JP4887838B2 - Method for producing porous body and porous body using the same - Google Patents
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- 238000004519 manufacturing process Methods 0.000 title claims description 36
- 239000011148 porous material Substances 0.000 claims description 104
- 239000011259 mixed solution Substances 0.000 claims description 86
- 239000002904 solvent Substances 0.000 claims description 64
- 238000001816 cooling Methods 0.000 claims description 61
- 229920000642 polymer Polymers 0.000 claims description 41
- 238000007710 freezing Methods 0.000 claims description 38
- 230000008014 freezing Effects 0.000 claims description 38
- 238000000034 method Methods 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 229920001577 copolymer Polymers 0.000 claims description 16
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 claims description 15
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims description 13
- 229910001220 stainless steel Inorganic materials 0.000 claims description 11
- 239000010935 stainless steel Substances 0.000 claims description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 3
- 230000007423 decrease Effects 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 210000004748 cultured cell Anatomy 0.000 claims description 2
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 2
- 230000005496 eutectics Effects 0.000 claims description 2
- 239000002245 particle Substances 0.000 description 14
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 10
- 238000007796 conventional method Methods 0.000 description 6
- 235000014655 lactic acid Nutrition 0.000 description 6
- 239000004310 lactic acid Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
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- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical compound C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000001172 regenerating effect Effects 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- JBFHTYHTHYHCDJ-UHFFFAOYSA-N gamma-caprolactone Chemical compound CCC1CCC(=O)O1 JBFHTYHTHYHCDJ-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000004062 sedimentation Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 229930182843 D-Lactic acid Natural products 0.000 description 1
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 description 1
- RZTOWFMDBDPERY-UHFFFAOYSA-N Delta-Hexanolactone Chemical compound CC1CCCC(=O)O1 RZTOWFMDBDPERY-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- -1 and among them Chemical compound 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229940022769 d- lactic acid Drugs 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
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- 230000035515 penetration Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 238000007151 ring opening polymerisation reaction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
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- 230000017423 tissue regeneration Effects 0.000 description 1
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Description
本発明は、多孔質体、特に、組織工学や再生医工学を中心とする医療分野において、細胞の足場（scaffold）材料として有用な多孔質体の製造方法に関する。 The present invention relates to a method for producing a porous body, in particular, a porous body useful as a cell scaffold material in the medical field centered on tissue engineering and regenerative medical engineering.
組織工学や再生医工学の分野においては、細胞を増殖させるために、通常、足場材料が使用されており、特に近年では、足場材料として、生体吸収性材料からなる多孔質体の利用が期待されている。このような生体吸収性の多孔質体であれば、その孔内に細胞を播種して増殖させ、これを生体に移植することにより、生体内で組織再生が起こると共に、足場である生体吸収性材料が徐々に生体内で分解吸収される。このため、細胞の増殖に利用した足場をそのまま増殖細胞と共に生体に移植することが可能となる。 In the fields of tissue engineering and regenerative medical engineering, scaffold materials are usually used to proliferate cells, and in recent years, the use of porous materials made of bioabsorbable materials is expected as scaffold materials. ing. With such a bioabsorbable porous body, cells are seeded and proliferated in the pores and transplanted into the living body, whereby tissue regeneration occurs in the living body and the bioabsorbable as a scaffold. The material is gradually decomposed and absorbed in vivo. For this reason, it is possible to transplant the scaffold used for cell proliferation into the living body together with the proliferating cells.
このような多孔質体の製造方法としては、凍結乾燥法が広く利用されており、一般的な方法として、例えば、生体吸収性ポリマーをジオキサン溶媒に溶解し、これを凍結乾燥させて多孔化する方法が開示されている（例えば、特許文献１参照）。しかしながら、この方法によって得られる多孔質体は、ポアサイズが100μm以下であるため、例えば、多孔質体内への細胞の浸入に適したポアサイズ100μm以上の多孔質体を得ることが困難である。 As a method for producing such a porous body, a freeze-drying method is widely used. As a general method, for example, a bioabsorbable polymer is dissolved in a dioxane solvent, and this is freeze-dried to make it porous. A method is disclosed (for example, see Patent Document 1). However, since the porous body obtained by this method has a pore size of 100 μm or less, for example, it is difficult to obtain a porous body having a pore size of 100 μm or more suitable for infiltration of cells into the porous body.
また、塩化ナトリウムや砂糖等の粒子をポリマー溶液に添加して凍結乾燥し、水等の洗浄により前記粒子を溶出除去することによって、多孔化する方法が提案されている（例えば、特許文献２、特許文献３参照）。これらの方法によれば、粒子の存在していた部分が孔となるため、使用した粒子と同程度のポアサイズである多孔質体が得られる。しかしながら、このような方法では、粒子の溶出が必要であるため製造工程が煩雑となり、また、ポリマー溶液における粒子の沈降により、得られる多孔質体の孔分布の均一性が確保し難いという問題がある。さらに、ポアサイズの均一性を向上するには、粒径が均一な粒子を使用する必要があり、高コスト化につながる。また、粒子を完全に除去することが困難であるため、前記粒子が多孔質体に残留するおそれもある。このように、多孔質体を製造する際に、所望のポアサイズ、特に大きなポアサイズ（数百μm）を実現することは極めて困難であった。 Further, a method has been proposed in which particles such as sodium chloride and sugar are added to a polymer solution and freeze-dried, and the particles are eluted and removed by washing with water or the like (for example, Patent Document 2, (See Patent Document 3). According to these methods, since the portion where the particles existed becomes pores, a porous body having a pore size comparable to the used particles can be obtained. However, in such a method, the elution of particles is necessary, so that the manufacturing process becomes complicated, and the problem that it is difficult to ensure the uniformity of the pore distribution of the obtained porous body due to the sedimentation of the particles in the polymer solution. is there. Furthermore, in order to improve the uniformity of the pore size, it is necessary to use particles having a uniform particle size, leading to an increase in cost. Further, since it is difficult to completely remove the particles, the particles may remain in the porous body. Thus, when producing a porous body, it has been extremely difficult to achieve a desired pore size, particularly a large pore size (several hundred μm).
この他にも、ポアサイズの制御方法として、コラーゲン溶液を凍結乾燥する際に、水と水に相溶性のある有機溶媒を添加して、両者の添加割合を調整することによってポアサイズを制御する方法が開示されている（例えば、特許文献４等）。しかしながら、この方法によっても、得られるポアサイズは50〜80μm程度あり、広い範囲でのポアサイズを実現することは困難である。また、凍結方法として液体窒素による急速凍結法が一般的であるが、ポアサイズが小さくなる傾向がある。
そこで、本発明の目的は、ポアサイズの調整、特に小さなポアサイズだけでなく、大きなポアサイズの調整をも可能とする多孔質体の製造方法を提供することである。 Accordingly, an object of the present invention is to provide a method for producing a porous body that enables adjustment of pore size, particularly not only small pore size but also large pore size.
本発明の多孔質体の製造方法は、ラクチドとカプロラクトンとの共重合体を含むポリマー、前記ポリマーに対して相対的に溶解度の低い溶媒、および、前記ポリマーに対して相対的に溶解度が高く且つ前記溶解度の低い溶媒と相溶性である溶媒を含む混合溶液を調製する工程、前記混合溶液を凍結処理する工程、前記混合溶液の凍結処理物を減圧乾燥する工程を含む多孔質体の製造方法であって、前記混合溶液の調製工程において、前記ポリマーに対して相対的に溶解度の低い溶媒の前記混合溶液中の含有率を変化させ、且つ、前記凍結工程において、前記混合溶液を300℃/hr以下の速度で冷却することによって、多孔質体のポアサイズを制御することを特徴とする。なお、以下、前記ポリマーに対して相対的に溶解度の低い溶媒を「貧溶媒」、前記ポリマーに対して相対的に溶解度が高い溶媒を「良溶媒」というが、本発明においてこれらの用語は、あくまでも前記ポリマーに対する相対的な溶解度により前記両者を区別するために使用するものである。 The method for producing a porous body according to the present invention includes a polymer containing a copolymer of lactide and caprolactone, a solvent having a relatively low solubility with respect to the polymer, and a relatively high solubility with respect to the polymer. A method for producing a porous body comprising a step of preparing a mixed solution containing a solvent that is compatible with the low-solubility solvent, a step of freezing the mixed solution, and a step of drying the frozen processed product of the mixed solution under reduced pressure. In the preparation step of the mixed solution, the content of the solvent having a relatively low solubility with respect to the polymer is changed in the mixed solution, and in the freezing step, the mixed solution is changed to 300 ° C / hr. The pore size of the porous body is controlled by cooling at the following speed. Hereinafter, a solvent having a relatively low solubility in the polymer is referred to as a “poor solvent”, and a solvent having a relatively high solubility in the polymer is referred to as a “good solvent”. It is only used to distinguish the two according to the relative solubility in the polymer.
本発明の多孔質体の製造方法によれば、混合溶液における貧溶媒の含有率を変化させ、且つ、300℃/hr以下の速度で混合溶液を冷却して前記混合溶液を凍結することにより、広範囲のポアサイズを容易に調整でき、また、比較的均一な孔形成をも実現できる。 According to the method for producing a porous body of the present invention, by changing the content of the poor solvent in the mixed solution, and cooling the mixed solution at a rate of 300 ° C./hr or less to freeze the mixed solution, A wide range of pore sizes can be easily adjusted, and relatively uniform hole formation can be realized.
前述のように、水のような貧溶媒と有機溶媒のような良溶媒との割合によってポアサイズを調整することは公知である（前記特許文献４）。しかしながら、本発明によれば、凍結処理時の冷却速度をさらに300℃/hr以下の速度に設定することによって、例えば、30〜1800μmという広範囲のポアサイズを可能とし、且つ、形成される孔の均一性も確保できる。すなわち、本発明者らは、例えば、貧溶媒の含有率が同じ混合溶液であっても、冷却速度（300℃/hr以下）の設定を変えることによって、形成される孔のサイズをさらに変化できることを見出し、結果として、前記含有率だけでなく冷却速度の設定を組み合わせることにより、さらにポアサイズの範囲を広げることを可能にしたのである。このようにして広範囲のポアサイズを設定できること、特に100μm以上のポアサイズをも実現できることは、本発明者らがはじめて見出したことである。なお、粒子を使用しない従来法による多孔質体のポアサイズは、一般に、10〜80μm程度であることからも、極めて広範囲の設定が可能であるといえる。また、前述のように粒子を混合しないため、粒子の沈降による分布の不均一化や粒子の残存等の問題もない。したがって、本発明によれば、貧溶媒の含有率と冷却温度の設定のみによって様々なポアサイズを実現でき、例えば、多孔質体の用途に応じたポアサイズが得られるため、組織工学や再生医療等において極めて有用な多孔質体の製造方法といえる。 As described above, it is known to adjust the pore size by the ratio of a poor solvent such as water and a good solvent such as an organic solvent (Patent Document 4). However, according to the present invention, by setting the cooling rate during the freezing process to a rate of 300 ° C./hr or less, for example, a wide pore size of 30 to 1800 μm is possible, and the formed pores are uniform. Can also be secured. That is, the present inventors can further change the size of the formed holes by changing the setting of the cooling rate (300 ° C./hr or less), for example, even in a mixed solution having the same poor solvent content. As a result, the pore size range can be further expanded by combining not only the content ratio but also the setting of the cooling rate. The present inventors have found for the first time that a wide pore size can be set in this way, and in particular that a pore size of 100 μm or more can be realized. In addition, since the pore size of the porous body by the conventional method which does not use particles is generally about 10 to 80 μm, it can be said that an extremely wide range can be set. Further, since the particles are not mixed as described above, there are no problems such as non-uniform distribution due to sedimentation of the particles and remaining particles. Therefore, according to the present invention, various pore sizes can be realized only by setting the content ratio of the poor solvent and the cooling temperature, and for example, pore sizes according to the use of the porous body can be obtained. This can be said to be a very useful method for producing a porous body.
本発明は、前述のように、ラクチドとカプロラクトンとの共重合体を含むポリマー、前記ポリマーに対する貧溶媒、および、前記貧溶媒と相溶性である前記ポリマーに対する良溶媒を含む混合溶液を調製する工程、前記混合溶液を凍結処理する工程、前記混合溶液の凍結処理物を減圧乾燥する工程を含む多孔質体の製造方法であって、前記混合溶液の調製工程において、前記ポリマーに対して相対的に溶解度の低い溶媒の前記混合溶液中の含有率を変化させ、且つ、前記凍結工程において、前記混合溶液を300℃/hr以下の速度で冷却することによって、多孔質体のポアサイズを制御することを特徴とする。 As described above, the present invention provides a step of preparing a mixed solution containing a polymer containing a copolymer of lactide and caprolactone, a poor solvent for the polymer, and a good solvent for the polymer that is compatible with the poor solvent. A method for producing a porous body comprising a step of freezing the mixed solution, and a step of drying a frozen processed product of the mixed solution under reduced pressure, wherein in the step of preparing the mixed solution, The pore size of the porous body is controlled by changing the content of the solvent having low solubility in the mixed solution and cooling the mixed solution at a rate of 300 ° C./hr or less in the freezing step. Features.
本発明における共重合体は、前述のようにラクチドとカプロラクトンとの共重合体であり、例えば、ランダム重合体、ブロック重合体のいずれであってもよい。また、前記共重合体は、異なるモル比のラクチド-カプロラクトン共重合体を２種類以上混合して使用することもできる。なお、本発明における共重合体は、前記共重合体のみを含有してもよいし、本発明に影響を与えない範囲で、さらにその他の重合体や共重合体を含んでもよい。 The copolymer in the present invention is a copolymer of lactide and caprolactone as described above, and may be, for example, a random polymer or a block polymer. The copolymer may be used by mixing two or more kinds of lactide-caprolactone copolymers having different molar ratios. In addition, the copolymer in this invention may contain only the said copolymer, and may also contain another polymer and copolymer in the range which does not affect this invention.
前記共重合体の分子量（重量平均分子量）は、特に制限されないが、例えば、5,000〜2,000,000であり、好ましくは10,000〜1,500,000であり、より好ましくは100,000〜1,000,000である。また、ラクチドとカプロラクトンとのモル比は、例えば、90：10〜10：90の範囲、好ましくは85：15〜20：80の範囲であり、より好ましくは80：20〜40：60の範囲である。 The molecular weight (weight average molecular weight) of the copolymer is not particularly limited, but is, for example, 5,000 to 2,000,000, preferably 10,000 to 1,500,000, and more preferably 100,000 to 1,000,000. The molar ratio of lactide to caprolactone is, for example, in the range of 90:10 to 10:90, preferably in the range of 85:15 to 20:80, and more preferably in the range of 80:20 to 40:60. is there.
前記共重合体の調製方法は、特に制限されず、従来公知の方法が使用できる。一般的に、出発原料としてラクチドとカプロラクトンとを開環重合により共重合させてもよいし、乳酸からラクチド（乳酸の環状二量体）を合成して、これをカプロラクトンと共重合させてもよい。なお、乳酸を用いたラクチドの合成方法も特に制限されず従来公知の方法が使用できる。前記ラクチドとしては、特に制限されず、L-ラクチド、D-ラクチドおよびそれらの混合物（D,L-ラクチド）が使用でき、また、乳酸としては、L-乳酸、D-乳酸、それらの混合物（D,L-乳酸）が使用できる。このように出発原料として乳酸を使用した場合、一量体の乳酸を二量体のラクチドに換算し、換算したラクチドとカプロラクトンとのモル比が前述の範囲であることが好ましい。また、カプロラクトンとしては、例えば、ε−カプロラクトン、γ−カプロラクトン、δ−カプロラクトン等があげられ、中でもε−カプロラクトンが好ましい。 The method for preparing the copolymer is not particularly limited, and a conventionally known method can be used. In general, lactide and caprolactone may be copolymerized by ring-opening polymerization as starting materials, or lactide (a cyclic dimer of lactic acid) may be synthesized from lactic acid and copolymerized with caprolactone. . The method for synthesizing lactide using lactic acid is not particularly limited, and a conventionally known method can be used. The lactide is not particularly limited, and L-lactide, D-lactide and a mixture thereof (D, L-lactide) can be used, and lactic acid includes L-lactic acid, D-lactic acid and a mixture thereof ( D, L-lactic acid) can be used. Thus, when lactic acid is used as a starting material, it is preferable that the monomeric lactic acid is converted into a dimeric lactide, and the molar ratio of the converted lactide to caprolactone is in the above range. Examples of caprolactone include ε-caprolactone, γ-caprolactone, and δ-caprolactone, and among them, ε-caprolactone is preferable.
本発明において、前記貧溶媒は、前記ポリマーに対して相対的に溶解度の低い溶媒であり、前記良溶媒は、前記ポリマーに対して相対的に溶解度が高く且つ前記溶解度の低い溶媒と相溶性である溶媒であればそれぞれ特に制限されず、通常、使用するポリマーの種類に応じて設定できる。一般的に、前記貧溶媒としては、水、エタノール、ターシャリーブチルアルコール（tBuOH）等が使用でき、前記良溶媒としては、前記貧溶媒に相溶性を示す、1,4-ジオキサン、炭酸ジメチル等の有機溶媒等が使用でき、特に、貧溶媒が水であり、良溶媒が1,4-ジオキサンである組合せが好ましい。 In the present invention, the poor solvent is a solvent having a relatively low solubility in the polymer, and the good solvent is relatively soluble in the polymer and compatible with the solvent having a low solubility. Each solvent is not particularly limited, and can usually be set according to the type of polymer used. In general, as the poor solvent, water, ethanol, tertiary butyl alcohol (tBuOH) or the like can be used, and as the good solvent, 1,4-dioxane, dimethyl carbonate, or the like that is compatible with the poor solvent. In particular, a combination in which the poor solvent is water and the good solvent is 1,4-dioxane is preferable.
以下に、本発明の多孔質体の製造方法について具体的に説明する。なお、ポアサイズの調整方法については後述する。 Below, the manufacturing method of the porous body of this invention is demonstrated concretely. A pore size adjustment method will be described later.
（混合溶液の調製工程）
ポリマー、貧溶媒および良溶媒を混合して混合溶液を調製する。各溶媒の添加順序は特に制限されない。
(Preparation process of mixed solution)
A polymer, a poor solvent, and a good solvent are mixed to prepare a mixed solution. The order of addition of each solvent is not particularly limited.
前記混合溶液におけるポリマー濃度は、特に制限されないが、通常、０．１〜２４質量％の範囲であり、好ましくは２〜８質量％の範囲であり、より好ましくは３〜５質量％の範囲である。前記混合溶液における良溶媒の添加割合は、例えば、後述する貧溶媒の添加量に応じて適宜決定されるが、前記ポリマーと前記良溶媒との質量比（ポリマー：良溶媒）が０．１：９９．９〜２４：７６であることが好ましく、より好ましくは２：９８〜６：９４、特に好ましくは４：９６である。 The polymer concentration in the mixed solution is not particularly limited, but is usually in the range of 0.1 to 24% by mass, preferably in the range of 2 to 8% by mass, more preferably in the range of 3 to 5% by mass. is there. The addition ratio of the good solvent in the mixed solution is appropriately determined according to, for example, the addition amount of the poor solvent described later, but the mass ratio of the polymer to the good solvent (polymer: good solvent) is 0.1: It is preferably 99.9 to 24:76 , more preferably 2:98 to 6:94 , and particularly preferably 4:96.
前記混合溶液における貧溶媒の添加割合は、後述するように、形成する多孔質体の所望のポアサイズならびに採用する一定冷却速度に応じて適宜決定できる。混合溶液における貧溶媒濃度は、例えば、０を超え２０質量％以下であり、好ましくは０．１〜２０質量％、より好ましくは６〜１２．５質量％の範囲、特に好ましくは６〜１２．２５質量％である。また、前記混合溶液におけるポリマー濃度が３．６質量％の場合、混合溶液における貧溶媒濃度は、例えば、０を超え１２．５質量％以下であり、好ましくは６〜１２．５質量％の範囲である。前記ポリマーと前記貧溶媒との質量比（ポリマー：貧溶媒）は、特に制限されないが、例えば、３．２：２０〜４：０．５の範囲である。 As will be described later, the addition ratio of the poor solvent in the mixed solution can be appropriately determined according to the desired pore size of the porous body to be formed and the constant cooling rate employed. The poor solvent concentration in the mixed solution is, for example, more than 0 and 20% by mass or less, preferably 0.1 to 20% by mass, more preferably 6 to 12.5% by mass, and particularly preferably 6 to 12%. 25% by mass. When the polymer concentration in the mixed solution is 3.6% by mass, the poor solvent concentration in the mixed solution is, for example, more than 0 and 12.5% by mass or less, preferably in the range of 6 to 12.5% by mass. It is. The mass ratio of the polymer to the poor solvent (polymer: poor solvent) is not particularly limited, but is, for example, in the range of 3.2: 20 to 4: 0.5.
（凍結処理工程）
前記混合溶液を300℃/hr以下の速度で冷却して、前記混合溶液を凍結させる。凍結工程においては、前記範囲の速度で冷却を行う以外は何ら制限されず、例えば、市販の凍結乾燥機を用いて前記混合溶液の凍結を行うことができる。前記凍結乾燥機としては、冷却速度の制御が可能な機種が好ましく、例えば、商品名TF5-85ATANCS（宝製作所製）等が使用できる。
(Freezing process)
The mixed solution is cooled at a rate of 300 ° C./hr or less to freeze the mixed solution. In the freezing step, there is no limitation except that the cooling is performed at a speed within the above range. For example, the mixed solution can be frozen using a commercially available freeze dryer. As the freeze dryer, a model capable of controlling the cooling rate is preferable. For example, a trade name TF5-85ATANCS (manufactured by Takara Seisakusho) or the like can be used.
前記凍結溶液を冷却する際には、例えば、前記混合溶液を容器に入れ、前記容器の底部から前記混合溶液を冷却することが好ましい。このように、容器の底部から冷却すれば、前記混合溶液を底部から上部方向へと一定速度で均一に冷却することができ、前記混合溶液を均一に徐々に凍結できる。具体的には、凍結機や凍結乾燥機を使用し、前記混合溶液が入った前記容器を前記凍結機の冷却棚に配置し、前記冷却棚の温度を300℃/hr以下の同じ一定速度で減少するように制御することが好ましい。このように、冷却棚自体の温度を前記所定の速度で下げていけば、前記冷却棚に配置した容器の底部を冷却でき、これによって混合溶液の底部から上部へと冷却していくことができる。なお、前記容器としては、特に制限されないが、例えば、ステンレス製容器があげられる。 When cooling the frozen solution, for example, it is preferable to put the mixed solution in a container and cool the mixed solution from the bottom of the container. Thus, if it cools from the bottom part of a container, the said mixed solution can be cooled uniformly from a bottom part to an upper direction at a fixed speed, and the said mixed solution can be uniformly frozen gradually. Specifically, using a freezer or a freeze dryer, the container containing the mixed solution is placed on a cooling shelf of the freezer, and the temperature of the cooling shelf is the same constant speed of 300 ° C./hr or less. It is preferable to control so as to decrease. In this way, if the temperature of the cooling shelf itself is lowered at the predetermined speed, the bottom of the container disposed on the cooling shelf can be cooled, and thereby the mixed solution can be cooled from the bottom to the top. . In addition, although it does not restrict | limit especially as said container, For example, a stainless steel container is mention | raise | lifted.
前記冷却速度は、300℃/hr以下であれば特に制限されず、後述するように、形成する多孔質体の所望のポアサイズならびに前記混合溶液の貧溶媒濃度に応じて適宜決定できる。前記冷却速度は、例えば、3〜300℃/hrの範囲であり、好ましくは3〜250℃/hrの範囲、より好ましくは3〜180℃/hrの範囲、特に好ましくは5〜180℃/hrの範囲である。なお、前述のように凍結機を使用する場合には、その冷却棚の温度を、このような範囲の一定速度で下げるように制御すればよい（以下、同様である）。 The cooling rate is not particularly limited as long as it is 300 ° C./hr or less, and can be appropriately determined according to the desired pore size of the porous body to be formed and the poor solvent concentration of the mixed solution, as will be described later. The cooling rate is, for example, in the range of 3 to 300 ° C./hr, preferably in the range of 3 to 250 ° C./hr, more preferably in the range of 3 to 180 ° C./hr, particularly preferably 5 to 180 ° C./hr. Range. In addition, when using a freezer as mentioned above, what is necessary is just to control so that the temperature of the cooling shelf may be lowered | hung at the fixed speed | rate of such a range (it is the same below).
凍結を施す混合溶液の温度は、特に制限されず、例えば、使用している溶媒の凝固点以上であり、好ましくは10℃〜室温（例えば、20〜37℃）、より好ましくは、10〜20℃の範囲である。特に、300℃/hrの一定速度での冷却を開始する際には、混合溶液の凍結処理開始時の温度が、10℃付近であることが好ましい。そして、このように凍結処理開始時の混合溶液の温度を10℃付近に設定する場合には、前記混合溶液全体を一定（10℃）にすべく、前記混合溶液を、前記開始時の温度（例えば、10℃）よりも高い温度（例えば、+10℃）に置いてから、前記開始時の温度にまで下げることが好ましい。この際、温度の下降に要する時間は、何ら制限されないが、例えば、60分程度（あるいはそれ以上の時間）であってもよい。一定速度での冷却前に、このような処理を施すことによって、より再現性よく多孔質体を製造することができる。 The temperature of the mixed solution subjected to freezing is not particularly limited, and is, for example, not lower than the freezing point of the solvent used, preferably 10 ° C. to room temperature (for example, 20 to 37 ° C.), more preferably 10 to 20 ° C. Range. In particular, when cooling at a constant rate of 300 ° C./hr is started, the temperature at the start of the freezing treatment of the mixed solution is preferably around 10 ° C. When the temperature of the mixed solution at the start of the freezing process is set to around 10 ° C. in this way, the mixed solution is set to the temperature at the start (in order to keep the entire mixed solution constant (10 ° C.)). For example, it is preferable that the temperature is higher than 10 ° C. (for example, + 10 ° C.) and then lowered to the starting temperature. At this time, the time required for the temperature to drop is not limited at all, but may be, for example, about 60 minutes (or more). By performing such treatment before cooling at a constant rate, a porous body can be produced with higher reproducibility.
前記最終凍結処理温度は、例えば、共晶点以下であり、-10℃以下であることが好ましく、より好ましくは-10〜-50℃の範囲である。前記最終凍結処理温度は、特に制限されないが、例えば、-10℃程度に設定すれば、冷却に係るコストをさらに削減できる。 The final freezing treatment temperature is, for example, not more than the eutectic point, preferably not more than -10 ° C, more preferably in the range of -10 to -50 ° C. Although the final freezing treatment temperature is not particularly limited, for example, if it is set to about −10 ° C., the cost for cooling can be further reduced.
前記混合溶液の温度が最終凍結温度に達した際、前記混合溶液の凍結状態に応じて、最終凍結温度での処理を適宜続行してもよい。これは前記混合溶液が完全に凍結するまででもよく、例えば、0を超え12時間以下であり、好ましくは1〜3時間程度である。 When the temperature of the mixed solution reaches the final freezing temperature, the processing at the final freezing temperature may be appropriately continued according to the frozen state of the mixed solution. This may be until the mixed solution is completely frozen, and is, for example, more than 0 and 12 hours or less, preferably about 1 to 3 hours.
なお、凍結乾燥に供する混合溶液の量は、特に制限されないが、前述の条件は、混合溶液を容器に入れた際に深さが0.5〜1cm程度となる液量に対して特に好ましい条件である。 The amount of the mixed solution to be subjected to lyophilization is not particularly limited, but the above-described conditions are particularly preferable conditions for the amount of liquid that has a depth of about 0.5 to 1 cm when the mixed solution is placed in a container. .
（減圧乾燥処理工程）
前記凍結処理工程において得られた混合溶液の凍結処理物を減圧乾燥することによって、多孔質体が得られる。減圧乾燥の条件は何ら制限されず、従来公知の方法で行うことができる。
(Decompression drying process)
A porous material is obtained by drying the freeze-treated product of the mixed solution obtained in the freezing treatment step under reduced pressure. The conditions for drying under reduced pressure are not limited at all and can be carried out by a conventionally known method.
つぎに、多孔質体のポアサイズの制御方法を具体的に説明する。本発明の制御方法によれば、例えば、貧溶媒の濃度を変化させた複数の混合溶液について、一定の冷却速度で凍結処理を行った場合、後述する図１に示すように、貧溶媒の濃度によってポアサイズが変動する。さらに、異なる冷却速度に設定した場合、ポアサイズの変動は各冷却速度によって同様の挙動、すなわちある貧溶媒濃度範囲でポアサイズが大きくなり、ある濃度範囲でポアサイズが小さくなるという同様の挙動を示すが、同じ濃度でのポアサイズは、冷却速度によって異なる。つまり、貧溶媒濃度の変化に加えて、冷却速度を変化させることによって、さらに広い範囲の孔設定が可能になる。したがって、冷却速度および貧溶媒濃度の条件を変えて多孔質材を作製し、前記速度と濃度と得られるポアサイズとの関係を示す検量線を作成することによって、例えば、約30〜1800μmの範囲である所望のポアサイズの多孔質体を再現性よく製造できる。 Next, a method for controlling the pore size of the porous body will be specifically described. According to the control method of the present invention, for example, when a freezing process is performed at a constant cooling rate for a plurality of mixed solutions in which the concentration of the poor solvent is changed, as shown in FIG. The pore size varies depending on. Furthermore, when different cooling rates are set, the pore size variation shows the same behavior depending on each cooling rate, that is, the pore size increases in a certain poor solvent concentration range, and the pore size decreases in a certain concentration range. The pore size at the same concentration depends on the cooling rate. In other words, by changing the cooling rate in addition to the change in the poor solvent concentration, a wider range of pores can be set. Therefore, by preparing a porous material by changing the conditions of the cooling rate and the poor solvent concentration, and creating a calibration curve showing the relationship between the rate and the concentration and the pore size obtained, for example, in the range of about 30-1800 μm A porous body having a desired pore size can be produced with good reproducibility.
混合溶液が前記共重合体と良溶媒と貧溶媒を含み、前記共重合体と良溶媒との質量比が96：4である場合、例えば、前記混合溶液の貧溶媒濃度と冷却速度とを下記表の条件に設定することによって、表中に記載するポアサイズ（30〜1800μm）の多孔質体を得ることができる。 When the mixed solution contains the copolymer, a good solvent, and a poor solvent, and the mass ratio of the copolymer and the good solvent is 96: 4, for example, the poor solvent concentration and the cooling rate of the mixed solution are as follows: By setting the conditions in the table, a porous body having a pore size (30 to 1800 μm) described in the table can be obtained.
冷却速度3℃/hr
貧溶媒濃度（質量％） ポアサイズ（μm）
6-9 30-200
9.25-9.75 ＜200-400
10 ＜400-800
10.25 ＜800-1000
冷却速度5℃/hr
貧溶媒濃度（質量％） ポアサイズ（μm）
6-9.5 30-200
4.75-10 ＜200-400
10.25-10.5 ＜400-800
10.75 ＜800-1200
11-11.5 ＜1200-1500
冷却速度10℃/hr
貧溶媒濃度（質量％） ポアサイズ（μm）
6-10 30-200
10.25 ＜200-400
10.5-10.75 ＜400-800
11 ＜800-1200
11-11.75 ＜1200-1800
冷却速度180℃/hr
貧溶媒濃度（質量％） ポアサイズ（μm）
6-10.25 30-200
10.5-11 ＜200-400
11.25-12 ＜400-800
Cooling rate 3 ℃ / hr
Poor solvent concentration (mass%) Pore size (μm)
6-9 30-200
9.25-9.75 <200-400
10 <400-800
10.25 <800-1000
Cooling rate 5 ℃ / hr
Poor solvent concentration (mass%) Pore size (μm)
6-9.5 30-200
4.75-10 <200-400
10.25-10.5 <400-800
10.75 <800-1200
11-11.5 <1200-1500
Cooling rate 10 ℃ / hr
Poor solvent concentration (mass%) Pore size (μm)
6-10 30-200
10.25 <200-400
10.5-10.75 <400-800
11 <800-1200
11-11.75 <1200-1800
Cooling rate 180 ° C / hr
Poor solvent concentration (mass%) Pore size (μm)
6-10.25 30-200
10.5-11 <200-400
11.25-12 <400-800
以上のようにして、本発明の多孔質体を得ることができる。本発明の製造方法によれば前述のように広い範囲のポアサイズを設定できるため、本発明の多孔質膜は、ポアサイズに応じて種々の用途に使用できる。特に、培養細胞の足場材料として使用する場合には、比較的大きいポアサイズのものが好ましく、例えば、ポアサイズ50〜1000μm、好ましくはポアサイズ100〜1000μmの多孔質体が有用である。この他にも種々の医療多孔質体として使用可能である。また、本発明の多孔質体の大きさや形状は、特に制限されず、用途に応じて決定できる。 As described above, the porous body of the present invention can be obtained. According to the production method of the present invention, since a wide range of pore sizes can be set as described above, the porous membrane of the present invention can be used for various applications depending on the pore size. In particular, when used as a scaffold material for cultured cells, those having a relatively large pore size are preferable. For example, a porous body having a pore size of 50 to 1000 μm, preferably a pore size of 100 to 1000 μm is useful. In addition, it can be used as various medical porous bodies. Further, the size and shape of the porous body of the present invention are not particularly limited and can be determined according to the application.
なお、本発明の多孔質体におけるポアサイズの測定方法は、特に制限されず、従来公知の方法が採用できる。 In addition, the measuring method of the pore size in the porous body of the present invention is not particularly limited, and a conventionally known method can be adopted.
以下、実施例および比較例により本発明を更に具体的に説明するが、本発明はこれらに限定されるものではない。 EXAMPLES Hereinafter, although an Example and a comparative example demonstrate this invention further more concretely, this invention is not limited to these.
混合溶液中の含水率を変化させて多孔質体を作製し、ポアサイズの制御を確認した。 The porous body was produced by changing the water content in the mixed solution, and the control of the pore size was confirmed.
L-ラクチドとε-カプロラクトンの組成比（モル比）が50：50であるラクチド-カプロラクトン共重合体（P(LA/CL=50/50)）と1,4-ジオキサンと水とを混合し、含水率の異なる混合溶液を29種類調製した。なお、P(LA/CL=50/50)と1,4-ジオキサンとの混合割合（質量比）は、一定（4：96）とし、前記混合溶液における水の混合割合（含水率）を、1, 2, 4, 6, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75, 10, 10.25, 10.5, 10.75, 11, 11.25, 11.5, 11.75, 12, 12.25, 12.5, 12.75, 13, 14, 16, 18, 20質量％に変化させた。そして、これらの混合溶液（20ｇ）をステンレスシャーレ（直径5cm、深さ1.5cm、以下同様）にそれぞれ供給した。 A lactide-caprolactone copolymer (P (LA / CL = 50/50)) having a composition ratio (molar ratio) of L-lactide and ε-caprolactone of 50:50, 1,4-dioxane and water are mixed. 29 kinds of mixed solutions having different moisture contents were prepared. In addition, the mixing ratio (mass ratio) of P (LA / CL = 50/50) and 1,4-dioxane is constant (4:96), and the mixing ratio of water in the mixed solution (water content) is 1, 2, 4, 6, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75, 10, 10.25, 10.5, 10.75, 11, 11.25, 11.5, 11.75, 12, 12.25, 12.5, 12.75, 13, It was changed to 14, 16, 18, and 20% by mass. And these mixed solutions (20g) were each supplied to the stainless steel petri dish (diameter 5cm, depth 1.5cm, and the same below).
凍結乾燥機（商品名TF5-85ATANCS：宝製作所製）内（室温）の冷却棚に前記ステンレスシャーレを配置し、前記冷却棚を10℃に設定して1時間放置した後、冷却棚の温度を3℃/hrの速度で-50℃まで冷却し、-50℃で180分放置した。なお、10℃での処理開始から-50℃での処理終了までの時間を合計20時間とした。そして、冷却処理の終了と同時に凍結乾燥機内の温度を25℃に調整して減圧乾燥処理を行い、29種類の多孔質体サンプルを作製した。 Place the stainless steel petri dish on the cooling shelf in the freeze dryer (trade name TF5-85ATANCS: Takara Seisakusho) (room temperature), set the cooling shelf at 10 ° C and let it stand for 1 hour, then set the temperature of the cooling shelf The solution was cooled to -50 ° C at a rate of 3 ° C / hr and left at -50 ° C for 180 minutes. The time from the start of treatment at 10 ° C. to the end of treatment at −50 ° C. was 20 hours in total. Simultaneously with the end of the cooling process, the temperature in the freeze dryer was adjusted to 25 ° C. and a vacuum drying process was performed to prepare 29 types of porous body samples.
前記ステンレスシャーレから円板状の多孔質体サンプルを取り出し、厚み方向の真中で切断した。この切断面について、ポアサイズの測定を以下の方法によって行った（n=5）。前記切断した多孔質体サンプルの切断面（0.5cm2）を電子顕微鏡で観察し、切断面全体の中で比較的ポアサイズが大きく、出現頻度の高いポアサイズの孔を選択し、得られた画像から、画像解析ソフト（NIH image）を用いて解析を行い、ポアサイズを算出した。 A disk-shaped porous body sample was taken out from the stainless steel petri dish and cut in the middle in the thickness direction. For this cut surface, the pore size was measured by the following method (n = 5). The cut surface (0.5 cm 2 ) of the cut porous body sample was observed with an electron microscope, and pores having a relatively large pore size and a high appearance frequency were selected from the obtained image. Analysis was performed using image analysis software (NIH image), and the pore size was calculated.
（比較例１）
従来法として凍結温度の設定によってポアサイズを変化させる方法を採用し、これにより多孔質体を作製した。前記実施例１と同様のP(LA/CL=50/50)と1,4-ジオキサンとを質量比4：96となるように混合して混合溶液を調製した。この混合溶液（20ｇ）をステンレスシャーレに供給し、前記ステンレスシャーレを冷凍庫内で所定の冷却温度（-80, -30, -15℃）に４時間静置して凍結させた。そして、これらのステンレスシャーレを凍結乾燥機（商品名Freeze dryer FDU-830：EYELA社製）に設置して減圧乾燥を行った。また、ステンレスシャーレに前記混合溶液（20ｇ）を供給し、これを液体窒素（-196℃）で凍結した後、同様にして減圧乾燥を行った。これにより、4種類の多孔質体サンプルを作製した。得られた多孔質体サンプルのポアサイズを下記表１に示す。
(Comparative Example 1)
As a conventional method, a method of changing the pore size according to the setting of the freezing temperature was adopted, and thereby a porous body was produced. P (LA / CL = 50/50) similar to Example 1 and 1,4-dioxane were mixed at a mass ratio of 4:96 to prepare a mixed solution. This mixed solution (20 g) was supplied to a stainless steel petri dish, and the stainless steel petri dish was allowed to stand at a predetermined cooling temperature (−80, −30, −15 ° C.) for 4 hours in a freezer and frozen. These stainless steel dishes were placed in a freeze dryer (trade name Freeze dryer FDU-830: manufactured by EYELA) and dried under reduced pressure. In addition, the mixed solution (20 g) was supplied to a stainless steel petri dish, which was frozen with liquid nitrogen (−196 ° C.), and then dried under reduced pressure in the same manner. As a result, four types of porous body samples were prepared. The pore size of the obtained porous body sample is shown in Table 1 below.
（比較例２）
従来法としてポリマー含有量によってポアサイズを変化させる方法を採用し、これにより多孔質体を作製した。前記実施例１と同様のP(LA/CL=50/50)と1,4-ジオキサンとを質量比2：98、4：96、6：94となるようにそれぞれ混合して混合溶液を調製した。そして、ドライアイスとエタノールを用いて-60℃で混合溶液を凍結した以外は、前記比較例１と同様にして凍結乾燥機（商品名Freeze dryer FDU-830：EYELA社製）により減圧乾燥を行い、多孔質体サンプルを作製した。得られたサンプルのポアサイズを下記表１に示す。
(Comparative Example 2)
As a conventional method, a method of changing the pore size depending on the polymer content was adopted, and thereby a porous body was produced. P (LA / CL = 50/50) similar to Example 1 and 1,4-dioxane were mixed at mass ratios of 2:98, 4:96, and 6:94, respectively, to prepare a mixed solution. did. Then, except that the mixed solution was frozen using dry ice and ethanol at −60 ° C., it was dried under reduced pressure by a freeze dryer (trade name Freeze dryer FDU-830: manufactured by EEYLA) in the same manner as in Comparative Example 1. A porous body sample was prepared. The pore size of the obtained sample is shown in Table 1 below.
（表１）
比較例１ 凍結温度 ポアサイズ（μm）
-196℃ 12
-80℃ 33
-30℃ 56
-15℃ 82
比較例２ 質量比 ポアサイズ（μm）
2：98 83
4：96 56
6：94 46
(Table 1)
Comparative Example 1 Freezing temperature Pore size (μm)
-196 ℃ 12
-80 ℃ 33
-30 ℃ 56
-15 ℃ 82
Comparative Example 2 Mass ratio Pore size (μm)
2: 98 83
4:96 56
6:94 46
前記混合溶液における含水率と前記サンプルのポアサイズの関係を図１に示す。また、図１には、前記比較例１および比較例２で得られた多孔質のポアサイズ範囲を点線（図中矢印矢印の範囲）で示した。同図に示すように、実施例１の方法によれば、含水率を変化させ、同じ一定速度で冷却することによって、多孔質体のポアサイズを調節し、且つ、均一なポアが形成できることがわかった。特に、表１に示すように、凍結温度によりポアサイズを調整する従来法の比較例１によれば、10-80μm程度のポアサイズ、ポリマー含有量によりポアサイズを調整する従来法の比較例２によれば、40-80μm程度のポアサイズしか実現できず、90μm以上の大きなポアサイズを形成できなかった。これに対して、実施例１によれば、30〜1800μmという広い範囲のポアサイズが実現でき、且つ、その均一性にも優れていた。 The relationship between the water content in the mixed solution and the pore size of the sample is shown in FIG. In FIG. 1, the porous pore size range obtained in Comparative Example 1 and Comparative Example 2 is indicated by a dotted line (the range indicated by the arrow in the figure). As shown in the figure, according to the method of Example 1, it is found that the pore size of the porous body can be adjusted and uniform pores can be formed by changing the moisture content and cooling at the same constant speed. It was. In particular, as shown in Table 1, according to the comparative example 1 of the conventional method in which the pore size is adjusted by the freezing temperature, according to the comparative example 2 of the conventional method in which the pore size is adjusted by the polymer content by the pore size of about 10-80 μm. Only a pore size of about 40-80 μm could be realized, and a large pore size of 90 μm or more could not be formed. On the other hand, according to Example 1, a pore size in a wide range of 30 to 1800 μm could be realized, and the uniformity was excellent.
冷却速度を変化させて多孔質体を作製し、ポアサイズの制御を確認した。 The porous body was produced by changing the cooling rate, and the control of the pore size was confirmed.
L-ラクチドとεカプロラクトンの組成比が51：49であるP(LA/CL=51/49)を使用した以外は、前記実施例１と同様にして含水率の異なる混合溶液を複数種類調製し、前記混合溶液（20g）をステンレスシャーレにそれぞれ供給した。そして、凍結乾燥機（商品名TF5-85ATANCS：宝製作所製）の冷却棚に前記ステンレスシャーレを配置し、冷却棚の温度を10℃に下げて（所要時間25分）、60分間放置した。放置後、前記冷却棚を所定速度（180℃/hr、10℃/hr、5℃/hr、3℃/hr）で-50℃まで冷却し、-50℃で180分間処理した。そして、冷却処理の終了と同時に凍結乾燥機内の温度を25℃に調整して減圧乾燥処理を行い、多孔質体サンプルを作製した。これらの多孔質体サンプルについて、前記実施例１と同様にしてポアサイズを測定した（n=2）。前記混合溶液における含水率と前記サンプルのポアサイズの関係を図２に示す。なお、組成比51：49のP(LA/CL)を用いて実施例１と同様の実験を行った場合、同様の挙動を示すことは確認済みである。 A plurality of mixed solutions having different moisture contents were prepared in the same manner as in Example 1 except that P (LA / CL = 51/49) having a composition ratio of L-lactide and ε-caprolactone of 51:49 was used. The mixed solution (20 g) was supplied to each stainless steel dish. Then, the stainless steel petri dish was placed on the cooling shelf of a freeze dryer (trade name TF5-85ATANCS: manufactured by Takara Seisakusho), the temperature of the cooling shelf was lowered to 10 ° C. (required time 25 minutes), and left for 60 minutes. Then, the cooling shelf was cooled to −50 ° C. at a predetermined rate (180 ° C./hr, 10 ° C./hr, 5 ° C./hr, 3 ° C./hr) and treated at −50 ° C. for 180 minutes. Then, simultaneously with the end of the cooling treatment, the temperature inside the freeze dryer was adjusted to 25 ° C., and a reduced pressure drying treatment was performed to produce a porous body sample. For these porous body samples, the pore size was measured in the same manner as in Example 1 (n = 2). The relationship between the water content in the mixed solution and the pore size of the sample is shown in FIG. In addition, when the same experiment as Example 1 was conducted using P (LA / CL) with a composition ratio of 51:49, it was confirmed that the same behavior was exhibited.
図２に示すように、いずれの冷却速度で冷却を行った場合でも、含水率の変化に伴って多孔質体のポアサイズが変動し、特にポアサイズが大きくなる含水率の範囲も同様であった。また、冷却速度を変化させることによって、同じ含水率の混合溶液であってもポアサイズを変化させることができ、冷却速度が速いほどポアサイズを小さく、冷却速度が遅いほどポアサイズを大きくできる傾向が得られた。以上のことから、含水率と冷却速度を調整することによって、所望のポアサイズ、特に従来法では作製困難であった大きなポアサイズの多孔質体を容易に製造できることがわかった。また、冷却速度180℃/hrで得られた多孔質体サンプルの断面写真を図４に示す。同図に示すように断面において孔が均一に分布し、そのポアサイズも均一性に優れることがわかる。 As shown in FIG. 2, regardless of the cooling rate, the pore size of the porous body fluctuated with the change of the moisture content, and the moisture content range in which the pore size was increased was also the same. In addition, by changing the cooling rate, the pore size can be changed even with a mixed solution having the same water content. The higher the cooling rate, the smaller the pore size, and the slower the cooling rate, the larger the pore size. It was. From the above, it was found that by adjusting the water content and the cooling rate, it is possible to easily produce a porous body having a desired pore size, particularly a large pore size that was difficult to produce by the conventional method. Moreover, the cross-sectional photograph of the porous body sample obtained with the cooling rate of 180 degreeC / hr is shown in FIG. As shown in the figure, the holes are uniformly distributed in the cross section, and the pore size is excellent in uniformity.
凍結温度の変化によるポアサイズへの影響を調べた。 The effect of the freezing temperature on the pore size was investigated.
冷却速度を180℃/hrとし、最終の冷却温度を所定温度（-20℃、-30℃、-40℃）とする以外は、前記実施例２と同様にして多孔質体サンプルを作製し、ポアサイズを測定した(n=3)。前記混合溶液における含水率と前記サンプルのポアサイズの関係を図３に示す。 A porous body sample was prepared in the same manner as in Example 2 except that the cooling rate was 180 ° C / hr and the final cooling temperature was a predetermined temperature (-20 ° C, -30 ° C, -40 ° C). The pore size was measured (n = 3). The relationship between the water content in the mixed solution and the pore size of the sample is shown in FIG.
同図に示すように、冷却速度180℃/hrの場合、最終の冷却温度の変化によっては、含水率に対応したポアサイズの挙動に大きな変化はなく、前記冷却温度には影響されないことがわかった。このことから、-20℃の冷却温度に設定すれば、過度な冷却が不要となり低コスト化が可能になるといえる。 As shown in the figure, when the cooling rate was 180 ° C / hr, depending on the final change in the cooling temperature, the pore size behavior corresponding to the moisture content did not change significantly, and it was found that the cooling temperature was not affected. . From this, it can be said that if the cooling temperature is set to −20 ° C., excessive cooling is not required and the cost can be reduced.
作製した多孔質体をラット体内に埋入させ、前記多孔質体の細胞・組織の浸入性を確認した。 The produced porous body was embedded in the rat body, and the cell / tissue penetration of the porous body was confirmed.
前記実施例１と同様にして、所定の含水率（8.5質量％、9.75質量％、10.25質量％）の混合溶液を用いて多孔質体を作製し、12×15ｍｍの大きさに切断してサンプルを調製した。得られたサンプルのポアサイズは、8.5質量％のサンプルが130μm、9.75質量％のサンプルが310μm、10.25質量％のサンプルが790μmであった。なお、前記サンプルの厚みは、それぞれ5ｍｍ程度であった。これらのサンプルをラット背部の皮下に埋入させ、2週間後および4週間後、前記サンプルをH-E染色（ヘマトキシリン−エオシン染色）を行い、前記サンプルへの組織の浸入状態を確認した。 In the same manner as in Example 1, a porous body was prepared using a mixed solution having a predetermined moisture content (8.5% by mass, 9.75% by mass, 10.25% by mass), and cut into a size of 12 × 15 mm. Was prepared. The pore size of the obtained sample was 130 µm for the 8.5 mass% sample, 310 µm for the 9.75 mass% sample, and 790 µm for the 10.25 mass% sample. Each sample had a thickness of about 5 mm. These samples were implanted subcutaneously on the back of the rat, and after 2 weeks and 4 weeks, the samples were subjected to H-E staining (hematoxylin-eosin staining) to confirm the state of tissue infiltration into the samples.
その結果、図５の写真（4週間）に示すように、大きなポアサイズを有する多孔質体サンプル（ポアサイズ310μm、790μm）において、特に著しい細胞の浸入が見られた。本発明の製造方法によれば、このように、細胞の担体（足場）に適したポアサイズの大きな多孔質体が得られることから、医療分野に極めて有用といえる。 As a result, as shown in the photograph of FIG. 5 (4 weeks), particularly significant cell infiltration was observed in the porous body sample (pore size 310 μm, 790 μm) having a large pore size. According to the production method of the present invention, a porous material having a large pore size suitable for a cell carrier (scaffold) can be obtained as described above, and thus can be said to be extremely useful in the medical field.
このように本発明によれば、多孔質体のポアサイズを広範囲に設定することができる。このため、例えば、細胞の足場材料等、目的に応じた孔径を設定でき、再生医療をはじめとする医療分野において極めて有用な製造方法といえる。 Thus, according to the present invention, the pore size of the porous body can be set in a wide range. For this reason, for example, the pore diameter can be set according to the purpose, such as a cell scaffolding material, which can be said to be an extremely useful production method in the medical field including regenerative medicine.
Claims (24)
前記混合溶液を凍結処理する工程、
前記混合溶液の凍結処理物を減圧乾燥する工程を含む多孔質体の製造方法であって、
前記混合溶液の調製工程において、前記ポリマーに対して相対的に溶解度の低い溶媒の前記混合溶液中の含有率を変化させ、且つ、前記凍結工程において、前記混合溶液を３００℃／ｈｒ以下の速度で冷却することによって、製造される多孔質体のポアサイズを制御することを特徴とする多孔質体の製造方法。 A polymer comprising a copolymer of lactide and caprolactone, a solvent having a relatively low solubility in the polymer, and a solvent having a relatively high solubility in the polymer and compatible with the solvent having a low solubility Preparing a mixed solution comprising:
Freezing the mixed solution;
A method for producing a porous body comprising a step of drying a frozen processed product of the mixed solution under reduced pressure,
In the mixed solution preparation step, the content of the solvent having a relatively low solubility in the polymer is changed in the mixed solution, and in the freezing step, the mixed solution is fed at a rate of 300 ° C./hr or less. The method for producing a porous body is characterized in that the pore size of the produced porous body is controlled by cooling in step (a).
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