US20100119564A1 - Guided bone regeneration membrane and manufacturing method thereof - Google Patents
Guided bone regeneration membrane and manufacturing method thereof Download PDFInfo
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- US20100119564A1 US20100119564A1 US12/591,258 US59125809A US2010119564A1 US 20100119564 A1 US20100119564 A1 US 20100119564A1 US 59125809 A US59125809 A US 59125809A US 2010119564 A1 US2010119564 A1 US 2010119564A1
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- bone regeneration
- guided bone
- regeneration membrane
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
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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
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- 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
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L31/125—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
- A61L31/128—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix containing other specific inorganic fillers not covered by A61L31/126 or A61L31/127
-
- 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
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/148—Materials at least partially resorbable by the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L67/00—Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Compositions of derivatives of such polymers
- C08L67/04—Polyesters derived from hydroxycarboxylic acids, e.g. lactones
-
- 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
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Definitions
- the present invention relates to a guided bone regeneration membrane and a manufacturing method thereof.
- the guided bone regeneration membrane is used in a guided bone regeneration (GBR) technique which is one of techniques for repairing bone defects and which is widely used in the field of oral surgery and maxillofacial surgery.
- GLR guided bone regeneration
- Guided bone regeneration membranes are masking membranes that cover bone defect areas so as to prevent invasion of non-osteogenesis-contributed cells and tissues into the bone defect areas and to allow the bone to reconstruct by taking full advantage of self-regenerative power thereof.
- Guided bone regeneration techniques using these membranes cure bone defects by using a healing potential which the living body inherently has. The techniques are not complicated in their operative procedures and have given many satisfactory outcomes in oral surgery.
- the guided bone regeneration membranes are broadly grouped under non-bioresorbable membranes and bioresorbable membranes.
- a polytetrafluoroethylene expanded polytetrafluoroethylene; ePTEF
- ePTEF expanded polytetrafluoroethylene
- This material places a not-so light burden on a patient, because it is not bioresorbable and thereby needs a secondary operation for the removal of the membrane after the target bone defect area is repaired.
- bioresorbable guided bone regeneration membranes that are bioresorbable can avoid the surgical stress caused by the secondary operation.
- exemplary materials for such bioresorbable guided bone regeneration membranes include poly(lactic acid)s as bioresorbable synthetic polyesters; and copoly(lactic acid/glycolic acid)s; and collagens and fasciae each of biological origin.
- Such bioresorbable guided bone regeneration membranes have been recently investigated and developed heavily, and some of them have already been commercialized.
- a bone regeneration membrane including a composite of a bioresorbable polymer with tricalcium phosphate or hydroxyapatite and having micropores Japanese Unexamined Patent Application Publication (JP-A) No. H06 (1994)-319794
- a protective membrane including a felt made from a bioresorbable material Japanese Unexamined Patent Application Publication (JP-A) No. H07 (1995)-265337; and Japanese Unexamined Patent Application Publication (JP-A) No.
- a multilayer membrane including a sponge-like collagen matrix layer and a relatively impermeable barrier layer Japanese Unexamined Patent Application Publication (Translation of PCT Application) (JP-A) No. 2001-519210)
- a bioresorbable tissue regeneration membrane for dental use which has a porous sheet-like structure including a polymer blend containing two or more different bioresorbable polymers
- Japanese Unexamined Patent Application Publication (JP-A) No. 2002-85547 Japanese Unexamined Patent Application Publication (JP-A) No. 2002-85547
- a resorbable flexible implant in the form of a continuous micro-porous sheet Japanese Unexamined Patent Application Publication (Translation of PCT Application) (JP-A) No. 2003-517326
- a biocompatible membrane prepared by three-dimensional powder sinter molding through application of laser light to a biodegradable resin powder Japanese Unexamined Patent Application Publication (JP-A) No. 2006-187303).
- the present invention provides, in an embodiment, a guided bone regeneration membrane which has a bi-layered structure including a first nonwoven fabric layer and a second nonwoven fabric layer.
- the first nonwoven fabric layer contains a silicon-releasable calcium carbonate (Si—CaCO 3 ) and a biodegradable resin, represented by a poly(lactic acid) (PLA), as principal components (hereinafter referred to as “Si—CaCO 3 /PLA layer”).
- the second nonwoven fabric layer contains biodegradable resin, representedbya PLA, as a principal component (hereinafter referred to as “PLA layer”).
- PLA poly(lactic acid)
- the Si—CaCO 3 /PLA layer may be further coated with an apatite.
- the PLA layer has the function of preventing the invasion of soft tissues, and the apatite-coated Si—CaCO 3 /PLA layer has the function of improving cellular affinity and/or osteogenic ability.
- a technique of manufacturing a nonwoven fabric through electrospinning is adopted to the manufacturing of such a guided bone regeneration membrane. This provides an easy manufacturing of a membrane that has continuous pores for supplying nutrients to cells and shows improved fitting ability to an affected area.
- Such a bioresorbable apatite that improves cellular initial adhesion can be easily applied to the Si—CaCO 3 /PLA layer by soaking the layer in a simulated body fluid (SEF).
- SEF simulated body fluid
- the guided bone regeneration membrane according to the present invention shows high cellular growth ability in cellular affinity tests using osteoblastic cells (MC3T3-E1 cells) and is expected as a bioresorbable guided bone regeneration membrane that excels in bone reconstruction ability.
- the method according to the present invention can easily and efficiently manufacture a guided bone regeneration membrane having the above possibility.
- FIG. 1 is a scanning electron micrograph (SEM photograph) of a PLA layer surface of a guided bone regeneration membrane prepared in Example 1;
- FIG. 2 is a scanning electron micrograph of a Si—CaCO 3 /PLA layer surface of the guided bone regeneration membrane prepared in Example 1;
- FIG. 3 is a scanning electron micrograph of a surface of a PLA layer prepared in Example 2;
- FIG. 4 is a scanning electron micrograph of a surface of a Si—CaCO 3 /PLA layer prepared in Example 2;
- FIG. 5 is a scanning electron micrograph of fibers configuring the Si—CaCO 3 /PLA layer prepared in Example 2;
- FIG. 6 is a scanning electron micrograph of fibers configuring the Si—CaCO 3 /PLA layer after soaking a composite membrane prepared in Example 2 in 1.5 SBF;
- FIG. 7 depicts X-ray diffraction patterns of the composite membrane prepared in Example 2, before and after soaking in 1.5SBF;
- FIG. 8 is a graph for the evaluation of the cellular affinity of the Si—CaCO 3 /PLA layer and PLA layer prepared in Example 2.
- such a guided bone regeneration membrane can be manufactured through the steps of electrospinning and soaking in a simulated body fluid (SBF).
- a positive high voltage is applied to a polymer solution, and the resulting polymer solution is sprayed as fibers to a negatively charged collector.
- a spinning solution for the formation of the PLA layer is prepared by dissolving a poly(lactic acid) in chloroform (CHCl 3 ) or dichloromethane (DCM).
- the PLA spinning solution preferably has a poly (lactic acid) concentration of from 4 to 12 percent by weight for easy spinning.
- the poly(lactic acid) generally has a molecular weight of from about 20 ⁇ 10 4 to about 30 ⁇ 10 4 .
- the PLA spinning solution may further contain dimethylformamide (DMF) and/or methanol (CH 3 OH) in an amount up to about 50 percent by weight relative to the amount of CHCl 3 or DCM.
- Si—CaCO 3 /PLA spinning solution Another spinning solution for the formation of the Si—CaCO 3 /PLA layer (Si—CaCO 3 /PLA spinning solution) is prepared by adding Si—CaCO 3 to the PLA spinning solution.
- the Si—CaCO 3 is preferably added to the solution so that the Si—CaCO 3 /PLA layer has a Si—CaCO 3 content of from 40 to 60 percent by weight. This allows an apatite to deposit efficiently on Si—CaCO 3 /PLA fibers in the SBF soaking step.
- a Si—CaCO 3 /PLA spinning solution can be prepared by kneading a poly (lactic acid) and Si—CaCO 3 in predetermined proportions using a heating kneader to give a composite, and dissolving the composite in a solvent.
- the Si—CaCO 3 may be prepared, for example, by the method described in Japanese Patent Application No. 2006-285429 (corresponding to Japanese Unexamined Patent Application Publication (JP-A) No. 2008-100878).
- the PLA layer preferably contains a poly(lactic acid) (PLA) alone or a copolymer between a poly (lactic acid) and a poly(glycolic acid) (PGA) (copoly(lactic acid/glycolic acid))
- PLA poly(lactic acid)
- PGA poly(glycolic acid)
- Exemplary other biodegradable resins usable herein include synthetic polymers such as polyethylene glycols (PEGS), polycaprolactones (PCLs), as well as copolymers among lactic acid, glycolic acid, ethylene glycol, and/or caprolactone; and natural polymers such as fibrin, collagens, alginic acids, hyaluronic acids, chitins, and chitosans.
- the Si—CaCO 3 /PLA layer and the PLA layer may further contain inorganic substances that are usable without biological problems.
- inorganic substances include tricalcium phosphate, calcium sulfate, sodium phosphate, sodium hydrogenphosphate, calcium hydrogenphosphate, octacalcium phosphate, tetracalcium phosphate, calcium pyrophosphate, and calcium chloride.
- each of the PLA layer spinning solution and the Si—CaCO 3 /PLA spinning solution is charged and sprayed from a nozzle, converted into fibers in an electric field while evaporating the solvent, the charged fibers are jetted toward a collector on a negative electrode and form a thin layer of fibers on the collector.
- a desired guided bone regeneration membrane can be prepared by changing spinning conditions such as the concentration, solvent type, and supply speed (feed rate) of the spinning solution; spinning time; applied voltage; and distance between the nozzle and the collector.
- the prepared nonwoven fabrics may be pressed so as to be compacted or to have a desired thickness.
- a guided bone regeneration membrane having a bi-layered structure is configured by spraying the PLA spinning solution to form a PLA layer, and thereafter spraying the Si—CaCO 3 /PLA spinning solution to form a Si—CaCO 3 /PLA layer on the PLA layer; or by preparing a PLA nonwoven fabric and a Si—CaCO 3 /PLA nonwoven fabric independently, and combining the two nonwoven fabrics.
- the guided bone regeneration membrane having a bi-layered structure is cut to a desired size and soaked in a simulated body fluid (SBF) or a solution with 1.5 times higher concentration of inorganic ions compared to SBF (1.5SBF) at about 37° C.
- SBF simulated body fluid
- the SBF soaking can be performed even after the combining (or laminating) the two layers. Even in this case, the apatite deposits substantially not on the PLA layer but selectively on the Si—CaCO 3 /PLA layer.
- Silicon-releasable calcium carbonate (Si—CaCO 3 ): Vaterite having a silicon content of 2.9 percent by weight and prepared by using slaked lime (Microstar T; purity 96% or more; Yabashi Industries Co., Ltd., Japan), methanol (analytical grade reagent; purity 99.8% or more; Kishida Chemical Co., Ltd., Japan), ⁇ -aminopropyltriethoxysilane (TSL 8331; purity 98% or more; GE Toshiba Silicones Co., Ltd., Japan), and carbon dioxide gas (high-purity liquefied carbon dioxide gas; purity 99.9%; Taiyo Kagaku Kogyo K.K.)
- PVA Poly(lactic acid)
- PURASORB Poly(L-lactide)
- molecular weight 20 ⁇ 10 4 to 30 ⁇ 10 4
- N,N-Dimethylformamide (DMF) Analytical grade reagent, purity 99.5% or more, Kishida Chemical Co., Ltd., Japan
- DMF N,N-Dimethylformamide
- a PLA spinning solution having a PLA concentration of 6.8 percent by weight was prepared by blending 10 g of PLA, 110 g of CHCl 3 , and 27.5 g of DMF.
- a Si—CaCO 3 /PLA spinning solution having a Si—CaCO 3 concentration of 7.5 percent by weight and a PLA concentration of 5.0 percent by weight was prepared by blending 15 g of Si—CaCO 3 , 10 g of PLA, 140 g of CHCl 3 , and 35 g of DMF.
- a guided bone regeneration membrane having a bi-layered structure of nonwoven fabrics was manufactured through electrospinning.
- Spinning solution feed rate about 0.1 ml/min.
- applied voltage 15 kV
- distance between the nozzle and collector 10 cm
- nozzle laterally moves in a width of 3 to 4 cm at a rate of 15 cm/min
- conveyor-type collector Conveyor speed: 5 to 6 m/min
- spinning time about 170 minutes
- Spinning solution feed rate about 0.16 ml/min
- applied voltage 20 kV
- distance between the nozzle and collector 10 cm
- nozzle laterally moves in a width of 3 to 4 cm at a rate of 15 cm/min
- conveyor-type collector Conveyor speed: 5 to 6 m/min
- spinning time about 130 minutes
- the microstructure of the prepared PLA layer (side for preventing soft tissue invasion) is shown in the scanning electron microscope (SEM) photograph of FIG. 1 .
- the microstructure of the Si—CaCO 3 /PLA layer (bone regeneration side) is shown in the scanning electronmicrograph of FIG. 2 , demonstrating that Si—CaCO 3 particles are attached to PLA fibers.
- a spinning solution having a PLA concentration of 9.0 percent by weight was prepared by blending 9 g of PLA and 91 g of CHCl 3 , and using this spinning solution, a PLA layer was prepared through electrospinning.
- Spinning solution feed rate 0.05 ml/min, applied voltage: 20 kV, distance between the nozzle and collector: 15 cm, nozzle: fixed, plate collector: fixed, spinning time: 60 minutes
- PLA and Si—CaCO 3 were kneaded in a heating kneader at 200° C. for 15 minutes to give a Si—CaCO 3 /PLA composite containing 60 percent by weight of Si—CaCO 3 .
- a spinning solution having a Si—CaCO 3 concentration of 13.0 percent by weight and a PLA concentration of 8.7 percent by weight was prepared by blending 25 g of the Si—CaCO 3 /PLA composite and 90 g of CHCl 3 , and using this spinning solution, a Si—CaCO 3 /PLA layer was prepared through electrospinning.
- Spinning solution feed rate 0.05 ml/min
- applied voltage is 20 kV
- distance between the nozzle and collector 15 cm
- nozzle fixed
- plate collector fixed
- spinning time 30 minutes
- the two nonwoven fabrics prepared by the above procedures were each cut to a desired size and affixed or combined with each other to give one membrane.
- the PLA layer was laid over the Si—CaCO 3 /PLA layer, and a stainless steel mesh (40-mesh) was laid over the PLA layer.
- a plate heated at 150° C. to 160° C. was placed on the stainless steel mesh and pressed under a suitable pressure for about 10 seconds to give the combined membrane (composite membrane).
- FIG. 3 and FIG. 4 The scanning electron micrographs of fibers configuring the Si—CaCO 3 /PLA layer is shown in FIG. 5 , demonstrating that Si—CaCO 3 particles are attached to PLA fibers.
- the Si—CaCO 3 /PLA layer surface of the resulting composite membrane was brought into contact with 1.5SBF at 37° C. for one day.
- the scanning electron micrograph of fibers on the side in contact with 1.5SBF is shown in FIG. 6 , demonstrating that a substance quite different from Si—CaCO 3 covers the surface of fibers, as compared to FIG. 5 .
- the X-ray diffraction patterns before and after soaking in 1.5SBF are shown in FIG. 7 , indicating that peaks of apatite appear after the soaking.
- FIG. 8 shows how cellular numbers (in terms of cellular numbers per 1 cm 2 ) vary after the inoculation of osteoblastic cells on the apatite-coated Si—CaCO 3 /PLA layer surface (Si-composite), on the PLA layer surface (PLA), and on a control (Thermanox: plastic disc for cell culture which has been treated on its surface).
- the data in FIG. 8 demonstrate that the layer including PLA in combination with a novel mechanism gives higher growth capability to osteoblasts, and the resulting guided bone regeneration membrane is expected as a bioresorbable guided bone regeneration membrane that excels in bone reconstruction ability.
- ⁇ -MEM containing 10% fetal bovine serum
- Cell counting method The measurement was performed using the Cell Counting Kit-8 (cellular growth/cellular toxicity analytical reagent; Dojindo Laboratories) in accordance with the protocol attached to the reagent.
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Abstract
Description
- The present invention relates to a guided bone regeneration membrane and a manufacturing method thereof. The guided bone regeneration membrane is used in a guided bone regeneration (GBR) technique which is one of techniques for repairing bone defects and which is widely used in the field of oral surgery and maxillofacial surgery.
- Guided bone regeneration membranes are masking membranes that cover bone defect areas so as to prevent invasion of non-osteogenesis-contributed cells and tissues into the bone defect areas and to allow the bone to reconstruct by taking full advantage of self-regenerative power thereof. Guided bone regeneration techniques using these membranes cure bone defects by using a healing potential which the living body inherently has. The techniques are not complicated in their operative procedures and have given many satisfactory outcomes in oral surgery.
- The guided bone regeneration membranes are broadly grouped under non-bioresorbable membranes and bioresorbable membranes. A polytetrafluoroethylene (expanded polytetrafluoroethylene; ePTEF) has been practically used as a material for a non-bioresorbable membrane, from which good clinical data have been obtained. This material, however, places a not-so light burden on a patient, because it is not bioresorbable and thereby needs a secondary operation for the removal of the membrane after the target bone defect area is repaired. In addition, it is difficult to adopt this material to a large defect area, because the material is bioinert (non-bioresorbable). In contrast, use of guided bone regeneration membranes that are bioresorbable can avoid the surgical stress caused by the secondary operation. Exemplary materials for such bioresorbable guided bone regeneration membranes include poly(lactic acid)s as bioresorbable synthetic polyesters; and copoly(lactic acid/glycolic acid)s; and collagens and fasciae each of biological origin. Such bioresorbable guided bone regeneration membranes have been recently investigated and developed heavily, and some of them have already been commercialized. Typically, there have been proposed a wide variety of guided bone regeneration membranes and manufacturing methods thereof; such as a bone regeneration membrane including a composite of a bioresorbable polymer with tricalcium phosphate or hydroxyapatite and having micropores (Japanese Unexamined Patent Application Publication (JP-A) No. H06 (1994)-319794); a protective membrane including a felt made from a bioresorbable material (Japanese Unexamined Patent Application Publication (JP-A) No. H07 (1995)-265337; and Japanese Unexamined Patent Application Publication (JP-A) No. 2004-105754); a multilayer membrane including a sponge-like collagen matrix layer and a relatively impermeable barrier layer (Japanese Unexamined Patent Application Publication (Translation of PCT Application) (JP-A) No. 2001-519210); a bioresorbable tissue regeneration membrane for dental use, which has a porous sheet-like structure including a polymer blend containing two or more different bioresorbable polymers (Japanese Unexamined Patent Application Publication (JP-A) No. 2002-85547); a resorbable flexible implant in the form of a continuous micro-porous sheet (Japanese Unexamined Patent Application Publication (Translation of PCT Application) (JP-A) No. 2003-517326); and a biocompatible membrane prepared by three-dimensional powder sinter molding through application of laser light to a biodegradable resin powder (Japanese Unexamined Patent Application Publication (JP-A) No. 2006-187303).
- In particular, oral or maxillary bone defects should be desirably cured as soon as possible, because it is very important to maintain and ensure mastication for the health maintenance in a super-graying society. To improve osteogenic ability, there have been attempts to incorporate to a bioresorbable membrane a factor such as an osteogenesis inducer (Japanese Unexamined Patent Application Publication (JP-A) No. H06 (1994)-319794), a growth factor or a bone morphogenic protein (Japanese Unexamined Patent Application Publication (Translation of PCT Application) (JP-A) No. 2001-519210; and Japanese Unexamined Patent Application Publication (JP-A) No. 2006-187303). However, it is difficult to handle these factors. Accordingly, demands have been made to develop a bioresorbable guided bone regeneration membrane having superior bone reconstruction ability to allow the bone to self-regenerate more reliably and more rapidly.
- In view of recent trends of researches and technologies for bio-related materials, the main stream of researches has been shifted from a materials design for the bonding of a material with the bone to a materials design for the regeneration of a real bone; in these researches, the role of silicon in osteogenesis has been received attention; and there have been designed a variety of materials containing silicon (TSURU Kanji, OGAWA Tetsuro, and OGUSHI Hajime, “Recent Trends of Bioceramics Research, Technology and Standardization”, Ceramics Japan, 41, 549-553 (2006)). For example, there has been reported that the controlled release of silicon genetically acts on cells to promote osteogenesis (H. Maeda, T. Kasuga, and L. L. Hench, “Preparation of Poly(L-lactic acid)-Polysiloxane-Calcium Carbonate Hybrid Membranes for Guided Bone Regeneration”, Biomaterials, 27, 1216-1222 (2006)). Independently, when composites of a poly(lactic acid) with one of three calcium carbonates (calcite, aragonite, and vaterite) are soaked in a simulated body fluid (SBF), the composite of a poly(lactic acid) with vaterite forms a bone-like apatite within a shortest time among the three composites (H. Maeda, T. Kasuga, M. Nogami, and Y Ota, “Preparation of Calcium Carbonate Composite and Their Apatite-Forming Ability in Simulated Body Fluid”, J. Ceram. Soc. Japan, 112, S804-808 (2004)). These findings demonstrate that the use of vaterite which gradually releases silicon is believed to be a key to provide a guided bone regeneration membrane that gives rapid bone reconstruction.
- An object of the present invention is to provide a bioresorbable guided bone regeneration membrane that includes a novel mechanism effectively inducing a bone reconstruction ability. Another object of the present invention is to provide a method for manufacturing a guided bone regeneration membrane of high performance (achieving rapid bone reconstruction) in an inexpensive and industrially advantageous manner.
- The present invention provides, in an embodiment, a guided bone regeneration membrane which has a bi-layered structure including a first nonwoven fabric layer and a second nonwoven fabric layer. The first nonwoven fabric layer contains a silicon-releasable calcium carbonate (Si—CaCO3) and a biodegradable resin, represented by a poly(lactic acid) (PLA), as principal components (hereinafter referred to as “Si—CaCO3/PLA layer”). The second nonwoven fabric layer contains biodegradable resin, representedbya PLA, as a principal component (hereinafter referred to as “PLA layer”). In the guided bone regeneration membrane, the Si—CaCO3/PLA layer may be further coated with an apatite.
- The PLA layer has the function of preventing the invasion of soft tissues, and the apatite-coated Si—CaCO3/PLA layer has the function of improving cellular affinity and/or osteogenic ability. In another embodiment, a technique of manufacturing a nonwoven fabric through electrospinning is adopted to the manufacturing of such a guided bone regeneration membrane. This provides an easy manufacturing of a membrane that has continuous pores for supplying nutrients to cells and shows improved fitting ability to an affected area. Such a bioresorbable apatite that improves cellular initial adhesion can be easily applied to the Si—CaCO3/PLA layer by soaking the layer in a simulated body fluid (SEF).
- The guided bone regeneration membrane according to the present invention shows high cellular growth ability in cellular affinity tests using osteoblastic cells (MC3T3-E1 cells) and is expected as a bioresorbable guided bone regeneration membrane that excels in bone reconstruction ability. The method according to the present invention can easily and efficiently manufacture a guided bone regeneration membrane having the above possibility.
- Other objects, features and advantages of the present invention will be understood more fully from the following detailed description made with reference to the accompanying drawings. In the drawings:
-
FIG. 1 is a scanning electron micrograph (SEM photograph) of a PLA layer surface of a guided bone regeneration membrane prepared in Example 1; -
FIG. 2 is a scanning electron micrograph of a Si—CaCO3/PLA layer surface of the guided bone regeneration membrane prepared in Example 1; -
FIG. 3 is a scanning electron micrograph of a surface of a PLA layer prepared in Example 2; -
FIG. 4 is a scanning electron micrograph of a surface of a Si—CaCO3/PLA layer prepared in Example 2; -
FIG. 5 is a scanning electron micrograph of fibers configuring the Si—CaCO3/PLA layer prepared in Example 2; -
FIG. 6 is a scanning electron micrograph of fibers configuring the Si—CaCO3/PLA layer after soaking a composite membrane prepared in Example 2 in 1.5 SBF; -
FIG. 7 depicts X-ray diffraction patterns of the composite membrane prepared in Example 2, before and after soaking in 1.5SBF; and -
FIG. 8 is a graph for the evaluation of the cellular affinity of the Si—CaCO3/PLA layer and PLA layer prepared in Example 2. - The present invention will be described further with reference to various embodiments in the drawings.
- According to a preferred embodiment of the present invention, such a guided bone regeneration membrane can be manufactured through the steps of electrospinning and soaking in a simulated body fluid (SBF). In the electrospinning step, a positive high voltage is applied to a polymer solution, and the resulting polymer solution is sprayed as fibers to a negatively charged collector.
- A spinning solution for the formation of the PLA layer (PLA spinning solution) is prepared by dissolving a poly(lactic acid) in chloroform (CHCl3) or dichloromethane (DCM). The PLA spinning solution preferably has a poly (lactic acid) concentration of from 4 to 12 percent by weight for easy spinning. In this connection, the poly(lactic acid) generally has a molecular weight of from about 20×104 to about 30×104. For maintaining conditions for satisfactory spinning, the PLA spinning solution may further contain dimethylformamide (DMF) and/or methanol (CH3OH) in an amount up to about 50 percent by weight relative to the amount of CHCl3 or DCM. Another spinning solution for the formation of the Si—CaCO3/PLA layer (Si—CaCO3/PLA spinning solution) is prepared by adding Si—CaCO3 to the PLA spinning solution. The Si—CaCO3 is preferably added to the solution so that the Si—CaCO3/PLA layer has a Si—CaCO3 content of from 40 to 60 percent by weight. This allows an apatite to deposit efficiently on Si—CaCO3/PLA fibers in the SBF soaking step. Alternatively, a Si—CaCO3/PLA spinning solution can be prepared by kneading a poly (lactic acid) and Si—CaCO3 in predetermined proportions using a heating kneader to give a composite, and dissolving the composite in a solvent. The Si—CaCO3 may be prepared, for example, by the method described in Japanese Patent Application No. 2006-285429 (corresponding to Japanese Unexamined Patent Application Publication (JP-A) No. 2008-100878). The PLA layer preferably contains a poly(lactic acid) (PLA) alone or a copolymer between a poly (lactic acid) and a poly(glycolic acid) (PGA) (copoly(lactic acid/glycolic acid)) Exemplary other biodegradable resins usable herein include synthetic polymers such as polyethylene glycols (PEGS), polycaprolactones (PCLs), as well as copolymers among lactic acid, glycolic acid, ethylene glycol, and/or caprolactone; and natural polymers such as fibrin, collagens, alginic acids, hyaluronic acids, chitins, and chitosans. Each of these can be used instead of the PLA component in the Si—CaCO3/PLA layer. The Si—CaCO3/PLA layer and the PLA layer may further contain inorganic substances that are usable without biological problems. Examples of such inorganic substances include tricalcium phosphate, calcium sulfate, sodium phosphate, sodium hydrogenphosphate, calcium hydrogenphosphate, octacalcium phosphate, tetracalcium phosphate, calcium pyrophosphate, and calcium chloride.
- Using an electrospinning apparatus, each of the PLA layer spinning solution and the Si—CaCO3/PLA spinning solution is charged and sprayed from a nozzle, converted into fibers in an electric field while evaporating the solvent, the charged fibers are jetted toward a collector on a negative electrode and form a thin layer of fibers on the collector. A desired guided bone regeneration membrane can be prepared by changing spinning conditions such as the concentration, solvent type, and supply speed (feed rate) of the spinning solution; spinning time; applied voltage; and distance between the nozzle and the collector. The prepared nonwoven fabrics may be pressed so as to be compacted or to have a desired thickness. A guided bone regeneration membrane having a bi-layered structure is configured by spraying the PLA spinning solution to form a PLA layer, and thereafter spraying the Si—CaCO3/PLA spinning solution to form a Si—CaCO3/PLA layer on the PLA layer; or by preparing a PLA nonwoven fabric and a Si—CaCO3/PLA nonwoven fabric independently, and combining the two nonwoven fabrics. The guided bone regeneration membrane having a bi-layered structure is cut to a desired size and soaked in a simulated body fluid (SBF) or a solution with 1.5 times higher concentration of inorganic ions compared to SBF (1.5SBF) at about 37° C. for a predetermined time to precipitate an apatite on the Si—CaCO3/PLA layer. This gives a bioresorbable guided bone regeneration membrane including a novel mechanism that effectively induces the bone reconstruction ability. The SBF soaking can be performed even after the combining (or laminating) the two layers. Even in this case, the apatite deposits substantially not on the PLA layer but selectively on the Si—CaCO3/PLA layer. This is because silicon contained in the Si—CaCO3/PLA layer induces nucleation of apatite, and the calcium component dissolves out to abruptly increase the degree of supersaturation of apatite, and the apatite selectively deposits on the surface of the Si—CaCO3/PLA layer; but the surface of the PLA layer is hydrophobic to avoid the deposition of apatite substantially.
- Manufacturing methods of guided bone regeneration membranes according to embodiments of the present invention will be illustrated with reference to several examples below. It should be noted, however, that these examples are included merely to aid in the understanding of the present invention and are not to be construed to limit the scope of the present invention.
- Raw materials used in the examples are as follows.
- Silicon-releasable calcium carbonate (Si—CaCO3): Vaterite having a silicon content of 2.9 percent by weight and prepared by using slaked lime (Microstar T; purity 96% or more; Yabashi Industries Co., Ltd., Japan), methanol (analytical grade reagent; purity 99.8% or more; Kishida Chemical Co., Ltd., Japan), γ-aminopropyltriethoxysilane (TSL 8331; purity 98% or more; GE Toshiba Silicones Co., Ltd., Japan), and carbon dioxide gas (high-purity liquefied carbon dioxide gas; purity 99.9%; Taiyo Kagaku Kogyo K.K.)
- Poly(lactic acid) (PLA): PURASORB PL Poly(L-lactide), molecular weight of 20×104 to 30×104, PURAC Biochem
- Chloroform (CHCl3): Analytical grade reagent, purity 99.0% or more, Kishida Chemical Co., Ltd., Japan
- N,N-Dimethylformamide (DMF): Analytical grade reagent, purity 99.5% or more, Kishida Chemical Co., Ltd., Japan Example 1
- A PLA spinning solution having a PLA concentration of 6.8 percent by weight was prepared by blending 10 g of PLA, 110 g of CHCl3, and 27.5 g of DMF. Independently, a Si—CaCO3/PLA spinning solution having a Si—CaCO3 concentration of 7.5 percent by weight and a PLA concentration of 5.0 percent by weight was prepared by blending 15 g of Si—CaCO3, 10 g of PLA, 140 g of CHCl3, and 35 g of DMF. Using the prepared spinning solutions, a guided bone regeneration membrane having a bi-layered structure of nonwoven fabrics was manufactured through electrospinning.
- [PLA Layer Preparation Conditions]
- Spinning solution feed rate: about 0.1 ml/min., applied voltage: 15 kV, distance between the nozzle and collector: 10 cm, nozzle: laterally moves in a width of 3 to 4 cm at a rate of 15 cm/min, conveyor-type collector (conveyor speed: 5 to 6 m/min), spinning time: about 170 minutes
- [Si—CaCO3/PLA Layer Preparation Conditions]
- Spinning solution feed rate: about 0.16 ml/min, applied voltage: 20 kV, distance between the nozzle and collector: 10 cm, nozzle: laterally moves in a width of 3 to 4 cm at a rate of 15 cm/min, conveyor-type collector (conveyor speed: 5 to 6 m/min), spinning time: about 130 minutes
- The microstructure of the prepared PLA layer (side for preventing soft tissue invasion) is shown in the scanning electron microscope (SEM) photograph of
FIG. 1 . The microstructure of the Si—CaCO3/PLA layer (bone regeneration side) is shown in the scanning electronmicrograph ofFIG. 2 , demonstrating that Si—CaCO3 particles are attached to PLA fibers. - A spinning solution having a PLA concentration of 9.0 percent by weight was prepared by blending 9 g of PLA and 91 g of CHCl3, and using this spinning solution, a PLA layer was prepared through electrospinning.
- [PLA Layer Preparation Conditions]
- Spinning solution feed rate: 0.05 ml/min, applied voltage: 20 kV, distance between the nozzle and collector: 15 cm, nozzle: fixed, plate collector: fixed, spinning time: 60 minutes
- Independently, PLA and Si—CaCO3 were kneaded in a heating kneader at 200° C. for 15 minutes to give a Si—CaCO3/PLA composite containing 60 percent by weight of Si—CaCO3. A spinning solution having a Si—CaCO3 concentration of 13.0 percent by weight and a PLA concentration of 8.7 percent by weight was prepared by blending 25 g of the Si—CaCO3/PLA composite and 90 g of CHCl3, and using this spinning solution, a Si—CaCO3/PLA layer was prepared through electrospinning.
- [Si—CaCO3/PLA Layer Preparation Conditions]
- Spinning solution feed rate: 0.05 ml/min, applied voltage: is 20 kV, distance between the nozzle and collector: 15 cm, nozzle: fixed, plate collector: fixed, spinning time: 30 minutes
- The two nonwoven fabrics prepared by the above procedures were each cut to a desired size and affixed or combined with each other to give one membrane. Specifically, the PLA layer was laid over the Si—CaCO3/PLA layer, and a stainless steel mesh (40-mesh) was laid over the PLA layer. A plate heated at 150° C. to 160° C. was placed on the stainless steel mesh and pressed under a suitable pressure for about 10 seconds to give the combined membrane (composite membrane). The scanning electron micrographs of the PLA layer surface and of the Si—CaCO3/PLA layer surface are shown in
FIG. 3 andFIG. 4 , respectively. The scanning electron micrograph of fibers configuring the Si—CaCO3/PLA layer is shown inFIG. 5 , demonstrating that Si—CaCO3 particles are attached to PLA fibers. - The Si—CaCO3/PLA layer surface of the resulting composite membrane was brought into contact with 1.5SBF at 37° C. for one day. The scanning electron micrograph of fibers on the side in contact with 1.5SBF is shown in
FIG. 6 , demonstrating that a substance quite different from Si—CaCO3 covers the surface of fibers, as compared toFIG. 5 . The X-ray diffraction patterns before and after soaking in 1.5SBF are shown inFIG. 7 , indicating that peaks of apatite appear after the soaking. These results demonstrate that the Si—CaCO3/PLA layer surface is coated with apatite. -
FIG. 8 shows how cellular numbers (in terms of cellular numbers per 1 cm2) vary after the inoculation of osteoblastic cells on the apatite-coated Si—CaCO3/PLA layer surface (Si-composite), on the PLA layer surface (PLA), and on a control (Thermanox: plastic disc for cell culture which has been treated on its surface). The data inFIG. 8 demonstrate that the layer including PLA in combination with a novel mechanism gives higher growth capability to osteoblasts, and the resulting guided bone regeneration membrane is expected as a bioresorbable guided bone regeneration membrane that excels in bone reconstruction ability. - Experimental Conditions
- Cultivation using 24-well plate
- Cell type; murine osteoblastic cells (MC3T3-E1 cells: Riken Institute of Physical and Chemical Research)
- Cellular inoculation number: 1×104 cells/well
- Medium: α-MEM (containing 10% fetal bovine serum)
- Medium exchange: on the day following the inoculation, thereafter every other day
- Cell counting method: The measurement was performed using the Cell Counting Kit-8 (cellular growth/cellular toxicity analytical reagent; Dojindo Laboratories) in accordance with the protocol attached to the reagent.
- While the above description is of the preferred embodiments of the present invention, it should be appreciated that the invention may be modified, altered, or varied without deviating from the scope and fair meaning of the following claims.
Claims (12)
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US16/227,582 US10814000B2 (en) | 2007-09-06 | 2018-12-20 | Guided bone regeneration membrane and manufacturing method thereof |
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US20120315319A1 (en) | 2012-12-13 |
US20180369382A1 (en) | 2018-12-27 |
US10092650B2 (en) | 2018-10-09 |
JP2009061109A (en) | 2009-03-26 |
US10814000B2 (en) | 2020-10-27 |
US20190117774A1 (en) | 2019-04-25 |
JP5179124B2 (en) | 2013-04-10 |
US10159737B1 (en) | 2018-12-25 |
US20140242186A1 (en) | 2014-08-28 |
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