EP1660292A1

EP1660292A1 - Methods for preparing medical implants from calcium phosphate cement and medical implants

Info

Publication number: EP1660292A1
Application number: EP04778022A
Authority: EP
Inventors: Jiin-Huey Chern Lin; Chien-Ping Ju; Chih-Hung Tsai; Yin-Chun Tien; Chao-Chin Ning; Chung-Po Chao
Original assignee: Cana Lab Corp
Current assignee: Calcitec Inc
Priority date: 2003-08-05
Filing date: 2004-08-05
Publication date: 2006-05-31
Also published as: TWI275386B; WO2005016616A1; KR20070028271A; JP2007501054A; TW200509872A; AU2004265260A1; CA2534826A1

Abstract

The present invention discloses a medical implant made from calcium phosphate cement, and in particular to a method of preparing a molded and hardened calcium phosphate cement article having a superior compressive strength for use as medical implant. The molded and hardened calcium phosphate cement article may be in the forms of a dense block, a porous block for use as tissue-engineered scaffold, or a dual function block comprising a dense cortical portion (D1) bearing the majority of load and a porous cancellous portion (P1) allowing a rapid blood/body fluid penetration and tissue growth.

Description

Methods for Preparing Medical Implants from Calcium Phosphate Cement and Medical Implants

Field of the Invention The present invention is related to a medical implant made from calcium phosphate cement, and in particular to a method of preparing a molded and hardened calcium phosphate cement article having a superior compressive strength for use as medical implant. The molded and hardened calcium phosphate cement block may be in the forms of a dense block, a porous block for use as tissue-engineered scaffold, or a dual function block comprising a dense cortical portion bearing the majority of load and a porous cancellous portion allowing a rapid blood/body fluid penetration and tissue ingrowth.

Background of the Invention It is advantageous if a prosthetic bone implant is bioresorbable and is supportive at the same time. Accordingly, an article made of calcium phosphate will be preferable than that made of a metal, if the former has strength which is comparable to a human cortical bone. One way of making such a bone implant is by sintering a calcium phosphate powder, particularly a hydroxyapatite (HA) powder, into a block material at a temperature generally greater than 1000°C. Despite the fact that the high temperature-sintered HA block material has an enhanced strength, the bioresorbability of the material is largely sacrificed, if not totally destroyed, due to the elimination of the micro- and nano-sized porosity during the sintering process. The conventional spinal fusing device is composed of a metallic cage and a bioresorbable material disposed in the metal cage, for example the one disclosed in US patent No. 5,645,598. An inevitable disadvantage of this fusion device is the sinking of the metallic cage sitting between two vertebrae to replace or repair a defect spinal disk, because the hardness and the relatively small size of the cage wear out or break the bone tissue, and in particular the endplate of the vertebra. A tissue-engineered scaffold (majority made from biodegradable polymers) has a very porous structure that allows living cells (usually taken from the patient being treated) to penetrate into the structure and be "seeded" in- vitro during a cell culture process. After a period of time (days or weeks) of cell culture, the cell-seeded scaffold is implanted into either an animal (e.g., rat) whose immune system has been removed, or into the patient himself (usually under the skin for easier later-on process). During this period of time (weeks to months) the cells quickly multiply from absorbing nutrients from the animal or the patient's body, and, at the same time, the scaffold itself is gradually dissolved or resorbed. When this process is substantially "mature", the implant (now a real bone) is removed from under the skin of the animal or the patient and re-implanted into the (wounded or diseased) site being treated. The following are some references describing some details about the background, requirements, applications, etc. of tissue-engineered scaffold: US 6,139,578; US 6,200,606; US 5,306,303; and US 6,132,463. It is advantageous if a tissue-engineered scaffold is bioresorbable, sufficiently porous and supportive at the same time. The conventional high temperature (usually >1000°C)-sintered porous hydroxyapatite (HA) block material does not possess sufficient micro/nano-sized porosity and is hardly bioresorbable. On the other hand, the conventional biodegradable polymer for scaffold application exhibits a relatively low strength and too high a dissolution rate.

Summary of the Invention An objective of the invention is to provide a molded and hardened calcium phosphate cement (CPC) article or block having a superior compressive strength for use as medical implant, which is free from the aforesaid drawbacks in the prior art. Another objective of the invention is to provide a porous hardened CPC article or block for use as a tissue-engineered scaffold, which is free from the aforesaid drawbacks in the prior art, or as a functional implant other than the tissue-engineered scaffold. Another objective of the invention is to provide a dual function hardened calcium phosphate cement (CPC) article or block for use as a prosthetic bone implant comprising a dense cortical portion and a porous cancellous portion, which is free from the aforesaid drawbacks in the prior art. The prosthetic bone implant constructed according to the present invention is made of a hardened calcium phosphate cement having an apatitic phase as a major phase, which comprises a dense cortical portion bearing the majority of load and a porous cancellous portion allowing a rapid blood/body fluid penetration and tissue ingrowth. The prosthetic bone implant of the present invention is made by a novel technique, which involves immersing an article molded from two different pastes of calcium phosphate cement (CPC), one of them having an additional pore-forming powder, in a liquid for a period of time, so that the compressive strength of the molded CPC article is significantly improved after removing from the liquid while the pore-forming powder is dissolved in the liquid, creating pores in a desired zone or zones of the molded article. Features and advantages of the present invention are as follows: 1. Easy process for different shape and size of the prosthetic bone implant of the present invention, so that the outer circumferential dense portion thereof can sit over the circumferential cortical portion of a bone and the porous portion thereof can contact the cancellous portion of the bone adjacent to a bone receiving treatment. 2. The dense cortical portion of the prosthetic bone implant made according to the present invention exhibits a high strength comparable to that of human cortical bone (about 110-170 MPa). The strength is adjustable by adjusting process parameters. 3. The dense cortical portion of the prosthetic bone implant made according to the present invention contains significant amount of micro- and nano-sized porosity, that improves bioresorbability thereof. Conventional high temperature-sintered HA block, on the other hand, does not possess sufficient micro/nano-sized porosity and is not bioresorbable. 4. The porous cancellous portion of the prosthetic bone implant made according to the present invention possesses a porosity greater than 40% in volume, prepferably 40-90%, allowing rapid blood/body fluid penetration and tissue ingrowth, thereby anchoring the prosthetic bone implant. 5. A wide range of medical application includes bone dowel, spacer, cavity filler, artificial disc and fixation devices for spine and other locations, to name a few. In another aspect of the present invention, a novel method for making a hardened CPC article for use as medical implant is provided, which involves impregnating an article molded from a paste of CPC in a liquid for a period of time, so that the compressive strength of the CPC block is significantly improved after removing from the liquid. It is apparent that the medical implant prepared according to this novel method has the features and advantages recited in the above-mentioned Items 3 and 5. In a further aspect of the present invention, a novel method for making a porous hardened CPC article for use as a tissue-engineered scaffold, which involves preparing a shaped article from a paste comprising a calcium phosphate cement, a pore-forming powder and a setting liquid; and immersing said shaped article in an immersing liquid for a period of time so that said pore-forming powder is dissolved in the immersing liquid, creating pores in said shaped article. In addition to the above-mentioned Item 4, the porous hardened CPC article made according to the present invention has the following features and advantages: - The porous hardened CPC article can transform into an apatite-dominated material shortly after immersion in physiological solution or after implantation. - The porous hardened CPC article exhibits a higher strength than most other bioactive or biodegradable porous blocks with a similar porosity level.

Brief Description of the Drawings Figs, la to Id show schematic cross sectional views of four different designs of prosthetic bone implants constructed according to the present invention. Figs. 2a to 2f are schematic cross sectional views showing steps of a method for preparing a prosthetic bone implant according to one embodiment of the present invention. Figs. 3a and 3b are schematic vertical and horizontal cross sectional views of a prosthetic bone implant prepared according to another embodiment of the present invention, respectively.

Detailed Description of the Invention The present invention discloses a method for making a hardened molded calcium phosphate cement (CPC) article comprising impregnating a rigid shaped article of calcium phosphate with an impregnating liquid for a period of time so that a compressive strength of the resulting impregnated article removed from the impregnating liquid is increased compared to that of the rigid shaped article without said impregnating treatment. Preferably, the impregnating liquid is an acidic solution, a basic solution, a physiological solution, an organic solvent, or a substantially pure water. Preferably, the impregnating liquid comprises at least one of Ca and P sources. Preferably, the impregnating liquid is a Hanks' solution, a HCl aqueous solution or an aqueous solution of (NH₄)₂HPO₄. Preferably, the rigid shaped article of calcium phosphate is a molded article from a paste of calcium phosphate cement. Preferably, the impregnating is carried out for a period longer than 10 minutes, and more preferably for about 12 hours to 96 hours. Preferably, the impregnating is carried out 30-90°C, and more preferably at room temperature. According to a first preferred embodiment of the present invention, a method for making a molded calcium phosphate article comprises the following steps: (a) preparing a powder of a calcium phosphate cement; (b) mixing said powder with a setting liquid to form a paste, wherein said paste undergoes a hardening reaction; (c) molding said paste into an article in a mold of a desired shape and size before said hardening reaction is complete; (d) impregnating the resulting hardened article from step (c) with an impregnating liquid to allow strength of said article to increase; and (e) removing said article from said impregnating liquid. Preferably, said calcium phosphate cement comprises at least one Ca source and at least one P source, or more preferably at least one calcium phosphate source. Said calcium phosphate source comprises one or more calcium phosphates selected from the group consisting of alpha-tricalcium phosphate (α-TCP), beta-tricalcium phosphate (β-TCP), tetracalcium phosphate (TTCP), monocalcium phosphate monohydrate (MCPM), monocalcium phosphate anhydrous (MCPA), dicalcium phosphate dihydrate (DCPD), dicalcium phosphate anhydrous (DCPA), octacalcium phosphate (OCP), calcium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, acid calcium pyrophosphate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium pyrophosphate, calcium triphosphate, calcium phosphate tribasic, calcium polyphosphate, calcium metaphosphate, anhydrous tricalcium phosphate, tricalcium phosphate hydrate, and amorphous calcium phosphate. Preferably, the calcium phosphate source comprises at least one calcium phosphate particle having calcium phosphate whiskers on the surface of said calcium phosphate particle, wherein said calcium phosphate whiskers have a length of about 1-5000 nm and a width of about 1-500 nm. Preferably, the setting liquid in step (b) is an acidic solution, a basic solution, or a substantially pure water. An acidic solution suitable for use in the present invention is selected from the group consisting of nitric acid (HNO₃), hydrochloric acid (HCl), phosphoric acid (H₃PO ), carbonic acid (H₂CO₃), sodium dihydrogen phosphate (NaH PO₄), sodium dihydrogen phosphate monohydrate (NaH PO₄ ^»H₂O), sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate dehydrate, potassium dihydrogen phosphate (KH₂PO₄), ammonium dihydrogen.phosphate (NH₄H PO₄), malic acid, acetic acid, lactic acid, citric acid, malonic acid, succinic acid, glutaric acid, tartaric acid, oxalic acid and their mixture. A basic solution suitable for use in the present invention is selected from the group consisting of ammonia, ammonium hydroxide, alkali metal hydroxide, alkali earth hydroxide, disodium hydrogen phosphate (Na₂HPO₄), disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphate heptahydrate, sodium phosphate dodecahydrate (Na₃PO ^»12H₂O), dipotassium hydrogen phosphate (K₂HPO₄), potassium hydrogen phosphate trihydrate (K₂HPO *3H₂O), potassium phosphate tribasic (K₃PO₄), diammonium hydrogen phosphate ((NH₄)₂HPO₄), ammonium phosphate trihydrate ((NH )₃PO₄*3H₂O), sodium hydrogen carbonate (NaHCO ), sodium carbonate Na₂CO₃, and their mixture. Step (c) of the method of the present invention preferably further comprises removing said article from said mold. Step (c) of the method of the present invention preferably further comprises removing a portion of liquid from said paste, so that a liquid/powder ratio of said paste decreases. Step (c) of the method of the present invention preferably further comprises pressurizing said paste in said mold, preferably between 1 and 500 MPa, before said hardening reaction is complete to remove a portion of liquid from said paste, so that a liquid/powder ratio of said paste decreases. More preferably, step (c) further comprises heating said paste during said pressurizing. Step (c) of the method of the present invention preferably further comprises heating said paste during molding. Step (d) of the method of the present invention preferably further comprises heating the impregnating liquid, preferably at a temperature between 30 and 90°C during said impregnating. The method of the present invention may further comprise drying said article after removing said article from said impregnating liquid. The method of the present invention may further comprise heating said article, preferably at a temperature between 50 and 500°C, after removing said article from said impregnating liquid. The molded calcium phosphate article made according to the method of the present invention may be used as a medical implant or a reinforcing constituent of a composite. According to a second preferred embodiment of the present invention, a method for making a porous hardened CPC article is provided. The second preferred embodiment is similar to the first embodiment with a major difference in that a pore-forming powder is mixed with the powder of calcium phosphate cement used in step (a). The method for making a porous hardened CPC article according to the second preferred embodiment comprises: i) preparing a shaped article from a paste comprising a calcium phosphate cement, a pore-forming powder and a setting liquid; ii) immersing said shaped article in an immersing liquid for a first period of time so that said pore-forming powder is dissolved in the immersing liquid, creating pores in said shaped article; iii) removing the resulting porous shaped article from said immersing liquid; and iv) immersing the porous shaped article from step iii) in an impregnating liquid for a second period of time so that a compressive strength of the resulting article removed from the impregnating liquid is increased compared to that of said porous shaped article without said impregnating treatment, wherein step iii) is omitted and a compressive strength of the resulting porous shaped article removed from the immersing liquid after the first and the second periods of time is increased compared to that of the resulting porous shaped article removed after the first period of time, when the immersing liquid and the impregnating liquid are the same. Said pore-forming powder preferably is selected from the group consisting of LiCl, KC1, NaCI, MgCl₂, CaCl₂, NaIO₃, KI, Na₃PO₄, K₃PO₄, Na₂CO₃, amino acid-sodium salt, amino acid-potassium salt, glucose, polysaccharide, fatty acid-sodium salt, fatty acid-potassium salt, potassium bitartrate (KHC H₄O₆), potassium carbonate, potassium gluconate (KC₆HπO₇), potassium-sodium tartrate (KNaC₄H O₆'4H₂O), potassium sulfate (K₂SO ), sodium sulfate, and sodium lactate. Preferably, said immersing liquid in step ii) and said impregnating liquid in step iv) independently are an acidic aqueous solution, a basic aqueous solution, a physiological solution, an organic solvent, or a substantially pure water. Said immersing liquid may comprises at least one of Ca and P sources. Said immersing liquid may be a Hanks' solution, a HCl aqueous solution or an aqueous solution of (NH₄)₂HPO₄. Said impregnating liquid in step iv) may be different from or the same as the immersing liquid in step i). Preferably, the first period of time in step ii) is longer than 10 minutes, and more preferably longer than 1 day. Preferably, the second period of time in step iv) is longer than 10 minutes, and more preferably longer than 1 day. Preferably, the immersing in step ii) and iv) is carried out at room temperature or at a temperature between about 30 and 90°C. Preferably, said paste in step i) further comprises living cells. Preferably, said immersing liquid in step ii) comprises living cells. Preferably, said impregnating liquid in step iv) comprises living cells. Preferably, said porous shaped article having an increased compressive strength removed from said impregnating liquid in step iv) has a porosity of at least 20 vol%, and more preferably of 40-90 vol%. The porous hardened CPC article made according to the method of the present invention may be used as a tissue-engineered scaffold, medical implant or a reinforcing constituent of a composite. According to a third preferred embodiment of the present invention, a method for making a dual function hardened CPC article for use as a prosthetic bone implant is provided. The third preferred embodiment basically is a combination of the first embodiment and the second embodiment, wherein a first CPC paste without the pore-forming powder and a second CPC paste containing the pore-forming powder are used to mold an integral article and immersing the integral article in the impregnating liquid, so that the pore-forming powder is dissolved in the immersing liquid, creating pores in the integral article while the hardened CPC gaining compressive strength. Features of the third preferred embodiments of the present invention includes (but not limited to) the following: 1. A prosthetic bone implant comprising a cortical portion having two opposite sides, and a cancellous portion integrally disposed in said cortical portion and being exposed through said two opposite sides, wherein said cortical portion comprises a hardened calcium phosphate cement has a porosity of less than 40%) in volume, and said cancellous portion comprises a porous hardened calcium phosphate cement having a porosity greater than 20% in volume, and greater than that of said cortical portion.

2. The prosthetic bone implant according to Feature 1, wherein the cortical portion is in the form of a hollow disk, and the cancellous portion is in the form of a column surrounded by the hollow disk.

3. The prosthetic bone implant according to Feature 2 further comprising a transitional portion between said column and said hollow disk surrounding said central cylinder, which has properties range from those of said cancellous portion to said cortical portion.

4. The prosthetic bone implant according to Feature 1, wherein the cortical portion is in the form of a disk having one or more longitudinal through holes, and the cancellous portion is in the form of one or more columns surrounded by said one or more longitudinal through holes.

5. The prosthetic bone implant according to Feature 1, wherein said hardened calcium phosphate cement of said cortical portion comprises an apatitic phase as a major phase giving rise to broadened characteristic X-ray diffraction peaks in comparison with a high-temperature sintered apatitic phase.

6. The prosthetic bone implant according to Feature 5, wherein said broadened characteristic the X-ray diffraction peaks are at 2-Theta values of 25-27° and 30-35°.

7. The prosthetic bone implant according to Feature 1, wherein said hardened calcium phosphate cement of said cortical portion is prepared without a high temperature sintering.

8. The prosthetic bone implant according to Feature 1, wherein said hardened calcium phosphate cement of said cortical portion comprises an apatitic phase as a major phase having a Ca/P molar ratio of 1.5-2.0. 9. The prosthetic bone implant according to Feature 1, wherein said hardened calcium phosphate cement of said cancellous portion comprises an apatitic phase as a major phase giving rise to broadened characteristic X-ray diffraction peaks in comparison with a high-temperature sintered apatitic phase.

10. The prosthetic bone implant according to Feature 9, wherein said broadened characteristic the X-ray diffraction peaks are at 2-Theta values of 25-27° and 30-35°.

11. The prosthetic bone implant according to Feature 1 , wherein said hardened calcium phosphate cement of said cancellous portion is prepared without a high temperature sintering.

12. The prosthetic bone implant according to Feature 1, wherein said hardened calcium phosphate cement of said cancellous portion comprises an apatitic phase as a major phase having a Ca/P molar ratio of 1.5-2.0.

13. The prosthetic bone implant according to Feature 1, wherein said cortical portion comprises 10-90% in volume of said implant.

14. The prosthetic bone implant according to Feature 1, wherein said cortical portion has a porosity of less than 30% in volume.

15. The prosthetic bone implant according to Feature 1, wherein said cancellous portion has a porosity greater than 40-90% in volume.

16. A method for preparing a prosthetic bone implant comprising a cortical portion having two opposite sides, and a cancellous portion integrally disposed in said cortical portion and being exposed through said two opposite sides, said method comprises the following steps: a) preparing a first paste comprising a first calcium phosphate cement and a first setting liquid; b) preparing a second paste comprising a second calcium phosphate cement, a pore-forming powder and a second setting liquid; c) i) preparing a shaped article in a mold having two or more cells separated by one more partition walls comprising introducing said first paste and said second paste into said two or more cells separately, and removing said one or more partition walls from said mold, so that said second paste in the form of a single column or two or more isolated columns is integrally disposed in the first paste in said mold; or ii) preparing a shaped article comprising introducing one of said first paste and said second paste into a first mold to form an intermediate in said first mold, placing said intermediate into a second mold after a hardening reaction thereof undergoes at least partially, and introducing another one of said first paste ad said second paste into said second mold, so that said second paste as a single column or as two or more isolated columns is integrally disposed in the first paste in said second mold; d) immersing the resulting shaped article from step c) in an immersing liquid for a first period of time so that said pore-forming powder is dissolved in the immersing liquid, creating pores in said single column or said two or more isolated columns; and e) removing the immersed shaped article from said immersing liquid.

17. The method according to Feature 16 further comprising f) drying the immersed shaped article.

18. The method according to Feature 16, wherein said pore-forming powder is the same as that used in the second preferred embodiment of the present invention.

19. The method according to Feature 16, wherein said first calcium phosphate cement comprises at least one Ca source and at least one P source, or at least one calcium phosphate source; and said second calcium phosphate cement comprises at least one Ca source and at least one P source, or at least one calcium phosphate source.

20. The method according to Feature 19, wherein said first calcium phosphate cement comprises at least one calcium phosphate source, and said second calcium phosphate cement comprises at least one calcium phosphate source. 21. The method according to Feature 20, wherein said calcium phosphate source is the same as that used in the first preferred embodiment of the present invention. 22. The method according to Feature 21, wherein said first calcium phosphate cement and said second calcium phosphate cement are identical. 23. The method according to Feature 22, wherein said first calcium phosphate cement and said second calcium phosphate cement are tetracalcium phosphate. 24. The method according to Feature 16, wherein the first setting liquid and the second setting liquid independently are an acidic solution, a basic solution, or a substantially pure water.

25. The method according to Feature 24, wherein said acidic solution is the same as that used in the first preferred embodiment of the present invention.

26. The method according to Feature 22, wherein said basic solution is the same as that used in the first preferred embodiment of the present invention.

27. The method according to Feature 16, wherein step c-i) further comprises allowing said first paste and said second paste undergoing a hardening reaction in said mold.

28. The method according to Feature 16, wherein step c-i) further comprises pressurizing said first paste and said second paste in said mold after removing said one or more partition walls from said mold to remove a portion of liquid from said first paste and said second paste, so that a liquid/powder ratio of said first paste and of said second paste decreases; and allowing said first paste and second paste undergoing a hardening reaction in said mold.

29. The method according to Feature 16, wherein step c-ii) further comprises allowing said intermediate undergoing a hardening reaction in said first mold, and allowing said another one of said first paste and said second paste undergoing a hardening reaction in said second mold.

30. The method according to Feature 16, wherein step c-ii) further comprises pressurizing said one of said first paste and said second paste in said first mold to remove a portion of liquid therefrom before the hardening reaction of said intermediate is completed; allowing said intermediate undergoing a hardening reaction in said first mold; pressuring said another one of said first paste and said second paste in said second mold, so that a liquid/powder ratio of said another one of said first paste and of said second paste decreases; and allowing said another one of said first paste and second paste undergoing a hardening reaction in said second mold. 31. The method according to Feature 28, wherein said pressuring is about 1 to 500 MPa. 32. The method according to Feature 30, wherein said pressuring is about 1 to 500 MPa. 33. The method according to Feature 16, wherein the immersing liquid is an acidic aqueous solution, a basic aqueous solution, a physiological solution, an organic solvent, or a substantially pure water. 34. The method according to Featur 33, wherein the immersing liquid comprises at least one of Ca and P sources. 35. The method according to Feature 33, wherein the immersing liquid is a Hanks' solution, a HCl aqueous solution or an aqueous solution of (NH₄)₂HPO₄. 36. The method according to Feature 16, wherein the immersing in step d) is carried out for a period longer than 10 minutes.

37. The method according to Feature 16, wherein the immersing in step d) is carried out for a period longer than 1 day.

38. The method according to Feature 16, wherein the immersing in step d) is carried out at a temperature of about 10 and 90°C.

39. The method according to Feature 38, wherein the immersing in step d) is carried out at room temperature.

40. The method according Feature 17 further comprising cleaning said immersed shaped article before said drying; and heating the resulting dried shaped article at a temperature between 50 and 500°C. Four different designs of prosthetic bone implants constructed according to the present invention are shown in Figs, la to Id. In Fig. la, the prosthetic bone implant of the present invention has a dense cortical portion DI in the tubular form and a porous cancellous portion PI formed in the central through hole of the tubular cortical portion DI . Both the dense cortical portion DI and the porous cancellous portion PI are made of a hardened calcium phosphate cement having an apatitic phase as a major phase. In Fig. lb, the prosthetic bone implant of the present invention has a dense cortical portion DI in the tubular form; a cylindrical porous cancellous portion PI in the center of the tubular cortical portion DI ; and an annular transitional portion P2 connecting the tubular cortical portion DI and the cylindrical cancellous portion PI . The transitional portion P2 is made of a hardened calcium phosphate cement having an apatitic phase as a major phase, and a porosity gradient increasing from the lower porosity of the cylindrical cancellous portion PI to the higher porosity of the tubular cortical portion DI, which may be formed in-situ during molding of two different two different CPC pastes, one of them having an additional pore-forming powder for forming the cylindrical cancellous portion PI, and another one being a regular CPC powder for forming the dense cortical portion DI. The porous cancellous portion PI may be in the forms of isolated columns surrounded by the dense cortical portion DI as shown in Figs, lc and Id. Other designs are also possible in addition to those shown in Figs, la to Id. A suitable method for preparing the prosthetic bone implant of the present invention includes placing a tubular partition wall 10 in a hollow cylindrical mold 20, as shown in Fig. 2a; pouring a first paste comprising a calcium phosphate cement and a setting liquid in the annular cell and a second paste comprising the calcium phosphate cement, a pore-forming powder and the setting liquid in the central cell, as shown in Fig. 2b; removing the partition wall and pressing the CPC pastes before hardening, as shown in Fig. 2c, wherein a portion of the setting liquid is removed from the gap between the mold 20 and the press 30 and/or holes (not shown in the drawing) provided on the press 30. The CPC paste will undergo a hardening reaction to convert into apatitic phase. The hardened disk is removed from the mold and is subjected to surface finishing to expose the central portion hardened from the second paste, as shown in Fig. 2d, followed by immersing in a bath of an immersing liquid as shown in Fig. 2e, where the pore-forming powder is dissolved in the immersing liquid while the hardened CPC thereof gaining compressive strength. The immersing may last from 10 minutes to several days. The composite disk so formed is washed with water after being removed from the bath, and dried and heated in an oven to obtain the prosthetic bone implant as shown in Fig. 2f. The heating is conducted at a temperature between 50 and 500°C for a period of several hours to several days, which enhance the compressive strength of the cortical portion of the prosthetic bone implant. An alternative method for preparing the prosthetic bone implant of the present invention from the same raw materials includes pouring the second paste in a first mold, pressing the second paste to remove a portion of the setting liquid from the second paste before the hardening reaction is completed, so that the liquid/powder ratio in the second paste decreases, and allowing the hardening reaction undergo in the mold for a period of time, e.g. 15 minutes starting from the mixing of the CPC powder, the pore-forming powder and the setting liquid, to obtain a cylindrical block having a diameter of 7 mm. Then, the cylindrical block is removed from the first mold, and placed in the center of a second mold having a diameter of 10 mm. The first paste is poured into the annular space in the second mold, and a press having a dimension corresponding to the annular shape is used to pressure the first paste to remove a portion of the setting liquid from the first paste before the hardening reaction is completed, so that the liquid/powder ratio in the first paste decreases. Again, the first paste will undergo a hardening reaction to convert into apatitic phase. The hardened cylinder having a diameter of 10 mm is removed from the second mold, followed by immersing in an immersing liquid, where the pore-forming powder contained in the second paste is dissolved in the immersing liquid while the hardened CPC thereof gaining compressive strength, to obtain the prosthetic bone implant of the present invention, as shown in Figs. 3a and 3b. It is apparently to people skilled in the art that the prosthetic bone implant shown in Figs. 3a and 3b can also be prepared by changing the sequence of the molding of the first paste and the second paste with modifications to the second mold used in this alternative method. The following examples are intended to demonstrate the invention more fully without acting as a limitation upon its scope, since numerous modifications and variations will be apparent to those skilled in this art.

PREPARATIVE EXAMPLE 1 : Preparation of TTCP Powder A Ca (PO )₂O (TTCP) powder was prepared by mixing Ca₂P₂O powder with CaCO₃ powder uniformly in ethanol for 24 hours followed by heating to dry. The mixing ratio of Ca₂P₂O₇ powder to CaCO₃ powder was 1 : 1.27 (weight ratio) and the powder mixture was heated to 1400°C to allow two powders to react to form TTCP. PREPARATIVE EXAMPLE 2: Preparation of conventional TTCP/DCPA-based CPC powder (abbreviated as C-CPC) The resulting TTCP powder from PREPARATIVE EXAMPLE 1 was sieved and blended with dried CaHPO₄ (DCPA) powder in a ball mill for 12 hours. The blending ratio of the TTCP powder to the DCPA powder was 1 : 1 (molar ratio) to obtain the conventional CPC powder. Particles of this C-CPC powder have no whisker on the surfaces thereof.

PREPARATIVE EXAMPLE 3 : Preparation of non-dispersive TTCP/DCPA-based CPC powder (abbreviated as ND-CPC) The TTCP powder prepared according to the method of PREPARATIVE EXAMPLE 1 was sieved and blended with dried CaHPO (DCPA) powder in a ball mill for 12 hours. The blending ratio of the TTCP powder to the DCPA powder was 1 : 1 (molar ratio). The resultant powder mixture was added to a 25 mM diluted solution of phosphate to obtain a powder/solution mixture having a concentration of 3 g powder mixture per 1 ml solution while stirring. The resulting powder/solution mixture was formed into pellets, and the pellets were heated in an oven at 50°C for 10 minutes. The pellets were then uniformly ground in a mechanical mill for 20 minutes to obtain the non-dispersive

TTCP/DCPA-based CPC powder (ND-CPC). The particles of this ND-CPC powder have whisker on the surfaces thereof.

Dense blocks EXAMPLE 1 : Effect of immersion time on compressive strength of CPC block To a setting solution of 1M phosphoric acid solution (pH = 5.89) the ND-CPC powder from PREPARATIVE EXAMPLE 3 was added in a liquid/powder ratio (L/P ratio) of 0.4, i.e. 4 ml liquid/10 g powder, while stirring. The resulting paste was filled into a cylindrical steel mold having a length of 12 mm and a diameter of 6 mm, and was compressed with a gradually increased pressure until a maximum pressure was reached. The maximum pressure was maintained for one minute, and then the compressed CPC block was removed from the mold. At the 15^th minute following the mixing of the liquid and powder, the compressed CPC block was immersed in a Hanks' solution for 1 day, 4 days, and 16 days. Each test group of the three different periods of immersion time has five specimens, the compressive strength of which was measured by using a AGS-500D mechanical tester (Shimadzu Co., Ltd., Kyoto, Japan) immediately following the removal thereof from the Hanks' solution without drying. The CPC paste in the mold was compressed with a maximum pressure of 166.6 MPa, and in the course of the compression the compression speeds were about 5 mm/min during 0-104.1 MPa; 3 mm/min during 104.1-138.8 MPa; 1 mm/min during 138.8-159.6 MPa: and 0.5 mm/min during 159.6-166.6 MPa. The measured wet specimen compressive strength is listed Table 1.

Table 1

*This value was measured before the compressed CPC blocks were immersed in the Hanks' solution, and it was substantially the same for the compressed CPC blocks not immersed in the Hanks' solution measured a few days after the preparation. It can seen from Table 1 that the compressive strength of the compressed

CPC blocks is increased remarkably after one-day immersion in comparison with the non-immersed block, and declines a little for a longer immersion time.

EXAMPLE 2: Effect of whiskers on compressive strength of TTCP/DCPA-based CPC block The procedures of EXAMPLE 1 were repeated by using the C-CPC powder prepared in PREPARATIVE EXAMPLE 2 and the ND-CPC powder prepared in PREPARATIVE EXAMPLE 3. The maximum pressure used to compress the CPC paste in the mold in this example was 156.2 MPa. The results for one-day immersion time are listed in Table 2.

Table 2

It can be seen from Table 2 that the compressive strength, 62.3 MPa, of the immersed compressed CPC block prepared from the conventional CPC powder (no whisker) is about 1.7 times of that (37.3 MPa) of the non-immersed compressed CPC block in Table 1, and the compressive strength, 138.0 MPa, of the immersed compressed CPC block prepared from the non-dispersive CPC powder (with whisker) is about 3.7 times of that of the non- immersed compressed CPC block in Table 1

EXAMPLE 3 : Effect of whiskers on compressive strength of TTCP-based CPC block Ca₄(PO₄)₂O (TTCP) powder as synthesized in PREPARATIVE EXAMPLE 1 was sieved with a #325 mesh. The sieved powder has an average particle size of about 10 μm. To the TTCP powder HCl aqueous solution (pH = 0.8) was added according to the ratio of lg TTCP/13ml solution. The TTCP powder was immersed in the HCl aqueous solution for 12 hours, filtered rapidly and washed with deionized water, and filtered rapidly with a vacuum pump again. The resulting powder cake was dried in an oven at 50°C. The dried powder was divided into halves, ground for 20 minutes and 120 minutes separately, and combined to obtain the non-dispersive TTCP-based CPC powder, the particles of which have whisker on the surfaces thereof. A setting solution of diammonium hydrogen phosphate was prepared by dissolving 20 g of diammonium hydrogen phosphate, (NH ) HPO₄, in 40 ml deionized water. The procedures in EXAMPLE 1 were used to obtain the wet specimen compressive strength for one-day immersion time, wherein the maximum pressure to compress the CPC paste in the mold was 156.2 MPa. The results are shown in Table 3.

Table 3

The trend same as the TTCP/DCPA-based CPC powder in Table 2 of EXAMPLE 2 can be observed in Table 3.

EXAMPLE 4: Effect of molding pressure on compressive strength of ND-CPC block (in low pressure regime: 0.09-3.5 MPa) The procedures of EXAMPLE 1 were repeated except that the maximum pressure used to compress the CPC paste in the mold was changed from 166.6 MPa to the values listed in Table 4. The period of immersion was one day. The results are listed in Table 4.

Table 4

The data in Table 4 indicate that the compressive strength of the CPC block increases as the pressure used to compress the CPC paste in the mold increases. EXAMPLE 5: Effect of reducing liquid/powder ratio during compression of the CPC paste in the mold on compressive strength of ND-CPC block The procedures of EXAMPLE 1 were repeated except that the maximum pressure used to compress the CPC paste in the mold was changed from 166.6 MPa to the values listed in Table 5. The liquid leaked from the mold during compression was measured, and the liquid/powder ratio was re-calculated as shown in Table 5. The period of immersion was one day. The results are listed in Table 5.

Table 5

The data in Table 5 show that the compressive strength of the CPC block increases as the liquid/powder ratio decreases during molding.

EXAMPLE 6: Effect of post-heat treatment on compressive strength of CPC block The procedures of EXAMPLE 1 were repeated. The period of immersion was one day. The CPC blocks after removing from the Hanks' solution were subjected to post-heat treatments: 1) 50°C for one day; and 2) 400°C for two hours with a heating rate of 10°C per minute. The results are listed in Table 6. Table 6

It can be seen from Table 6 that the post-heat treatment enhances the compressive strength of the CPC block.

Porous blocks

EXAMPLE 7: Effect of KCl content and immersion time on compressive strength of porous CPC block To a setting solution of 1M phosphoric acid solution (pH = 5.89) the ND-CPC powder from PREPARATIVE EXAMPLE 3 was added in a liquid/powder ratio (L/P ratio) of 0.4, i.e. 4 ml liquid/10 g powder, while stirring. KCl powder in a predetermined amount was mixed to the resulting mixture by stirring intensively. The resulting paste was filled into a cylindrical steel mold having a length of 12 mm and a diameter of 6 mm, and was compressed with a gradually increased pressure until a maximum pressure of 3.5 MPa was reached. The maximum pressure was maintained for one minute, and then the compressed CPC block was removed from the mold. At the 15^th minute following the mixing of the liquid and powders, the compressed CPC block was immersed in a deionized water at 37°C for 4 days, 8 days, and 16 days. The compressive strength of the specimens of the three different periods of immersion time was measured by using a AGS-500D mechanical tester (Shimadzu Co., Ltd., Kyoto, Japan) after the specimens were dry. The measured dry specimen compressive strength is listed Table 7. Table 7

It can seen from Table 7 that the dry compressive strength of the porous CPC blocks decreases as the KC1/CPC ratio by weight increases.

EXAMPLE 8: Porosity and compressive strength of porous CPC blocks prepared from different pore-forming powders The procedures of EXAMPLE 7 were repeated by using sugar, KI, C₁₇H₃₃COONa and C₁₃H₂₇COOH instead of KCl. The immersion time was 14 days in deionized water. In the cases where the C₁₇H₃₃COONa and C₁₃H ₇COOH were used, the CPC blocks were further immersed in ethanol for additional four days. The conditions and the results are listed in Table 8.

Table 8

^& S = Pore-forming powder/CPC by volume. b) C.S. = dry compressive strength (hereinafter abbreviated as C.S.). c) Porosity: Porosity (vol%) was measured by Archimedes' method, and calculated as in ASTM C830. It can be seen from Table 8 that various powders which are soluble in ^• water can be used in the preparation of a porous CPC block according to the method of the present invention. Dual-Functional block Example 9 To a setting solution of IM phosphoric acid solution (pH = 5.89) the ND-CPC powder from PREPARATIVE EXAMPLE 3 was added in a liquid/powder ratio (L/P ratio) of 0.4, i.e. 4 ml liquid/10 g powder, while stirring. KCl powder in a ratio of KCl powder/CPC by volume of 2 was mixed to the resulting mixture by stirring intensively. The resulting paste was filled into a cylindrical steel mold having a length of 12 mm and a diameter of 7 mm, and was compressed with a gradually increased pressure until a maximum pressure of 3.5 MPa was reached. The maximum pressure was maintained for one minute, and then the compressed CPC block was removed from the mold at the 15^th minute following the mixing of the liquid and powders. The resulting cylinder having a diameter of 7 mm was placed in another cylindrical steel mold having a diameter of 10 mm. To a setting solution of IM phosphoric acid solution (pH = 5.89) the ND-CPC powder from PREPARATIVE EXAMPLE 3 was added in a liquid/powder ratio (L/P ratio) of 0.4, i.e. 4 ml liquid/10 g powder, while stirring. The resulting paste was filled into the gap between said cylinder and said another mold, and was compressed with a gradually increased pressure until a maximum pressure of 50 MPa was reached. The maximum pressure was maintained for one minute. At the 15* minute following the mixing of the liquid and ND-CPC powder, the CPC/KCl composite block was immersed in a deionized water at 37°C for 4 days. KCl powder was dissolved in the deionized water, and a dual-functional CPC block having a porous CPC cylinder surround by a dense CPC annular block was obtained. The compressive strength of the specimen was measured by using a AGS-500D mechanical tester (Shimadzu Co., Ltd., Kyoto, Japan) after the specimens were dry. The measured dry specimen compressive strength is 68.8 MPa. The porosities of the porous CPC cylinder and the dense CPC annular block were measured by Archimedes' method, and calculated as in ASTM C830, after the dual-functional CPC block was broken intentionally, and the results are 74% and 30%, respectively. X-ray diffraction pattern of the powder obtained by grinding the dual-functional CPC block shows broadened characteristic X-ray diffraction peaks of apatite at 2Θ = 25-27° and 2Θ = 20-35° with a scanning range of 2Θ of 20-40° and a scanning rate of l°/min. The results indicate that the powder is a mixture of apatite and TTCP with apatite as a major portion. Although the present invention has been described with reference to specific details of certain embodiments thereof, it is not intended that such details should be regarded as limitations upon the scope of the invention except as and to the extent that they are included in the accompanying claims. Many modifications and variations are possible in light of the above disclosure

Claims

What Is Claimed Is:

1. A prosthetic bone implant comprising a cortical portion having two opposite sides, and a cancellous portion integrally disposed in said cortical portion and being exposed through said two opposite sides, wherein said cortical portion comprises a hardened calcium phosphate cement has a porosity of less than 40% in volume, and said cancellous portion comprises a porous hardened calcium phosphate cement having a porosity greater than 20% in volume, and greater than that of said cortical portion.

2. The implant according to claim 1, wherein the cortical portion is in the form of a hollow disk, and the cancellous portion is in the form of a column surrounded by the hollow disk.

3. The implant according to claim 2 further comprising a transitional portion between said column and said hollow disk surrounding said central cylinder, which has properties range from those of said cancellous portion to said cortical portion.

4. The implant according to claim 1, wherein the cortical portion is in the form of a disk having one or more longitudinal through holes, and the cancellous portion is in the form of one or more columns surrounded by said one or more longitudinal through holes.

5. The implant according to claim 1, wherein said hardened calcium phosphate cement of said cortical portion comprises an apatitic phase as a major phase giving rise to broadened characteristic X-ray diffraction peaks in comparison with a high-temperature sintered apatitic phase.

6. The implant according to claim 5, wherein said broadened characteristic the X-ray diffraction peaks are at 2-Theta values of 25-27° and 30-35°.

7. The implant according to claim 1, wherein said hardened calcium phosphate cement of said cortical portion is prepared without a high temperature sintering.

8. The implant according to claim 1, wherein said hardened calcium phosphate cement of said cortical portion comprises an apatitic phase as a major phase having a Ca/P molar ratio of 1.5-2.0.

9. The implant according to claim 1, wherein said hardened calcium phosphate cement of said cancellous portion comprises an apatitic phase as a major phase giving rise to broadened characteristic X-ray diffraction peaks in comparison with a high-temperature sintered apatitic phase.

10. The implant according to claim 9, wherein said broadened characteristic the X-ray diffraction peaks are at 2-Theta values of 25-27° and 30-35°.

11. The implant according to claim 1, wherein said hardened calcium phosphate cement of said cancellous portion is prepared without a high temperature sintering.

12. The implant according to claim 1, wherein said hardened calcium phosphate cement of said cancellous portion comprises an apatitic phase as a major phase having a Ca/P molar ratio of 1.5-2.0.

13. The implant according to claim 1, wherein said cortical portion comprises 10-90% in volume of said implant.

14. The implant according to claim 1, wherein said cortical portion has a porosity of less than 30% in volume.

15. The implant according to claim 1, wherein said cancellous portion has a porosity of 40-90% in volume.

17. The method according to claim 16 further comprising f) drying the immersed shaped article.

18. The method according to claim 16, wherein said pore-forming powder is selected from the group consisting of LiCl, KCl, NaCI, MgCl₂, CaCl₂, NaIO₃, KI, Na₃PO₄, K₃PO , Na₂CO₃, amino acid-sodium salt, amino acid-potassium salt, glucose, polysaccharide, fatty acid-sodium salt, fatty acid-potassium salt, potassium bitartrate (KHC₄H₄O₆), potassium carbonate, potassium gluconate (KC₆HπO ), potassium-sodium tartrate (KNaC₄H₄O₆ ^»4H₂O), potassium sulfate (K₂SO₄), sodium sulfate, and sodium lactate.

19. The method according to claim 16, wherein said first calcium phosphate cement comprises at least one Ca source and at least one P source, or at least one calcium phosphate source; and said second calcium phosphate cement comprises at least one Ca source and at least one P source, or at least one calcium phosphate source.

20. The method according to claim 19, wherein said first calcium phosphate cement comprises at least one calcium phosphate source, and said second calcium phosphate cement comprises at least one calcium phosphate source.

21. The method according to claim 20, wherein said calcium phosphate source is selected from the group consisting of alpha-tricalcium phosphate (α-TCP), beta-tricalcium phosphate (β-TCP), tetracalcium phosphate (TTCP), monocalcium phosphate monohydrate (MCPM), monocalcium phosphate anhydrous (MCPA), dicalcium phosphate dihydrate (DCPD), dicalcium phosphate anhydrous (DCPA), octacalcium phosphate (OCP), calcium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, acid calcium pyrophosphate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium pyrophosphate, calcium triphosphate, calcium phosphate tribasic, calcium polyphosphate, calcium metaphosphate, anhydrous tricalcium phosphate, tricalcium phosphate hydrate, and amorphous calcium phosphate.

22. The method according to claim 21, wherein said first calcium phosphate cement and said second calcium phosphate cement are identical.

23. The method according to claim 22, wherein said first calcium phosphate cement and said second calcium phosphate cement are tetracalcium phosphate.

24. The method according to claim 16, wherein the first setting liquid and the second setting liquid independently are an acidic solution, a basic solution, or a substantially pure water.

25. The method according to claim 24, wherein said acidic solution is selected from the group consisting of nitric acid (HNO₃), hydrochloric acid (HCl), phosphoric acid (H₃PO₄), carbonic acid (H₂CO₃), sodium dihydrogen phosphate (NaH₂PO₄), sodium dihydrogen phosphate monohydrate (NaH PO₄*H₂O), sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate dehydrate, potassium dihydrogen phosphate (KH₂PO₄), ammonium dihydrogen.phosphate (NH H₂PO ), malic acid, acetic acid, lactic acid, citric acid, malonic acid, succinic acid, glutaric acid, tartaric acid, oxalic acid and their mixture.

26. The method according to claim 22, wherein said basic solution is selected from the group consisting of ammonia, ammonium hydroxide, alkali metal hydroxide, alkali earth hydroxide, disodium hydrogen phosphate (Na₂HPO₄), disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphate heptahydrate, sodium phosphate dodecahydrate (Na₃PO₄»12H₂O), dipotassium hydrogen phosphate (K₂HPO ), potassium hydrogen phosphate trihydrate (K₂HPO₄ ^»3H₂O), potassium phosphate tribasic (K₃PO ), diammonium hydrogen phosphate ((NH₄)₂HPO ), ammonium phosphate trihydrate ((NH₄)₃PO ^«3H₂O), sodium hydrogen carbonate (NaHCO₃), sodium carbonate Na₂CO₃, and their mixture.

27. The method according to claim 16, wherein step c-i) further comprises allowing said first paste and said second paste undergoing a hardening reaction in said mold.

28. The method according to claim 16, wherein step c-i) further comprises pressurizing said first paste and said second paste in said mold after removing said one or more partition walls from said mold to remove a portion of liquid from said first paste and said second paste, so that a liquid/powder ratio of said first paste and of said second paste decreases; and allowing said first paste and second paste undergoing a hardening reaction in said mold.

29. The method according to claim 16, wherein step c-ii) further comprises allowing said intermediate undergoing a hardening reaction in said first mold, and allowing said another one of said first paste and said second paste undergoing a hardening reaction in said second mold.

30. The method according to claim 16, wherein step c-ii) further comprises pressurizing said one of said first paste and said second paste in said first mold to remove a portion of liquid therefrom before the hardening reaction of said intermediate is completed; allowing said intermediate undergoing a hardening reaction in said first mold; pressuring said another one of said first paste and said second paste in said second mold, so that a liquid/powder ratio of said another one of said first paste and of said second paste decreases; and allowing said another one of said first paste and second paste undergoing a hardening reaction in said second mold.

31. The method according to claim 28, wherein said pressuring is about 1 to 500 MPa.

32. The method according to claim 30, wherein said pressuring is about 1 to 500 MPa.

33. The method according to claim 16, wherein the immersing liquid is an acidic aqueous solution, a basic aqueous solution, a physiological solution, an organic solvent, or a substantially pure water.

34. The method according to claim 33, wherein the immersing liquid comprises at least one of Ca and P sources.

35. The method according to claim 33, wherein the immersing liquid is a Hanks' solution, a HCl aqueous solution or an aqueous solution of (NH₄)₂HPO₄.

36. The method according to claim 16, wherein the immersing in step d) is carried out for a period longer than 10 minutes.

37. The method according to claim 16, wherein the immersing in step d) is carried out for a period longer than 1 day.

38. The method according to claim 16, wherein the immersing in step d) is carried out at a temperature of about 10 and 90°C.

39. The method according to claim 38, wherein the immersing in step d) is carried out at room temperature.

40. The method according claim 17 further comprising cleaning said immersed shaped article before said drying; and heating the resulting dried shaped article at a temperature between 50 and 500°C.

41. A method for making a molded calcium phosphate article comprising impregnating a rigid shaped article of calcium phosphate with an impregnating liquid for a period of time so that a compressive strength of the resulting impregnated article removed from the impregnating liquid is increased compared to that of said rigid shaped article without said impregnating treatment.

42. The method according to claim 41, wherein the impregnating liquid is an acidic solution, a basic solution, a physiological solution, an organic solvent, or a substantially pure water.

43. The method according to claim 42, wherein the impregnating liquid comprises at least one of Ca and P sources.

44. The method according to claim 42, wherein the impregnating liquid is a Hanks' solution, a HCl aqueous solution or an aqueous solution of (NH₄)₂HPO₄.

45. The method according to claim 41, wherein the rigid shaped article of calcium phosphate is a molded article from a paste of calcium phosphate cement.

46. The method according to claim 41, wherein the impregnating is carried out for a period longer than 10 minutes.

47. The method according to claim 46, wherein the impregnating is carried out for about 12 hours to 96 hours.

48. The method according to claim 1, wherein the impregnating is carried out at room temperature or at a temperature between about 30 and 90°C.

49. The method according to claim 45, wherein said calcium phosphate cement comprises one or more calcium phosphates selected from the group consisting of alpha-tricalcium phosphate (α-TCP), beta-tricalcium phosphate (β-TCP), tetracalcium phosphate (TTCP), monocalcium phosphate monohydrate (MCPM), monocalcium phosphate anhydrous (MCPA), dicalcium phosphate dihydrate (DCPD), dicalcium phosphate anhydrous (DCPA), octacalcium phosphate (OCP), calcium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, acid calcium pyrophosphate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium pyrophosphate, calcium triphosphate, calcium phosphate tribasic, calcium polyphosphate, calcium metaphosphate, anhydrous tricalcium phosphate, tricalcium phosphate hydrate, and amorphous calcium phosphate.

50. The method according to claim 49, wherein the calcium phosphate cement comprises at least one calcium phosphate particle having calcium phosphate whiskers on the surface of said calcium phosphate particle, wherein said calcium phosphate whiskers have a length of about 1-5000 nm and a width of about 1-500 nm.

51. The method according to claim 45, wherein said paste is formed by mixing said calcium phosphate cement with a setting liquid.

52. A method for making a molded calcium phosphate article comprising the following steps: a) preparing a powder comprising at least one Ca source and at least one P source, or at least one calcium phosphate source; b) mixing said powder with a setting liquid to form a paste, wherein said paste undergoes a hardening reaction; c) molding said paste into an article in a mold of a desired shape and size before said hardening reaction is complete; d) impregnating the resulting hardened article from step (c) with an impregnating liquid to allow strength of said article to increase; and e) removing said article from said impregnating liquid.

53. The method according to claim 52, wherein said calcium phosphate source in step (a) comprises one or more calcium phosphates selected from the group consisting of alpha-tricalcium phosphate (α-TCP), beta- tricalcium phosphate (β-TCP), tetracalcium phosphate (TTCP), monocalcium phosphate monohydrate (MCPM), monocalcium phosphate anhydrous (MCPA), dicalcium phosphate dihydrate (DCPD), dicalcium phosphate anhydrous. (DCPA), octacalcium phosphate (OCP), calcium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, acid calcium pyrophosphate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium pyrophosphate, calcium triphosphate, calcium phosphate tribasic, calcium polyphosphate, calcium metaphosphate, anhydrous tricalcium phosphate, tricalcium phosphate hydrate, and amorphous calcium phosphate.

54. The method according to claim 52, wherein the calcium phosphate source comprises at least one calcium phosphate particle having calcium phosphate whiskers on the surface of said calcium phosphate particle, wherein said calcium phosphate whiskers have a length of about 1-5000 nm and a width of about 1-500 nm.

55. The method according to claim 52, wherein the setting liquid in step (b) is an acidic solution, a basic solution, or a substantially pure water.

56. The method according to claim 55, wherein said acidic solution is selected from the group consisting of nitric acid (HNO₃), hydrochloric acid (HCl), phosphoric acid (H PO ), carbonic acid (H₂CO₃), sodium dihydrogen phosphate (NaH₂PO₄), sodium dihydrogen phosphate monohydrate (NaH₂PO₄»H₂O), sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate dehydrate, potassium dihydrogen phosphate (KH₂PO₄), ammonium dihydrogen.phosphate (NH₄H₂PO₄), malic acid, acetic acid, lactic acid, citric acid, malonic acid, succinic acid, glutaric acid, tartaric acid, oxalic acid and their mixture.

57. The method according to claim 55, wherein said basic solution is selected from the group consisting of ammonia, ammonium hydroxide, alkali metal hydroxide, alkali earth hydroxide, disodium hydrogen phosphate (Na₂HPO₄), disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphate heptahydrate, sodium phosphate dodecahydrate (Na₃PO₄ ^#12H₂O), dipotassium hydrogen phosphate (K₂HPO₄), potassium hydrogen phosphate trihydrate (K₂HPO₄»3H₂O), potassium phosphate tribasic (K₃PO₄), diammonium hydrogen phosphate ((NH₄)₂HPO ), ammonium phosphate trihydrate ((NH₄)₃PO «3H₂O), sodium hydrogen carbonate (NaHCO₃), sodium carbonate Na₂CO₃, and their mixture.

58. The method according to claim 52, wherein step (c) further comprises removing said article from said mold.

59. The method according to claim 52, wherein step (c) further comprises removing a portion of liquid from said paste, so that a liquid/powder ratio of said paste decreases.

60. The method according to claim 52, wherein step (c) further comprises pressurizing said paste in said mold before said hardening reaction is complete to remove a portion of liquid from said paste, so that a liquid/powder ratio of said paste decreases.

61. The method according to claim 60, wherein step (c) further comprises heating said paste during said pressurizing.

62. The method according to claim 52, wherein step (c) further comprises heating said paste during molding.

63. The method according to claim 52, wherein step (d) further comprises heating the impregnating liquid during said impregnating.

64. The method according to claim 63, wherein step (d) further comprises heating the impregnating liquid at a temperature between about 30 and 90°C during said impregnating.

65. The method according to claim 52 further comprising drying said article after removing said article from said impregnating liquid.

66. The method according to claim 52 further comprising heating said article after removing said article from said impregnating liquid.

67. The method according to claim 66, wherein said article after being removed from said impregnating liquid is heated at a temperature between 50 and 500°C.

68. The method according to claim 52, wherein the impregnating liquid in step (d) is an acidic solution, a basic solution, a physiological solution, an organic solvent, or a substantially pure water.

69. The method according to claim 68, wherein the impregnating liquid comprises at least one of Ca and P sources.

70. The method according to claim 68, wherein the impregnating liquid is a Hanks' solution, a HCl aqueous solution or an aqueous solution of (NH₄)₂HPO₄.

71. The method according to claim 52, wherein the impregnating in step (d) is carried out for a period longer than 10 minutes.

72. The method according to claim 71, wherein the impregnating is carried out for about 12 hours to 96 hours.

73. The method according to claim 52, wherein the impregnating in step (d) is carried out at room temperature.

74. A method for making a porous calcium phosphate article comprising the following steps: i) preparing a shaped article from a paste comprising a calcium phosphate cement, a pore-forming powder and a setting liquid; ii) immersing said shaped article in an immersing liquid for a first period of time so that said pore-forming powder is dissolved in the immersing liquid, creating pores in said shaped article; iii) removing the resulting porous shaped article from said immersing liquid; and iv) immersing the porous shaped article from step iii) in an impregnating liquid for a second period of time so that a compressive strength of the resulting article removed from the impregnating liquid is increased compared to that of said porous shaped article without said impregnating treatment, wherein step iii) is omitted and a compressive strength of the resulting porous shaped article removed from the immersing liquid after the first and the second periods of time is increased compared to that of the resulting porous shaped article removed after the first period of time, when the immersing liquid and the impregnating liquid are the same.

75. The method according to claim 74, wherein said pore-forming powder is selected from the group consisting of LiCl, KCl, NaCI, MgCl₂, CaCl₂, NaIO₃, KI, Na₃PO₄, K₃PO₄, Na₂CO₃, amino acid-sodium salt, amino acid-potassium salt, glucose, polysaccharide, fatty acid-sodium salt, fatty acid-potassium salt, potassium bitartrate (KHC₄H₄O₆), potassium carbonate, potassium gluconate (KC₆HπO₇), potassium-sodium tartrate (KNaC H₄O₆*4H₂O), potassium sulfate (K₂SO₄), sodium sulfate, and sodium lactate.

76. The method according to claim 74, wherein the immersing liquid is an acidic aqueous solution, a basic aqueous solution, a physiological solution, an organic solvent, or a substantially pure water.

77. The method according to claim 76, wherein the immersing liquid comprises at least one of Ca and P sources.

78. The method according to claim 76, wherein the immersing liquid is a Hanks' solution, a HCl aqueous solution or an aqueous solution of (NH₄)₂HPO₄.

79. The method according to claim 76, wherein the immersing liquid and the impregnating liquid are the same.

80. The method according to claim 77, wherein the immersing liquid and the impregnating liquid are the same.

81. The method according to claim 78, wherein the immersing liquid and the impregnating liquid are the same.

82. The method according to claim 74, wherein the immersing liquid and the impregnating liquid are different.

83. The method according to claim 82, wherein the impregnating liquid is an acidic solution, a basic solution, a physiological solution, or a substantially pure water.

84. The method according to claim 83, wherein the impregnating liquid comprises at least one of Ca and P sources.

85. The method according to claim 83, wherein the impregnating liquid is a Hanks' solution, a HCl aqueous solution or an aqueous solution of (NH₄)₂HPO₄.

86. The method according to claim 74, wherein the first period of time is longer than 10 minutes.

87. The method according to claim 86, wherein the first period of time is longer than 1 day.

88. The method according to claim 74, wherein the second period of time is longer than 10 minutes.

89. The method according to claim 88, wherein the second period of time is longer than 1 day.

90. The method according to claim 74, wherein the immersing in step ii) and iv) is carried out at room temperature or at a temperature between about 30 and 90°C.

91. The method according to claim 74, wherein said preparing of step i) comprises the following steps: (a) preparing a first powder as said calcium phosphate cement comprising at least one Ca source and at least one P source, or at least one calcium phosphate source; (b) mixing said first powder and the pore-forming powder with said setting liquid to form said paste, wherein said first powder and said setting liquid undergo a hardening reaction; (c) molding said paste into an article in a mold of a desired shape and size before said hardening reaction is complete; and (d) removing said molded article from said mold.

92. The method according to claim 91, wherein said calcium phosphate source in step (a) comprises one or more calcium phosphates selected from the group consisting of alpha-tricalcium phosphate (α-TCP), beta-tricalcium phosphate (β-TCP), tetracalcium phosphate (TTCP), monocalcium phosphate monohydrate (MCPM), monocalcium phosphate anhydrous (MCPA), dicalcium phosphate dihydrate (DCPD), dicalcium phosphate anhydrous (DCPA), octacalcium phosphate (OCP), calcium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, acid calcium pyrophosphate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium pyrophosphate, calcium triphosphate, calcium phosphate tribasic, calcium polyphosphate, calcium metaphosphate, anhydrous tricalcium phosphate, tricalcium phosphate hydrate, and amorphous calcium phosphate.

93. The method according to claim 92, wherein said calcium phosphate source in step (a) is tetracalcium phosphate (TTCP).

94. The method according to claim 92, wherein the calcium phosphate source comprises at least one calcium phosphate particle having calcium phosphate whiskers on the surface of said calcium phosphate particle, wherein said calcium phosphate whiskers have a length of about 1-5000 nm and a width of about 1-500 nm.

95. The method according to claim 92, wherein the setting liquid in step (b) is an acidic solution, a basic solution, or a substantially pure water.

96. The method according to claim 95, wherein said acidic solution is selected from the group consisting of nitric acid (HNO₃), hydrochloric acid (HCl), phosphoric acid (H₃PO₄), carbonic acid (H₂CO₃), sodium dihydrogen phosphate (NaH₂PO₄), sodium dihydrogen phosphate monohydrate (NaH₂PO₄ ^»H₂O), sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate dehydrate, potassium dihydrogen phosphate (KH₂PO₄), ammonium dihydrogen.phosphate (NH H₂PO ), malic acid, acetic acid, lactic acid, citric acid, malonic acid, succinic acid, glutaric acid, tartaric acid, oxalic acid and their mixture.

97. The method according to claim 95, wherein said basic solution is selected from the group consisting of ammonia, ammonium hydroxide, alkali metal hydroxide, alkali earth hydroxide, disodium hydrogen phosphate (Na₂HPO ), disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphate heptahydrate, sodium phosphate dodecahydrate (Na₃PO₄*12H₂O), dipotassium hydrogen phosphate (K₂HPO ), potassium hydrogen phosphate trihydrate (K₂HPO₄*3H₂O), potassium phosphate tribasic (K₃PO₄), diammonium hydrogen phosphate ((NH )₂HPO₄), ammonium phosphate trihydrate ((NH₄)₃PO₄ ^»3H₂O), sodium hydrogen carbonate (NaHCO₃), sodium carbonate Na CO₃, and their mixture.

98. The method according to claim 91, wherein step (c) further comprises removing a portion of liquid from said paste, so that a liquid/powder ratio of said paste decreases.

99. The method according to claim 91, wherein step (c) further comprises pressurizing said paste in said mold before said hardening reaction is complete to remove a portion of liquid from said paste, so that a liquid/powder ratio of said paste decreases.

100. The method according to claim 99, wherein said pressuring is about 1 to 500 MPa.

101. The method according to claim 99, wherein step (c) further comprises heating said paste during said pressurizing.

102. The method according to claim 91, wherein step (c) further comprises heating said paste during molding.

103. The method according to claim 74 further comprising removing the resulting porous shaped article having an increased compressive strength from said impregnating liquid; and cleaning and drying said porous shaped article after removed from said impregnating liquid.

104. The method according to claim 103 further comprising heating the resulting cleaned and dried porous shaped article.

105. The method according to claim 104, wherein said heating is conducted at a temperature between 50 and 500°C.

106. The method according to claim 74, wherein said paste in step i) further comprises living cells.

107. The method according to claim 74, wherein said immersing liquid in step ii) comprises living cells.

108. The method according to claim 74, wherein said impregnating liquid in step iv) comprises living cells.

109. The method according to claim 74, wherein said porous shaped article having an increased compressive strength removed from said impregnating liquid in step iv) has a porosity of at least 30 vol%.

110. The method according to claim 74, wherein said porous shaped article having an increased compressive strength removed from said impregnating liquid in step iv) has a porosity of 50-90 vol%.