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WO2006028244A1 - Objet poreux bioabsorbable - Google Patents

Objet poreux bioabsorbable Download PDF

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Publication number
WO2006028244A1
WO2006028244A1 PCT/JP2005/016698 JP2005016698W WO2006028244A1 WO 2006028244 A1 WO2006028244 A1 WO 2006028244A1 JP 2005016698 W JP2005016698 W JP 2005016698W WO 2006028244 A1 WO2006028244 A1 WO 2006028244A1
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WO
WIPO (PCT)
Prior art keywords
porous body
fiber structure
bioabsorbable polymer
average
fiber
Prior art date
Application number
PCT/JP2005/016698
Other languages
English (en)
Japanese (ja)
Inventor
Eiichi Kitazono
Takanori Miyoshi
Hiroaki Kaneko
Chiaki Fukutomi
Original Assignee
Teijin Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Teijin Limited filed Critical Teijin Limited
Priority to JP2006535862A priority Critical patent/JP4481994B2/ja
Publication of WO2006028244A1 publication Critical patent/WO2006028244A1/fr

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Classifications

    • 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
    • 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
    • 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
    • D—TEXTILES; PAPER
    • D04—BRAIDING; LACE-MAKING; KNITTING; TRIMMINGS; NON-WOVEN FABRICS
    • D04H—MAKING TEXTILE FABRICS, e.g. FROM FIBRES OR FILAMENTARY MATERIAL; FABRICS MADE BY SUCH PROCESSES OR APPARATUS, e.g. FELTS, NON-WOVEN FABRICS; COTTON-WOOL; WADDING ; NON-WOVEN FABRICS FROM STAPLE FIBRES, FILAMENTS OR YARNS, BONDED WITH AT LEAST ONE WEB-LIKE MATERIAL DURING THEIR CONSOLIDATION
    • D04H1/00—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres
    • D04H1/40—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres from fleeces or layers composed of fibres without existing or potential cohesive properties
    • D04H1/42—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres from fleeces or layers composed of fibres without existing or potential cohesive properties characterised by the use of certain kinds of fibres insofar as this use has no preponderant influence on the consolidation of the fleece
    • D—TEXTILES; PAPER
    • D04—BRAIDING; LACE-MAKING; KNITTING; TRIMMINGS; NON-WOVEN FABRICS
    • D04H—MAKING TEXTILE FABRICS, e.g. FROM FIBRES OR FILAMENTARY MATERIAL; FABRICS MADE BY SUCH PROCESSES OR APPARATUS, e.g. FELTS, NON-WOVEN FABRICS; COTTON-WOOL; WADDING ; NON-WOVEN FABRICS FROM STAPLE FIBRES, FILAMENTS OR YARNS, BONDED WITH AT LEAST ONE WEB-LIKE MATERIAL DURING THEIR CONSOLIDATION
    • D04H3/00—Non-woven fabrics formed wholly or mainly of yarns or like filamentary material of substantial length

Definitions

  • the present invention relates to a porous body comprising a fiber structure of a bioabsorbable polymer.
  • prosthetic materials are an important factor that gives an optimal environment for tissue construction.
  • the properties required for this scaffold material include: 1) bioabsorbability, 2) cell adhesion, 3) porosity, 4) mechanical strength, etc., and create materials that satisfy these properties.
  • Synthetic polymers polyglycolic acid, polylactic acid, poly force prolagtone, etc.
  • N inorganic materials hydroxyapatite, ⁇ ⁇ -tricalcium phosphate
  • prosthetic materials sinaffolding materials
  • It is porous. This is important in terms of providing sufficient oxygen and nutrients to the cells needed to regenerate the tissue and expelling carbon dioxide and waste products quickly. Therefore, lyophilization methods (for example, to achieve the porosity of the scaffold material)
  • phase separation eg.
  • the pores of the obtained structure have a scaly shape, which makes it difficult for cells to invade and has an unsatisfactory problem as a scaffold material.
  • Another problem with the foaming method is that it is difficult for cells to enter because there is a single pore.
  • WO 2 0 4/8 8 0 24 discloses an aggregate of fibers made of a thermoplastic polymer having an average fiber diameter of 0.1 to 20 ⁇ m, and any fiber of the fibers.
  • a nonwoven fabric having an irregular cross-sectional surface and an average apparent density of 10 to 95 kg Zm 3 is described.
  • a scaffold material having further thickness and strength is required.
  • the actual living tissue shows a continuous gradient structure rather than a uniform structure.
  • the cell density of the surface layer is low, but the closer to the lower bone, the higher the cell density.
  • the purpose of this effort is to provide a bioabsorbable porous body, particularly a porous body suitable for a cell culture substrate in the field of regenerative medicine. Specifically, it is to provide a bioabsorbable porous body composed of a fiber structure of a bioabsorbable polymer, and the bioabsorbable porous body by a simple method.
  • the present invention is as follows.
  • the fiber structure consists of a fiber structure of a bioabsorbable polymer, the fiber structure has an average fiber diameter of 0.05 to 10 ⁇ . ⁇ , an average apparent density of 10 to 35 O kg / m 3 , and a height. Is a porous body characterized by being 0.5 or more.
  • porous body according to 1, wherein the porous body has an average fiber diameter of 0.2 to 8 ⁇ um.
  • porous material according to 3 wherein the porous material has a gradient structure in which the porosity is 10 to 90% and different porosity is continuously present.
  • porous body according to 1 further comprising 0 ⁇ 01 to 50 parts by weight of a dispersion aid with respect to 100 parts by weight of the bioabsorbable polymer.
  • the dispersion aid is at least one selected from the group consisting of phospholipids, carbohydrates, glycolipids, steroids, polyamino acids, protein koji, and polyoxyalkylenes. 7.
  • porous body according to 8 wherein the aliphatic polyester is at least one selected from the group consisting of polydalicolic acid, polylactic acid, polyprolacton, and copolymers thereof.
  • a prosthetic material comprising the porous material according to 10.1. 1 1.
  • the fiber structure of the bioabsorbable polymer has an average fiber diameter of 0 ⁇ 05 to 10 ⁇ m, and an average apparent density. Is a porous body having a thickness of 0.5 to 5 thighs. .
  • a bioabsorbable polymer characterized by using a static eliminator between a nozzle and a collecting electrode in a method of spinning a solution comprising a volatile solvent and a bioabsorbable polymer by an electrostatic spinning method.
  • a porous structure having an average fiber diameter of 0.05 to 10 m, an average apparent density of 10 to 35 kg / m3, and a thickness of 0.5 mm or more. Body manufacturing method. The invention's effect ,
  • the bioabsorbable porous material of the present invention is useful as a prosthetic material.
  • a molded body having a desired shape can be provided, and it is useful as a prosthetic material in a portion where a high load such as a cartilage damaged portion is applied.
  • the bioabsorbable porous material of the present invention is useful as a cell culture substrate in the field of regenerative medicine, particularly as a substrate for cartilage regeneration, among prosthetic materials. ,
  • FIG. 1 shows an example of an apparatus used in an electrostatic spinning method for discharging a spinning solution into an electrostatic field in the production method of the present invention.
  • FIG. 2 shows an example of an apparatus used in the electrospinning method in which fine droplets of a spinning solution are introduced into an electrostatic field in the production method of the present invention.
  • FIG. 3 shows an example of an apparatus used in the electrospinning method of production method 2 of the present invention.
  • FIG. 10 Optical micrograph of the porous material obtained in Example 7 'Fig. 1 Microscopic photo of the porous body in the vicinity of the 8th week after surgery in Example 8 Fig. 1 2. 8 weeks after surgery in Example 9 Fig. 1 3 Photomicrograph of the vicinity of the defect at 8 weeks after the operation of Comparative Example 1.
  • Figure 1 4 Items and scores used in histological evaluation
  • Fibrous material collection electrode 1 Fibrous material collection electrode 1 2. High voltage generator
  • the fiber structure used in the present invention is a three-dimensional structure formed by laminating and accumulating single or plural fibers.
  • the average fiber diameter of the fiber structure is 0.05 to 10 ⁇ . If the average fiber diameter is smaller than 0.05 ⁇ , the strength of the fiber structure cannot be maintained, which is not preferable. On the other hand, if the average fiber diameter is larger than 10 ⁇ m, the specific surface area of the fiber is small and the number of engrafted cells is reduced, which is not preferable. More preferably, the average fiber diameter is 0.2 to 10 ⁇ , more preferably the average fiber diameter is 0.2 to 8 m.
  • the arbitrary cross section of the fiber may be a substantially perfect circle or an irregular shape. If the cross section of an arbitrary fiber is irregular, the specific area of the fiber increases, so that a sufficient area for the cell to adhere to the fiber surface can be taken during cell culture.
  • the arbitrary cross section of the fiber is irregular, which means any shape in which the cross section of the fiber does not take a substantially circular shape, and the fiber surface has uniform recesses and / or protrusions. And the case where it is roughened.
  • the irregular shape includes fine concave portions on the fiber surface, fine convex portions on the fiber surface, It may be due to at least one selected from the group consisting of concave portions formed in a streak shape in the fiber axis direction, convex portions formed in a streak shape in the fiber axis direction on the fiber surface, and fine pores on the fiber surface. Preferably, these may be formed singly or a plurality thereof may be mixed.
  • the above-mentioned “fine concave portions” and “fine convex portions” mean that the concave or convex portions of 0.1 to 1 ⁇ are formed on the fiber surface, and “fine pores”.
  • the term “pores” having a diameter of 0.1 to 1 ⁇ is present on the fiber surface.
  • the above-described concave and ridges or protrusions formed in a streak shape means that a ridge shape having a width of 0.1 to 1 ⁇ m is formed in the fiber axis direction.
  • the porous body made of the fiber structure of the present invention has an average apparent density: I 0 to 35 O kg / m 3 . If the average apparent density is lower than 1 O kg / m 3 , the cell penetration is good, but the mechanical strength is low, and if it is higher than 35 O kg / m 3 , it is difficult for cells to enter, which is not preferable as a scaffold material. .
  • the average sheep density can be calculated by measuring the volume (area X thickness) and mass of the obtained porous material.
  • the average apparent density is preferably 50 to 3 OO kg / ⁇ 3 . More preferably, it is 100-25 O kg / m ⁇ 3 >. .
  • the porous body composed of the fiber structure of the present invention preferably has a porosity of 10 to 90%. If the porosity is lower than 10%, the number of cells to be engrafted is small. If the porosity is higher than 90%, the number of cells to be engrafted is large, but most of them are spaces, so the mechanical strength is low and it is not preferable as a scaffold material. There is a case. Furthermore, the porosity is preferably 20 to 70%, more preferably 2050%. The porosity can be calculated from the average apparent density and the inherent polymer density.
  • the porous body comprising the fiber structure of the present invention may be either uniform in average apparent density and / or porosity or may have a gradient, and can be selected according to the required scaffold site.
  • the gradient structure in which different porosities exist continuously may be a gradient structure having two or more stages, and may be two or more stages. Even with such a gradient structure, the average apparent density of the entire porous body is 10 to 35 O kg / m 3 . In this case, the porosity is 10 to 90%.
  • the porous body of the present invention is a three-dimensional shape such as a cylinder, a polygonal column, a truncated cone, a truncated cone,
  • the height is 0.5 thigh or more, and it can be said that it depends on the site used as the cell culture substrate regardless of the upper limit of the height. If the height is less than 0.5 mm, the mechanical strength is low, and it is not preferable as a cell culture substrate for tissues with high loads such as knee joints.
  • the porous body of the present invention can be used for, for example, piercing and embedding in a damaged part of a living body, and regenerating cells on the surface of a binding material, but the porous body of the present invention is adapted to a desired shape. It has the characteristic that a molded object can be provided. Since a substrate with the required thickness can be provided, it is superior in shape stability without interfacial delamination compared to, for example, a laminate in which non-woven fabrics are stacked and pressure-bonded. Useful as a binding material, 'cell culture substrate.
  • a porous body when used for transplantation, mechanical strength that can withstand weighted compression in the initial stage of transplantation is required.
  • a porous body having mechanical strength according to the application can be provided.
  • the bioabsorbable polymer constituting the porous body of the present invention is preferably mainly composed of an aliphatic polyester.
  • the aliphatic polyester include polydaricholic acid, polylactic acid, polystrength prolatatone, polydioxanone, trimethylene carbonate, polybutylene succinate, polyethylene succinate, and copolymers thereof.
  • the aliphatic polyester is preferably at least one selected from the group consisting of polyglycolic acid, polylactic acid, polystrength prolactone, and copolymers thereof.
  • the porous body of the present invention preferably further contains a dispersion aid. More preferably, the dispersion aid exhibits bioabsorbability.
  • the dispersion aid is preferably at least one selected from the group consisting of phospholipids, carbohydrates, glycolipids, steroids, polyamino acids, proteins, and polyoxyalkylenes. Les.
  • Specific dispersing agents include phospholipids such as phosphatidinorecholine, phosphatidylethanolanolamine, phosphatidylserine, phosphatidinoregliceronorole and Z or polygalacturonic acid, heparin, chondroitin sulfate, Hyanorelon acid, dermatan sulfate, chondroitin, dextran sulfate, sulfated cellulose, alginic acid, dextran, canoleboxymethyl chitin, galactmann Naan, gum arabic, tragacanth gum, dillang gum, sulfated dielan, cara gum, carrageenan, agar, xanthan gum, curdlan, pullulan, cellulose, starch, canolepoxymethinoresenorelose, methinoresenorelose, gnolecomannan, chitin, Carbohydrates such as chitosan, xylog
  • a preferable content of the dispersion aid in the bioabsorbable porous material is 0.001 to 50 parts by weight with respect to 100 parts by weight of the bioabsorbable polymer. If the content is less than 0.01 part by weight, the wettability with water is poor and it may be difficult to cut the fiber with a homogenizer, and the fiber may be difficult to settle upon centrifugation. If it is longer than 50 parts by weight, fibers are hardly formed at the spinning stage. More preferably, the content is 0.1 to 20 parts by weight. Moreover, cell penetration into the porous material is enhanced by including a dispersion aid. .
  • the bioabsorbable porous material of the present invention may further contain a third component other than the bioabsorbable polymer and the dispersion aid.
  • a third component other than the bioabsorbable polymer and the dispersion aid include, for example, FGF (fibroblast growth factor), EGF (epidermal growth factor), PDG F_ (platelet-derived growth factor), TGF— (type 3 transforming growth factor), NG F (nerve growth factor) ), HGF (hepatocyte growth factor), BMP (bone morphogenetic factor) and other cell growth factors.
  • the porous body of the present invention is useful as a prosthetic material.
  • the treatment method can be performed by the following procedure. First, the joint is operated to expose the cartilage. Next, a hole is made in the damaged part of the cartilage with a drill or the like. It is preferable that the hole is deep enough to reach the subchondral bone below the cartilage tissue with a thickness of about 2 mm. Therefore, the depth of the hole is preferably about 3-8 mm. Thereafter, the prosthetic material of the present invention having a shape substantially coinciding with the inner diameter of the hole is embedded. Thereafter, the surgical site is repaired and cartilage is regenerated by natural healing.
  • the present invention includes a step of spinning a solution comprising a volatile solvent and a bioabsorbable polymer by an electrostatic spinning method to obtain a fiber structure, a step of cutting the obtained fiber structure, and a cut fiber structure.
  • This is a method for producing a porous body having a density of 10 to 35 O kg / m 3 and a thickness of not less than 5 mm (Method 1). It is preferable to perform spinning using a solution containing a dispersion aid in the solution.
  • the present invention is characterized in that in a method of spinning a solution comprising a volatile solvent and a bioabsorbable polymer by an electrostatic spinning method, a static eliminator is used between the nozzle and the collecting electrode. It is composed of a fiber structure of a bioabsorbable polymer, and the average fiber diameter of the fiber structure is from 0.05 to 10 ⁇ , the average apparent density is from 10 to 35 kg / m 3 , and the thickness is 0. This is a method for producing a porous body of 5 mm or more (Method 2).
  • the volatile solvent that forms a solution in the present invention is a substance that dissolves a bioabsorbable polymer, has a boiling point of 200 ° C. or less at normal pressure, and is liquid at room temperature.
  • Specific volatile solvents include, for example, methylene chloride, chlorophenol, acetone, methanol, ethanol, propanol, isopropanol, toluene, tetrahydrofuran, 1,1,1,3,3,3 —hexafluoro Examples include roisopropanol, water, 1,4-dioxane, carbon tetrachloride, cyclohexane, cyclohexanone, N, N-dimethylformamide, and acetonitrile.
  • methylene chloride, black mouth form, and acetone are particularly preferable in view of solubility of bioabsorbable polymers, particularly aliphatic polyesters.
  • These solvents may be used alone or in combination with multiple solvents. You may let them. In the present invention, other solvents may be used in combination as long as the object is not impaired.
  • the electrospinning method used in the present invention is a method in which a bioabsorbable polymer or a solution in which a bioabsorbable polymer and a dispersion aid are dissolved in a volatile solvent is discharged into an electrostatic field formed between electrodes.
  • This is a method for producing a fibrous material by spinning the yarn toward the electrode.
  • the fibrous material indicates not only the state in which the solvent in the solution has already been distilled off, but also the state in which the solvent is still contained.
  • the electrode used in the present invention may be any metal, inorganic, or organic material as long as it exhibits conductivity.
  • a thin film of conductive metal, inorganic, or organic material may be provided over the insulator.
  • the electrostatic field in the present invention is formed between a pair or a plurality of electrodes, and a high voltage may be applied to any of the electrodes.
  • a high voltage may be applied to any of the electrodes. This includes, for example, the use of two high-voltage electrodes with different voltage values (for example, 15 kV and 10 kV) and a total of three electrodes connected to ground, or a number exceeding three. This includes the case of using other electrodes.
  • the concentration of the bioabsorbable polymer in the bioabsorbable polymer solution in the present invention is preferably 1 to 30% by weight.
  • concentration of the bioabsorbable polymer is lower than 1% by weight, it is not preferable because the concentration is too low to form a fibrous substance.
  • concentration of the bioabsorbable polymer is 2 to 20% by weight. Any method can be used to discharge the solution into the electrostatic field. For example:-As an example, we will explain below using FIG.
  • the solution By supplying Solution 2 to the nozzle, the solution is placed in an appropriate position in the electrostatic field, and the solution is electrolyzed from the nozzle to fiber.
  • an appropriate device can be used.
  • a syringe-like solution is discharged by applying appropriate means, for example, a high voltage generator 6 to the tip of the cylindrical solution holding tank 3 of the syringe.
  • the tip of the ejection nozzle 1 is placed at an appropriate distance from the grounded fibrous material collecting electrode 5 and when the solution 2 exits the tip of the ejection nozzle 1, this tip and the fibrous material collecting electrode 5 A fibrous material is formed between them.
  • the production rate of the fibrous material can be increased by using several nozzles.
  • the distance between the electrodes depends on the charge amount, nozzle dimensions, spinning fluid flow rate, spinning fluid concentration, etc., but when it was about 10 kV, a distance of 5 to 20 cm was appropriate.
  • the applied electrostatic potential is generally 3 to: 100 kV, preferably 5 to 50 kV, more preferably 5 to 30 kV. 'The desired potential can be created by any appropriate method! /.
  • the electrode also serves as a collector.
  • a collector can be provided separately from the electrode by installing an object that can be a collector between the electrodes. Sheets and tubes can be obtained by selecting the shape of the collector. Furthermore, for example, continuous production is possible by installing a belt-like substance between the electrodes and collecting it.
  • the solvent evaporates depending on the conditions, and a fibrous material is formed. At normal room temperature, the solvent completely evaporates until it is collected on the collecting electrode, but if the solvent evaporation is insufficient, it may be spun under reduced pressure conditions.
  • the spinning temperature depends on the evaporation behavior of the solvent and the viscosity of the spinning solution, but is usually 0 to 50 ° C.
  • the method for cutting the fiber of the present invention is not particularly limited, but it is preferable to use a homogenizer, a pulverizer, or a mill.
  • the fibrous material may be cut directly or in a frozen state, or the fibrous material may be suspended in a solvent and cut.
  • the dispersion aid mentioned as the second component at the stage of spinning the fibrous material is used. It is preferable to contain.
  • the dispersion aid is preferably contained in an amount of 0.01 to 50 parts by weight with respect to 100 parts by weight of the bioabsorbable polymer. Centrifugation performed in the present invention is performed by suspending the fibrous material in a solvent.
  • the concentration of the fiber structure in the solvent is usually about 0.001 to 50% by weight, and the solvent is not particularly limited as long as it can be freeze-dried. However, when handling and safety are considered, Mixed water is preferred.
  • the porous body having the desired average apparent density and porosity can be controlled by controlling the centrifugal acceleration and Z or the eccentric time. Can be obtained. Specifically, when the centrifugal acceleration is high and the centrifugal time is long, the average apparent density of the obtained porous body is high and the porosity is low.
  • centrifugal acceleration when the centrifugal acceleration is low and the centrifugation time is short, the average apparent density of the obtained porous body is low and the porosity is high.
  • Preferable conditions for centrifugal acceleration are 10 00 to 6,00 G, and preferable conditions for centrifugation time are 10 to 40 minutes.
  • the freeze-drying step is a step of removing the organic solvent under reduced pressure at the ultimate temperature, and is not particularly limited.
  • the freeze-drying process is preferably performed at 10 to 30 Pa.
  • the lyophilization time is preferably 8 to 24 hours.
  • freezing a method in which a temperature gradient is provided and the method of gradually freezing is preferred in terms of obtaining a porous material with few defect structures.
  • the type of freeze-dried t « is not particularly limited, and commercially available freeze-dried; can be suitably used.
  • the spinning process is the same as in Method 1 above, except that a static eliminator 20 is installed between the nozzle 13 and the electrode 17 to perform spinning, and the yarn accumulated between the nozzle and the electrode 17 is removed. It is collected by a scraper 19 and the collected fiber structure is rolled out using a biopsy trepan to obtain a well-shaped porous body.
  • the static eliminator used here is a device that applies ion air to the spun yarn to maintain a uniform ion balance and relaxes the charged state of the yarn before it reaches the electrode, thereby depositing it in the air. By using this apparatus, it is possible to produce a porous body having a height of 0.5 mm or more.
  • the average apparent density and porosity of the porous material depend on the rotation speed of the scraper. In other words, it is possible to obtain a porous body having a desired average apparent density and porosity by controlling the rotation speed of the scraper. Specifically, when the number of rotations is high, the obtained porous body has a high average power and a low porosity. On the other hand, when the rotational speed is low, the average apparent density of the obtained porous body is low and the porosity is high. As a preferable condition of the rotation speed, 5 to 200 rpm is used.
  • Intrinsic viscosity 1. 08 dL / g, 30 ° C, hexafluoroisopropanol, phosphatidylethanolaminediole oil
  • Polylactic acid-polyglycolic acid copolymer 0.9 g ', phosphatidylethanolaminediol oil 0.1 g, salt-hethylene methylene Zethanol 7/2 (parts by weight, amount' parts) 9 g at room temperature (25 ° C)
  • a 10% by weight dope solution was prepared by mixing.
  • the fibrous material collecting electrode 11 was discharged for 5 minutes. Inside diameter 0. 8 mm of the jet Nozunore 7, voltage 14.K V, the fibrous material 0.
  • Table 1 shows the fiber diameter, average apparent density, and porosity of the obtained porous material.
  • the sample was treated with a spatter coating (P t 1. O nm), S EM (J SM-53 10 type (manufactured by JEOL)), Calo fast voltage: 2. O kV, shooting angle 3 0 Observation was carried out by °).
  • the apparent density and porosity of the porous material were calculated by the following formula. p— 4 mZ ⁇ d ⁇ n
  • a porous material was obtained in the same manner as in Example 1 except that centrifugation was performed for 15 minutes.
  • Table 1 shows the fiber diameter, average apparent density, and porosity of the obtained porous material.
  • a porous material was obtained in the same manner as in Example 1 except that centrifugation was performed for 20 minutes.
  • Table 1 shows the fiber diameter, average apparent density, and porosity of the obtained porous material.
  • Fig. 4 shows an optical micrograph of the porous material obtained in Example 3 (D.I GITAL MICROSC OPEE, KEYENCE, magnification: 450 times).
  • a porous material was obtained in the same manner as in Example 1 except that centrifugation was performed for 5 minutes.
  • Table 1 shows the fiber diameter, average apparent density, and porosity of the obtained porous material.
  • Fig. 5 shows an optical micrograph (magnification: 450 times) of the porous material obtained in Example 4.
  • Polylactic acid-polyglycolanolic acid copolymer 0.9 g, phosphatidylethanolamine dioleoinole 0.1 g, methylene chloride Zethanol 7Z2 (parts by weight / parts) 9 g mixed at room temperature (25 ° C)
  • a dope solution having a concentration of 10% was prepared.
  • the fibrous material collecting electrode 5 was discharged for 5 minutes.
  • the inner diameter of the ejection nozzle 7 was 0.8 mm, the voltage was 14 kV, and the distance from the ejection nozzle 7 to the fibrous material collecting electrode was 10 cm.
  • 0.2 g of the obtained fibrous material was put into 5 Oml of ION-exchanged water, and cut with a homogenizer (registered trademark POLY TRON PT 2100) at a rotation speed of 22, O 2 O pm for 5 minutes.
  • a part of the obtained suspension was centrifuged for 10 minutes using a centrifuge (KUBOTA KN_70, rotation radius: 15 cm) at a rotation speed of 1 O O Orpm (170 G). Further, the suspension was added thereto, followed by centrifugation at 2, O O O rpm (700 G) for 10 minutes, and in the same manner, and centrifugation was performed at 3,000 rpm (1,500 G) for 10 minutes. Then, after freezing at 20 ° C.
  • Table 2 shows the fiber diameter and porosity of the obtained porous body.
  • the sample was sputter coated (Ptl. Onm) and observed with SEM JSM-5310 type (manufactured by JEOL Ltd., acceleration voltage: 2.0 kV, shooting angle 30 °) to determine the fiber diameter.
  • Fig. 6 shows the upper SEM photo
  • Fig. 7 shows the middle
  • Fig. 8 shows the lower SEM.
  • Table 2 Fiber diameter and porosity of porous materials
  • the dope solution was adjusted to 0 / 0.
  • install an electrostatic remover Kerat Electric Co., Ltd.
  • HE I DON scraper between the nozzle and electrode.
  • the yarn was discharged for 1 minute, and the yarn spun by the winder 1 9 was wound up to obtain a fiber structure, at which time the rotational speed of the winder was 10 Q r pm.
  • Example 7 A fiber structure was obtained in the same manner as in Example 6 except that the spinning time was 45 minutes and the number of revolutions of the winder was 20 rpm. Table 3 shows the fiber diameter, average apparent density, and porosity of the obtained porous material. FIG. 10 shows an optical microscopic photograph (magnification: 450 times) of the porous body obtained in Example 7. The compressive strength was 0.006 MPa.
  • the upper layer was produced with a spinning time of 60 minutes and a winder speed of 100 rpm, and then the lower layer was made with a spinning time of 20 minutes and a winder speed of 20 rpm.
  • a fiber structure was obtained in the same manner as in Example 6. Table 3 shows the fiber diameter, average apparent density, and porosity of the obtained porous material.
  • NZW Usagi The New Zealand White Rabbit used in the experiment (hereinafter NZW Usagi) was male and was purchased from SLC, Inc., and reared normally on a gauge. The age at the time of surgery was 24 weeks.
  • Ketarar and Seractal were given intramuscularly to the hind limb thighs of NZW Usagi that were normally bred, and the following surgery was performed under general anesthesia.
  • the area around the knee joint on both hind limbs was shaved and disinfected with ethanol. Thereafter, the inside of the knee joint was incised, and the femoral patella groove was exposed by dislocation of the patella.
  • the entire thickness of the knee joint cartilage was lost by creating a cylindrical defect part with an inner diameter of 5 mm and a depth of 5 mm with a surgical drill in the pulley groove part about 5 mm above the medial collateral ligament. .
  • Example 3 After embedding a porous body with an average apparent density of 208 kg / cm 3 (porosity 38%) produced in Example 3 in the defect, the patella was returned to its original position and the muscle was used as a surgical suture. And sutured. Penicillin was dropped on the affected area to prevent infection, and the skin was sutured. Finally, it was sterilized with iodine tincture and returned to Gai'ji for normal breeding.
  • the defect site was removed, and the cartilage tissue was visually observed, immersed in 10% neutral buffered formalin solution and fixed for histological evaluation.
  • the fixed tissue was degreased and EDTA decalcified, then embedded in paraffin, and a specimen was prepared by slicing the vicinity of the center of the defect into a sagittal plane. 0— Fa st Green stained.
  • Example 9 A biological evaluation was carried out in the same manner as in Example 8, using a porous material of Example 4 (average apparent density 100 kg / cm 3 , porosity '70%).
  • FIG. 12 A micrograph of the specimen is shown in Fig. 12.
  • the cartilage tissue repaired at 8 weeks after the operation was formed with a thickness almost equal to that of the normal part, and most of the cartilage was like hyaline cartilage, and the production of cartilage matrix was observed to be good.
  • the connection with the normal part was good, and continuity of the tissue was observed. ⁇ '
  • Example 8 Biological evaluation was performed in the same manner as in Example 8 except that the porous material was not embedded in the defect. A micrograph of the specimen is shown in Fig. 13. At 8 weeks after the operation, the cartilage tissue was missing and the subchondral bone was exposed. In addition, the trabecular bone of the subchondral bone was scarce and repair of the cartilage tissue was not observed. Histological evaluation was performed by scoring the following items for Examples 8 and 9 and Comparative Example 1.
  • the score grade used for histological evaluation is a modified version of Wakitani S et. Al., J Bone Joint Surg Am. 76, 579-92 (1994) Makino T et al., Kobe J Med Sci. 48: It carried out according to 97-104 (2002).
  • Figure 14 shows the items and scores used in the histological evaluation.
  • the total is 14 points, and it is evaluated on a 3-5 scale depending on the item.
  • the items are: repaired tissue morphology (0 to .4 points), matrix staining (0 to 3 points), surface condition (0 to 3 points), cartilage tissue thickness (0 2 points from the point), and the degree of connectivity with the non-deficient part (0 to 2 points). In this method, the closer to normal tissue, the higher the score.

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  • Health & Medical Sciences (AREA)
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Abstract

Objet poreux caractérisé en ce qu'il comprend une structure fibreuse faite d'un polymère bioabsorbable et en ce que la structure fibreuse a un diamètre moyen des fibres de 0,05-10 µm, une densité apparente moyenne de 10-350 kg/m3 et une hauteur supérieure ou égale à 0,5 mm. Il convient pour être utilisé comme objet poreux bioabsorbable, en particulier comme matériau prothétique ou comme substrat pour l'incubation de cellules dans le domaine de la médecine régénérative.
PCT/JP2005/016698 2004-09-07 2005-09-06 Objet poreux bioabsorbable WO2006028244A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02206457A (ja) * 1989-02-07 1990-08-16 Terumo Corp 生体器官用補綴材
US5607474A (en) * 1992-02-14 1997-03-04 Board Of Regents, University Of Texas System Multi-phase bioerodible implant/carrier and method of manufacturing and using same
JP2004162215A (ja) * 2002-11-14 2004-06-10 Teijin Ltd ポリグリコール酸繊維構造体、およびその製造方法
JP2004238749A (ja) * 2003-02-04 2004-08-26 Japan Vilene Co Ltd 静電紡糸方法及び静電紡糸装置

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02206457A (ja) * 1989-02-07 1990-08-16 Terumo Corp 生体器官用補綴材
US5607474A (en) * 1992-02-14 1997-03-04 Board Of Regents, University Of Texas System Multi-phase bioerodible implant/carrier and method of manufacturing and using same
JP2004162215A (ja) * 2002-11-14 2004-06-10 Teijin Ltd ポリグリコール酸繊維構造体、およびその製造方法
JP2004238749A (ja) * 2003-02-04 2004-08-26 Japan Vilene Co Ltd 静電紡糸方法及び静電紡糸装置

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