JP2003180814A - Scaffold - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a scaffold with which a joint part can be regenerated. <P>SOLUTION: A scaffold 1 for regenerating a bone and a tarsus is obtained by connecting a first layer 11 consisting of ceramics material which is dissolved and absorbed within the living body and through which a large number of hole are formed to a second layer 22 which is formed so that it can be abutted on at least one surface of this ceramic material and which is dissolved and absorbed within the living body and consists of polymeric materials through which a large number of holes are formed, with the abutting surface of the first layer on which the second layer is abutted as a border plane. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a scaffold used for regeneration of bone and cartilage.

[0002]

2. Description of the Related Art As an organism grows older, it becomes more difficult for bones to be regenerated. Therefore, artificial bone made of metal or plastic has been developed as an auxiliary material due to damage or deterioration of bone.

For example, Japanese Patent Laid-Open Publication No. 62-87406,
A method for producing a bioceramic material used as a raw material for artificial bone or the like is disclosed. Especially as a ceramic material, a method for producing β-tricalcium phosphate is shown. β-tricalcium phosphate is non-toxic, safe, has high mechanical strength, and easily binds to living tissue.
This β-tricalcium phosphate further disappears spontaneously in the living body and is replaced with new bone, and thus it is a material having a desirable function for the living body.

Such bioceramic materials are also used for bone regenerative medicine. For example, JP-A-63-4
Porous scaffolds have been created, as disclosed in Japanese Patent 0782. This scaffold is
A β-tricalcium phosphate material, an apatite material, or the like is sintered and formed as a ceramic material. This scaffold has a large number of holes, and bone marrow cells, osteoblasts and the like collected from the living body are arranged in the holes of the scaffold. Then, the cells are cultured by immersing the scaffold in a predetermined culture solution. In this way, after a predetermined time, the scaffold having the cultured cells is placed in the injured site or the deteriorated site of the bone in the living body. Due to the natural healing power of the living body, while the cells divide and the number of cells increases over time, the ceramic material disappears and is replaced by bone.

Attempts have also been made to regenerate cartilage in addition to bone. In order to regenerate cartilage, a scaffold in which a polymer material such as collagen fiber or polylactic acid is combined has been proposed. Similarly, the chondrocytes collected from the living body are cultured in the scaffold, and the scaffold is placed in the living body.

[0006]

[Problems to be Solved by the Invention] Between cartilage and bone,
For example, there are bone called subchondral bone and rams.
This ramus is formed in the shape of a protrusion, it is easily damaged,
Hard to play.

For this reason, cartilage and bone may come into contact with each other, and joints may be inflamed, which is one of the causes of harm to the joints of the living body. In addition, scaffolds applicable to joints have not been developed so far.

Furthermore, cartilage has few chondrocytes per se and is difficult to regenerate.

The present invention has been made to solve the above problems, and an object of the present invention is to provide a scaffold capable of regenerating joints such as bone, cartilage, subchondral bone and rams.

[0010]

In order to solve the above-mentioned problems, the scaffold for regenerating bone and cartilage of the present invention is a ceramic that is decomposed and absorbed in a living body and has a large number of pores communicated with each other. And a polymer material that is formed so as to be able to abut against at least one surface of this ceramic material, is decomposed and absorbed in the living body, and has a large number of holes communicating with each other, with the surfaces that can abut against each other as a boundary surface It is characterized by what is done.

Further, a composite layer made of the ceramic material and the polymer material is further provided between the ceramic material and the polymer material, and the composite layer is provided with a large number of holes communicating with each other. Is preferred.

Further, it is preferable that the diameter of the communication hole communicating the holes of the ceramic material and the polymer material is formed to be 20 μm or more.

Further, the particle size of the ceramic material is 3
It is preferable that the thickness is μm or less.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the present invention will be described below with reference to the drawings.

(First Embodiment) First, the first embodiment will be described with reference to FIG. As shown in FIG. 1, a scaffold 1 serving as a base material for regenerating a joint part such as regenerating bone and cartilage simultaneously comprises two layers. One first layer 11 is used as a scaffold for bone regeneration, and the other second layer 22 is used as a scaffold for cartilage regeneration.

The first layer 11 has, for example, β- as a main component.
It is made of a ceramic material such as TCP called β-tricalcium phosphate. A large number of pores are communicated with the β-TCP, and a large number of communication holes having a diameter of 20 μm or more are provided. That is, a large number of communication holes connecting at least two pores with a diameter of 20 μm or more are provided. These communicating hole diameters may have the same diameter as the pores. Moreover, the pore diameter and the communication pore diameter are 100 μm.
It is preferably about m to 200 μm. Then, these communication holes are provided at random and are formed in a state in which a large number are connected.

The second layer 22 is made of a polymer material such as polylactic acid as a main component. Similarly, this polylactic acid is provided with a large number of communication holes having a diameter of 20 μm or more. There are two communication holes that connect at least two pores.
Many are provided with a diameter of 0 μm or more. These communication holes may have the same diameter as the pores. The pore diameter and the communication pore diameter are 100 μm to 200 μm.
It is preferably about the same. Then, these communication holes are provided at random and are formed in a state in which a large number are connected.

The β-tricalcium phosphate and polylactic acid used in the first and second layers 11 and 22 are nontoxic, safe and biodegradable.

Next, an example of a method of creating such a scaffold 1 will be described. In this scaffold 1, the first layer 11 and the second layer 22 are separately formed, and they are integrated after the layers 11 and 22 are formed.

First, the first layer 11 is preferably made of β-TCP fine powder having a particle size of 3 μm or less. To this β-TCP fine powder, for example, a polyacrylic acid ammonium salt is added as a deflocculant and ultrasonically mixed. Then, after adding, for example, a liquid containing polyoxyethylene nonylphenol ether as a foaming agent, the mixture is stirred with a stirrer to uniformly foam. After stirring, the fluid having air bubbles is poured into a container having a desired shape lined with paraffin paper, and then placed in a thermo-hygrostat and dried at 40 ° C. for about 15 hours. After drying, a container made of alumina (Al ₂ O ₃ purity; 99.
9%) and, for example, at a heating rate of 300 ° C./hr,
The temperature is raised to about 00 ° C., and this temperature is maintained for 40 minutes to sinter the fluid to form the first layer 11.

The sintered products obtained in this embodiment are all open-pore products without closed pores, and the diameter of the communication hole that communicates between the pores is 20 μm or more as described above. . In addition, as a result of X-ray diffraction, it was confirmed that the porous body was β-TCP, which is the same as the starting material.

As the above-mentioned foaming agent, for example, polyoxyethylene alkyl ether, polyoxyethylene alkyl allyl ether, polyoxyethylene alkylamine, polyethylene glycol fatty acid ester decaglycerin monouralate, alkanolamide polyethylene glycol / polypropylene. A nonionic surfactant such as a glycol copolymer and this nonionic surfactant can also be used.

On the other hand, the second layer 22 liquefies polylactic acid by adding an organic solvent such as methylene chloride to polylactic acid which is a soft resin material. Then, after foaming while maintaining a temperature of about 40 ° C. from room temperature, after pouring into a container having a desired shape lined with a predetermined surface of the first layer 11 and lined, for example, a drafter or the like. The solid is dried and solidified by evaporating methylene chloride. In this way, the second layer 22 is formed.

Similar to the first layer 11, it was confirmed that the diameter of the communication holes between the pores of the second layer 22 obtained in this embodiment is 20 μm or more as described above. It was
It was also confirmed that the porous body was polylactic acid.

Then, as described above, at least one surface of each of the first and second layers 11 and 22 is formed in such a shape that they can abut against each other. Therefore, these surfaces are abutted, and the first layer 11 and the second layer 22 are joined together with this surface serving as a boundary surface, whereby one scaffold 1 is created.

Since the scaffold 1 is provided with a large number of holes (communication holes and pores) having a diameter of 20 μm or more,
For example, living cell tissues having a diameter of at most about 10 μm, such as bone marrow cells and osteoblasts, easily enter the scaffold 1 and the culture solution easily flows. For this reason, the culture fluid can be spread throughout the scaffold 1 together with the cells, and cell regeneration can be activated.

Next, a process of culturing cells using such a scaffold 1 will be described. Bone marrow cells were collected from the femur or iliac part of the living body and
After culturing at -75flask for, for example, 7 days to 10 days, cells detached by trypsin treatment are adhered to scaffold 1. Next, the bone marrow cells and scaffold 1 are cultured for 1 hour in a CO ₂ incubator. Then, Dexamethasone is added and the culture is continued for 2 hours. The first layer 11 for culturing osteoblasts is immersed in a predetermined culture solution in a normal culture atmosphere. On the other hand, the second layer 22 for culturing the chondrocytes has, for example, 0 to 10 MP.
The hydrostatic pressure of a is given at a repetition frequency of, for example, 0 to 1 Hz. The oxygen partial pressure in the incubator for the second layer 22 is set lower than that in the atmosphere. This is because chondrocytes have a strong anti-angiogenic effect,
This is because the invasion of blood vessels into the inside of chondrocytes is suppressed, and the oxygen partial pressure thereof is low. Therefore, the second
The oxygen partial pressure in the incubator for the layer 22 is made to reproduce the internal environment. After that, the scaffold 1 is first placed at a desired boundary position between bone and cartilage in the living body.
The layer 11 is placed at a desired position with the second layer 22 facing the cartilage side and the second layer 22 facing the bone side. Then, with the passage of time, in the living body, the bone cells and chondrocytes repeatedly divide and grow to be replaced with bones and cartilage, and the subchondral bones and rams are also regenerated at the same time. The scaffold 1 is gradually decomposed as it is eroded by these cell divisions, and is absorbed into the cells. After a lapse of an arbitrary time, bone and cartilage are formed into a desired shape, and the ceramic material and polymer material forming the scaffold 1 disappear. That is, the scaffold 1 disappears. Therefore, the cultured bone or cartilage is completely replaced by the bone or cartilage of the living body.

In particular, β- which constitutes a ceramic material
Since the TCP particles are formed to have a size of 3 μm or less as described above, they are easily decomposed in vivo and easily absorbed, and do not inhibit bone growth.

Therefore, the following can be said with respect to this embodiment. By regenerating bone and cartilage at the same time, the target cartilage and bone can be integrated and regenerated to facilitate cartilage regeneration. By joining the scaffold 1 for bone and cartilage at the desired interface,
In particular, it can assist the growth of bone, cartilage, etc. at the interface between cartilage and bone. Furthermore, since a material having a good biocompatibility is used, no rejection reaction occurs. In addition, since a material that is decomposed and absorbed in the living body is used, foreign matter is not left on cartilage and bone. Also, the first layer 11
Since the subchondral bone, rams and the like can be regenerated at the interface between the and second layer 22, the scaffold can be more reliably replaced as a joint.

(Second Embodiment) Next, a second embodiment will be described with reference to FIG. This embodiment is a modification of the first embodiment. Therefore, the first
Since the second layers 11 and 22 are formed in the same manner as the first and second layers 11 and 22 described in the first embodiment, the same reference numerals are given and description thereof is omitted.

As shown in FIG. 2, the scaffold 2 as a base material for simultaneously regenerating bone and cartilage is composed of three layers. The third layer 33 is formed between the first layer 11 and the second layer 22 described above.

The third layer 33 comprises the first and second layers 11,
It is formed as a graded layer (composite layer) having an intermediate property of 22. The third layer 33 is preferably composed mainly of, for example, calcium phosphate. The third layer 33 also has a hole diameter of 2 as in the first and second layers 11 and 22.
It is preferably 0 μm or more and about 100 μm to 200 μm. The calcium phosphate arranged in the third layer 33 has no toxicity in vivo, is safe, and has biodegradability.

Further, since the third layer 33 contains a calcium component, when it reacts with water and biodegrades, it becomes weakly alkaline. On the other hand, as described above, the second layer 22
Mainly contains, for example, polylactic acid. When such a polymer material reacts with water and undergoes biodegradation, there is a possibility that the inside of the living body becomes acidic. Since the second layer 22 and the first layer 11 are provided adjacent to each other, the pH in the living body is kept weakly alkaline, and migration to the acidic direction is prevented. For this reason, the environment in the living body can be maintained in a good state, and it is difficult for rejection reactions to occur.

When culturing, for example, osteoblasts, chondrocytes and bone marrow cells using this scaffold 2, the osteoblasts are embedded in the first layer 11 as in the first embodiment, and the second layer is used. The chondrocytes are embedded in the layer 22 of. Further, bone marrow cells are embedded in the third layer 33. Then, like the first embodiment, the scaffold 2 is immersed in a predetermined culture solution in the incubator. Third layer 33
In, the bone marrow cells, the osteoblasts, and the chondrocytes are mixed and cultured. After a lapse of a predetermined time, the scaffold 2 is placed in the joint between cartilage and bone in the living body. Chondrocytes grow by the action of cytokines in the body.
Of course, osteoblasts and bone marrow cells also grow. After a lapse of an arbitrary time, the scaffold 2 is replaced with bone or cartilage to regenerate the joint, and the scaffold 2 is decomposed and absorbed as the number of cells increases.

Therefore, the following can be said with respect to this embodiment. By regenerating bone and cartilage at the same time, cartilage can be easily regenerated. Also,
By providing the third layer 33 between the first layer 11 and the second layer 22, it is possible to replace the scaffold 2 with bone or cartilage while maintaining a good in-vivo condition.

(Third Embodiment) Next, a third embodiment will be described. This embodiment is a modification of the first and second embodiments. Therefore, for the first to third layers 11, 22, 33 the first and second layers
First to third layers 11 and 2 described in the embodiment
Since they are formed in the same manner as Nos. 2 and 33, the same reference numerals are given and the description thereof is omitted.

When forming the first layer 11 shown in FIGS. 1 and 2, rod-shaped wax patterns formed in various lengths and in desired diameters of 20 μm or more are used. This wax pattern disappears when incinerated at a high temperature of 100 ° C or higher.

The first layer 11 is prepared by first adding, for example, a polyacrylic acid ammonium salt as a deflocculant to β-TCP fine powder having a particle size of 3 μm or less and ultrasonically mixing. A large number of wax patterns are put in this and stirred by using a stirrer so that the wax pattern is almost uniformly distributed. After stirring, pour the fluid containing the wax pattern into a container of the desired shape lined with paraffin paper, and then put in a constant temperature and humidity bath,
Dry at 40 ° C. for about 15 hours. After drying, it is transferred to an alumina container (Al ₂ O ₃ purity; 99.9%), for example, 3
The temperature is raised to about 1000 ° C. at a heating rate of 00 ° C./hr,
This temperature is maintained for 40 minutes to sinter the fluid to form the first layer 11. In the first layer 11, a rod-shaped hole is formed in the shape of the original wax pattern at the position where the wax pattern disappeared by sintering was arranged. Further, it is preferable that these holes are adjacent to each other and a large number of holes are communicated with each other.

Hereinafter, similar to the first and second embodiments, scaffolds 1 and 2 are formed to form the first and second scaffolds, respectively.
The osteoblasts, bone marrow cells, and chondrocytes are cultured in the second layers 11 and 22, and the scaffolds 1 and 2 are placed at desired joint positions in the living body. After a lapse of an arbitrary time, the scaffolds 1 and 2 are replaced with bones and cartilage to be regenerated, and the scaffolds 1 and 2 are decomposed and absorbed by cells.

Therefore, the following can be said with respect to this embodiment. Since the wax pattern is formed in a rod shape, particularly in the first layer 11, a large number of substantially straight holes are formed and communicated with each other, so that the scaffolds 1, 2 are connected.
Since the culture solution is easily formed inside, regeneration of bone cells and chondrocytes can be accelerated.

As described above, the following can be said with respect to these first to third embodiments. By integrally regenerating bone and cartilage, it is possible to provide a scaffold capable of forming a joint part in a desired shape. In addition, by providing a hole communicating with the first layer 11 with a desired pore size, cells and culture solution can be easily spread within the hole, so that cell regeneration is accelerated and decomposition / absorption of scaffold is accelerated. be able to. Furthermore, since the joints such as bone and cartilage can be regenerated in vitro and then returned to the living body, it is possible to provide a scaffold that makes it easy to recognize the regeneration state and enables efficient regeneration. it can.

In the first to third embodiments, for example, β-tricalcium phosphate is used as the first layer 11 and polylactic acid is used as the second layer 22. However, such a material is used. It is not limited to For example, the second layer 22 may be made of a mixture of collagen (polylactide, glycolide, cuprolactone, etc.) and polylactic acid, etc. at an arbitrary ratio. That is, ceramic materials and polymer materials should be non-toxic, safe, have arbitrary mechanical strength, be easily bound to living tissues, and be naturally disappeared in the living body to be replaced by new bone. However, materials other than those described above may be used. In addition, a coupling material may be applied to the boundary surface to bond the first and second layers, the first and third layers, the second layer and the third layer. Furthermore, these layers may be bonded to each other by any of mechanical, physical and chemical bonding modes. Although the method of forming the first layer and the second layer has been described in the first and third embodiments, the method described above is an example, and the method is not limited to such a method, and other methods may be used. Various methods can be used to create the first through third layers.

So far, some embodiments have been concretely described with reference to the drawings.
The present invention is not limited to the above-described embodiments, but includes all implementations performed within the scope of the invention.

According to the above description, the invention of the following matters can be obtained. Also, a combination of each term is possible.

[Supplementary Note] (Supplementary Note 1) A ceramic material, which is a scaffold for regenerating bones and cartilage, is decomposed and absorbed in a living body, and has a communicating hole in which a large number of holes are communicated, A polymer material which is formed so as to be able to abut on at least one surface of a ceramic material, is decomposed and absorbed in a living body, and has a communication hole in which a large number of holes are communicated with each other, with a surface where the abutment is possible as a boundary surface. A scaffold characterized by being joined together.

(Supplementary Note 2) A composite layer of the ceramic material and the polymer material is further provided between the ceramic material and the polymer material, and a large number of holes communicating with the composite layer are provided. The scaffold according to the additional item 1.

(Additional remark 3) The particle size of the ceramic material is 3 μm or less.
Alternatively, the scaffold described in the additional item 2.

(Supplementary Note 4) The ceramic material is β-
The scaffold according to any one of appendices 1 to 3, which contains tricalcium phosphate.

(Supplementary note 5) The scaffold according to any one of Supplementary note 1 to Supplementary note 4, characterized in that the communication holes that communicate with the respective holes of the ceramic material are formed to have a size of 20 μm or more.

(Supplementary Note 6) The scaffold according to Supplementary Note 1 or Supplementary Note 2, wherein the polymer material contains polylactic acid.

(Supplementary note 7) The scaffold according to any one of Supplementary note 1 to Supplementary note 6, characterized in that the communicating holes for communicating the respective pores of the polymer material are formed to have a size of 20 μm or more. .

(Supplementary Note 8) The scaffold according to Supplementary Note 2, wherein the composite layer contains calcium phosphate.

[0053]

As described above, according to the present invention, it is possible to provide a scaffold capable of reproducing a joint.

[Brief description of drawings]

FIG. 1 is a bone / cartilage regeneration scaffold consisting of two layers showing a state in which a first layer of a ceramic material according to a first embodiment and a second layer of a polymer material are joined together. The schematic perspective view of a hold.

FIG. 2 shows a first layer of a ceramic material according to a second embodiment, a second layer of a polymer material, and a ceramic material between the ceramic material and the polymer material layer. 3 is a schematic perspective view of a scaffold for bone / cartilage regeneration consisting of three layers showing a state in which a graded layer (third layer) composed of a composite having both properties of a polymer and a polymeric material is joined. .

[Explanation of symbols]

1, 2 ... Scaffold, 11 ... First layer, 22 ... Second
Layer, 33 ... Third layer

   ─────────────────────────────────────────────────── ─── Continued front page    F-term (reference) 4C081 AB03 AB04 AC03 BA13 BA16                       BB07 BC02 CA171 CD34                       CF021 DA01 DB04 DB06                       DC05 DC13 EA02 EA03 EA04                 4C097 AA03 BB01 CC02 CC14 DD02                       DD07 EE08 FF03 MM04 SC01

Claims (4)

[Claims] 1. A scaffold for regenerating bone or cartilage, which is decomposed and absorbed in a living body and has a large number of pores communicated with each other, and a butted surface of at least one surface of the ceramic material. A scaffold characterized by being joined to each other with a surface that can be abutted with a polymeric material that is formed as much as possible, is decomposed and absorbed in a living body, and has a large number of pores communicating with each other. 2. A composite layer comprising the ceramic material and the polymer material is further provided between the ceramic material and the polymer material, and the composite layer is provided with a large number of holes communicating with each other. The scaffold according to claim 1, wherein: 3. The scaffold according to claim 1, wherein a diameter of a communication hole that communicates the holes of the ceramic material and the polymer material is formed to be 20 μm or more. 4. The scaffold according to claim 1, wherein a particle size of the ceramic material is 3 μm or less.