JP6090990B2 - Meniscal recycled substrate - Google Patents
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- JP6090990B2 JP6090990B2 JP2013059594A JP2013059594A JP6090990B2 JP 6090990 B2 JP6090990 B2 JP 6090990B2 JP 2013059594 A JP2013059594 A JP 2013059594A JP 2013059594 A JP2013059594 A JP 2013059594A JP 6090990 B2 JP6090990 B2 JP 6090990B2
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- 239000000758 substrate Substances 0.000 title claims description 17
- 239000000515 collagen sponge Substances 0.000 claims description 79
- 230000005499 meniscus Effects 0.000 claims description 71
- 210000000629 knee joint Anatomy 0.000 claims description 52
- 238000011069 regeneration method Methods 0.000 claims description 39
- 230000008929 regeneration Effects 0.000 claims description 38
- 239000000463 material Substances 0.000 claims description 28
- 210000000577 adipose tissue Anatomy 0.000 claims description 22
- 239000011148 porous material Substances 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 9
- 230000007547 defect Effects 0.000 claims description 8
- 210000002468 fat body Anatomy 0.000 claims description 8
- 238000011156 evaluation Methods 0.000 description 42
- 238000012360 testing method Methods 0.000 description 39
- 210000001519 tissue Anatomy 0.000 description 24
- 210000000845 cartilage Anatomy 0.000 description 16
- 102000008186 Collagen Human genes 0.000 description 15
- 108010035532 Collagen Proteins 0.000 description 15
- 229920001436 collagen Polymers 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- 238000004132 cross linking Methods 0.000 description 12
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 11
- 210000002901 mesenchymal stem cell Anatomy 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 230000001575 pathological effect Effects 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 230000007850 degeneration Effects 0.000 description 4
- 210000002303 tibia Anatomy 0.000 description 4
- 210000000689 upper leg Anatomy 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 201000008482 osteoarthritis Diseases 0.000 description 3
- 210000004417 patella Anatomy 0.000 description 3
- OARRHUQTFTUEOS-UHFFFAOYSA-N safranin Chemical compound [Cl-].C=12C=C(N)C(C)=CC2=NC2=CC(C)=C(N)C=C2[N+]=1C1=CC=CC=C1 OARRHUQTFTUEOS-UHFFFAOYSA-N 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- 102000012422 Collagen Type I Human genes 0.000 description 2
- 108010022452 Collagen Type I Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010072970 Meniscus injury Diseases 0.000 description 2
- 241000283977 Oryctolagus Species 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000003431 cross linking reagent Substances 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 210000000281 joint capsule Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000001172 regenerating effect Effects 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 208000003947 Knee Osteoarthritis Diseases 0.000 description 1
- 206010069364 Meniscal degeneration Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000001612 chondrocyte Anatomy 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
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- GYZLOYUZLJXAJU-UHFFFAOYSA-N diglycidyl ether Chemical compound C1OC1COCC1CO1 GYZLOYUZLJXAJU-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
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- 238000003703 image analysis method Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 210000002414 leg Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 210000004353 tibial menisci Anatomy 0.000 description 1
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- Materials For Medical Uses (AREA)
Description
本発明は、半月板の再生治療において、膝関節の半月板の欠損部分に充填することで、半月板の再生を促進することができる半月板再生基材に関する。 The present invention relates to a meniscal regeneration base material capable of promoting the regeneration of the meniscus by filling the defect portion of the meniscus of the knee joint in the regeneration treatment of the meniscus.
半月板は、膝関節内にある軟骨様組織である。以下に図１及び２を用いて膝関節の構造について説明する。図１は、右膝関節の矢状面での断面模式図であり、図２は右膝関節の横断面での断面模式図である。図１に示すように、膝関節は大腿骨４と脛骨５との間に半月板１を有し、大腿骨４と脛骨５とが対向する側にはそれぞれ軟骨３が形成されている。膝の前面には膝蓋骨６があり、その下部には膝蓋下脂肪体（ＩＰＦＰ：Ｉｎｆｒａｐａｔｅｌｌａｒ Ｆａｔ Ｐａｄ）２がある。膝関節は関節包７で包まれており、関節内部は関節液８で満たされている。図２に示すように、半月板１は膝関節の内側と外側で対抗するように一対形成されており、膝関節の前面側と後面側が厚くなっている。 The meniscus is a cartilage-like tissue in the knee joint. The structure of the knee joint will be described below with reference to FIGS. FIG. 1 is a schematic cross-sectional view of the right knee joint taken along the sagittal plane, and FIG. 2 is a schematic cross-sectional view of the right knee joint taken along the transverse plane. As shown in FIG. 1, the knee joint has a meniscus 1 between a femur 4 and a tibia 5, and cartilage 3 is formed on each side where the femur 4 and the tibia 5 face each other. There is a patella 6 on the front surface of the knee, and an infrapatellar fat pad (IPFP) 2 is located below the patella 6. The knee joint is wrapped with a joint capsule 7, and the inside of the joint is filled with joint fluid 8. As shown in FIG. 2, a pair of meniscuses 1 are formed so as to oppose the inside and outside of the knee joint, and the front side and the back side of the knee joint are thick.
半月板の変性や損傷は、変形性膝関節症（ＯＡ：ｏｓｔｅｏａｒｔｈｒｉｔｉｓ）における軟骨変性とともによく見られる病態の一つである。また、半月板を切除することで、軟骨組織が減少し、変形性膝関節症が進行するという報告もある。半月板は、無血管領域を多く含む組織であるため、自己再生能力が乏しく自己修復は困難である。そのため、手術では半月板の治癒を促進する目的で、半月縫合術に加えて、成長因子、滑膜移植、骨髄刺激等の追加処置がなされてきたが、半月板の再生は不充分であった。 Meniscal degeneration or damage is one of the common conditions associated with cartilage degeneration in osteoarthritis (OA). There are also reports that cartilage tissue is reduced and osteoarthritis of the knee progresses by excising the meniscus. Since the meniscus is a tissue containing many avascular regions, the self-regeneration ability is poor and self-repair is difficult. Therefore, in surgery, in order to promote meniscus healing, additional treatments such as growth factor, synovial transplantation, and bone marrow stimulation have been performed in addition to meniscus suture, but meniscus regeneration was insufficient. .
近年、間葉系幹細胞（ＭＳＣ：Ｍｅｓｅｎｃｈｙｍａｌ Ｓｔｅｍ Ｃｅｌｌ）を用いた再生医療が注目され、膝関節に間葉系幹細胞を注入する方法が実験的に用いられている（例えば、非特許文献１参照。）。しかし、治療に充分な間葉系幹細胞を培養するためには長期間培養を要することにより感染を起こす恐れがあり、また、間葉系幹細胞を採取、移植の複数回手術と培養設備を要する。 In recent years, regenerative medicine using mesenchymal stem cells (MSC) has attracted attention, and a method of injecting mesenchymal stem cells into the knee joint has been experimentally used (see, for example, Non-Patent Document 1). ). However, in order to cultivate mesenchymal stem cells that are sufficient for treatment, infection may occur due to the necessity of culturing for a long time, and mesenchymal stem cells are collected and transplanted multiple times and transplanted.
他の方法としては、半月板を全切除した後、膝関節に膝蓋下脂肪体を移植する方法が検討されている。膝蓋下脂肪体は、間葉系幹細胞を多く含む組織であり、関節液の産生を行い、外傷から関節を保護する機能がある。また、末期の変形性関節症において、関節の変形を抑制することが知られていることから、半月板損傷においても膝関節への移植が有用であると考えられる。 As another method, a method of transplanting a subpatellar fat pad to a knee joint after excision of the entire meniscus has been studied. The subpatellar fat pad is a tissue containing a lot of mesenchymal stem cells, and has a function of producing joint fluid and protecting the joint from trauma. Moreover, since it is known that joint deformation is suppressed in end-stage osteoarthritis, it is considered that transplantation to the knee joint is useful even in meniscus injury.
しかし、この方法によると、一時的に軟骨の保護効果は得られるものの、その効果は恒久的ではなく、膝蓋下脂肪体は半月板の代替部材には適さないことが報告されている（非特許文献２参照。）。そこで、恒久的に半月板を再生できる方法が求められていた。 However, according to this method, although the cartilage protective effect is temporarily obtained, the effect is not permanent, and it has been reported that the subpatellar fat pad is not suitable as an alternative member for the meniscus (Non-patent document) Reference 2). Therefore, there has been a demand for a method that can permanently regenerate the meniscus.
本発明は、半月板の再生治療において、膝関節の半月板の欠損部分に充填することで、半月板の再生を促進することができる半月板再生基材を提供することを目的とする。 It is an object of the present invention to provide a meniscal regeneration base material that can promote the regeneration of the meniscus by filling the defect of the meniscus of the knee joint in the regeneration treatment of the meniscus.
本発明は、半月板の再生治療において、膝関節の半月板の欠損部分に充填することで、半月板の再生を促進することができる半月板再生基材であって、架橋コラーゲンスポンジと膝蓋下脂肪体とからなり、前記架橋コラーゲンスポンジは、厚みが１〜３０ｍｍ、平均孔径が１〜１０００μｍである半月板再生基材である。
以下に本発明を詳述する。
The present invention relates to a meniscal regeneration base material that can promote meniscus regeneration by filling a defect portion of the meniscus of a knee joint in regeneration treatment of the meniscus. The cross-linked collagen sponge is a meniscal recycled base material having a thickness of 1 to 30 mm and an average pore diameter of 1 to 1000 μm.
The present invention is described in detail below.
本発明の半月板再生基材は、架橋コラーゲンスポンジと膝蓋下脂肪体とからなる。
架橋コラーゲンスポンジと膝蓋下脂肪体とを併せて用いることで、半月板の再生を促進することができる。これは、膝蓋下脂肪体に多く含まれる間葉系幹細胞が、架橋コラーゲンスポンジを足場として半月板を再生することができるためと考えられる。また、膝蓋下脂肪体は、関節液の産生を行う機能を有するため、半月板の欠損部分に充填することで、外傷から関節を保護しながら半月板の再生を促進することができる。架橋コラーゲンスポンジのみを移植した場合であっても、膝蓋下脂肪体のみを移植した場合であっても、恒久的に充分な半月板を再生することができない。半月板の欠損部分とは、半月板の損傷又は変形により半月板の一部又は全部を切除した場合を含む。
The meniscal regeneration base material of the present invention comprises a crosslinked collagen sponge and a subpatellar fat pad.
By using a cross-linked collagen sponge and a subpatellar fat body in combination, regeneration of the meniscus can be promoted. This is considered to be because mesenchymal stem cells contained in a large amount in the subpatellar fat pad can regenerate the meniscus using the cross-linked collagen sponge as a scaffold. Further, since the subpatellar fat pad has a function of producing joint fluid, filling the deficient portion of the meniscus can promote the regeneration of the meniscus while protecting the joint from trauma. Even when only the cross-linked collagen sponge is transplanted or when only the subpatellar fat pad is transplanted, a sufficient meniscus cannot be regenerated permanently. The deficient portion of the meniscus includes a case where part or all of the meniscus is removed due to damage or deformation of the meniscus.
上記架橋コラーゲンスポンジの材料となるコラーゲンとしては、コラーゲンの末端を酵素処理して抗原性をなくしたものを用いることが好ましい。このようなコラーゲンとしては、従来公知のコラーゲンスポンジの原料が広く使用でき、例えば、酸可溶性コラーゲン、中性塩可溶性コラーゲン、酵素可溶化コラーゲン等の可溶性コラーゲン、天然の又は化学修飾されたコラーゲン繊維、及び、可溶性コラーゲンを不溶化した再生コラーゲン繊維等を用いることができる。特にＩ型コラーゲンを用いることが好ましい。 As the collagen used as the material of the cross-linked collagen sponge, it is preferable to use a collagen having its antigenicity removed by enzymatic treatment at the end of collagen. As such collagen, conventionally known collagen sponge raw materials can be widely used, for example, acid-soluble collagen, neutral salt-soluble collagen, soluble collagen such as enzyme-solubilized collagen, natural or chemically modified collagen fibers, And the regenerated collagen fiber etc. which insolubilized soluble collagen can be used. It is particularly preferable to use type I collagen.
上記架橋コラーゲンスポンジの厚みの下限は１ｍｍ、上限は３０ｍｍである。
架橋コラーゲンスポンジの厚みが１ｍｍより薄くても、３０ｍｍより厚くても、半月板の切除部分又は欠損部分を充分に埋めることができないことがある。架橋コラーゲンスポンジの厚みの好ましい下限は２ｍｍ、好ましい上限は１０ｍｍである。架橋コラーゲンスポンジの厚みは、例えば、ノギスにより架橋コラーゲンスポンジと膝蓋下脂肪体との接合面から、接合面と反対面までの距離を、５箇所で測定しその平均値を算出することにより得られる。
The lower limit of the thickness of the crosslinked collagen sponge is 1 mm, and the upper limit is 30 mm.
Even if the thickness of the crosslinked collagen sponge is less than 1 mm or more than 30 mm, the excision or defect of the meniscus may not be sufficiently filled. The preferable lower limit of the thickness of the crosslinked collagen sponge is 2 mm, and the preferable upper limit is 10 mm. The thickness of the cross-linked collagen sponge is obtained, for example, by measuring the distance from the joint surface between the cross-linked collagen sponge and the sub-patellar fat pad to the opposite surface with a caliper at five locations and calculating the average value. .
上記架橋コラーゲンスポンジの平均孔径の下限は１μｍ、上限は１０００μｍである。
上記架橋コラーゲンスポンジは、スポンジ状であり、微細な多数の小孔を有する。上記架橋コラーゲンスポンジの平均孔径が１μｍ未満であると、線維芽細胞が浸入しにくく治癒が遅れることがあり、１０００μｍを超えると、半月板再生基材の強度が不足したり、かえって治癒に時間がかかったりすることがある。架橋コラーゲンスポンジの好ましい平均孔径の下限は１０μｍ、好ましい上限は３００μｍである。架橋コラーゲンスポンジの平均孔径は、例えば、電子顕微鏡（日立社製、Ｍｉｎｉｓｃｏｐｅ、ＴＭ−１０００）による画像解析法等の従来公知の方法により測定することができる。
The lower limit of the average pore diameter of the crosslinked collagen sponge is 1 μm, and the upper limit is 1000 μm.
The crosslinked collagen sponge is sponge-like and has a large number of fine pores. When the average pore size of the crosslinked collagen sponge is less than 1 μm, fibroblasts are difficult to enter and healing may be delayed. When the average pore size exceeds 1000 μm, the meniscal regeneration base material has insufficient strength, or on the other hand, it takes time to heal. It may take. The preferable lower limit of the average pore diameter of the crosslinked collagen sponge is 10 μm, and the preferable upper limit is 300 μm. The average pore diameter of the crosslinked collagen sponge can be measured by a conventionally known method such as an image analysis method using an electron microscope (manufactured by Hitachi, Ltd., Miniscope, TM-1000).
上記架橋コラーゲンスポンジは、コラーゲンスポンジを架橋することで得られる。
生体内でのコラーゲンスポンジの分解速度は、架橋度を変えることでコントロールすることができ、架橋度が高いほど、生体内でのコラーゲンスポンジの分解速度は遅くなる。架橋コラーゲンスポンジの製造方法の一例を挙げると、まずｐＨ３程度のコラーゲンの希釈溶液を調製し、ホモジナイザーによりホモジナイズして発泡液を得る。得られた発泡液を凍結乾燥し１次コラーゲンスポンジとし、架橋剤により１次コラーゲンスポンジを架橋することで架橋コラーゲンスポンジを得ることができる。
The crosslinked collagen sponge is obtained by crosslinking a collagen sponge.
The degradation rate of the collagen sponge in vivo can be controlled by changing the degree of crosslinking. The higher the degree of crosslinking, the slower the degradation rate of the collagen sponge in vivo. An example of a method for producing a crosslinked collagen sponge is as follows: First, a diluted solution of collagen having a pH of about 3 is prepared, and homogenized by a homogenizer to obtain a foamed liquid. The obtained foamed liquid is freeze-dried to obtain a primary collagen sponge, and the crosslinked collagen sponge can be obtained by crosslinking the primary collagen sponge with a crosslinking agent.
架橋剤としては、特に限定されないが、Ｎ−（３−ｄｉｍｅｔｈｙｌａｍｉｎｏｐｒｏｐｙｌ）−Ｎ´−ｅｔｈｙｌｃａｒｂｏｄｉｉｍｉｄｅ（ＥＤＣ）、１，４−ｄｉｂｕｔａｎｄｉｏｌ ｄｉｇｌｙｃｉｄｙｌ ｅｔｈｅｒ（ＢＤＤＧＥ）、グルタルアルデヒド（ＧＡ：ｇｌｕｔａｒａｌｄｅｈｙｄｅ）が挙げられる。上記架橋コラーゲンスポンジは、グルタルアルデヒドを用いて架橋されることが好ましく、グルタルアルデヒド濃度の好ましい下限は０．０１重量％であり、好ましい上限は１重量％である。０．０１重量％以上のグルタルアルデヒドを用いて架橋することで、半月板が生成するまでの間、半月板再生基材を半月板の切除部分又は損傷部分に残存させることができるため、より半月板の再生を促進することができる。グルタルアルデヒド濃度のより好ましい下限は０．１重量％であり、より好ましい上限は０．２重量％である。グルタルアルデヒド濃度を０．１重量％以上、０．２重量％以下とすることで、半月板再生基材を充填した部分の周辺組織への影響が少なく、軟骨組織の変性を防ぐことができる。 Although it does not specifically limit as a crosslinking agent, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (EDC), 1,4-dibutandiol diglycidyl ether (BDDDGE) and glutaraldehyde (GA: glutaaldehyde) are mentioned. The cross-linked collagen sponge is preferably cross-linked using glutaraldehyde. The preferable lower limit of the glutaraldehyde concentration is 0.01% by weight, and the preferable upper limit is 1% by weight. By cross-linking with 0.01% by weight or more of glutaraldehyde, the meniscal regenerated substrate can be left in the excised or damaged part of the meniscus until the meniscus is formed. The regeneration of the board can be promoted. A more preferable lower limit of the glutaraldehyde concentration is 0.1% by weight, and a more preferable upper limit is 0.2% by weight. By setting the glutaraldehyde concentration to 0.1 wt% or more and 0.2 wt% or less, the influence of the portion filled with the meniscal regeneration base material on the surrounding tissue is small, and degeneration of the cartilage tissue can be prevented.
上記膝蓋下脂肪体は、手術の際に膝関節から採取することができる。
より低侵襲で拒絶反応を起こし難い半月板再生基材を得ることができるため、患者本人の膝蓋下脂肪体を用いることがより好ましい。また、間葉系幹細胞を多く含むため、関節面側の膝蓋下脂肪体を用いることがより好ましい。
The subpatellar fat pad can be collected from the knee joint during surgery.
It is more preferable to use the patient's own subpatellar fat pad because a meniscal regeneration base material that is less invasive and hardly causes a rejection reaction can be obtained. Further, since it contains a lot of mesenchymal stem cells, it is more preferable to use a subpatellar fat pad on the joint surface side.
上記半月板再生基材は、上記架橋コラーゲンスポンジと上記膝蓋下脂肪体とが積層されている構造であってもよいし、上記架橋コラーゲンスポンジが上記膝蓋下脂肪体に包埋されている構造であってもよい。このような構成とすることで、半月板の再生を促進することができる。 The meniscal regeneration base material may have a structure in which the cross-linked collagen sponge and the sub-patellar fat pad are laminated, or the cross-linked collagen sponge is embedded in the sub-patellar fat pad. There may be. With such a configuration, the reproduction of the meniscus can be promoted.
上記半月板再生基材は、上記架橋コラーゲンスポンジに対する上記膝蓋下脂肪体の割合は、下限が１重量％、上限が９９重量％であることが好ましい。
架橋コラーゲンスポンジに対する膝蓋下脂肪体の割合が１重量％未満であると、半月板を充分に再生できないことがあり、９９重量％より高いと、半月板再生基材としての強度が弱くなることがある。上記架橋コラーゲンスポンジに対する上記膝蓋下脂肪体の割合のより好ましい下限は１０重量％、より好ましい上限は９８重量％である。
The meniscus regenerated base material preferably has a lower limit of 1% by weight and an upper limit of 99% by weight of the subpatellar fat body relative to the crosslinked collagen sponge.
If the ratio of the sub-patellar fat body to the cross-linked collagen sponge is less than 1% by weight, the meniscus may not be sufficiently regenerated, and if it is higher than 99% by weight, the strength as a meniscal regeneration substrate may be weakened. is there. The more preferable lower limit of the ratio of the subpatellar fat body to the crosslinked collagen sponge is 10% by weight, and the more preferable upper limit is 98% by weight.
上記半月板再生基材を用いて半月板を再生する方法としては特に限定されないが、損傷又は変形した半月板の一部又は全部を切除し、切除した部分に上記半月板再生基材を充填したり、損傷した半月板の欠損部分に上記半月板再生基材を充填したりする術式が挙げられる。 The method for regenerating the meniscus using the meniscus regenerated substrate is not particularly limited, but a part or all of the damaged or deformed meniscus is excised, and the excised portion is filled with the meniscus regenerated substrate. Or a method of filling the above-mentioned meniscus-regenerated base material into a damaged portion of the meniscus.
本発明によれば、半月板の再生治療において、膝関節の半月板の欠損部分に充填することで、半月板の再生を促進することができる半月板再生基材を提供することができる。 ADVANTAGE OF THE INVENTION According to this invention, the meniscus reproduction | regeneration base material which can accelerate | stimulate the reproduction | regeneration of a meniscus can be provided by filling the defect | deletion part of the meniscus of a knee joint in the meniscus regeneration treatment.
以下に実施例を挙げて本発明の態様を更に詳しく説明するが、本発明はこれら実施例にのみ限定されるものではない。 Hereinafter, embodiments of the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.
（実施例１）
Ｉ型コラーゲン溶液（新田ゼラチン社製、Ｌｏｔ：１２０３１２）を原料とし、精製水及び５Ｎ−酢酸を用いて濃度０．３％、ｐＨ３．０のコラーゲン希釈溶液を調製した。得られたコラーゲン希釈溶液１３２ｇを凍結乾燥用のステンレス製枠（１２ｃｍ×１６ｃｍ）内に流し込んだ。ステンレス製枠を−４０℃に冷却してコラーゲン溶液を凍結し、真空減圧下（０．０１ｍｍＨｇ）４０℃で２４時間凍結乾燥を行った。更に真空減圧下（０．０１ｍｍＨｇ）１１０℃で２４時間加熱乾燥を行い、１次コラーゲンスポンジを得た。
Example 1
Using a type I collagen solution (manufactured by Nitta Gelatin Co., Ltd., Lot: 121212) as a raw material, a diluted collagen solution having a concentration of 0.3% and a pH of 3.0 was prepared using purified water and 5N-acetic acid. 132 g of the obtained diluted collagen solution was poured into a stainless steel frame (12 cm × 16 cm) for freeze-drying. The stainless steel frame was cooled to −40 ° C. to freeze the collagen solution, and freeze-dried at 40 ° C. for 24 hours under vacuum and reduced pressure (0.01 mmHg). Furthermore, it heat-dried at 110 degreeC under vacuum pressure reduction (0.01mmHg) for 24 hours, and obtained the primary collagen sponge.
得られた１次コラーゲンスポンジを０．１重量％のグルタルアルデヒド／酢酸溶液中に浸漬し、５℃で２４時間架橋反応を行った。得られた架橋コラーゲンスポンジをイオン交換水で充分洗浄した後、１５％エタノール水溶液で置換した。−１３５℃で凍結し、真空減圧下（０．０１ｍｍＨｇ）４０℃で２４時間凍結乾燥して２次コラーゲンスポンジ（以下、ＧＡ０．１％架橋コラーゲンスポンジともいう。）を作製した。２次コラーゲンスポンジを１ｃｍ×１ｃｍ、厚さ３ｍｍに切断し、それを半分に折り、重ねあわせ、ウサギから採取した膝蓋下脂肪体を２次コラーゲンスポンジの表面に積層し、実施例１の半月板再生基材を得た。コラーゲンスポンジに対する膝蓋下脂肪体の割合は、９８重量％であった。 The obtained primary collagen sponge was immersed in a 0.1% by weight glutaraldehyde / acetic acid solution and subjected to a crosslinking reaction at 5 ° C. for 24 hours. The obtained cross-linked collagen sponge was thoroughly washed with ion exchange water, and then replaced with a 15% aqueous ethanol solution. The mixture was frozen at −135 ° C. and lyophilized at 40 ° C. for 24 hours under vacuum and reduced pressure (0.01 mmHg) to prepare a secondary collagen sponge (hereinafter also referred to as GA 0.1% cross-linked collagen sponge). Cut the secondary collagen sponge into 1 cm × 1 cm and 3 mm thickness, fold it in half, overlap it, and layer the subpatellar fat body collected from the rabbit on the surface of the secondary collagen sponge. A recycled substrate was obtained. The ratio of subpatellar fat pad to collagen sponge was 98% by weight.
実施例１の半月板再生基材が有する架橋コラーゲンスポンジについて、厚さ及び平均孔径を測定した。厚さは、ノギスで測定した。平均孔径は、電子顕微鏡で測定した。実施例１の半月板再生基材が有する架橋コラーゲンスポンジの厚さは６ｍｍ、平均孔径は１００μｍであった。 About the crosslinked collagen sponge which the meniscus reproduction | regeneration base material of Example 1 has, thickness and average pore diameter were measured. The thickness was measured with calipers. The average pore diameter was measured with an electron microscope. The thickness of the cross-linked collagen sponge of the meniscal recycled substrate of Example 1 was 6 mm, and the average pore diameter was 100 μm.
（実施例２）
実施例１と同様にして得た１次コラーゲンスポンジを０．２重量％のグルタルアルデヒド／酢酸溶液中に浸漬し、５℃で２４時間架橋反応を行った。その後、実施例１と同様に２次コラーゲンスポンジ（以下、ＧＡ０．２％架橋コラーゲンスポンジともいう。）を作製し、膝蓋下脂肪体と積層し、実施例２の半月板再生基材を得た。実施例１と同様に実施例２の半月板再生基材が有する架橋コラーゲンスポンジの厚さ及び平均孔径を測定した。実施例２の半月板再生基材が有する架橋コラーゲンスポンジの厚さは６ｍｍ、平均孔径は１００μｍであった。
(Example 2)
The primary collagen sponge obtained in the same manner as in Example 1 was immersed in a 0.2% by weight glutaraldehyde / acetic acid solution and subjected to a crosslinking reaction at 5 ° C. for 24 hours. Thereafter, a secondary collagen sponge (hereinafter also referred to as GA 0.2% cross-linked collagen sponge) was produced in the same manner as in Example 1 and laminated with a sub-patellar fat pad to obtain a meniscal recycled base material of Example 2. . In the same manner as in Example 1, the thickness and average pore diameter of the crosslinked collagen sponge possessed by the meniscal recycled substrate of Example 2 were measured. The thickness of the crosslinked collagen sponge of the meniscal recycled substrate of Example 2 was 6 mm, and the average pore diameter was 100 μm.
（実施例３）
実施例１と同様にして得た１次コラーゲンスポンジを０．４重量％のグルタルアルデヒド／酢酸溶液中に浸漬し、５℃で２４時間架橋反応を行った。その後、実施例１と同様に２次コラーゲンスポンジ（以下、ＧＡ０．４％架橋コラーゲンスポンジともいう。）を作製し、膝蓋下脂肪体と積層し、実施例３の半月板再生基材を得た。実施例１と同様に実施例３の半月板再生基材が有する架橋コラーゲンスポンジの厚さ及び平均孔径を測定した。実施例３の半月板再生基材が有する架橋コラーゲンスポンジの厚さは６ｍｍ、平均孔径は１００μｍであった。
(Example 3)
The primary collagen sponge obtained in the same manner as in Example 1 was immersed in a 0.4% by weight glutaraldehyde / acetic acid solution and subjected to a crosslinking reaction at 5 ° C. for 24 hours. Thereafter, a secondary collagen sponge (hereinafter also referred to as GA 0.4% cross-linked collagen sponge) was produced in the same manner as in Example 1 and laminated with a sub-patellar fat pad to obtain a meniscus regenerated base material of Example 3. . In the same manner as in Example 1, the thickness and average pore diameter of the crosslinked collagen sponge possessed by the meniscal recycled substrate of Example 3 were measured. The thickness of the cross-linked collagen sponge of the meniscal recycled substrate of Example 3 was 6 mm, and the average pore diameter was 100 μm.
（比較例１）
実施例１と同様にして得た１次コラーゲンスポンジを架橋せずに、−１３５℃で凍結し、真空減圧下（０．０１ｍｍＨｇ）４０℃で２４時間凍結乾燥して２次コラーゲンスポンジ（以下、未架橋コラーゲンスポンジともいう。）を作製した。２次コラーゲンスポンジを１ｃｍ×１ｃｍ、厚さ３ｍｍに切断し、それを半分に折り、重ねあわせ、ウサギから採取した膝蓋下脂肪体を２次コラーゲンスポンジの表面に積層し、比較例１の半月板再生基材を得た。未架橋コラーゲンスポンジに対する膝蓋下脂肪体の割合は、９８重量％であった。また、比較例１の半月板再生基材が有する架橋コラーゲンスポンジの厚さは６ｍｍ、平均孔径は１００μｍであった。
(Comparative Example 1)
The primary collagen sponge obtained in the same manner as in Example 1 was frozen at −135 ° C. without cross-linking, and freeze-dried at 40 ° C. for 24 hours under vacuum under reduced pressure (0.01 mmHg) to obtain a secondary collagen sponge (hereinafter, (Also referred to as uncrosslinked collagen sponge). Cut the secondary collagen sponge into 1 cm x 1 cm and 3 mm thickness, fold it in half, overlap and laminate the subpatellar fat body collected from the rabbit on the surface of the secondary collagen sponge, the meniscus of Comparative Example 1 A recycled substrate was obtained. The ratio of the subpatellar fat pad to the uncrosslinked collagen sponge was 98% by weight. Moreover, the thickness of the crosslinked collagen sponge which the meniscus reproduction | regeneration base material of the comparative example 1 has was 6 mm, and the average hole diameter was 100 micrometers.
（評価試験１）
評価試験１では、上記で得られた半月板再生基材を用いて動物実験を行い、半月板の再生程度について検討を行った。
(Evaluation Test 1)
In the evaluation test 1, an animal experiment was performed using the meniscus regeneration substrate obtained above, and the degree of regeneration of the meniscus was examined.
まず、実験動物として日本白ウサギ（体重：３．０〜３．５ｋｇ）を準備し、右膝関節の内側半月板の前節〜中節（図２の点線で囲んだ部分）を切除した。その後、下記表１に示すＡ〜Ｃの検体を作製した。検体Ａ〜Ｃは、半月板除去部にそれぞれ、膝蓋下脂肪体（ＩＰＦＰ）、０．２重量％のグルタルアルデヒド／酢酸溶液中に浸漬し架橋したコラーゲンスポンジ、上記実施例２の半月板再生基材を移植して縫合した。 First, a Japanese white rabbit (weight: 3.0 to 3.5 kg) was prepared as an experimental animal, and the anterior segment to middle segment (portion surrounded by a dotted line in FIG. 2) of the medial meniscus of the right knee joint were excised. Thereafter, specimens A to C shown in Table 1 below were prepared. Specimens A to C were each a meniscus removal part, a sub-patellar fat pad (IPFP), a collagen sponge that was immersed in a 0.2 wt% glutaraldehyde / acetic acid solution and crosslinked, and the meniscal regeneration group of Example 2 above. The material was implanted and sutured.
各検体を術後８週目に犠牲死させ、右膝関節を観察した。図３〜５は、それぞれ評価試験１における検体Ａ〜Ｃの右膝関節の矢状面写真である。図３に示すように、検体Ａでは、脂肪様組織の再生は確認されたが、半月板除去部を完全に埋めることができなかった。図４に示すように、検体Ｂでは、除去部分を埋める程度に組織が再生しているものの、不充分であった。図５に示すように、検体Ｃでは、除去部分を完全に埋める程度に半月板様組織が再生していた。 Each specimen was sacrificed 8 weeks after the operation, and the right knee joint was observed. 3 to 5 are photographs of sagittal planes of the right knee joint of Samples A to C in Evaluation Test 1, respectively. As shown in FIG. 3, in the specimen A, regeneration of the adipose-like tissue was confirmed, but the meniscus removal part could not be completely filled. As shown in FIG. 4, in the specimen B, the tissue was regenerated enough to fill the removed portion, but it was insufficient. As shown in FIG. 5, in the specimen C, the meniscus-like tissue was regenerated so that the removed portion was completely filled.
評価試験１の結果から、半月板除去部に、架橋コラーゲンスポンジとＩＰＦＰとを積層した半月板再生基材を移植することで、半月板様組織が充分に生成することが分かった。 From the result of the evaluation test 1, it was found that a meniscus-like tissue was sufficiently formed by transplanting a meniscus regeneration base material in which a cross-linked collagen sponge and IPFP were laminated to the meniscus removal portion.
（評価試験２）
評価試験２では、コラーゲンスポンジの架橋度を変えて、再生した半月板様組織の病理学的特性を評価した。
(Evaluation test 2)
In evaluation test 2, the pathological characteristics of the regenerated meniscus-like tissue were evaluated by changing the degree of crosslinking of the collagen sponge.
評価試験２では、評価試験１と同様に、実験動物として日本白ウサギ（体重：３．０〜３．５ｋｇ）を準備し、右脚の内側半月板の前節〜中節を切除した。下記表２に示すように、検体Ｄ、Ｆ，Ｈ、Ｊでは、半月板を除去した部分に、それぞれ、未架橋コラーゲンスポンジ、架橋度が異なるコラーゲンスポンジを移植した。検体Ｅ、Ｇ、Ｉ、Ｋでは、半月板を除去した部分に、それぞれ、未架橋コラーゲンスポンジとＩＰＦＰとを積層した基材、架橋度が異なるコラーゲンスポンジとＩＰＦＰとを積層した基材を移植した。検体Ｅ、Ｇ、Ｉ及びＫに用いた基材は、それぞれ上記比較例１、実施例１、２及び３の半月板再生基材である。 In Evaluation Test 2, as in Evaluation Test 1, Japanese white rabbits (body weight: 3.0 to 3.5 kg) were prepared as experimental animals, and the anterior segment to middle segment of the inner meniscus of the right leg were excised. As shown in Table 2 below, in specimens D, F, H, and J, uncrosslinked collagen sponges and collagen sponges having different degrees of crosslinking were transplanted into the portions from which the meniscus was removed. In specimens E, G, I, and K, the base material on which the meniscus was removed was transplanted with a base material on which uncrosslinked collagen sponge and IPFP were laminated, and a base material on which collagen sponge and IPFP with different degrees of crosslinking were laminated. . The base materials used for the specimens E, G, I, and K are the meniscal recycled base materials of Comparative Example 1, Examples 1, 2, and 3, respectively.
各検体を術後８週目に犠牲死させ、肉眼所見及び病理所見を得た。半月板様組織の肉眼所見、病理所見ともに、半月板の切除を行っていないモデルを「正常」として評価を行った。図６は、正常モデルの右膝関節の写真であり、図６（ａ）は横断面写真、図６（ｂ）は矢状面写真である。図７〜１４は、それぞれ検体Ｄ〜Ｋの右膝関節の写真であり、各図の（ａ）は横断面写真、（ｂ）は前面側の矢状面拡大写真である。図６〜１４の（ｂ）は、右膝関節の述部の切片を作製した後、サフラニンＯにより染色した。 Each specimen was sacrificed 8 weeks after surgery, and gross and pathological findings were obtained. A model in which the meniscus was not removed was evaluated as “normal” for both macroscopic and pathological findings of the meniscus-like tissue. FIG. 6 is a photograph of the right knee joint of a normal model, FIG. 6 (a) is a cross-sectional photograph, and FIG. 6 (b) is a sagittal plane photograph. 7 to 14 are photographs of the right knee joints of specimens D to K, respectively, (a) of which is a cross-sectional photograph, and (b) is an enlarged photograph of the sagittal plane on the front side. 6B to 14B, sections of the predicate of the right knee joint were prepared and then stained with safranin O. FIG.
半月板様組織の肉眼所見としては、図７〜１４の（ａ）により、横断面での再生半月板様組織の幅、色調、表面の状態、及び、周囲半月板との結合を観察し、下記表３に示した項目及び評価基準（Ｍｏｄｉｆｉｅｄ Ｍａｎｋｉｎ ｓｃｏｒｅ）に基づいて点数をつけた。半月板様組織の病理所見としては、図７〜１４の（ｂ）により、欠損部の再生半月板様組織の形状及び染色性、構造を観察し、下記表４に示した項目及び評価基準（Ｍｏｄｉｆｉｅｄ Ｍａｎｋｉｎ ｓｃｏｒｅ）に基づいて点数をつけた。表３及び４では、点数が低い方が良好な結果であることを示す。 As macroscopic findings of the meniscus-like tissue, according to (a) of FIGS. 7 to 14, the width, color tone, surface state of the regenerated meniscus-like tissue in the cross section, and the connection with the surrounding meniscus, A score was assigned based on the items shown in Table 3 below and the evaluation criteria (Modified Mankin score). As the pathological findings of the meniscus-like tissue, the shape and staining properties and structure of the regenerated meniscus-like tissue of the defect were observed according to FIGS. 7 to 14, and the items and evaluation criteria shown in Table 4 below ( The score was given based on Modified Mankin score. Tables 3 and 4 show that a lower score is a better result.
図１５は、表３及び４から得られた検体Ｄ〜Ｋのスコアグラフである。図１５に示すように、未架橋コラーゲンスポンジを用いた検体Ｄ、Ｆよりも、架橋コラーゲンスポンジを用いた検体Ｆ〜Ｋの方がスコアが低く、再生した半月板様組織の病理学的特性が優れていることが分かった。 FIG. 15 is a score graph of specimens D to K obtained from Tables 3 and 4. As shown in FIG. 15, the specimens F to K using the crosslinked collagen sponge have lower scores than the specimens D and F using the uncrosslinked collagen sponge, and the pathological characteristics of the regenerated meniscus-like tissue are I found it excellent.
評価試験１及び２の結果から、架橋コラーゲンスポンジとＩＰＦＰとを積層した半月板再生基材を移植することで、半月板様組織が充分に再成し、かつ、再生した半月板様組織は正常な半月板に近い組織であることが分かった。 From the results of evaluation tests 1 and 2, the meniscus-like tissue was sufficiently regenerated by transplanting the meniscus-regenerated base material laminated with the cross-linked collagen sponge and IPFP, and the regenerated meniscus-like tissue was normal. It turned out to be close to the meniscus.
（評価試験３）
評価試験３では、評価試験２で用いた検体Ｄ〜Ｋについて、軟骨組織及び周辺組織への影響を評価した。
(Evaluation Test 3)
In the evaluation test 3, the influence on the cartilage tissue and the surrounding tissue was evaluated for the samples D to K used in the evaluation test 2.
評価試験２と同様に、各検体を術後８週目に犠牲死させ、病理所見を得た。図１６は、正常モデルの右膝関節の矢状面写真であり、図１７は、半月板の切除のみを行ったモデルの右膝関節の矢状面写真であり、図１８〜２５は、それぞれ検体Ｄ〜Ｋの右膝関節の矢状面写真である。図１６〜２５は、右膝関節の述部の切片を作製した後、サフラニンＯにより染色した。サフラニンＯは、軟骨組織を赤く染色するため、軟骨組織の状態を観察することができる。 As in Evaluation Test 2, each specimen was sacrificed 8 weeks after the operation, and pathological findings were obtained. FIG. 16 is a sagittal photograph of the right knee joint of a normal model, FIG. 17 is a sagittal photograph of the right knee joint of a model in which only the meniscus has been removed, and FIGS. It is a sagittal plane photograph of the right knee joint of specimens D to K. 16 to 25, sections of the predicate of the right knee joint were prepared and then stained with safranin O. Since safranin O stains cartilage tissue in red, the state of cartilage tissue can be observed.
評価試験３では、図１８〜２５により、軟骨組織の染色性及び厚さ、軟骨細胞の形状、周囲組織の形状及び染色性を観察し、下記表５に示した項目及び評価基準（Ｍｏｄｉｆｉｅｄ Ｍａｎｋｉｎ ｓｃｏｒｅ）に基づいて点数をつけた。表５では、点数が低い方が良好な結果であることを示す。図１７〜２５では、図１６の四角で囲んだ部分に相当する大腿骨及び脛骨の前面側の軟骨組織について評価を行った。 In the evaluation test 3, the staining property and thickness of the cartilage tissue, the shape of the chondrocytes, the shape and staining property of the surrounding tissue were observed according to FIGS. 18 to 25, and the items and evaluation criteria (Modified Mankin score shown in Table 5 below) were observed. ) Based on the score. Table 5 shows that the lower the score, the better the result. 17 to 25, the cartilage tissue on the front side of the femur and tibia corresponding to the portion surrounded by the square in FIG. 16 was evaluated.
図２６は、表５から得られた検体Ｄ〜Ｋのスコアグラフである。図２６に示すように、ＧＡ０．１％及びＧＡ０．２％架橋コラーゲンスポンジとＩＰＦＰとを併せて用いた検体Ｇ、Ｉでは、軟骨及び周辺組織への影響を抑えることができることが分かった。特に、検体Ｇでは、軟骨組織及び周辺組織への影響が小さいことが分かった。
一方で、未架橋コラーゲンスポンジとＩＰＦＰとを併せて用いた検体Ｅは、未架橋コラーゲンスポンジのみを用いた検体Ｄよりもスコアが顕著に高く、ＧＡ０．４％架橋コラーゲンスポンジとＩＰＦＰとを併せて用いた検体Ｋは、ＧＡ０．４％架橋コラーゲンスポンジのみを用いた検体Ｊよりもスコアが顕著に高いことから、軟骨組織及び周辺組織への影響が大きいことが分かった。
FIG. 26 is a score graph of specimens D to K obtained from Table 5. As shown in FIG. 26, it was found that the effects on cartilage and surrounding tissues can be suppressed in specimens G and I using both GA 0.1% and GA 0.2% cross-linked collagen sponge and IPFP. In particular, sample G was found to have a small effect on the cartilage tissue and surrounding tissues.
On the other hand, Specimen E using both uncrosslinked collagen sponge and IPFP has a significantly higher score than Specimen D using only uncrosslinked collagen sponge, and GA 0.4% crosslinked collagen sponge and IPFP are combined. Since the used specimen K has a significantly higher score than the specimen J using only GA 0.4% cross-linked collagen sponge, it was found that the influence on the cartilage tissue and surrounding tissues was great.
評価試験１〜３の結果から、濃度が０．１重量％以上、０．２重量％以下のグルタルアルデヒドを用いて架橋された架橋コラーゲンスポンジとＩＰＦＰとを積層した半月板再生基材を移植することで、正常な半月板に近い半月板様組織を充分に再生することができ、かつ、軟骨組織の変性及び周辺組織への影響を防ぐことができることが分かった。 From the results of the evaluation tests 1 to 3, a meniscus regeneration base material in which a cross-linked collagen sponge cross-linked with glutaraldehyde having a concentration of 0.1 wt% or more and 0.2 wt% or less and IPFP are laminated is transplanted. Thus, it was found that a meniscus-like tissue close to a normal meniscus can be sufficiently regenerated, and cartilage tissue degeneration and influence on surrounding tissues can be prevented.
本発明によれば、半月板損傷の再生治療において、膝関節の半月板の欠損部分に充填することで、半月板の再生を促進し、かつ、軟骨組織の変性を防ぐことができる半月板再生基材を提供することができる。 According to the present invention, meniscus regeneration that promotes meniscus regeneration and prevents cartilage tissue degeneration by filling a defect in the meniscus of the knee joint in regeneration treatment of meniscus injury. A substrate can be provided.
１：半月板
２：膝蓋下脂肪体
３：軟骨
４：大腿骨
５：脛骨
６：膝蓋骨
７：関節包
８：関節液
1: meniscus 2: subpatellar fat pad 3: cartilage 4: femur 5: tibia 6: patella 7: joint capsule 8: synovial fluid
Claims (4)
架橋コラーゲンスポンジと膝蓋下脂肪体とからなり、
前記架橋コラーゲンスポンジは、厚みが１〜３０ｍｍ、平均孔径が１〜１０００μｍである
ことを特徴とする半月板再生基材。 In the meniscus regeneration treatment, by filling the defect portion of the meniscus of the knee joint, a meniscal regeneration base material that can promote the regeneration of the meniscus,
It consists of a cross-linked collagen sponge and a subpatellar fat body,
The meniscus recycled substrate, wherein the crosslinked collagen sponge has a thickness of 1 to 30 mm and an average pore diameter of 1 to 1000 μm.
The meniscal regeneration substrate according to any one of claims 1 to 3, wherein the ratio of the subpatellar fat body to the crosslinked collagen sponge is 1 to 99% by weight.
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