JP5008135B2 - Porous body comprising apatite / collagen composite and method for producing the same - Google Patents

Description

  The present invention relates to a porous composite structure made of an apatite / collagen composite and used for an artificial bone, a cell scaffold, a dental implant, and the like, and particularly has a high compressive strength and has a bone replacement property and a tissue penetration property. The present invention relates to a composite structure and a manufacturing method thereof.

  Artificial bone containing calcium phosphate such as apatite has affinity for autologous bone and can directly bind to autologous bone. Therefore, its usefulness has been evaluated, and it has been clinically applied mainly in orthopedics, neurosurgery, plastic surgery, oral surgery and the like. However, the mechanical properties and physiological properties of ceramic-based artificial bones such as apatite are not exactly the same as autologous bones. For example, a so-called ceramic artificial bone made only of apatite is harder and more brittle than autologous bone. Therefore, there is a problem that it is difficult to mold in accordance with the transplant site, and it is easy to drop off from the transplant site. In addition, autologous bone repeats metabolism of absorption and regeneration, whereas artificial bone made of apatite hardly dissolves in the living body, and therefore remains semi-permanently in the living body. For this reason, the remaining artificial bone may destroy the autologous bone at the interface with the autologous bone and cause a fracture.

  In recent years, artificial bones that are closer to the composition of autologous bones than apatite artificial bones and decompose in vivo have been studied. For example, Japanese Patent No. 3048289 (Patent Document 1) and Japanese Patent Publication No. 11-513590 (Patent Document 2) disclose a porous body having a network in which collagen and other binders are bonded to hydroxyapatite if necessary. . When an apatite porous body having properties similar to autologous bone is used as a bio-implant material, cells involved in bone formation are attracted into the artificial bone transplanted to the bone defect, and autologous bone grows and transplants. It is described that the artificial bone thus obtained is decomposed and absorbed by the host, is replaced by the grown bone tissue, has a low risk of being rejected by the host, and has a high bone forming ability, so that the healing period is short. Therefore, it can be used for spinal fixation, bone defect compensation, fracture repair, and transplantation to the jaw bone defect. However, since these porous bodies do not have a pore structure, there is a problem that the tissue penetration is low and the blood and cell entry speeds are different.

  Japanese Patent Application Laid-Open No. 2003-190271 (Patent Document 3) is a microporous structure composed of a composite containing hydroxyapatite and collagen having an average fiber length of 60 μm or more and oriented so that the C-axis of hydroxyapatite follows the collagen fiber An organic-inorganic composite biomaterial having a mechanical strength and biodegradability suitable for artificial aggregates are disclosed. However, the organic-inorganic composite biomaterial described in JP-A-2003-190271 (Patent Document 3) has a problem of low mechanical strength.

  Japanese Patent Application Laid-Open No. 2004-275202 (Patent Document 4) discloses a porous ceramic implant material containing calcium phosphate, characterized by comprising a sintered body having a diameter of 10 to 500 μm and pores oriented in one direction. Describes that an implant material having high biocompatibility and excellent mechanical properties can be obtained. Japanese Patent Laid-Open No. 2005-1943 (Patent Document 5) contains hexagonal columnar crystal particles having a side length of 0.1 to 100 μm and an aspect ratio in the range of 2 to 20, and the porosity is 20 to 20 μm. A porous ceramic material characterized by 90% and a method for producing the same are disclosed, and it is described that an implant material having excellent mechanical properties can be obtained. However, the implant materials described in Japanese Patent Application Laid-Open No. 2004-275202 (Patent Document 4) and Japanese Patent Application Laid-Open No. 2005-1943 (Patent Document 5) are inferior in bone replacement property and tissue penetration property, and their speed cannot be controlled. .

Japanese Patent No. 3048289 Japanese National Patent Publication No. 11-513590 JP 2003-190271 A JP 2004-275202 A JP 2005-1943 A

  Accordingly, an object of the present invention is to provide a method for controlling bone replacement and tissue penetration by controlling the pore diameter of a porous body having pores oriented in one direction. Another object of the present invention is to provide a porous body used for artificial bones, cell scaffolds and the like having excellent bone replacement and tissue penetration.

  As a result of diligent research in view of the above object, the inventors of the present invention can obtain a pore structure oriented in one direction by cooling and freezing from one direction when freeze-drying the gel of the apatite / collagen complex. The inventors have found that the pore structure can be controlled by changing the cooling temperature, and have come up with the present invention.

  In the method of the present invention for producing a porous body composed of an apatite / collagen composite, a slurry obtained by dispersing a raw material powder composed of an apatite / collagen composite in water is frozen by cooling from one direction and dried. Thus, a method for producing a porous body having a pore structure oriented in one direction, wherein the pore structure is controlled by changing the temperature during cooling.

  The apatite / collagen composite is preferably in the form of a fiber having a length of 1 mm or less. The apatite in the apatite / collagen composite is preferably hydroxyapatite.

  The porous body comprising the apatite / collagen composite of the present invention is produced by the above method.

  The method of the present invention for producing a porous body composed of an apatite / collagen composite can control the pore diameter of the apatite / collagen composite having a pore structure oriented in one direction, so that tissue penetration can be adjusted. It is. A porous body made of an apatite / collagen composite obtained by the method of the present invention is suitable as a biomaterial for artificial bones, artificial joints and the like because it has high bone replacement and bone forming ability and excellent biocompatibility.

[1] Porous body made of apatite / collagen composite
(1) Structure The porous body of the present invention is made of a material composed of an apatite / collagen composite and has a pore structure (hereinafter also referred to as uniaxial structure) oriented in one direction. As shown in FIG. 1, the pore structure oriented in one direction has a mesh section when cut along a plane perpendicular to the orientation direction, and a stripe section when cut along a plane parallel to the orientation direction. It is the structure which is.

  As shown in FIG. 2, the uniaxial structure is classified into Types 1 to 3 depending on the penetration of pores. Type1 indicates that one side of pores oriented in one direction is completely closed, Type2 indicates that one side is thin, and Type3 indicates that they are almost parallel.

(2) Composition The porous body having a uniaxial structure of the present invention is made of an apatite / collagen composite material.

  Examples of the apatite in the apatite / collagen composite include calcium hydrogen phosphate, octacalcium phosphate, tricalcium phosphate, apatite (hydroxyapatite, carbonate apatite, fluorapatite, etc.), tetracalcium phosphate and the like. From the viewpoint of biocompatibility, apatite is preferable, and hydroxyapatite is particularly preferable.

  As the collagen in the apatite / collagen complex, those extracted from animals or the like can be used, but the species, tissue site, age, etc. of the animal from which it is derived are not particularly limited. In general, collagen obtained from the skin, bone, cartilage, tendon, organ, etc. of mammals (eg, cows, pigs, horses, rabbits, mice, etc.) and birds (eg, chickens, etc.) can be used. Collagen-like proteins obtained from the skin, bones, cartilage, fins, scales, organs, etc. of fish (eg cod, flounder, flounder, salmon, trout, tuna, mackerel, Thai, sardine, shark etc.) may also be used. . The method for extracting collagen is not particularly limited, and a general extraction method can be used. Further, instead of extraction from animal tissue, collagen obtained by gene recombination technology may be used. Particularly preferred collagen is atelocollagen obtained by removing telopeptide at the molecular end having immunogenicity by enzymatic treatment.

[2] Method for producing uniaxial porous body made of apatite / collagen composite A uniaxial porous body made of an apatite / collagen composite was placed in a mold with a slurry obtained by dispersing the composite in water, frozen and dried. Later, it is formed by crosslinking. After forming, it can be cut into a desired shape and used.

  These apatite / collagen composites can form a pore structure oriented in one direction by cooling from one direction when the dispersion of the apatite / collagen composite material is frozen. The pore diameter can also be controlled by cooling conditions.

(1) Production of Ceramic Material Using Apatite / Collagen Composite A method for producing an apatite / collagen composite and a method for producing a porous material using the same will be described in detail below.

(a) Manufacture of apatite / collagen complex Apatite and collagen may be simply mixed, but in order to improve biocompatibility and osteogenesis, an apatite / collagen complex in which apatite and collagen are chemically bonded is used. It is preferable to use it. A preferred example of this complex is an apatite / collagen complex having a self-organized structure (a structure similar to living bone) in which the C-axis of apatite is oriented along collagen fibers. As the apatite, hydroxyapatite is particularly preferable.

(i) Preparation of Raw Material for Apatite / Collagen Complex An apatite / collagen complex is prepared by, for example, an aqueous solution of phosphoric acid or a salt thereof (hereinafter simply referred to as “phosphoric acid (salt)”) and an aqueous solution of calcium salt in a solution containing collagen. Alternatively, it is produced by adding a suspension. Examples of phosphoric acid (salt) include phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and the like. Examples of calcium salts include calcium carbonate, calcium acetate, and calcium hydroxide.

  Since the fiber length of the apatite / collagen composite can be controlled by the mixing ratio of the apatite raw material [phosphoric acid (salt) and calcium salt] and collagen, the mixing ratio of the apatite raw material and collagen is the target fiber of the apatite / collagen composite. It is determined appropriately according to the length. The mixing ratio of apatite / collagen in the apatite / collagen composite used in the present invention is preferably 9/1 to 6/4 (mass ratio), more preferably 8.5 / 1.5 to 7/3 (mass ratio), about 8 / 2 (mass ratio) is most preferred.

(ii) Preparation of solution (suspension) Prepare collagen / phosphoric acid (salt) aqueous solution and calcium salt aqueous solution (or suspension). The collagen / phosphoric acid (salt) aqueous solution is an aqueous solution in which collagen and phosphoric acid (salt) are dissolved, and the concentration of collagen is preferably 0.1 to 1.5% by mass, particularly preferably about 0.85% by mass. The concentration of phosphoric acid (salt) is preferably 15 to 240 mM, particularly preferably about 120 mM. The concentration of the calcium salt aqueous solution (or suspension) is preferably 50 to 800 mM, particularly preferably about 400 mM.

(iii) Production of apatite / collagen complex Phosphoric acid (salt) aqueous solution containing collagen at about 40 ° C and calcium salt aqueous solution or suspension in about the same amount of water as the calcium salt aqueous solution or suspension to be added. The apatite / collagen complex is formed by simultaneously dropping the suspension. By controlling the dropping conditions, the fiber length of the apatite / collagen complex can be controlled. The dropping rate is preferably 1 to 60 mL / min, more preferably about 30 mL / min. The stirring speed is preferably 1 to 400 rpm, more preferably about 200 rpm. The mixing ratio of phosphoric acid (salt) and calcium salt is preferably 1: 1 to 2: 5, and more preferably 3: 5. The mixing ratio of collagen and apatite (total amount of phosphate and calcium salt) is preferably 1: 9 to 4: 6, and more preferably 1.5: 8.5 to 3: 7.

  It is preferable to maintain the pH of the reaction solution at 8.9 to 9.1 by maintaining the calcium ion concentration in the reaction solution at 3.75 mM or less and the phosphate ion concentration at 2.25 mM or less. When the concentration of calcium ions and / or phosphate ions exceeds the above range, self-assembly of the complex is prevented. By the above dropping conditions, the fiber length of the self-organized apatite / collagen composite becomes 2 mm or less which is suitable as a raw material for the apatite / collagen crosslinked porous body.

  The obtained slurry-like mixture of apatite / collagen complex and water is preferably dried. Drying can be performed by freeze-drying or air-drying by replacing water with a solvent such as ethanol, but freeze-drying is preferred. Freeze-drying is performed by evacuation in a state frozen at −10 ° C. or lower.

(b) Production of dispersion containing apatite / collagen complex Water, phosphoric acid aqueous solution and the like are added to the powder of apatite / collagen complex and stirred to prepare a paste-like dispersion (slurry). The addition amount of an aqueous solution or the like is preferably 80 to 99% by volume, more preferably 90 to 97% by volume of the apatite / collagen complex. The porosity P (%) of the porous material depends on the volume ratio of the apatite / collagen complex in the dispersion to the aqueous solution, and the following formula (1):
P = B / (A + B) × 100 ... (1)
Where A represents the volume of the apatite / collagen complex in the dispersion and B represents the volume of the liquid in the dispersion. Therefore, the porosity P of the porous body can be controlled by controlling the amount of liquid added. When the dispersion is stirred after the liquid is added, a part of the fibers of the apatite / collagen composite is cut, and the fiber length distribution increases. By adjusting the stirring conditions, the strength of the resulting porous body can be improved.

  In order to obtain a porous body having a stable shape, it is preferable to further add a binder to the dispersion. Examples of the binder include soluble collagen. The addition amount of the binder is preferably 1 to 10% by mass and more preferably 3 to 6% by mass with respect to 100% by mass of the apatite / collagen complex.

  As in the case of producing an apatite / collagen complex, the binder is preferably added in the form of an aqueous phosphoric acid solution. The concentration of the binder solution to be added is not particularly limited, but practically the binder concentration is preferably about 0.85% by mass and the phosphoric acid concentration is about 20 mM.

  After adding the phosphoric acid (salt) aqueous solution of the binder, the pH of the dispersion is adjusted to about 7 with an aqueous sodium hydroxide solution. The pH of the dispersion is preferably 6.8 to 7.6, and more preferably 7.0 to 7.4 in order to prevent collagen from being denatured into gelatin during the gelation treatment described below.

  In order to promote the fiberization of collagen added as a binder, a concentrated solution (about 10 times) of phosphate buffered saline (PBS) is added to the dispersion, and the ionic strength is adjusted to 0.2-1. A more preferred ionic strength is about 0.8, similar to PBS.

  In addition to the dispersion, antibiotics (tetracycline, etc.), anticancer agents (cisplatin, etc.), bone marrow cells, cell growth factors (BMP, FGF, TGF-β, IGF, PDGF, VEGF, etc.) Additives such as physiologically active factors (hormones, cytokines, etc.) can be added.

(c) Gelation After the dispersion is put in a mold, the temperature of the dispersion is maintained at 35 to 45 ° C., whereby collagen added as a binder is fibrillated and the dispersion becomes a gel. Gelation prevents the apatite / collagen composite from settling in the dispersion and provides a uniform porous body. A more preferable holding temperature is 35 to 40 ° C. The holding time is preferably 0.5 to 3.5 hours, more preferably 1 to 3 hours.

(d) Freeze-drying The gelled dispersion is freeze-dried consisting of a freezing step and a drying step. By cooling and freezing the gelled dispersion from one direction, a uniaxial porous body can be formed.

(i) Freezing The gelled dispersion can be cooled and frozen from one direction using, for example, a freezing apparatus 1 equipped with a jig as shown in FIG. The freezing apparatus 1 includes a cooling and heating plate 3 and a metal plate 4 installed on the cooling and heating plate 3 in a heat insulating container 2 [a perspective view is shown in FIG. ]. The cooling and heating plate 3 is thermally connected to a cooling and heating device 5 outside the heat retaining container 2, and can be cooled or heated with high accuracy by the cooling and heating device 5. In order to cool from one direction as described above, for example, a commercially available shelf-type freezing apparatus can be used.

  The gelled dispersion 10 filled in the mold 11 is refrigerated to about 4 ° C. in advance and then placed on the metal plate 4 cooled to a predetermined temperature, so that it is cooled only from the contact surface with the metal plate 4. Is done. The temperature in the heat insulating container 2 is maintained at a temperature (about 4 ° C.) that does not freeze the gelled dispersion 10 from the mold or the upper end. By cooling in this way, freezing starts from the contact surface with the metal plate 4, and water crystals grow in a direction perpendicular to the metal plate 4 [upward in FIG. 3 (a)]. In 3 (a), a pore structure oriented in the vertical direction is formed. In order to efficiently cool only from the metal plate 4, it is preferable to use a material having a low thermal conductivity for the mold 11.

  By changing the temperature during cooling, the uniaxial pore structure can be controlled. Since this method cools only from the contact surface with the metal plate 4, for example, when cooling at a constant temperature, the cold air escapes and the temperature rises as freezing progresses upward, resulting in a pore structure close to Type 2 in FIG. For this reason, in order to approach the Type 3 pore structure, it is desirable to gradually lower the temperature of the metal plate 4 to keep the temperature of the portion where freezing occurs constant. At this time, the change in the freezing rate is preferably small, and a constant rate is more preferable. Specifically, the temperature change of the portion where freezing occurs during freezing is preferably in the range of −20 to 20 ° C./hr, more preferably in the range of −10 to 10 ° C./hr. Moreover, when the temperature is gradually raised during cooling, it approaches Type 1 pore structure. The cooling temperature is preferably changed in the range of -80 to -10 ° C, more preferably -80 to -20 ° C.

(iii) Drying Using a freeze dryer, the dispersion is vacuum-dried while being frozen at −10 ° C. or lower. As long as the dispersion is sufficiently dried, the freeze-drying time is not particularly limited, but generally it is preferably about 1 to 3 days. The apatite / collagen porous body having a uniaxial structure can be obtained by freeze-drying as described above.

(e) Crosslinking The freeze-dried apatite / collagen complex preferably crosslinks collagen in order to increase mechanical strength and to maintain the shape of the artificial bone inserted into the body for a desired period of time. Crosslinking of collagen can be performed using methods such as physical crosslinking using γ rays, ultraviolet rays, electron beams, thermal dehydration, and the like, and chemical crosslinking using a crosslinking agent or a condensing agent. The chemical cross-linking is performed, for example, by immersing the lyophilized porous body in a solution of a cross-linking agent, by allowing a vapor containing a cross-linking agent to act on the lyophilized porous body, or when manufacturing an apatite / collagen composite. Can be carried out by adding a crosslinking agent to the aqueous solution or suspension.

  Examples of crosslinking agents include aldehydes such as glutaraldehyde and formaldehyde, isocyanates such as hexamethylene diisocyanate, carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and epoxy compounds such as ethylene glycol diethyl ether, Examples thereof include transglutaminase. Of these crosslinking agents, glutaraldehyde is particularly preferred from the viewpoint of easy control of the degree of crosslinking and the biocompatibility of the resulting apatite / collagen crosslinked porous body.

  When the porous body is immersed in a glutaraldehyde solution for crosslinking, the concentration of the glutaraldehyde solution is preferably 0.005 to 0.015% by mass, and more preferably 0.005 to 0.01% by mass. When an alcohol such as ethanol is used as a solvent for glutaraldehyde, dehydration is performed at the same time as crosslinking, so that crosslinking occurs in a contracted state of the apatite / collagen composite, and the elasticity of the resulting apatite / collagen crosslinked porous body is improved. .

  After the crosslinking treatment, in order to remove unreacted glutaraldehyde, the apatite / collagen porous porous body is immersed in an aqueous solution of about 2% by mass of glycine and washed with water. Further, it is immersed in ethanol, dehydrated, and dried at room temperature.

(f) Processing The obtained apatite / collagen crosslinked porous body is formed by cutting with a lathe or the like. The obtained porous body may be sterilized by ultraviolet rays, γ rays, electron beams, drying and heating, and the like.

  The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1
A porous body made of an apatite / collagen composite having a pore structure oriented in one direction was produced.

(A) Synthesis of apatite / collagen composite
Solution A was prepared by mixing 50 ml of water and 410 g of collagen / phosphoric acid aqueous solution (collagen: 0.6 mass%, phosphoric acid: 120 mM). Dispersion B was prepared by adding 6 g of calcium hydroxide to 230 ml of water and stirring and dispersing. Solution A and solution B were simultaneously added dropwise to a container containing 200 ml of water while adjusting the speed so that the pH was 9 with a pH controller to prepare a dispersion of hydroxyapatite and collagen complex fibers. This dispersion was frozen and lyophilized under reduced pressure for 7 days to obtain a fibrous hydroxyapatite / collagen complex having an average length of about 1 to 2 mm.

(B) Production of porous body containing apatite / collagen composite 5.5 g of water was added to 1 g of the obtained fibrous hydroxyapatite / collagen composite and stirred to obtain a paste-like dispersion. Further, 2 g of a collagen / phosphoric acid aqueous solution (collagen: 0.6% by mass, phosphoric acid: 20 mM) was added and stirred, and then the pH was adjusted to 7 with 1N NaOH.

  The obtained dispersion was put in a mold and kept at 37 ° C. for 2 hours to gel the dispersion. The gel-like molded body cooled to 4 ° C. was placed in close contact with the metal plate 4 of the freezing apparatus 1 shown in FIGS. 3 (a) and 3 (b) and frozen from one direction. The metal plate 4 was held at −20 ° C. for 10 minutes, and then the temperature was linearly changed (−20 ° C./hr) from −20 ° C. to −40 ° C. over 1 hour, and held at −40 ° C. The cooling pattern at this time is shown in FIG. While changing the temperature from -20 ° C to -40 ° C, the gelled dispersion completely frozen. The inside of the heat insulating container 2 was kept at 4 ° C. at 1 atmosphere. After the entire molded body was frozen, it was dried under vacuum. The molded body after lyophilization was immersed in a 0.01% glutaraldehyde solution prepared using ethanol (concentration 99.5%) as a solvent for crosslinking treatment. The porous body was washed with water, immersed in a 2% glycine aqueous solution to remove unreacted glutaraldehyde, and washed again with water. Further, it was dehydrated by soaking in ethanol (concentration 99.5%), and then dried at room temperature to obtain a porous body composed of an apatite / collagen composite having a pore structure oriented in one direction.

Example 2 and Comparative Example 1
One direction of Example 2 and Comparative Example 1 except that the temperature pattern of the metal plate 4 when frozen from one direction was changed as shown in FIGS. 4B and 4C, respectively. A porous body having pores oriented in the direction was obtained.

  The average pore diameters of the obtained porous bodies of Examples 1 and 2 and Comparative Example 1 were measured by the following method at two locations on the cooled side (lower side) and the opposite side (upper side). Moreover, the average porosity of the whole porous body was measured by the following method. The results are shown in Table 1. FIG. 5 shows scanning electron microscope (SEM) photographs of the pore structures of the porous bodies of Examples 1 and 2 and Comparative Example 1. FIG. 6 is an enlarged view showing the pore structure on the cooled side (lower side) and the opposite side (upper side) of the porous body shown in FIG.

Measurement of average pore diameter The average pore diameter of a porous body having a uniaxial structure was determined by an image analysis method from a scanning electron microscope (SEM) photograph of a cross section parallel to the orientation direction of oriented pores. As shown in FIG. 7, in the SEM cross-sectional view, an auxiliary line L perpendicular to the orientation direction of the pores is drawn, and the size of each pore intersecting with the auxiliary line (the portion indicated as A μm to E μm in FIG. 7) is measured. did. Actually, the pores at 20 or more locations were measured and the average value was obtained.

Measurement of porosity The porosity of the porous body is expressed by the following formula (2):
Porosity (%) = {(apparent volume) − (true volume)} × 100 / (apparent volume) (2)
Determined by Here (true volume) = (mass) / (density).
For example, in the case of a porous body made of hydroxyapatite and collagen, (true volume) is expressed by the following formula (3):
(True volume) = V _A + V _C = m _A / ρ _A + m _C / ρ _C (3)
(Ρ _A , m _A and V _A represent the density, mass and volume of hydroxyapatite, respectively, and ρ _C , m _C and V _C represent the density, mass and volume of collagen).

When freezing [pattern of FIG. 4 (c)] is performed at a constant temperature, the pore diameter on the cooled side (lower side) decreases and the pore diameter on the opposite side (upper side) increases (Comparative Example 1). ). On the other hand, when freezing [pattern (a) in Fig. 4] was performed while gradually lowering the cooling temperature, the difference in pore diameter between the cooled side (lower side) and the opposite side (upper side) became smaller. (Example 1). Conversely, if freezing is performed while gradually increasing the cooling temperature (pattern in Fig. 4 (b)), the pore size on the cooled side (lower side) will be very small, and the air on the opposite side (upper side) will be reduced. The difference from the hole diameter was increased (Example 2). It was found that the pore structure can be controlled by adjusting the cooling temperature pattern during freezing.

It is the schematic diagram and SEM photograph which show the porous body which has the pore structure orientated to one direction. It is a schematic diagram explaining the pore structure oriented in one direction of the present invention. It is a schematic diagram which shows the freezing apparatus provided with the jig | tool for cooling and freezing the gelatinized dispersion from one direction. It is a graph which shows the temperature pattern of (a) Example 1, (b) Example 2, and (c) Comparative Example 1 when the gelatinized dispersion is cooled and frozen from one direction. It is a SEM photograph which shows the pore structure of the porous body of (a) Example 1, (b) Example 2, and (c) Comparative Example 1. It is a SEM photograph which shows the pore structure of the cooling side (lower end) and the opposite side (upper end) of the porous body of (a) Example 1, (b) Example 2 and (c) Comparative Example 1. It is the schematic diagram which showed the method of calculating | requiring the average pore diameter of the porous body which has the pore structure oriented in one direction of this invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 ... Freezing apparatus 2 ... Thermal insulation container 3 ... Cooling heating plate 4 ... Metal plate 5 ... Cooling heating device
10 ... dispersion
11 ... Mold

Claims (6)

A slurry obtained by dispersing a raw material powder composed of an apatite / collagen composite in water is filled in a mold, the slurry is refrigerated together with the mold, and the molding is performed in a heat-retaining container maintained at the refrigeration temperature. A porous body having a pore structure oriented in one direction by placing the mold on a plate cooled to a predetermined temperature, cooling the slurry only from the contact surface with the plate, freezing, and drying. A method for producing a porous body comprising an apatite / collagen composite, wherein the pore structure is controlled by gradually lowering or gradually raising the temperature of the plate during the cooling. 2. The method for producing a porous body made of an apatite / collagen composite according to claim 1, wherein the pores oriented in one direction have the same diameter. 2. The method for producing a porous body comprising an apatite / collagen composite according to claim 1, wherein pores oriented in one direction are partially different in diameter. Method. The method for producing a porous body comprising an apatite / collagen composite according to any one of claims 1 to 3, wherein the porous body having a pore structure oriented in one direction has pores penetrating in the orientation direction. A method for producing a porous body comprising a characteristic apatite / collagen composite. The method for producing a porous body comprising an apatite / collagen composite according to any one of claims 1 to 4, wherein the apatite / collagen composite is in a fibrous form having a length of 1 mm or less. A method for producing a porous body comprising: The method for producing a porous body comprising an apatite / collagen composite according to any one of claims 1 to 5, wherein the apatite in the apatite / collagen composite is hydroxyapatite. The manufacturing method of the porous body which becomes.