Method for filling in defects or hollow portions of bones

A filler for filling in defects or hollow portions of bones to coalesce with the bone tissues is provided which comprises powders of a calcium phosphate compound having the apatite crystalline structure of each crystal grain size of from 50 .orgate. to 10 microns and represented by the following general formula of Ca.sub.m (PO.sub.4).sub.n OH (1.33.ltoreq.m/n.ltoreq.1.95); and said powders being adapted for filling in a fluidized or plasticized state. A method of treating a bone with the filler is also provided wherein at least a portion of said filler is filled in to reach the bone-marrow cavity of said bone.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates generally to a medical material, and 
particularly to an inorganic filler to be filled in defects or hollow 
portions formed by a removal operation of bone tumor or other causes in 
the bones of a living body to promote formation of new bone tissue at the 
filled portions and to coalesce with the bone tissue after the injured 
portions are completely cured. The present invention also relates to a 
medical treatment for curing the injured bones by the use of said filler. 
2. Prior Art 
In the surgical or orthopedic field, defects or hollow portions of bones 
are frequently formed by highly complicated fractures or a removal 
operation of bone tumor, and such defects or hollow portions should be 
cured by symphysis. In the prior art method, a cancellous bone is taken up 
from flank bones or other bones of the patient per se to be filled in the 
injured portion of bone to promote the cure of bone tissue. However, this 
prior art method is disadvantageous in that the patient suffers a greater 
pain from cumbersome labours necessitated in the operation, since a bone 
tissue other than the injured portion is taken out for use. Moreover, a 
sufficient amount of autoplastic bone cannot always be taken up from the 
patient's body for filling in a large defect or hollow portion of bone, 
and a certain substitute material is required to supplement the shortage 
of the required bone tissue in such a case. 
Other than the method of autoplastic filling, there are a homogeneous bone 
implantation method and a heterogeneous bone implantation method. As to 
the homogeneous bone implantation method, uses of frozen bones and 
decalcified bones have been investigated but have not yet reached the 
stage of clinical practice. In the heterogeneous bone implantation method, 
a so-called keel bone, which is prepared by removing proteins from a bone 
of cattle, is used in some cases. However, both of these known methods are 
not only accompanied with foreign body reactions but also lack osteogenic 
capacity, so that the post-operation course is not always good. 
Accordingly, there is an increasing demand for an artificial filler 
material for filling in defects or hollow portions of bones which is 
excellent in compatibility with the living body and has high osteogenic 
capacity to promote the bone-forming reaction at the filled portion and at 
the vicinity thereof to accelerate curing of the structure and function of 
injured bone tissue. 
With the aim to reducing the period of time required for curing the 
fractured bone, an internally fixing method is sometimes adopted wherein 
the fractured bone is directly fixed by the use of a metal plate, nail or 
screw. However, adopting such a method, there is often a case where so 
lengthy a time as six months or a whole year is necessary for complete 
curing. Furthermore, if the internally fixing method is adopted, the 
materials used for internal fixing shall be removed from the patient's 
body after the fractured bone is cured, and thus the patient suffers 
tremendous physical, psycological and economical burdens. If a filler 
material of the aforementioned kind for promoting the osteogenic capacity 
and for accelerating the remedy or cure of the fractured or injured 
portion is developed, it will be made possible to attain the object of 
therapy for a short period of time without the application of the 
internally fixing method. The filler material of the aforementined kind 
may be also used for the therapy of pseudoarthrosis. It is, therefore, 
considered that the development of such filler is of great medical value 
and contributes to welfare of humankind. 
On the other hand, various metals and plastics materials have hitherto been 
used as the substitute materials for hard tissues of living body. However, 
these conventional materials are apt to be dissolved or deteriorated under 
the severe environment in the living body and are often accompanied with 
poisonous actions or foreign body reactions. For this reason, biomaterials 
of ceramics which have improved compatibilities with a living body 
attracted public attention in recent years. At the present time, an 
artificial bone, an artificial joint and an artificial radix dentis made 
of single crystalline or polycrystalline alumina (Al.sub.2 O.sub.3) and an 
artificial radix dentis made of sintered calcium tertiary phosphate 
(Ca.sub.3 (PO.sub.4).sub.2) or sintered hydroxyapatite (Ca.sub.5 
(PO.sub.4).sub.3 OH) have been proposed. It has been reported that these 
materials are excellent in compatibility with a living body, for example, 
no appreciable formation of membrane caused by the foreign body reaction 
is observed when a sintered article of hydroxyapatite is implanted in a 
bone of a living body, which shows the direct connection between the 
sintered article and the bone tissue. However, these implantation 
materials are disadvantageously too hard and fragile, similarly as is the 
case of common ceramic materials, and should be improved in toughness and 
impact strength in order to use in the form of artificial bone or 
artificial radix dentis practically. 
OBJECTS AND SUMMARY OF THE INVENTION 
An object of the present invention is to provide a filler for filling in 
defects or hollow portions of bones which is excellent in compatibility 
with the living body and free from foreign body reaction. 
Another object of the present invention is to provide a filler for filling 
in defects or hollow portions of bones which can facilitate formation of 
new bone tissue remarkably and can considerably cut down the period of 
time required for curing the structure and function of bone tissue. 
A further object of the present invention is to provide a filler for 
filling in defects or hollow portions of bones which can coalesce with the 
bone tissue to form an integral autoplastic bone. 
Another object of the present invention is to provide a method of treating 
bones with a filler for facilitating formation of new bone remarkably and 
for leaving an adequate quantity of bone at the requisite portion. 
A further object of the present invention is to provide a method of 
treating bones with a filler for curing the structure and function of bone 
tissue not accompanied with any foreign body reaction for a short period 
of time. 
Yet a further object of the present invention is to provide a simple method 
for curing the defects or hollow portions of bones. 
According to the present invention, there is provided a filler for filling 
in defects or hollow portions of bones to coalesce with the bone tissues, 
comprising powders of a calcium phosphate compound having the apatite 
crystalline structure of each crystal grain size of from 50 .ANG. to 10 
microns and represented by the following general formula of Ca.sub.m 
(PO.sub.4).sub.n OH (1.33.ltoreq.m/n.ltoreq.1.95), and said powders being 
adapted for filling in a fluidized or plasticized state. 
Accordingg to another aspect of the present invention, there is provided a 
method of treating bones with the aforementioned filler, wherein at least 
a portion of said filler is filled in to reach the bone-marrow cavities of 
said bones.

DESCRIPTION OF THE INVENTION 
Various forms of calcium phosphate compounds are known including a compound 
referred to as hydroxyapatite and represented by the rational formula of 
Ca.sub.5 (PO.sub.4).sub.3 OH. A group of minerals referred to as generally 
apatite is represented by the rational formula of M.sub.m (RO.sub.4).sub.n 
X, wherein the site shown by M is occupied by a divalent cation such as 
Ca.sup.2+, Sr.sup.2+, Ba.sup.2+, Pb.sup.2+, Zn.sup.2+, Mg.sup.2+ and 
Fe.sup.2+ or a trivalent or monvalent cation such as Al.sup.3+, Y.sup.3+, 
La.sup.3+, Na.sup.+, K.sup.+ and H.sup.+, the site shown by RO.sub.4 is 
occupied by an anion such as PO.sub.4.sup.3-, VO.sub.4.sup.3-, 
BO.sub.3.sup.3-, CrO.sub.4.sup.3-, SO.sub.4.sup.2-, CO.sub.3.sup.2- and 
SiO.sub.4.sup.4- and the site shown by X is occupied by an anion such as 
OH.sup.-, F.sup.-, Cl.sup.-, O.sup.2- and CO.sub.3.sup.2-. Many compounds 
having resembling crystalline structures are included in this group. The 
aforementioned hydroxyapatite is a typical compound having the apatite 
crystalline structure and the composition theoretically represented by 
Ca.sub.5 (PO.sub.4).sub.3 OH. However, the composition of this compound 
produced by an artificial synthesis is not always represented by the 
theoretical formula but is represented by the formula of Ca.sub.m 
(PO.sub.4).sub.n OH wherein the molar ratio of m/n ranges within 
1.33.ltoreq.m/n.ltoreq.1.95. Although many hypotheses have been presented 
with regard to the phenomenon of variation of the value m/n (molar ratio) 
in a wide range, this is considered due to the particular crystalline 
structure of the apatite compound. If the composition is within the range 
as set forth above, the aimed compound may be artificially synthesized 
while avoiding the intermingled presence of different phases. In the 
present invention, the compounds having the compositions within the range 
as set forth above and having the apatite structure from the 
crystallographical viewpoint are referred to as the calcium phosphate 
compounds having the apatite crystalline structures or the apatite calcium 
phosphate compounds which include hydroxyapatite of the theoretical 
composition. The calcium phosphate compounds represented by the formula of 
Ca.sub.m (PO.sub.4).sub.n OH are readily modified by incorporating various 
different ions at the sites of Ca, PO.sub.4 and OH. It is to be noted here 
that the compounds used in the present invention include such 
modifications modified by the presence of any different ions so far as the 
compatibility with the living body is not lost and the composition range 
of m/n is maintained within 1.33.ltoreq.m/n.ltoreq.1.95. 
The crystal grain size (or crystallite) of the apatite calcium phosphate 
compound used in the present invention should be within the range of from 
50 .ANG. to 10 microns. A particularly preferred range is more than 200 
.ANG. and less than 3 microns. The crystal grain size of the 
hydroxyapatite forming the hard tissue of the living body ranges from 
several hundreds to several thousands .ANG.. It is desirous that the 
crystal grain size of the powders used in the filler of the present 
invention approximates the crystal grain size of the hydroxyapatite 
constituting the living body in order to promote formation of new bones at 
the vicinity of particles of the filler filled in the defects or hollow 
portions and to form a uniform living tissue as the result of the 
coalescence between the new bones and the particles of the filler. If the 
crystal grain size of the apatite calcium phosphate compound is more than 
10 microns, the formation of new bones is retarded resulting in delayed 
curing of the defects and further the newly formed bones lack uniformity. 
On the contrary, if the crystal grain size is less than 50 .ANG., the 
filler particles in the new bone is less crystallizable so that the 
coalescing capacity thereof does not reach the satisfactory level. 
It is preferred that the particle size distribution of the apatite calcium 
phosphate compound used in the present invention is such that powders each 
having the particle size of 300 microns or less occupy 90% or more of the 
total weight. If the content of particles having the particle size of 300 
microns or less does not reach 90% by weight, when the filler is added 
with water or an isotonic sodium chloride solution to be fluidized or 
plasticized, the particles tend to separate from water. As a result, there 
is a fear that the filler cannot be plasticized or the particles are 
sedimented only to the lower portion of the hollow portion to result in 
formation of unfilled vacancy at the top portion when the filler is filled 
in the living body. As far as the particle size distribution is within the 
range as aforementioned, the presence of some quantities of larger 
particles having the particle size of about several mm may be allowed. 
Natural materials, for example, bone ashes prepared by baking bones of 
animals may be used as the apatite calcium phosphate compound of the 
present invention, and synthetic materials prepared by the known wet 
process, dry process and hydrothermal process may also be used for the 
same purpose. The apatite calcium phosphate having a composition within 
the range as defined above and synthesized by the wet process is generally 
obtained in the form of precipitate composed of minute particles while 
being somewhat altered depending on the temperature and other conditions 
at the synthesis step, and may be separated from the solvent by means of 
filtration or centrifugal separation and then dried at a temperature of 
lower than 500.degree. C. followed by pulverization to form a material of 
impalpable powder. This powder form material may be directly fluidized or 
plasticized, as will be described hereinafter, to be filled in defects or 
hollow portions of bones as a filler having the osteogenic capacity. 
However, the aforementioned material prepared by the wet process is 
preferably calcined at a temperature ranging with 500.degree. C. to 
1100.degree. C., preferably 700.degree. to 900.degree. C., optionally 
subjected to a pulverization treatment to form a powdered material, and 
then fluidized or plasticized for use as a filler for filling in defects 
or hollow portions of bones, in order to improve the crystallinity of the 
particles and to sufficiently sterilize by heating for preventing 
infection by bacteria and for preventing foreign body reaction caused by 
organic materials. Calcination effected at a temperature of not higher 
than 500.degree. C. is unsatisfactory, since no appreciable growth of 
particles takes place. As the calcination temperature is raised to higher 
than 900.degree. C., growth of crystal grain becomes somewhat excessive. 
If the heating temperature exceeds 1100.degree. C., the particles are 
rapidly sintered with each other to form lumps. 
An apatite calcium phosphate compound having a relatively coarse crystal 
grain size is prepared by the dry process or by the hydrothermal synthesis 
process. The case where lumps are included, such lumps are crushed to 
obtain powders or particles. If these powders or particles are heated 
again at a temperature of lower than 1100.degree. C. to be sterilized, 
they can be smoothly filled in defects or hollow portions of bones to 
fulfill their functions as the filler. 
The powders or particles prepared by any of the aforementioned wet, dry and 
hydrothermal synthesis processes may be molded using a hydraulic press and 
then sintered, optionally followed by pulverization, to produce porous 
particles. A preferable sintering temperature range is 1100.degree. C. to 
1350.degree. C., and particularly preferred sintering temperature range is 
1200.degree. to 1300.degree. C. When the temperature is raised to higher 
than 1100.degree. C., particles are fused with each other to form larger 
particles having pores or voids. This tendency is accelerated as the 
temperature is raised to higher than 1200.degree. C. As the temperature is 
raised to higher than 1300.degree. C., the apatite calcium phosphate 
compound begins to be converted to calcium tertiary phosphate and the 
decomposition is accelerated seriously if the temperature reaches to 
1350.degree. C. If such porous particles are used as the filler, the 
living tissue is allowed to penetrate into the pores of the particle. As a 
result, the growth of new bone is promoted by the use of larger particles 
provided with pores. 
The powders prepared by any of the aforementioned synthesis processes 
and/or the particles obtained by calcinating or sintering the powders are 
fluidized or plasticized by the addition of a liquid, such as water or an 
isotonic sodium chloride solution, and then filled in the defects or 
hollow portions of bones. By fluidizing or plasticizing the powders or 
particles, the fine powders are prevented from scattering to adhere to 
undesired portions of the patient's body other than the injured portions 
so that any adverse influence caused by adherence of scattering powders is 
excluded. Another advantage attained by the use of a fluidized or 
plasticized filler is that the defects or hollow portions of bones are 
wholly and uniformly filled with the filler by a simple injection 
operation. The quantity of the liquid to be added is varied depending on 
the particle size of the used filler and the presence or absence of pores. 
If water or an isotonic sodium chloride solution is used, the added 
quantity thereof may be determined within the range in which separation of 
water does not occur and the powders or particles are sufficiently 
plasticized to be easily filled in the hollow portions. In general cases, 
0.1 to 2 parts by weight of water or an isotonic sodium chloride solution 
is added to 1 part by weight of the filler. 
The aforementioned powders or particles may be put into a granulator, for 
example a rolling granulating machine, and added with a liquid, such as 
water or isotonic sodium chloride solution, to form granules. A preferred 
shape of granules is spherical or pilular to facilitate filling, and the 
diameter of granules may be varied depending on the dimensions of defects 
or hollow portions in which the granular filler is filled with the 
generally preferred diameter ranges from 0.5 to 5 mm. The quantity of the 
liquid used for granulation preferably ranges from 20 to 50% by weight 
based on the total weight. These granules may be stored in a container, 
such as a glass bottle, with a seal and poured into the injured portion 
when in use. By the use of granular filler, the hollow portion can be 
uniformly filled with such granules with voids left therebetween. If dense 
filling is desired, the granules may be simply pushed into the hollow 
portion using a bar or like implement since the granules are plastic. This 
plastic granules have advantages that they can be easily handled when in 
use and that the filling density may be controlled as desired. 
The aforementioned granules may be sintered at 1100.degree. to 1350.degree. 
C., preferably 1200.degree. to 1300.degree. C. to form sintered beads. The 
sintering temperature is limited as aforementioned for the same reason 
described hereinbefore in the case of sintering the powders. Since the 
thusly formed sintered beads are porous, the living tissue is allowed to 
penetrate into the pores, so that formation of new bone at the vicinity of 
particles forming the sintered bead is remarkably promoted and the 
sintered material coalesces with the new bone rapidly. In order to make 
use of this advantage, the porosity of the sintered beads is preferably 
more than 30%. If the porosity is not more than 30%, the advantageous 
effect is diminished. The living tissue can easily penetrate into the 
pores having the diameter of larger than 100 microns. Accordingly, it is 
preferred that more than 50% of the pores have the diameter of larger than 
100 microns. This sintered beads are preferably spherical, so that they 
are fluent nevertheless individual beads are solid. Therefore, it may be 
said that this sintered beads can be fluidized, as referred to in the 
present invention, to be poured into the injured portion to fill the same 
easily and immediately. Moreover, the particle size of these beads can be 
freely adjusted at the bead formation step. If the particle size 
distribution is controlled in a narrow range, the injured portion of bone 
can be filled at low density with increased voids. On the contrary, if the 
particles size distribution is spread and beads having different diameters 
are included, relatively high density filling may be realized. Generally 
speaking, completion of new bone is accelerated when a relatively large 
space is void. 
The aforementioned porous sintered beads may be used in the dry state as 
they are, since they are fluent as mentioned hereinabove. However, the 
porous sintered beads may be added to the powder form filler and then 
added and kneaded with water or an isotonic sodium chloride solution for 
use in the form of a paste. If the porous beads are mixed in the paste, 
the porosity of the entire paste may be increased. The sintered beads may 
be added in a ratio at which the fluidity or plasticity of the filler of 
paste form is not lost, and the preferred ratio being less than 30% by 
weight based on the total weight of the paste. 
As the filler for filling in defects of bones according to the invention, 
the aforementioned apatite calcium phosphate compound may be used singly. 
However, it is preferred that a cancellous bone obtained by crushing a 
bone may be mixed together to further increase the bone formation speed. 
The cancellous bone of autoplastic origin has been conventionally used 
singly as a filler for filling in a defect of bone. However, there is 
often a case where a sufficient quantity of cancellous bone enough for 
filling the defect cannot be taken up, or it is desired that the quantity 
of cancellous bone of autoplastic origin is reduced as small as possible. 
The apatite calcium phosphate compound of the present invention may be 
mixed at a desired ratio with the autoplastically obtained cancellous 
bone. On the other hand, a bone of foreign origin has hitherto been 
limitedly used singly so as to avoid the foreign body reaction or other 
problems. However, when the bone of foreign origin is mixed with the 
apatite calcium phosphate compound of the present invention, the adverse 
reactions including the foreign body reaction can be considerably reduced 
to facilitate therapy. The mixing ratio of bone of foreign origin is 
preferably less than 50% by weight of the total weight, and a particularly 
preferable mixing ratio is less than 20% by weight. If more than 50% by 
weight of bone of foreign origin is mixed, reduction in adverse reaction 
becomes unsatisfactory nevertheless the bone formation speed is increased. 
Similarly as in the case where the apatite calcium phosphate compound is 
used singly, the mixture of the compound and the cancellous bone may be 
added with water or an isotonic sodium chloride solution to be fluidized 
or plasticized to prepare a filler to be filled in a defect of bone. 
The filler of the invention having the construction as aforementioned, has 
the fluidity or plasticity so that it can be uniformly and wholly filled 
in any defects or hollow portions of bones irrespective of how complexly 
shaped they are. Furthermore, the filler of the invention is different 
from the conventional implant materials made of integral articles in that 
it is made of powders, which are added in a fluidized or plasticized state 
prior to filling in an injured portion of bone, so that the powders are 
diffused in the implanted living body uniformly and the surfaces of the 
powders are readily covered with the growing tissue. More detailed 
description of the characteristic feature of the filler of the present 
invention in this respect will be given as follows. When the apatite 
calcium phosphate compound is filled in the injured portion of bone 
directly in the form of powder, the particles tend to coagulate with each 
other to form aggregations to hinder the growing tissue from penetrating 
inbetween the particles. However, the filler of the present invention is 
added in a fluidized or plasticized state to allow the particles to be 
dispersed in a relatively dense condition, as shown in FIG. 1, whereby the 
growing tissue is allowed to penetrate inbetween the particles. It is an 
important feature of the present invention that the particles are not 
coagulated but dispersed in a dense condition. Fine powders have the 
water-repellent property in the dry state to hinder the living tissue from 
diffusing in the dry filler. However, since the filler of the invention is 
used after being wetted with water or an isotonic sodium chloride solution 
or after being granulated the living tissues diffuse easily in the filler 
filled in the defect of bone. As a result of the combined function of 
dispersion of powders and diffusion of living tissues, formation of new 
bone is promoted. More specifically, when the filler of the invention is 
filled in a defect or hollow portion of bone, new granulation tissues 
surround the particles after the lapse of a short period of time and the 
particles are present while being dispersed in the granulation tissues. It 
should be noted here that no giant cells caused by foreign bodies appear 
at all, since the powders of the present invention made of the apatite 
calcium phosphate compound have remarkably improved compatibilities with 
the living tissues. Under such condition, osteoid with attendant 
osteoblast adheres to the peripheral portions of the particles without 
forming membranes caused by foreign bodies, and new bone tissues are 
rapidly formed from the peripheral surfaces of the particles towards their 
vicinities and the granulation tissues are changed to the connection 
tissues with the lapse of time. The filler of the invention composed of 
powders has a large surface area to increase the new bone formation speed 
considerably. The new bone tissues formed on the surfaces of the particles 
continue to grow and cross-link the particles which are present by close 
spacings. As the cross-linking structures grow, new cancellous bones are 
formed here and there and finally all of the filler particles are 
connected with each other by the newly formed dense cancellous bone 
integrally. As a result, an integral structure is formed, where powder 
particles of the apatite calcium phosphate compound are dispersed in a 
newly formed bone beam which has a low calcium density. Then, the new bone 
becomes denser to form a new bone tissue having the same composition as 
that of the surrounding old bone for covering the defect or hollow portion 
of bone. Finally, the injured portion is completely cured without any 
appreciable difference, as the particles of the filler assimilate with the 
new bone. However, formation of bone tissue stimulated by the filler of 
the invention does not proceed too far beyond the functional requirement 
generally required for normal bone tissue. In this connection, the filler 
of the invention has another advantage in that the portions thereof filled 
in the unnecessary portions are absorbed in the living body. As has been 
mentioned hereinabove, new bone tissues are initially formed on the 
surfaces of the particles of the filler. Accordingly, it is preferred that 
the specific surface area of the particles is increased and a larger 
number of particles is present in a unit volume, in order to increase the 
bone formation speed. Also, the spacings between the particles should be 
preferably closer at some extent for allowing the new bone to cross-link 
the particles to form a bone beam and further to connect the entire 
structure to form a cancellous bone. The speed of assimilation is 
accelerated as the particle size is smaller, since the compound is 
assimilated with the newly formed bone from the surfaces of the particles 
toward the inner portions thereof. In view of the foregoing, smaller 
particles are preferred to increase the bone formation speed. However, 
since osteogenic materials shall be fed from the living body inbetween the 
particles, the particle size is spontaneously limited and the lower limit 
of the particle size is determined by the supply of the osteogenic 
materials. 
As will be clearly understood from the foregoing description with regard to 
the construction, action and function of the present invention, the 
present invention is entirely different from the conventional technical 
concept of providing substitute materials for hard tissues including 
artificial bones and artificial radix dentis which are made of sintered 
single crystalline alumina (sapphire), sintered polycrystalline alumina or 
sintered hydroxyapatite and developed with the aim to simply avoiding the 
foreign body reaction between the bone tissue and to improving the 
adherence property. In other words, the filler of the present invention 
promotes the regeneration or self-curing action of the patient's bone 
tissue of itself taking place at the defects or hollow portions of bones, 
and the filler composition per se is incorporated into the bone tissue and 
coalesces therewith. For this reason, the inherent strength of the 
material used in the present invention is out of the question. 
Although an appreciable effect can be obtained only by filling the filler 
of the invention in the defects or hollow portions of bones formation of 
new bone will be further promoted if a portion of the filler reaches the 
bone marrow cavity. New bones are initially formed at the portions of 
defects where the filler particles contact with the bone marrow and then 
gradually grow into the hollow portions. However, the newly formed bone 
tissue formed in the bone marrow cavity and essentially to be discarded 
ultimately is absorbed in the living body by the action of osteoblasts and 
the requisite amount of new bone is left only at the necessary portion. 
According to this method, it is possible to ensure curing and to shorten 
the time required for therapy. The filler according to the invention 
exhibits its function only when it is used under the environment of a 
living body where the bone tissue is to be formed, in other words only 
when it is used at the defects or hollow portions of bones. The result of 
the experiment, where the filler of the invention is injected into the 
femoral muscle tissue of a rabbit, reveals no sign of bone formation in 
the muscle tissue after all. 
As has been described in detail hereinbefore, the powder or particle form 
apatite calcium phosphate compound according to the invention has a 
remarkably improved compatibility or adaptability with the living tissues 
and also has an excellent osteogenic capacity. Moreover, the filler of the 
invention is advantageous in that it coalesces with the bone tissue to be 
incorporated thereinto and exhibits a synergistic action to promote the 
regeneration or self-curing function of the bone tissue per se remarkably. 
The filler of the invention is used in a simple manner and the materials 
for the filler can be supplied from inexhaustible sources to make it 
possible to supplement the shortage in supply of autoplastic bone. 
The filler of the invention can be used not only for filling in defects or 
hollow portions of bones to remedy the bone tumor or the fractured bone 
and in the arthroplasty operation, the spinal fusion operation and the 
intervertebral disk fusion operation, but also for filling in the injured 
portion formed in the processes alveolaris caused by pyorrhea alveolaris. 
EXAMPLES OF THE INVENTION 
The present invention will now be described more specifically by referring 
to several examples thereof. However, it should be appreciated that the 
present invention is not limited only to the examples given below. 
Throughout the specification and appended claims, the crystal grain size of 
the calcium phosphate compound having the apatite crystalline structure 
will be indicated by the value of each crystallite in the direction of 
C-axis obtained from the half-width of the peak of diffraction measured by 
the X-ray diffractiometry wherein the spacing (002) is 
2.theta.=25.9.degree. when the crystal grain size is less than 0.1 
microns; and will be indicated by the practically determined average 
diameter of crystal grains along the longitudinal direction measured by 
using a scanning electron microscope, when the crystal grain size is more 
than 0.1 microns. 
EXAMPLE 1 
An apatite calcium phosphate compound (Molar Ratio of Ca/P=1.65) was 
synthesized by a wet process wherein phosphoric acid was dropwise added 
into a solution of calcium hydroxide. The dried powders of this compound 
were calcined at 850.degree. C. for 5 hours. The size or dimensions of 
crystallites was measured by the X-ray diffractiometry to reveal that the 
average diameter of crystallite along the c-axis was about 600 .ANG. and 
the average diameter of crystallite along the a-axis was about 500 .ANG.. 
Coarser powders were removed such that all particles pass through a net of 
300-micron meshes. The thus obtained powders were added with an isotonic 
sodium chloride solution to form a paste which was injected into the 
bone-marrow of the femur of a rabbit. The injected portion was kept 
observed. Formation of new bones in the neighbourhood the injected powders 
was observed after only one week from the time of injecting the paste of 
the apatite calcium phosphate compound, and no appreciable sign of foreign 
body reaction was observed at all. Then, the formed new bones were rapidly 
grown and it was observed that the particles composed of said compound 
were entirely incorporated into the newly growing bones and coalesced with 
the bone tissue. As will be apparent from the foregoing, the powders 
composed of said compound exhibits a remarkable osteogenic capacity which 
may be deemed as the particular effect of the apatite calcium phosphate 
compound when compared to the result of a similar comparative experiment 
wherein powders of alumina were used. 
EXAMPLE 2 
Each of the powders of the compounds synthesized by the wet processes and 
each having the ratio of m/n of 1.38, 1.56, 1.73 and 1.89 was calcined at 
850.degree. C. for 2 hours. The crystal grain sizes of these samples 
determined by measuring the diameters of crystallites by means of the 
X-ray diffractiometry were as follows: 
______________________________________ 
Average Diameter along 
Average Diameter along 
m/n the c-Axis the a-Axis 
______________________________________ 
1.38 580 .ANG. 400 .ANG. 
1.56 640 .ANG. 450 .ANG. 
1.73 720 .ANG. 520 .ANG. 
1.89 800 .ANG. 600 .ANG. 
______________________________________ 
Every calcined powders were screened to obtain sample powders of less than 
149 microns in size. Every powders were subjected to the X-ray 
diffractiometry to ascertain that all of these powders showed the 
diffraction pattern of hydroxyapatite and did not contain any other 
compounds. In accordance with the general procedure as set forth in 
Example 1, each of the powders was injected into the bone-marrow of the 
femur of a rabbit, and the formation of new bone at the injected portion 
was observed to ascertain that the function of each of these powders on 
the formation of bone tissue was equivalent to that observed in Example 1. 
As has been described hereinbefore, the compositions of the apatite calcium 
phosphate compounds artificially synthesized are not always represented by 
the theoretical rational formula of Ca.sub.5 (PO.sub.4).sub.3 OH, but may 
be represented by the general formula of Ca.sub.m (PO.sub.4).sub.n OH 
wherein the ratio of m/n, i.e. the molar ratio of Ca to P, varies within 
the range of from 1.33 to 1.95. In the present invention, all such 
compounds having the compositions as mentioned above are inclusively 
referred to as apatite calcium phosphate compound. When reviewing the 
results of this Example, it will be reasonably seen that every such 
compounds having the compositions as defined above exhibit similar effects 
to those obtained in the animal experiment shown in Example 1. 
EXAMPLE 3 
The powders used in Example 1 and composed of the apatite calcium phosphate 
compound having the molar ratio of m/n=1.65 and synthesized by the wet 
process were sufficiently dried at 110.degree. C., and then screened to 
obtain a sample which passed a net of 149-micron meshes. The dried and 
screened powders were molded by compression molding to form a rectangular 
parallelpiped of 2.times.3.times.5 cm in dimension and having a porosity 
of about 50%. This rectangular parallelpiped was sintered in air at 
1300.degree. C. for 2 hours to from a sintered body having a density of 
about 95% of the theoretical density. The sintered body was crushed and 
pulverized, and then the pulverized particles were fractionized to obtain 
another sample having a particle size distribution of 0.3 to 0.04 mm. 
These two samples, i.e. the dried powder sample and the sintered sample, 
were subjected to similar animal experiments as conducted in the preceding 
Examples where the calcined powders were used. The results of the animal 
experiments showed that new bones were formed rapidly in the neighbourhood 
of dried powders and also in the neighborhood of sintered granules, 
similarly as in the preceding Examples. 
Comparison was made between the bone tissue formation speed obtained by the 
use of the calcined powders as in Examples 1 and 2, the bone tissue 
formation speed obtained by the use of the dried powders as in Example 3 
and the bone tissue formation speed obtained by the use of the sintered 
granules as in Example 3 to learn the effects of calcination and sintering 
in cases where the apatite calcium phosphate compound synthesized by the 
wet process is used. The result of comparison showed that the calcined 
powders were the most excellent, the sintered granules occupied the next 
best place and the dried powders were somewhat inferior to the other two. 
According to the X-ray diffractiometry analysis, each of the dried powders 
was composed of fine crystallites each having a dimension (along the 
C-axis) of 50 to 300 .ANG. and each of the calcined powders was composed 
of crystallites each having a dimension (along the C-axis) of about 200 to 
1000 .ANG. whereas the crystal grain size of each of the sintered granules 
used in this Example ranges from 0.5 microns at the minimum to 7.5 microns 
at the maximum, the average size being 5 microns, as determined by a 
scanning electron microscope. 
It should be clearly understood from these results that the powders or 
granules of a calcium phosphate compound substantially composed of 
hydroxyapatite crystals and represented by the formula of Ca.sub.m 
(PO.sub.4).sub.n OH having the molar ratio of 1.33.ltoreq.m/n.ltoreq.1.95 
have excellent osteogenic capacity of themselves to remarkably promote the 
regeneration of the bone tissue when they are filled in any defect or 
hollow portion of bone. It will be also understood that the aforementioned 
compound is made of the same inorganic material forming the bone tissue of 
the living body so that the compound coalesces with the surrounding bone 
tissue as the new bone grows to be calcificated. Any apatite calcium 
phosphate compounds may be used as the starting material for the filler of 
the present invention irrespective of the synthesis processes employed for 
preparing the same. In addition to the powders synthesized by said wet 
process, powders or particles prepared by the dry process of the 
hydrothermal process can be used to fill in the defects of bones. When any 
of the apatite calcium phosphate compounds synthesized by various 
processes and subjected to after-treatments is used, the new bone 
formation speed at the vicinity of particles varies depending on the grain 
size of crystals constituting individual powders of said compound. For 
this reason, it is not preferred that the grain size of the crystals in 
the powder becomes too coarse, and the crystal grain size shall be limited 
within the range of from 50 .ANG. to 10 microns according to the technical 
concept of the invention. It is preferred to use the powdered product 
obtained by calcining the compound synthesized by the wet process at a 
temperature of 500.degree. to 1100.degree. C., when it is required to 
promote the formation of new bone rapidly. The filler prepared by 
sintering the apatite calcium phosphate compound at a temperature in the 
range of from 1100.degree. to 1350.degree. C. and the filler prepared by 
the dry synthesis process might contain a small amount of crystal of 
calcium tertiary phosphate (Ca.sub.3 (PO.sub.4).sub.2) which has not the 
apatite crystalline structure. About 3 to 5% by weight of calcium tertiary 
phosphate was mixed in the sintered powders used in this Example and 
detected by the X-ray diffractiometry analysis. However, the intermingled 
calcium tertiary phosphate does not seriously affect the essential 
function of the filler of the invention as far as the mixing ratio thereof 
is limited to about 5% by weight and the filler containing a small amount 
of calcium tertiary phosphate may be used as the filler of the invention 
without any adverse influence. 
EXAMPLE 4 
740 g of calcium hydroxide (a special grade chemical reagent produced by 
Junsei Kagaku K.K.) was suspended in 20 liters or water. An about 30 wt% 
phosphoric acid solution (prepared by diluting a special grade chemical 
reagent produced by Wako Junyaku K.K.) was dropwise added to the 
suspension while agitating the suspension and maintained at 40.degree. C. 
until the pH value of the liquid reached 8.8. Agitation was continued for 
additional one hour, and then the suspension was allowed to stand 
stationarily at 40.degree. C. for 48 hours to age the same. A precipitate 
of apatite calcium phosphate was obtained. This precipitate was filtered 
by the use of a suction filter, rinsed and then dried in a hot air 
circulation drier maintained at 105.degree. C. for 24 hours to form a cake 
which was pulverized in a ceramic pot mill to obtain dried powders having 
the particle size passing through a net of 300-micron meshes. Then, the 
powders were calcined in an electric furnace maintained at 800.degree. C. 
for 6 hours. The crystal grain size of the calcined powders was measured 
by the X-ray diffractiometry to find the diameter of crystal grain along 
the C-axis was about 550 .ANG. and that the long the a-axis was about 470 
.ANG.. After cooling outside of the furnace, the calcined powders were 
screened using a net of 149-micron meshes to remove coarser particles and 
sterilized by heating again at 800.degree. C. for one hour in the electric 
furnace. A calcined powder sample to be used in an animal experiment was 
thus prepared and sealed in a clean glass ampoule. 
The powder sample was subjected to the X-ray diffractiometry to ascertain 
that the sample was composed of the hydroxyapatite crystalline and no 
other compound was contained therein, and also subjected to a chemical 
analysis to find that the molar ratio of Ca to P, namely the ratio of m/n, 
was 1.67 which was coincident with the theoretical composition of a 
hydroxyapatite compound represented by Ca.sub.5 (PO.sub.4).sub.3 OH. 
Rabbits each having the weight of about 4 kg were selected as the animals 
used in the following animal experiment. Under intravenous anaesthesia two 
holes each having a diameter of about 3 mm were drilld through the femur 
of each rabbit by a spacing of 15 mm. A paste prepared by adding 10 g of 
said powder with 8 ml of an isotonic sodium chloride solution was injected 
into the bone marrow space between the two holes. The rabbits were killed 
from one week to six months after implantation, and after labelling with 
tetracycline, the femurs were cut crosswise at the portion intermediate of 
the two holes. The decalcified and undecalcified specimens were prepared 
from every killed rabbits, and the histological changes of these specimens 
were observed. 
FIG. 1 is a microphotograph (about 200 magnifications) of a crosswise 
section of the decalcified specimen showing the portion injected with the 
paste and taken out of the rabbit after one week from the time of 
implantation. 
As will be apparent from the Figure, particles 1 of the apatite calcium 
phosphate compound are scattered in the young granulation tissue 3, and 
the osteoid with attendant osteoblast adhered to the peripheral portions 
of the particles 1. New cancellous bones 2 are formed at the portions 
where the particles 1 are relatively closer and these newly formed bones 
crosslink the particles. No giant cells caused by foreign bodies are 
observed at all. It should be a distinguishing feature that the newly 
formed bones contact the peripheries of the particles 1 of the apatite 
calcium phosphate compound without forming any foreign body membrane. This 
shows that the compound has a remarkably improved compatibility with the 
living body and a considerably high osteogenic capacity. In the Figure, 
reference numeral 7 designates the cortical bone. 
After four weeks from the time of implantation, all particles of the 
apatite calcium phosphate compound are connected with each other through 
the new bones and form an integral and dense body of cancellous bone. 
FIG. 2 is a microradiographical photograph (about 200 magnifications) of a 
crosswise section of the undecalcified specimen showing the portion 
injected with the paste containing the particles of the apatite calcium 
phosphate compound and taken out of the rabbit after four weeks from the 
time of implantation. It is shown that high density particles 1 of the 
apatite calcium phosphate compound are scatteringly present in a low 
density new bone beam 4 and that the spacing between the new cancellous 
bones are filled with the bone-marrow tissue 5. It is also observed that 
the new bone is formed rapidly without being accompanied with any foreign 
body reaction and that all of the injected particles 1 are incorporated 
into the newly formed bone beam 4 and interconnected with each other. 
FIG. 3 is a microphotograph (about 400 magnifications) of the decalcified 
specimen showing the drilled portion of the femur of the rabbit taken out 
of the rabbit after 3 months from the time of implantation. The drilled 
portion, i.e. the artificially formed defect of bone in the femur 
(cortical bone) is completely repaired with the new cortical bone 6 and 
the drilled portion forms an integral body with the surrounding original 
fumur (cortical bone 7). Although scattering particles 1 are observed at 
the newly formed bone portion, no foreign body reaction is observed to 
show excellent compatibility of the filler with the living body. It is 
also observed that yound bone-marrow tissue 5 is present in the 
bone-marrow cavity. It is further shown that the bone-marrow tissue at 
that portion is refreshed and becomes rejuvenated by the injection of the 
paste of the apatite calcium phosphate compound. 
Although bone formation is observed at some portions even after six months 
after the implantation, the absorption of bone prevails in the bone-marrow 
cavity and the cancellous bone beams are reduced in number as a whole and 
become coarser. On the other hand, the new bone formed at the drilled 
portion is changed to the cortical bone to coalesce with the surrounding 
original femur. This shows that formation of new bone in the defect and in 
the bone-marrow cavity does not continued unlimitedly but is adapted for 
the functional demand of the living body ultimately. In view of this fact, 
the filler of the invention should be appreciated to be an ideal filler 
material. 
EXAMPLE 5 
A calcium phosphate compound synthesized by the wet process was dehydrated 
and dried to form a cake which was calcined at 1000.degree. C. for 2 
hours. The crystal grain size was measured by a scanning electron 
microscope to find that the average crystal grain size was 0.2 microns, 
the minimum crystal grain size was 0.1 microns and the maximum crystal 
grain size was 0.4 microns. This cake was pulverized in a ceramic pot mill 
to obtain a powder sample which passed a net of 149-micron meshes. The 
powder sample was subjected to the X-ray diffractiometry to ascertain that 
the sample was composed of the crystalline hydroxyapatite and no other 
compound was contained therein, and also subjected to a chemical analysis 
to find that the molar ratio of Ca/P was 1.63. This powder sample was 
heated again at 500.degree. C. for 5 hours to be sterilized. A powder 
sample to be used in an animal experiment was thus prepared and sealed in 
a clean glass ampoule. 
A portion of the cortical bone of the femur of an adult rabbit having the 
weight of about 4 kg was removed to artifically form a defect of about 2 
mm.times.5 mm. One part by weight of cancellous bone taken up from the 
rabbit per se was mixed with one part by weight of the powder of said 
apatite calcium phosphate compound, and 0.3 part by weight of distilled 
water was additionally added and kneaded to be plasticized. The 
plasticized mixture was filled in said defect formed in the bone. The same 
operations were performed on a group of rabbits which were killed one 
after another. The portion of the femur containing the defect was cut 
crosswise to prepare a histological specimen therefrom, and the 
histological change was observed. 
After one week from the operation, appreciable formation of new bones was 
observed in the neighbourhood of the particles of the apatite calcium 
phosphate compound, and the particles of the apatite calcium phosphate 
compound and the autoplastically implanted bone pieces were interconnected 
with each other by the crosslinking structure of said new bones without 
any foreign body reaction occurring. After four weeks, considerable 
development of growth of a new bone beam was observed, and all of the 
particles of the apatite calcium phosphate compound and the cancellous 
bone pieces were interconnected by the new bone beams, whereby the portion 
filled with the filler was made of the cancellous bone tissue in its 
entirety. After 3 months from the operation, it was observed that said 
cancellous bone tissue was changed to the cortical bone tissue to coalesce 
with the surrounding original femur so that the artificially formed defect 
of bone was completely repaired. This result shows that the shortage in 
autoplastically taken-up bone may be supplemented with powders of calcium 
phosphate compound having the apatite crystalline structure to be filled 
in a defect of bone, whereby the object of therapy can be attained for a 
shorter period of time according to the present invention. 
Comparative Example 1 
A high purity alumina powder produced by Iwatani Kagaku K.K. (Trade Name: 
RA-30, Al.sub.2 O.sub.3 =99.9%, 100% passing through a net of 149-micron 
meshes) was used. Following a similar procedure as in the preceding 
Examples, a paste was prepared from said alumina powder which was injected 
into the bone-marrow cavity of the femur of a group of rabbits. The 
progress of new bone formation was investigated. 
FIG. 4 is a microphotograph (about 400 magnifications) of a decalcified 
histological specimen obtained by cutting the femur of a rabbit after one 
month from the operation. In view of the fact that no appreciable giant 
cells nor membrane caused by foreign bodies was present in the vicinity of 
the alumina particles, it is considered that the particles have good 
compatibility with the living body. Although the alumina particles 1 are 
scattered in the granulation tissue 3, no new bone is formed in the 
neighbourhood thereof. Nevertheless a few new cancellous bones 2 which are 
considered to be formed under the stimulation of the injected paste is 
observed at the vicnity of the cortical bone 7, it is seen that the 
alumina particles 8 have no osteogenic capacity (Under a certain 
stimulation, some new bones are formed in the bone-marrow.) 
Comparative Example 2 
A paste was prepared from a commercially available organic bone cement 
powder (produced by Howmedica Co.; a polymethylmethacrylate resin sold 
under the Trade Name of "Simplex"). This paste was injected into the 
bone-marrow of the femur of a rabbit similarly as in the preceding 
Examples, and the histological change of the injected portion was 
observed. FIG. 5 shows a microphotograph (about 200 magnifications) of a 
decalcified histological specimen of the injected portion after one month 
from the operation. 
The bone-marrow of the femur injected with the bone cement paste is filled 
with giant cells 9 caused by foreign bodies shows the intensive foreign 
body reaction, and no formation of new bone is observed anywhere. It is 
also observed that the particles 11 of the Simplex are present 
scatteringly and fat spots 10 are present here and there. 
Although the present invention has been described with reference to the 
specific examples thereof, it should be understood that various 
modifications and variations can be easily made by those skilled in the 
art without departing from the sprit of the invention. Accordingly, the 
foregoing disclosure should be interpreted as illustrative only and not to 
be interpreted in a limiting sense. The present invention is limited only 
by the scope of the following claims.