JP2002325830A - Bone tissue regeneration guiding membrane - Google Patents
Bone tissue regeneration guiding membraneInfo
- Publication number
- JP2002325830A JP2002325830A JP2001131355A JP2001131355A JP2002325830A JP 2002325830 A JP2002325830 A JP 2002325830A JP 2001131355 A JP2001131355 A JP 2001131355A JP 2001131355 A JP2001131355 A JP 2001131355A JP 2002325830 A JP2002325830 A JP 2002325830A
- Authority
- JP
- Japan
- Prior art keywords
- bone tissue
- tissue regeneration
- membrane
- lactic acid
- rigidity
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 210000000988 bone and bone Anatomy 0.000 title claims abstract description 73
- 239000012528 membrane Substances 0.000 title claims abstract description 64
- 230000017423 tissue regeneration Effects 0.000 title claims abstract description 53
- 239000000463 material Substances 0.000 claims abstract description 45
- 230000009477 glass transition Effects 0.000 claims abstract description 20
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 78
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 44
- 230000001939 inductive effect Effects 0.000 claims description 39
- 239000004310 lactic acid Substances 0.000 claims description 39
- 235000014655 lactic acid Nutrition 0.000 claims description 39
- 239000001506 calcium phosphate Substances 0.000 claims description 25
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 25
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 23
- 235000011010 calcium phosphates Nutrition 0.000 claims description 23
- 229920001577 copolymer Polymers 0.000 claims description 23
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 claims description 23
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 17
- 239000004626 polylactic acid Substances 0.000 claims description 17
- 239000002131 composite material Substances 0.000 claims description 15
- 229920000642 polymer Polymers 0.000 claims description 8
- 229920001897 terpolymer Polymers 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 5
- 229920006027 ternary co-polymer Polymers 0.000 claims description 5
- 238000010030 laminating Methods 0.000 claims description 3
- 230000004927 fusion Effects 0.000 claims 1
- 230000010478 bone regeneration Effects 0.000 abstract description 6
- 239000010408 film Substances 0.000 description 51
- 230000000052 comparative effect Effects 0.000 description 9
- 238000005520 cutting process Methods 0.000 description 9
- 238000012423 maintenance Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 238000011282 treatment Methods 0.000 description 8
- 230000036760 body temperature Effects 0.000 description 6
- 230000007547 defect Effects 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- 238000001356 surgical procedure Methods 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 5
- 239000002861 polymer material Substances 0.000 description 5
- 210000004872 soft tissue Anatomy 0.000 description 5
- 229920001059 synthetic polymer Polymers 0.000 description 5
- 238000005336 cracking Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000002054 transplantation Methods 0.000 description 4
- 239000002250 absorbent Substances 0.000 description 3
- 230000002745 absorbent Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000007769 metal material Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 2
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 2
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 229910010293 ceramic material Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 2
- 230000000399 orthopedic effect Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 2
- 235000019731 tricalcium phosphate Nutrition 0.000 description 2
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 2
- 229940078499 tricalcium phosphate Drugs 0.000 description 2
- NYHNVHGFPZAZGA-UHFFFAOYSA-N 2-hydroxyhexanoic acid Chemical compound CCCCC(O)C(O)=O NYHNVHGFPZAZGA-UHFFFAOYSA-N 0.000 description 1
- JRHWHSJDIILJAT-UHFFFAOYSA-N 2-hydroxypentanoic acid Chemical compound CCCC(O)C(O)=O JRHWHSJDIILJAT-UHFFFAOYSA-N 0.000 description 1
- GZYXPXGNODDCBD-UHFFFAOYSA-N 3,3,6,6-tetramethyl-1,4-dioxane-2,5-dione Chemical compound CC1(C)OC(=O)C(C)(C)OC1=O GZYXPXGNODDCBD-UHFFFAOYSA-N 0.000 description 1
- JVZACCIXIYPYEA-UHFFFAOYSA-N CC[Zn](CC)CC Chemical compound CC[Zn](CC)CC JVZACCIXIYPYEA-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- UKLDJPRMSDWDSL-UHFFFAOYSA-L [dibutyl(dodecanoyloxy)stannyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)O[Sn](CCCC)(CCCC)OC(=O)CCCCCCCCCCC UKLDJPRMSDWDSL-UHFFFAOYSA-L 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- GSCLMSFRWBPUSK-UHFFFAOYSA-N beta-Butyrolactone Chemical compound CC1CC(=O)O1 GSCLMSFRWBPUSK-UHFFFAOYSA-N 0.000 description 1
- 239000003012 bilayer membrane Substances 0.000 description 1
- 238000009529 body temperature measurement Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000000748 compression moulding Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000012975 dibutyltin dilaurate Substances 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 239000005001 laminate film Substances 0.000 description 1
- 239000002648 laminated material Substances 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000007151 ring opening polymerisation reaction Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229920001169 thermoplastic Polymers 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical compound [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- YFHICDDUDORKJB-UHFFFAOYSA-N trimethylene carbonate Chemical compound O=C1OCCCO1 YFHICDDUDORKJB-UHFFFAOYSA-N 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
Landscapes
- Materials For Medical Uses (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、骨の損傷や骨折時にお
いて手術現場での易操作性、易成形性及び骨再生のため
の形状維持安定性に優れた、骨が形成されるまで患部に
固定、遮蔽及び骨再生を誘導する膜に関するものであ
る。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for treating a diseased part until a bone is formed, which is excellent in operability at the operation site, easy formability, and stability in shape maintenance for bone regeneration at the time of bone damage or fracture. And a membrane that induces fixation, shielding and bone regeneration.
【０００２】[0002]
【従来の技術と課題】整形外科や口腔外科での骨欠損に
対する治療法は自家骨移植、同種骨移植、異種骨移植及
び人工骨移植が適用されている。しかし、骨採取量及び
免疫問題などから人工骨による治療が有効である。人工
骨材料としては金属材料、セラミックス材料、合成高分
子材料等がインプラント材料として使用されている。現
在、金属材料及びセラミックス材料が広く臨床に使用さ
れているが、特に金属材料は生体組織より物理的、機械
的強度が大きくなりすぎることと、腐食による含有金属
の生体に対する毒性のため生体親和性も劣っており、生
体内に於いても非吸収性材料であるため形成された骨組
織内に残存して新生骨の成長に影響を与え、骨の強度が
低下するという問題がある。2. Description of the Related Art Autologous bone transplantation, allogeneic bone transplantation, xenogeneic bone transplantation, and artificial bone transplantation have been applied as treatments for bone defects in orthopedic surgery and oral surgery. However, treatment with artificial bone is effective due to problems such as the amount of bone collected and immunity. As an artificial bone material, a metal material, a ceramic material, a synthetic polymer material, or the like is used as an implant material. At present, metal materials and ceramic materials are widely used clinically, but especially metal materials have physical and mechanical strengths that are too large compared to living tissues, and biocompatibility due to the toxicity of contained metals to living bodies due to corrosion. However, since it is a non-absorbable material even in a living body, it remains in the formed bone tissue, affects the growth of new bone, and has a problem that the strength of the bone is reduced.
【０００３】このようなことから機械的強度が高すぎる
ことなく、かつ生体内で分解吸収され生体適合性にすぐ
れた材料であるポリ乳酸系共重合体材料が活発に開発さ
れ、臨床に用いられている。また、これらの材料を使用
した骨組織再生誘導（ＧＢＲ）法が注目され研究されて
いる。この治療法は骨の自己再生能力を活かして治療部
位に軟組織の侵入を防ぐ遮蔽膜を固定する方法であり、
手術法も極めて簡便な治療法であり、口腔外科では多く
の良好な結果が得られている。[0003] For these reasons, polylactic acid-based copolymer materials, which do not have excessively high mechanical strength, are decomposed and absorbed in vivo, and have excellent biocompatibility, have been actively developed and are used clinically. ing. In addition, a bone tissue regeneration induction (GBR) method using these materials has attracted attention and has been studied. This treatment uses a self-renewal ability of bone to fix a shielding film that prevents soft tissue from entering the treatment site.
Surgery is also a very simple treatment, and oral surgery has yielded many good results.
【０００４】しかし、整形外科では口腔外科の比較的小
さな治療部位とは異なり、大きな骨欠損部への治療が対
象となる。そのため、吸収性合成高分子材料による遮蔽
膜においても骨形成の初期段階で軟組織の侵入を防ぐ膜
の形状維持が特に重要となっている。However, in orthopedic surgery, unlike a relatively small treatment site in oral surgery, treatment for a large bone defect is targeted. For this reason, it is particularly important to maintain the shape of the membrane for preventing invasion of soft tissue in the initial stage of bone formation even in a shielding membrane made of an absorbable synthetic polymer material.
【０００５】ここでの形状維持は、膜の単一方向への引
張りもしくは伸び等の機械強度に依存するものではな
く、骨組織が再生されるまでの軟組織等の侵入圧力に対
する膜の剛性が大きく関係する。しかし、臨床で実際に
使用されているものは易操作性もしくは形状維持を優先
させたものに二分され、それぞれに問題が生じている。The maintenance of the shape here does not depend on mechanical strength such as tension or elongation of the membrane in a single direction. Rigidity of the membrane against penetration pressure of soft tissue or the like until bone tissue is regenerated is large. Involved. However, those actually used in the clinic are divided into those which prioritize easy operability or shape maintenance, and each has a problem.
【０００６】室温において剛性率１，０００ＭＰａ程度
を示す吸収性合成高分子材料膜はハサミによる切断ある
いは骨欠損部位への縫合、設置など易操作性及び易成形
性に優れている。しかし、生体内の体温付近では剛性率
の極端な減少から形態維持安定性に乏しく遮蔽効果が弱
まり、骨組織再生を妨げる軟組織が侵入して治療効果に
悪影響を及ぼす。また、形態維持安定性を優先し、体温
付近で剛性率１，０００ＭＰａ程度を示す吸収性合成高
分子材料膜は、室温において剛性率は極端に高くなり、
骨欠損部への固定するための曲げ成形、ハサミによる切
断、縫合糸での縫合等の処置において膜が割れるなどに
よる問題が生じる。そのため実作業では高温の滅菌生理
食塩液中に浸漬して膜を柔軟化して使用する場合もあり
術式は簡便であるものの、極めて操作性が悪いものであ
った。An absorptive synthetic polymer material film having a rigidity of about 1,000 MPa at room temperature is excellent in operability and formability such as cutting with scissors or suturing or setting at a bone defect site. However, near body temperature in a living body, the rigidity is extremely reduced, the shape maintenance stability is poor, and the shielding effect is weakened, and soft tissue which hinders bone tissue regeneration invades and adversely affects the therapeutic effect. Also, giving priority to shape maintenance stability, the absorbent synthetic polymer material film showing a rigidity of about 1,000 MPa near body temperature, the rigidity becomes extremely high at room temperature,
Problems such as breakage of the membrane occur in procedures such as bending for fixing to a bone defect, cutting with scissors, and suturing with a suture. For this reason, in actual work, the membrane may be softened by immersion in a high-temperature sterile physiological saline solution, so that the operation method is simple, but the operability is extremely poor.
【０００７】このようなことから、使用する温度範囲
（４℃から４０℃）全般において剛性率が５００〜２０
００ＭＰａの範囲内である吸収性合成高分子材料膜の開
発が望まれていた。しかし、ポリ乳酸系共重合体材料
は、本来熱可塑性高分子の一種であり、その熱的性質の
ひとつのガラス転移温度（Ｔｇ）は０〜６５℃付近であ
り、温度に対して膜の物性が非常に影響を受けやすい。
そのため温度依存的に剛性率の変化が大きく、単一材料
では適用する温度範囲において剛性率が上記条件を満た
す材料は存在しない。特許平９−１４７８５では乳酸／
ε−カプロラクトン共重合体の積層した材料を使用して
いるが適切な剛性は得られていない。この問題を解決す
るために、リン酸カルシウム材料等の他の吸収性材料に
よって複合材料化して剛性の調整を行っているが、いま
だ適切な材料には到っていない。Therefore, the rigidity is 500 to 20 over the entire temperature range (4 ° C. to 40 ° C.).
It has been desired to develop an absorbent synthetic polymer material film having a pressure within the range of 00 MPa. However, a polylactic acid-based copolymer material is originally a kind of thermoplastic polymer, and one of its thermal properties has a glass transition temperature (Tg) of about 0 to 65 ° C. But very susceptible.
For this reason, the change in the rigidity is large in a temperature-dependent manner, and there is no single material having a rigidity satisfying the above condition in the temperature range to be applied. Patent Hei 9-14785 states that lactic acid /
Although a laminated material of ε-caprolactone copolymer is used, appropriate rigidity has not been obtained. In order to solve this problem, the rigidity is adjusted by forming a composite material using another absorbent material such as a calcium phosphate material, but an appropriate material has not yet been obtained.
【０００８】[0008]
【課題を解決するための手段】［１］本発明は、少なく
とも二層膜よりなる骨組織再生誘導膜において、外層膜
は、室温において、剛性率が５００〜５０００ＭＰａ、
ガラス転移温度が４０〜６０℃の範囲にある材料から構
成され、内層膜は、室温において、剛性率が２．０〜５
００ＭＰａ、ガラス転移温度が４〜３７℃の範囲にある
材料から構成され、かつ骨組織再生誘導膜全体は、４〜
４０℃において、剛性率が５００〜２０００ＭＰａの範
囲にある骨組織再生誘導膜を提供する。 ［２］本発明は、外層膜は乳酸系重合体を２０重量％以
上含有した材料より構成され、内層膜は乳酸／グリコー
ル酸／ε−カプロラクトンの三元系共重合体とリン酸カ
ルシウム系材料の複合体よりなり、かつ三元系共重合体
を５重量％以上含有した材料より構成されている［１］
に記載の骨組織再生誘導膜を提供する。 ［３］本発明は、前記外層膜を構成する乳酸系重合体
は、（ａ）生体吸収性のポリ乳酸単体または（ｂ）ポリ
乳酸とリン酸カルシウム系材料との複合体または（ｃ）
乳酸／グリコール酸／ε−カプロラクトンの三元系共重
合体とリン酸カルシウム系材料の複合体または（ｄ）乳
酸と乳酸以外のヒドロキシカルボン酸からなる共重合体
である［１］ないし［２］に記載の骨組織再生誘導膜を
提供する。 ［４］本発明は、外層膜及び内層膜を構成する乳酸／グ
リコール酸／ε−カプロラクトンの三元系共重合体の数
平均分子量は２００００から２０００００である［１］
ないし［３］に記載の骨組織再生誘導膜を提供する。 ［５］本発明は、乳酸／グリコール酸／ε−カプロラク
トンの三元系共重合体の組成モル比が５〜９０：３〜７
５：５〜４０モル％の範囲である［１］ないし［４］に
記載の骨組織再生誘導膜を提供する。 ［６］本発明は、骨組織再生誘導膜が外層膜と内層膜と
を熱融着することにより積層されたものである［１］な
いし［５］に記載の骨組織再生誘導膜を提供する。Means for Solving the Problems [1] The present invention provides a bone tissue regeneration-inducing membrane comprising at least a bilayer membrane, wherein the outer layer membrane has a rigidity of 500 to 5000 MPa at room temperature.
The inner layer film is made of a material having a glass transition temperature in the range of 40 to 60 ° C., and has a rigidity of 2.0 to 5 at room temperature.
00MPa, made of a material having a glass transition temperature in the range of 4-37 ° C.
At 40 ° C., a bone tissue regeneration-inducing membrane having a rigidity in the range of 500 to 2000 MPa is provided. [2] In the present invention, the outer layer film is composed of a material containing 20% by weight or more of a lactic acid-based polymer, and the inner layer film is a composite of a tertiary copolymer of lactic acid / glycolic acid / ε-caprolactone and a calcium phosphate-based material. [1] composed of a material and composed of a material containing 5% by weight or more of a terpolymer.
2. A bone tissue regeneration-inducing membrane according to item 1. [3] In the present invention, the lactic acid-based polymer constituting the outer layer film may be (a) a bioabsorbable polylactic acid simple substance or (b) a composite of polylactic acid and a calcium phosphate-based material or (c)
[1] or [2], which is a complex of a tertiary copolymer of lactic acid / glycolic acid / ε-caprolactone and a calcium phosphate-based material or (d) a copolymer of lactic acid and a hydroxycarboxylic acid other than lactic acid. And a bone tissue regeneration-inducing membrane. [4] In the present invention, the ternary copolymer of lactic acid / glycolic acid / ε-caprolactone constituting the outer layer film and the inner layer film has a number average molecular weight of 20,000 to 200,000 [1].
Or a bone tissue regeneration-inducing membrane according to [3]. [5] In the present invention, the terpolymer of lactic acid / glycolic acid / ε-caprolactone has a composition molar ratio of 5 to 90: 3 to 7
5: The bone tissue regeneration-inducing membrane according to [1] to [4], which is in a range of 5 to 40 mol%. [6] The present invention provides the bone tissue regeneration-inducing membrane according to any one of [1] to [5], wherein the bone tissue regeneration-inducing membrane is laminated by heat-sealing an outer layer film and an inner layer film. .
【０００９】[0009]
【発明の実施の形態】図１は、本発明の骨組織再生誘導
膜１の一例を示す概略図である。図２は、骨組織再生誘
導膜１を構成する積層体２の一部拡大断面図である。骨
組織再生誘導膜１は外層膜３と内層膜４より構成され
る。本発明で外層膜３とは骨組織再生誘導膜１を構成す
る最外層の膜で、本発明で内層膜４とは骨組織再生誘導
膜１を構成する最内層の膜である。積層体２を三層以上
で構成する場合、これらの外層膜３と内層膜４の間に一
層以上の中間層膜が配置される。FIG. 1 is a schematic view showing one example of a bone tissue regeneration-inducing membrane 1 of the present invention. FIG. 2 is a partially enlarged cross-sectional view of the laminate 2 constituting the bone tissue regeneration-inducing membrane 1. The bone tissue regeneration-inducing membrane 1 is composed of an outer membrane 3 and an inner membrane 4. In the present invention, the outer membrane 3 is the outermost layer constituting the bone tissue regeneration-inducing membrane 1, and in the present invention, the inner layer membrane 4 is the innermost membrane constituting the bone tissue regeneration-inducing membrane 1. When the laminate 2 is composed of three or more layers, one or more intermediate layer films are arranged between the outer layer film 3 and the inner layer film 4.
【００１０】前記外層膜３は乳酸系重合体より構成さ
れ、該乳酸系重合体は、（ａ）生体吸収性のポリ乳酸単
体または（ｂ）ポリ乳酸とリン酸カルシウム系材料との
複合体または（ｃ）乳酸／グリコール酸／ε−カプロラ
クトンの三元系共重合体とリン酸カルシウム系材料の複
合体または（ｄ）乳酸と乳酸以外のヒドロキシカルボン
酸からなる共重合体である。乳酸と乳酸以外のヒドロキ
シカルボン酸からなる共重合体とは、グリコール酸、α
・β・γ−ヒドロキシ酪酸、α−ヒドロキシ吉草酸、ヒ
ドロキシカプロン酸等あるいはグリコリド、ε−カプロ
ラクトン、テトラメチルグリコリド、トリメチレンカー
ボネート、δ−バレロラクトン、β−ブチロラクトン、
γ−ブチロラクトン等との環状モノマーが例示される。
これら化合物は各々組み合わせで使用してもよいし、ラ
クチドに関しては、Ｌ体・ＤＬ体・Ｄ体等の何れも単独
あるいは混合物として使用できる。外層膜３は、室温に
おいて、ガラス転移温度が４０〜６０℃であり、かつ剛
性率が５００〜５０００ＭＰａに設定される。ガラス転
移温度が４０℃未満では生体内での形状が維持できず、
６０℃を超えると手術場での成形が困難であるため不適
である。また外層膜３をポリ乳酸とリン酸カルシウム系
材料との複合体より構成する場合は、重量比でポリ乳酸
を８０重量％から１００重量％未満、より好ましくは９
０重量％から１００重量％未満含むことが好ましい。外
層膜３はより好ましくはポリ乳酸単体で形成するのが好
ましい。The outer layer film 3 is composed of a lactic acid-based polymer. The lactic acid-based polymer is composed of (a) a bioabsorbable polylactic acid alone or (b) a composite of polylactic acid and a calcium phosphate-based material or (c). A) a ternary copolymer of lactic acid / glycolic acid / ε-caprolactone and a calcium phosphate-based material, or (d) a copolymer of lactic acid and a hydroxycarboxylic acid other than lactic acid. A copolymer comprising lactic acid and a hydroxycarboxylic acid other than lactic acid is glycolic acid, α
Β-γ-hydroxybutyric acid, α-hydroxyvaleric acid, hydroxycaproic acid or the like or glycolide, ε-caprolactone, tetramethyl glycolide, trimethylene carbonate, δ-valerolactone, β-butyrolactone,
Examples include cyclic monomers with γ-butyrolactone and the like.
Each of these compounds may be used in combination, and lactide may be used alone or as a mixture of any of L-form, DL-form and D-form. The outer layer film 3 has a glass transition temperature of 40 to 60 ° C. and a rigidity of 500 to 5000 MPa at room temperature. If the glass transition temperature is less than 40 ° C., the shape in vivo cannot be maintained,
If the temperature is higher than 60 ° C., it is not suitable because molding at the operating site is difficult. When the outer layer film 3 is composed of a composite of polylactic acid and a calcium phosphate-based material, the polylactic acid is contained in a weight ratio of 80% by weight to less than 100% by weight, more preferably 9% by weight.
Preferably, it contains 0% to less than 100% by weight. The outer layer film 3 is more preferably formed of polylactic acid alone.
【００１１】前記内層膜４は乳酸／グリコール酸／ε−
カプロラクトンの三元系共重合体とリン酸カルシウム系
材料との複合体より構成され、室温において、剛性率が
２．０〜５００ＭＰａ、ガラス転移温度が４〜３７℃に
設定される。ガラス転移温度が３７℃を超えるとハサミ
による切断、縫合糸での縫合等の処置において膜が割れ
るので、好ましくない。前記外層膜３及び内層膜４を構
成する乳酸／グリコール酸／ε−カプロラクトンの三元
系共重合体の数平均分子量は２００００以上から２００
０００以下のものが使用される。数平均分子量が２００
００以下では硬いワックス状となるため、膜としての成
形が困難であるため不適である。２０００００を超える
と加水分解速度が低下して組織再生を阻害する可能性が
あることに加えて、後述のリン酸カルシウムとの混合操
作が困難となり、共重合体中におけるリン酸カルシウム
の分散性が不均一となる。The inner layer film 4 is made of lactic acid / glycolic acid / ε-
It is composed of a composite of a terpolymer of caprolactone and a calcium phosphate material, and has a rigidity of 2.0 to 500 MPa and a glass transition temperature of 4 to 37 ° C. at room temperature. If the glass transition temperature exceeds 37 ° C., it is not preferable because the membrane breaks in a procedure such as cutting with scissors or suturing with a suture. The number average molecular weight of the tertiary copolymer of lactic acid / glycolic acid / ε-caprolactone constituting the outer layer film 3 and the inner layer film 4 is from 20,000 or more to 200
000 or less are used. Number average molecular weight is 200
If it is less than 00, it becomes hard wax, and it is not suitable because it is difficult to form a film. When it exceeds 200,000, in addition to the possibility that the rate of hydrolysis is reduced and tissue regeneration may be inhibited, the mixing operation with calcium phosphate described below becomes difficult, and the dispersibility of calcium phosphate in the copolymer becomes uneven. .
【００１２】前記外層膜３（乳酸／グリコール酸／ε−
カプロラクトンの三元系共重合体とリン酸カルシウム系
材料の複合体より構成する場合）は重量比で乳酸／グリ
コール酸／ε−カプロラクトンの三元系共重合体を８０
重量％から２０重量％、より好ましくは６０重量％から
４０重量％、より好ましくは５０重量％含むことが好ま
しい。また前記内層膜４は重量比で乳酸／グリコール酸
／ε−カプロラクトンの三元系共重合体を５重量％以
上、より好ましくは２０重量％以上から４０重量％、よ
り好ましくは５０重量％含むことが好ましい。The outer layer film 3 (lactic acid / glycolic acid / ε-
In the case of a composite of a terpolymer of caprolactone and a calcium phosphate-based material), the terpolymer of lactic acid / glycolic acid / ε-caprolactone is 80% by weight.
Preferably, it comprises from 20% to 20% by weight, more preferably from 60% to 40% by weight, more preferably 50% by weight. The inner layer film 4 contains a tertiary copolymer of lactic acid / glycolic acid / ε-caprolactone in a weight ratio of 5% by weight or more, more preferably 20% by weight to 40% by weight, and more preferably 50% by weight. Is preferred.
【００１３】本発明で、前記外層膜３及び内層膜４に前
記乳酸系重合体を使用するのは、生体内において分解吸
収され、分解生成物も組織に対する毒性が少ない生体適
合性に優れた材料であり、さらに、その組成、分子量を
調整することにより適正な強度、分解速度、また可撓性
から高強度をすることができるためである。前記乳酸系
重合体の製法は、一般的な方法により製造するものであ
れ何れの方法によるものであってもよい。その一例を挙
げれば、ラクチド、グリコリド、ε−カプロラクトンを
オクタン酸スズ、塩化スズ、ジラウリン酸ジブチルス
ズ、アルミニウムイソプロポキシド、チタニウムテトラ
イソプロポキシド、トリエチル亜鉛等の触媒存在下で加
熱して、１００℃〜２５０℃で開環重合を行うことによ
って製造することができる。本発明で、前記外層膜３及
び内層膜４の膜厚はそれぞれ１００〜１０００μｍ、よ
り好ましくは５０〜５００μｍの範囲が好ましい。必要
とされる膜厚は適応部位によって異なるが、１００μｍ
以下では分解が速く、１０００μｍ以上では分解が遅く
治療効果に悪影響を及ぼす。In the present invention, the use of the lactic acid-based polymer for the outer layer film 3 and the inner layer film 4 is made of a material which is decomposed and absorbed in a living body, and a decomposition product is less toxic to tissues and has excellent biocompatibility. In addition, by adjusting the composition and the molecular weight, it is possible to increase the strength from the appropriate strength, decomposition rate, and flexibility. The method for producing the lactic acid-based polymer may be any of the general method and any method. For example, lactide, glycolide, and ε-caprolactone are heated in the presence of a catalyst such as tin octoate, tin chloride, dibutyltin dilaurate, aluminum isopropoxide, titanium tetraisopropoxide, and triethylzinc at 100 ° C. It can be produced by performing ring-opening polymerization at ~ 250 ° C. In the present invention, the thickness of each of the outer layer film 3 and the inner layer film 4 is preferably in the range of 100 to 1000 μm, more preferably 50 to 500 μm. The required film thickness depends on the application site,
In the following, the decomposition is fast, and when it is 1000 μm or more, the decomposition is slow, which adversely affects the therapeutic effect.
【００１４】本発明の骨組織再生誘導膜１は、（ａ）生
体吸収性のポリ乳酸単体または（ｂ）ポリ乳酸とリン酸
カルシウム系材料との複合体または（ｃ）乳酸／グリコ
ール酸／ε−カプロラクトンの三元系共重合体とリン酸
カルシウム系材料の複合体または（ｄ）乳酸と乳酸以外
のヒドロキシカルボン酸からなる共重合体より構成され
る外層膜３と、乳酸／グリコール酸／ε−カプロラクト
ンの三元系共重合体とリン酸カルシウム系材料との複合
体より構成される内層膜４を積層することにより、骨組
織再生誘導膜全体として、４℃から４０℃において剛性
率が５００〜２０００ＭＰａに設定される。本発明では
積層体として、二層の例を示したが、三層以上の積層体
としても良い。要するに最外層は、室温において、剛性
率が５００〜５０００ＭＰａ、ガラス転移温度が４０〜
６０℃の材料から構成され、最内層は、室温において、
剛性率が２．０〜５００ＭＰａ、ガラス転移温度が４〜
３７℃の材料から構成され、骨組織再生誘導膜全体は、
４℃から４０℃において、剛性率が５００〜２０００Ｍ
Ｐａであれば良い。The bone tissue regeneration-inducing membrane 1 of the present invention comprises (a) a bioabsorbable polylactic acid alone or (b) a complex of polylactic acid and a calcium phosphate material or (c) lactic acid / glycolic acid / ε-caprolactone. (D) an outer layer film 3 composed of a composite of a terpolymer and a calcium phosphate-based material or (d) a copolymer of lactic acid and a hydroxycarboxylic acid other than lactic acid; and a lactic acid / glycolic acid / ε-caprolactone By laminating the inner layer film 4 composed of the composite of the base copolymer and the calcium phosphate-based material, the rigidity of the whole bone tissue regeneration-inducing membrane is set at 500 to 2000 MPa at 4 ° C. to 40 ° C. . In the present invention, an example of a two-layer laminate is shown, but a laminate of three or more layers may be used. In short, the outermost layer has a rigidity of 500 to 5000 MPa and a glass transition temperature of 40 to
60 ° C. material, the innermost layer at room temperature
Rigidity is 2.0 ~ 500MPa, glass transition temperature is 4 ~
Consisting of 37 ° C. material, the entire bone tissue regeneration-inducing membrane is
From 4 ° C to 40 ° C, rigidity is 500-2000M
Pa may be used.
【００１５】また、前記内外層の材料に含まれるリン酸
カルシウム材料にはリン酸三カルシウム、ヒドロキシア
パタイト、第二リン酸カルシウム等が例示される。その
中でも、共重合体と親和性がよく、生体内で吸収崩壊し
て新組織と置換され骨組織修復を促進するリン酸三カル
シウムが最も好ましい。平均粒径としては、２００μｍ
以下のリン酸カルシウムを用いる。平均粒径２００μｍ
を超えると薄膜成形が困難であるため不適である。The calcium phosphate material contained in the material of the inner and outer layers is exemplified by tricalcium phosphate, hydroxyapatite, dibasic calcium phosphate and the like. Among them, tricalcium phosphate, which has a good affinity for the copolymer, absorbs and disintegrates in vivo, is replaced by new tissue, and promotes bone tissue repair, is most preferred. The average particle size is 200 μm
The following calcium phosphate is used. Average particle size 200μm
If it exceeds, it is not suitable because it is difficult to form a thin film.
【００１６】また本発明に使用する前記三元系共重合体
の乳酸：グリコール酸：ε−カプロラクトンの組成モル
比は、５〜９０：３〜７５：５〜４０モル％の範囲であ
る乳酸／グリコール酸／ε−カプロラクトンの三元系共
重合体であることが望ましい。また、数平均分子量は２
００００〜２０００００であることが望ましい。共重合
体の分子量がこの範囲を逸脱し、２００００を下回ると
硬いワックス状となるため、膜としての成形が困難であ
るため不適である。また逆に、２０００００を超えると
加水分解速度が低下して組織再生を阻害する可能性があ
ることに加えて、後述のリン酸カルシウムとの混合操作
が困難となり、共重合体中におけるリン酸カルシウムの
分散性が不均一となる。The tertiary copolymer used in the present invention has a composition molar ratio of lactic acid: glycolic acid: ε-caprolactone of 5 to 90: 3 to 75: 5 to 40 mol%. It is preferably a terpolymer of glycolic acid / ε-caprolactone. The number average molecular weight is 2
Desirably, it is 0000 to 200,000. If the molecular weight of the copolymer deviates from this range and is lower than 20,000, the copolymer becomes a hard wax and is not suitable because it is difficult to form a film. Conversely, if it exceeds 200,000, the rate of hydrolysis may be reduced and tissue regeneration may be inhibited. In addition, the mixing operation with calcium phosphate described below becomes difficult, and the dispersibility of calcium phosphate in the copolymer is reduced. It becomes uneven.
【００１７】また、若干の誤差、幅の変動はあるが、本
発明の骨組織再生誘導膜を使用する温度範囲とは４から
４０℃を意味し、室温とは１０〜３０℃を意味し、低温
とは１０℃未満を意味し、体温とは３５から３８℃を意
味する。Although there are slight errors and fluctuations in width, the temperature range in which the bone tissue regeneration-inducing membrane of the present invention is used means 4 to 40 ° C., and the room temperature means 10 to 30 ° C. Low temperature means below 10 ° C and body temperature means 35 to 38 ° C.
【００１８】また本発明の骨組織再生誘導膜１の製造方
法としては圧縮成形が好適である。例えば、図３に示す
ように、各層の材料５をそれぞれプレス金型６の上に置
き、プレス機７にて加熱圧縮し、それぞれの膜８、９を
成形する。次に膜８、９を重ね合わせてプレス金型１０
の上に置きプレス機１１にて圧縮して積層膜１２を得
る。As a method for producing the bone tissue regeneration-inducing membrane 1 of the present invention, compression molding is preferred. For example, as shown in FIG. 3, the material 5 of each layer is placed on a press die 6 and heated and compressed by a press machine 7 to form respective films 8 and 9. Next, the membranes 8 and 9 are superimposed, and the
And press it with a press 11 to obtain a laminated film 12.
【００１９】[0019]
【実施例】以下に実施例を挙げて更に本発明を詳細に説
明するが、本発明はこれに限定されるものではない。ポ
リ乳酸単体のみまたは該ポリ乳酸とリン酸カルシウム系
材料との複合体より構成される外層３と、数平均分子量
が５００００から１０００００の乳酸／グリコール酸／
ε−カプロラクトンの三元系共重合体とリン酸カルシウ
ム系材料との複合体より構成される内層４を前記図３の
ように積層して骨組織再生誘導膜１（積層膜）を製造
し、以下の項目を調べ評価した。なお、種々の条件（実
施例１から５、比較例１から６）で作製した骨組織再生
誘導膜１の構成材料、ガラス転移温度、複合体組成及び
剛性率を表１、表２に示した。また、その骨組織再生誘
導膜１（積層膜）の剛性率・低温時の切断・４０℃での
加工性・骨組織再生誘導能評価を表３に示した。 （１）剛性率 ＪＩＳ Ｋ６７４５ プラスチックの転移温度測定方法
に準拠し、クラッシュバーグ式柔軟度試験機を使用し
て、剛性率を測定した。 （２）低温時の切断性 一日以上の４℃の冷蔵庫保存を行った後、手術バサミに
よる切断を行った。それによる膜の割れ、破損の有無を
観測した。 （３）４０℃での加工性 ４０℃の温生理食塩液中に３分間浸漬した後、手作業に
より円筒状に成形した。それによる膜の成形性、割れ、
破損の有無を観測した。 （４）骨再生誘導能評価 ビーグル犬（体重約１０ｋｇ）の脛骨骨欠損（２０ｍ
ｍ）人工モデルを作製、エチレンオキサイドガス滅菌さ
れた膜を、欠損部を覆う形で円筒状に縫合固定し、創外
固定器により固定しながら、固定後４週間、８週間にエ
ックス線および切開して目視により骨組織の再生の程度
を調べた。EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto. An outer layer 3 composed of polylactic acid alone or a composite of the polylactic acid and a calcium phosphate-based material, and a lactic acid / glycolic acid / polylactic acid having a number average molecular weight of 50,000 to 100,000
An inner layer 4 composed of a composite of a ternary copolymer of ε-caprolactone and a calcium phosphate-based material is laminated as shown in FIG. 3 to produce a bone tissue regeneration-inducing membrane 1 (laminated membrane). The items were examined and evaluated. Tables 1 and 2 show the constituent materials, glass transition temperature, composite composition, and rigidity of the bone tissue regeneration-inducing membrane 1 produced under various conditions (Examples 1 to 5 and Comparative Examples 1 to 6). . Table 3 shows the rigidity of the bone tissue regeneration-inducing film 1 (laminated film), cutting at low temperature, workability at 40 ° C., and evaluation of bone tissue regeneration-inducing ability. (1) Rigidity The rigidity was measured using a Crashberg type flexibility tester in accordance with JIS K6745 Plastic Transition Temperature Measurement Method. (2) Cutting properties at low temperature After storing in a refrigerator at 4 ° C. for one day or more, cutting was performed with surgical scissors. It was observed whether the film was cracked or damaged. (3) Workability at 40 ° C. After being immersed in a warm physiological saline solution at 40 ° C. for 3 minutes, it was formed into a cylindrical shape by hand. The resulting film formability, cracking,
The presence or absence of damage was observed. (4) Evaluation of bone regeneration inducing ability Tibial bone defect (20 m) of a beagle dog (body weight: about 10 kg)
m) The artificial model was prepared, and the membrane sterilized with ethylene oxide gas was fixed by suture and fixed in a cylindrical shape so as to cover the defect, and while fixed with an external fixator, X-ray and incision were performed 4 weeks and 8 weeks after the fixation. The extent of bone tissue regeneration was visually examined.
【００２０】[0020]
【表１】 [Table 1]
【００２１】[0021]
【表２】 [Table 2]
【００２２】[0022]
【表３】 [Table 3]
【００２３】表１と表３に示すように実施例１〜６の積
層膜では、室温（２５℃）においての剛性率が２．０〜
５００ＭＰａ、ガラス転移温度４〜３７℃の軟質膜から
なる内層と室温（２５℃）においての剛性率５００〜５
０００ＭＰａ、ガラス転移温度４０〜６０℃である硬質
膜からなる外層を張り合わせることにより、この積層膜
は全ての温度条件（４〜３７℃）で剛性率範囲５００〜
２，０００ＭＰａの条件を満たし、低温での切断性・４
０℃での加工性にも問題も見られず、易操作性・易成形
性・形態維持安定性の特性を有する積層膜であった。ま
た、骨組織再生誘導能評価も、積層膜の固定後４週間、
８週間に切開して目視により骨組織の再生を調べた結
果、術部は良好な骨組織の修復が認められた。As shown in Tables 1 and 3, in the laminated films of Examples 1 to 6, the rigidity at room temperature (25 ° C.) was 2.0 to 2.0.
500 MPa, inner layer made of a soft film having a glass transition temperature of 4 to 37 ° C. and a rigidity of 500 to 5 at room temperature (25 ° C.)
By laminating an outer layer composed of a hard film having a glass transition temperature of 40 to 60 ° C., the laminated film has a rigidity range of 500 to 500 ° C. under all temperature conditions (4 to 37 ° C.).
Satisfies the condition of 2,000MPa, cutting performance at low temperature.
No problem was observed in the workability at 0 ° C., and the laminate film had characteristics of easy operability, easy moldability, and shape maintenance stability. In addition, the evaluation of the ability to induce bone tissue regeneration was performed 4 weeks after the fixation of the laminated film.
As a result of incision for 8 weeks and visual inspection of the regeneration of the bone tissue, good repair of the bone tissue was confirmed in the surgical site.
【００２４】表２と表３に示すように比較例１のガラス
転移温度４℃の乳酸／グリコール酸／ε−カプロラクト
ンの三元系共重合体からなる単一膜では、低温での切断
性は良好であるものの、室温・体温（２５〜３７℃）付
近での剛性率が２から５ＭＰａと非常に低いため形状維
持が不可能であった。また、比較例２のガラス転移温度
３７℃の乳酸／グリコール酸／ε−カプロラクトンの三
元系共重合体の単一膜では、低温（４℃）での剛性率が
２０００ＭＰａを超える（２１５７ＭＰａ）ためハサミ
による切断で破損・割れが発生し、さらに、体温付近
（３７℃）での剛性率が５００ＭＰａをはるかに下まわ
るため（２７ＭＰａ）比較例１と同様に形状維持が不可
能であった。そのため骨組織再生誘導能評価も比較例１
・２では形態維持安定性を有していないことにより術部
は骨組織の修復が少なく、骨組織表面に軟組織の進入が
認められた。As shown in Tables 2 and 3, the single film composed of a tertiary copolymer of lactic acid / glycolic acid / ε-caprolactone having a glass transition temperature of 4 ° C. in Comparative Example 1 had a low-temperature cuttability. Although good, the rigidity near room temperature and body temperature (25 to 37 ° C.) was very low at 2 to 5 MPa, so that the shape could not be maintained. Further, in the single film of the tertiary copolymer of lactic acid / glycolic acid / ε-caprolactone having a glass transition temperature of 37 ° C. in Comparative Example 2, the rigidity at low temperature (4 ° C.) exceeds 2000 MPa (2157 MPa). Breaking and cracking occurred by cutting with scissors, and the rigidity near body temperature (37 ° C.) was much lower than 500 MPa (27 MPa), so that the shape could not be maintained as in Comparative Example 1. Therefore, the evaluation of the ability to induce bone tissue regeneration was also performed in Comparative Example 1.
In the case of No. 2, the operative site had little bone tissue repair due to lack of morphological maintenance stability, and penetration of soft tissue on the bone tissue surface was observed.
【００２５】比較例３のガラス転移温度が６０℃のポリ
乳酸の単一膜では、体温付近（３７℃）での剛性率が５
００ＭＰａを超える（７３９ＭＰａ）ため形状維持性は
有するものの、低温（４℃）での剛性率が２０００ＭＰ
ａを大きく超えるため（３６７２ＭＰａ）ハサミによる
切断で破損・割れが発生し、骨再生誘導能評価も縫合糸
による固定の際に割れてしまい評価不可能であった。In the polylactic acid single film having a glass transition temperature of 60 ° C. in Comparative Example 3, the rigidity around body temperature (37 ° C.) was 5%.
Although it has a shape retention because it exceeds 00MPa (739MPa), its rigidity at low temperature (4 ° C) is 2000MPa.
Since it greatly exceeded a (3672 MPa), breakage and cracking occurred by cutting with scissors, and the bone regeneration inducing ability was also broken at the time of fixation with a suture, making evaluation impossible.
【００２６】比較例４〜６の積層膜では、比較例４は内
層のガラス転移温度が３７℃を超え（４１℃）、比較例
５・６では外層のガラス転移温度が６０℃を超える（６
５℃）膜の組み合わせによる積層膜であるため、低温
（４℃）での剛性率が３０００ＭＰaを超え（３５８１
から３６５４ＭＰａ）、低温（４℃）での切断性は全て
破損・割れてしまう状態であった。また５０℃の加工性
は良好であるものの、室温（２５℃）での剛性率も２０
００ＭＰaを大きく超える（２７６０から２８４６ＭＰ
ａ）ことから、手術場での加工後に破損・割れが発生
し、骨組織再生誘導能評価も縫合糸による固定により全
て破損してしまうため評価不可能となり、極めて取り扱
いの悪い積層膜であった。In the laminated films of Comparative Examples 4 to 6, in Comparative Example 4, the glass transition temperature of the inner layer exceeded 37 ° C. (41 ° C.), and in Comparative Examples 5.6, the glass transition temperature of the outer layer exceeded 60 ° C. (6
5 ° C.), the rigidity at low temperature (4 ° C.) exceeds 3000 MPa (3581).
To 3654 MPa) at a low temperature (4 ° C.). Although the workability at 50 ° C. is good, the rigidity at room temperature (25 ° C.) is also 20%.
Greatly exceeds 00MPa (2760 to 2846MPa
a) Therefore, damage / cracking occurred after processing in the operating theater, and the evaluation of the ability to induce bone tissue regeneration was completely impossible due to breakage due to fixation with sutures, and the laminated film was extremely poorly handled. .
【００２７】[0027]
【発明の作用効果】本発明は、生体適合性に優れ、且
つ、適正な強度及び分解速度を有する組織再生に有効な
膜材料を使用して、特別な処理や装置を使用することな
く軟質膜と硬質膜のプレス成形の応用により、易操作性
・易成形性及び生体内での形態維持安定性等の機能性を
両立する骨組織再生誘導（ＧＢＲ）法のために使用され
る剛性率範囲５００〜２，０００ＭＰaの骨組織再生誘
導膜を提供することができる。The present invention uses a membrane material which is excellent in biocompatibility and has an appropriate strength and decomposition rate and which is effective for tissue regeneration without using any special treatment or device. Stiffness range used for bone tissue regeneration induction (GBR) method that achieves both easy operability, easy moldability, and functions such as stability of shape maintenance in a living body by applying press forming of hard film and hard film It is possible to provide a bone tissue regeneration-inducing membrane of 500 to 2,000 MPa.
【図１】本発明の骨組織再生誘導膜の一例を示す概略図FIG. 1 is a schematic view showing an example of a bone tissue regeneration-inducing membrane of the present invention.
【図２】本発明の骨組織再生誘導膜を構成する積層体の
一部拡大断面図FIG. 2 is a partially enlarged cross-sectional view of a laminate constituting the bone tissue regeneration-inducing membrane of the present invention.
【図３】本発明の骨組織再生誘導膜の製造方法の一例を
示す概略図FIG. 3 is a schematic view showing an example of the method for producing a bone tissue regeneration-inducing membrane of the present invention.
【図４】本発明の骨組織再生誘導膜の製造方法の一例を
示す概略図FIG. 4 is a schematic view showing an example of the method for producing a bone tissue regeneration-inducing membrane of the present invention.
１ 骨組織再生誘導膜 ２ 積層体 ３ 外層 ４ 内層 ５ 各層の材料 ６ プレス金型 ７ プレス機 ８ 膜 ９ 膜 １０ プレス金型 １１ プレス機 REFERENCE SIGNS LIST 1 bone tissue regeneration-inducing membrane 2 laminate 3 outer layer 4 inner layer 5 material of each layer 6 press mold 7 press machine 8 membrane 9 membrane 10 press mold 11 press machine
───────────────────────────────────────────────────── フロントページの続き (72)発明者 岡田 隆雄 兵庫県加古川市平岡町新在家2081−５ (72)発明者 今村 由賀里 兵庫県姫路市東今宿４−２−22 Ｆターム(参考） 4C081 AB02 AB04 BA16 BB08 CA171 CB011 CC01 CF012 DA02 DC02 DC04 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Takao Okada 2081-5 Hiraoka-cho Shinzai, Kakogawa-shi, Hyogo Prefecture (72) Inventor Yukari Imamura 4-2-22 Higashi-Imajuku, Himeji-shi, Hyogo Prefecture BB08 CA171 CB011 CC01 CF012 DA02 DC02 DC04
Claims (6)
膜において、 外層膜は、室温において、剛性率が５００〜５０００Ｍ
Ｐａ、ガラス転移温度が４０〜６０℃の範囲にある材料
から構成され、 内層膜は、室温において、剛性率が２．０〜５００ＭＰ
ａ、ガラス転移温度が４〜３７℃の範囲にある材料から
構成され、 かつ骨組織再生誘導膜全体は、４〜４０℃において、剛
性率が５００〜２０００ＭＰａの範囲にある、ことを特
徴とする骨組織再生誘導膜。1. A bone tissue regeneration-inducing membrane comprising at least a two-layer membrane, wherein the outer membrane has a rigidity of 500 to 5000 M at room temperature.
The inner layer film has a rigidity of 2.0 to 500MP at room temperature.
a, It is made of a material having a glass transition temperature in the range of 4 to 37 ° C, and the whole bone tissue regeneration-inducing membrane has a rigidity in the range of 500 to 2000 MPa at 4 to 40 ° C. Bone tissue regeneration-inducing membrane.
有した材料より構成され、 内層膜は乳酸／グリコール酸／ε−カプロラクトンの三
元系共重合体とリン酸カルシウム系材料の複合体よりな
り、かつ三元系共重合体を５重量％以上含有した材料よ
り構成されている、ことを特徴とする請求項１に記載の
骨組織再生誘導膜。2. The outer layer is made of a material containing 20% by weight or more of a lactic acid-based polymer, and the inner layer is made of a composite of a tertiary copolymer of lactic acid / glycolic acid / ε-caprolactone and a calcium phosphate-based material. 2. The bone tissue regeneration-inducing membrane according to claim 1, wherein the membrane is made of a material containing 5% by weight or more of a ternary copolymer.
（ａ）生体吸収性のポリ乳酸単体または（ｂ）ポリ乳酸
とリン酸カルシウム系材料との複合体または（ｃ）乳酸
／グリコール酸／ε−カプロラクトンの三元系共重合体
とリン酸カルシウム系材料の複合体または（ｄ）乳酸と
乳酸以外のヒドロキシカルボン酸からなる共重合体であ
る、ことを特徴とする請求項１ないし請求項２に記載の
骨組織再生誘導膜。3. The lactic acid-based polymer constituting the outer layer film,
(A) Bioabsorbable polylactic acid alone or (b) a composite of polylactic acid and a calcium phosphate-based material or (c) a composite of a tertiary copolymer of lactic acid / glycolic acid / ε-caprolactone and a calcium phosphate-based material Or (d) a copolymer of lactic acid and a hydroxycarboxylic acid other than lactic acid, wherein the bone tissue regeneration-inducing membrane according to claim 1 or 2, wherein
ール酸／ε−カプロラクトンの三元系共重合体の数平均
分子量は２００００から２０００００である、ことを特
徴とする請求項１ないし請求項３に記載の骨組織再生誘
導膜。4. The ternary copolymer of lactic acid / glycolic acid / ε-caprolactone constituting the outer layer film and the inner layer film has a number average molecular weight of 20,000 to 200,000. 4. The bone tissue regeneration-inducing membrane according to 3.
の三元系共重合体の組成モル比が５〜９０：３〜７５：
５〜４０モル％の範囲である請求項１ないし請求項４に
記載の骨組織再生誘導膜。5. The terpolymer of lactic acid / glycolic acid / ε-caprolactone has a composition molar ratio of 5 to 90: 3 to 75:
The bone tissue regeneration-inducing membrane according to any one of claims 1 to 4, wherein the amount ranges from 5 to 40 mol%.
融着することにより積層されたものであることを特徴と
する請求項１ないし請求項５に記載の骨組織再生誘導
膜。6. The bone tissue regeneration-inducing membrane according to claim 1, wherein the bone tissue regeneration-inducing membrane is formed by laminating an outer layer film and an inner layer film by heat fusion. .
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| JP2001131355A JP4448260B2 (en) | 2001-04-27 | 2001-04-27 | Bone tissue regeneration inducing membrane |
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| EP1757315A1 (en) * | 2004-04-30 | 2007-02-28 | Sunstar Suisse SA | Biocompatible membrane and process for producing the same |
| JP2012024384A (en) * | 2010-07-26 | 2012-02-09 | Gunze Ltd | Bioabsorbable film for bone regeneration, and membrane for gbr |
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| AT516116A1 (en) * | 2014-08-05 | 2016-02-15 | Dietmar Dr Sonnleitner | Method for producing a multilayer film |
| KR20180058347A (en) * | 2016-11-24 | 2018-06-01 | (주)오스테오닉 | Biodegradable plate for fixing bone, which is capable of forming in normal temporature |
| CN113713184A (en) * | 2021-07-13 | 2021-11-30 | 扬子江药业集团广州海瑞药业有限公司 | Bone tissue regeneration guide membrane and preparation method thereof |
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2001
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| JPWO2005105164A1 (en) * | 2004-04-30 | 2008-03-13 | サンスター スイス エスエー | Biocompatible membrane and method for producing the same |
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| AT516116A1 (en) * | 2014-08-05 | 2016-02-15 | Dietmar Dr Sonnleitner | Method for producing a multilayer film |
| AT516116B1 (en) * | 2014-08-05 | 2016-05-15 | Dietmar Dr Sonnleitner | Method for producing a multilayer film |
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| KR20180058347A (en) * | 2016-11-24 | 2018-06-01 | (주)오스테오닉 | Biodegradable plate for fixing bone, which is capable of forming in normal temporature |
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