Fibrous bone filler and process of producing the same

A fibrous bone filler having an excellent biocompatibility. The bone filler comprises fibers containing hydroxyl apatite. The hydroxyl apatite is "intact", that is, the hydroxyl apatite substantially retains its hydroxyl groups.

BACKGROUND OF THE INVENTION 
I. Field of the Invention 
This invention relates to a bone filler which is filled in a defect or a 
void of a bone. 
II. Description of the Prior Art 
A defect or a void may be formed in a bone due to, for example, a fracture 
or an operation for eliminating a bone tumor. Conventionally, to fill such 
a defect or void in the bone, autoplasty is conducted by filling with a 
bone material collected from another portion of the patient. In other 
cases, the bone material is collected from a near relative of the patient. 
However, in those methods, the bone material to be filled in the defect or 
void must be collected by conducting an operation from the patient or the 
near relative of the patient. Thus, the burden on the patient or the near 
relative of the patient is great. Further, when the defect or the void to 
be filled is large, it may be difficult to obtain sufficient bone 
material. 
To overcome this problem, artificial bone fillers have been developed. The 
materials of the known bone fillers include metals and ceramics. Among 
these, from the view point of biocompatibility, calcium phosphate-based 
compounds are preferred. Among the calcium phosphate-based compounds, it 
is known that hydroxyl apatite which is a component of the bone is 
especially preferred. Conventional hydroxyl apatite bone fillers include 
those in the forms of granules, powder (Japanese Patent Disclosure (Kokai) 
No. 54841/81) or fibers (Japanese Patent Disclosure (Kokai) No. 7-117621). 
The bone filler in the form of granules or powder has the drawback that it 
is inconvenient to handle in an operation. As to the bone filler in the 
form of fibers, although the handling is easier than those in the form of 
granules or powder, the hydroxyl groups of the hydroxyl apatite are 
decomposed when the fibers are melt-spun, so that the biocompatibility is 
reduced. 
SUMMARY OF THE INVENTION 
Accordingly, an object of the present invention is to provide a bone filler 
which has an excellent biocompatiblity, which is easy to handle, and which 
fits into the complicated shape of the defect or the void in the bone. 
This and other objects of the present invention may be accomplished by 
providing a fibrous bone filler comprising fibers containing intact 
hydroxyl apatite. The term "intact" herein used means that the hydroxyl 
apatite substantially retains its hydroxyl groups. The bone filler of the 
present invention is preferably in the form of a non-woven fabric, cotton, 
absorbent cotton, or roving. 
Since the bone filler of the present invention comprises the "intact" 
hydroxyl apatite, the biocompatibility of the bone filler is very high, so 
that rejection reaction does not occur, and giant cells do not emerge. 
Further, since the bone filler is fibrous, it may be pushed into the 
defect or the void of a complicated shape. Thus, the handling thereof in 
an operation is easy and it fits well into the defect or the void. 
Further, the bone filler has a great osteogenesis-causing ability, so that 
the defect or the void may be recovered in a shorter time than in the 
conventional methods. Still further, since the bone filler of the present 
invention has the intact hydroxyl apatite, it is well taken by the bone 
when a new bone tissue generates, and it becomes a part of the bone.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
As described above, if the hydroxyl apatite is melt-spun into a fiber, at 
least a part of the hydroxyl groups of the hydroxyl apatite is decomposed, 
so that the biocompatibility of the bone filler is reduced. The present 
inventors have found a process by which a fiber containing intact hydroxyl 
apatite which retains substantially all of the hydroxyl groups may be 
obtained. The intact hydroxyl apatite fiber may be obtained by a solution 
spinning method which employs a specific binder. The method will be 
described later in detail. 
The fibers constituting the fibrous bone filler of the present invention 
comprise intact hydroxyl apatite. The content of the hydroxyl apatite is 
preferably at least 25% by weight, and more preferably at least 50% by 
weight. Since hydroxyl apatite is a component of the bone, from the view 
point of biocompatibility, it is preferred that the fiber essentially 
consist of intact hydroxyl apatite. It should be noted, however, if the 
fiber essentially consists of hydroxyl apatite, the strength thereof is 
reduced. Thus, for increasing the strength of the fiber, a reinforcing 
material, such as, for example, calcium phosphate-based compound and water 
glass, may be incorporated in the fiber Among the reinforcing materials, 
from the view point of biocompatibility, calcium phosphate-based compounds 
are preferred. The content of the reinforcing material in the fiber is 
usually 25% by weight or less. The filler may contain water. The water 
content in the filler is usually 50% by weight or less. 
The diameter of the fiber constituting the bone filler of the present 
invention is not limited, but typically from 1 to 30 .mu.m, and preferably 
1 to 10 .mu.m. The weight of the fibrous bone filler of the present 
invention is also not limited, but usually 5 g/m.sup.2 to 500 g/m.sup.2. 
The fibrous bone filler of the present invention may be produced by a 
solution spinning process which utilizes a specific binder. The binder 
should be harmless to the human body and is preferred to be water-soluble. 
The macromolecules which satisfy these conditions may preferably be used. 
Among the water-soluble macromolecules which may be used as the binder, 
preferred are polyvinyl alcohol, polycarboxymethyl cellulose, 
hydroxypropyl cellulose, collagen, pullulan and chitin. Among these, 
pullulan is most preferred. The molecular weight of the macromolecules may 
preferably be 20,000 to 2,000,000, and more preferably 50,000 to 
1,000,000. These macromolecules may be used independently or in 
combination. 
The hydroxyl apatite which is used as a starting material of the process 
may preferably be in the form of super fine particles. The super fine 
particles are preferably in the form of a rod, of which diameter is 
preferably 5 nm to 1 .mu.m. Such hydroxyl apatite particles may be 
produced by a well-known conventional method. For example, they can be 
produced by adding an aqueous phosphoric acid solution to a basic solution 
(pH7-11) containing calcium ions. 
In the process of producing the fibrous bone filler of the present 
invention, an aqueous suspension containing the above-described binder and 
hydroxyl apatite is used as the starting material. The aqueous suspension 
preferably contains 10-90% by weight, more preferably 50-70% by weight, 
and still more preferably 60-65% by weight of water; 5-70% by weight, more 
preferably 15-30% by weight, and still more preferably 15-20% by weight of 
hydroxyl apatite; and 5-40% by weight, more preferably 15-30% by weight, 
and still more preferably 20-25% by weight of the binder. If the hydroxyl 
apatite content is less than 5% by weight, the strength of the produced 
fibrous material is small, and if the hydroxyl apatite content is more 
than 70% by weight, the viscosity of the aqueous suspension becomes 
undesirably too high. 
To increase the fluidity of the suspension to improve the dispersion of the 
hydroxyl apatite, a surface active agent of carbonic acid-based, 
plasticizer and/or softening agent may be added to the suspension, if 
desired. A defoaming agent may also be added. The content of such agents 
may typically be 0.01-5% by weight. When the above-described reinforcing 
material is used, the reinforcing material is dispersed in the suspension. 
It should be noted, however, when the reinforcing material is Ca.sub.3 
(PO.sub.4).sub.2, it can be formed in the sintering step as described 
later. 
The aqueous suspension may be prepared under a temperature of about 
20.degree.-70.degree. C. 
An example of the process of producing the fibrous bone filler of the 
present invention, which utilizes the above-described aqueous suspension 
as the starting material will now be described referring to the 
accompanying drawing. 
The aqueous suspension is supplied to a tank 2 through a supplying duct 1. 
The suspension is then supplied to a spinning nozzle 5, and is jetted from 
the nozzle by gear pumps 4 actuated by a motor 3. Air is supplied from a 
blower 6 to an air nozzle 7 which encircles the spinning nozzle 5, and is 
jetted from the air nozzle 7. The velocity of the air flow may be about 5 
to about 1000 m/s, and the temperature of the air may be about 20.degree. 
to 60.degree. C. A plularity of the spinning and air nozzle assemblies may 
be provided, and the air nozzles may be disposed in a row, or in a circle. 
By the simultaneous jetting of the aqueous suspension and the air, the 
aqueous suspension is spun into a bundle of fine fibers 8. The diameter of 
the fibers may be adjusted by controlling the air velocity, to typically 
about 1 to 30 .mu.m, and preferably about 1 to 10 .mu.m. The higher the 
velocity of the air, the smaller the diameter of the fibers. When the air 
velocity is 1000 m/s, fibers of about 1 .mu.m diameter are obtained. When 
the air velocity is 300 m/s and 30 m/s, fibers of about 3-5 .mu.m 
diameter, and 20 .mu.m diameter are obtained, respectively. 
The thus formed bundle of fine fibers 8 is then heat-dried by a heater 9. 
The heater 9 may be, for example, an infrared heater, far infrared heater, 
or a microwave heater. The fibers are dried and solidified by the heater 9 
to the water content of, for example, 10% by weight or less and preferably 
7% by weight or less. If the drying is not sufficient, a fibrous material 
consisting of the fine fibers may not be obtained. The heating temperature 
varies depending on the amount of the material ejected from the spinning 
nozzle 5, on the temperature of the air jet, and on the amount of the air 
jet. Usually, the temperature of the heater 9 is in the range of about 
200.degree. to 500.degree. C. (the temperature of the fibers being about 
80.degree. to 150.degree. C.) If the heating temperature is too high, the 
binder may be decomposed. 
The thus dried fibers are then collected on a moving collecting means 11 by 
dropping the fibers on the moving collecting means in an intercrossing 
manner to obtain a fibrous material. The collecting means 11 may be, for 
example, a wire net drum or a wire net belt. Two wire net drums rotating 
in the opposite direction may preferably be used. If the fibers are 
dropped on the contact portion of the two drums, a voluminous fibrous 
material in which the intercrossed fibers are three-dimensionally 
disposed, i.e., a fibrous material in the form of cotton or absorbent 
cotton, may be obtained. If the fibers are dropped on a portion other than 
the contact portion of the drums, a planar fibrous material in which the 
intercrossed fibers are arranged two-dimensionally, i.e., a fibrous 
material in the form of a non-woven fabric, may be obtained. The fibrous 
material in the form of a roving may be obtained by using a plularity of 
spinning nozzles disposed in a circle. By controlling the moving speed of 
the collecting means, fibrous material of 5 g/m.sup.2 to 500 g/m.sup.2 may 
be obtained. The thus formed fibrous material may be spooled on a reel 13. 
It is preferred that the thus obtained fibrous material in which the fibers 
are bound each other by the binder be sintered to eliminate the binder. 
The sintering may be conducted under a temperature of about 500.degree. to 
1300.degree. C., preferably about 600.degree. to 1200.degree. C., and more 
preferably about 650.degree. to 1100.degree. C. If the sintering is 
conducted under a temperature higher than 1300.degree. C., the hydroxyl 
groups of the hydroxyl apatite may be decomposed. If the sintering is 
conducted under a temperature of 1100.degree. C. to 1300.degree. C., 
Ca.sub.3 (PO.sub.4).sub.2 is generated, so that the strength of the fibers 
may be improved. 
The thus obtained fibrous bone filler may be filled in a defect or void in 
a bone. Good results may also be obtained if the fibrous bone filler is 
used in combination with a hydroxyl apatite filler in the form of granules 
or powder. The biocompatibility of the bone filler may be further promoted 
by immersing the filler in water, physiological saline, chondroitin 
solution, hyaluronic acid solution, or in a collagen solution. The amount 
of the impregnated liquid is typically about 1 to 20% by weight, 
preferably 5 to 10% by weight. The preferred solvent of the chondroitin 
solution and hyaluronic acid solution and collagen solution is water, and 
the preferred concentration of the solutes is about 1 to 20% by weight. If 
desired, the thickness of the fibrous bone filler may be controlled by 
subjecting the bone filler to a calender process. The biocompatibility may 
also be promoted by using such calendered fibrous material immersed in 
water, physiological saline, chondroitin solution, hyaluronic acid 
solution or in a collagen solution. 
EXAMPLE 1 
An aqueous suspension containing 9% by weight of pullulan powder of which 
average molecular weight is 200,000, 42% by weight of hydroxyl apatite 
powder (particles of 5 to 80 nm diameter), 1% by weight of dispersant 
(carbonic acid-based surface active agent), and 48% by weight of water was 
vigorously stirred under the room temperature to uniformly disperse the 
pullulan in the aqueous system. The aqueous suspension was then defoamed. 
The aqueous suspension was then jetted from a spinning nozzle of 0.3 mm 
diameter. Air was jetted simultaneously from an air nozzle encircling the 
spinning nozzle at a velocity of 300 m/s to form a bundle of fibers. The 
fibers were then heated by an infrared heater to evaporate the water. The 
dried fibers were dropped on the contact portion of rotating wire net 
drums rotating in opposite directions with respect to each other, to 
obtain a fibrous material in the form of cotton. The thus obtained 
cotton-like hydroxyl apatite fibrous material was sintered at an elevating 
temperature of 50.degree. C./h up to 1100.degree. C., and was kept at this 
temperature for 2 hours. 
The thus obtained fibrous material in the form of cotton had a weight of 
about 200 g/m.sup.2 and had sufficient strength. The average diameter of 
the fibers constituting the cotton was 5 .mu.m. 
In the center portion of the tibiae of twelve cats (male and female), two 
holes are formed along the longitudinal direction of the bone, to form 
artificial bone defects. The fibrous bone filler obtained as above was 
filled in the holes up to the bone marrow cavity. 
After 1 week, 2 weeks and 4 weeks from the filling operation of the bone 
filler, the bone tissues around the holes were separated and were 
immediately fixed with 10% formalin solution. After removing ash, they 
were embedded in a resin, and cross sections were prepared. The cross 
sections were stained by various staining method to prepare pathologic 
specimens. The specimens were observed with a microscope. The results of 
the observation were as follows: 
After 1 Week 
In the portion of the sponge layer contacting the hydroxyl apatite filler, 
fibroblasts were grown, and new bone beam and osteoblasts were generated. 
The binding of the hydroxyl apatite with the bone cortex was sparse. Only 
a portion of the periosteum invaded into the hydroxyl apatite. No foreign 
body membrane was observed around the hydroxyl apatite. 
After 2 Weeks 
Generation of new bone beam in the sponge layer, osteogenesis and growth of 
osteoblasts at the cut edge of the bone cortex were very great. Hydroxyl 
apatite was tighter than the week 1 group. Periosteum covered 
substantially the whole hydroxyl apatite. The cortex and the hydroxyl 
apatite were strongly bound each other by collagen fibers. Generation of 
giant cells and other foreign body reactions were not observed at all. 
After 4 Weeks 
The hydroxyl apatite had been constracted, and the intervals between fibers 
had been made small. The osteogenesis in the sponge layer was further 
promoted. Osteogenesis at the cortex cut edge was also further promoted. 
Collagen fibers invaded the hydroxyl apatite. Periosteum completely 
covered the hydroxyl apatite. 
As described above, by using the bone filler of the present invention, the 
growth of fibroblasts, and generation of bone beam and osteoblasts are 
observed after only 1 week from the embedment of the hydroxyl apatite 
filler. If a conventional filler is used, such phenomena are observed 
after 1 to 3 months from the embedment of the filler. Further, no foreign 
body reactions occur. As the time elapses, the osteogenesis and growth of 
osteoblasts are rapidly promoted, so as to cover the whole hydroxyl 
apatite. Further, newly generated bone tissue is rapidly integrated with 
the bone tissue at the peripheral portion of the artificial defect. Thus, 
the bone filler of the present invention has a much greater 
biocompatibility than the conventional hydroxyl apatite bone fillers, and 
has an osteogenesis-causing ability. 
EXAMPLE 2 
The hydroxyl apatite filler in the form of cotton obtained in Example 1 was 
mixed with hydroxyl apatite powder (spherical hydroxyl apatite particles 
of 20 to 100 .mu.m diameter which was sintered at 700.degree. C.) in a 
weight ratio of 5:1, and the test was conducted as in Example 1. Good 
results as in Example 1 were obtained. 
EXAMPLE 3 
A fibrous hydroxyl apatite in the form of cotton, of which fibers had an 
average diameter of 10 .mu.m was obtained by the same manner as in Example 
1. The obtained bone filler was tested as in Example 1, and good results 
as in Example 1 were obtained. 
EXAMPLE 4 
To the hydroxyl apatite filler obtained in Example 1, water or 
physiological saline was added, and the wetted hydroxyl apatite filler was 
tested as in Example 1. Good results as in Example 1 were obtained. 
EXAMPLE 5 
To the bone filler of Examples 1, 2 and 3, 20% by weight aqueous solution 
of chondroitin was added, respectively, in the amount of 20% by weight 
with respect to the filler. The fillers were tested as in Example 1, and 
good results as Example 1 were obtained. 
EXAMPLE 6 
To the bone filler of Examples 1, 2 and 3, 20% by weight aqueous solution 
of collagen was added, respectively, in the amount of 20% by weight with 
respect to the filler. The fillers were tested as in Example 1, and good 
results as Example 1 were obtained.