Resin chip for tissue implantation, tissue implantation device, retinal tissue implantation method and retinal tissue implantation kit

Abstract

[Problem] To provide a resin chip for tissue implantation by which a tissue aspirated therein can be easily implanted, etc. [Solution] A resin chip 10 for tissue implantation that is provided with a needle tube 1 to be inserted into the eyeball. The needle tube comprises a body part 11 that extends linearly and a tip part 12 that bends against the body part, extends linearly and discharges a tissue T from the tip end 121. The length L1 of the needle tube is 25-50 mm inclusive. The cross-sectional outline of the tip part has an elliptical shape with a major diameter D1 of 0.8-1.5 mm inclusive and a minor diameter D2 of 0.5-1.0 mm inclusive. The tip end of the tip part, which extends in a nearly orthogonal direction to the body part, is a bevel face with a bevel angle θ1 of 50-85° inclusive. The hardness of the tip part is 0.15-0.30 N inclusive. The hardness at the center of the needle tube is 0.80-1.50 N inclusive.

Description

Resin chip for tissue transplantation, tissue transplantation device, retinal tissue transplantation method, and retinal tissue transplantation kit

[0001] The present invention relates to a tissue transplantation resin chip used for subretinal transplantation of tissue into the eyeball, a tissue transplantation device including the same, a retinal tissue transplantation method using the same, and a retinal tissue transplantation kit. In particular, the present invention relates to a tissue transplantation resin chip, a tissue transplantation device, a retinal tissue transplantation method, and a retinal tissue transplantation kit that facilitate transplantation of tissue sucked into the chip.

[0002] Conventionally, tissue transplantation resin chips have been proposed that are used to transplant tissues such as retinal tissue into the subretinal space within the eyeball (see, for example, Patent Document 1 and the Supplementary Appendix of Non-Patent Document 1). These tissue transplantation resin chips are used as follows: After tissue is aspirated into the tissue transplantation resin chip, the tissue transplantation resin chip is inserted into the subretinal space within the patient's eyeball, and the tissue is then ejected from the tip of the tissue transplantation resin chip into the subretinal space, thereby transplanting the tissue.

[0003] However, conventional resin chips for tissue transplantation are not necessarily sufficiently easy to transplant tissue into, and there has been a demand for a resin chip for tissue transplantation that is even easier to transplant.

[0004] U.S. Pat. No. 5,941,250

[0005] M. Mandai, et. Al, “Autologous Induced Stem-Cell-Derived Retinal Cells for Macular Degeneration”, The New England Journal of Medicine, March 16, 2017, 376, p.1038-1046

[0006] An object of the present invention is to provide a resin chip for tissue transplantation, which allows tissue sucked inside to be easily transplanted, a tissue transplantation device, a retinal tissue transplantation method, and a retinal tissue transplantation kit.

[0007] In order to solve the above problems, the inventors conducted extensive research and repeatedly produced prototypes of resin tissue transplantation chips. As a result, they discovered that by optimizing the shape, dimensions, and hardness of the needle tube of a resin tissue transplantation chip, a resin tissue transplantation chip can be obtained that makes it easy to transplant tissue sucked inside it into the subretinal space inside the eyeball, and thus completed the present invention.

[0008] That is, in order to solve the above-mentioned problems, the present invention provides a resin chip for tissue transplantation used for transplanting tissue subretinally into an eyeball, the chip comprising a needle tube that can be inserted into the eyeball, the needle tube comprising a main body portion that extends linearly and a tip portion that bends relative to the main body portion, extending linearly, and ejecting the tissue from its tip, the length of the needle tube being 25 mm or more and 50 mm or less, the cross-sectional outline of the tip portion being an ellipse with a major axis of 0.8 mm or more and 1.5 mm or less and a minor axis of 0.5 mm or more and 1.0 mm or less, the tip of the tip portion extending in a direction approximately perpendicular to the main body portion and having a bevel surface with a bevel angle of 50° or more and 85° or less, the hardness of the tip portion being 0.15 N or more and 0.30 N or less, and the hardness of the center of the needle tube being 0.80 N or more and 1.50 N or less.

[0009] In the present invention, "tissue" refers to a cell population structure in which one or more types of cells with different morphologies and properties are arranged three-dimensionally in a specific pattern. Furthermore, in the present invention, the "length of the needle tube" refers to the dimension between the tip of the needle tube (the tip of the tip portion of the needle tube) and the rear end of the needle tube (the rear end of the main body portion of the needle tube) in a direction parallel to the longitudinal direction (extension direction) of the main body portion (the dimension parallel to the central axis of the main body portion of the needle tube). The "tip" refers to the end of the needle tube that is inserted first into the eyeball, and the "rear end" refers to the opposite end. In one aspect of the present invention, when the tissue transplantation resin tip includes a "connection portion" described below, the "rear end" of the needle tube refers to the tip of the connection portion or the boundary between the needle tube and the connection portion. Furthermore, in the present invention, the "cross-sectional outline of the tip portion" refers to the cross-sectional outline in a direction perpendicular to the longitudinal direction (extension direction) of the tip portion of the needle tube. Furthermore, in the present invention, the "direction substantially perpendicular to the main body portion" refers to a direction substantially perpendicular to the central axis of the main body portion of the needle tube. In one aspect of the present invention, the "direction substantially perpendicular to the main body" refers to a direction that is 80° or more (preferably 85° or more, 87° or more, 88° or more, or 89° or more) and 100° or less (preferably 95° or less, 93° or less, 92° or less, or 91° or less) relative to the central axis of the main body of the needle tube. Furthermore, in the present invention, the "bevel angle" refers to the acute angle formed between the tip (bevel surface) of the distal end of the needle tube and the outer surface of the distal end of the needle tube adjacent to the tip. Furthermore, in the present invention, the "hardness" refers to the load required to displace the site where the hardness is measured by 5 mm with the rear end of the resin tip for tissue transplantation fixed.

[0010] According to the tissue transplant resin chip of the present invention, the tip of the needle tube is bent relative to the main body of the needle tube and extends linearly, and the tip of the tip of the needle tube extends in a direction approximately perpendicular to the main body of the needle tube, with a bevel surface having a bevel angle of 50° or more and 85° or less (e.g., approximately 60°), preferably 60° or more and 85° or less (e.g., approximately 75° (75°±3°, 75°±2°, 75°±1°)). This makes it easier to insert the tip of the needle tube into the subretinal space in a patient's eyeball to lift the retina and to expel tissue from the tip of the needle tube. Furthermore, according to the tissue transplant resin chip of the present invention, the hardness of the tip of the needle tube is 0.15 N or more and 0.30 N or less, and the hardness of the center (longitudinal center) of the needle tube is 0.80 N or more and 1.50 N or less. This prevents the needle tube from shaking within the eyeball. It should be noted that a person skilled in the art can manufacture a resin chip for tissue transplantation having a needle tube with a central portion and a tip portion having different hardnesses. In one embodiment, by designing the resin so that the thickness and cross-sectional outer shape become smaller toward the tip, it is possible to manufacture a resin chip for tissue transplantation having different hardnesses depending on the region, as described above. In addition to having the above-described bevel angle and hardness characteristics, the tissue transplantation resin chip according to the present invention allows for the length of the needle tube and the shape of the cross-sectional outer shape of the tip portion of the needle tube to be specified within the above-described predetermined ranges, thereby enabling the tissue aspirated into the needle tube to be easily and reliably transplanted into the desired subretinal region.

[0011] Preferably, the hardness of the tip portion is 0.20N or more and 0.30N or less.

[0012] According to the above-described preferred configuration, it is possible to further prevent the needle tube from shaking inside the eyeball.

[0013] Preferably, the length of the tip is 2 mm or more and less than 6 mm.

[0014] In the above-mentioned preferred configuration, the "length of the tip" means the dimension between the tip of the needle tube and the rear end of the needle tube, in a direction parallel to the longitudinal direction (extension direction) of the tip (the dimension parallel to the central axis of the needle tube's tip). According to the above-mentioned preferred configuration, the tissue aspirated into the needle tube can be transplanted more easily and reliably into the desired subretinal area.

[0015] Preferably, the tip portion is bent at an angle of 120° or more and 160° or less with respect to the main body portion. More preferably, the tip portion is bent at an angle of 120° or more (more preferably 130° or more) and 150° or less with respect to the main body portion.

[0016] According to the above-described preferred configuration, the tip of the needle tube can be easily inserted into the subretinal space along the retina in the patient's eyeball.

[0017] Preferably, the outer diameter of the center of the needle tube is 1.5 mm or more and 3.5 mm or less.

[0018] According to the above-described preferred configuration, it is possible to further prevent the needle tube from shaking inside the eyeball.

[0019] Preferably, the needle tube has a transparency that allows the tissue moving inside the needle tube to be visually observed from the outside.

[0020] According to the above-described preferred configuration, the position of the tissue inside the needle tube can be visually confirmed from the outside, making it possible to transplant the tissue even more easily.

[0021] The tissue transplant resin chip according to the present invention is formed from at least one resin selected from the group consisting of polyolefin resins (polypropylene, polyethylene, polymethylpentene), cycloolefin resins (cycloolefin polymer (COP), cycloolefin copolymer (COC)), polyester resins (polyethylene terephthalate), fluorine-containing resins (polytetrafluoroethylene (PTFE), perfluoroalkoxyalkane (PFA), perfluoroethylenepropene copolymer (FEP), ethylenetetrafluoroethylene copolymer (ETFE), polyvinylidene fluoride (PVDF), polychlorotrifluoroethylene (PCTFE), or ethylenechlorotrifluoroethylene copolymer (ECTFE)), polycarbonate, and polyimide.

[0022] Preferably, the tissue transplant resin tip according to the present invention includes a stopper in the main body that prevents the tissue from moving toward the rear end of the needle tube. The location of the stopper in the main body (the location where the internal space of the main body is narrowed), the shape of the stopper, and the length of the stopper can be freely designed by those skilled in the art. In one embodiment, the stopper can be located, for example, 10 mm to 30 mm from the tip of the needle tube. The stopper can be, for example, a tubular member made of resin or stainless steel that is inserted into the main body of the needle tube or integrally molded with the main body. It is also possible to provide a reduced-diameter portion that compresses the surface of the main body of the needle tube to narrow the internal space, and have this reduced-diameter portion function as a stopper.

[0023] According to the above-described preferred configuration, the tissue does not move further rearward than the position where the stopper is provided, so that too much tissue is not sucked into the needle tube, and the tissue can be transplanted more reliably.

[0024] Preferably, the tissue is retinal tissue. In the above-mentioned preferred configuration, "retinal tissue" refers to a tissue in which one or more types of retinal cells, such as photoreceptors, horizontal cells, bipolar cells, amacrine cells, retinal ganglion cells, retinal pigment epithelial cells, their precursor cells, or retinal progenitor cells, which constitute each retinal layer in a living retina, are arranged three-dimensionally in layers. In one embodiment, one or more of the above-mentioned retinal cells may form a single layer or multiple layers in a certain pattern. Layers that may be included in retinal tissue are also referred to as the retinal pigment epithelial layer, outer limiting membrane, photoreceptor layer (external nuclear layer), outer plexiform layer, inner nuclear layer, inner plexiform layer, ganglion cell layer, nerve fiber layer, and inner limiting membrane.

[0025] The retinal tissue may be retinal tissue excised from a living organism (e.g., a fetus) or retinal tissue induced to differentiate from autologous or allogeneic pluripotent stem cells (e.g., embryonic stem cells (ES cells), induced pluripotent stem cells (iPS cells)). The retinal tissue may be retinal tissue containing neural retina (including photoreceptor cells). Methods for preparing retinal tissue from a living organism are well known to those skilled in the art. Specifically, retinal tissue can be excised under anesthesia. Methods for inducing differentiation of pluripotent stem cells into retinal tissue include those described in WO2011 / 055855, WO2013 / 077425, WO2015 / 025967, WO2016 / 063985, WO2016 / 063986, WO2017 / 183732, "PLoS One. 2010 Jan 20;5(1):e8763.", "Stem Cells. 2011 Aug;29(8):1206-18.", "Proc Natl Acad Sci USA. 2014 Jun 10;111(23):8518-23.", and "Nat Commun. 2014 Jun 10;111(23):8518-23." 10;5:4047", WO2012 / 173207, WO2015 / 053375, WO2015 / 053376, WO2015 / 068505, WO2017 / 043605, "Stem Cell Reports, 2(2), 205-218 (2014)", "Cell Stem Cell, 10(6), 771-785 (2012)", and the like, but are not particularly limited thereto.

[0026] The size of the tissue is not particularly limited as long as it can move inside the needle tube. For example, it is preferable that the tissue has a minor axis of 400 μm or more and 800 μm or less and a thickness of 400 μm or more and 600 μm or less and be movable inside the needle tube. Retinal tissue of the above size can be prepared by cutting out retinal tissue prepared by the above-mentioned method.

[0027] The tissue transplantation resin chip according to the present invention can aspirate and discharge tissue by connecting it to, for example, a syringe, but is not limited to this.

[0028] In one embodiment, an injection syringe is connected to the tissue transplant resin chip according to the present invention, and the tissue is aspirated into the needle tube of the tissue transplant resin chip by pulling the injection syringe. The tissue is ejected from the needle tube of the tissue transplant resin chip by pushing the injection syringe. In another ejection method, the tissue may be ejected using an injection kit connected to a cataract / vitreous surgery device. Specifically, the tissue transplant resin chip with the tissue aspirated into the needle tube is detached from the injection syringe and connected to the injection kit. The needle tube of the tissue transplant resin chip is then inserted into the subretinal space in the patient's eyeball, and the injection kit is operated by the cataract / vitreous surgery device to eject the tissue from the needle tube into the subretinal space.

[0029] Alternatively, the syringe of an injection kit connected to a cataract / vitreous surgery device may be directly connected to the tissue transplantation resin tip of the present invention. Since cataract / vitreous surgery devices are typically equipped with a suction function, this suction function is activated to aspirate tissue into the needle of the tissue transplantation resin tip. The tissue is then ejected from the needle into the subretinal space in the same manner as described above.

[0030] On the other hand, as mentioned above, when a tissue transplantation resin tip that has aspirated tissue into the needle tube is reconnected to an injection kit, the tissue is exposed to the external environment, and the reconnection may cause the tissue to shift position within the tissue transplantation resin tip. Therefore, it is preferable to connect the tissue to the syringe via a stopcock, which will be described later. Furthermore, even if the tissue transplantation resin tip is connected to the injection kit from the beginning, there are limitations to the suction control function, making it difficult to precisely control the position of the tissue within the tissue transplantation resin tip. Therefore, it is preferable to use a stopcock, which will be described later.

[0031] In order to solve the above problems, the present invention also provides a tissue transplantation device comprising a stopcock, the tissue transplantation resin tip connected to one port of the stopcock, and a syringe connected to the other port of the stopcock. The tissue transplantation resin tip and the syringe may be connected to the respective ports via a tube (e.g., "Ocular Irrigation Tube" REF# 169-30L-6 manufactured by EAGLE LABS) rather than being directly connected to the respective ports of the stopcock.

[0032] In the present invention, a three-way stopcock or a two-way stopcock can be used as the "stopcock." According to the tissue transplantation device of the present invention, for example, when a three-way stopcock is used as the stopcock, it can be used as follows. That is, a tissue transplantation resin chip is connected to one port of the three-way stopcock, and a syringe is connected to the other port. Then, the port connected to the tissue transplantation resin chip and the port connected to the syringe are turned on (open) and the syringe is pulled, thereby aspirating tissue into the needle tube of the tissue transplantation resin chip. Next, for example, an injection kit is connected to the remaining port of the three-way stopcock, and a cataract / vitreous surgery device is connected to the injection kit. The port connected to the tissue transplantation resin chip and the port connected to the injection kit are turned on (open). Next, the needle tube of the tissue transplantation resin chip is inserted into the subretinal space in the patient's eyeball, and the injection kit is operated by the cataract / vitreous surgery device to eject tissue from the needle tube into the subretinal space. The tissue can be transplanted through the above operations. The tissue transplantation resin chip, syringe, and injection kit may be connected directly to the respective ports of the three-way stopcock, or may be connected via a tube (e.g., EAGLE LABS' "Ocular Irrigation Tube" REF# 169-30L-6). Furthermore, when the tissue transplantation device according to the present invention includes a two-way stopcock, it can be used as follows: That is, the tissue transplantation resin chip is connected to one port of the two-way stopcock, and a syringe is connected to the other port. Then, the port connected to the tissue transplantation resin chip and the port connected to the syringe are turned on (open), and the syringe is pulled to aspirate the tissue into the needle of the tissue transplantation resin chip. Next, the port to which the syringe is connected is turned off (closed), the syringe is removed, and then, for example, an injection kit is connected to this port, a cataract / vitreous surgery device is connected to the injection kit, and this port is turned on (open).Next, the needle tube of the tissue transplant resin tip is inserted into the subretinal space in the patient's eyeball, and the injection kit is operated by the cataract / vitreous surgery device to eject tissue from inside the needle tube into the subretinal space. The tissue can be transplanted by these operations. The tissue transplant resin tip, syringe, and injection kit may be connected directly to the respective ports of the two-way stopcock, or may be connected via tubing (e.g., EAGLE LABS "Ocular Irrigation Tube" REF# 169-30L-6).

[0033] To solve the above-mentioned problems, the present invention also provides a method for transplanting retinal tissue into the subretinal space in the eyeball of a patient suffering from a disease caused by retinal tissue damage or injury, the method comprising the steps of: using the tissue transplantation device to pull the syringe to aspirate the retinal tissue into the needle tube of the tissue transplantation resin chip; inserting the needle tube containing the aspirated retinal tissue into the subretinal space in the patient's eyeball; and discharging the retinal tissue from the needle tube into the subretinal space. Examples of diseases caused by retinal tissue damage include ophthalmic diseases such as retinal degenerative diseases, macular degeneration, age-related macular degeneration, retinitis pigmentosa, glaucoma, corneal diseases, retinal detachment, central serous chorioretinopathy, cone dystrophy, and cone-rod dystrophy. Examples of diseases caused by retinal tissue damage (damaged states of retinal tissue) include degeneration, atrophy, and cell death of photoreceptors, retinal pigment epithelial cells, etc.

[0034] Furthermore, to solve the above-mentioned problems, the present invention also provides a retinal tissue transplant kit comprising retinal tissue and the tissue transplant resin chip. The retinal tissue transplant kit according to the present invention may further comprise at least one of a syringe, an injection kit, and a tube (e.g., "Ocular Irrigation Tube" REF# 169-30L-6 manufactured by EAGLE LABS).

[0035] In summary, the present invention relates to the following: [1] A resin tip used for transplanting tissue into a subretinal space within an eyeball, the resin tip for tissue transplantation comprising a needle tube that can be inserted into the eyeball, the needle tube comprising a main body portion that extends linearly and a tip portion that bends relative to the main body portion, extends linearly, and ejects the tissue from its tip, the length of the needle tube being 25 mm to 50 mm, the cross-sectional outline of the tip portion being an ellipse with a major axis of 0.8 mm to 1.5 mm and a minor axis of 0.5 mm to 1.0 mm, the tip of the tip portion extending in a direction approximately perpendicular to the main body portion and having a bevel surface with a bevel angle of 50° to 85°, the hardness of the tip portion being 0.15 N to 0.30 N, and the hardness of the center of the needle tube being 0.80 N to 1.50 N. [2] The tissue transplant resin chip according to [1], wherein the hardness of the tip is 0.20 N or more and 0.30 N or less. [3] The tissue transplant resin chip according to [1] or [2], wherein the length of the tip is 2 mm or more and less than 6 mm. [4] The tissue transplant resin chip according to any one of [1] to [3], wherein the tip is bent at an angle of 120° or more and 160° or less with respect to the main body. [5] The tissue transplant resin chip according to any one of [1] to [4], wherein the outer diameter of the center of the needle tube is 1.5 mm or more and 3.5 mm or less. [6] The tissue transplant resin chip according to any one of [1] to [5], wherein the needle tube has a transparency that allows the tissue moving inside the needle tube to be visible from the outside. [7] The tissue transplant resin chip according to any one of [1] to [6], which is formed from at least one resin selected from the group consisting of polyolefin resin, cycloolefin resin, polyester resin, fluorine-based resin, polycarbonate, and polyimide. [8] The tissue transplant resin chip according to any one of [1] to [7], wherein the main body portion is provided with a stopper that prevents the tissue from moving toward the rear end of the needle tube. [9] The tissue transplant resin chip according to any one of [1] to [8], wherein the tissue is retinal tissue, and the retinal tissue has a minor axis of 400 μm or more and 800 μm or less and a thickness of 400 μm or more and 600 μm or less and is movable inside the needle tube.

[10] A tissue transplant device comprising a stopcock, the tissue transplant resin chip described in any one of [1] to [9] connected to one port of the stopcock, and a syringe connected to the other port of the stopcock.

[11] A method for transplanting retinal tissue into the subretinal space in the eyeball of a patient suffering from a disease caused by retinal tissue damage or injury, the method comprising the steps of using the tissue transplant device described in

[10] and pulling the syringe to aspirate the retinal tissue into the needle tube of the tissue transplant resin chip, inserting the needle tube with the aspirated retinal tissue into the subretinal space in the patient's eyeball, and discharging the retinal tissue from the needle tube into the subretinal space.

[12] A retinal tissue transplant kit comprising retinal tissue and the tissue transplant resin chip described in any one of [1] to [8].

[0036] According to the present invention, it is possible to provide a resin chip for tissue transplantation, a tissue transplantation device, a retinal tissue transplantation method, and a retinal tissue transplantation kit, which allow tissue sucked inside to be easily transplanted.

[0037] FIG. 5 is a diagram showing a schematic configuration of a resin tip for tissue transplantation according to one embodiment of the present invention. FIG. 6 is a diagram explaining a method for measuring the hardness of the needle tube shown in FIG. 1. FIG. 7 is a perspective view schematically showing an example of the schematic configuration of tissue transplanted by the tip shown in FIG. 1. FIG. 8 is a diagram showing a schematic configuration of a modified example of the tip shown in FIG. 1. FIG. 9 is a plan view showing a schematic configuration of a tissue transplant device according to one embodiment of the present invention. FIG. 10 is a diagram showing an example of a method for transplanting tissue using the device shown in FIG. 5. FIG. 11 is a diagram explaining the contents of an evaluation test using each tip. FIG. 12 is a side view showing a schematic configuration of a tip described in Non-Patent Document 1.

[0038] Hereinafter, an embodiment of the present invention will be described with reference to the accompanying drawings. Note that each drawing is for reference purposes only, and the dimensions, scale, and shapes of the components depicted in each drawing may differ from the actual ones. FIG. 1 is a diagram showing the schematic configuration of a resin tip for tissue transplantation (hereinafter, abbreviated as "tip") according to one embodiment of the present invention. FIG. 1(a) is a plan view showing the schematic configuration of the tip according to this embodiment (viewed from a direction along a plane passing through the main body and tip of a needle tube provided in the tip). FIG. 1(b) is a side view showing the schematic configuration of the tip according to this embodiment (viewed from a direction perpendicular to the plane passing through the main body and tip of a needle tube provided in the tip). FIG. 1(c) is a side view showing an enlarged schematic configuration of the vicinity of the tip of the tip according to this embodiment. FIG. 1(d) is a cross-sectional view taken along the arrow AA shown in FIG. 1(c). The tip 10 according to this embodiment shown in FIG. 1 is a resin tip used for subretinal transplantation of tissue into the eyeball. Specifically, the chip 10 according to this embodiment is suitable for use in subretinal transplantation of retinal tissue into the eye of a patient suffering from a disease resulting from retinal tissue damage or injury. As shown in FIG. 1 , the chip 10 according to this embodiment includes a needle tube 1 that can be inserted into the eye. The chip 10 according to this embodiment also includes a hollow connection section 2 that is connected to the rear end of the needle tube 1 and communicates with the needle tube 1, and wing sections 3 that are provided on the outer surface of the connection section 2. The "tip" refers to the end of the needle tube 1 that is inserted first into the eye (the left side in FIGS. 1( a ) to 1 ( c )), and the "rear end" refers to the opposite end (the right side in FIGS. 1( a ) to 1 ( c )). The wing sections 3 function to ensure connection of the chip 10 to the port 20 a of the stopcock 20 (described below). The wing sections 3 can also be used as a marker for the rear end of the needle tube 1 when the needle tube 1 is inserted into the eye.

[0039] The needle tube 1 comprises a main body 11 that extends linearly, and a tip portion 12 that bends relative to the main body 11, extends linearly, and ejects tissue from a tip 121. The main body 11 of the needle tube 1 in this embodiment has a circular cross-sectional outer shape and a tapered outer shape in which the outer diameter of the cross section decreases toward the tip portion 12. The tapered outer diameter of the main body 11 increases the hardness of the rear end of the needle tube 1, effectively preventing shaking of the needle tube 1 within the eyeball.

[0040] The length L1 of the needle tube 1 is 25 mm or more and 50 mm or less. Here, the length L1 of the needle tube 1 refers to the dimension between the tip 121 of the needle tube 1 (the tip 121 of the tip portion 12 of the needle tube 1) and the rear end 111 of the needle tube 1 (the rear end 111 of the main body 11 of the needle tube 1) in a direction parallel to the longitudinal direction (extension direction) of the main body 11 (the dimension parallel to the central axis CL1 of the main body 11 of the needle tube 1). The rear end 111 of the needle tube 1 coincides with the tip of the wing portion 3.

[0041] The cross-sectional outline of the tip portion 12 of the needle tube 1 (the cross-sectional outline in a direction perpendicular to the longitudinal direction (extension direction) of the tip portion 12 of the needle tube 1) is an ellipse with the long diameter on the side of the tip portion 12 (the side when viewed from a direction perpendicular to a plane passing through the main body portion 11 and tip portion 12 of the needle tube 1), and the long diameter D1 is 0.8 mm or more and 1.5 mm or less, and the short diameter D2 is 0.5 mm or more and 1.0 mm or less.

[0042] The tip 121 of the tip portion 12 of the needle tube 1 extends in a direction substantially perpendicular to the main body portion 11 and has a bevel surface with a bevel angle θ1 of 50° or more and 85° or less. Here, as shown in FIG. 1( c), the "direction substantially perpendicular to the main body portion 11" means a direction substantially perpendicular to the central axis CL1 of the main body portion 11 of the needle tube 1. Furthermore, the "bevel angle θ1" means an acute angle formed between the tip 121 (bevel surface) of the tip portion 12 of the needle tube 1 and an outer surface 122 of the tip portion 12 of the needle tube 1 adjacent to the tip 121. The tip 12 of the needle tube 1 is bent relative to the main body 11 of the needle tube 1 and extends in a straight line, and the tip 121 of the tip 12 of the needle tube 1 extends in a direction approximately perpendicular to the main body 11 of the needle tube 1, and the bevel surface has a bevel angle θ1 of 50° or more and 85° or less, making it easy to insert the tip 12 of the needle tube 1 into the subretinal space in the patient's eyeball to lift the retina and to expel tissue from the tip 121 of the tip 12 of the needle tube 1.

[0043] The hardness of the tip 12 of the needle tube 1 is 0.15 N or more and 0.30 N or less (preferably 0.20 N or more and 0.30 N or less), and the hardness of the center of the needle tube 1 (the longitudinal center of the needle tube 1, a portion having an outer diameter D3 in FIG. 1( a) that is half the length L1 from the tip 121 of the needle tube 1) is 0.80 N or more and 1.50 N or less. Here, "hardness" refers to the load required to displace the portion where hardness is measured (the tip 12 of the needle tube 1, the center of the needle tube 1) by 5 mm while the rear end of the tip 10 is fixed. Setting the hardness of the tip 12 and the center of the needle tube 1 within the above ranges prevents the needle tube 1 from shaking inside the eyeball. The hardness of each portion of the needle tube 1 can be adjusted by appropriately setting the material and thickness of the needle tube 1.

[0044] FIG. 2 is a diagram illustrating a method for measuring the hardness of the needle tube 1. FIG. 2 illustrates a case in which the hardness of the distal end 12 of the needle tube 1 is measured. As shown in FIG. 2, when measuring the hardness of the needle tube 1, a flat support base 50, a small vise (mini-vice) 60, a syringe (e.g., a 0.5 mL syringe manufactured by Bethel) 70, a force gauge (e.g., a digital force gauge "DVS-5N" manufactured by Imada) 80, and a V-shaped attachment 81 attached to the force gauge 80 are used. When measuring the hardness of the distal end 12 of the needle tube 1, the small vise 60 is fixed to the support base 50, and a syringe 70 is attached to the small vise 60. Then, the tip 10 is attached to the luer portion (not shown) of the syringe 70 with the distal end 12 facing downward. In this state (a state in which the rear end of the tip 10 is fixed), the V-shaped attachment 81 is brought into contact with the tip portion 12 (specifically, the rear end of the tip portion 12) from above, and the force gauge 80 and the V-shaped attachment 81 are displaced downward by 5 mm (thereby displacing the tip portion 12 downward by 5 mm), and the load (peak load) measured by the force gauge 80 in this state is taken as the hardness of the tip portion 12 of the needle tube 1. When measuring the hardness of the center of the needle tube 1, the V-shaped attachment 81 is brought into contact with the center of the needle tube 1 from above, and the force gauge 80 and the V-shaped attachment 81 are displaced downward by 5 mm (thereby displacing the center of the needle tube 1 downward by 5 mm), and the load (peak load) measured by the force gauge 80 in this state is taken as the hardness of the center of the needle tube 1.

[0045] The tip 10 of this embodiment has the above-mentioned characteristics of bevel angle θ1 and hardness, and in addition, the length L1 of the needle tube 1 and the cross-sectional shape of the tip 12 of the needle tube 1 are specified within the above-mentioned specified ranges, so that the tissue aspirated inside the needle tube 1 can be easily and reliably transplanted under the desired retina.

[0046] The length L2 of the distal end portion 12 of the needle tube 1 is 2 mm or more and less than 6 mm (less than 4 mm in one embodiment). Here, the length L2 of the distal end portion 12 of the needle tube 1 means the dimension in a direction parallel to the longitudinal direction (extension direction) of the distal end portion 12 (the dimension in a direction parallel to the central axis CL2 of the distal end portion 12 of the needle tube 1) between the distal end 121 of the distal end portion 12 of the needle tube 1 and the rear end of the distal end portion 12 of the needle tube 1 (the distal end of the main body portion 11).

[0047] The tip 12 of the needle tube 1 is bent at an angle (bending angle) θ2 of 120° or more and 160° or less with respect to the main body 11 of the needle tube 1. Setting the bending angle θ2 within the above range makes it easier to insert the tip 12 of the needle tube 1 into the subretinal space along the retina in the patient's eyeball.

[0048] The outer diameter of the center of the needle tube 1 is 1.5 mm or more and 3.5 mm or less.

[0049] The needle tube 1 has a transparency that allows visual recognition from the outside of the tissue moving inside the needle tube 1. The transparency of the needle tube 1 can be adjusted by appropriately setting the material and thickness of the needle tube 1.

[0050] The tip 10 (needle tube 1, connecting portion 2, and wing portions 3) according to this embodiment is formed from at least one resin selected from the group consisting of polyolefin resins (polypropylene, polyethylene, polymethylpentene), cycloolefin resins (cycloolefin polymer (COP), cycloolefin copolymer (COC)), polyester resins (polyethylene terephthalate), fluorine-containing resins (polytetrafluoroethylene (PTFE), perfluoroalkoxyalkane (PFA), perfluoroethylenepropene copolymer (FEP), ethylenetetrafluoroethylene copolymer (ETFE), polyvinylidene fluoride (PVDF), polychlorotrifluoroethylene (PCTFE), or ethylenechlorotrifluoroethylene copolymer (ECTFE)), polycarbonate, and polyimide. The needle tube 1, connecting portion 2, and wing portions 3 may be molded integrally using a mold from the above resins, or may be molded separately and joined with an adhesive or the like.

[0051] FIG. 3 is a perspective view schematically illustrating an example of the general configuration of tissue transplanted using the chip 10 according to the present embodiment. The tissue T shown in FIG. 3 is retinal tissue, having a minor diameter D4 of 400 μm or more and 800 μm or less, and a thickness H of 400 μm or more and 600 μm or less. The major diameter D5 is approximately 1200 μm. The chip 10 according to the present embodiment is configured so that the major diameter D5 of the tissue T is aligned along the longitudinal direction of the needle tube 1, the minor diameter D4 of the tissue T is aligned along the major diameter D1 direction of the distal end 12 of the needle tube 1, and the thickness H of the tissue T is aligned along the minor diameter D2 direction of the distal end 12 of the needle tube 1, allowing the tissue T to move inside the needle tube 1 (the inner diameter of the needle tube 1 is set to a dimension that does not hinder the movement of the tissue T). As the tissue T moves through the distal end 12 of the needle tube 1, the minor diameter D4 and thickness H of the tissue T may reversibly deform (contract).

[0052] FIG. 4 is a diagram showing a schematic configuration of a modified example of the tip 10 according to the present embodiment. FIG. 4( a) is a side view showing the schematic configuration of a modified tip 10A (viewed from a direction perpendicular to a plane passing through the main body 11 and the distal end 12 of the needle tube 1 provided in the tip 10A). FIG. 4( b) is an enlarged cross-sectional view taken along the arrows BB in FIG. 4( a). The modified tip 10A shown in FIG. 4 differs from the tip 10 only in that a stopper 4 is provided on the main body 11 of the needle tube 1. The stopper 4 serves to prevent the tissue T from moving toward the rear end of the needle tube 1. Specifically, in the example shown in FIG. 4, the stopper 4 is a blunt needle (e.g., a 25G non-bevel needle) inserted into the main body 11 of the needle tube 1 and having an inner diameter that prevents the tissue T from passing through (even if the tissue T contracts). According to the modified tip 10A, the tissue T does not move further rearward than the position where the stopper 4 is provided (does not move to the right of the line BB shown in Figure 4(a)), so the tissue T is not sucked too much into the needle tube 1, and the tissue T can be transplanted more reliably.

[0053] 4 illustrates an example in which a blunt needle inserted into the needle tube 1 is used as the stopper 4, but the invention is not limited to this and various configurations can be adopted as long as they function to prevent the tissue T from moving toward the rear end of the needle tube 1. For example, the needle tube 1 itself can be provided with a reduced diameter portion, and this reduced diameter portion can function as the stopper 4.

[0054] FIG. 5 is a plan view showing a schematic configuration of a tissue transplantation device according to one embodiment of the present invention. As shown in FIG. 5 , the tissue transplantation device 100 according to this embodiment includes a stopcock 20, a chip 10 according to this embodiment connected to one port of the stopcock 20, and a syringe (e.g., a 1 ml syringe or a 0.5 ml syringe) 30 connected to the other port of the stopcock 20. In this embodiment, at least the tissue T and the chip 10 constitute a retinal tissue transplantation kit. In addition to the tissue T and the chip 10, the retinal tissue transplantation kit may further include at least one of the syringe 30, an injection kit, and a tube, as described below. The tissue transplantation device 100 according to this embodiment includes a three-way stopcock with three ports 20a, 20b, and 20c as the stopcock 20. However, the present invention is not limited to this, and a configuration including a two-way stopcock as the stopcock 20 may also be adopted. In the example shown in FIG. 5, the chip 10 is connected to the port 20a via the lock adapter 40, and the syringe 30 is connected to the port 20b.

[0055] An example of a method for transplanting tissue T (retinal tissue) using the tissue transplant device 100 is described below. First, a typical vitreous stalk microsurgical detachment is performed using a cataract / vitreous surgery device (e.g., an Alcon Constellation Vision System). If necessary, a posterior vitreous detachment is also induced. Next, an injection kit (e.g., a MedOne injection kit) is connected to the cataract / vitreous surgery device, the injection kit is filled with a balanced salt solution, and a cannula (e.g., a MedOne cannula, certification number 226AFBZI00075000) is connected to the injection kit. Then, using the liquid injection function of the cataract / vitreous surgery device, the balanced salt solution filled in the injection kit is injected into the subretinal space via the cannula, creating a localized retinal detachment. The detached retina is then partially incised with vitreous scissors or the like to form a wound for transplantation.

[0056] Meanwhile, the tissue T to be transplanted is transferred from the storage container into a Petri dish and floated therein. Then, with the port 20a connected to the chip 10 of the tissue transplant device 100 and the port 20b connected to the syringe 30 turned on (open) as shown in FIG. 5 , the tip 121 of the chip 10 is brought close to the tissue T floating in the Petri dish. Next, the syringe 30 is pulled back to aspirate the tissue T into the needle tube 1 of the chip 10 (e.g., up to the center of the needle tube 1). Before pulling the syringe 30 to aspirate the tissue T, it is preferable to prime the needle tube 1 by filling it with an eye irrigation solution for ophthalmic surgery. After the tissue T has been aspirated into the needle tube 1, at least the port 20b connected to the syringe 30 is turned off (closed), and the syringe 30 is removed from the port 20b. In addition, in order to effectively prevent the tissue T from moving due to the suction pressure generated when the syringe 30 is removed from the port 20b or the discharge pressure due to the movement of air, it is preferable to turn off (block) both the port 20b to which the syringe 30 is connected and the remaining port 20c and then remove the syringe 30 from the port 20b.

[0057] Next, with the tissue T still being sucked into the needle tube 1 of the tip 10, an injection kit (e.g., a MedOne injection kit) is connected to the remaining port 20c of the stopcock 20, the injection kit is connected to the above-mentioned cataract / vitreous surgery device, and the port 20a connected to the tip 10 and the port 20c connected to the injection kit are turned on (open). When connecting the injection kit to port 20c, it is preferable to fill the dead space of port 20c with an ophthalmic surgical eye irrigation solution. It is also possible to connect the injection kit to port 20c via a tube rather than directly.

[0058] Next, as shown in Figure 6, the needle tube 1 of the tip 10 is inserted into the patient's eyeball E through an incision made in the sclera E1, and the tip 12 is brought to the transplant wound R1 made in the retina R. After inserting the tip 12 of the needle tube 1 through the transplant wound R1 into the subretinal space, the injection kit is operated using the liquid injection function of the cataract and vitreous surgery device, thereby ejecting tissue T from inside the needle tube 1 into the subretinal space. If necessary, the position of the tissue T after ejection may be adjusted using subretinal forceps or the like. Through the above operations, the tissue T can be transplanted subretinaly within the eyeball E.

[0059] Below, an example of test results will be described in which a doctor actually performed a tissue T transplant operation using the tip 10 according to this embodiment, the tip described in Non-Patent Document 1, and a tip prototyped in the process of conceiving the present invention, and evaluated the ease of transplantation. FIG. 7 is a diagram illustrating the contents of the evaluation test. FIG. 7(a) is a diagram illustrating the conditions and evaluation results of each tip. FIG. 7(b) is a diagram illustrating the meaning of the tip of the tip having an "upward bevel surface." FIG. 8 is a side view (viewed from a direction perpendicular to a plane passing through the main body and tip of the needle tube provided in the tip) showing the schematic configuration of the tip described in Non-Patent Document 1. The "Comparative Example" shown in FIG. 7(a) shows the conditions and evaluation results of the tip described in Non-Patent Document 1, "Reference Example 1" to "Reference Example 4" show the conditions and evaluation results of prototype tips, and "Example 1" to "Example 5" show the conditions and evaluation results of the tip 10 according to this embodiment.

[0060] As shown in FIG. 8 , the tip 10B according to the comparative example includes a needle tube 1 (main body portion 11 and tip portion 12) and a connecting portion 2, similar to the tip 10 according to the present embodiment. Also, like the tip 10A according to the aforementioned modified example, it includes a stopper 4. However, the tip 10B according to the comparative example does not include a wing portion 3. Furthermore, the tip 121 of the tip portion 12 of the tip 10B according to the comparative example is not a beveled surface, but rather a surface extending in a direction perpendicular to the longitudinal direction (extension direction) of the tip portion 12. In FIG. 7( a ), for convenience of illustration, the bevel angle of the comparative example is described as 90°, which means that the tip 121 extends in a direction perpendicular to the longitudinal direction of the tip portion 12, as described above. The same applies to Reference Example 1 shown in FIG. 7( a ).

[0061] Furthermore, the column for "Bevel angle [°]" of Reference Example 3 shown in Fig. 7(a) states "70 (upward)," but "upward" means that the tip 121 of the tip portion 12 has an upward bevel surface, as shown in Fig. 7(b). The upward bevel surface means a surface that extends in a direction substantially parallel to the main body 11 of the needle tube 1 (a direction substantially parallel to the central axis CL1 of the main body 11 of the needle tube 1). Furthermore, "70 (upward)" in the column for "Bevel angle [°]" means that the acute angle θ1 formed between the tip 121 (upward bevel surface) and the outer surface 122 of the tip portion 12 of the needle tube 1 adjacent to the tip 121 is 70°, as shown in Fig. 7(b). In addition, the notation "(horizontal)" in the "Bevel angle [°]" column of Reference Example 2, Reference Example 4, and Examples 1 to 5 shown in FIG. 7(a) means that the tip 121 of the tip portion 12 is a bevel surface that extends in a direction approximately perpendicular to the main body portion 11, as described above with reference to FIG. 1(c).

[0062] In FIG. 7( a), the values ​​in the hatched columns indicate that the conditions required for the tissue transplantation resin chip according to the present invention are not satisfied. Furthermore, the "△" in the "Transplantation Evaluation" column in FIG. 7( a) indicates that the subretinal transplantation of tissue T was somewhat difficult. "◯" indicates that the subretinal transplantation of tissue T was generally successful. "◎" indicates that the subretinal transplantation of tissue T was satisfactory without any problems. "◎◎" indicates that the subretinal transplantation of tissue T was the best without any problems. Specifically, in the Comparative Example, Reference Examples 1 to 4, Example 1, and Example 2, the tissue transplantation resin chip was used to evaluate the subretinal transplantation of tissue T in monkeys. In Examples 3 to 5, the tissue transplantation resin chip was used to evaluate the subretinal transplantation of tissue T in excised pig eyes.

[0063] As shown in Figure 7, when the chip 10 according to this embodiment (Examples 1 to 5) was used, the transplantation of tissue T into the subretinal space was generally satisfactory or satisfactory without any problems. In particular, when the tissue transplant resin chips of Examples 2 to 5 were used, it was found that the transplantation of tissue T into the subretinal space in large animals was particularly satisfactory. In other words, it was confirmed that the tissue transplant resin chip according to the present invention makes it easy to transplant the tissue T aspirated inside.

[0064] DESCRIPTION OF SYMBOLS 1...Needle tube 2...Connecting portion 3...Wing portion 10, 10A...Resin tip for tissue transplantation 11...Main body portion 12...Tip portion 100...Tissue transplant device 111...Rear end of needle tube 121...Tip of needle tube L1...Length of needle tube D1...Major axis of cross-sectional outline of tip of needle tube D2...Minor axis of cross-sectional outline of tip of needle tube T...Tissue θ1...Bevel angle θ2...Bending angle

Claims

1. A resin chip used for transplanting tissue into the subretinal space of an eyeball, a needle tube that can be inserted into the eyeball; The needle tube includes a main body portion extending linearly and a tip portion bending relative to the main body portion and extending linearly, and ejecting the tissue from a tip thereof; The length of the needle tube is 25 mm or more and 50 mm or less, The cross-sectional outer shape of the tip portion is an ellipse having a major axis of 0.8 mm or more and 1.5 mm or less and a minor axis of 0.5 mm or more and 1.0 mm or less, a tip of the tip portion extends in a direction substantially perpendicular to the main body portion and has a bevel surface with a bevel angle of 50° or more and 85° or less; The hardness of the tip portion is 0.15 N or more and 0.30 N or less, and the hardness of the center of the needle tube is 0.80 N or more and 1.50 N or less. Resin chip for tissue transplantation.

2. The hardness of the tip is 0.20 N or more and 0.30 N or less. The resin chip for tissue transplantation according to claim 1.

3. The length of the tip is 2 mm or more and less than 6 mm. The resin chip for tissue transplantation according to claim 1 or 2.

4. The tip portion is bent at an angle of 120° or more and 160° or less with respect to the main body portion. The resin chip for tissue transplantation according to claim 1 or 2.

5. The outer diameter of the center of the needle tube is 1.5 mm or more and 3.5 mm or less. The resin chip for tissue transplantation according to claim 1 or 2.

6. The needle tube has transparency that allows the tissue moving inside the needle tube to be visible from the outside. The resin chip for tissue transplantation according to claim 1 or 2.

7. The insulating layer is formed from at least one resin selected from the group consisting of polyolefin resin, cycloolefin resin, polyester resin, fluorine resin, polycarbonate, and polyimide. The resin chip for tissue transplantation according to claim 1 or 2.

8. The main body portion includes a stopper that prevents the tissue from moving toward the rear end of the needle tube. The resin chip for tissue transplantation according to claim 1 or 2.

9. the tissue is retinal tissue, The retinal tissue has a minor axis of 400 μm or more and 800 μm or less and a thickness of 400 μm or more and 600 μm or less, and is movable inside the needle tube. The resin chip for tissue transplantation according to claim 1 or 2.

10. A stopcock and The tissue transplant resin chip according to claim 1 or 2, which is connected to one port of the stopcock; a syringe connected to the other port of the stopcock; Equipped with Tissue transplant devices.

11. A method for transplanting retinal tissue into the subretinal space of an eyeball of a patient suffering from a disease based on retinal tissue damage or injury, comprising: a step of using the tissue transplantation device according to claim 10 to draw the syringe to aspirate the retinal tissue into the needle tube of the tissue transplantation resin tip; inserting the needle tube with the retinal tissue aspirated into the subretinal space within the patient's eye; and ejecting the retinal tissue from the inside of the needle tube into the subretinal space. Retinal tissue transplantation method.

12. Retinal tissue, The resin chip for tissue transplantation according to claim 1 or 2, Equipped with Retinal tissue transplant kit.