WO2013125663A1 - 製剤注入具 - Google Patents
製剤注入具 Download PDFInfo
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- WO2013125663A1 WO2013125663A1 PCT/JP2013/054430 JP2013054430W WO2013125663A1 WO 2013125663 A1 WO2013125663 A1 WO 2013125663A1 JP 2013054430 W JP2013054430 W JP 2013054430W WO 2013125663 A1 WO2013125663 A1 WO 2013125663A1
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- WIPO (PCT)
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- end side
- distal end
- outer needle
- stem cells
- side opening
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/34—Trocars; Puncturing needles
- A61B17/3417—Details of tips or shafts, e.g. grooves, expandable, bendable; Multiple coaxial sliding cannulas, e.g. for dilating
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/16—Bone cutting, breaking or removal means other than saws, e.g. Osteoclasts; Drills or chisels for bones; Trepans
- A61B17/1604—Chisels; Rongeurs; Punches; Stamps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/34—Trocars; Puncturing needles
- A61B17/3472—Trocars; Puncturing needles for bones, e.g. intraosseus injections
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/34—Trocars; Puncturing needles
- A61B17/3478—Endoscopic needles, e.g. for infusion
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/178—Syringes
- A61M5/31—Details
- A61M5/32—Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
- A61M5/3286—Needle tip design, e.g. for improved penetration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/178—Syringes
- A61M5/31—Details
- A61M5/32—Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
- A61M5/3287—Accessories for bringing the needle into the body; Automatic needle insertion
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/178—Syringes
- A61M5/31—Details
- A61M5/32—Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
- A61M5/3295—Multiple needle devices, e.g. a plurality of needles arranged coaxially or in parallel
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/178—Syringes
- A61M5/31—Details
- A61M5/32—Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
- A61M5/3295—Multiple needle devices, e.g. a plurality of needles arranged coaxially or in parallel
- A61M5/3297—Needles arranged coaxially
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B2017/00969—Surgical instruments, devices or methods, e.g. tourniquets used for transplantation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/34—Trocars; Puncturing needles
- A61B17/3417—Details of tips or shafts, e.g. grooves, expandable, bendable; Multiple coaxial sliding cannulas, e.g. for dilating
- A61B2017/3454—Details of tips
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/0067—Catheters; Hollow probes characterised by the distal end, e.g. tips
- A61M25/0082—Catheter tip comprising a tool
- A61M25/0084—Catheter tip comprising a tool being one or more injection needles
- A61M2025/0089—Single injection needle protruding axially, i.e. along the longitudinal axis of the catheter, from the distal tip
- A61M2025/009—Single injection needle protruding axially, i.e. along the longitudinal axis of the catheter, from the distal tip the needle having a bent tip, i.e. the needle distal tip is angled in relation to the longitudinal axis of the catheter
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/0067—Catheters; Hollow probes characterised by the distal end, e.g. tips
- A61M25/0082—Catheter tip comprising a tool
- A61M25/0084—Catheter tip comprising a tool being one or more injection needles
- A61M2025/0092—Single injection needle protruding laterally from the distal tip
Definitions
- the present invention relates to a preparation injecting device for injecting a preparation into a patient's body, and more particularly to a preparation injecting device that can stimulate the body to enhance the therapeutic effect of the preparation. To do.
- a pharmaceutical injection catheter disclosed in Patent Document 1 is known as a conventional pharmaceutical injection tool.
- an inner tube having an injection needle at its tip is slidably inserted into an outer tube.
- a drug injection lumen is formed in the inner tube, and the injection needle of the inner tube protrudes from the outer tube and punctures the lesion site to inject the drug.
- the conventional drug infusion catheter described above is capable of local puncture and drug infusion, but there is room for improvement in terms of improving the therapeutic effect because of insufficient stimulation applied to the body.
- an object of the present invention is to provide a preparation injection device that can easily enhance the therapeutic effect of the preparation.
- the object of the present invention is to provide an outer needle formed in a straight tube shape having a distal end side opening and a proximal end side opening and having a reference puncture portion on the distal end side, and a peripheral puncture portion inserted detachably in the outer needle and on the distal end side.
- An inner needle, and the inner needle is configured such that the peripheral puncture portion can be projected and retracted from the opening on the distal end side by an advancing / retreating operation on the base side, and the inner needle is withdrawn from the outer needle,
- a preparation injection device capable of injecting a preparation supplied from a proximal end side opening from the distal end side opening, wherein the outer needle has the peripheral puncture part on the opposite side of the reference puncture part across a plane including an axis. This is achieved by a pharmaceutical injection tool that guides the inner needle to protrude.
- the reference puncture portion preferably has a puncture direction parallel to the axis of the outer needle, and the peripheral puncture portion may be separated from the axis with advancement from the distal end side opening. preferable.
- the inner needle includes a locking portion that regulates a protruding length from the tip side opening.
- the locking portion preferably includes a tapered portion that gradually decreases in diameter from the proximal end side toward the distal end side, and is preferably locked to the periphery of the distal end side opening.
- the distal end opening is preferably formed on an inclined surface formed on the distal end side of the outer needle with its center being eccentric from the center of the outer needle, and the distal end of the reference puncture portion is It is preferable that the outer needle is disposed on the opposite side of the center of the distal end opening with the center of the outer needle interposed therebetween.
- the outer needle includes a mark portion on the base side that can recognize the position of the peripheral puncture portion with respect to the reference puncture portion.
- the outer needle can be inserted into a gap between joints that join bones together, and the cartilage of one bone is punctured by the reference puncture portion, It is preferable that the cartilage can be punctured by the peripheral puncture portion.
- FIG. 1 is a plan view of a pharmaceutical injection device according to an embodiment of the present invention.
- the preparation injection tool 1 includes an outer needle 10 and an inner needle 20 that is detachably inserted into the outer needle 10.
- the outer needle 10 and the inner needle 20 are shown separately. .
- the outer needle 10 includes a flexible main body 11 made of a metal such as stainless steel or a synthetic resin such as polyethylene, and a sharp reference puncture portion 12 is provided on the distal end side of the main body 11.
- the main body 11 is a straight pipe having a distal end side opening 15 and a proximal end side opening 16 on the distal end side and the proximal end side, respectively.
- a cylindrical mounting portion 13 is provided on the base end side of the main body 11.
- a distal end portion of a syringe (not shown) for supplying a preparation or the like can be attached to the attachment portion 13 by screwing or the like.
- the outer needle 10 configured as described above can discharge a liquid preparation, washing water or the like supplied from the proximal end side opening 16 from the distal end side opening 15, and inject the preparation or wash the outer needle 10. Etc. can be performed.
- FIG. 2 is a perspective view of the distal end side of the outer needle 10 shown in FIG.
- the distal end surface of the outer needle 10 is an inclined surface 14, and a distal end side opening 15 is formed in the inclined surface 14.
- the center C1 of the distal opening 15 is eccentric from the center C2 through which the axis of the outer needle 10 passes, and the distal opening 15 opens above the center C2 of the inclined surface.
- the distal end 12 a of the reference puncture portion 12 is located on the opposite side of the center C 1 of the distal end side opening 15 across the center C 2 of the outer needle 10, and is provided so as to protrude from the lower part of the inclined surface 14.
- the reference puncture unit 12 may use the lower part of the inclined surface 14 as the reference puncture unit 12.
- a mark portion 13 a is provided on the upper portion so that the positions of the reference puncture portion 12 and the distal end side opening 15 in the circumferential direction can be recognized on the base side of the outer needle 10.
- the inner needle 20 includes a flexible main body 21 made of a material such as metal or synthetic resin, like the main body 11 of the outer needle 10.
- the main body 21 is a solid bar.
- a tapered portion 26 that is gradually reduced in diameter from the proximal end side toward the distal end side is formed at the distal end side of the main body 21, and a sharp peripheral puncture portion 22 is formed at the distal end of the tapered portion 26.
- a grip portion 23 is provided on the base side of the main body 21.
- the inner needle 20 is inserted into the proximal end side opening 16 of the outer needle 10, and the peripheral puncture portion 22 can be caused to appear and disappear from the distal end side opening 15 by grasping the grasping portion 23 and performing an advance / retreat operation. .
- the pharmaceutical injection device 1 having the above-described configuration is such that the inner needle 20 is inserted into the outer needle 10 and the peripheral puncture portion 22 is projected from the distal end side opening 15 as indicated by an arrow in FIG.
- the lower portion of the tapered portion 26 comes into contact with the peripheral edge of the distal end side opening 15 as shown in FIG.
- the peripheral puncture portion 22 changes its direction along the normal direction of the distal end side opening 15 and further protrudes from the distal end side opening 15 as shown by an arrow in FIG. To do.
- the entire outer periphery of the tapered portion 26 is locked to the distal end side opening 15, and the inner needle 20 is locked to the outer needle 10.
- the pharmaceutical injection device 1 of the present embodiment has a cross section in which the peripheral puncture portion 22 includes the axis L of the outer needle 10 (a plane orthogonal to the paper surface of FIG. 3). Since the inner needle 20 is guided inside the outer needle 10 so as to protrude to the opposite side of the reference puncture portion 12 with the nip interposed therebetween, it is separated from the puncture position of the reference puncture portion 12 together with the puncture by the reference puncture portion 12 The position can be punctured by the peripheral puncture unit 22. Therefore, before the preparation is injected, the area around the place where the preparation is injected can be easily stimulated, so that the therapeutic effect of the preparation can be enhanced.
- FIG. 4 is a diagram for explaining a treatment method for a human knee joint as an example of a treatment method using the pharmaceutical injection device 1 of the present embodiment.
- the distal end portion of the outer needle 10 is inserted into the gap between the femur 51 and the tibia 52 constituting the knee joint 50, and the cartilage 52 a of the tibia 52 (or the cartilage of the femur 51 is inserted by the reference puncture portion 12. 51a), the inner needle 20 is advanced, and the peripheral puncture portion 22 punctures the cartilage 51a of the femur 51 (or the cartilage 52a of the tibia 52).
- the cartilages 51a and 52a of the femur 51 and the tibia 52 are stimulated.
- the outer needle 10 is rotated while the reference puncture unit 12 is punctured, other portions around the reference puncture unit 12 can be quickly and easily punctured by the peripheral puncture unit 22.
- a plurality of positions of the cartilage 51a, 52a of the femur 51 and the tibia 52 are punctured by the reference puncture unit 12, and a plurality of peripheral positions of each puncture position by the reference puncture unit 12 are punctured by the peripheral puncture unit 22, thereby Can be effectively stimulated.
- the inner needle 20 is withdrawn from the outer needle 10
- a syringe or the like containing the preparation is attached to the attachment portion 13, and the preparation is supplied to the gap between the knee joints 50 from the distal end side opening 15, so
- the therapeutic effect can be improved by the synergistic effect.
- the pharmaceutical injection device 1 of the present embodiment has a puncture direction of the reference puncture portion 12 parallel to the axis L of the outer needle 10, whereas a peripheral puncture portion 22 is provided. Is separated from the axis L with advancement from the distal end side opening 15. According to such a configuration, a position away from the puncture position of the reference puncture unit 12 can be easily punctured by the peripheral puncture unit 22, and an area that can be punctured by the peripheral puncture unit 22 can be expanded. The stimulation can be applied more efficiently.
- the protruding length is regulated by the taper portion 26 of the inner needle 20 being locked to the peripheral edge portion of the distal end side opening 15.
- an appropriate stimulation can be given by suppressing excessive advancement of the peripheral puncture unit 22, and puncture can be performed effectively and safely.
- What is necessary is just to set suitably the protrusion length of the inner needle 20 from the front end side opening 15 according to the use application of the formulation injection tool 1. FIG. For example, when used for the treatment of the knee joint shown in FIG.
- one of the cartilages 51a and 52a of the femur 51 and the tibia 52 is punctured with the reference puncture portion 12, and the other can be punctured with the peripheral puncture portion 22.
- the tip of the reference puncture portion 12 and the tip of the peripheral puncture portion 22 at the maximum projecting position are on the same plane P perpendicular to the axis L of the outer needle 10.
- the protruding length of the inner needle 20 is set so as to exist above.
- the mark portion 13a is provided on the proximal end side of the outer needle 10, the peripheral puncture with respect to the reference puncture portion 12 even when the distal end side of the outer needle 10 is inserted into the body.
- the position of the part 22 can be easily grasped by the mark part 13a. Therefore, a desired puncturing operation can be performed efficiently.
- the distal end side opening 15 is formed in the inclined surface 14 on the distal end side of the outer needle 10, but as shown in FIG. 5A, the distal end side opening 15 is formed on the outer needle main body 11. It can also be formed on the side wall.
- the guide member 18 by inserting the guide member 18 into the distal end side of the main body 11 so that the guide surface 18a of the guide member 18 faces the distal end side of the inner needle 20, as shown in FIG. Since the distal end side of the needle 20 is guided to the distal end side opening 15 along the guide surface 18a, the inner needle 20 can be advanced smoothly.
- the reference puncture portion 12 can be provided on the guide member 18 instead of being provided on the main body 11 of the outer needle 10.
- the tapered portion 26 is formed on the distal end side of the inner needle 20, and the peripheral edge of the tapered portion 26 is locked to the peripheral edge of the distal end side opening 15.
- the locking portion for regulating the protruding length is not necessarily the tapered portion 26.
- the ring-shaped member 261 is fixed to the proximal end side of the inner needle 20, and the ring-shaped member 261 is moved into the main body 11 of the outer needle 10 by the advancement of the inner needle 20. It is possible to set the protrusion length of the inner needle 20 to a desired value.
- the preparation injection device of the present invention can be preferably used for the treatment of an interosseous joint, but is not limited to this application, and is not limited to this use, and is an mesoderm-derived organ other than the interosseous joint (for example, Dermis, muscle, bone / cartilage, gonadal, vas deferens, fallopian tube, uterus, pericardium, pleura, peritoneum, endocardium, endovascular endothelium, etc.).
- mesoderm-derived organ other than the interosseous joint for example, Dermis, muscle, bone / cartilage, gonadal, vas deferens, fallopian tube, uterus, pericardium, pleura, peritoneum, endocardium, endovascular endothelium, etc.
- a preparation to be injected into an interosseous joint such as a knee joint
- a known preparation used for conventional joint treatment such as hyaluronic acid and steroid can be used, but a cell preparation containing fat cells is preferable. Can be used.
- the present inventors have found that when fat cells are injected into a patient complaining of joint pain, symptoms are relieved at an early stage and the effect is sustained. Furthermore, it has been found that when adipocytes and adipose stem cells are injected in combination, bone tissue and cartilage tissue in the joint are efficiently regenerated in addition to the relief of the joint pain. Furthermore, it has been found that the therapeutic effect is further enhanced by giving an appropriate stimulus in the vicinity of the injection site using the preparation injection device of the present invention before the injection. That is, by using the pharmaceutical injection device of the present invention, the present invention can provide a method for treating an animal or human body according to the following embodiment. Item 1.
- the treatment method which inject
- Item 2. Item 2. The treatment method according to Item 1, wherein the cell preparation further comprises mesodermal stem cells.
- Item 3. Item 3. The treatment method according to Item 2, wherein the mesodermal stem cell is an adipose stem cell.
- Item 6. The treatment method according to any one of Items 1 to 5, wherein the disease site is an interosseous junction.
- Item 7. Item 7. The method according to Item 6, wherein the disease of the interosseous joint is any one selected from the group consisting of spinal diseases, joint diseases, autoimmune diseases, and osteonecrosis.
- the treatment method of the present invention slippage of joints and the like is improved by fat cells and ECM (extracellular matrix) existing around fat cells, and joint pain can be relieved at an early stage.
- ECM extracellular matrix
- the effect which was excellent in the pain relief resulting from this disease can be acquired.
- by injecting a cell preparation into an intervertebral disc or the like it plays the role of a cushion and has an effect of improving (improving) the movement of the vertebral body.
- the joint pain relieving effect of the cell preparation lasts for a long time.
- the cell preparation includes adipocytes and mesoderm stem cells
- the adipocytes relieve pain caused by diseases such as interosseous joints, and during that time, bone tissue, cartilage tissue, soft tissue caused by mesoderm stem cells Tissue regeneration within a joint such as a tissue is prompted.
- adipocytes and mesodermal stem cells are used to alleviate the above-mentioned pain, but also mesodermal stem cells are retained in the affected area by the action of adipocytes, and the engraftment efficiency of mesodermal stem cells.
- tissue regeneration efficiency is further promoted, a cell preparation containing adipocytes and mesoderm stem cells is more effective for the treatment of diseases such as interosseous junctions.
- a cell preparation fat cell is a cell that has the function of synthesizing, storing, and releasing fat, and that forms adipose tissue.
- Adipocytes do not undergo cell division because they are completely differentiated.
- the fat cells include white fat cells and brown fat cells. In the present invention, any of these may be used, or a mixture of both may be used.
- the origin of adipocytes is not particularly limited.
- mammalian adipocytes preferably primate adipocytes, more preferably human adipocytes are used.
- as fat cells only fat cells can be used alone, but a mixture of extracellular matrix (ECM) existing around fat cells and fat cells may be used.
- ECM extracellular matrix
- the collected adipose tissue may be used as it is as the adipocyte, or one obtained by removing the extracellular matrix from the collected adipose tissue may be used.
- Adipocytes are collected from adipose tissue.
- the method for collecting adipose tissue is not particularly limited, and can be appropriately selected from conventionally known methods. Examples thereof include liposuction, lipotomy, and defatting. Collection by liposuction is preferable because it is relatively easy and minimally invasive.
- the method for obtaining fat cells from the collected fat is not particularly limited, but preferably the following 2. The method described in the preparation method of a cell formulation is mentioned.
- the cell preparation used in the present invention may further contain mesodermal stem cells.
- mesodermal stem cells tissue regeneration at the interosseous junction is promoted, and the therapeutic effect of the cell preparation is further enhanced.
- the mesodermal stem cells used in the cell preparation used in the treatment method of the present invention mainly mean intermediate stem cells that differentiate into cells belonging to mesodermal tissues such as bone, cartilage, myocardium and fat.
- the origin of mesodermal stem cells is not particularly limited, and for example, mammalian mesodermal stem cells, preferably primate mesodermal stem cells, more preferably human mesoderm stem cells are used.
- mesodermal stem cells include adipose stem cells, bone marrow stem cells, hematopoietic stem cells, and the like, and these stem cells can be obtained from each tissue according to the type of cells according to a conventionally known method.
- the mesodermal stem cells are preferably exemplified by adipose stem cells.
- Adipose stem cells can be collected from adipose tissue.
- the adipose tissue that is the source of adipose stem cells can be collected by any of the methods such as liposuction, lipectomy, degreasing, etc., similar to the above-mentioned adipocytes, but prevents outflow and damage of adipose stem cells, From the viewpoint that it can be collected more safely, liposuction is preferred.
- the method for obtaining adipose stem cells from the collected fat is preferably 2.
- the method described in the preparation method of a cell formulation is mentioned.
- the cell preparation used in the treatment method of the present invention contains mesodermal stem cells
- the content of the mesodermal stem cells in the cell preparation is particularly limited as long as the therapeutic effect on the disease of the interosseous joint is obtained.
- the higher the content of mesodermal stem cells the more excellent therapeutic effect can be obtained.
- at least one mesodermal stem cell per fat cell preferably 5 Or more, more preferably 1 to 10, more preferably 5 to 10.
- the number of mesodermal stem cells per 1 mL of the cell preparation is usually 100,000 or more, preferably 150,000 or more, More preferably, it is 150,000 to 200,000.
- the preparation of the cell preparation used in the treatment method of the present invention using an adipocyte (and mesodermal stem cell) derived from another person is not limited.
- adipocyte and mesodermal stem cell
- Mesodermal stem cells are usually cells that do not have immunogenicity, but those subjected to the treatment may be used if necessary.
- cell preparations used in the treatment method of the present invention include those containing adipocytes and adipose stem cells.
- adipose tissue contains adipocytes and adipose stem cells. Therefore, as a cell preparation containing adipocytes and adipose stem cells, the collected adipose tissue may be used as it is, and impurities (for example, an anesthetic solution (injected at the time of adipose collection) ( So-called Tumecent liquid), aged adipocytes, blood, tissue fluid, etc.) removed, or those obtained by removing impurities and some fat cells from the collected adipose tissue may be used.
- impurities for example, an anesthetic solution (injected at the time of adipose collection) ( So-called Tumecent liquid), aged adipocytes, blood, tissue fluid, etc.
- the method for preparing the cell preparation include methods (a) to (c) described later.
- conventionally known pharmaceutically acceptable carriers, excipients, anti-inflammatory agents, analgesics, immunosuppressants, and the like can be added to the cell preparation used in the treatment method of the present invention as necessary.
- collagen, fibroblasts, growth factors, growth factors, cytokines, etc. may be added.
- the dosage of the cell preparation used in the treatment method of the present invention is not particularly limited as long as the therapeutic effect on the disease of the interosseous joint is obtained, and the size of the administration site, the site of the disease, the degree of the disease, although it can be appropriately set depending on the sex, physique, etc. of the patient, for example, 100,000 to 4 million cells, preferably 200,000 to 2 million cells, more preferably 200,000 to 1 million cells in terms of the number of fat cells can be mentioned. It is done.
- the dosage is 0.5 to 20 mL, preferably 1 to 10 mL, more preferably 1 to 5 mL. It is done.
- a cell preparation of 1 to 20 mL, preferably 1 to 10 mL, more preferably 5 to 10 mL can be administered to the knee joint, and a cell preparation of 0.5 to 20 mL, preferably 1 can be administered to the intervertebral disc. -15 mL, more preferably 1-2 mL can be administered.
- Administration of the cell preparation is performed by using the preparation injection tool of the present invention to puncture the vicinity of a disease site (for example, joint space, intervertebral disc (intervertebral disc), etc.) at the interosseous joint from the reference puncture portion.
- a disease site for example, joint space, intervertebral disc (intervertebral disc), etc.
- a plurality of positions around the puncture position by the reference puncture section are punctured by the peripheral puncture section.
- the target site to be punctured can be, for example, a disease site or its vicinity, but is not necessarily limited to this, and may be another location that can stimulate the disease site or its vicinity.
- the cell preparation used in the treatment method of the present invention has an excellent therapeutic effect on diseases of the interosseous joint.
- the interosseous joint refers to the connecting part of the bone, by cartilage or a combination of cartilage and a fibrous connective tissue, a synovial connection connected by a synovium that wraps the cartilage and joint capsule, and a fibrous connective tissue In the present invention, it refers to a portion having mobility that is connected by a cartilage connection and a synovial connection.
- the interosseous joint examples include a spinal joint, a knee joint, an ankle joint, a toe joint, a hip joint, a wrist joint, an elbow joint, a shoulder joint, a finger joint, an acromioclavicular joint, and a sacroiliac joint.
- soft tissues such as ligaments and meniscus
- a disc intervertebral disc
- diseases of the interosseous joint include hernia (prolapse), deformation, degeneration, inflammation, etc.
- spinal diseases such as intervertebral disc herniation, osteoarthritis, etc .; osteoarthritis (degenerative Hip arthritis, knee osteoarthritis, etc.), joint diseases such as chronic arthropathy; autoimmune diseases such as rheumatoid arthritis; osteonecrosis such as idiopathic osteonecrosis of the knee joint, femoral head necrosis, etc.
- Preferred examples include intervertebral hernia, osteoarthritis, chronic arthropathy, idiopathic osteonecrosis of the knee joint, and femoral head necrosis.
- the cell preparation When the cell preparation is administered to a patient having these diseases, it may be administered after treatment by a known method as necessary.
- the prolapsed intervertebral disc may be removed by a conventionally known method, and then the cell preparation may be administered (injected). Pain (arthralgia) due to the disease of the interosseous joint is alleviated by the action of adipocytes contained in the cell preparation, and when the mesodermal stem cells are contained, the bone at the interosseous joint is caused by the function of the cells. Tissue, cartilage tissue, soft tissue, etc. are regenerated.
- fat cells can be collected, separated and concentrated as necessary, and prepared as a cell preparation.
- a cell preparation containing adipocytes and mesodermal stem cells
- a cell preparation may be used.
- the mesodermal stem cell is an adipose stem cell
- the following methods (a) to (c) are exemplified as preferred methods.
- the preparation of cell preparations from tissues other than fat is not limited, and the following method is used even when cell preparations are prepared from tissues other than fat tissues (for example, blood, bone marrow fluid, muscle, etc.).
- cell preparations can be prepared by appropriately setting conditions in consideration of the type and properties of cells.
- the methods (a) to (c) will be described in detail.
- Method (a) for preparing a cell preparation used in the treatment method of the present invention includes (1a) a step of removing a liquid fraction from collected fat to obtain a cell fraction.
- the collected fat refers to a mixture of a cell fraction and a liquid fraction derived from adipose tissue collected from adipose tissue by liposuction, lipotomy, degreasing, and the like.
- the cell fraction contains adipocytes, adipose stem cells, and impurities (blood cells, dead / alive cells, senescent cells, etc.).
- the liquid fraction includes a tumecent liquid, a cell tissue liquid, and the like.
- the separation of the liquid fraction and the cell fraction can be carried out simply by allowing the collected fat to stand and allowing the cell fraction to settle.
- the method for removing the liquid fraction is not particularly limited, and examples thereof include decantation and suction. Moreover, you may perform centrifugation, filtration, etc. as needed.
- the conditions for centrifugation and filtration are not particularly limited as long as they do not damage fat cells and adipose stem cells and can remove impurities.
- 700 to 2500 ⁇ g for 1 to 15 minutes, preferably 2000 to 2200 ⁇ g for 5 A condition of ⁇ 10 minutes is mentioned.
- the collected fat is subjected to a mesh filter having a hole size of, for example, 10 to 300 ⁇ m, preferably 10 to 150 ⁇ m, more preferably 10 to 100 ⁇ m, and still more preferably 15 to 20 ⁇ m.
- the mixture of fat cells and adipose stem cells can be obtained on the filter by removing blood, tissue fluid, anesthetic (tumecent solution) and the like administered to the site where the fat is collected.
- a container including such a mesh filter may be filled with collected fat containing impurities and subjected to centrifugation.
- adipose tissue containing adipose cells (including extracellular matrix) and adipose stem cells from which the liquid fraction has been removed can be obtained, and this can be used as a cell preparation.
- Method (b) In the method (b) for preparing the cell preparation used in the treatment method of the present invention, the following: (1b) removing the liquid fraction from the collected fat to obtain a cell fraction; (2b) including a step of separating fat cells and adipose stem cells from at least a part of the cell fraction obtained in the step (1b).
- step (1b) is as described in the above method (1a).
- step (2b) when preparing a cell preparation containing adipocytes, all the cell fraction obtained in the step (1b) is subjected to the treatment of the step (2b), and only the adipocytes to be separated are obtained. May be used.
- the adipose stem cells are separated from at least a part, preferably half, of the cell fraction obtained in step (1b), and further separated in step (1b). ) To obtain the cell preparation containing adipocytes and adipose stem cells.
- a proteolytic enzyme is added to the cell fraction in order to facilitate separation of adipocytes and adipose stem cells by decomposing bonds between cells.
- proteolytic enzymes include collagenase, trypsin, lipase and the like, and one kind selected from these may be used alone, or two or more kinds may be used in combination.
- the method for separating fat cells and adipose stem cells from the cell fraction treated with the enzyme is not particularly limited and may be appropriately selected from conventionally known methods, and examples thereof include centrifugation and filtration. Centrifugation conditions are not particularly limited as long as they can be separated without damaging fat cells and adipose stem cells. For example, 100 to 500 ⁇ g for 0 to 20 minutes, preferably 100 to 300 ⁇ g for 5 to 5 minutes. A condition of 10 minutes is mentioned. By subjecting to such centrifugation, adipose stem cells are obtained as a precipitate, and the adipocytes are concentrated in the supernatant.
- the cell fraction or suspension thereof is passed through a mesh filter having a hole size of 10 to 100 ⁇ m, preferably 10 to 50 ⁇ m, more preferably 15 to 20 ⁇ m.
- Adipose stem cells can be obtained on top, and adipocytes can be obtained in the filtrate.
- the enzyme-treated adipocytes and adipose stem cells are preferably subjected to a washing treatment after separation, and washing can be performed with a phosphate buffer solution (PBS), physiological saline, Ringer's solution, dextran, or the like.
- PBS phosphate buffer solution
- the washing treatment may be repeated a plurality of times as necessary, and may be subjected to centrifugation as necessary when cells are collected after washing. Centrifugation may be performed according to the conditions employed when separating adipocytes and adipose stem cells from the enzyme-treated cell fraction.
- the fat cells separated in this step (2b) can be used as a cell preparation after washing.
- the cell preparation obtained using the fat cells obtained by the present method (b) has an excellent effect on alleviating pain caused by the disease of the interosseous joint.
- this method (b) includes the step (3b) of mixing the cell fraction obtained in the step (1b) and the adipose stem cell obtained in the step (2b) after the step (2b). May be included.
- the cell fraction obtained in step (1b) and the adipose stem cells obtained in step (2b) can be mixed to obtain a cell preparation containing adipocytes and adipose stem cells.
- the cell preparation thus prepared contains a high amount of adipose stem cells and is effective not only for the relief of pain caused by diseases of the interosseous joint, but also excellent for tissue regeneration of the interosseous joint. It is effective.
- Method (c) The method (c) for preparing the cell preparation used in the treatment method of the present invention is as follows: (1c) removing the liquid fraction from the collected fat to obtain a cell fraction; and (2c) removing impurities from the cell fraction obtained in the step (1c) to concentrate adipocytes and adipose stem cells. Obtaining a product.
- step (1c) is as described in the above method (1a).
- impurities are removed from the cell fraction and concentrated.
- the method for removing and concentrating impurities is not particularly limited and may be appropriately selected from conventionally known methods.
- a syringe equipped with a weight filter described in JP-T-2007-533396 is used for convenience.
- impurities such as free oil, dead and active cells, and senescent cells released from broken fat cells are removed, and a healthy fat cell and adipose stem cell concentrate is obtained.
- Such a syringe is commercially available.
- a syringe manufactured for LIPOMAX-SC manufactured by Medikan Corp., Seoul, Korea
- the collected fat is filled in a syringe equipped with a filter inside, and the fat is separated into a liquid fraction and a cell fraction by centrifugation, and free oil (drained oil) is further separated by a filter. ) Are separated.
- the liquid fraction separated here is not completely separated in the step (1c) but is mixed in the cell fraction. That is, in the syringe, free oil in the upper layer, a concentrate of fat cells and adipose stem cells in the intermediate layer, and a liquid fraction in the lower layer are separated, and a healthy fat cell and adipose stem cell concentrate by discarding other than the intermediate layer And can be used as a cell preparation.
- the cell preparation obtained in this way has selected and concentrated healthy adipocytes and adipose stem cells, it is difficult to cause necrosis, calcification, etc. after transplantation, alleviation of symptoms of diseases at the interosseous joint, More useful for treatment.
- Centrifugation conditions are not particularly limited as long as impurities and adipose cells and adipose stem cells can be separated without damaging adipocytes and adipose stem cells, but for example, 1 to 15 at 700 to 2500 ⁇ g.
- the conditions are for 5 minutes, preferably 2000 to 2200 ⁇ g for 5 to 10 minutes.
- the pore size of the filter is not particularly limited as long as fat cells and adipose stem cells do not pass through and impurities can pass through.
- the pore size of the filter is 10 to 300 ⁇ m, preferably 10 to 150 ⁇ m, more preferably 10 to 100 ⁇ m. More preferably, it is 15 to 20 ⁇ m.
- this method (c) isolate separates an adipocyte and an adipose stem cell from at least one part of the concentrate obtained at the process (2c),
- the obtained adipose stem cell is the concentrate obtained at the said process (2c).
- (3c ′) may be included.
- the method for separating adipose stem cells is as described for step (2b) of method (b) above.
- this step (3c ′) when adipose stem cells are separated using a proteolytic enzyme, it is usually about 700,000 or more, preferably about 1.5 million or more, more preferably 1 cc of the concentrate obtained in step (2c). Can obtain about 2 million or more adipose stem cells.
- the cell preparation prepared through this step (3c ′) contains adipose stem cells at a higher concentration in addition to the selection and concentration of healthy adipocytes. It has an even better therapeutic effect.
- the adipocytes separated in this step (3c ′) can be used as a cell preparation after washing. Since the adipocytes obtained here are selected and concentrated as healthy adipocytes, the adipocytes are more effective in alleviating the pain caused by the disease of the interosseous junction.
- the fat cells in the obtained concentrate are refined, and the refined fat cells and adipose stem cells are separated as a mixture (3c ′′). May be included.
- a fat cell can be refined by a method usually employed in the art, and is not particularly limited. For example, if necessary, a fat cell is cut with a drill or the like, Isolate the mixture of adipose stem cells. As the separation method, the above-mentioned centrifugation conditions can be employed.
- the concentrate may be filled in a syringe and subjected to refinement and centrifugation of adipocytes.
- the free oil and the mixture of micronized adipocytes and adipose stem cells are separated in the syringe, so that the free oil can be discarded to obtain a mixture of micronized adipocytes and adipose stem cells. it can.
- a cell preparation containing fine fat cells and adipose stem cells at a high concentration can be prepared through such a separation step.
- the fine fat cells refer to fat cells having a size that can pass through an injection needle of 26 to 30 gauge, preferably 18 to 30 gauge.
- the treatment for refining fat cells can be performed at least once, preferably 1 to several times, more preferably 1 to 2 times.
- the fat cells and the adipose stem cells are separated from at least a part of the mixture of the refined adipocytes and adipose stem cells obtained in the step (3c ′′), and the obtained adipose stem cells are obtained in the step (2c).
- the method for separating adipose stem cells is as described for step (2b) of method (b) above.
- the adipocytes obtained by separating the adipose stem cells in this step (4c ′′) can be used as a cell preparation containing adipocytes, which is used for the treatment method of the present invention after washing.
- the washing can be performed by the same method as the washing treatment performed on the adipose stem cells described above. Since the adipocytes obtained here are selected and concentrated as healthy, refined adipocytes, the adipocytes have an even more remarkable effect on alleviating pain caused by diseases of the interosseous junction.
- this method (c) by using the syringe described in JP-T-2007-533396, all steps can be carried out without bringing the cells into contact with the outside air.
- a syringe described in JP-T-2007-533396 can be equipped with a cannula or the like, filled with fat collected by liposuction, and directly subjected to removal of impurities, concentration treatment, and the like to obtain a cell preparation. . Thereafter, when the cell preparation is administered, since the syringe can be connected to the preparation injection device of the present invention and administered to the affected area, the cell preparation can be made highly safe without problems such as contamination.
- this method (c) can also be carried out using a commercially available kit. Specific examples of such a kit include LIPOMAX-SC (manufactured by MEDIKAN Corp.). Is done.
- the cell preparation can be obtained by any of the above methods, but is preferably the method (b) or (c), more preferably the method (c), and further preferably the step (3 ′) of the method (c). It is preferable that the preparation is a cell preparation containing finely-divided adipocytes prepared through the step (4)).
- the cell preparation containing micronized adipocytes obtained through the step (4 '') of the method (c) contains impurities at a high concentration and contains fine adipose fat cells, It has a remarkable effect on the treatment of diseases of the interosseous joint (especially pain relief).
- the cell preparation containing finely divided adipocytes and adipose stem cells obtained through the step (3 ′′) of the method (c) contains adipose stem cells at a high concentration in addition to finely divided healthy adipocytes.
- Such a cell preparation can exert a significantly more excellent effect on the disease of the interosseous joint.
- adipocytes and adipose stem cells were derived from each patient by autologous transplantation, the above operation was performed on each patient.
- Test Example 1 For 2 women with knee osteoarthritis, a cell preparation (5-10 mL, about 750,000 to 2 million adipose stem cells) containing the refined adipocytes and adipose stem cells prepared in the above step (i) Were injected into the knee joint.
- Table 1 below shows the diseased part, the specific part of liposuction, the amount of collected fat, the injection amount of the cell preparation, and the presence or absence of an operation for stimulating the vicinity of the injection part.
- Table 1 below summarizes the treatment results for each subject, the measurement results of the knee joint space, and the evaluation results according to the Kellgren & Lawrence classification, which are the evaluation criteria for the X-ray findings of knee osteoarthritis.
- the preparation injection device of the present invention can quickly and accurately give the target site stimulation in Test Example 1, the above effects can be obtained more easily.
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Abstract
Description
する。
項1.本発明の製剤注入具を用いて目的部位を穿刺することにより疾患部位に刺激を付与した後、脂肪細胞を含む細胞製剤を疾患部位に注入する治療方法。
項2.細胞製剤が、更に中胚葉系幹細胞を含む、項1に記載の治療方法。
項3.前記中胚葉系幹細胞が脂肪幹細胞である、項2に記載の治療方法。
項4.脂肪細胞1個に対して中胚葉系幹細胞が1~10個含まれる、項2又は3に記載の治療方法。
項5.脂肪細胞がγ線照射された細胞である、項1~4のいずれかに記載の治療方法。
項6.疾患部位が骨間接合部である、項1~5のいずれかに記載の治療方法。
項7.骨間接合部の疾患が、脊椎疾患、関節疾患、自己免疫疾患及び骨壊死症からなる群より選択されるいずれか1種である、項6に記載の治療方法。
脂肪細胞(fat cell)とは、脂肪を合成、貯蔵、放出する機能を有し、脂肪組織を形成する細胞である。また、脂肪細胞は、完全に分化しているため細胞***を起こさない。脂肪細胞には、白色脂肪細胞及び褐色脂肪細胞が存在するが、本発明においてはこれらのいずれを用いてもよく、両者の混合物を使用してもよい。本発明において脂肪細胞の由来は特に限定されないが、例えば、哺乳類の脂肪細胞、好ましくは霊長類の脂肪細胞、更に好ましくはヒト脂肪細胞を使用する。本発明において、脂肪細胞としては、脂肪細胞のみを単独で使用することもできるが、脂肪細胞周辺に存在する細胞外基質(extracellular matrix:ECM)と脂肪細胞の混合物を使用してもよい。具体的には、本発明では、脂肪細胞として、採取された脂肪組織をそのまま使用してもよく、また採取された脂肪組織から細胞外基質を取り除いたものを使用してもよい。
本発明においては、脂肪細胞を採取し、必要に応じて分離、濃縮を行い、細胞製剤として調製することができる。また、脂肪細胞と中胚葉系幹細胞を含む細胞製剤を調製する場合には、これらの細胞の混合物として採取したものを使用してもよく、それぞれの細胞を個別に採取し、その後、両者を混合して細胞製剤としてもよい。例えば、中胚葉系幹細胞が脂肪幹細胞である場合には、脂肪細胞と同じ組織から同時に調製でき簡便であるため、脂肪組織から脂肪細胞と脂肪幹細胞の混合物を得て、細胞製剤とすることが好ましい。また、より簡便には、これらの細胞を含む脂肪組織を使用してもよい。
本発明の治療方法に用いる細胞製剤を調製する方法(a)は、(1a)採取された脂肪から液体画分を除去し、細胞画分を得る工程を含む。
本発明の治療方法に用いる細胞製剤を調製する方法(b)においては、下記:
(1b)採取された脂肪から液体画分を除去し、細胞画分を得る工程;
(2b)前記工程(1b)で得られた細胞画分の少なくとも一部から脂肪細胞と脂肪幹細胞を分離する工程を含む。
本発明の治療方法に用いる細胞製剤を調製する方法(c)は下記:
(1c)採取された脂肪から液体画分を除去し、細胞画分を得る工程;ならびに
(2c)前記工程(1c)で得られた細胞画分から不純物を除去し、脂肪細胞及び脂肪幹細胞の濃縮物を得る工程、を含む。
細胞製剤の調製には、LIPOMAX-SC(Medikan Corp.製,韓国 ソウル)キットを使用した。本細胞製剤の調製工程においては、細胞を全く外気に触れさせることなく行うことが可能であった。具体的な方法は以下の通りである。
変形性膝関節症の女性2名に対して、上記工程(i)で調製された微細化された脂肪細胞及び脂肪幹細胞を含む細胞製剤(5~10mL、脂肪幹細胞を約75万~200万個を含む)を、膝関節に注入した。疾患部位、脂肪吸引の具体的な部位、採取された脂肪の量、細胞製剤の注入量、注入部位近傍を刺激する操作の有無については、下表1に示される。各被験者に対する処置、膝関節裂隙の計測結果、及び変形性膝関節症のX線所見の評価基準となっているKellgren&Lawrence分類による評価結果を下表1に要約する。
10 外針
12 基準穿刺部
13 装着部
14 傾斜面
15 先端側開口
16 基端側開口
20 内針
22 周辺穿刺部
26 テーパ部
Claims (7)
- 先端側開口および基端側開口を有する直管状に形成され先端側に基準穿刺部を有する外針と、
前記外針に着脱可能に挿入され先端側に周辺穿刺部を有する内針とを備え、
前記内針は、基部側の進退操作により前記周辺穿刺部を前記先端側開口から出没可能に構成されており、
前記外針から前記内針を抜き取った状態で、前記基端側開口から供給された製剤を前記先端側開口から注入可能な製剤注入具であって、
前記外針は、軸線を含む平面を挟んで前記基準穿刺部と反対側に前記周辺穿刺部が突出するように前記内針を案内する製剤注入具。 - 前記基準穿刺部は、穿刺方向が前記外針の軸線と平行であり、
前記周辺穿刺部は、前記先端側開口からの進出に伴い前記軸線から離隔する請求項1に記載の製剤注入具。 - 前記内針は、前記先端側開口からの突出長さを規制する係止部を備える請求項1または2に記載の製剤注入具。
- 前記係止部は、基端側から先端側に向けて徐々に縮径されるテーパ部からなり、前記先端側開口の周縁に係止される請求項3に記載の製剤注入具。
- 前記先端側開口は、前記外針の先端側に形成された傾斜面に、中心が前記外針の中心から偏心して形成されており、
前記基準穿刺部の先端は、正面視において、前記外針の中心を挟んで前記先端側開口の中心と反対側に配置された請求項1に記載の製剤注入具。 - 前記外針は、前記基準穿刺部に対する前記周辺穿刺部の位置を認識可能なマーク部を基部側に備える請求項1に記載の製剤注入具。
- 前記外針は、骨同士を接合する関節の隙間に挿入可能であり、一方の骨の軟骨を前記基準穿刺部により穿刺した状態で、他方の骨の軟骨を前記周辺穿刺部により穿刺可能とされた請求項1に記載の製剤注入具。
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US20100004651A1 (en) * | 2008-06-13 | 2010-01-07 | The University Of Toledo | Transpedicular access to the intervertebral disc space for discectomy, end plate preparation, and interbody fusion |
US8936575B2 (en) * | 2009-03-19 | 2015-01-20 | Becton, Dickinson And Company | Cannula-tip shielding mechanism |
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2012
- 2012-02-24 JP JP2012038396A patent/JP2013172803A/ja active Pending
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2013
- 2013-02-22 WO PCT/JP2013/054430 patent/WO2013125663A1/ja active Application Filing
- 2013-02-22 CN CN201380010893.1A patent/CN104136066A/zh active Pending
- 2013-02-22 KR KR1020147023383A patent/KR20140114891A/ko not_active Application Discontinuation
- 2013-02-22 US US14/380,616 patent/US20150011941A1/en not_active Abandoned
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JP2001506144A (ja) * | 1996-12-02 | 2001-05-15 | ソシエ デ コンシェーユ デ ルシェルシェ エ ダプリカシオン シエンティフィック スクラ | 非経口投与用の固体または半固体製剤および遅効性製剤の局部的投与のための装置および調剤プロセス |
JP2004329485A (ja) * | 2003-05-06 | 2004-11-25 | Asahi Intecc Co Ltd | 薬液注入装置 |
Cited By (2)
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CN110339435A (zh) * | 2019-08-20 | 2019-10-18 | 中国人民解放军总医院 | 一种用于深部组织穿刺的三联套管针装置和方法 |
CN110339435B (zh) * | 2019-08-20 | 2024-06-11 | 中国人民解放军总医院 | 一种用于深部组织穿刺的三联套管针装置和方法 |
Also Published As
Publication number | Publication date |
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US20150011941A1 (en) | 2015-01-08 |
JP2013172803A (ja) | 2013-09-05 |
KR20140114891A (ko) | 2014-09-29 |
CN104136066A (zh) | 2014-11-05 |
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