WO2016063970A1 - Procédé de contrôle de qualité pour rétines artificielles - Google Patents

Procédé de contrôle de qualité pour rétines artificielles Download PDF

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Publication number
WO2016063970A1
WO2016063970A1 PCT/JP2015/079934 JP2015079934W WO2016063970A1 WO 2016063970 A1 WO2016063970 A1 WO 2016063970A1 JP 2015079934 W JP2015079934 W JP 2015079934W WO 2016063970 A1 WO2016063970 A1 WO 2016063970A1
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Prior art keywords
surface potential
artificial
artificial retina
potential change
quality control
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PCT/JP2015/079934
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English (en)
Japanese (ja)
Inventor
内田 哲也
松尾 俊彦
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国立大学法人 岡山大学
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Publication of WO2016063970A1 publication Critical patent/WO2016063970A1/fr

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007Methods or devices for eye surgery
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses

Definitions

  • the present invention relates to an artificial retina quality control method in which an organic pigment compound that induces a receptor potential in response to light stimulation is fixed in the optic nerve.
  • Patent Document 1 describes a receptor potential inducer comprising an organic dye compound that induces a receptor potential in response to light stimulation in the optic nerve.
  • the receptor potential inducer of the present invention is a visual disorder such as visual field stenosis, visual acuity, night blindness, etc. due to retinal disorders associated with wounds, drug addiction, visual center neuropathy, retinal diseases,
  • retinal replacement materials such as artificial retina for alleviating or eliminating color vision abnormalities caused by the lack of specific weights, it is said to be extremely useful as a material that replaces visual related substances.
  • quality control capable of selecting whether or not it can be used as an artificial retina is very important, and in particular, the required performance of the artificial retina varies depending on the state of the eyeball of the patient. There was a need for a method for quality control of an artificial retina.
  • the present invention has been made in order to solve the above-mentioned problems, and the performance of an artificial retina is evaluated by measuring the amount of light-induced surface potential change for an artificial retina that induces a receptor potential in response to light stimulation.
  • An object of the present invention is to provide a quality control method capable of performing quality evaluation.
  • Another object of the present invention is to provide an artificial retina in which the amount of photoinduced surface potential change is controlled because the amount of photoinduced surface potential change required varies depending on the state of the patient's eyeball.
  • the above-mentioned problem is a quality control method for an artificial retina in which an organic dye compound is fixed to a base material made of a polymer film, and the organic dye compound induces a receptor potential in response to light stimulation,
  • the problem is solved by providing a quality control method for an artificial retina characterized in that the artificial retina is selected by measuring the amount of light-induced surface potential change of the artificial retina.
  • a package containing an artificial retina is a preferred embodiment of the present invention.
  • a packaging kit including a plurality of artificial retinas each having a different size and describing the amount of light-induced surface potential change measured by the quality control method is also a preferred embodiment of the present invention.
  • a packaging kit including a plurality of artificial retinas each having a different amount and magnitude of light-induced surface potential measured by the quality control method is also described. It is an aspect.
  • the quality control method of the present invention can perform performance evaluation and quality evaluation of an artificial retina by measuring a light-induced surface potential change amount for an artificial retina that induces a receptor potential in response to light stimulation. . Further, since the required amount of change in the photoinduced surface potential varies depending on the state of the eyeball of the patient, an artificial retina in which the amount of change in the photoinduced surface potential is controlled can be provided. Furthermore, it is possible to provide a package including an artificial retina and a package kit including a plurality of the artificial retinas, each of which describes the amount of photoinduced surface potential change measured by the quality control method of the present invention.
  • FIG. 2 is an infrared absorption spectrum measured in Example 1.
  • FIG. 2 is a graph showing photoresponsiveness obtained in Example 1.
  • FIG. 2 is a graph showing the light intensity dependency obtained in Example 1.
  • FIG. 2 is a graph showing the wavelength dependency obtained in Example 1.
  • FIG. 2 is a graph showing the dye fixing amount dependency obtained in Example 1.
  • the quality control method of the present invention is characterized in that, for an artificial retina that induces a receptor potential in response to a light stimulus, the artificial retina is selected by measuring a light-induced surface potential change amount.
  • the light-induced surface potential change amount in the present invention refers to a difference between a work function or surface potential value obtained when light is irradiated on the surface of an artificial retina and a work function or surface potential value when light is not irradiated. Measured using a scanning Kelvin probe.
  • a scanning Kelvin probe is a non-contact, non-destructive device that measures a work function difference, a surface potential, and the like on a sample surface from vibrations of capacitance between a vibrating probe and a sample.
  • the quality control method of the present invention makes it possible to perform nondestructive performance evaluation and quality evaluation of the artificial retina. That is, a significant difference in the amount of change in the photoinduced surface potential between when the white pigment is irradiated in the dark room and when the artificial retina has an organic pigment compound fixed on a polymer film substrate. It was confirmed that the photoresponsiveness of the artificial retina can be evaluated. With respect to the artificial retina, the value of the light-induced surface potential change increases as the intensity of white light irradiation increases in the dark room, confirming that the light intensity dependence of the artificial retina can be evaluated. It was.
  • the present inventors proposes that if it has a light-induced surface potential change amount of several tens of mV, it will function as an artificial retina. Therefore, the present invention is significant because it can be selected whether or not it can be used as an artificial retina according to the present invention.
  • the present invention since the required amount of photoinduced surface potential change varies depending on the state of the patient's eyeball, the present invention that can provide an artificial retina in which the amount of photoinduced surface potential change is controlled is significant. Therefore, a method for selecting an artificial retina having a light-induced surface potential change suitable for the symptoms of the patient's eyeball is a preferred embodiment of the present invention.
  • the artificial retina used in the present invention is obtained by fixing an organic dye compound on a base material made of a polymer film.
  • the substrate include polyolefin, polyester, polyamide, polyvinyl chloride and the like, and polyolefin is preferably used among them.
  • the polyolefin include polyethylene, polypropylene, propylene-ethylene block copolymer, propylene-ethylene random copolymer, ethylene-vinyl acetate copolymer, and polyethylene is preferably used from the viewpoint of being stable in vivo. Of these, those for medical use are preferably used.
  • polyethylenes high-density polyethylene is preferably used.
  • the present inventors presume that when impurities such as fine particles are present on the surface of the substrate, the reaction between the surface of the substrate and the organic dye compound is inhibited. Therefore, it is preferable that the substrate used in the present invention has a small amount of residue such as fine particles and catalyst amount.
  • polyethylene having an ash content of 0.005 wt% or less, an n-hexane soluble content of 0.06 wt% or less, and a number of fine particles of 0.2 ⁇ m or more of 30/10 mL (isopropyl alcohol) is preferably used. .
  • the substrate made of the polymer film used in the present invention is preferably a film having a thickness of 5 to 100 ⁇ m.
  • the thickness of the base material is less than 5 ⁇ m, the strength of the obtained artificial retina may be reduced, and it is more preferably 10 ⁇ m or more.
  • the thickness of the base material exceeds 100 ⁇ m, it may be difficult to insert into the eyeball, and it is more preferably 80 ⁇ m or less.
  • the organic dye compound used in the present invention is not particularly limited as long as it induces a receptor potential in response to light stimulation.
  • polymethine, porphyrin, and rhodamine are preferably used.
  • polymethine-based organic dye compound those exemplified as Chemical Formulas 1 to 17 in Japanese Patent No. 5090431 can be preferably used.
  • the artificial retina used in the present invention is obtained by fixing an organic pigment compound that induces a receptor potential in response to light stimulation to a base material made of a polymer film.
  • an organic pigment compound that induces a receptor potential in response to light stimulation As shown in Japanese Patent No. 5090431, Matsuo et al., One of the present inventors, composes the optic nerve, particularly the optic nerve, using an organic dye compound that induces a receptor potential in response to light stimulation. In retinal neurons, it was confirmed that a remarkable receptor potential was observed as an intracellular potential. Therefore, it can be seen that a membrane in which an organic dye compound that induces a receptor potential in response to light stimulation is fixed to a base material made of a polymer film is useful as an artificial retina.
  • the artificial retina used in the present invention preferably has a breaking elongation of 50% or more.
  • An artificial retina having a breaking elongation of 50% or more is excellent in mechanical properties, and therefore has good stability when inserted into an eyeball.
  • the breaking elongation is more preferably 100% or more, further preferably 200% or more, and particularly preferably 300% or more.
  • the elongation at break is usually 3000% or less.
  • the artificial retina used in the present invention preferably has a contact angle of water of 90 ° or less with respect to the artificial retina surface.
  • An artificial retina having a water contact angle of 90 ° or less has an advantage of good biocompatibility.
  • the contact angle of water is more preferably 85 ° or less.
  • the contact angle of water is preferably 50 ° or more.
  • the method for producing the artificial retina used in the present invention is not particularly limited, but the organic dye compound is formed on the substrate made of the polymer film by reacting the organic solvent containing the organic dye compound with the substrate made of the polymer film.
  • a method of fixing is preferably employed.
  • the organic solvent used is not particularly limited, but halogenated hydrocarbon solvents such as chlorobenzene, dichlorobenzene, trichlorobenzene, dichloroethane, trichloroethane, methylene chloride, chloroform, carbon tetrachloride; pentane, hexane, heptane, octane, cyclohexane, etc.
  • Saturated aliphatic hydrocarbon solvents such as benzene, toluene, xylene; ether solvents such as dimethyl ether, ethyl methyl ether, diethyl ether, tetrahydrofuran, 1,4-dioxane; acetonitrile, propionitrile, Examples thereof include nitrile solvents such as benzonitrile; aprotic polar solvents such as dimethyl sulfoxide, N, N-dimethylformamide, and N-methylpyrrolidone.
  • at least one organic solvent selected from the group consisting of halogenated hydrocarbon solvents, saturated aliphatic hydrocarbon solvents, and aromatic hydrocarbon solvents is preferably used, and halogenated hydrocarbon solvents are more preferable. Used for.
  • the method for producing an artificial retina used in the present invention it is preferable to perform fuming nitric acid treatment on a base material made of a polymer film.
  • a carboxyl group can be introduce
  • the fuming nitric acid treatment is not particularly limited, but a method in which a base material made of a polymer film is placed in fuming nitric acid and treated at 10 to 100 ° C. is suitably employed.
  • the present inventors increase the amount of carboxyl groups introduced, but on the other hand, the elongation at break decreases to less than 50%, resulting in poor mechanical properties of the resulting artificial retina. I have confirmed that. Therefore, it is preferable to perform the fuming nitric acid treatment so that the breaking elongation of the base material made of the polymer film after the fuming nitric acid treatment satisfies 50% or more.
  • the method for modifying the diamine is not particularly limited.
  • a method of reacting a base material composed of a polymer film after fuming nitric acid treatment with ethylenediamine and DCC (N, N-diccyclohexylcarbide) is preferably employed. Is done. Thereby, the carboxyl group and amine introduced on the surface of the base material made of the polymer film are dehydrated and condensed to form an amide bond, and a base material made of the polymer film having an amino group can be obtained.
  • an artificial retina used in the present invention can be obtained by reacting a base material composed of a diamine-modified polymer film with an organic dye compound.
  • the method of reacting the organic dye compound is not particularly limited.
  • a method of reacting using DCC is preferably employed in the same manner as the above-described diamine modification method. Is done.
  • the amino group of the substrate made of the polymer film and the carboxyl group of the organic dye compound are dehydrated and condensed to form an amide bond, whereby the organic dye compound is formed on the substrate made of the polymer film.
  • a fixed artificial retina can be obtained.
  • an organic solvent containing an organic dye compound reacts with a base material made of a polymer film, and then the organic dye compound is formed on the base material made of the polymer film by washing.
  • a method for obtaining a fixed artificial retina is preferably employed.
  • the washing method a method of washing with water and then washing with an organic solvent is suitably employed.
  • an organic solvent used The organic solvent used when fixing an organic pigment
  • At least one organic solvent selected from the group consisting of halogenated hydrocarbon solvents, saturated aliphatic hydrocarbon solvents, and aromatic hydrocarbon solvents is preferably used, and halogenated hydrocarbon solvents are more preferable. Used for.
  • Such a washing method makes it possible to wash away organic pigment compounds that are not fixed to a substrate made of a polymer film, and in the optic nerve, a highly reliable artificial retina that induces a receptor potential in response to light stimulation. The present inventors have confirmed that it can be obtained.
  • the quality control method of the present invention can perform performance evaluation and quality evaluation of an artificial retina by measuring a light-induced surface potential change amount. It is possible to select whether or not it can be used as an artificial retina. Furthermore, the amount of light-induced surface potential change required differs depending on the state of the patient's eyeball. An artificial retina having a controlled amount can be provided. Therefore, a package including an artificial retina, in which a photoinduced surface potential change amount measured by the quality control method of the present invention is described, is a preferred embodiment of the present invention, and is measured by the quality control method of the present invention.
  • a package kit including a plurality of artificial retinas each having a different amount of light-induced surface potential change and a different amount of light-induced surface potential change is also a preferred embodiment of the present invention.
  • a package kit including a plurality of artificial retinas each having a different size is described, wherein the amount of photoinduced surface potential change measured by the quality control method of the present invention is described.
  • a suitable embodiment is to prepare an artificial retina having a diameter of 2 to 15 mm at intervals of 1 mm.
  • a package kit including a plurality of artificial retinas each having a different amount and magnitude of the photoinduced surface potential measured by the quality control method of the present invention is also described.
  • High-purity additive-free high-density polyethylene is Tosoh's high-density polyethylene (“NH8022”, Mw: 150,000, ash content: 0.002 wt%, n-hexane soluble content: 0.04 wt%, number of fine particles of 0.2 ⁇ m or more. : About 15/10 mL (isopropyl alcohol)) was used.
  • an infrared spectrophotometer of IRAffinity-1 manufactured by Shimadzu Corporation was used.
  • the UV-visible absorption spectrum was measured using a UV-visible spectrophotometer manufactured by Hitachi “U-1900”.
  • the water contact angle was measured using a “CA-D type” contact angle meter manufactured by Kyowa Interface Chemical Co., Ltd.
  • a tensile and compression tester “SV-201NA” manufactured by Imada Seisakusho was used.
  • a scanning kelvin probe of “SKP5050” manufactured by KP Technology was used. The probe diameter was 2 mm.
  • Example 1 [Purification of polyethylene] Into a 1000 ml eggplant type flask, 333 g of 90 wt% xylene was added, 10 g of high purity non-added high density polyethylene pellets (weight fraction of high density polyethylene 3 wt%) were added, and heated in an oil bath at 120 ° C. to completely dissolve. Thereafter, it was gradually cooled to 70 ° C. to precipitate polyethylene crystals, which were filtered. The obtained sample was washed with xylene heated to 70 ° C., normal temperature ethanol, distilled water in this order and dried to obtain a purified high-density polyethylene powder.
  • the contact angle of water was measured with a contact angle meter.
  • the contact angle of water after dye fixation was 80.4 °.
  • the breaking elongation was 200% or more.
  • the absorbance of the dye-fixed thin film was measured using an ultraviolet-visible spectrophotometer and the absorbance derived from polyethylene was subtracted from the baseline, the absorbance near 539 nm was 0.06. This concentration is compared to a calibration curve prepared using a known dye solution, was converted to the dye fixing amount per 1 mm 2, was 37 ⁇ 10 12 pieces / mm 2.
  • a Kelvin probe is a non-contact, non-destructive device that measures a work function difference, a surface potential, and the like on the surface of a sample from vibration of capacitance between a vibrating probe and a sample. References are shown below. 1.ID Baikie, M. Porterfield, P. Smith and PJ Estrup, 'A Novel Matrix Head Scanning BioKelvin Probe', Review Scientific Instruments 70, 1842 (1999). 2.ID Baikie and PJ Estrup, 'Low Cost PC Based Scanning Kelvin Probe', Review of Scientific Instruments 69, 3902 (1998). 3. ID Baikie, S.
  • dye fixing thin films having different dye fixing amounts were prepared in the same manner as the preparation of the dye fixing thin film (dye fixing amount: 1.8 ⁇ 10 12 pieces / mm 2). 8.0 ⁇ 10 12 pieces / mm 2 , 15 ⁇ 10 12 pieces / mm 2 , 37 ⁇ 10 12 pieces / mm 2 ). Each of the obtained dye-fixed thin films was cut into 1 cm ⁇ 1 cm, dried under reduced pressure, fixed to a sample table of a scanning Kelvin probe, and static electricity on the sample surface was removed.
  • the amount of change in light-induced surface potential when irradiated with 300 lx white light in a dark room was measured with a scanning Kelvin probe. The obtained results are shown in FIG. As the dye fixing amount increases, the value of the photoinduced surface potential change amount increases, and the dependency of the photoinduced surface potential change amount on the dye fixing amount is confirmed. Therefore, it can be seen that the dye-fixed thin film can be selected by measuring the photoinduced surface potential change.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Ophthalmology & Optometry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Transplantation (AREA)
  • Surgery (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Medicinal Chemistry (AREA)
  • Dermatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Materials For Medical Uses (AREA)
  • Prostheses (AREA)

Abstract

Ce procédé de contrôle de qualité pour rétines artificielles dans lesquelles un composé colorant organique est fixé à un matériau de base comprenant un film polymère est caractérisé en ce que : le composé colorant organique induit un potentiel récepteur correspondant à la stimulation de la lumière ; et les rétines artificielles sont criblées par mesure de la quantité de changement dans le potentiel de surface induite par la lumière de chaque rétine artificielle. En conséquence, l'évaluation de performance et l'évaluation de qualité des rétines artificielles peuvent être réalisées par mesure de la quantité de changement dans le potentiel de surface induite par la lumière de chaque rétine artificielle qui induisent un potentiel récepteur correspondant à la stimulation de la lumière.
PCT/JP2015/079934 2014-10-24 2015-10-23 Procédé de contrôle de qualité pour rétines artificielles WO2016063970A1 (fr)

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JP2014216997A JP2016083083A (ja) 2014-10-24 2014-10-24 人工網膜の品質管理方法
JP2014-216997 2014-10-24

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3127558A4 (fr) * 2014-03-31 2018-01-03 National University Corporation Okayama University Procédé de production de rétine artificielle

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7272633B2 (ja) * 2019-03-14 2023-05-12 国立大学法人 岡山大学 人工網膜及びその製造方法

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JP2004121292A (ja) * 2002-09-30 2004-04-22 Hayashibara Biochem Lab Inc 受容器電位誘発剤
WO2015152233A1 (fr) * 2014-03-31 2015-10-08 国立大学法人 岡山大学 Procédé de production de rétine artificielle

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JP2004121292A (ja) * 2002-09-30 2004-04-22 Hayashibara Biochem Lab Inc 受容器電位誘発剤
WO2015152233A1 (fr) * 2014-03-31 2015-10-08 国立大学法人 岡山大学 Procédé de production de rétine artificielle

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MATSUO T ET AL.: "Safety, efficacy, and quality control of a photoelectric dye-based retinal prosthesis (Okayama University-type retinal prosthesis) as a medical device", JOURNAL OF ARTIFICIAL ORGANS, vol. 12, no. 4, 25 December 2009 (2009-12-25), pages 213 - 225, XP019763135 *
SHOKO KANESHIMA ET AL.: "Koden Henkan Shikiso Kotei Polyethylene Hakumaku Gata Jinko Momaku no Hyomen Den'i Hikari Otosei ni Kansuru Kenkyu", POLYMER PREPRINTS, vol. 62, no. 1, 2013, pages 1485 *
TOSHIHIKO MATSUO ET AL.: "Koden Henkan Shikiso Ketsugo Polyethylene Film (Okayama University Hoshiki Jinko Momaku) no Kelvin Probe ni yoru Hyomen Den'i Sokutei", THE JAPANESE JOURNAL OF ARTIFICIAL ORGANS, vol. 38, no. 2, 26 October 2009 (2009-10-26), pages S-41 *
TOSHIHIKO MATSUO ET AL.: "Koden Henkan Shikiso o Tsukatta Jinko Momaku (Okayama University Hoshiki Jinko Momaku) no Hyoka Hoho", THE JAPANESE JOURNAL OF ARTIFICIAL ORGANS, vol. 37, no. 2, 1 October 2008 (2008-10-01), pages S-11 *
TOSHIHIKO MATSUO ET AL.: "Okayama University Hoshiki no Jinko Momaku (Koden Henkan Shikiso Ketsugo Polyethylene Film) no Hinshitsu", JOURNAL OF JAPANESE OPHTHALMOLOGICAL SOCIETY, vol. 116, 1 March 2012 (2012-03-01), pages 340 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3127558A4 (fr) * 2014-03-31 2018-01-03 National University Corporation Okayama University Procédé de production de rétine artificielle
US10039861B2 (en) 2014-03-31 2018-08-07 National University Corporation Okayama University Method for producing artificial retina

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