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WO2016035772A1 - Filtre de capture de substance biologique, et système de capture de substance biologique - Google Patents

Filtre de capture de substance biologique, et système de capture de substance biologique Download PDF

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Publication number
WO2016035772A1
WO2016035772A1 PCT/JP2015/074768 JP2015074768W WO2016035772A1 WO 2016035772 A1 WO2016035772 A1 WO 2016035772A1 JP 2015074768 W JP2015074768 W JP 2015074768W WO 2016035772 A1 WO2016035772 A1 WO 2016035772A1
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Prior art keywords
filter
metal
biological material
polymer
plating
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PCT/JP2015/074768
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English (en)
Japanese (ja)
Inventor
高井　健次
理美 八木
達也 松永
鈴木　崇裕
アンソニー エイチ ツァイ
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日立化成株式会社
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Priority to JP2016546646A priority Critical patent/JP6390707B2/ja
Publication of WO2016035772A1 publication Critical patent/WO2016035772A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology
    • C12M1/26—Inoculator or sampler

Definitions

  • the present invention relates to a biological material capturing filter and a biological material capturing system that can efficiently capture biological materials such as circulating tumor cells (hereinafter referred to as CTC).
  • CTC circulating tumor cells
  • CTC cancer prognosis and treatment
  • Detecting CTC is a useful means of determining the progression of cancer pathology when the initial spread of cancer cells extends into peripheral blood.
  • blood components such as red blood cells and white blood cells are overwhelmingly present in blood, it is difficult to detect a very small amount of CTC.
  • Patent Document 1 a method for efficiently detecting a small amount of CTC by using a resin filter using parylene has been proposed.
  • Patent Document 2 a method of improving the strength of the filter by using a metal filter instead of a resin and separating it by the difference in leukocyte and cancer cell deformability has been proposed (Patent Document 2).
  • the inventors found that the following problems existed while studying a filter using a metal.
  • Metals have low biocompatibility, so blood components such as white blood cells and red blood cells are easily adsorbed, and clogging easily occurs. Furthermore, since the metal surface has high water repellency and easily repels water, bubbles are likely to be generated on the filter.
  • the present invention improves a conventional biological material capturing filter, and maintains a pressure resistance while preventing cell adsorption to the filter and efficiently capturing the biological material and biological body
  • a material capture system is provided.
  • a biological material capturing filter includes a metal filter made of gold, platinum, palladium, or an alloy thereof, and biocompatibility chemically bonded to the surface of the metal filter. And a polymer.
  • a mode in which the contact angle of pure water on the surface of the filter is 60 degrees or less can be employed.
  • the metal ratio on the surface of the metal filter obtained by measurement with an X-ray photoelectron spectrometer may be 10 at% or less.
  • the biocompatible polymer may be a 2-methacryloyloxyethyl phosphorylcholine homopolymer (MPC) or a copolymer containing the MPC.
  • MPC 2-methacryloyloxyethyl phosphorylcholine homopolymer
  • the biocompatible polymer and the metal filter surface may be bonded by an amide bond.
  • the copolymer containing the MPC has a carboxyl group, and the surface is bonded to the metal filter having an amino group.
  • the metal filter having an amino group on the surface may be an embodiment of the metal filter in which a polymer having an amino group is adsorbed on the surface.
  • the polymer having an amino group may be polyethyleneimine.
  • the polymer having an amino group may be bonded to the metal filter having a carboxyl group on the surface.
  • the metal filter having a carboxyl group may be an embodiment in which the metal surface is treated with a thiol having a carboxyl group.
  • the MPC-containing copolymer may have an amino group and be bonded to the metal filter having a carboxyl group on the surface.
  • the metal filter having a carboxyl group on the surface may be an embodiment of the metal filter in which a polymer having a carboxyl group adsorbed on the surface is adsorbed.
  • the polymer having a carboxyl group may be polyacrylic acid.
  • the polymer having a carboxyl group may be bonded to the metal filter having an amino group on the surface.
  • the metal filter having an amino group on the surface can be an embodiment in which the metal surface is treated with a thiol having an amino group.
  • a biological material capturing system is characterized by using the biological material capturing filter described above.
  • a biological material capturing filter and a biological material capturing system capable of efficiently capturing biological material while maintaining pressure resistance and preventing cell adsorption to the filter.
  • the biological material capture cartridge 100 is connected to an inlet 130 to which an inflow pipe 125 into which a sample liquid containing biological material flows is connected, and an outflow pipe 135 from which the sample liquid containing biological material flows out.
  • a housing 120 having an outflow port 140 and a filter 105 (a biological material capturing filter) disposed in the housing 120 and having a capturing region for capturing the biological material contained in the sample liquid.
  • Biological material which is a capture target in the biological material capture system, refers to a specific type of cells contained in a biological sample. Examples of such a biological substance include cells in a living body. Examples of cells in the living body include cells in blood. Among cells in blood, examples of cells that can be captured include circulating cancer cells in the blood (CTC: Circulating Tumor Cell) and circulating endothelial cells (CEC: Circulating Endothelial Cell). CTCs are cancer (cancer) cells in the blood. When cells in blood are capture targets, they can be captured even if the cells are alive. The biological material capturing system is suitably used for capturing cancer cells in blood including CTC.
  • CTC Circulating Tumor Cell
  • CEC Circulating Endothelial Cell
  • CEC is an endothelial cell of a blood vessel and becomes a mature cell that has been detached from the blood vessel wall by metabolism.
  • CTC is said to increase in pathological conditions such as cardiovascular diseases (such as myocardial infarction).
  • the biological material capture system has a function of selectively capturing specific types of cells contained in a biological sample such as CTC and CEC.
  • CTC or CEC is a capture target, blood or a liquid obtained by adding an additive such as a buffer to blood can be used as a sample liquid containing a biological substance.
  • the housing 120 is a member for holding the filter 105 and includes an upper member 110 and a lower member 115.
  • the shape of the housing 120 may be a rectangular parallelepiped or a cylinder, and is not particularly limited.
  • a processing solution such as a sample solution or a cleaning solution is connected upstream of the inflow pipe 125. Further, by connecting the pump P downstream of the outflow pipe 135, the sample liquid and the like are supplied from the inflow pipe 125 to the inside of the housing 120 by driving the pump P. Then, it is discharged from the outflow pipe 135 to the outside.
  • a through hole 106 is formed in the filter 105.
  • the filter 105 includes a metal filter 105A made of gold, platinum, palladium, or an alloy thereof, and a biocompatible polymer 105B that is chemically bonded to the surface of the metal filter. This point will be described later.
  • the shape of the biological material capturing cartridge 100 is not limited to the above.
  • the configuration of the apparatus is not particularly limited as long as the biological material can be captured by filtration using a filter.
  • FIG. 2 is a schematic cross-sectional view showing a method for producing a metal thin film filter using a substrate in which peelable copper foil (Ni foil in the case of performing copper plating) is bonded to MCL.
  • FIG. 2A shows a substrate in which peelable copper foil 2 (Ni foil when copper plating is performed) is laminated on MCL1. First, this substrate is prepared.
  • the material used as the substrate for producing the filter is preferably copper (nickel when the plating is copper). Copper can be easily removed by chemical dissolution with a chemical solution, and is superior to other materials in adhesion to the photoresist.
  • a photoresist 3 is formed on the peelable copper foil 2 of the substrate.
  • the thickness of this photoresist is preferably 1.0 to 2.0 times the thickness of the subsequent conductor. If this thickness is thin, resist peeling will be difficult later, and if it is thick, circuit formability will be difficult. Specifically, a thickness of 15 ⁇ m to 50 ⁇ m is preferable.
  • a photomask is overlapped to perform photoresist exposure.
  • the photoresist development and removal of the unexposed portion is performed with an alkaline solution or the like.
  • plating is performed on a portion not covered with the photoresist by pattern electroplating. This plated portion becomes the material of the filter.
  • the photosensitive resin composition that is a photoresist is preferably a negative photosensitive resin composition.
  • the negative photosensitive resin composition preferably contains at least a binder resin, a photopolymerizable compound having an unsaturated bond, and a photopolymerization initiator.
  • the photoresist is exposed. Thereby, the exposure part 3a is formed in the area
  • the photoresist development and removal of the unexposed portion 3b is performed with an alkaline solution or the like. Thereby, the exposure part 3a remains in the position corresponding to the through-hole of the filter.
  • the plating layer 5 is formed by performing electrolytic plating on the portion not covered with the photoresist. This plated portion becomes the material of the filter.
  • peelable copper foil 2 on which plating layer 5 has been formed by electrolytic plating is peeled off from MCL1.
  • the peelable copper foil 2 is removed by chemical dissolution with a chemical solution, and the free-standing film formed by the exposed portion 3a and the plating layer 5 is taken out.
  • the exposed portion 3 a made of the photoresist remaining in the free-standing film is removed, and a through hole 6 is formed in the plating layer 5.
  • electroless gold plating is performed to form a gold plating layer 7 on the filter surface.
  • the filter 105 used in the biological material capturing cartridge 100 can be manufactured.
  • FIG. 3 is a schematic cross-sectional view showing a method for producing a metal thin film filter using a copper plate (Ni plate when copper plating is performed).
  • the method shown in FIG. 3 is the same as the manufacturing method shown in FIG. 2 except that a copper plate (or Ni plate) 2 ′ is used instead of the MCL 1 and the peelable copper foil 2 in the method shown in FIG. 2.
  • FIG. 3A shows a process of preparing a copper plate 2 'used as a substrate.
  • FIG. 3B shows a process of laminating the photoresist 3 on the copper plate 2 ′.
  • FIG. 3C shows the photoresist exposure with the photomask 4 overlaid.
  • FIG. 3D shows development removal of the photoresist in the unexposed portion 3b.
  • FIG. 3E shows a step of forming a plating layer by electrolytic plating on a portion of the photoresist not covered with the exposed portion 3a.
  • FIG. 3F shows a process of removing the copper plate 2 ′ by chemical dissolution (chemical etching) with a chemical solution and taking out a free-standing film formed by the exposed portion 3 a and the plating layer 5.
  • FIG. 3B shows a process of laminating the photoresist 3 on the copper plate 2 ′.
  • FIG. 3C shows the photoresist exposure with the photomask 4 overlaid.
  • FIG. 3D shows development removal of the photoresist in the unexposed portion 3b.
  • FIG. 3E shows
  • FIG. 3G shows a step of removing the exposed portion 3 a of the photoresist remaining in the free-standing film and forming a through hole 6 in the plating layer 5.
  • FIG. 3H shows a process of performing electroless gold plating to form a gold plating layer 7 on the filter surface.
  • the metal filter 105A in the filter 105 used in the biological material capturing cartridge 100 can be manufactured by using any of the method shown in FIG. 2 and the method shown in FIG.
  • the material of the metal filter 105A in the filter 105 is metal.
  • metal any of nickel, silver, palladium, copper, and iridium is preferable. These metals can be electroplated.
  • the main component of the metal is preferably nickel, silver, palladium, copper, iridium, or an alloy thereof. These metals can be electroplated.
  • the “main component” indicates that the weight ratio of the component to the total weight of the metal filter 105A is 50% or more.
  • Palladium and iridium have high redox potential, poor solubility and good characteristics, but have the disadvantage of being expensive.
  • Nickel has a lower oxidation-reduction potential than hydrogen, so it is easily dissolved but is inexpensive.
  • Silver and palladium are noble metals and are relatively inexpensive compared to iridium.
  • the material used as the substrate (copper plate 2 ': see FIG. 3) for producing the filter is preferably copper (nickel when the filter material is copper). Copper can be easily removed by chemical dissolution with a chemical solution, and is superior to other materials in adhesion to the photoresist.
  • copper when the filter material is copper, nickel is preferable.
  • the formation of the plating layer 5 shown in FIGS. 2E and 3E is performed by electrolytic plating.
  • electrolytic nickel plating Watts bath (mainly nickel sulfate, nickel chloride, boric acid), sulfamic acid bath (mainly nickel sulfamate, boric acid), strike bath (mainly nickel chloride, hydrogen chloride) Etc.
  • Examples of electrolytic silver plating include a bath mainly composed of potassium silver cyanide or potassium tartrate.
  • electrolytic palladium plating examples include a bath made of a water-soluble palladium salt and a naphthalene sulfonic acid compound.
  • Electrolytic iridium plating includes a bath containing a soluble iridium salt containing halogen and alcohols.
  • Examples of the electrolytic copper plating include a bath mainly composed of copper sulfate, sulfuric acid, and chloride ions.
  • Electrolytic plating is performed using these plating baths.
  • the current density during electroplating is preferably in the range of 0.3 to 4 A / dm 2 , and more preferably in the range of 0.5 to 3 A / dm 2 .
  • the location of the resist when plating is the location of the through hole.
  • the opening shape of the through hole include a circle, an ellipse, a square, a rectangle, a rounded rectangle, and a polygon. From the viewpoint of efficiently capturing the target component, a circle, rectangle, or rounded rectangle is preferable. In addition, a rounded rectangle is particularly preferable from the viewpoint of preventing clogging of the filter.
  • the hole diameter of the through hole 6 is set according to the size of the component to be captured.
  • the hole diameter in a shape other than a circle such as an ellipse, rectangle, or polygon is the maximum value of the diameter of a sphere that can pass through each through hole.
  • the opening shape is a rectangle or a rounded rectangle, as shown in FIG. 4, the short hole diameter on the short side and the long hole diameter on the long side can be defined, but the hole diameter of the through hole 6 is the short hole diameter. It becomes.
  • the diameter is the diameter of the inscribed circle of the polygon.
  • the length of the short pore diameter of the filter is preferably 5 ⁇ m to 15 ⁇ m, more preferably 7 ⁇ m to 9 ⁇ m.
  • the average aperture ratio of the through holes of the metal filter 105A in the filter 105 is preferably 3% to 50%, more preferably 3% to 20%, and particularly preferably 3% to 10%.
  • the aperture ratio refers to the ratio of the area occupied by the through hole to the area of the region functioning as a filter (see FIG. 4).
  • the area of the region functioning as a filter is a region (region A1 surrounded by a broken line in FIG. 4) obtained by connecting the outermost portions of the through holes among the plurality of through holes included in the filter. If the aperture ratio is too high, the pressure applied to the white blood cells decreases, and the white blood cell residue increases. If the aperture ratio is low, the amount of blood that can flow is reduced. Note that the aperture ratio of the filter 105 is smaller than that of the metal filter 105A due to adhesion of a biocompatible polymer described later, but it can be considered as an error level.
  • the thickness of the metal filter 105A in the filter 105 is preferably 3 ⁇ m to 50 ⁇ m, more preferably 5 ⁇ m to 30 ⁇ m, and particularly preferably 8 ⁇ m to 20 ⁇ m.
  • the film thickness of the metal filter 105A is less than 3 ⁇ m, the strength of the filter may be lowered, and handling may be difficult.
  • the thickness exceeds 50 ⁇ m there is a concern that productivity decreases due to a longer processing time, cost disadvantage due to unnecessarily consuming materials, and difficulty in fine processing itself, and leukocytes are difficult to escape.
  • the thickness of the filter 105 is larger than that of the metal filter 105A due to adhesion of a biocompatible polymer described later, but it can be considered as an error level.
  • the resin layer is peeled off and the copper foil is etched (FIG. 2), or the copper plate is removed (FIG. 3), so that plating is performed as shown in FIG. 2 (H) or FIG. 3 (G).
  • the filter with layer 5 is completed.
  • the resist (exposed portion 3a) remaining on the filter is removed with strong alkali.
  • strong alkali 0.1 wt% to 10 wt% NaOH or KOH aqueous solution is preferable.
  • Monoethanolamine (1 vol% to 20 vol%) or the like may be added to promote peeling.
  • the resist can be removed with a solution obtained by adding alkali (0.1 wt% to 10 wt% NaOH or KOH) to sodium permanganate or potassium permanganate.
  • ⁇ Precious metal plating should be applied to the filter from which the resist has been removed.
  • noble metal plating gold, palladium, platinum, ruthenium, indium and the like are desirable.
  • gold is said to have the highest oxidation-reduction potential among all metals as described above, and has no cytotoxicity. There is almost no discoloration during long-term storage.
  • a plating method in the case of performing gold plating will be described.
  • Gold plating can be performed electrolessly or electrolyzed. In the case of performing electrolysis, it is desirable to perform the electroless process because the thickness variation increases and the accuracy of the hole diameter of the filter 105 is easily affected. However, electrolytic gold plating can improve the coverage.
  • Gold plating is effective only by displacement plating, but the combination of displacement plating and reduction plating is more effective.
  • the surface of the filter before gold plating may be oxidized. Therefore, the oxide film is removed, but here it is preferable to wash with an aqueous solution containing a compound that forms a complex with a metal ion.
  • an aqueous solution containing cyanides, EDTAs or citric acids is preferable.
  • citric acids are most suitable as a pretreatment for gold plating.
  • citric acid anhydride, citric acid hydrate, citrate or citrate hydrate may be used.
  • citric acid anhydride, citric acid monohydrate, Sodium citrate, potassium citrate and the like can be used.
  • the concentration is preferably 0.01 mol / L to 3 mol / L, more preferably 0.03 mol / L to 2 mol / L, and particularly preferably in the range of 0.05 mol / L to 1 mol / L. preferable.
  • the immersion in a solution containing citric acid is preferably performed at 70 ° C. to 95 ° C. for 1 to 20 minutes.
  • the solution containing citric acid it is possible to add a buffer such as a reducing agent and a pH adjusting agent contained in the plating solution as long as the effects of the invention can be obtained.
  • a buffer such as a reducing agent and a pH adjusting agent contained in the plating solution
  • an aqueous solution of citric acid alone is most preferred.
  • the pH of the solution containing citric acid is preferably 5 to 10, more preferably 6 to 9.
  • the pH adjuster is not particularly limited as long as it is an acid or an alkali.
  • As the acid hydrochloric acid, sulfuric acid, nitric acid and the like can be used.
  • As the alkali alkali metals such as sodium hydroxide, potassium hydroxide and sodium carbonate can be used. Or the alkaline-earth metal hydroxide solution is mentioned. As described above, it can be used as long as the effect of citric acid is not inhibited.
  • the nitric acid is contained at a high concentration of 100 ml / L in the solution containing citric acid, the effect of improving the adhesiveness is reduced as compared with the case where the solution is treated with the solution containing only citric acid.
  • the reducing agent is not particularly limited as long as it is reducible, and examples thereof include hypophosphorous acid, formaldehyde, dimethylamine borane, and sodium borohydride.
  • the displacement gold plating includes a cyan bath and a non-cyan bath, but the non-cyan bath is desirable in view of environmental load or remaining cytotoxicity.
  • the gold salt contained in the non-cyan bath include chloroaurate, gold sulfite, gold thiosulfate, and gold thiomalate. Only one type of gold salt may be used, or two or more types may be used in combination.
  • a cyan bath has an effect of dissolving a metal too much, some metals are liable to be dissolved to cause pinholes.
  • a non-cyan plating bath is preferable.
  • Gold sulfite is particularly preferred as the gold source.
  • gold sulfite sodium gold sulfite, potassium gold sulfite, gold ammonium sulfite and the like are preferable.
  • the gold concentration is preferably in the range of 0.1 g / L to 5 g / L. If it is less than 0.1 g / L, gold is difficult to precipitate, and if it exceeds 5 g / L, the liquid tends to decompose.
  • the displacement gold plating bath may contain an ammonium salt or ethylenediaminetetraacetate as a gold complexing agent.
  • the ammonium salt include ammonium chloride and ammonium sulfate.
  • the ethylenediaminetetraacetate include ethylenediaminetetraacetic acid, sodium ethylenediaminetetraacetate, potassium ethylenediaminetetraacetate, and ammonium ethylenediaminetetraacetate.
  • the concentration of the ammonium salt is preferably used in the range of 7 ⁇ 10 ⁇ 3 mol / L to 0.4 mol / L. If the concentration of the ammonium salt is outside this range, the liquid tends to become unstable.
  • the concentration of ethylenediaminetetraacetate is preferably used in the range of 2 ⁇ 10 ⁇ 3 mol / L to 0.2 mol / L. If the concentration of ammonium salt is outside this range, the liquid tends to become unstable. .
  • sulfite In order to keep the liquid stable, 0.1 g / L to 50 g / L of sulfite should be contained.
  • the sulfite include sodium sulfite, potassium sulfite, and ammonium sulfite.
  • hydrochloric acid or sulfuric acid When reducing the pH as a pH adjuster, it is preferable to use hydrochloric acid or sulfuric acid. Moreover, when raising pH, it is preferable to use sodium hydroxide, potassium hydroxide, or aqueous ammonia. The pH should be adjusted to 6-7. Outside this range, the stability of the solution or the appearance of the plating is adversely affected.
  • Replacement plating is preferably used at a liquid temperature of 30 to 80 degrees. Outside this range, the stability of the liquid or the appearance of the plating is adversely affected.
  • displacement plating is performed as described above, it is difficult to completely cover the metal with displacement plating. Therefore, next, reduction-type gold plating containing a reducing agent is performed.
  • the thickness of the displacement plating is preferably in the range of 0.02 ⁇ m to 0.1 ⁇ m.
  • gold sulfite and thiosulfate are preferable, and the content thereof is preferably in the range of 1 g / L to 10 g / L as gold. If the gold content is less than 1 g / L, the gold precipitation reaction decreases, and if it exceeds 10 g / L, the stability of the plating solution decreases and the amount of gold consumed increases due to the removal of the plating solution. It is not preferable.
  • the content is more preferably 2 g / L to 5 g / L.
  • the reducing agent examples include hypophosphorous acid, formaldehyde, dimethylamine borane, sodium borohydride, and the like, but a phenyl compound-based reducing agent is more preferable.
  • diamine, p-phenylenediamine, o-toluidine, o-ethylaniline, and p-ethylaniline One or more of these can be used.
  • the content of the reducing agent is preferably 0.5 to 50 g / L. If the content of the reducing agent is less than 0.5 g / L, it tends to be difficult to obtain a practical deposition rate, and if it exceeds 50 g / L, the stability of the plating solution tends to decrease. .
  • the content of the reducing agent is more preferably 2 to 10 g / L, and particularly preferably 2 to 5 g / L.
  • the electroless gold plating solution may contain a heavy metal salt.
  • the heavy metal salt is preferably at least one selected from the group consisting of thallium salt, lead salt, arsenic salt, antimony salt, tellurium salt and bismuth salt.
  • thallium salt examples include inorganic compound salts such as thallium sulfate salt, thallium chloride salt, thallium oxide salt, and thallium nitrate salt, and organic complex salts such as dithallium malonate salt.
  • Lead salts include lead sulfate salt, nitric acid salt, and the like. Examples thereof include inorganic compound salts such as lead salts and organic acetate salts such as acetates.
  • arsenic salts include inorganic compound salts such as arsenic salts and arsenic arsenate trioxide, and organic complex salts.
  • antimony salts include organic complex salts such as antimony tartrate, antimony chloride salts, and antimony oxysulfate. And inorganic compound salts such as salts and antimony trioxide.
  • tellurium salt examples include inorganic compound salts such as tellurite and tellurate, and organic complex salts.
  • examples of the bismuth salt include bismuth sulfate (III), bismuth chloride (III), and bismuth nitrate (III). And organic complex salts such as bismuth (III) oxalate.
  • the total addition amount is preferably 1 ppm to 100 ppm, more preferably 1 ppm to 10 ppm, based on the total capacity of the plating solution. If it is less than 1 ppm, the effect of improving the deposition rate may not be sufficient, and if it exceeds 100 ppm, the stability of the plating solution tends to deteriorate.
  • the electroless gold plating solution may contain a sulfur compound.
  • a sulfur compound in an electroless gold plating solution containing a phenyl compound reducing agent and a heavy metal salt, a sufficient deposition rate can be obtained even at a low temperature of about 60 to 80 ° C.
  • the stability of the plating solution is particularly excellent.
  • sulfur compounds include sulfide salts, thiocyanates, thiourea compounds, mercaptan compounds, sulfide compounds, disulfide compounds, thioketone compounds, thiazole compounds, and thiophene compounds.
  • Examples of the sulfide salt include potassium sulfide, sodium sulfide, sodium polysulfide, potassium polysulfide, and the like.
  • Examples of the thiocyanate include sodium thiocyanate, potassium thiocyanate, potassium dithiocyanate, and the like.
  • Examples of the thiourea compound include thiourea, methylthiourea, dimethylthiourea and the like.
  • Mercaptan compounds include 1,1-dimethylethanethiol, 1-methyl-octanethiol, dodecanethiol, 1,2-ethanedithiol, thiophenol, o-thiocresol, p-thiocresol, o-dimercaptobenzene, m -Dimercaptobenzene, p-dimercaptobenzene, thioglycol, thiodiglycol, thioglycolic acid, dithioglycolic acid, thiomalic acid, mercaptopropionic acid, 2-mercaptobenzozoimidazole, 2-mercapto1-methylimidazole, 2- Examples include mercapto-5-methylbenzimidazole.
  • Examples of the sulfide compound include diethyl sulfide, diisopropyl sulfide, ethyl isopropyl sulfide, diphenyl sulfide, methyl phenyl sulfide, rhodanine, thiodiglycolic acid, thiodipropionic acid, and the like.
  • Examples of the disulfide compound include dimethyl disulfide, diethyl disulfide, disulfide. A propyl disulfide etc. can be illustrated.
  • examples of the thioketone compound include thiosemicarbazide
  • examples of the thiazole compound include thiazole, benzothiazole, 2-mercaptobenzothiazole, 6-ethoxy-2-mercaptobenzothiazole, 2-aminothiazole, 2,1,3- Examples include benzothiadiazole, 1,2,3-benzothiadiazole, (2-benzothiazolylthio) acetic acid, 3- (2-benzothiazolylthio) propionic acid and the like.
  • examples of thiophene compounds include thiophene and benzothiophene. It can be illustrated.
  • Sulfur compounds may be used alone or in combination of two or more.
  • the content of the sulfur compound is preferably 1 ppm to 500 ppm, more preferably 1 ppm to 30 ppm, and particularly preferably 1 ppm to 10 ppm. If the content of the sulfur-based compound is less than 1 ppm, the deposition rate is reduced, poor plating adhesion occurs, and the coating appearance deteriorates. If it exceeds 500 ppm, the concentration management becomes difficult and the plating solution becomes unstable.
  • the electroless gold plating solution preferably contains at least one of a complexing agent, a pH buffering agent and a metal ion concealing agent in addition to the above-described gold salt, reducing agent, heavy metal salt and sulfur compound. Etc. are more preferable.
  • the electroless gold plating solution of the present invention preferably contains a complexing agent.
  • a complexing agent include non-cyanide complexing agents such as sulfites, thiosulfates, and thiomalates.
  • the content of the complexing agent is preferably 1 g / L to 200 g / L based on the total capacity of the plating solution. When the content of the complexing agent is less than 1 g / L, the gold complexing power decreases and the stability decreases. If it exceeds 200 g / L, the plating stability is improved, but recrystallization occurs in the solution, which is not economically good.
  • the content of the complexing agent is more preferably 20 g / L to 50 g / L.
  • the electroless gold plating solution preferably contains a pH buffer.
  • the pH buffering agent has an effect of keeping the deposition rate constant and stabilizing the plating solution.
  • a plurality of buffering agents may be mixed. Examples of pH buffering agents include phosphates, acetates, carbonates, borates, citrates, sulfates, etc. Among these, boric acid and sulfates are particularly preferable.
  • the content of the pH buffering agent is preferably 1 g / L to 100 g / L based on the total capacity of the plating solution.
  • the content of the pH buffering agent is less than 1 g / L, there is no pH buffering effect, and when it exceeds 100 g / L, recrystallization may occur.
  • a more preferable content is 20 g / L to 50 g / L.
  • a concealing agent in the gold plating solution.
  • a benzotriazole-based compound can be used, and examples of the benzotriazole-based compound include benzotriazole sodium, benzotriazole potassium, tetrahydrobenzotriazole, methylbenzotriazole, and nitrobenzotriazole.
  • the content of the metal ion concealing agent is preferably 0.5 g / L to 100 g / L based on the total capacity of the plating solution.
  • the content of the metal ion concealing agent is less than 0.5 g / L, there is a tendency that the effect of concealing impurities is small and sufficient liquid stability cannot be ensured.
  • it exceeds 100 g / L recrystallization may occur in the plating solution.
  • the range of 2 g / L to 10 g / L is most preferable.
  • the pH of the gold plating solution is preferably in the range of 5-10.
  • the pH of the plating solution is less than 5, sulfite or thiosulfate, which is a complexing agent of the plating solution, may be decomposed to generate toxic sulfite gas.
  • the pH exceeds 10 the stability of the plating solution tends to decrease.
  • the pH of the electroless gold plating solution is preferably in the range of 8-10.
  • gold plating is performed by immersing the filter after replacement gold plating.
  • the plating solution temperature is preferably 50 ° C to 95 ° C. If it is less than 50 ° C., the deposition efficiency is poor, and if it is 95 ° C. or more, the liquid tends to become unstable.
  • the outermost gold plating layer 7 thus formed is preferably made of gold having a purity of 99% by weight or more.
  • the gold purity of the gold plating layer 7 is less than 99% by weight, the cytotoxicity of the contact portion is increased. From the viewpoint of improving reliability, the purity of the gold layer is more preferably 99.5% by weight or more.
  • the thickness of the gold plating layer 7 is preferably 0.005 ⁇ m to 3 ⁇ m, more preferably 0.05 ⁇ m to 1 ⁇ m, and still more preferably 0.1 ⁇ m to 0.5 ⁇ m.
  • the gold surface (metal surface) of the metal filter 105A formed as described above has no cytotoxicity and is stable in the air or most aqueous solutions containing blood. However, since the gold surface is relatively hydrophobic and has low biocompatibility, a treatment for improving biocompatibility is performed.
  • a treatment for improving biocompatibility is performed.
  • an example of the process for chemically bonding biocompatible polymer 105B to the surface of metal filter 105A is shown.
  • the biocompatible polymer is chemically and strongly adsorbed to the surface of the metal filter 105A (the surface of the gold plating layer 7).
  • Biocompatible polymers include vertebrate albumin or artificial synthetic polymers, and artificial synthetic polymers are preferred in view of filter storage stability and lot differences in polymer properties.
  • vertebrate albumin it is necessary to perform a filter treatment immediately before blood treatment, which complicates the work.
  • the artificial synthetic polymer has better characteristics.
  • the artificial synthetic polymer examples include silicone, various polyurethanes, polyphosphazene, and the like, and particularly excellent is a homopolymer of 2-methacryloyloxyethyl phosphorylcholine (abbreviation: MPC) or a copolymer containing MPC.
  • MPC 2-methacryloyloxyethyl phosphorylcholine
  • the structural formula is shown below.
  • MPC polymer can also be used.
  • MPC polymers include Biolipideure 103, Biolipidure 203, Biolipidure 206, Biolipidure 405, Biolipidure 502, Biolipidure 702, Biolipidure 802, Biolipidure 1002, Biolipidure 1201, Biolipidure 1301, and the like.
  • the MPC polymers those in which R is hydrogen in the chemical formula or those containing an amino group are preferable because the bondability with the filter is improved. That is, when the biocompatible polymer contains an amino group or a carboxyl group, an alternating lamination method using electrostatic adsorption can be used and the cytotoxicity is low.
  • the surface of the gold plating layer 7 of the filter (the surface of the metal filter 105A) and the biocompatible polymer are preferably bonded by an amide bond.
  • the gold plating layer 7 is treated with a compound having a mercapto group (thiol group). Thereby, a mercapto group is formed on the surface of the gold plating layer 7.
  • the mercapto group on the surface of the gold plating layer 7 is reacted with a biocompatible polymer containing a structural unit having an amide group at its terminal. Thereby, the surface of the gold plating layer 7 and the biocompatible polymer are bonded by an amide bond. In this case, the connectivity between the two is improved.
  • a method of forming a polymer having a carboxyl group or an amino group on the surface of the gold plating layer 7 of the filter 105 (the surface of the metal filter 105A: the same for other materials such as palladium or platinum) will be shown.
  • the gold surface can be modified with a compound having any of a mercapto group, a sulfide group, and a disulfide group that forms a coordinate bond with gold.
  • the compounds used for modifying the gold surface include 2-aminoethanethiol, o-fluorobenzenethiol, m-hydroxybenzenethiol, 2-methoxybenzenethiol, 4-aminobenzenethiol, cysteamine, cysteine , Dimethoxythiophenol, furfuryl mercaptan, thioacetic acid, thiobenzoic acid, thiosalicylic acid, or dithiodipropionic acid.
  • the method for modifying the gold surface using the above compound is not particularly limited, but a compound such as mercaptoacetic acid is dispersed in an organic solvent such as methanol or ethanol in an amount of about 10 mmol / L to 100 mmol / L, and the gold is contained therein. Conductive particles having a surface are dispersed.
  • the polymer may be coated using electrostatic interaction.
  • Such a method is called an alternating lamination method (Layer-by-Layer assembly).
  • the alternate lamination method is described in G.H. This is a method for forming an organic thin film published in 1992 by Decher et al. (Thin Solid Films, 210/211, p831 (1992)).
  • a polycation adsorbed on a substrate by electrostatic attraction by alternately immersing the base material in an aqueous solution of a polymer electrolyte having a positive charge (polycation) and a polymer electrolyte having a negative charge (polyanion).
  • a combination of polyanions is laminated to obtain a composite film (alternate laminated film).
  • the film is grown by attracting the charge of the material formed on the substrate and the material having the opposite charge in the solution by electrostatic attraction, so that the adsorption proceeds and the charge is neutralized. When this occurs, no further adsorption occurs. Therefore, when reaching a certain saturation point, the film thickness does not increase any more.
  • polymers examples include polyethylene glycol, poly (2-hydroxyl methacrylate), polyacrylic acid, polyethyleneimine, and polyallylamine, and are not particularly limited.
  • the polymer may be copolymerized with acrylic acid or methacrylic acid. From the viewpoint of charge density and cost, polyethyleneimine is preferable for a cation, and polyacrylic acid is preferable for an anion.
  • the concentration of the polymer electrolyte in the aqueous polymer electrolyte solution is generally preferably about 0.01% to 10% (weight). Further, the pH of the polymer electrolyte solution is not particularly limited.
  • the coverage can be controlled by adjusting the type, molecular weight, and concentration of the polymer electrolyte thin film.
  • concentration of the polymer in the aqueous polymer electrolyte solution is preferably in the range of 0.1% to 5.0%.
  • a biocompatible polymer having a carboxyl group or an amino group After coating a cationic or anionic polymer in this way, it is preferable to finally coat a biocompatible polymer having a carboxyl group or an amino group.
  • the filter surface When the filter surface is coated with a polymer having an amino group, it is preferable to coat a biocompatible polymer having a carboxyl group. Conversely, when the filter surface is coated with a polymer having a carboxyl group, a biocompatible polymer having an amino group may be coated.
  • a biocompatible polymer having a carboxyl group may be coated on the biocompatible polymer having an amino group.
  • the thickness of the biocompatible polymer thus produced is desirably 20 mm (angstrom) or more.
  • the thickness of the biocompatible polymer can be controlled by the treatment concentration and the number of treatments.
  • the thickness of the biocompatible polymer is 20 mm or less, the effect tends to be insufficient.
  • the upper limit of the thickness of the biocompatible polymer is not particularly limited, but if it exceeds 0.1 ⁇ m, the pore diameter of the filter is affected, and leukocytes are difficult to escape.
  • the contact angle may be measured with an apparatus conforming to JIS R3265 “Testing method for wettability of substrate glass surface”.
  • the contact angle on the filter surface after treatment with the biocompatible polymer is preferably 90 degrees or less, and more preferably 60 degrees or less.
  • the contact angle of pure water is said to be wet when it is below 90 degrees, but it is not perfect.
  • bubbles are generated and a part of the filter tends to become unusable.
  • the biocompatible polymer should be completely covered with the metal surface of the filter. Specifically, when analysis is performed using XPS (X-ray Photoelectron Spectroscopy), the lower the surface metal (Au, Pd, Pt) ratio, the better. Desirably, it is more desirable that it is 5 at% or less. When the proportion of surface metal is high, the coverage of the biocompatible polymer is low and the effect is reduced.
  • XPS X-ray Photoelectron Spectroscopy
  • the measurement result by XPS also differs strictly depending on the measuring device. Therefore, in this embodiment, it shall measure on the conditions shown in Table 1.
  • the blood collection tube examples include an EDTA blood collection tube that preserves cells alive and a fixed blood collection tube, but a fixed blood collection tube is preferable.
  • a blood collection tube examples include Cyto-Cex, Cell-Free-DNA (trade name, manufactured by Streck).
  • it is preferable to use a fixed blood collection tube because a fixed blood collection tube can be used for a long time after blood collection compared to an EDTA blood collection tube.
  • the filter 105 is attached to a device such as the biological material capturing cartridge 100 to allow blood to pass therethrough.
  • the blood may be treated with a negative pressure from below the filter, may be treated with pressure from above the filter, or may be treated with a centrifugal force like centrifugation. In either method, it is important to control the linear velocity at which blood passes through the pores of the filter.
  • the linear velocity (blood volume / total area of the pores) through which the blood passes through the pores of the filter is preferably in the range of 0.5 cm / min to 100 cm / min, and in the range of cm / min to 5 to 20 cm / min. Is more desirable.
  • rare cells such as CTC concentrated can be concentrated.
  • a biocompatible polymer to the filter chemically and firmly, it is possible to exclude components such as red blood cells, white blood cells, and plasma plates.
  • Photosensitive resin composition PHOTEC RD-1225: thickness 25 ⁇ m, manufactured by Hitachi Chemical Co., Ltd.
  • MCL-E679F substrate in which peelable copper foil is bonded to the surface of MCL, manufactured by Hitachi Chemical Co., Ltd.
  • Lamination conditions were performed at a roll temperature of 90 ° C., a pressure of 0.3 MPa, and a conveyor speed of 2.0 m / min.
  • a glass mask having a light-transmitting portion with a rounded rectangular shape, a size of 8.8 ⁇ 30 ⁇ m, and a pitch of 60 ⁇ m in both the minor axis and major axis directions was allowed to stand on the photoresist laminate surface of the substrate.
  • a glass mask in which rounded rectangles facing in the same direction are arranged at a constant pitch in the major axis and minor axis directions was used.
  • ultraviolet rays having an exposure amount of 30 mJ / cm 2 were irradiated from above the substrate on which the glass mask was placed by an ultraviolet irradiation device.
  • the obtained nickel plating layer is peeled off together with the peelable copper foil of the substrate, and this peelable copper foil is chemically dissolved by a chemical solution in a stirring process at a temperature of 40 ° C. for about 120 minutes (MEC BRIGHT SF-5420B, MEC shares).
  • the self-supporting membrane (20 mm ⁇ 20 mm) to be a metal filter was removed by removing it by the company.
  • the photoresist remaining in the free-standing film was removed by resist stripping (P3 Poleve, Henkel) by ultrasonic treatment at a temperature of 60 ° C. for about 40 minutes to produce a metal filter having fine through holes.
  • the metal filter was immersed in an acidic degreasing solution Z-200 (manufactured by World Metal: trade name) to remove organic substances on the metal filter (40 ° C. for 3 minutes).
  • Z-200 manufactured by World Metal: trade name
  • immersion gold plating was performed by immersing in HGS-100 (trade name, manufactured by Hitachi Chemical Co., Ltd.), which is a non-cyan substitutional electroless Au plating, at 80 ° C. for 20 minutes.
  • the thickness of the displacement gold plating was 0.05 ⁇ m.
  • HGS-5400 (trade name, manufactured by Hitachi Chemical Co., Ltd.), which is non-cyan reduced electroless Au plating, at 65 ° C. for 10 minutes, plated with gold, washed with water and dried. The total thickness of the gold plating was 0.2 ⁇ m. Thereby, a metal filter is created.
  • reaction solution was prepared by dissolving 8 mmol of dithiodipropionic acid having a carboxyl group in the molecule in 200 mL of methanol. Next, a metal filter after gold plating was added to the reaction solution, reacted at room temperature for 2 hours, and then washed with methanol to prepare a filter having a carboxyl group on the surface.
  • a filter having an amino group on the surface was prepared by immersing in a metal filter having a carboxyl group in a 0.3 wt% polyethyleneimine 0.3 wt% aqueous solution having a large number of amino groups in the molecule for 15 minutes and washing.
  • the filter having an amino group on the surface is immersed for 15 minutes in a methanol solution containing 0.3 wt% of a copolymer polymer BL405 (manufactured by NOF CORPORATION: trade name) of an MPC monomer and a carboxyl group-containing monomer. Finally, a 30 minute treatment at 80 ° C in a vacuum dryer facilitates dehydration condensation of carboxyl groups and amino groups, and captures biological materials in which biocompatible polymers are firmly chemically bonded to the surface of the metal filter.
  • a filter 1 was prepared.
  • a reaction solution was prepared by dissolving 8 mmol of 2-aminoethanethiol having an amino group in the molecule in 200 mL of methanol. Next, a metal filter after gold plating was added to the reaction solution, reacted at room temperature for 2 hours, and then washed with methanol to prepare a filter having an amino group on the surface.
  • a filter having a carboxyl group on the surface was prepared by immersing in a metal filter having a carboxyl group in a 0.3 wt% polyacrylic acid 0.3 wt% aqueous solution having a number of carboxyl groups in the molecule for 15 minutes and washing. .
  • the filter having a carboxyl group on the surface is immersed for 15 minutes in a methanol solution containing 0.3 wt% of a copolymer polymer BL502 (manufactured by NOF Corporation: trade name) of a monomer having an MPC monomer and an amino group for washing. Finally, by performing a treatment at 80 ° C. for 30 minutes in a vacuum dryer, it promotes dehydration condensation of carboxyl groups and amino groups, and for capturing biological substances in which the biocompatible polymer is firmly chemically bonded to the filter surface. Filter 4 was produced.
  • Filter 5 A filter was produced in the same manner as Filter 1 except that one-stage electroless platinum plating was performed instead of the two-stage gold plating. Rectres Pt100 (Nippon Electroplating Engineers Co., Ltd. product name) was used as the electroless platinum plating solution. The thickness of platinum was 0.1 ⁇ m.
  • a filter 6 was prepared in the same manner as the filter 1 except that one-stage electroless palladium plating was performed instead of the two-stage gold plating.
  • Paradex Strike 3 (manufactured by Nippon Electroplating Engineering Co., Ltd .: trade name) was used as the electroless palladium plating solution.
  • the thickness of palladium was 0.1 ⁇ m.
  • a filter 7 was produced in the same manner as the filter 1 except that electrolytic palladium plating was used instead of electrical Ni plating.
  • Paradix LF-5 (Nippon Electroplating Engineers Co., Ltd .: trade name) was used as the electropalladium plating solution.
  • Plating is performed under the same conditions as filter 1 except that the plating temperature is 50 ° C., the current density is 1 A / dm 2, and the electroplating is performed to be about 20 ⁇ m under the condition of about 4.2 minutes / ⁇ m. went.
  • a peelable nickel foil was used in place of the MCL peelable copper foil (the nickel foil was removed after electroplating). Further, a surface-treated filter 8 was produced in the same manner as the filter 1 except that electrolytic copper plating was used instead of electrical Ni plating.
  • electrolytic copper plating solution Microfab Cu200 (Nippon Electroplating Engineers Co., Ltd .: trade name) was used. Plating is performed under the same conditions as filter 1 except that the plating temperature is 25 ° C. and the current density is 3 A / dm 2, and the electroplating is performed so as to be about 20 ⁇ m at about 1.5 minutes / ⁇ m. went.
  • a filter 9 was produced in the same manner as the filter 1 except that the surface treatment was not performed.
  • a filter 10 was produced in the same manner as the filter 1 except that gold plating was not performed.
  • a filter 11 was prepared in the same manner as the filter 1 except that CM5206 (manufactured by NOF Corporation: trade name), which is an MPC-containing polymer having no hydrophobic and reactive functional group, was used instead of BL405.
  • CM5206 manufactured by NOF Corporation: trade name
  • NOF Corporation trade name
  • Filter 12 was prepared in the same manner as filter 1 except that the dithiodipropionic acid treatment was omitted.
  • a filter 13 was prepared in the same manner as the filter 1 except that the dithiodipropionic acid treatment and the polyethyleneimine treatment were omitted.
  • a filter 14 was prepared in the same manner as the filter 1 except that BL203 (manufactured by NOF Corporation: trade name), which is a pure MPC polymer having no hydrophobic and reactive functional groups, was used instead of BL405.
  • NCI-H358 cells a non-small cell carcinoma cell line, were statically cultured in RPMI-1640 medium containing 10% fetal bovine serum (FBS) at 37 ° C. and 5% CO2. Cells were detached from the culture dish by trypsin treatment and recovered, washed with phosphate buffered saline (PBS), and then washed with 10 ⁇ M CellTracker Red CMTPX (Life Technologies Japan, Inc.) at 37 ° C. for 30 minutes. NCI-H358 cells were stained by allowing to stand. Thereafter, the cells were washed with PBS and allowed to stand at 37 ° C.
  • PBS phosphate buffered saline
  • PBS is phosphate buffered saline, and product code 166-23555 manufactured by Wako Pure Chemical Industries, Ltd. was used.
  • BSA bovine serum albumin
  • SIGMA-ALDRICH Product Name: Albumin from bovine serum-Lyophilized powder, Bio Reagent for cell culture.
  • EDTA 2Na (ethylenediamine-N, N, N ′, N′-4 acetic acid disodium salt dihydrate) (product code 345-01865 manufactured by Wako Pure Chemical Industries, Ltd.) was used.
  • a blood sample was introduced into a CTC recovery device to concentrate cancer cells.
  • a sample containing 1000 cancer cells per mL of blood was used in healthy blood sampled in Cell Free DNA (manufactured by Streck Inc .: trade name), which is a vacuum blood collection tube containing a cell stabilizer as a blood sample.
  • Cell Free DNA manufactured by Streck Inc .: trade name
  • As a cancer cell the above human non-small cell lung cancer cell line NCI-H358 was used.
  • the blood used was 6 hours after blood collection.
  • a washing solution 2 mM EDTA-0.5% BSA-PBS
  • a washing solution 1 mL of 2 mM EDTA-0.5% BSA-PBS
  • liquid feeding was started using a peristaltic pump at a flow rate of 200 ⁇ L / min. Thereafter, 1 mL of blood was added. After about 5 minutes, 2 mL of 2 mM EDTA-0.5% BSA-PBS was introduced into the reservoir to wash the cells.
  • the pump flow rate was changed to 20 ⁇ L / min, and 600 ⁇ L of cell staining solution (Hoechst 33342: 30 ⁇ l, Wash buffer: 300 mL) was introduced into the reservoir, and the cancer cells or leukocytes on the filter were fluorescently stained. After staining the cells captured on the filter for 30 minutes, 1 mL of 2 mM EDTA-0.5% BSA-PBS was introduced into the reservoir to wash the cells.
  • cell staining solution Hoechst 33342: 30 ⁇ l, Wash buffer: 300 mL
  • the filter was observed using a fluorescence microscope (BX61, Olympus Corporation) equipped with a computer-controlled electric stage and a cooled digital camera (DP70, Olympus Corporation), and the number of cancer cells and leukocytes on the filter was determined. I counted.
  • Tables 5 and 6 show the filter type, material, and information on surface treatments 1 to 3 according to each evaluation example, and Table 6 shows the contact angle, the results of elemental analysis on Au, the white blood cell count, and the NCI-H358 recovery rate. And the result of the evaluation which concerns on a bubble is shown. Note that “A” related to bubbles indicates that almost no bubbles were generated in the cartridge. “B” indicates that bubbles are generated in a part (less than 5% by volume) of the cartridge. “C” indicates that more bubbles than the result B (5% by volume or more in the cartridge) were generated.
  • Evaluation Example 4 the treatment order of cations and anions is changed, and a biocompatible polymer is chemically bonded onto the gold plating filter.
  • the number of white blood cells is relatively small and the recovery rate of cancer cells is high.
  • Evaluation examples 5 and 6 perform Pt and Pd plating instead of gold plating. In the case of Pt and Pd, an effect close to that of Au plating can be obtained.
  • Evaluation examples 7 and 8 change the bulk metal from Ni to Pd, Cu.
  • the characteristics are slightly better than Ni.
  • Evaluation Example 9 is a case where the surface treatment of the metal filter was not performed. In this case, the white blood cell count increases and the recovery rate decreases. The hydrophobicity was high and bubbles were generated.
  • Evaluation Example 10 is a case where Au plating was not performed. In this case, the polymer coverage is low (the gold element ratio is high) due to the influence of the Ni oxide film, and the white blood cell count increases and the recovery rate decreases.
  • Evaluation Example 11 is a case where MPC polymer (CM5206) having no reactive functional group is coated. In this case, the contact angle becomes extremely high and bubbles are likely to be generated. The white blood cell count increases and the recovery rate decreases.
  • Evaluation examples 12 and 13 are cases where some or more of the surface treatments are omitted.
  • the evaluation example 13 has low chemical adsorption, and the polymer is easily peeled off.
  • Evaluation Example 14 is a case where a homopolymer of MPC was used. The chemical reactivity with the filter was slightly reduced, and the polymer coverage was low (the gold element ratio was high).

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Abstract

　La présente invention concerne un filtre de capture d'une substance biologique, le filtre ayant un filtre métallique comprenant l'or, le platine, le palladium, ou un alliage de ceux-ci, et un polymère biocompatible lié chimiquement à la surface du filtre métallique.
PCT/JP2015/074768 2014-09-03 2015-08-31 Filtre de capture de substance biologique, et système de capture de substance biologique WO2016035772A1 (fr)

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WO2018190379A1 (fr) * 2017-04-13 2018-10-18 日立化成株式会社 Méthode de prédiction de l'efficacité d'un inhibiteur de point de contrôle immunitaire sur un sujet test
WO2018190382A1 (fr) * 2017-04-13 2018-10-18 日立化成株式会社 Méthode de détection de cellules cancéreuses pd-l1 positives
WO2018211706A1 (fr) * 2017-05-19 2018-11-22 日立化成株式会社 Procédé de capture de cellule rare

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012157244A (ja) * 2011-01-28 2012-08-23 Kinki Univ セルアレイソータ、その製造方法及び細胞ソート方法
WO2012173097A1 (fr) * 2011-06-13 2012-12-20 日立化成工業株式会社 Agent pour l'amélioration de l'adhésivité de cellules cancéreuses
JP2013215109A (ja) * 2012-04-05 2013-10-24 Seiko Epson Corp 分離装置
WO2014162810A1 (fr) * 2013-04-04 2014-10-09 日立化成株式会社 Filtre pour capturer une substance biologique

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JPWO2002009857A1 (ja) * 2000-07-27 2004-01-08 旭メディカル株式会社 改質された中空糸膜

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012157244A (ja) * 2011-01-28 2012-08-23 Kinki Univ セルアレイソータ、その製造方法及び細胞ソート方法
WO2012173097A1 (fr) * 2011-06-13 2012-12-20 日立化成工業株式会社 Agent pour l'amélioration de l'adhésivité de cellules cancéreuses
JP2013215109A (ja) * 2012-04-05 2013-10-24 Seiko Epson Corp 分離装置
WO2014162810A1 (fr) * 2013-04-04 2014-10-09 日立化成株式会社 Filtre pour capturer une substance biologique

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018190379A1 (fr) * 2017-04-13 2018-10-18 日立化成株式会社 Méthode de prédiction de l'efficacité d'un inhibiteur de point de contrôle immunitaire sur un sujet test
WO2018190382A1 (fr) * 2017-04-13 2018-10-18 日立化成株式会社 Méthode de détection de cellules cancéreuses pd-l1 positives
WO2018211706A1 (fr) * 2017-05-19 2018-11-22 日立化成株式会社 Procédé de capture de cellule rare

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