintered nanostructured carbonated hydroxyapatite (CHA), comprising:

a sintering module for sintering a CHA structure formed by pre-pressed CHA powders mixed with a sintering aid at a first predetermined temperature for a first predetermined period without supplying external C0₂ gas; and

a carbonate refurbish module for refurbishing the sintered CHA at a second predetermined temperature for a second predetermined period, wherein the second predetermined temperature is lower than the first predetermined period, and the second predetermined period is longer than the first predetermined period;

wherein the carbonate refurbish module comprises a wet C0₂ gas source, a high pressure tube with two ends, and a desiccator, where one end of the high pressure tube is conducively coupled with the wet C0₂ gas source and the other end of the high pressure tube with the desiccator, so that the wet C0₂ gas is channeled from the wet C0₂ gas source to the desiccator; and

wherein the desiccator has a chamber in which the sintered CHA is refurbished with external carbonate.

The system of claim 11, wherein the sintering module is a Lenton tube furnace.

13. The system of claim 1 1, wherein the sintering aid is magnesium hydroxide ( g(OH) ₂).

14. The system of claim 1 1 , wherein the first predetermined temperature is 700-900 , and the first predetermined time period is 1 to 3 hours.

15. The system of claim 11, wherein the second predetermined temperature is 200- 400^°C.

16. The system of claim 1 1, wherein the second predetermined time period is 24 hours.