CA1297039C

CA1297039C - Calcium phosphate bone substitute materials

Info

Publication number: CA1297039C
Application number: CA000558717A
Authority: CA
Inventors: Eugene W. White
Original assignee: Interpore International Inc
Current assignee: Interpore International Inc
Priority date: 1987-02-13
Filing date: 1988-02-11
Publication date: 1992-03-10
Anticipated expiration: 2009-03-10
Also published as: US4861733A; EP0278583A2; EP0278583A3

Abstract

CALCIUM PHOSPHATE BONE SUBSTITUTE MATERIALS
ABSTRACT OF THE DISCLOSURE

Calcium phosphates useful as bone substitute materi-al or for the manufacture of prosthetic devices have been prepared from calcium hydroxyapatite material which has a uniformly permeable microporous structure chacter-ized by a substantially uniform pore volume in the range from about 10 to about 90% and by a pronounced three-dimensional fenestrate structure corresponding to the microstructure of the porous carbonate echinoderm or scleractinian coral skeletal material of marine life by reacting said calcium hydroxyapatite material which has a calcium to phosphorus atomic ratio of about 1.66 with a phosphate-contributing or phosphorus-contributing moiety or with a calcium-contributing or calcium oxide-contributing moiety so as to alter the calcium to phos-phorus Ca/P atomic ratio to yield a calcium phosphate material retaining the above-described microstructure of the porous carbonate echinoderm or scleractinian coral skeletal material but having a calcium to phosphorus Ca/P atomic ratio less than or greater than 1.6, such as a calcium phosphate material comprising dicalcium phos-phate and/or tricalcium phosphate and having a calcium to phosphorus Ca/P atomic ratio in the range 1.0 1.5 when the calcium hydroxyapatite material is reacted with said phosphate-contributing or phosphorus-contributing moiety or a calcium phosphate material having a calcium to phosphorus Ca/P atomic ratio greater than 1.66 up to 2.0 when the calcium hydroxyapatite material is reacted with said calcium-contributing or calcium oxide-contrib-uting moiety and comprising tetracalcium phosphate.

Description

~2~3g C~ P~OS~T~ BO~ 5~BSTITDT~ ~A~

RQ~ OF T~ INV~TIO~

Porous carbonate echinoderm or scleractinian skele-tal material of marine life has a unique structure.
This material has a uniformly permeable microporou~
structure characterized by a substantially uniform pore volume in the range from about 10 to about 904 and by a pronounced three-dimensional fenestrate structure. The microstructure of this material is somewhat sirnilar to the cancellous structure characteristic of boney tissue or ~one. Because of this unique microstructure of the porou~ carbonate echinoderm or scleractinian coral skeletal material of marine life these materialq would appear to be use~ul as bone substitute material. Howev-er, the carbonate of this material, such as provided in echinoid spine calcite and Porites skeletal aragonite, do not have the desired durability for employment as bone substitutes. These materialsi however, including their unique above-mentioned microporous structure~ have been replicated in other materials, such as metals, which would appear to possess better physical properties from the point of strength and durability while at the sam2 time providing the distinct unique microporous structure of the original porous carbonate coral skele-tal mat~rial. U.s. 3,890,107 discloses techniques, and products resultinq therefrom, for replicating the unique microporous structure of the above-mentioned coral material including deriva~ives thereof.

It is also known that the aforementioned coral materials may be converted by chemical techniques em-ploying a hydrothermal exchange reaction so as ~o con-, .~ , . .

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vert the carbonate or the calciu~ carbonate of the coralmaterial to hydroxyapatite while at the same time re-taining the unique microstructure of the coral material.
U.S. 3,929,971 discloses a hydrothermal exchange reac-tion for converting the porous carbonate skeletal mate-rial of marine life into a phosphate or hydroxyapatite skeletal material possessing the same microstructure as the carbonate skeletal material. These synthetic hy-droxyapatite materials have been produced commercially and are available from Interpore International Inc., Irvine, California, under the tradename Interpore-200, which is derived from certain coral o~ the genus ~Q~
ites, which have an average pore diameter of about 200 um, and under the tradename Interpore-500 der~ved from certain members of the fa~ily 5~L~e~, whieh have pore diameters of about 500 um~

These special Interpore hydroxyapatite material~
have also been identified as replamineform hydroxy-apaptite and coralline hydroxyapatite. Interpore-200 and Interpore-500 have been found to be useful as bone substitute materials. More information concerning these materials is to be found in the article by Eugene White and Edwin C. Shors entitled "Biomaterial Aspects of Interpore-200 Porou~ Hydroxyapatite~, which appeared in Pen~al_Ç~inics of North America, Vol. 30, No. 1, January 1985, pp. 4~-67.

In addition to the above-described materials which have the unique microstructure of porous skeletal coral material, other materials have been proposed as bone substitute materials, see ~.S. Patents 4,097,935, 4,195,366, 4,308,064 and 4,314,380. For the most part, however, these other bone substitute materials which do not possess the unique structure of coral material which ' ~
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is possessed by Interpore-200 and Interpore-S00, have not been completely satisfactory.

Despite the fact that calcium phosphates have been well investigated, see the publication entitled BiQ-i~L~is~Q ~L~I~IL~e~s~ha~, particularly Chapter 1 of F.C.M. Driessens entitled "Formation and Stability of Calcium Phosphates in Relation to the Phase Composition of the Mineral in Calcified Tissues~, and Chapter S by Rlaas deGroot entitled "Ceramics of Calcium Phosphates:
Preparation and Pcoperties~, other calcium phosphate materials which possess the advantages and the unique coral-derived microporous structure of Interpore-200 and Interpore-500 have not yet been satisfactorily produced.

The physical properties of the apatite bone substi-tute materials which possess the unique microstructure of skeletal material, such as Interpore-200 and Interpore-500, although satisfactory, do not provide for all the needs of surgeons employing the same as bone replacements and bone implant materials. For example, some surgeons would prefer a similar material but made up of a more readily absorbable or resorbable material~
such as a material which would be absorbed by the body or would disintegrate within about six months to two years. Other surgeons would prefer to employ a similar such material which is more refractory, lasts about ten years, more or less, or be substantially permanent. The presently available materials, such as Interpore-200 and Interpore-500, possess properties somewhat intermediate and are rather fixed since these materials are comprised substantially only o~ hydroxyapatite.

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~X~9~dO~9 ~4--It is an object of this invention to provide bone substitute materials and a method for their man~facture derived from hydroxyapatite or other calcium phosphate bone substitute material having the unique microstruc-ture of the porous ~arbonate echinoderm scleractinian coral skeletal material of marine life.

It is ancther object of this invention to provide bone substitute materials derived from hydroxyapatite material or other calcium phosphate bone substitute material which has the unique microstructure of the porou~ carbonate echinoderm or scleractinian coral skeletal material of marine life or the cancellou~
structure characteristic of boney tissue or bone but which is chemically different from hydroxapatite or the material from which it is derived but yat pos~essing substantially the same microstructure of the material from which it is derived and which is relatively more or less readily absorbabl e by the body .

How these and other objects of the invention are achieved will become apparent in the light of the accom-panying disclosure made with reference to the accompany ing drawing which illustrate~ a portion of the phase diagram of the system CaO-P20 S~ 0~ T~ I~VE~TIQ~

Calcium phosphates chemically differing f rom hydroxapatite and useful as bone substitute materials for the manufacture of prosthetic devices have been prepared from hydroxyapatite material. The hydroxy-apatite materi~ employed in one ~mbodiment of this invention for the manufacture of these calcium phos-~ .. . .
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~ILf~ 3~' phate~ is d~sirably itself useful as a bon~ substitutematerial and has the cancellous structure characteristic of boney tissue or bone or a uniformly permeable micro-porous structure characterized by a substantially uni-form pore volume in the range from about 10-90~ and by a pronounced three-dimensional fenestrate material corre-sponding to the microstructure of the porous carbonate echinoderm scleractinian coral skeletal material of marine bife.

The calcium phosphates of thi~ invention in accor-dance with one embodiment are prepared by reacting hydroxyapatite CalO(po4)6(o~)2 materlal which has the above-described microporous structure and which ha~ a calcium to phosphorus atomic to phosphorus atomic ratio of about 1.66 with one or more other materials, calcium or phosphorus compounds, so as to produce a reaction product wherein the Ca/P ratio is less than 1.66 or -~ greater than l.66.

~: Suitable such hydroxya2atite material is the above-described lnterpore-200 and Interpore-500. The hydroxy-apatite material is reacted with a phosphate-contribut-ing or phosphorus-contributing moiety or with a calcium-contributing or calcium oxide-contributing moiety so as to alt~r the calcium to phosphorus Ca/P atomic ratio of the resulting reaction product to yield a calcium phos-phate material which, while retaining the above de-scribed microstructure of the porous carbonate echino-derm or scleractinian coral skeletal material, has an altered, increased or decreased, calcium to phosphours Ca/P atomic ratio greater than 1.6 or less than about 1.6. The resulting calcium phosphate has a Ca/P atomic ratio in the range 1.0-1.5, or less than 1.66 when hydroxyapatite material i5 reacted with a phosphate-3~

contributing or phosphorus-contributing moiety. This resulting calcium phosphate material would contain tricalcium phosphate or dicalcium phosphate or mixtures thereof, depending upon the e~tent of the addition and the reaction of the phosphate-containing or pho~phorus-contributing moiety ~ith the hydroxyapatite material being treated. By employing, instead of phosphate-contributing or phosphorus contributing moiety for reaction with the hydroxyapatiite material, a calcium-contributing or calcium oxide-contributing moiety for reaction with the hydroxyapatite material, there would be produced a calcium phosphate material which would have a Ca/P atomic ratio greater than 1.66 up to about 2.0 and which would comprise tetracalcium phosphate Ca4P2Og, usually a mixture of tetracalcium phosphate and hydr oxy apatite.

The calcium phosphates produced in accordance with this invention, e.g. from hydroxyapatite material, ar~
produced by adding to or incorporating in the hydroxy-ap~tite material the phosphate-contributing or phos-phorus-contributing moiety in the instance when it is desired to produce a calcium phosphate material having a lower Ca/P atomic ratio in the range 1.0-1.5, such as a calcium phosphate material containing dicalcium phos-j phate and tricalcium phosphate, or by adding to or incorporating in the hydroxyapatite material a calcium-contributing or calcium oxide-contributing moiety when it is desired to produce a calcium phosphate material having Ca/P atomic ratio above 1.6, such as greater than 1.66 up to 2.0, and to produce a calcium phosphate material which contains therein tetracalcium phosphate.

The above-mentioned moieties for reaction with the calcium phosphate or hydroxyapatite material whose Ca/P
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ratio i5 to be altered, are added to or incorporated therein, preferably in the form of an aqueous solution or finely divided suspensionr ~y employing water-solu-ble moieties or by employing very finely divided moi-eties in suspension in a suitable carrier, such as an aqueous suspension. These moi.eties are added to the hydroxyapatite material so as to substantially complete ly and uniformly occupy and coat or cover the surfaces, internal and external, of the hydroxyapatite or calcium phosphate material undergoing treatment. By alternate-ly and successively wetting and drying the material to be treated, a substantial layer or amount of the desired moiety can be deposited onto and within the material.

Thereupon, the treated calcium phosphate material, such as hydroxyapatite, is heated or fired to an elevated temperature without melting to carry out the solid state reaction to effect the alteration of the Ca/P atomlc ratio, such as from a value of about 1.6 characteristic of hydroxyapatite up to a.o characteristic of tetra alcium phosphate or to a lower valu~ of 1.0 characteristic of dicalcium phosphate. A
firing temp~rature up to about 1350-1550Co is employed for the production of a calcium phosphate product containing tetracacl ium phosphate or a firing temperature up to about 1275C., such as a temperature in the range 1000-1250C. for a dicalcium phosphate and/or a tricalcium phosphate product. At these relatively firing lower temperatures there wo~ d be produced upon the employment of phosphate-contrlbuting or phosphorus-contributing moiety, a resulting treated calcium phosphate which~ as indicated, would have a Ca/P atomic ratio less than 1.6, such as a ratio of less than I.S or in the range 1.0-1.5, and containing dicalcium phosphate or tricalcium phosphate or mixtures thereof .

': ' Suitable phosphate-contributing or phosphorus-con-tributing moieties for use in the practice of this invention include phosphoric acid, H3P04 the ammonium phosphates, such as diammonium phosphate (NH4)2Hpo4 and other, preferably water-soluble and volatilizable phos-phate compounds . Sui tabl e cal ci um oxide-contrihuting or calcium-contributing moieties useful in the practice of this invention include the water-soluble, also pre~era-bly volatilizable calcium compounds. Particularly useful are solutions and/or finely divided suspensions of calcium oxide, calcium hydroxide, calcium nitrate and other calcium organic compounds, such as calcium ace-tate, calcium butyrate and calci~n propionate.

The firing operation during which the calcium phos-phate material, e.g. hydroxyapatite, undergoing alter-ation of its Ca/P ratio to a higher or lower value along with the added calcium-contributing or phosphorus-contributing moiety is carried out in an inert or, preferably, in an oxidizing atomosphere, e.g~ in the presence of air or oxygen, for a sufficient period of time to effect the desired alteration of the Ca/P ratio of the calcium phosphate being fired to a higher or lower value. The lowest Ca/P ratio sought or desired is 1.0, equivale~t to dicalcium phosphate, and the highest Ca/P ratio sought or desired is 2, equivalent to tetra-calcium phosphate.

The duration of firing varies with the firing tem-perature employed, a hi~her firing temperature tending to increase the reaction rate with the result that shorter firing times are experienced. For example, or the production of a fired calcium phospphate material having a Ca/P ratio of 2.0, the firing and temeprature is desirably carried out at a temperature in the range ;33~
g 1300-1550C. The firing time is longer, abo~t 12-24 hours, more or less, when carried out at a firing temp-erature of about 1300C. and shorter, about 6-16 hours, more or less, when the firinc1 temperature employed is about 1300-1550C. When it is desired to produce a fired calcium phosphate material having a lower Ca/P
ratio down to 1.0, the firing temperature employed is desirably in the range from about 1000 to about 1250C., preferably in the range 1000-1125C. A lower firing temperature would require a longer firing time, in the range about 8-20 hours and a higher firing t~mperat~ur3e would yield a shorter firing time in the ranye J~ J~
hours, more or less. If desired, multiple firing opera-tions, also including multiple additions of a calcium-contributing moiety or a phosphorus-contributing moiety, may be employed.

The firing time required to produce the fired calci-um phosphate product of desired quality, composition and Ca/P ratio, also depends upon the calcium-contributiny or phosphorus-contributing moiety employed. Some such moieties are more effective reactive than others at a given firing temperature. The use of a firing adju-vant to improv2 or increase the effectiveness or reac-tivity of the added calcium-contributing or phosphorus-contributing moiety to the calcium phosphate material undergoing firing is helpful, particularly in reducing the firing time required. The use of a scavenger when the calcium-contributing moiety or the phosphorus-contributing moiety includes one or more elements which would be undesirable to be present in the finished fired calcium phosphate product, might also tend not only to decrease the firing time, but also increase the effectiveness of the calcium contributing or phosphorus-contributing moiety employed in the firing operationO

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In general, the firing operation is carried out for a sufficient period of time so that the finished fired calcium phosphate product has the desired Ca/P ratio with respect to the startiny calcium phosphate material.

8U~MARY OF THE~ I~ENTION

The invention accordingly provides a uniform calcium phosphate-containing material useful as bone substitute material or for the manufacture of prosthetic devices, having a cancellous structure characteristic of boney tissue or bone or a substantially uniformly permeable microporous structure characterized by a substantially uniform pore volume in the range from about 10 to about 90% and by a pronounced three-dimensional fenestrate structure corresponding to the microstructure of the porous carbonate echinoderm or scleractinian coral skeletal material of marine life and providing a periodic minimal surface.
The periodic minimal surface divides the volume of the material into two interpenetrating regions, each of which is a single multipl4 connected domain~ The material has a substantially uniform pore size diameter and substantially uniform pore connections or openings in the range from about 5 microns to about 500 microns, the makerial comprising a calcium phosphate having a calcium to phosphorus Ca/P atomic ratio in the range 1.0-2.0 and consisting essentially of a mixture of dicalcium phosphate Ca2P2O7 and tricalcium phosphate Ca3P2O8 or a mixture of tricalcium phosphate Ca3P208 and hydroxyapatite or a mixture of tetracalcium phosphate Ca4P2Og and hydroxyapatite.
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; The invention further provides as an article of manufacture a shaped structure consisting essentially of substantially organic-free uniform calcium phosphate material having a substantially uniformly permeable microporous structure characterized by a substantially uniform pore volume in the range ; from about 10 to about 90% and by a pronounced three-dimensional fenestrate structure corresponding to the microstructure of the '~ .

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-lOa-porous carbonate echinoderm or scleractinian coral skeletal material of marine life and providiny a periodic minimal surface.
The pe~iodic minimal surface divides the volume of the material comprising the shaped structure into two interperletrating regions, each of which is a single multiple connected domain.
The material has a substantially uniform pore size diameter and substantially uniform pore connections or openings in the ranye from about 5 microns to about 500 microns the material comprisiny a calcium phosphate having a calcium to phosphorus Ca/P atomic ratio in the range 1.0-2.0 and consistiny Ca2P207 and tricalcium phosphate Ca3P208 or a mixture of tricalcium phosphate Ca3P208 and hydroxyapatite or a mixture of tetracalcium phosphate Ca4P209 and hydroxyapatite.

The invention further provides finely divided substantially organic-frae uniform calcium phosphate material useful as bone substitute material and the like the particles making up the finely divided calcium phosphate material having a substantially uniformly permeable microporous structure characterized by a substantially uniform pore volume in the range o~ from about 10 to about 90% by a pronounced three-dimensional fenestrate structure corresponding to the microstructure o~ the porous carbonate echinoderm or scleractinian coral skeletal material of marine life and providing a periodic minimal surface. The periodic minimal surface divides the volume of the material into two interpenetrating regions, each of which is a single multiple connected domain. The material has a substantially uniform pore size diameter and substantially uniform pore connections or openings in the range from about 5 microns to about 500 microns the material comprising a calcium phosphate having a calcium phosphorus Ca/P atomic ratio in the range 1.0-2.0 and consisting essentially of a mixture of dicalcium phosphate Ca2P207 and tricalcium phosphate Ca3P208 or a mixtura of tricalcium phosphate Ca3P20B and hydroxyapatite or a mixture of hydroxyapatite and tetracalcium phosphate Ca~P209.
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-lOb-Accordiny to another aspect of the invention, there is provided a method of converting calcium hydroxyapatite material having a calcium to phosphorus Ca/P atomic ratio of 1.66 to a uniform calcium phosphate material useful as bone substitute material or for the manufacture of prosthetic devices, the hydroxyapatite material having a substantially uniformly permeable microporous structure characterized by a substantially uniform pore volume in the range from about 10 to about 90% and by a pronounced three-dimensional fenestrate structure corresponding to the microstructure of the porous carbonate echinoderm or scleractinian coral skeletal material of marine life and providing a periodic minimal surface. The periodic minimal surface divides the volume of the hydroxyapatite material into two interpenetrating regions, each of which is a single multiple connected domain. The hydroxyapatite material has a substantially uniform pore size diameter and substantially uniform pore connections or openings in the range from about 5 microns to about 500 microns, the calcium pho~phate material having a calcium to phosphorus Ca/P atomic ratio lower than 1.66 and consisting essentially of a mixture of dicalcium phosphate Ca2P207 and tricalcium phosphate Ca3P208. The method comprises contacting the hydroxyapatite material with a phosphate solution to effect substantially unifo~n wetting of the hydroxyapatite material by the phosphate solution, drying the resulting treated hyd~oxyapatite material to effect deposition of the phosphate from the solution substantially uniformly onto the surface of the hydroxyapatite material and heating or firiny the resulting phosphate treated hydroxyapatite material to decrease the calcium to phosphorus Ca/P atomic ratio thereof to a value less than 1.66 to produce a calcium phosphate material consisting essentially of a mixture of dicalcium phosphate Ca2P207 and tricalcium Ca3P208 or a mixture of dicalcium phosphate Ca2P207 tricalcium phosphate Ca3P208 and hydroxyapatite.

The invention further provides a method of converting calcium hydroxyapatite material having a calcium to phosphorus ' ' --.l.OC--Ca/P atomic ratio of 1.66 to a uniform phosphate material useful as bone substitute material or for the manufacture of prosthetic devices, the hydroxyapatite material having a substantially uniformly permeable microporous structure characterized by a substantially uniform pore volume in the range from about 10 to about 90% and by a pronounced t:hree-dimensional fenestrate structure corresponding to the microstructure of the porous carbonate echinoderm or scl~ractini,an coral skeletal material of marine life and providing a periodic minimal surface. The periodic minimal surface divides the!volume of the hydroxyapatite material into two interpenetrating regions, each of which is a single multiple connected domain. 'rhe hydroxyapatite material has a substantially uniform pore size diameter and substantially uniform pore connections or openings in the range from about 5 microns to about 500 microns, the calcium phosphate material having a calcium to phosphorus Ca/P atomic ratio greater than 1.66 and up to 2.0 and containing tetracalcium phosphate Ca4P209.
The method comprises contacting the hydroxyapatite material with a calcium-containing solution to eff~ct substantially uniform absorption or wetting of the calcium-containing solution by the hydroxyapatite material or substantially uniform wetting of the hydroxyapatite material by the calcium-containing solution, drying the resulting treated hydroxyapatite material to effect deposition of the calcium-containing component of the solution substantially uniformly onto the surface of the hydroxyapatite material and heating or firing the resulting calcium treated hydroxyapatite material to increase the calcium to phosphorus Ca/P atomic ratio thereof to a value greater than 1.66 and up to 2.0 and to produce a calcium phosphate material consisting essentially of a mixture of hydroxyapatite and tetracalcium phosphate Ca4P209.

The invention further provides a method of converting calcium hydroxyapatite material having a calcium to phosphorus Ca/P atomic ratio of 1.66 to a uniform calcium phosphate material useful as bone substitute material or of the manufacture of :, 7~3~3 -10~ -prosthetic devices, the hydroxyapatite material having a substantially uniformly permeable microporous structure characterized by a substantially uniform pore volume in the range from about 10 to about 90% and by a pronounced three-dimensional fenestrate structure corresponding to the microstructure of the porous carbonate echinoderm or scleractinian coral skeletal material of marine life and providing a periodic minimal surface.
The periodic minimal surface divides the volume of the hydroxyapatite material into two interpenetrating regions, each o~ which is a single multiple connected domain. The hydroxyapatite material has a substantially uni~orm pore size diameter and substantially uniform pore connections or openings in the range from about 5 microns to about 500 microns, the calcium phosphate material having a calcium to phosphorus Ca/P
atomic ratio lower than 1.66 and consisting essentially of a mixture of dicalcium phosphate Ca2P207 and tricalcium phosphate Ca3P208 or a mixture of tricalcium phosphate and hydroxyapatite or the calcium phosphate material having a calcium to phosphorus Ca/P atomic ratio greater than 1.66 and containing hydroxyapatite and tetracalcium phosphate Ca4P209. The method comprises contacting the hydroxyapatite material with a phosphate solution or with a calcium-containing solution to effect substan~ially uniform absorption of the phosphate solution or the calcium-containing solution by the hydroxyapatite material or substantially uni~orm wetting of the hydroxyapatite material by the phosphate solution or the calcium-containing solution, drying the resulting treated hydroxyapatite material to ef~ect deposition of the phosphate from the phosphate solution or the calcium from the calcium-containing solution onto the surfac2 of the hydroxyapatite material and heating or firing the resulting treated hydroxyapatite material to decrease the calcium to phosphorus Ca/P atomic ratio thereo~ to a value less than 1.66 and in the range 1.0 1.5 and to produce a calcium phosphate material consisting essentially of a mixture of dicalcium phosphate Ca2P207 and tricalcium phosphate Ca3P208 when the solution applied to the hydroxyapatite material is the phosphate :

-lOe-solution and to produce a calcium phospha-t,e material having a calcium to p~osphate Ca/P atomic ratio greater than 1.66 and up to 2.0 and consisting essentially of hydroxyapatite and tetracalcium phosphate Ca4P209 when the solution is a calcium-containing solution.

The invention further provides a method of treating calcium phosphate material, the calcium phosphate material having a substantially uniform permeable microporous structure characterized by a substantially uniform pore volume in the range from about 10 to about 90% and by a pronounced three-dimensional fenestrate structure correspondiny to the microstructure of the porous echinoderm or scleractinian coral skeletal material of marine life and providing a periodic minimal sur~ace. The periodic minimal surface divides the volume of the calcium phosphate material into two interpenetrating regions, each of which is a single multiple-connected domain. The calcium phosphate material has a substantially uniform pore size diameter and substantially uniform pore connections or openings in the range from about 5 microns to about 500 microns, the calcium phosphate material having a calcium to phosphorus Ca~P atomic ratio in the range 1.0 to 2.0 to change tha Ca/P ratio to a higher value in the range 1.0-2Ø The method comprises, wherein the Ca/P ratio o~ the calcium phosphate material is l.O or greater but less than 2, adding or incorporating a solution of a calcium-contributing moiety to the calcium phosphate material and firing the resulting treated calcium phosphate material to yield a fired uniform calcium phosphate produce which has a calcium to phosphate atomic ratio greater than the Ca/P ratio o~ the calcium phosphate material.

The invention further provides a method of treating a calcium phosphate material wherein the calcium phosphate material has a substantially uniformly permeable microporous structure characterized by a substantially uniform pore volume in the range from about 10 to about 90% and by a pronounced three-dimensional -10~~

fenestrate structure corresponding to the microstructure of the porous echinoderm or scleractinian coral skeletal material of marine life and providing a periodic minimal surface. The periodic minimal surface divides the vo:Lume of the calcium phosphate material into two interpenetrating regions, each of which is a single multiple-connected domain. The calcium phosphate material has a substantially uniform pore size diameter and substantially uniform pore connections or openings in the range from about 5 microns to about 500 microns, the calcium phosphate material having calcium to phosphate Ca/P atomic ratio in the range 1.0 to 2.0 to chanye the Ca/P ratio to a lower value in the range 1.0-2Ø The method comprises, where the Ca/P ratio of the calcium phosphate material is 2.0 or less but greater than 1, adding or incorporating a phosphate-contributing or phosphorus-contributing moiety to the calcium phosphate material and firing the resulting treated calcium phosphate material to yield a fired uniform calcium phosphorus product which has a calcium to phosphate atomic ratio less than the Ca/P ratio of the calcium phosphate material.

DE~AIL~D D~CRIPTION OF THE INVENTION

Tests were carried out to alter hydroxyapatite material having the above~described microstructure of porous carbonate echinoderm or scleractinian coral skeletal material of marine life, said hydroxyapatite material having a Ca/P atomic ratio of 1.66 to a lower Ca/P ratio. Specifically, experiments were carried out to convert the hydroxyapatite material to tricalcium phosphate, more specifically, whitlockite beta-Ca3P2O8. This work was carried out to produce from the hydroxyapatite material, tricalcium phosphate which is more resorbable than hydroxyapatite while at the same time retaining the microstructure of the starting hydroxyapatite material.

In these tests blocks of hydroxyapatite material Interpore 500 or IP 500 measuring 15 x 3Q x 30 mm were suspended from a '~

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-lOg-stainless steel wire loop and lowered into a concentrate 1:2 aqueous solution of (NH4)2HPO4:H20. After a two minute soaking in the solution, the blocks were removed and the treating solution removed by shaking the blocks. The blocks were placed on an lalumina substrate and rotated in 90 increments every Pew minutes~ After air drying for about 2 hours, the blocks on the alumina substrate were placed in a warm (50 C.) oven. The rotation was again continued every few minutes for an hour and the temperature increased to 80 C. and the blocks lePt in the oven overnight. The dry weight of the blocks increased by /

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about 12.6%. There~pon, the blocks were heated in an oven over a period of 2-3/4 hours to about 1170C. and maintained at about this temperature (heat soaked) for abou~ 2 hours. Thereupon the blocks were reduced in temperature to about 100C. or lower over a period of 8 hours. It was observed that the final fired or heated weight of the blocks increased about 4.1~ above the starting hydroxyapatite material.

Upon examination, the fired hydroxyapatite blocks were found to have been converted to 60~ whitlockite or beta-Ca3P2O8 and 40~ alpha-Ca2P2O7- Whitlockite, the familiar form of tricalcium phosphate, is absorbed in the body more readily than hydroxyapaptite and the tricalcium phosphate alpha-Ca2P2O7, in turn, is more quickly absorbable than whitlockite. From the various tests carried out following the above procedures and employing different hydroxyapatite starting material, the following re~ults were obtained.

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TAB LE NO .
SUMMARY OF CONVERSION RU~I DATA

Starting Added (dry) C1~3 28 %
Hydroxy- w~ Phosphate % Hydroxy-apatite Run # (~H4)2HP4 (Wh.itlockite) c( Ca P20 apatite IP500 HT-22 12.6~ 60 ~ 40 --IP500 HT-2lA 21% 60 40 ~-IP 500 HT-2l~ l 1, 9 70 30 __ IP500 HT-21C 36 70 30 __ 200 I{T-21D l 5 85 l 5 __ Bone HA _l 5 29% -85 l 5 _~

B one HA HT-l 9 - NA~ 90 l O _ _ IP 500 HT-l 8A 32 . 8 60 40 O~.
HT-l 8B 32 0 8 60 40 -- :

IP500 HT-23A 4. 2~ 70 l 5 l 5 IP500 HT-23B 0. 8% 70 -- 20 IP200 HT-230 3 . 0 60 -- 40 -. :
:~'IP 500 HT-24A NA? 60 -_ 40 IP200 XT~24B NA? 80 -- 20 IP500 HT-24C J~A? 80 lO*~ lO
IP200 HT-24D JIA? 90 l 0~ -IP500 HT-24E 8 . 3 80 l 0~* l O
IP200 HT-24F 5. l 90 _ l O
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~, * NA - Not Available ,~ *~ Mixture of Oc ancl~ -Ca2P207 A

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Referring now to the drawing which is a binary phase diagram of the system CaO-P2o5, the phase boundaries for the phases of interest, Ca2P207~ Ca2P208 and C~4P209~
are represented as sharp lines. In the interpretation of this binary diagram, if the Ca/P ratio is not almost exactly 1.5, then traces of either Ca2P207 will appear or trace~ of hydroxyapatite will remain, depending upon which side of the Ca3p2o8 boundary the bulk composition occurs. It should b2 understood, therefore, that pure tricalcium phosphate crystalline would b~ difficult to obtain and the usual result is that a less pure product is obtained + 5-10~. It is pointed out that hydro~y-apatite which has a nominal Ca/P ratio of l.S does not actually plot on the diagram because it contains som~
hydroxyl groups. It was observed that the hydroxy-apatite material tested, the IP 200 and the IP 500, maintained its hydroxyapatite crystal structure even when heated for 2 hours at 1350~C. Thus, the resulting fired products Ca3P2O8 and Ca2P~07 derived from the resulting ammonium phosphate treated hydroxyapatite were not just the result of heat treatment.

Tests were also carried out involving the heat treabment of hydroxyapatite material, such as Interpore-200, at a temperature of 1500C. and these tests did not ~how any significant conversion of hydroxyapatite to whitl ocki te .

Additional tests were carried out involving the treabment of hydroxyapatite material, such as InterpQre-2ao ~ with a phosphorus-contributing or phosphate-con-tributing moiety, such as phosphoric acid, and an ammo-nium phosphate, such as diammonium phosphate (NH4)~HPo4.
In khese test~ the hydroxyapaptite materials were also immersed in or soaked in solutions of phosphoric acid .

7~
14~

PO4 or (N~4)2HPO~ dried and ~hen fired in air at a temperature of 1175C. for about 2 hours. It was observed that dipping or immersing the hydroxyapaptite material in concentrated phosplloric acid ~3PO4, followed by drying and firing at 1175C. resulted in substantially complete conversion of the hydroxyapatite to produce a material containin~ about 15-20%
whitlockite and a major amount of the remainder compris-ing dicalcium phosphate, particularly beta-Ca2P2O7- It was observed that one sample oi. hydroxyapatite 50 treat-ed contained a small amount of delta-Ca(PO4)2- This material delta-Ca(PO4)2 would be unstable in contact with water or body fluids.

In the above tests, when the hydroxyapatite material was immersed in 1 1 .H3Po4/H20 solution followed by drying and firing at 1175C., the hydroxyapatite was completely converted to 50-70~ whitlockite and 30-50 alpha-Ca2P2O7. In contrast with those hydroxyapatite ~aterials which had been treated to produce beta-Ca2P2O7, the alpha-Ca2P2O7 materials were considerably stronger than the starting hydroxyapatite material Nhen hydroxyapatite material was immersed in a 1:3 ~3PO4/~2O solution and dried and at 1175C., there was produced a fired material comprising 70~ hydroxyapatite and 30% whitlockite.

In the treatment of hydroxyapatite with diammonium phosphate solutions, one sample of hydroxyapatite wAs immersed in a hot saturated solution of diammonium pho~phate, dried and fired at 1150C. for 2.5 hsurs.
The resulting fired sample was predominantly, about 70%, whitlockite with minor amounts of hydroxyapatite, about 10~, and alpha-Ca2P2o7, about 20~. Another sample of hydroxyapatite material, when immersed in a 1:3.75 .:
, ~ :
, .

7(:~3~1 801ution of (NH4)2HPO4:H2O solution, and dried and ~ired at 1175C. for 2 hours yielded a material comprisiny 30~
hydroxyapatite, 70% whitlockite and a trace of alpha-Ca2P207 -Another sample, 10 x 15 x 82 mm of hydroxyapatite, was dipped into a 1:3 (NH4)2~lPO4:H2O solution for 10 minutes and dried while suspending in air~ When this material was fired for 2.25 hours at 1175C., the top end of the fired material was converted to 10%
hydroxyapatite, 80% whitlockite and 10% alpha-Ca2P2O7.
The bottom end of this vertically hung piece, however, presumably having a high concen~ration of phosphate therein, was converted to 80% whitlockite and 20~ alpha-Ca2P207 Another similarly treated hydroxyapatite sample was fired for 2 hours at 1175C. and produced a finished material comprising 30% hydroxya~atite and 70%
whitlockite with traces of alpha-Ca2P207. The res~ts of these tests are set fQrth in accompanying Table No.
2.

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The above-described tests which involved the addi-tion of a phosphate-contributing or phosphoru~-contrib-uting moiety, such as phosphoric acid ~3PO4 or an ammo-nium phosphate, such as (N~4)2HPO4, to hydroxyapatite material, such as Interpore--500 and Interpore-200, followed by subsequent heat treatment or firing in the presence of air at an elevated temperature of about 1125-1175C. for a number of hours, such as 1.5-2 hours, produced a material which contained tricalcium phos-phate. In these tests, as indicated hereinabove, when larger amounts of the phosphate-contributing or phospho-rus-contributing moiety were incorporated in the hy-droxyapatite undergoing treatment there were produced materials which contained tricalcium phosphate and dicalcium phosphate. In these tests, however, where the hydroxyapatite materials were immersed in a solution of phosphoric acid or diammonium phosphate and then drained, dried and fired, it was not always possible to obtain reproducible results. Further, it has been noted that when the firing of the phosphate-treated hydroxy-apatite material was carried out at 1175C. for conver-sion of the hydroxyapatite to dicalcium phosphate Ca2P207, th~ produced dicalcium phosphate was in both the alpha and beta crystal form or structure. As indi-cated in the accompanying CaO-P205 phase diagram, beta-Ca2p2o7 is the low temperature form of dicalcium pho~
phate.

, ~ , ~ ' .

3~31 In order to improve reproducibility of the test results, the phosphate-contributing or phosphorus-con-trihuting moiety, i.e. the aqueous solution of H3PO4 or ammonium phosphate, e.g. 1:2 (NH4)2~pO~ O was pipetted directly onto the hydroxyapatite material, a block of Interpore-500. This technique eliminated the uncertain-ty introduced by dipping and soaking and draining the hydroxyapatite material into the treating solution.
When pipette additions of the treatiny solution are made to the hydroxyapatite material, the ~olution does not immediately completely wet the entire structure. A few minutes are required for the treating solution to wick into all areas or surfaces of the block. This so~called pipette/wick method of add tion of the treating solution to the hydroxyapaite material was found to be satisfac-tory and yielded more or less reproducible results. The results of these tests employing the pipette/wick tech-nique are set forth in accompanying Table No. 3.

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~SIC l~IG~ DQT9 P~ ~P UI~IS
PI~D ~ 1125^C

.. _ . . _ . .. . _ SdnDple ~!SOOIr5$U- ~ Pho ~ ph ~ t c Fir ~d ~ TC P Add i t i o n ~ignAtioo, ~eight ~olution Addicion ~ei~ht Method . . . _ _ ~T-2S-I 11.15 13. 3 4. 4 12 . 2 60 4() -I~t 14.1 15.2 2.6 13.9 55 45 -III 10.1 11.1 3. 3 10.1 50 50 12.85 . 14.4 4.0 12.8 40 60 ~T-26-I 10. 3 15 . 9 18. 1 10. 9 lS 85 Dip/ Soa~
-II 10.6 16.7 19.2 11.3 10 90 -III 13 . Z 18 . 9 14 . 4 13 . ~S 5 95 oIV 10.9 14.9 12.2 11.3 5 95 E~-27-I 11.0 14.4 10.3 11.3 10 90 -II 15.8 la.2 5.1 15.8 40 60 -III 14. 2 16. 5 5. 4 14 . 2 20 RO ~, llT-28-I 10.5 11.3 2.5 10.4 60 40 -II 12 . 9 14 . 85 5 . 0 13 . 0 30 70 -III 12.2 14.95 7.S i2.3 20 ao Pipete~.
-~ 11.35 14.76 10.0 11.55 /7 93 Wic~
1~-29-~ 13.6 ~5.65, 5.0 13.65 30 70 -II 11.85 15.4 10.0 12.15 5 95 -III 16.65 22.89 12.5 17.15 10 90 -IV 1Z.3 1~.5~ 15.0 13.50 5 95 " ~ , . - , :
. .

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In th~ reported Table No. 3 tests, the hydroxy-apatite blocks, Interpore-500 blocks, measured 30 x 30 x50 mm and weighed in the range 10.1-16005 grams. The phase compositions reported in Table No. 3 were obtained by x-ray p~wder diffraction analysis~

In the samples designated HT-25, ~T-26 and HT-27 reported in Table No. 3 the blocks were handled by dipping and soaking. The pipette/wick method employed for the test series Ht-28 and HT-29 controlled phosphate addition at a predetermined level. It sho~ d he noted, as reported in Table No. 3, that the fired weight~ of the hydroxyapatite blocks were only 81 ightly greater than the starting hydroxyapatite material~ This was due not only to loss of NH4 but also to the loss during firing of some structural hydro~yl OH and carbon dioxide From the data presented in Table No. 3, it sho~ d be noted that ammonium phosphate additions, as small as 2.5% by weight, res~ ted in approximately 50% tricalcium phosphate yields. A 10~ ammonium phosphate addition gave 85-95% conversionO Even the addition of 18%
ammonium phosphate did not eliminate some residual hydro~yapatite. Based on the res~ts reported, it would appear ~hat co nv er s i o n of hy dr o xya patite to tricalcium phosphate is preferably carried out by the so-called pipette/wick technique for the addition of 1~%
~NH4)2HPO4 aqueous solution (1:2 aqueous solution) with firing at 1125~C. for 2 hours. Further, satisfactory results would also likely be obtained by employing more concentrated ammonium phosphate solutions and to carry out the draining and drying operations under a reduced atmospheric pressure and at a low temperature, below room temperature.

:

' ~2~ 9 Additional tests were carried out on hydroxyap~tite material, Interpore-500 and Interpore-200, for the conversion of the hydroxyapatite therein to tricalcium phosphate. These tests were carried out using the pipette/wick techn8ique of phosphate addition. The results of these tests are set forth in accompanying Table No. 4.

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In the tests reported in Table No. 4 a 1:2 (N~4)2~PO4:H2O solution was employed and the treated hydroxyapatite samples were :Eired at 1125C. for 2.3 hours. As indicated in Table No. 4, the hydroxyapatite sample materials readily converted to tricalcium phos-phate. The hydroxyapatite was substantially completely eliminated and dicalcium phosphate appeared in the finished fired samples only as a trace con3tituent.

In order to determine if firing temperature had an effect on dicalcium phosphate yield for a given phos-phate addition, three samples which had been fired at a temperature of 1125C. were refired at a temperature of 1250C. Accompanyiny Table No. 5 summarizes the res~ ts of these tests and indicates that the higher firing temperature produces a higher yield of dicalcium phosphate and reduces the concentration of hydroxy-apatite.

' 7~3~9 Reheat Eacperi~nt t~ See Ef'rect o8' 1125~C Y~ 1250C on Yleld o~ TCP/DCP.

l 1~5-C
Rehe~t Reh~at Deai~nat ion ~ HA

~T-31 -I I - 80 20 5- tO 90-95 - ;IT-29 IV

~-31-III 30 65 10-20 80-90 - 1~-28 III

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ln the foregoing tests there was employed the addi-tion of a phosphate-contributing or phosphorus-contrib-uting moiety to the hydroxya~tite material so as to alter the Ca/P ratio thereof from 1.66 to a lower value approaching 1.0, the value for dicalcium phosphate or to a lower value of 1.5, the value for tricalcium phos-phate.

Tests have also been carried out in accordance with the practices of this invention for converting the hydroxyapatite starting materi~ to a calcium phosphate material which has a higher Ca/P ratio, for example, from the hydroxyapatite Ca/P ratio of 1.66 to a higher Ca/P ratio up to a Ca/P ratio of 2Ø In these tests the starting material was Interpore-200 hydroxyapatite blocks measuring 2.5 x 2.5 x 1.2 ~cm and an Interpore-500 block measuring 2.5 x 2.5 x 1.5 cm.

The calcium-contributing or calcium oxide-contribut-ing moiety employed to increase the Ca/P ratio, was an aqueous solution of calcium nitrate. The calcium ni-trate was added to the hydroxyapatite blocks by the pipette/wick technique. After the addition of the calcium nitrate solution to the hydroxyapatite blocks, the blocks were placed on a polyethylene plastic mesh in a drying oven at a temperature of 80F. and 30~ relative humidity. The blocks were rotated at approximately 20 minute intervals for 6 hours and left overnight in the oven. Thereupon, the oven was heated to 75C. and the blocks dried for about 4 hours. The resulting treated, dried blocks were placed on an al ~lina substrate and placed in a LeMont* silicon carbide resistance heated laboratory furnace. The blocks were heated in the presence of air at a temperature of 1350C. for a period of about 7 hours and then left overnight in the furnace for cooling down.

Trade-mark ' , ~, '. : . , , :' :

3~

The blocks were cut in two and microscopic examina-tion showed excellent preservation of the internal pore structure as compared wi~h the hydroxyapatite starting material~ X-ray powder diffraction analysis of the firing samples indicated that the treated Interpore-500 material was more completely converted to tetracalcium phosphate Ca4P2Og than the Interpore-200 material. It was noted that a temperature of below about 1350C. is not likely usefully satisfactory for the conversion of the hydroxyapatite to tetracalcium phosphate since when the firing is carried out at 1250C., the c4nversion takes place too slowly. By firing at a temperature of about 1350C., the conversion of the hydroxyapatite to tetracalcium phosphate occurs more quickly, about 5--8 hours, more or less.

In these tests the hydroxyapatite material wa~
substantially converted. For example, in one of these tests only about 10% by weight hydroxyapatite remained in the treated hydroxyapatite material, the remainder being at least 50~ tetracalcium phosphate. Another test yielded a material which analyzed 50~ tetracalciwn phosphate, 40% hyroxyapatite. Still another yielded a material which analyzed 60~ tetracalcium phosphate and 30% hydroxyapatite. Yet other tests yielded materials which contained primarily, at least about 50-80~, tetra-calcium phosphate and a minor, small amount, about 5-10%, of hydroxyapatite.

Further tests were carried out employing granular hydroxyapatite material of the type used in the practices of this invention, particular IP 200 and IP
500 hydroxyapatite. In these tests the granular material measuring 1-2 mm for IP 500 hydroxyapatite and ' ' .

~2~7~13!g~

0.425-1.0 mm for IP 200 hydroxyapatite in amounts measuring 41.7 grams for IP 500 and 100.2 grams for IP
200 were separately loaded and mixed in Teflon*lined cylinders. With the cylinders tilted about 30 from the horizontal and rotated about their cylindrical axis the mass of the granular materi~ ~as tumbled therein. For each test there was added 253 by weight of a 1:2 (N~4)2~PO4:H2O, amounting to 8.5~ by weight dry ammonium phosphate. The ammonium phosphate solution was slowly added by pipette while the granular material was tumbled.

After the addition of the ammoniwn phosphate solution tumbling of the wetted granular material was continued intermittently evey 20-30 minutes to prevent too rapid drying of the surface layer granules. The granular material was fired on an alumina su~stratej the IP 500 granules were neated at a rate of 400C. per hour and held at 1125C. for two hours and ten minutes and the IP 200 granules were heated at a rate of about 600'C. per hour and held at 1125C. for two hours.

After firing and cooling, the granular materials were analyzed by X-ray powder diffraction and both the IP 500 and the IP 200 granular materials assayed 95% by weight tricalcium phosphate and 5% by ~eight hydro~apatite, showing the substantially complete conversion of hydroxyapatite, Ca/P ratio of 1.66, to a Ca/P ratio of 1.5, the Ca/P ratio for tricalcium phosphate.
.
As ~ill be apparent to those skilled in the art in the light of the ~ocegoing disclosure, many modifications, alterations and substitutions are possible in the practice of this invention without departing from the spirit or scope thereof.
* Trade-mark i ,:
. - , .:
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Claims

1. A uniform calcium phosphate-containing material useful as bone substitute material or for the manufacture of prosthetic devices, having a cancellous structure characteristic of boney tissue or bone or a substantially uniformly permeable microporous structure characterized by a substantially uniform pore volume in the range from about 10 to about 90% and by a pronounced three-dimensional fenestrate structure corresponding to the microstructure of the porous carbonate echinoderm or scleractinian coral skeletal material of marine life and providing a periodic minimal surface, said periodic minimal surface dividing the volume of said material into two interpenetrating regions, each of which is a single multiple connected domain, said material having a substantially uniform pore size diameter and substantially uniform pore connections or openings in the range from about 5 microns to about 500 microns, said material comprising a calcium phosphate having a calcium to phosphorus Ca/P atomic ratio in the range 1.0-2.0 and consisting essentially of a mixture of dicalcium phosphate Ca2P2O7 and tricalcium phosphate Ca3P2O8 or a mixture of tricalcium phosphate Ca3P2O8 and hydroxyapatite or a mixture of tetracalcium phosphate Ca4P2O9 and hydroxyapatite.

2. A uniform calcium phosphate-containing material in accordance with claim 1 wherein said mixture consists essentially of hydroxyapatite and tetracalcium phosphate.

3. A uniform calcium phosphate material in accordance with claim 1 wherein said mixture consists essentially of dicalcium phosphate and tricalcium phosphate.

4. A uniform calcium phosphate material in accordance with claim 2 wherein said mixture contains a major amount of hydroxyapatite.

5. A uniform calcium phosphate-containing material in accordance with claim 2 wherein said mixture comprises a substantially equimolar amount of hydroxyapatite and tetracalcium phosphate.

6. A uniform calcium phosphate material in accordance with claim 2 wherein said mixture comprises a major molal or a major amount by weight of tetracalcium phosphate.

7. A uniform calcium phosphate material in accordance with claim 3 wherein said mixture comprises a major molal amount or a major amount by weight of dicalcium phosphate.

8. A uniform calcium phosphate material in accordance with claim 3 wherein said mixture comprises a major molal amount or a major amount by weight of tricalcium phosphate.

9. A uniform calcium phosphate material in accordance with claim 1 wherein said mixture consist essentially of dicalcium phosphate.

10. A uniform calcium phosphate material in accordance with claim 1 wherein said mixture consists essentially of tetracalcium phosphate.

11. A uniform calcium phosphate material in accordance with claim 2 wherein said mixture contains about 10-30% by weight of hydroxyapatite and about 90-70% by weight of tetracalcium phosphate.

12. A uniform calcium phosphate material in accordance with claim 11 wherein said mixture contains 25% by weight hydroxyapatite.

13. A uniform calcium phosphate material in accordance with claim 3 wherein said mixture contains substantially equimolar amounts or substantially equal amounts of dicalcium phosphate and tricalcium phosphate.

14. A uniform calcium phosphate material in accordance with claim 4 wherein said mixture contains about 75% by weight tetracalcium phosphate.

15. A uniform calcium phosphate material in accordance with claim 1 wherein said material comprises substantially only dicalcium phosphate Ca2P2O7 and has a calcium to phosphorus Ca/P
atomic ratio of about 1.

16. A uniform calcium phosphate material in accordance with claim 1 wherein said material comprises substantially only tricalcium phosphate Ca3P2O8 and has a calcium to phosphorus Ca/P
atomic ratio of about 1.5.

17. A uniform calcium phosphate material in accordance with claim 1 wherein said material comprises substantially only tetracalcium phosphate Ca4P2O9 and has a calcium to phosphorus Ca/P atomic ratio of about 2Ø

18. As an article of manufacture a shaped structure consisting essentially of substantially organic-free uniform calcium phosphate material having a substantially uniformly permeable microporous structure characterized by a substantially uniform pore volume in the range from about 10 to about 90% and by a pronounced three-dimensional fenestrate structure corresponding to the microstructure of the porous carbonate echinoderm or scleractinian coral skeletal material of marine life and providing a periodic minimal surface, said periodic minimal surface dividing the volume of said material comprising said shaped structure into two interpenetrating regions, each of which is a single multiple connected domain, said material having a substantially uniform pore size diameter and substantially uniform pore connections or openings in the range from about 5 microns to about 500 microns, said material comprising a calcium phosphate having a calcium to phosphorus Ca/P atomic ratio in the range 1.0-2.0 and consisting Ca2P2O7 and tricalcium phosphate Ca3P2O8 or a mixture of tricalcium phosphate Ca3P2O8 and hydroxyapatite or a mixture of tetracalcium phosphate Ca4P2O9 and hydroxyapatite.

19. A shaped structure in accordance with claim 18 wherein said mixture consists essentially of tricalcium phosphate and hydroxyapatite.

20. A shaped structure in accordance with claim 18 wherein said mixture consists essentially of tetracalcium phosphate and hydroxyapatite.

21. A shaped structure in accordance with claim 18 wherein said mixture consists essentially of dicalcium phosphate and tricalcium phosphate.

22. Finely divided substantially organic-free uniform calcium phosphate material useful as bone substitute material and the like, the particles making up said finely divided calcium phosphate material having a substantially uniformly permeable microporous structure characterized by a substantially uniform pore volume in the range of from about 10 to about 90% by a pronounced three-dimensional senestrate structure corresponding to the microstructure of the porous carbonate echinoderm or scleractinian coral skeletal material of marine life and providing a periodic minimal surface, said periodic minimal surface dividing the volume of said material into two interpenetrating regions, each of which is a single multiple connected domain, said material having a substantially uniform pore size diameter and substantially uniform pore connections or openings in the range from about 5 microns to about 500 microns, said material comprising a calcium phosphate having a calcium phosphorus Ca/P atomic ratio in the range 1.0-2.0, and consisting essentially of a mixture of dicalcium phosphate Ca2P2O7 and tricalcium phosphate Ca3P2O8 or a mixture of tricalcium phosphate Ca3P2O8 and hydroxyapatite or a mixture of hydroxyapatite and tetracalcium phosphate Ca4P2O9.

23. Finely divided calcium phosphate material in accordance with claim 22 wherein said material consists essentially of tricalcium phosphate and hydroxyapatite.

24. Finely divided calcium phosphate material in accordance with claim 22 wherein said material consists essentially of dicalcium phosphate, tricalcium phosphate and also contains hydroxyapatite.

25. Finely divided organic-free calcium phosphate material in accordance with claim 22 wherein said finely divided calcium phosphate material comprises substantially only dicalcium phosphate Ca2P2O7 and has a calcium to phosphorus Ca/P atomic ratio of about 1Ø

26. Finely divided substantially organic-free calcium phosphate material in accordance with claim 16 wherein said substantially organic-free calcium phosphate material comprises substantially only tricalcium phosphate Ca3P2O8 and has a calcium to phosphorus Ca/P atomic ratio of about 1.5.

27. Finely divided substantially organic-free calcium phosphate material in accordance with claim 22 wherein said organic-free calcium phosphate material comprises substantially only tetracalcium phosphate Ca4P2O9 and has a calcium to phosphorus Ca/P atomic ratio of about 2Ø

28. A method of converting calcium hydroxyapatite material having a calcium to phosphorus Ca/P atomic ratio of 1.66 to a uniform calcium phosphate material useful as bone substitute material or for the manufacture of prosthetic devices, said hydroxyapatite material having Z1 substantially uniformly permeable microporous structure characterized by a substantially uniform pore volume in the range from about 10 to about 90% and by a pronounced three-dimensional fenestrate structure corresponding to the microstructure of the porous carbonate echinoderm or scleractinian coral skeletal material of marine life and providing a periodic minimal surface, said periodic minimal surface dividing the volume of said hydroxyapatite material into two interpenetrating regions, each of which is a single multiple connected domain, said hydroxyapatite material having a substantially uniform pore size diameter and substantially uniform pore connections or openings in the range from about 5 microns to about 500 microns, said calcium phosphate material having a calcium to phosphorus Ca/P atomic ratio lower than 1.66 and consisting essentially of a mixture of dicalcium phosphate Ca2P2O7 and tricalcium phosphate Ca3P2O8 which comprises contacting said hydroxyapatite material with a phosphate solution to effect substantially uniform wetting of said hydroxyapatite material by said phosphate solution, drying the resulting treated hydroxyapatite material to effect deposition of the phosphate from said solution substantially uniformly onto the surface of said hydroxyapatite material and heating or firing the resulting phosphate treated hydroxyapatite material to decrease the calcium to phosphorus Ca/P atomic ratio thereof to a value less than 1.66 to produce a calcium phosphate material consisting essentially of a mixture of dicalcium phosphate Ca2P2O7 and tricalcium Ca3P2O8 or a mixture of dicalcium phosphate Ca2P2O7 tricalcium phosphate Ca3P2O8 and hydroxyapatite.

29. A method in accordance with claim 28 wherein said phosphate solution contains a phosphoric acid.

30. A method in accordance with claim 28 wherein said phosphate solution is aqueous phosphoric acid H3PO4.

31. A method in accordance with claim 28 wherein said phosphate solution contains ammonium phosphate.

32. A method in accordance with claim 31 wherein said ammonium phosphate is diammonium phosphate.

33. A method in accordance with claim 28 wherein said hydroxyapatite material is heated or fired to a temperature in the range about 1000°-1250°C.

34. A method in accordance with claim 28 wherein said hydroxyapatite material is heated or fired to a temperature in the range about 1150°-1175°C.

35. A method of converting calcium hydroxyapatite material having a calcium to phosphorus Ca/P atomic ratio of 1.66 to a uniform phosphate material useful as bone substitute material or for the manufacture of prosthetic devices, said hydroxyapatite material having a substantially uniformly permeable microporous structure characterized by a substantially uniform pore volume in the range from about 10 to about 90% and by a pronounced three-dimensional fenestrate structure corresponding to the microstructure of the porous carbonate echinoderm or scleractinian coral skeletal material of marine life and providing a periodic minimal surface, said periodic minimal surface dividing the volume of said hydroxyapatite material into two interpenetrating regions, each of which is a single multiple connected domain, said hydroxyapatite material having a substantially uniform pore size diameter and substantially uniform pore connections or openings in the range from about 5 microns to about 500 microns, said calcium phosphate material having a calcium to phosphorus Ca/P atomic ratio greater than 1.66 and up to 2.0 and containing tetracalcium phosphate Ca4P2O9 which comprises contacting said hydroxyapatite material with a calcium-containing solution to effect substantially uniform absorption or wetting of said calcium-containing solution by said hydroxyapatite material or substantially uniform wetting of said hydroxyapatite material by said calcium-containing solution, drying the resulting treated hydroxyapatite material to effect deposition of the calcium-containing component of said solution substantially uniformly onto the surface of said hydroxyapatite material and heating or firing the resulting calcium treated hydroxyapatite material to increase the calcium to phosphorus Ca/P atomic ratio thereof to a value greater than 1.66 and up to 2.0 and to produce a calcium phosphate material consisting essentially of a mixture of hydroxyapatite and tetracalcium phosphate Ca4P2O9.

36. A method in accordance with claim 35 wherein said calcium-containing solution is an aqueous solution of a calcium-containing compound.

37. A method in accordance with claim 35 wherein said calcium-containing solution is an aqueous solution of calcium nitrate.

38. A method in accordance with claim 35 wherein said calcium-containing solution is a solution containing calcium hydroxide.

39. A method in accordance with claim 35 wherein said calcium-containing solution is an aqueous solution containing a calcium compound selected from the group consisting of calcium nitrate, calcium acetate, calcium chloride, calcium perchorate, calcium hypochlorite, calcium propionate and calcium butyrate.

40. A method in accordance with claim 35 wherein said hydroxyapatite material is heated or fired to a temperature in the range about 1300°-1400°C.

41. A method in accordance with claim 35 wherein said hydroxyapatite material is heated or fired to a temperature in the range about 1250°-1350°C.

42. A method of converting calcium hydroxyapatite material having a calcium to phosphorus Ca/P atomic ratio of 1.66 to a uniform calcium phosphate material useful as bone substitute material or of the manufacture of prosthetic devices, said hydroxyapatite material having a substantially uniformly permeable microporous structure characterized by a substantially uniform pore volume in the range from about 10 to about 90% and by a pronounced three-dimensional fenestrate structure corresponding to the microstructure of the porous carbonate echinoderm or scleractinian coral skeletal material of marine life and providing a periodic minimal surface, said periodic minimal surface dividing the volume of said hydroxyapatite material into two interpenetrating regions, each of which is a single multiple connected domain, said hydroxyapatite material having a substantially uniform pore size diameter and substantially uniform pore connections or openings in the range from about 5 microns to about 500 microns, said calcium phosphate material having a calcium to phosphorus Ca/P atomic ratio lower than 1.66 and consisting essentially of a mixture of dicalcium phosphate Ca2P2O7 and tricalcium phosphate Ca3P2O8 or a mixture of tricalcium phosphate and hydroxyapatite or said calcium phosphate material having a calcium to phosphorus Ca/P atomic ratio greater than 1.66 and containing hydroxyapatite and tetracalcium phosphate Ca4P2O9 which comprises contacting said hydroxyapatite material with a phosphate solution or with a calcium-containing solution to effect substantially uniform absorption of said phosphate solution or said calcium-containing solution by said hydroxyapatite material or substantially uniform wetting of said hydroxyapatite material by said phosphate solution or said calcium-containing solution, drying the resulting treated hydroxyapatite material to effect deposition of the phosphate from said phosphate solution or the! calcium from said calcium-containing solution onto the surface of said hydroxyapatite material and heading or firing the resulting treated hydroxyapatite material to decrease the calcium to phosphorus Ca/P atomic ratio thereof to a value less than 1.66 and in the range 1.0-1.5 and to produce a calcium phosphate material consisting essentially of a mixture of dicalcium phosphate Ca2P2O7 and tricalcium phosphate Ca3P2O8 when the solution applied to said hydroxyapatite material is said phosphate solution and to produce a calcium phosphate material having a calcium to phosphate Ca/P
atomic ratio greater than 1.66 and up to 2.0 and consisting essentially of hydroxyapatite and tetracalcium phosphate Ca4P2O9 when said solution is a calcium-containing solution.

43. A method of treating calcium phosphate material, said calcium phosphate material having a substantially uniform permeable microporous structure characterized by a substantially uniform pore volume in the range from about 10 to about 90% and by a pronounced three-dimensional fenestrate structure corresponding to the microstructure of the porous echinoderm or scleractinian coral skeletal material of marine life and providing a periodic minimal surface, said periodic minimal surface dividing the volume of said calcium phosphate material into two interpenetrating regions, each of which is a single multiple-connected domain, said calcium phosphate material having a substantially uniform pore size diameter and substantially uniform pore connections or openings in the range from about S microns to about 500 microns, said calcium phosphate material having a calcium to phosphorus Ca/P atomic ratio in the range 1.0 to 2.0 to change the Ca/P ratio to a higher value in the range 1.0-2.0 which comprises, wherein the Ca/P ratio of said calcium phosphate material is 1.0 or greater but less than 2, adding or incorporating a solution of a calcium-contributing moiety to said calcium phosphate material and firing the resulting treated calcium phosphate material to yield a fired uniform calcium phosphate produce which has a calcium to phosphate atomic ratio greater than the Ca/P ratio of said calcium phosphate material.

44. A method of treating a calcium phosphate material wherein said calcium phosphate material has a substantially uniformly permeable microporous structure characterized by a substantially uniform pore volume in the range from about 10 to about 90% and by a pronounced three-dimensional fenestrate structure corresponding to the microstructure of the porous echinoderm or scleractinian coral skeletal material of marine life and providing a periodic minimal surface, said periodic minimal surface dividing the volume of said calcium phosphate material into two interpenetrating regions, each of which is a single multiple-connected domain, said calcium phosphate material having a substantially uniform pore size diameter and substantially uniform pore connections or openings in the range from about 5 microns to about 500 microns, said calcium phosphate material having calcium to phosphate Ca/P atomic ratio in the range 1.0 to 2.0 to change the Ca/P ratio to a lower value in the range 1.0-2.0, which comprises, where the Ca/P ratio of said calcium phosphate material is 2.0 or less but greater than 1, adding or incorporating a phosphate-contributing or phosphorus-contributing moiety to said calcium phosphate material and firing the resulting treated calcium phosphate material to yield a fired uniform calcium phosphorus product which has a calcium to phosphate atomic ratio less than the Ca/P ratio of said calcium phosphate material.