WO2018221140A1 - 半月板再生基材 - Google Patents
半月板再生基材 Download PDFInfo
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- WO2018221140A1 WO2018221140A1 PCT/JP2018/017911 JP2018017911W WO2018221140A1 WO 2018221140 A1 WO2018221140 A1 WO 2018221140A1 JP 2018017911 W JP2018017911 W JP 2018017911W WO 2018221140 A1 WO2018221140 A1 WO 2018221140A1
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- Prior art keywords
- meniscus
- nonwoven fabric
- polyglycolide
- fabric layer
- meniscal
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/30—Joints
- A61F2/38—Joints for elbows or knees
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/56—Porous materials, e.g. foams or sponges
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/06—Materials or treatment for tissue regeneration for cartilage reconstruction, e.g. meniscus
Definitions
- 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.
- FIG. 1 is a schematic cross-sectional view of the right knee joint taken along the sagittal plane
- FIG. 2 is a schematic cross-sectional view of the right knee joint taken along the transverse plane.
- 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.
- IPFP Infrapatella Fat Pad
- the knee joint is wrapped with a joint capsule 7, and the inside of the joint is filled with joint fluid 8.
- 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.
- Meniscal degeneration or damage is one of the common conditions associated with cartilage degeneration in osteoarthritis (OA).
- OA osteoarthritis
- 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. .
- a regenerative medical base material for example, it has been proposed to use a nonwoven fabric made of a bioabsorbable material as disclosed in Patent Document 1.
- a nonwoven fabric made of a bioabsorbable material is used as a base material for regenerative medicine or a suture reinforcing material, cells invade into the voids and proliferate, and the tissue is regenerated at an early stage.
- tissue regeneration base material for example, it has been proposed to use such a tissue regeneration base material.
- the present invention relates to a meniscal regeneration base material that can promote meniscus regeneration by filling a defect portion of the meniscus of the knee joint in regeneration treatment of the meniscus, and has a degradation rate higher than that of polyglycolide.
- a non-woven fabric having a structure in which a sponge layer made of a bioabsorbable material having a low rate, a non-woven fabric layer made of polyglycolide, and a sponge layer made of a bioabsorbable material having a slower decomposition rate than polyglycolide are combined in this order.
- a meniscal recycled base material in which the 50% compressive stress of the layer is 0.5 MPa or more and the thickness of the nonwoven fabric layer is 2 mm or more. The present invention is described in detail below.
- the present inventors examined the reason why regeneration is not sufficiently promoted when the meniscus is regenerated using a conventional tissue regeneration substrate.
- a conventional tissue regeneration substrate is used, an animal experiment using a small animal such as a rabbit can give good results, but it is sufficient when applied to a large animal such as a pig or cow. Found the fact that the meniscus has not been regenerated.
- the present inventors have found that the lack of physical strength in the conventional tissue regeneration substrate is the reason why sufficient results cannot be obtained in large animals.
- the knee joint has a total weight when standing or walking. Especially in large animals including humans, the impact is extremely large. No matter how calm after transplantation, the transplanted meniscal regeneration substrate continues to be heavily stressed during long-term healing.
- the nonwoven fabric constituting the conventional tissue regeneration base material preferably has an average pore diameter of about 5 to 30 ⁇ m in order to ensure cell invasion.
- the nonwoven fabric constituting the conventional tissue regeneration base material preferably has an average pore diameter of about 5 to 30 ⁇ m in order to ensure cell invasion.
- tissue regeneration substrate is superior in terms of cell invasiveness, it does not have sufficient mechanical strength and is damaged before the meniscus is regenerated or the surface is worn. In other words, it was thought that the thickness of the meniscus was reduced, and it was impossible to serve as a scaffold for regenerating a meniscus of sufficient thickness.
- non-woven fabric layer made of polyglycolide having a 50% compressive stress of 0.5 MPa.
- a sponge layer made of a bioabsorbable material whose degradation rate is slower than that of the laminate having a certain thickness or more, a large stress is applied after transplantation.
- the inventors have found that a sufficient meniscus can be regenerated while maintaining a sufficient thickness without causing damage or surface wear, and the present invention has been completed.
- the meniscal recycled base material of the present invention has a structure in which the sponge layer, the nonwoven fabric layer, and the sponge layer are combined and integrated in this order.
- the non-woven fabric layer serves as a scaffold for cell proliferation that invades from surrounding tissues after transplantation, has a role of promoting meniscus regeneration, and has a role of exhibiting sufficient mechanical strength when stress is applied after transplantation.
- the nonwoven fabric layer has a 50% compression stress of 0.5 MPa or more.
- the 50% compressive stress of the nonwoven fabric layer is preferably 0.8 MPa or more, and more preferably 1.0 MPa or more.
- the upper limit of the 50% compressive stress of the nonwoven fabric layer is not particularly limited, the preferable upper limit is 8.0 MPa because regeneration of the meniscal structure can be further promoted.
- the 50% compressive stress can be measured by a method based on JIS-K6767.
- the nonwoven fabric layer preferably has a density of 300 mg / cm 3 or more.
- the density of the nonwoven fabric layer is more preferably 350 mg / cm 3 or more, and still more preferably 400 mg / cm 3 or more.
- the upper limit of the density of the said nonwoven fabric layer is not specifically limited, Since regeneration of a meniscus structure
- the average fiber diameter of the nonwoven fabric which comprises the said nonwoven fabric layer is not specifically limited, A preferable minimum is 25 denier and a preferable upper limit is 40 denier. When the average fiber diameter of the nonwoven fabric constituting the nonwoven fabric layer is within this range, it becomes easy to adjust the 50% compression stress of the nonwoven fabric layer to 0.5 MPa or more.
- the more preferable lower limit of the average fiber diameter of the nonwoven fabric constituting the nonwoven fabric layer is 30 denier, and the more preferable upper limit is 32 denier.
- the nonwoven fabric layer has a thickness of 2 mm or more. By setting the thickness of the nonwoven fabric layer to 2 mm or more, a meniscus having a sufficient thickness can be regenerated.
- the thickness of the nonwoven fabric layer is preferably 4 mm or more. Although the upper limit of the thickness of the said nonwoven fabric is not specifically limited, 10 mm is practically an upper limit practically.
- the nonwoven fabric layer is made of polyglycolide. As described above, the nonwoven fabric layer has a 50% compressive stress of 0.5 MPa or more. In order to achieve such a high 50% compressive stress, the nonwoven fabric layer must have an extremely dense structure. According to the common general technical knowledge so far, the average pore diameter of the nonwoven fabric constituting the tissue regeneration base material is preferably about 5 to 30 ⁇ m in order to ensure the invasion of cells. However, with such a low density nonwoven fabric, the 50% compressive stress cannot be made 0.5 MPa or more.
- the nonwoven fabric layer made of polyglycolide has infiltrated cells even if it has a very dense structure in which it is difficult for cells to enter conventionally with 50% compression stress of 0.5 MPa or more, The meniscus can be fully regenerated.
- polyglycolide is fibrous and immersed in physiological saline at 37 ° C., the period until the tensile strength becomes 1 ⁇ 2 before immersion is about 14 days.
- cells can invade and proliferate as the decomposition and absorption progress gradually, even if the structure is extremely dense so that the 50% compression stress is 0.5 MPa or more.
- polyglycolide means a polymer of glycolide such as polyglycolic acid, but other bioabsorbables such as lactide, ⁇ -caprolactone, p-dioxanone and the like within the range not inhibiting the effect of the present invention. It is good also as a copolymer with these components. Moreover, it is good also as a mixture with other bioabsorbable materials, such as a polylactide, in the range which does not inhibit the effect of this invention.
- the preferred lower limit of the blended amount of the glycolide component in the copolymer is 60 mol%. .
- the preferred lower limit of the blended amount of the glycolide component in the copolymer is 60 mol%. .
- the preferred lower limit of the blending amount of polyglycolide in the mixture is 50 mol%.
- the minimum with a preferable weight average molecular weight of the said polyglycolide is 30000, and a preferable upper limit is 600000. If the weight average molecular weight of the polyglycolide is less than 30,000, the strength may be insufficient and a 50% compression stress of 0.5 MPa or more may not be obtained, and if it exceeds 600,000, the degradation rate in vivo becomes slow, May cause a foreign body reaction.
- the minimum with a more preferable weight average molecular weight of the said polyglycolide is 50000, and a more preferable upper limit is 400,000.
- a melt flow rate may be used as an alternative indicator of the molecular weight of the polyglycolide.
- the preferable lower limit of the melt flow rate of the polyglycolide is 0.1 g / 10 minutes, and the preferable upper limit is 100 g / 10 minutes. Within this range, it becomes easy to produce a nonwoven fabric made of polyglycolide.
- a more preferable lower limit of the melt flow rate of polyglycolide is 1 g / 10 minutes, and a more preferable upper limit is 50 g / 10 minutes.
- the measurement condition of the melt flow rate means a value measured under the condition of a load of 4 kgf after the polyglycolide is melted while being held in a cylinder at 240 ° C. for 10 minutes.
- the method for preparing the nonwoven fabric layer is not particularly limited.
- the electrospinning deposition method, the melt blow method, the needle punch method, the spun bond method, the flash spinning method, the hydroentanglement method, the airlaid method, the thermal bond method, and the resin bond method A conventionally known method such as a wet method can be used.
- a wet method can be used in a nonwoven fabric manufactured by a normal manufacturing method.
- the 50% compressive stress can be adjusted to 0.5 MPa or more by laminating a plurality of non-woven fabrics and combining them together and then compressing them by a method such as hot pressing.
- the compressed nonwoven fabric is sewn with a thread made of a bioabsorbable material.
- a thread made of a bioabsorbable material.
- the pitch for sewing is not particularly limited, but a pitch of 5 mm or less is preferable in order to securely fix the thickness.
- the sponge layer is made of a bioabsorbable material having a slower decomposition rate than polyglycolide.
- the bioabsorbable material having a slower degradation rate than the above polyglycolide is not particularly limited, and polylactide (D, L, DL form), polycaprolactone, glycolide-lactide (D, L, DL form) copolymer, glycolide- Examples include ⁇ -caprolactone copolymer, lactide (D, L, DL form) - ⁇ -caprolactone copolymer, polydioxanone, glycolide-lactide (D, L, DL form) - ⁇ -caprolactone copolymer, and the like.
- a lactide (D, L, DL form) - ⁇ -caprolactone copolymer that is sufficiently slower in degradation rate than polyglycolide and excellent in flexibility and wear resistance is preferable.
- a sponge layer made of lactide (D, L, DL form) - ⁇ -caprolactone copolymer it is possible to impart appropriate flexibility to the meniscal recycled substrate of the present invention. It is possible to prevent the surface of the base material from being worn when the base material and the cartilage are brought into contact with each other by the movement of the knee joint and a frictional force is generated after the transplantation.
- the density of the sponge layer is not particularly limited, but a preferred lower limit is 40 mg / cm 3 and a preferred upper limit is 120 mg / cm 3 . When the density of the sponge layer is within this range, sufficient flexibility and wear resistance can be exhibited. A more preferable lower limit of the density of the sponge layer is 70 mg / cm 3 , and a more preferable upper limit is 90 mg / cm 3 .
- the thickness of the said sponge layer is not specifically limited, A preferable minimum is 0.1 mm and a preferable upper limit is 1.0 mm. When the thickness of the sponge layer is within this range, the surface of the base material is prevented from being worn when the base material and cartilage come into contact with each other due to the movement of the knee joint and a frictional force is generated after transplantation. Can fully fulfill its role.
- the method for preparing the sponge layer is not particularly limited, and a conventionally known method such as freeze-drying a solution obtained by dissolving the bioabsorbable material in an appropriate solvent can be used.
- the meniscus recycled base material of the present invention is provided on one or both surfaces of a laminate comprising a sponge layer / nonwoven fabric layer / sponge layer as an outermost layer for the purpose of imparting slipperiness and further exhibiting wear resistance.
- You may have a film layer which consists of a bioabsorbable material whose degradation rate is slower than polyglycolide.
- the film means a thin film-like body that does not have at least a ⁇ m-order hole that can be observed with an optical microscope.
- the bioabsorbable material having a slower decomposition rate than the polyglycolide constituting the film layer is not particularly limited, but for example, lactide (D, L, DL form) - ⁇ -caprolactone copolymer is preferable.
- the film layer may contain a lubricant for the purpose of further improving the slipperiness as long as the medical use is not impaired.
- the thickness of the said film layer is not specifically limited, A preferable minimum is 0.1 mm and a preferable upper limit is 0.3 mm. If the thickness of the film layer is less than 0.1 mm, it may not be possible to sufficiently prevent the surface of the substrate from being worn by friction due to contact with cartilage after transplantation. , The handleability may be inferior.
- the sponge layer and the nonwoven fabric layer (and the film layer) are combined and integrated. If the above layers are not combined and integrated, when transplanting the meniscal recycled substrate of the present invention, some or all of the above layers may be peeled off. If even a part of each of the above-mentioned layers is peeled off, cell accumulation may occur in the space formed in the peeled portion, and normal tissues or organs may not be regenerated.
- composite integration means that the sponge layer and the nonwoven fabric layer (and the film layer) are stacked with an adhesive force that cannot be separated by hand pulling.
- the meniscus recycled substrate of the present invention was subjected to a repeated compression test in which a load of 300 N was repeatedly applied 20 times in warm water at a temperature of 37 ° C. to a meniscus recycled substrate having a length of 20 mm and a width of 20 mm. It is preferable that the maintenance ratio of the thickness of the meniscal recycled substrate is 95% or more. Thereby, even if a large stress is repeatedly applied after transplantation, the meniscus regenerated base material can maintain a sufficient thickness, and a meniscus having a sufficient thickness can be regenerated.
- the maintenance ratio of the thickness is more preferably 98% or more, and still more preferably 100%.
- the said maintenance rate of thickness means ratio (%) of the thickness of the meniscus reproduction
- the method for producing the meniscal recycled substrate of the present invention is not particularly limited. For example, after the nonwoven fabric layer and the sponge layer (and the film layer) are separately prepared, they are bonded using a medical adhesive. And a method in which a part of the surface of each layer is dissolved with a solvent and then bonded.
- regeneration of a meniscus can be provided by filling the defect
- FIG. 6 is a hematoxylin-eosin-stained image of the transplanted portion at 8 weeks after transplanting the meniscus regenerated substrate obtained in Example 1 into the meniscus-removed portion of a pig.
- FIG. 3 is an overall view of a meniscus obtained by transferring the meniscus regenerated substrate obtained in Example 1 to the meniscus removing part of a pig 4 weeks after transplantation.
- FIG. 3 is an overall view of the meniscus obtained by removing the meniscus regenerated substrate obtained in Example 1 in the porcine meniscus removing portion 8 weeks after transplantation.
- FIG. 3 is an overall view of a meniscus taken out 12 weeks after transplanting the meniscus regenerated substrate obtained in Example 1 into a meniscus removal part of a pig.
- Example 1 Preparation of non-woven fabric layer Using a polyglycolide having a weight average molecular weight of 250,000 colored in green as a bioabsorbable material and spinning it, a cloth made of yarn having an average fiber diameter of 31 denier is used as a needle punch method.
- a non-woven fabric having an average fiber diameter colored in green of about 20 ⁇ m and a thickness of about 300 ⁇ m was obtained. 14 sheets of the obtained non-woven fabrics were stacked, and in this state, needle punching was performed from one side to perform composite integration.
- the composite-integrated laminate was hot-pressed at a temperature of 100 ° C. for 1 minute and then machined at a pitch of 5 mm using a 400 denier yarn made of polyglycolide to obtain a non-woven fabric layer having a thickness of 3.7 mm. It was.
- the 50% compressive stress was measured by a method based on JIS-K6767, and it was 3.5 MPa.
- the density of the resulting nonwoven fabric layer was 400 mg / cm 3.
- a meniscal recycled substrate made of an integrated laminate was obtained. With respect to the obtained meniscus recycled substrate, the 50% compressive stress was measured by a method according to JIS-K6767, and it was 3.8 MPa.
- the obtained meniscus recycled substrate was cut into a size of 20 mm in length and 20 mm in width to prepare a sample.
- the obtained sample was submerged in warm water at a temperature of 37 ° C., and a repeated compression test was performed in which a load of 300 N was repeatedly applied 20 times.
- the thickness of the meniscus recycled substrate before the repeated compression test and the thickness of the meniscus recycled substrate after the repeated compression test were measured, and the thickness maintenance factor was calculated to be 100%.
- FIGS. 4 and 5 show micrographs of the obtained specimens stained with hematoxylin and eosin and safranin. From FIG.
- cartilage is regenerated first from the jointed portion. 4 and 5, 8 weeks after the operation, regeneration of the cartilage tissue (the portion stained red in the stained image of FIG. 5) was observed in the portion where the meniscal regeneration base material was transplanted.
- ⁇ Evaluation by animal experiment 2> A large pig was prepared as an experimental animal, and the anterior segment of the medial meniscus of the right knee joint was excised. The meniscus regenerated substrate obtained in Example 1 was transplanted and sutured to the meniscus removal part. A total of 3 pigs were transplanted. At 4, 8, and 12 weeks after the operation, one animal was sacrificed one by one, and the inner meniscus of the right knee joint was taken out and the whole image was taken. As a control, the outer meniscus of the right knee joint not transplanted with the meniscal regeneration substrate was also taken out and photographed. The photographs are shown in FIGS. In each figure, the left side is a control, and the right side is a meniscus transplanted with a meniscal regeneration substrate.
- regeneration of a meniscus can be provided by filling the defect
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Abstract
Description
しかしながら、実際には、従来の組織再生基材を用いても、期待したほどには半月板の再生が促進されないという問題があった。
以下に本発明を詳述する。
膝関節には、立時や歩行時に全体重がかかる。とりわけ、ヒトを含む大型動物では、その衝撃は極めて大きくなる。移植後、いかに安静にするとしても、長期にわたる治癒の間には、移植した半月板再生基材には大きな応力がかかり続ける。また、半月板再生においては、移植した基材と軟骨とが膝関節の動きにより接触し、その摩擦によって基材の表面が磨耗してしまうという、半月板の再生に独特の問題もあった。
従来の組織再生基材を構成する不織布は、細胞の侵入性を確保するために5~30μm程度の平均孔径であることが好適であることが知られている。しかしながら、このような従来の組織再生基材は、細胞の侵入性の点では優れているとしても、充分な機械的強度を有せず、半月板が再生する以前に損傷したり、表面が磨耗してしまったりして、厚みを減じてしまい、充分な厚みの半月板を再生するための足場材としての役割を果たし得なくなると考えられた。
上記不織布層は、移植後に周囲組織から侵入する細胞増殖の足場となり、半月板の再生を促進する役割を有するとともに、移植後に応力がかかったときに充分な機械的強度を発揮する役割を有する。
なお、上記50%圧縮応力は、JIS-K6767に準拠した方法により測定することができる。
上述のように上記不織布層は、50%圧縮応力が0.5MPa以上である。これほどの高い50%圧縮応力を達成するためには、上記不織布層は極めて緻密な構造とならざるを得ない。これまでの技術常識では、組織再生基材を構成する不織布の平均孔径は、細胞の侵入性を確保するために5~30μm程度が好適であるとされていた。しかしながら、そのような低密度な不織布では、到底50%圧縮応力を0.5MPa以上とすることはできない。ところが、驚くべきことに、ポリグリコリドからなる不織布層は、50%圧縮応力が0.5MPa以上の従来では細胞の侵入が困難とされる極めて緻密な構造であっても、細胞が侵入して、充分に半月板を再生することができる。
ポリグリコリドは、繊維状にして37℃の生理食塩水中に浸漬した場合に、引張強度が浸漬前の1/2になるまでの期間が約14日である。このような分解性を有することにより、50%圧縮応力が0.5MPa以上となるように極めて緻密な構造としても、徐々に分解吸収が進むにつれ細胞が侵入、増殖することができ、不織布層の内部まで再生した組織が構築され、その結果として良質な再生組織が構築されるものと考えられる。更に、生体内に埋入後数日間で炎症系の細胞が消失することから、組織の癒着を引き起こしにくいという優れた効果をも発揮できる。
上記ポリグリコリドがラクチド、ε-カプロラクトン、p-ジオキサノン等の他の生体吸収性の成分との共重合体である場合、該共重合体におけるグリコリド成分の配合量の好ましい下限は60モル%である。グリコリド成分の配合量を60モル%以上とすることにより、細胞の侵入性に優れ、かつ、正常な組織の再生を行うという本発明の優れた効果を特に発揮することができる。
上記ポリグリコリドとポリラクチド等の他の生体吸収性材料との混合物を用いる場合、該混合物におけるポリグリコリドの配合量の好ましい下限は50モル%である。ポリグリコリドの配合量を50モル%以上とすることにより、細胞の侵入性に優れ、かつ、正常な組織の再生を行うという本発明の優れた効果を特に発揮することができる。
なお、メルトフローレートの測定条件は、ポリグリコリドを240℃、10分間、シリンダー内で保持して溶融した後、荷重4kgfの条件で測定した値を意味する。
しかしながら、通常の製造方法で製造した不織布では、不織布層の50%圧縮応力を0.5MPa以上とすることが困難な場合がある。そのような場合には、複数の不織布を積層して複合一体化した後、熱プレス等の方法により圧縮することにより、50%圧縮応力を0.5MPa以上に調整することができる。
更に必要に応じて、圧縮後の不織布に生体吸収性材料からなる糸でミシン掛けを行うことが好ましい。圧縮した不織布には、元の厚みに戻ろうとする応力が働くが、ミシン掛けして厚みを固定しておくことにより、密度が低下してしまうのを防止することができる。ミシン掛けのピッチは特に限定されないが、確実に厚みを固定するためには5mm以下のピッチとすることが好ましい。
なお、本明細書においてフィルムとは、少なくとも光学顕微鏡により観察可能なμmオーダーの孔を有しない、薄い膜状体を意味する。
上記各層が複合一体化していないと、本発明の半月板再生基材を移植する際に、上記各層間の一部又は全部が剥離してしまうことがある。上記各層間が一部でも剥離すると、該剥離部に形成された空間に細胞溜まりが生じて、正常な組織又は器官が再生されないことがある。
なお、本明細書において複合一体化とは、手で引っ張った程度では上記スポンジ層と上記不織布層(及び上記フィルム層)とを分離できない程度の密着力で積層されていることを意味する。
なお、上記厚みの維持率とは、繰り返し圧縮試験前の半月板再生基材の厚みに対する、繰り返し圧縮試験後の半月板再生基材の厚みの比(%)を意味する。
(1)不織布層の調製
生体吸収性材料として緑色に着色された重量平均分子量が250000のポリグリコリドを用い、これを紡糸して得た平均繊維径が31デニールの糸からなる布をニードルパンチ法により不織布化する方法により、緑色に着色された平均繊維径が約20μm、厚さが約300μmの不織布を得た。
得られた不織布を14枚重ね、その状態で一方の面から ニードルパンチを行うことにより複合一体化した。次いで、複合一体化した積層体を、温度100℃で1分間熱プレスした後、ポリグリコリドからなる400デニールの糸を用いて5mmピッチでミシン掛けして、厚みが3.7mmの不織布層を得た。
L-ラクチド-ε-カプロラクトン共重合体(モル比50:50、重量平均分子量20万)をジオキサンに溶解して4重量%ジオキサン溶液を調製した。ガラスシャーレに不織布層を静置して、得られた溶液をガラスシャーレに液面の高さが不織布層の高さとほぼ同等になるように流し入れた。-80℃で1時間凍結した後、凍結乾燥機(ADVANTEC社製、DRZ350WA)を用いて、-40℃で12時間凍結乾燥することにより、不織布層の両面に厚さ約100μmのスポンジ層を形成し、スポンジ層/不織布層/スポンジ層が積層一体化した積層体を得た。
L-ラクチド-ε-カプロラクトン共重合体(モル比50:50、重量平均分子量40万)をジオキサンに溶解して4重量%ジオキサン溶液を調製した。得られた溶液をガラスシャーレに流し入れ、風乾及び熱処理することにより厚さ約100μmのフィルムを得た。
得られたフィルムの一方の面の表面にジオキサンを少量塗布することにより一部溶解させ、スポンジ層/不織布層/スポンジ層が積層一体化した積層体の上下面(両表面)のスポンジ層にフィルムが接するように積層し、乾燥させてフィルムと積層体とを複合一体化させて、厚さ約100μmのフィルム層を形成して、フィルム層/スポンジ層/不織布層/スポンジ層/フィルム層が積層一体化した積層体からなる半月板再生基材を得た。得られた半月板再生基材について、JIS-K6767に準拠した方法により50%圧縮応力を測定したところ、3.8MPaであった。
実験動物として大型動物であるブタを準備し、右膝関節の内側半月板の前節を切除した。半月板除去部に、実施例1で得られた半月板再生基材を移植して縫合した。
術後、0、4、8週後に右膝関節の核磁気共鳴画像(MRI)を撮影した。撮影した核磁気共鳴画像(MRI)を図3に示した。
また、術後8週目に犠牲死させ、右膝関節の内側半月板を取り出し、移植部分を摘出した。得られた標本をヘマトキシリンエオジン染色、サフラニン染色した顕微鏡写真像を図4及び図5に示した。
図3より、関節のあたる部分から先に軟骨が再生していることがわかる。また、図4及び図5より、術後8週後には、半月板再生基材を移植した部分において、軟骨組織の再生(図5の染色像において赤く染色された部分)が認められた。
実験動物として大型動物であるブタを準備し、右膝関節の内側半月板の前節を切除した。半月板除去部に、実施例1で得られた半月板再生基材を移植して縫合した。計3頭のブタに対して移植を行った。
術後4、8、12週目に1頭ずつ犠牲死させ、右膝関節の内側半月板を取り出して全体像を撮影した。なお、コントロールとして、半月板再生基材を移植していない右膝関節の外側半月板も取り出して撮影した。写真を図6~8に示した。各図において、左側がコントロール、右側が半月板再生基材を移植した半月板である。
図6より、術後4週目では、半月板再生基材の移植部に緑色に着色された不織布層が残存しているのが確認できたが、術後8、12週目には、不織布層が残存はほとんど確認されなくなった。同時に、次第に半月板組織が再生されていくのが認められた。
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
Claims (6)
- 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、
ポリグリコリドよりも分解速度が遅い生体吸収性材料からなるスポンジ層、ポリグリコリドからなる不織布層、及び、ポリグリコリドよりも分解速度が遅い生体吸収性材料からなるスポンジ層がこの順に複合一体化した構造を有し、
前記不織布層の50%圧縮応力が0.5MPa以上であり、かつ、前記不織布層の厚みが2mm以上であることを特徴とする半月板再生基材。 - 不織布層の密度が300mg/cm3以上であることを特徴とする請求項1記載の半月板再生基材。
- 不織布層を構成する不織布の平均繊維径が25~40デニールであることを特徴とする請求項1又は2記載の半月板再生基材。
- ポリグリコリドよりも分解速度が遅い生体吸収性材料は、ラクチド-ε-カプロラクトン共重合体であることを特徴とする請求項1、2又は3記載の半月板再生基材。
- 一方又は両方の表面にポリグリコリドよりも分解速度が遅い生体吸収性材料からなるフィルム層を有することを特徴とする請求項1、2、3又は4記載の半月板再生基材。
- 縦20mm、横20mmの半月板再生基材に対して、温度37℃の温水中で300Nの荷重を20回繰り返して印加する繰り返し圧縮試験を行った後の半月板再生基材の厚みの維持率が95%以上であることを特徴とする請求項1、2、3、4又は5記載の半月板再生基材。
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