JP3451417B2 - Bioceramic-containing cell structure and method for producing the same - Google Patents

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention
Replaceable biodegradable and absorbable bioceramics
The present invention relates to a cell structure and a method of manufacturing the same. [0002] Biodegradability and absorbability for medical use
As a cell structure (porous body) of No. 63-649
No. 88, a biodegradable and absorbable sponge,
Materials for periodontal tissue reconstruction disclosed in JP-A-2-63465
Which is known. The former biodegradable and absorbable sponge is used for surgery.
Hemostasis at the time and suturing of soft tissues of the living body (for example, organs such as liver)
It is used as a prosthetic material at the time of molecular weight (weight
(Molecular molecular weight) of 2,000-600,000
It is a flexible sponge having an open cell structure. This sport
Is to convert the above polylactic acid etc. into benzene or dioxane
Dissolve and freeze-dry the polymer solution.
It is manufactured by [0004] The latter material for periodontal tissue reconstruction is weight
Lactic acid-caprolactone copolymer having an average molecular weight of 40,000 to 500,000
Porous flexible film formed from coalescence etc.
Is a sheet-like thin material, which is also the same as above
Manufactured by freeze-drying method using
You. [0005] The above-mentioned sponge and periodontal
Tissue reconstruction material is a porous material that is biodegradable and absorbable
Is a biological activity that induces and forms bone tissue inside the body in vivo
Since it does not contain essential substances, it has a strong
Since the conductivity and replacement with bone tissue are poor, completely replace the skeleton.
It takes a considerable amount of time before the weave is rebuilt. Further, the above-mentioned material is produced by a freeze-drying method.
It is difficult to get a thick one more than 1mm
No. A thin material of less than 1 mm is used for
Apply the shape to a relatively large three-dimensional space and temporarily
Three-dimensional damaged part while exhibiting the function as a simple prosthetic material
It is difficult to rebuild the rank. Further, the material produced by the freeze-drying method is foamed.
Low magnification, such a material with low foaming ratio is used in vivo
Temporarily large amount of decomposed particles in the process of decomposition and absorption
Is generated by a transient flame due to foreign substance reaction of the decomposed strip.
There is probably a worry that causes the disease. And freeze-dried
Use harmful solvents such as benzene and dioxane
If the solvent remains, there is a danger of harm to the living body
There is. [0008] Due to these problems, conventional freeze-drying
The porous material manufactured by the method is used for reconstruction of bone damage site
As a filler, prosthesis or biomaterial for a scaffold
It was difficult to use. In addition, the binding with living bone
Of artificial joints and other implants and living bone
Fixing strength of implant by interposing porous material between
It could not be used for the purpose of improving [0009] The present invention solves the above problems at once, and
It can be suitably used as a biomaterial for reconstruction of the site of bone injury
To provide a bio-ceramic containing cell structure
Aim. [0010] The bioceramics of the present invention.
Cell structure containing biodegradable biodegradable polymer
A cell structure having formed continuous pores,
Contains bioactive bioceramic powder inside
The content of bioceramic powder is cell structure
Increases gradually from one side of the body to the other
It is characterized by the following. Here, the cell structure surrounds the pores.
One structural unit, the cell wall, is interconnected
Is a solid consisting of
Even if expressed, there is no essential difference. The above-mentioned bioceramic-containing cell structure
Is the biodegradable and absorbable polymer as its solvent and its solvent.
Dissolved in a mixed solvent with a non-solvent having a high boiling point.
Prepare a suspension in which ioceramic powder is dispersed,
The mixed solvent evaporates from this suspension at a temperature lower than the boiling point of the solvent.
Biodegradation that contains bioceramic powder
The present invention is characterized in that the absorbent polymer is precipitated.
It can be easily manufactured by a manufacturing method. That
The principle of cell structure formation is considered as follows. That is, from the above suspension, a mixed solvent is
If the gas is diffused at a temperature lower than the boiling point, the solvent with the lower boiling point has priority.
The proportion of non-solvents with high boiling points
Solvent dissolves polymer when agent and non-solvent reach a certain ratio
become unable. As a result, the polymer starts to precipitate and precipitate.
Of bioceramics that have started to settle from the beginning
A high ratio of polymer that contains powder and precipitates and precipitates
Shrinks and solidifies due to the bioceramic powder.
Thin cell walls of connected and immobilized polymer
To form a cell structure in which a mixed solvent is included.
Then, the remaining solvent destroys part of the cell wall while thinning.
Creates pores and disperses and disappears.
Gradually dissipate through it and eventually completely dissipate and disappear
You. As a result, the mixed solution wrapped in the polymer cell walls
Traces of medium remained as pores, and pores were basically continuous
It has continuous pores. Thus, the cell wall surface or interior
Bioceramics holding powder of ioceramics
A containing cell structure is formed. In this case, the polymer concentration of the above suspension is adjusted.
When adjusted, the expansion ratio of the cell structure can be widened to 2 to 30 times.
Bio ceramics that can be adjusted to the surroundings without distortion
A containing cell structure can be formed. Also, the above
Control the viscosity of the suspension and the speed at which the mixed solvent evaporates
When it is used, a bioceramic with a thickness of 1 mm or more
The cell containing cell structure can be easily formed. The bioceramic thus formed is
The cell structure containing biomass is initially made of bioceramic powder.
From the sedimentation and the rate of sedimentation
If the speed is much faster than the discharge / sedimentation rate,
From the side (upper side) to the opposite side (lower side)
The content of bioceramic powder is gradually increasing. Toes
The content gradient in the settling direction of the bioceramic powder.
Is obtained. A cell containing bioceramics as described above
When the structure is applied to a damaged site in living bone, it passes through the continuous pores.
As a result, bodily fluid penetrated into the cell structure and came into contact with bodily fluid
As the cell wall gradually hydrolyzes, the surface of the cell wall or
Due to the bioceramic powder held inside,
Bone tissue is induced and formed inside the cell structure,
The structure bonds with the living bone. And finally the cell structure
Induced bone tissue that is absorbed and absorbed throughout the body
And disappears. In that case, the bioceramic of the cell structure
One side (lower part) with the higher powder content is
Degradation due to apparent hydrolysis of metal wall proceeds rapidly
And high concentration of bioceramic powder
Because of its high ability to form and induce bone tissue (the degree of bioactivity)
Good bonding with living bone. In contrast, biose
One side with lower Lamix powder content (upper part
Min) is not very large in the ability to induce and form bone tissue
Is brittle due to the low content of bioceramic powder
High strength and fast hydrolysis of cell walls
, Maintain practical strength and shape for several months in vivo
I do. The average content of the bioceramic powder is 5
~ 60% by weight is desirable, and the average content is
When the ratio is higher than 60% by weight, the ability to induce and form bone tissue becomes
Overall improvement, but lower overall cell structure strength
And the rate of degradation due to apparent hydrolysis is more than necessary
This causes inconvenience such as speeding up. Meanwhile, bioceramics
When the average content of the powder is lower than 5% by weight,
The overall strength of the structure increases, but the bone tissue
Overall performance is reduced and the rate of hydrolysis is significantly slower
Not so desirable. Also, the bioceramic-containing cell structure
Corona discharge treatment, plasma treatment, or peracid
Oxidation treatment for surface activation such as hydrogen fluoride treatment
When such an oxidation treatment is performed, the surface becomes
Because it will be wet well, the surface of the cell structure
Induced formation of bone tissue becomes more active, and it is connected to living bone
Is further improved. As described above, the bioceramics of the present invention
The cell structure contains good binding to living bone and
Combines practical strength and shape retention for several months in the body
In the end, everything eventually replaces the bone tissue and disappears,
Extremely useful as a biomaterial such as a scaffold for reconstruction of bone injuries
Useful. This is not only for hard tissue, but also for soft tissue
Also as a material for tissue engineering, a scaffold for reconstruction
It is valid. In particular, a thick cell structure of 1 mm or more is
Geometrically fit in complex three-dimensional space of injured body
3D while exhibiting the function as a temporary prosthetic material
It is possible to reconstruct a damaged area. Furthermore, foaming times
Cell structures with high percentages have low polymer content and
During the solution / absorption process, a large number of strips are temporarily generated
No transients, so transients due to foreign substance reaction of degraded strips
It can also eliminate inflammation. Also, for example, implants such as artificial joints
Gap inevitable between the bone and the reamed living bone
The bioceramic-containing cell structure of the present invention is interposed
When both are brought into close contact, the cell structure eventually becomes bone tissue
To replace this bone tissue with the shape of the implant
For better adhesion, fix the implant to living bone.
Can be up. DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, specific embodiments of the present invention will be described.
Will be described in detail. Cell Structure Containing Bioceramics of the Present Invention
The biodegradable and absorbent polymer used for the body is 100,000
Polylactic acid having a viscosity average molecular weight of up to 700,000
Licolic acid copolymer, lactic acid-caprolactone copolymer
Are preferred, and these may be used alone or in combination of two or more.
used. The polylactic acid is a homopolymer of L-lactic acid.
-Or random or block of L-lactic acid and D-lactic acid
A copolymer is used, and lactic acid is used as the copolymer.
And mol of lactic acid and caprolactone
Those having a ratio in the range of 99: 1 to 75:25 are used
You. Glycolic acid or caprolactone ratio is within the above range
Higher, the hydrolysis resistance of the cell structure decreases and
Cell structure with high expansion ratio, which may lead to strength deterioration
It is also difficult to form a body. In addition, these copolymers
Besides, a copolymer of polylactic acid and polyethylene glycol
Or a copolymer of polylactic acid and polypropylene glycol
Etc. can also be used. These polylactic acids and copolymers are as described above.
With a viscosity average molecular weight in the range of 100,000 to 700,000
It is desirable to use such a high molecular weight poly.
The use of lactic acid or copolymers makes non-porous solid polymers
Low strength, but relatively high strength (tensile strength
And bending strength), and the strength maintenance period in vivo
High foaming from short ones up to two months to several months long
A magnification cell structure can be formed. The ratio and average molecular weight of the polylactic acid in the polymer are
The higher, the higher the hardness, strength and strength of the cell structure.
The retention time is improved, but the viscosity average molecular weight exceeds 700,000
Polymer becomes difficult to dissolve in the solvent.
It becomes difficult to obtain a cell structure. On the other hand, viscosity average molecule
If the amount is lower than 100,000, the strength of the cell structure decreases.
In addition, the strength maintenance period in the living body is shortened. Polylactic acid and
A more desirable range of the viscosity average molecular weight of the polymer is 150,000 to
600,000. The above-mentioned high molecular weight polylactic acid and copolymer
An appropriate amount of a low-molecular-weight compound may be added to the combination. Low
The initial hydrolysis of the cell structure
The speed can be increased appropriately. The biocell to be contained in the cell structure of the present invention
As Lamix powder, sintered bioactive surface bioactive
Roxyapatite, bioglass or crystallized glass
Glass for living organisms (eg, bioglass and AW glass)
Ceramics, etc.), bio-absorbable wet hydroxy
Apatite, dicalcium phosphate, tricalcium
Muphosphate, tetracalcium phosphate, octane
Tacalcium phosphate, diopsite, calcite
Etc. are suitable, and these may be used alone or in combination of two or more.
Used mixed. These bioceramic powders are
Particles having a particle size in the range of 0.1 to 100 μm
It is desirable to use. Further, more preferably several μm
To several tens of μm. Biocera larger than 100 μm
The use of a mixed powder allows for the
Precipitating bioceramic powder to form cell structure
The settling speed of the bioceramic powder is too fast
Most of the powder is deposited at the bottom and
Cell structure containing almost no bioceramic powder
Will be done. Such a cell structure is
The lower side where a large amount of ceramic powder is deposited is strong
Very brittle and contains almost no bioceramic powder
On the top side, only the inherent properties of the polymer are exhibited,
Poor ability to induce and form the weave; differences in physical properties and functions between the two
There are differences, and the two are easy to separate,
It is difficult to achieve the object of the present invention well. Generally, bioceramic powders are
The smaller the particles, the slower the sedimentation velocity, and the cell structure
Since the difference in powder content between the upper side and the lower side of
Select the size of bioceramic powder within the above range
If the viscosity is selected by adjusting the polymer solution concentration,
Control the powder content gradient of
Can be Cell Structure Containing Bioceramics of the Present Invention
The body uses the biodegradable and absorbable polymer as its solvent and
Dissolved in a mixed solvent with a non-solvent with a higher boiling point than
In both cases, the above-mentioned bioceramics powder is suspended
Prepare a liquid, put this suspension in a mold, and
By volatilizing at a temperature lower than the boiling point,
Precipitates biodegradable and absorbable polymer containing powder
The principle of cell structure formation is already
As described above. The bioceramic formed by such a method
Cell structure is a polymer that surrounds continuous pores
Cell walls are connected in a network and the surface of the cell walls
Or a structure in which bioceramic powder is held inside
are doing. Also, polymer concentration, bioceramic powder
By choosing the particle size of the body and the ratio of solvent to non-solvent
The content of the powder is changed from the upper surface side to the lower surface side of the cell structure.
As it approaches (ie, in the direction of sedimentation)
Can be obtained, and the concentration gradient can also be adjusted.
it can. The preparation of the above-mentioned suspension is performed by
A polymer solution prepared by dissolving a polymer in a solvent;
Mix the powder mixture with a dispersion of non-solvent
It is desirable to prepare
Dissolving the polymer and suspending the bioceramics powder
I can. As the solvent, the above-mentioned biodegradable absorbent
Can dissolve limers and easily diffuse at temperatures slightly higher than room temperature
Low boiling point solvents such as methylene chloride (CH _Two Cl _Two ),
Chloroform (CHCl _Three ), 1,1-dichloroethane
(CH _Three CHCl _Two ) Is used. Of these,
Low-toxicity methyle chloride with low boiling point and highest vapor pressure
Is most suitable, and chloroform is also suitable. On the other hand, non-solvents have a boiling point higher than that of the above-mentioned solvents.
Use a solvent that is high and compatible with the above solvents.
If a non-solvent with poor compatibility is used,
Bioceramics with high efficiency and uniform fine pores
It becomes difficult to obtain a containing cell structure. This non-solvent
The boiling point has an upper limit of up to around 110 ° C (1 atm).
When determining the combination of
However, it is desirable to select a non-solvent having a considerably high boiling point. Insoluble
If the agent has a boiling point higher than 110 ° C.,
The vapor pressure in the cell is too low and air diffusion at room temperature is too slow.
Structural formation takes time and non-solvent remains in the cell
It will be easier. The difference in boiling point between the non-solvent and the solvent is about 15 ° C.
If it is too small, the solvent will evaporate easily with the non-solvent.
As a result, the function of the non-solvent as a precipitant is reduced. Preferred non-solvents include the aforementioned methyl chloride
Compatible with solvents such as ren and has a boiling point of 60 ° C to 110 ° C
Monohydric alcohols (for example,
Tanol, ethanol, 1-propanol, 2-propa
Nol (isopropyl alcohol), 2-butanol,
ter-butanol, ter-pentanol and the like.
However, considering the toxicity and odor, ethanol, 1
-Propanol, 2-propanol are particularly preferably used.
It is. Add a small amount of water to these monohydric alcohols
Non-solvents are also preferably used. Water is better than alcohol
It acts as a strong precipitant and promotes polymer precipitation.
Because it advances. Table 1 lists preferred solvents and non-solvents,
The respective boiling points and vapor pressures at 20 ° C. are shown. Also,
Table 2 shows the boiling point of methylene chloride, chloroform and each non-solvent.
The point difference and the vapor pressure difference are shown. The combination of solvent and non-solvent
It should be selected appropriately in consideration of the boiling point and vapor pressure in Table 1.
When methylene chloride or chloroform is selected as the solvent
Is to select a non-solvent in consideration of the boiling point difference and vapor pressure difference shown in Table 2.
You can choose. [Table 1] [Table 2] The ratio of the solvent to the non-solvent in the mixed solvent is determined by volume ratio.
It is important to set the range of 10: 1 to 10:10
If the ratio is within the range, a cell structure is formed.
be able to. When the solvent ratio is larger than the above range
Means that the dissolution of the polymer continues until the end of
Precipitation of polymer does not occur.
Bubbles-free, transparent with most of the powder settling on the bottom
Only a polymer mass is obtained. On the other hand, the solvent ratio is above
If it is smaller than the range, only a small amount of solvent
Polymer precipitates at once with bioceramic powder
As a result, welding between cells becomes incomplete and physical
A brittle cell structure with no connection or a connection between cells
Ungrained powder or granules are completed,
Different shrinkage and deformed cell structure
No. Cells are connected in a three-dimensional space
Range of ratio suitable for formation of stable cell structure
Varies depending on the type of solvent and non-solvent,
10: 7. In the mixed solvent of the solvent and the non-solvent as described above,
Dissolve biodegradable and absorbable polymer and
The solution in which the Lamix powder was suspended was filled into the mold
After that, a temperature lower than the boiling point of the solvent, preferably 20 ° C. or less
At a temperature, the mixed solvent may be diffused under normal pressure or reduced pressure.
is important. If gas is diffused at a temperature higher than the boiling point of the solvent,
As the agent boils and destroys the cell walls and welds, high quality cell
No structure can be obtained. This process of air diffusion
In a closed device that can recover the solvent
Use the recovered solvent over and over again
It is safe and does not inhale during operation.
It is resource saving. As described above, the mixed solvent is diffused from the suspension.
Then, a thin film or sheet of several hundred μm or less
If you are looking for a cell structure containing bioceramics
It can be formed in a short time in between. And 1mm or less
Top thick plate or irregular shaped bioceramics
In the case of containing cell structure, suspend by changing the mold depth and shape
It takes a little longer time just to increase the filling amount of liquid
However, it can be easily formed similarly. Then mix
Make sure that the solvent is evenly diffused from the entire surface of the mold.
Do not pass through the polymer but pass through the mixed solvent.
Porous molds with countless fine vents, such as unglazed
One preferred method is to use a ceramic mold, etc.
is there. Further, by fixing the cell wall to be formed,
Avoid collapse and deformation of structures, bioceramics
Slow down the sedimentation speed of powder to reduce powder content gradient
For the purpose of speeding up the gas diffusion of the mixed solvent,
The suspension thickens at a low temperature of about 10 ° C. or less while stirring,
Take the operation of leaving the solvent under reduced pressure and forcibly evaporating the solvent
This is another desirable method. However, the mixed solvent
The diffusion rate depends on the molecular weight, type, concentration,
Delicately adjusted according to the thickness, shape, expansion ratio, etc.
There is a need to. In this way, the thickness is more than 5cm
Block or irregularly shaped
Cell structure with relatively small gradient of ceramics powder content
The structure can be easily formed. Foaming of Cell Structure Containing Bioceramics
Magnification is 2 to 30 times, 5 to 25 times is relatively acceptable
Such a cell structure having a high expansion ratio can be easily obtained.
Due to the small amount of fragments generated by hydrolysis in the body,
Due to foreign body reaction caused by temporary mass production of debris
Has the advantage that there is almost no fear of causing transient inflammation
You. Factors that determine the expansion ratio include polymers.
-Concentration (viscosity of suspension), molecular weight of polymer, mixed solvent
The composition ratio, the air diffusion rate, etc. are listed, but the
Polymer precipitates with the bioceramic powder and
According to the principle of forming the polymer structure, the polymer concentration is
Is also an important factor. The relationship between the polymer concentration and the expansion ratio is inversely proportional.
Yes, the higher the polymer concentration, the lower the expansion ratio
You. And the polymer concentration in the mixed solvent is 10% by weight or less.
When it comes to the top, a cell structure with an expansion ratio of 5 times or more
It becomes difficult to form. Therefore, cells with high expansion ratio
In order to obtain a structure, it is necessary to lower the polymer concentration.
You. The polymer concentration in the mixed solvent is about 2% by weight
And 20 to 3 depending on the composition ratio of the mixed solvent.
To form a cell structure having a high expansion ratio of about 0 times
Can be. However, by further reducing the polymer concentration,
% Or less, a satisfactory cell structure can be obtained.
It will be difficult. At the same time, the deposition of bioceramic powder
Is increased, resulting in a cell structure that is excessively biased in one direction. The relationship between the molecular weight of the polymer and the expansion ratio is as follows.
Foaming ratio is the highest in the
Foaming ratio decreases even if it becomes larger or smaller than the area
Tend to. Viscosity average molecule with highest expansion ratio
The amount is about 200,000 to 350,000 for the above-mentioned polylactic acid and copolymer.
If the temperature is lower than 100,000, bio
It is difficult to form ceramic-containing cell structures.
You. Further, the relationship between the composition ratio of the mixed solvent and the expansion ratio is shown.
Regarding the relationship, the ratio of the above-mentioned ratio at which the cell structure can be formed is
Within the range, the higher the ratio of non-solvent, the higher the foaming ratio
The rate is high. Thus, the polymer concentration, polymer molecule
If the amount and composition ratio of the mixed solvent are variously changed, the cell structure
The expansion ratio of the body can be freely controlled,
Bioceramic-containing cell having foaming ratio of up to 30 times
Can be formed. Such expansion ratio
Has a mean pore diameter of continuous pores of 3 to 300 μm.
And particularly, an average pore diameter of about 150 to 300 μm.
When the cell structure is implanted in the damaged site of living bone
Easy entry of body fluids and soft or hard tissue cells into the
Bioceramic powder present on or inside the cell wall
The body is particularly effective at inducing the formation of bone tissue.
Therefore, it is useful as a biomaterial for bone tissue reconstruction. Cell Structure Containing Bioceramics of the Present Invention
The body contains bioceramic powder, as described above.
The amount is from one side (upper side) to the opposite side (lower side) of the cell structure.
Side).
The average content of bioceramic powder is 5
It is desirable to set within the range of 〜60% by weight. average
If the content is higher than 60% by weight,
Of bioactivity such as the ability to induce and form bone tissue by powder
Improves overall, but reduces the overall strength of the cell structure.
And apparent deterioration due to hydrolysis is faster than necessary
This is not preferable because it causes inconveniences such as on the other hand,
Average content of bioceramics powder is lower than 5% by weight
The overall strength of the cell structure is
Improves to the same degree as cell structure, but the degree of bioactivity
Overall decrease, and apparent degradation due to hydrolysis
Because it causes inconvenience such as slowing down.
Not good. The cell structure containing the bioceramics
Should be subjected to oxidation treatment such as corona discharge treatment.
If such a treatment is applied to the surface,
Since the wettability with bodily fluids increases, it can be applied to the surface layer of the cell structure.
Remarkably expresses the degree of biological activity in
The properties such as properties are further improved. The above-described bioceramics of the present invention
Contains cell structure, representing good bonding to living bone
The nature of the biological activity
It has both utility strength and shape retention, and ultimately everything
It replaces the surrounding bone tissue and disappears.
As a biomaterial for reconstruction of tissue or for tissue reconstruction
Excellent as a scaffold or material for tissue engineering
And useful. In particular, a thick cell structure of 1 mm or more,
Applying the shape to the complex three-dimensional space of the injury site,
Three-dimensional loss while exhibiting the function as a temporal prosthesis
It is possible to reconstruct the wound site, and the expansion ratio
High cell structure, the polymer is quantitatively lean,
During the decomposition and absorption process, many degraded strips are produced
Is not formed, so that there is no
It is really effective because there is almost no fear of causing sexual inflammation.
You. Further, the bioceramic-containing cell of the present invention
Structures, such as artificial joints (eg, hip heads)
When interposed between the plant and living bone, the cell
The structure replaces the bone tissue, and this bone tissue
Improve the fixation strength of the implant
It is effective for FIG. 1 is a partial sectional view showing an example.
One of the artificial joints made of ultra-high molecular weight polyethylene
When the hemispherical shell 1 is fixed to the end of the living bone 2, the hemisphere
Cell structure containing bioceramics of the present invention formed in a shell shape
The structure 3 is used as a spacer between the hemispherical shell 1 and the living bone 2.
It was made to exist. Thus, bioceramics
When the cell structure 3 is interposed, bone tissue is induced inside the cell structure 3.
Is formed and replaced by the decomposition and absorption of the cell structure 3,
The reconstructed living bone is brought into close contact with the surface of the hemispherical shell 1 to form a hemispherical shell.
The fixation of the body 1 is ensured. In that case, the surface layer of the hemispherical shell 1
When the bioceramic powder is embedded in the part,
The surface layer bonds to the living bone, and the fixability is further improved. Next, more specific examples and comparative examples of the present invention will be described.
Will be described. Comparative Example 1 Methylene chloride (C
H _Two Cl _Two ) And a viscosity average molecular weight of 300,000
Of poly-L-lactic acid at a rate of 4 g / dl
Green hydroxyapatite having an average particle size of 3 μm
Powder (U-HA powder) at a rate of 2.7 g / dl (U-H powder)
A powder content: 40% by weight) to prepare a suspension.
did. Then, this suspension is put in a Petri dish with a diameter of 10 cm.
Into the container so that the liquid level is 13 mm
Cover and let stand at room temperature (10-20 ° C) under atmospheric pressure for 24 hours
To disperse the solvent. However, no cell structure was formed,
A 0.7mm thick sheet containing a lot of U-HA powder
Been formed. This means that until the solvent
As it dissolves and disperses, the pores of the solvent
This is because they did not form a cell structure. For this sheet, phosphate buffer at 37 ° C.
Hydrolysis experiment in liquid and high
An experiment of droxyapatite formation was performed. As a result,
As for the decomposition experiment, the results shown in FIG. 3 were obtained.
In addition, about the hydroxyapatite formation experiment,
After immersion for a week, the bottom surface of the sheet having a high U-HA powder content
In which hydroxyapatite crystals are dotted
It was confirmed with an electron microscope that
Crystal formation could not be confirmed on the upper surface where the number was small. Example 1 Methylene chloride (C
H _Two Cl _Two ), Ethanol (C _Two H _Five OH)
Use a solvent to non-solvent volume ratio (solvent / non-solvent) of 10
Change to / 1, 10/3, 10/5, 10/7, 10/9
The five types of mixed solvents were added to a mixture having a viscosity average molecular weight of 300,000.
While dissolving l-lactic acid at a rate of 4 g / dl,
2.7 g / dl U-HA powder having an average particle size of 3 μm
To prepare five types of suspensions. These suspensions were washed with a 10 cm diameter shield.
Into the tray so that the liquid level is 13 mm high.
Leave the lid on and leave it at room temperature (10-20 ° C) under atmospheric pressure.
U-HA powder-containing cell structure (average content of U-HA powder)
(Rate: 40% by weight). Suspension after 24 hours
The mixed solvent in the solvent evaporates, and the composition ratio of the mixed solvent (solvent
(Non-solvent) is only 10/7 and 10/9.
It just left a tanol odor. Then decompress
After drying, the gas chromatograph cannot detect the solvent.
became. Table 3 below shows the properties of each of the obtained cell structures.
Shown together. Next, the cross section of each cell structure was scanned with a scanning electron microscope.
Observed with a mirror (SEM), the pore size and U-HA powder
The distribution was examined. As a result, the pore size of each cell structure is large.
The size is as shown in Table 3 below, and any cell structure
In the body, the U-HA powder is coarsely distributed on the upper surface side and close to the lower surface side.
The distribution was densely distributed as The bending strength and tensile strength of each cell structure
Was measured, the results shown in Table 3 were obtained. In addition,
The bending strength is determined by a three-point bending test method (JIS K7221).
The tensile strength is determined by a universal testing machine (JIS)
K 7113). [Table 3] As can be seen from the results shown in Table 3,
In the case of a mixed solvent of methylene and ethanol, the composition of the solvent
The ratio (methylene chloride / ethanol) is 10/1 to 10/6
, A relatively good cell structure can be obtained. And the solvent group
When the composition ratio is 10/5, the expansion ratio is as high as 10.0 times.
Cell structure with high value
My body is getting thicker. This is in contact with the outside air of the suspension
The polymer immediately precipitates and solidifies from the
And maintain the thickness by forming and fixing the cell walls.
It is thought that it was done. This fact indicates that a certain expansion ratio
When a cell structure with a small thickness is required, the composition ratio of the solvent
Suggest that the concentration of the polymer solution should be adjusted
I have. When the ratio of the solvent is high, the
The volume decreases, and when the thickness decreases,
The cell structure is solidified and the cell walls are fixed.
It is considered that the thickness of the structure and the expansion ratio were reduced. vice versa,
If the initial non-solvent ratio is high, a slight
Immediately exerts the effect as a non-solvent precipitant
And a precipitate is formed at once. At this time, dissolve the polymer
And leave enough solvent to form continuous cell walls.
Does not significantly shrink or settle when pores form.
The fused polymer particles simply fuse to form a link,
A cell such as a kind of sintered body with pores interposed
It is thought to form a structure. In fact, the solvent composition ratio
In 10/7, shrinkage during precipitation and solidification is severe, and the surface
In this way, a deformed cell structure with many wrinkles
When the composition ratio is 10/9, the cell structure is fragile and particles easily fall off.
A structure was obtained. However, the ratio of forming the cell structure
The upper limit is considered to be 10/10. This fact is the reason for the present invention.
This well supports the generation mechanism of the structure. When the solvent composition ratio is 10/1, 10/3,
As it becomes 10/5, the expansion ratio increases,
As a result, both bending strength and tensile strength are reduced.
You. This is because when the expansion ratio increases, the number of pores increases.
Cell walls are thin due to their large size.
It is considered that the strength decreased and the strength decreased. Next, from a suspension having a solvent composition ratio of 10/5,
About the formed U-HA powder-containing cell structure,
Hydrolysis experiments in phosphate buffer at 37 ° C.
Hydroxyapatite formation experiment in body fluid
Was. As a result, FIG.
As shown in FIG.
The water splitting is fast, and the immersion for 12-16 weeks makes PLLA
Viscosity average molecular weight of about 1/2 to the initial viscosity average molecular weight
It decreased to 1/3. This is because the above cell structure
The phosphate buffer easily penetrates through the pores on the surface at the bubble ratio.
It is considered that the hydrolysis was accelerated because the contact area was increased.
available. In addition, a hydroxyapatite formation experiment was performed.
After immersion for 4 weeks, the cell structure containing U-HA powder was
In the surface layer on the lower surface side where there is much
Tight crystals are formed in stripes with a rather large area and contain
Even in the surface layer on the upper side where the amount is small, crystals are dotted and slightly shaped
It was confirmed that it was done. From this, UH
A powder is a form of hydroxyapatite of the same quality as living bone
Cell structure with a high expansion ratio
The body contains U-HA powder and is held on the inner cell wall
Contact with simulated body fluid penetrating through pores on the surface
To quickly induce hydroxyapatite to the inside
It can be seen that it can be formed. On the other hand, the non-
The U-HA powder exposed on the surface is slightly
Only comes into contact with the simulated body fluid,
The formation of hydroxyapatite is slight and polylactic acid
A large amount of hydro-
It takes a long time before xiapatite is formed.
Therefore, the cell structure containing the U-HA powder is embedded in the living body.
Is much more than a non-cell structure U-HA powder-containing sheet
Quickly induces and forms bone tissue and strongly binds to living bone,
It is estimated that the whole will be replaced with bone tissue in a relatively short time.
Wear. [Example 2] The composition ratio of the solvent (CH _Two Cl _Two /
C _Two H _Five OH) made from a 10/5 suspension
The U-HA powder-containing cell structure of Example 1 was prepared at normal temperature and normal pressure.
Corona discharge treatment for 5 minutes from a distance of 5 cm (Kyoto Denki
(Using a processing machine manufactured by K.K.)
Hydroxia in simulated body fluid for cell structures
An experiment on the formation of patite was performed. As a result, after immersion for 1 to 2 weeks, the cell structure was
Nearly the surface layer on the lower surface side where the U-HA powder content of the structure is large
A large amount of hydroxyapatite crystals covering the whole
Formed on the surface layer on the top side with low content
It was confirmed that the amount of formation increased. This thing
The corona discharge treatment can form hydroxyapatite
Means that significantly promote and further enhance the guided formation of bone tissue
It turns out that it is useful as. Example 3 Composition ratio of solvent (CH _Two Cl _Two /
C _Two H _Five OH) to 10/5
Maximum particle size 45μm, average particle size 10μ as mixed powder
m biograss (US Biomaterials, registered
(Trademark) was fixed at 40% by weight, and
-L-lactic acid concentration of 1.0, 2.0, 3.0, 4.0,
Prepare 6 types of suspensions by changing to 5.0 and 7.0 g / dl
did. Then, each suspension was placed in a petri dish as in Example 1.
Filling to form a bioglass-containing cell structure. The properties of the obtained cell structure, bending strength,
The tensile strength is summarized in Table 4 below. [Table 4] From the results in Table 4, it can be seen that the expansion ratio is inverse to the concentration.
It is clear that it depends proportionally. Also, polymer
As the concentration decreases, the expansion ratio of the cell structure increases.
However, the bending strength and tensile strength decrease accordingly.
Was. This is due to the gas structure becoming less volatile as the polymer concentration decreases.
As the number and size of the holes increase, the strength of the cell
It is thought that it was. Example 4 Composition ratio of solvent (CH _Two Cl _Two /
C _Two H _Five OH) 10/5, polymer concentration 2 g / dl,
High fired at 900 ° C as bioceramic powder
Droxyapatite (HA) (maximum particle size 150 μm, flat
(Average particle size 30 μm) fixed at 1.35 g / dl
And the viscosity average molecular weight is about 400,000, about 300,000, about 18.5.
As in Example 1, using 10,000 poly-L-lactic acid, respectively.
Cell structure containing HA powder (average content of HA powder)
%; 40% by weight). The properties of each cell structure obtained and the bending strength
Table 5 shows the degree and the tensile strength. [Table 5] As a result, the viscosity average molecular weight of poly-L-lactic acid
As the amount increases, the bending strength and tensile strength of the cell structure
Both have grown. In addition, the viscosity average molecular weight of about 300,000
If you compare the one with about 185,000,
Even though the cell structure has a smaller expansion ratio,
Both tensile strength and tensile strength showed small values. This is a minute
The difference in the amount of cells is the difficulty of forming the cell structure and the quality of the cell.
Cell structure having a viscosity average molecular weight of about 300,000
Has more uniformity of cells than about 18,000 cell structures,
Good cell structure in terms of pore size, number, cell wall hardness, etc.
It is thought that it was made. Comparative Example 2 A polymer having a viscosity average molecular weight of about 90,000
HA powder using Li-L-lactic acid in the same manner as in Example 4.
A containing cell structure was formed. This is the same as that of Example 4
Unlike porous structures, porous particles aggregated and stuck together
It was such a brittle cell structure. The bending strength and tensile strength of this cell structure were
As a result of the measurement, an intensity that could be measured was not obtained.
That is, when compared with the value of the cell structure of the fourth embodiment,
And vulnerable. From this, the strength suitable for practical use
In order to form an HA powder-containing cell structure having a degree of viscosity,
Using poly-L-lactic acid having a degree average molecular weight of about 100,000 or more
It turns out that it is necessary to Example 5 Composition ratio of solvent (CH _Two Cl _Two /
C _Two H _Five OH) is 10/5 and the viscosity average molecular weight is 300,000.
-Fix the concentration of L-lactic acid to 4 g / dl,
AW (Apatite-Worastenay)
G) Glass ceramic powder (maximum particle size 50 μm, average
(The particle size is 10 μm) in an amount of 1.7, 2.7, 4.0 g /
dl, and a suspension was prepared.
A-W glass ceramic powder having an average content of 30, 4
A cell structure of 0.50% by weight was formed. The properties of each cell structure obtained and the bending strength
The degree and tensile strength are shown in Table 6 below. [Table 6] As can be seen from Table 6, the AW glass cell
As the content of Lamix powder increases, the cell structure
Both bending strength and tensile strength decreased. This is the content of the powder
It is considered that when the rate increases, the cell wall becomes brittle.
Therefore, a cell structure with a content ratio suitable for the purpose and location of use
It may be desirable to select the body appropriately. Further, for each of the obtained cell structures, a pseudo
Conducted an experiment to form hydroxyapatite in a similar body fluid
Was. As a result, each of the cell structures was A-W glass.
The surface layer on the lower side where the ceramic powder content is high
However, compared to the surface layer on the upper surface side where the content is low,
The amount of crystals of sheapatite was much larger. Soshi
High average content of AW glass ceramic powder
The lower the surface layer and the upper surface layer, the higher the cell structure
Increased amount of droxyapatite crystals formed
Was confirmed. [Comparative Example 3] AW glass ceramic powder
Except that the amount of body was changed to 0.5 and 8.0 g / dl
In the same manner as in Example 5, the A-W glass ceramic powder
A cell structure with an average content of 11% by weight and 67% by weight
Done. Then, for each cell structure,
The experiment of hydroxyapatite formation was carried out. As a result, AW glass ceramic powder
Cell structure with an average content of 11% by weight is immersed for one month
After that, a slight amount of hydroxyapatite
Crystal formation was only observed. In contrast, A
The average content of -W glass ceramic powder is 67% by weight
1 week after immersion, the upper and lower surface layers
A large amount of hydroxyapatite crystals are formed in the part
Was. However, this cell structure has powder exposed on the surface.
Because it falls off easily and has low strength and is very brittle,
It is not suitable for practical use. [Example 7] Glycolic acid (GA) and L-
Lactic acid (LLA) copolymer [GA / LLA: 80/20
(Molar ratio), weight average molecular weight Mw: 539,000, media
Soave Technik], chloroform and isopropyl
Alcohol mixed solvent (10/3 volume ratio)
dl and dissolved as bioceramic powder
Calcined hydroxyapatite (U-HA) powder (average grain
Diameter of 3.0 μm) and the blending amount is 30% by weight.
Then, a petri dish was filled in the same manner as in Example 1 and U-H
An A powder-containing cell structure was obtained. The cell structure obtained was a GA / LLA
Because it is a polymer, it is softer than that of Example 1.
Cell structure. This cell structure can be
Induces and breaks down and absorbs in vivo within about 3 months
It is useful as a biomaterial. As can be understood from the above description, the present invention
Ming's bioceramic-containing cell structure is
Good bioactivity and in vivo performance over several months
It has both utility strength and shape retention, and ultimately all bone tissue
For example, reconstruction of a bone injury site
Very suitable as a biomaterial for medical applications, prostheses and scaffolds
In particular, a cell structure thicker than 1 mm
Temporary prosthesis by geometrically applying it to a complex three-dimensional space
Reconstruction of three-dimensional damaged parts while exhibiting the function as a material
A cell structure that can be built and has a high expansion ratio
Is a large number of degraded particles that temporarily and rapidly
Is not generated due to foreign matter reaction of the decomposed strip.
It can also eliminate the fear of causing temporary inflammation
You. Furthermore, surface oxidation treatment such as corona discharge treatment is performed.
In addition, the good wettability of the surface increases the affinity of the tissue
The ability to form induction is further improved and is extremely bioactive. Only
The cell structure containing bioceramics of the present invention
Safe because it contains no harmful benzene or other solvents and does not remain
It is excellent in the property and between the implant and the living bone.
Improve the fixation strength of the implant by intervening
Is also possible. The manufacturing method according to the present invention uses a special device.
Easily produce homogeneous cell structures without using
Can easily adjust the expansion ratio and thickness.
It has the effect of doing so.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a cross-sectional view showing one usage example of a bioceramic-containing cell structure of the present invention. FIG. 2 is a graph showing the relationship between the hydrolysis period and the viscosity average molecular weight of the bioceramic-containing cell structure of one example of the present invention. FIG. 3 is a graph showing a relationship between a hydrolysis period and a viscosity average molecular weight of a bioceramic-containing sheet of a comparative example. [Description of Signs] 1 One hemispherical shell of artificial joint 2 Living bone 3 Cell structure containing bioceramics of the present invention

Continuation of front page (56) References JP-A-3-68370 (JP, A) WO 95/019796 (WO, A1) DEVIN, J. E. FIG. et al, Three-dimensional degradable porous polymer-ceramic matrices for use in bone repair, J. et al. Bioma ter. Sci. Polym. Ed. , Vol. 7, No. 8, p. 661-669 GOGOLEWSKI, S.M. et al. , Resorbable materials reals of poly (L-lactide), Colloid & Polymer Sci. , Vol. 261, no. 6, p. 477-484 (58) Field surveyed (Int. Cl. ⁷ , DB name) A61L 15/00-33/18 C08J 9/00-9/42 A61F 2/00-4/00 CA (STN) MEDLINE (STN) )

Claims (1)

(57) [Claim 1] A cell structure having continuous pores formed from a biodegradable and absorbable polymer, wherein a bioactive bioceramic powder is contained therein. Yes,
A bioceramic-containing cell structure characterized in that the content of the bioceramic powder gradually increases from one side to the opposite side of the cell structure.