WO2016149851A1 - 双离子电荷偏差型血球筛选用材料及从血液样品中移除白血球的方法 - Google Patents
双离子电荷偏差型血球筛选用材料及从血液样品中移除白血球的方法 Download PDFInfo
- Publication number
- WO2016149851A1 WO2016149851A1 PCT/CN2015/000192 CN2015000192W WO2016149851A1 WO 2016149851 A1 WO2016149851 A1 WO 2016149851A1 CN 2015000192 W CN2015000192 W CN 2015000192W WO 2016149851 A1 WO2016149851 A1 WO 2016149851A1
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- WIPO (PCT)
- Prior art keywords
- blood cell
- screening
- structural unit
- ion charge
- double
- Prior art date
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/34—Esters containing nitrogen, e.g. N,N-dimethylaminoethyl (meth)acrylate
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D39/00—Filtering material for liquid or gaseous fluids
- B01D39/14—Other self-supporting filtering material ; Other filtering material
- B01D39/16—Other self-supporting filtering material ; Other filtering material of organic material, e.g. synthetic fibres
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
- B01J20/26—Synthetic macromolecular compounds
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/38—Esters containing sulfur
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/38—Esters containing sulfur
- C08F220/382—Esters containing sulfur and containing oxygen, e.g. 2-sulfoethyl (meth)acrylate
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2800/00—Copolymer characterised by the proportions of the comonomers expressed
- C08F2800/20—Copolymer characterised by the proportions of the comonomers expressed as weight or mass percentages
Definitions
- the invention relates to a double ion charge deviation type material and a method for removing white blood cells from a blood sample, in particular to a double ion charge deviation type blood cell screening material and a method for passing a blood sample through a double ion A filter material made of a material for charge-deviating blood cell screening to remove white blood cells from the blood sample.
- white blood cells can be filtered from the blood by, for example, a filter containing fibrous material.
- the surface of the filter material is generally treated to be positively charged, except for the sponge structure (polyporous) using the filter material.
- the negatively charged platelets and white blood cells are adsorbed on the surface of the positively charged filter material.
- an anticoagulant needs to be added to the blood sample, or the surface of the filter material needs to be further surface treated to prevent coagulation.
- 5,407,581 discloses a negatively charged filter material for treating blood, using a PET (polyethylene terephthalate) fiber material as a substrate, and grafting a charged polymer on the surface to filter
- the surface of the material is slightly negatively charged, because the positively charged surface is prone to cause an increase in the concentration of bradykinin, which is likely to cause an allergic reaction during transfusion.
- it is necessary to consider selectivity, cause no coagulation, allergic reaction, etc., and it is disclosed in the literature (U.S. Patent No.
- Another object of the present invention is to provide a material for screening double-ion charge-deviating blood cells, which has a specific double ion charge by controlling the distance, distribution and ratio between charged groups having different charges. Deviation of the range of materials to achieve the effect of blood cell screening.
- Another object of the present invention is to provide a material for screening a double ion charge-deviating blood cell, which does not cause a blood coagulation reaction when separating white blood cells from a blood sample, and does not cause clogging of the filter material.
- a material for screening a double ion charge deviation type blood cell which is a copolymer composed of a double ion structure unit and a charged structure unit, wherein the double ion structure unit includes at least one a positively charged group and a negatively charged group, the distance between the positively charged group and the negatively charged group being from 1 to 5 carbon-carbon bonds, the charged structural unit and the double ion structural unit being irregular Arrange to form a double ion charge deviation.
- the diionic building block is a group derived from one or more of the following groups:
- a phosphoryl betaine methacrylate represented by the following formula
- the above diionic building block is preferably derived from Sulfobetaine methacrylate.
- the above charged structural unit comprises one or both of a positively charged structural unit and a negatively charged structural unit.
- the positively charged building block is a group derived from one or more of the following groups:
- 2-aminoethyl methacrylate having the following formula
- the negatively charged building block is a group derived from one or more of the following groups:
- 3-sulfopropyl methacrylate having the following formula
- the material for dual ion charge-deviating blood cell screening has a positive charge deviation range of 5% to 34%, and the material for screening the double-ion charge-displacement blood cell has no activation effect on platelets.
- the charge deviation range is such that when the sum of the diionic structural unit and the positively charged structural unit is 100 mol%, the molar ratio of the diionic structural unit is 70 to 90 mol%, and the molar ratio of the positively charged structural unit is 30 to It is composed of 10 mol%.
- the material for dual ion charge-displacement blood cell screening has a positive charge deviation range of 35% to 75%, and the material for screening the double-ion charge-displacement blood cell has an activation effect on platelets.
- the charge deviation range is 100 mol% of the total of the diionic structural unit and the positively charged structural unit
- the molar ratio of the diionic structural unit is 30 to 60 mol%
- the molar ratio of the positively charged structural unit is 70 to 40.
- the mole % consists of.
- the material for dual ion charge-deviating blood cell screening has a negative charge deviation range of 15% to 59%, and the material for screening the double-ion charge-displacement blood cell has no activation effect on platelets.
- the charge deviation range is 100 mol% of the total of the diionic structural unit and the negatively charged structural unit
- the molar ratio of the diionic structural unit is 51 to 80 mol%
- the molar ratio of the negatively charged structural unit is 49 to 20
- the mole % consists of.
- the material for dual ion charge-deviating blood cell screening has a negative charge deviation range of 60% to 90%, and the material for screening the double-ion charge-displacement blood cell has an activation effect on platelets.
- the charge deviation range is such that when the sum of the diionic structural unit and the negatively charged structural unit is 100 mol%, the molar ratio of the diionic structural unit is 30 to 50 mol%, and the molar ratio of the negatively charged structural unit is 70 to 50% by mole.
- the material for double ion charge-deviating blood cell screening has a positive charge deviation ranging from 5% to 35%, and a white blood cell-containing sample passes through the double-ion charge-displacement blood cell screening material, and the white blood cell in the sample is The double ion charge-displacement blood cell screening material is filtered.
- the above range of charge deviation is for the dual ion structure
- the sum of the element and the positively charged structural unit is 100% by mole
- the molar ratio of the double ion structural unit is 70 to 90% by mole
- the molar ratio of the positively charged structural unit is 30 to 10% by mole.
- the distance between the positively charged group and the negatively charged group is preferably 2 to 4 carbon-carbon bonds.
- a material for screening a double ion charge deviation type blood cell which is a copolymer composed of a positively charged structural unit and a negatively charged structural unit, wherein the positively charged structural unit
- the distance between the negatively charged structural units is 1 to 5 carbon-carbon bonds, and the positively-charged structural unit and the negatively-charged structural unit are randomly arranged to form a double ion charge deviation.
- the positively charged structural unit is a group derived from one or more of the following groups:
- the negatively charged structural unit is a group derived from one or more of the following groups:
- the material for dual ion charge-deviating blood cell screening has a positive charge deviation range of 15% to 65%, and the material for screening the double-ion charge-displacement blood cell has an activation effect on platelets.
- the material for dual ion charge-deviating blood cell screening has a negative charge deviation range of 50% to 80%, and the material for screening the double-ion charge-displacement blood cell has no activation effect on platelets.
- the material for dual ion charge-deviating blood cell screening has a positive charge deviation ranging from 20% to 70%, and a white blood cell-containing sample passes through the double-ion charge-displacement blood cell screening material, and the white blood cell in the sample is The double ion charge-displacement blood cell screening material is filtered.
- a method of removing white blood cells from a blood sample the method of removing white blood cells from a blood sample by making a blood sample through a double ion charge deviation type blood cell screening material.
- the above method further comprises performing a fixing procedure for bonding the double ion charge-deviating blood cell screening material to the surface of a substrate, and the filter material prepared by the substrate can be more easily combined with other medical accessories.
- the assembly is carried out, so that the method for removing white blood cells from blood samples according to the present invention can be more widely applied to related industrial fields.
- the double ion charge-deviating blood cell screening material is a copolymer composed of a dual ion structural unit and a charged structural unit, wherein the dual ion structural unit includes at least one positively charged group and one a negatively charged group having a distance from the negatively charged group to the negatively charged group of from 1 to 5 carbon-carbon bonds, the charged The structural unit and the double ion structural unit are randomly arranged to form a double ion charge deviation.
- the double ion charge-displacement blood cell screening material is a copolymer composed of a positively-charged structural unit and a negatively-charged structural unit, wherein the positively-charged structural unit and the negatively-charged structural unit are The distance is a length of 1 to 5 carbon-carbon bonds, and the positively-charged structural unit and the negatively-charged structural unit are randomly arranged to form a double ion charge deviation.
- the method for removing white blood cells from a blood sample according to the present invention further comprises a fixing procedure for bonding the double ion charge-deviating blood cell screening material to a surface of the substrate, comprising the substrate.
- the filter material can be assembled more easily with other medical tubing, and the leukocyte removal rate of the filter material is also greater than 95%.
- the immobilization procedure is a plasma induced surface grafting reaction or a physically induced surface bridging graft.
- the substrate comprises polypropylene fibers and polyester fibers.
- the substrate is polypropylene fibers.
- the filter material made by the above fixed procedure is a film.
- the blood sample comprises whole blood, red blood cell thick liquid, and platelet thick liquid.
- the filter material In order to effectively remove white blood cells from blood samples and meet industry regulatory requirements, the filter material must have a leukocyte removal rate greater than 95%.
- the combination and the molar ratio of the positively charged structural unit or the negatively charged structural unit can enable the filter medium to have white blood cells.
- the removal rate is greater than 95%.
- the diionic structural unit is a diionic sulfobetaine; Zwitterionic sulfobetaine
- the diionic sulfobetaine is 2-(Methacryloyloxyethyl) dimethyl (3-sulfopropyl)-ammonium hydroxide (sulfobetaine methacrylate, SBMA)
- the positively charged structural unit is [2-(Methacryloyloxy)ethyl]trimethylammonium; [TMA)
- the negatively charged structural unit is a group derived from one or more of the following groups:
- the material for double ion charge-deviating blood cell screening is 60% by mole of [2-(Methacryloyloxy)ethyl]trimethylammonium; [TMA) And a copolymer of 40 mol% of 3-sulfopropyl methacrylate, the filter material prepared by the copolymer has a white blood cell removal rate of 97% or more.
- the material for double ion charge-deviating blood cell screening is 70 mol% of [2-(Methacryloyloxy)ethyl]trimethylammonium; [TMA) And a copolymer composed of 30 mol% of 3-sulfopropyl methacrylate, which has a leukocyte removal rate of 95% or more.
- the material for double ion charge-deviating blood cell screening is 80% by mole of [2-(Methacryloyloxy)ethyl]trimethylammonium; (TMA) And a copolymer composed of 20 mol% of 3-sulfopropyl methacrylate having a white blood cell removal rate of 99.9% or more.
- the material for dual ion charge-deviating blood cell screening is 30 mol% of [2-(methacryloyloxy)ethyl]trimethylammonium; [2-(Methacryloyloxy)ethyl]trimethylammonium; TMA And a copolymer of 70% by mole of methacrylic acid thiocarbamate (SBMA) (3-(sulfopropyl)ethyl]dimethyl (3-sulfopropyl)-ammonium hydroxide Has a white blood cell removal rate of more than 99%.
- SBMA methacrylic acid thiocarbamate
- Fig. 1 is a bar graph showing the results of double ion charge deviation and platelet, red blood cell and leukocyte adsorption experiments of a material for double ion charge-deviating blood cell screening (copolymer I) according to a first embodiment of the present invention.
- Fig. 2 is a bar graph showing the results of the double ion charge deviation and the results of platelet, red blood cell and white blood cell adsorption experiments of the material for the double ion charge deviation type blood cell screening (copolymer II) according to the second embodiment of the present invention.
- porous fibrous materials such as PET (polyethylene terephthalate) are still used as the filter material.
- the substrate is subjected to a surface modification treatment of a graft polymer such as a fiber material to obtain a surface of the filter material having a slight negative charge, so that an allergic reaction is not obtained.
- a fibrous material such as PET is not used as a substrate for a filter medium for blood cell screening, and the material itself is porous, and the self-contained filter material for blood cell screening is not used.
- the surface modification treatment of the material is performed.
- the material for screening a double ion charge-deviating blood cell of the present invention can be used in combination with a fiber material such as PP (polypropylene) fiber or PET, and can be used as a blood cell screen.
- a material for screening a double ion charge deviation type blood cell which is a copolymer composed of a double ion structure unit and a charged structure unit, wherein the double ion structure unit includes at least one positively charged group. And a negatively charged group, the positively charged group and the negatively charged group are at a distance of 1 to 5 carbon-carbon bonds, and the charged structural unit and the double-ionic structural unit are randomly arranged to form a pair Ion charge deviation.
- the double ion structure unit has a double-positive charge group to provide a double
- the above-mentioned diionic structural unit includes at least one positively charged group and one negatively charged group, and the length of the positively charged group and the negatively charged group is preferably from 1 to 5 carbon-carbon bonds, 2 The length of the ⁇ 4 carbon-carbon bonds is more desirable.
- the diionic building block is a group derived from one or more of the following groups:
- the above charged structural unit comprises one or both of a positively charged structural unit and a negatively charged structural unit.
- the positively charged building block is a group derived from one or more of the following groups:
- the negatively charged building block is a group derived from one or more of the following groups:
- the material for dual ion charge-deviating blood cell screening has a positive charge deviation range of 5% to 34%, and the material for screening the double-ion charge-displacement blood cell has no activation effect on platelets.
- the charge deviation range is such that when the sum of the diionic structural unit and the positively charged structural unit is 100 mol%, the molar ratio of the diionic structural unit is 70 to 90 mol%, and the molar ratio of the positively charged structural unit is 30 to It is composed of 10 mol%.
- the above-mentioned charge deviation range is defined by the case where the material for the double ion charge deviation type blood cell screening is composed of a positively charged ionic monomer (for example, TMA) and a negatively charged ionic monomer (for example, SA), and is defined as an X-ray photoelectron spectroscopy (XPS).
- XPS X-ray photoelectron spectroscopy
- the peak position 399eV is a signal contributed by the quaternary nitrogen group (N+) on the positively charged ionic monomer (TMA)
- the peak position 168eV is the sulfur element on the negatively charged ionic monomer (SA) (SO 3 -
- the contribution signal is divided into two peaks and the integrated area under the peak is calculated.
- the ratio of the area used is the content of the positive and negative charge monomer in the double ion charge deviation type blood cell screening material.
- the material for dual ion charge-displacement blood cell screening has a positive charge deviation range of 35% to 75%, and the material for screening the double-ion charge-displacement blood cell has an activation effect on platelets.
- the charge deviation range is such that when the sum of the diionic structural unit and the positively charged structural unit is 100 mol%, the molar ratio of the diionic structural unit is 30 to 60 mol%, and the molar ratio of the positively charged structural unit is 70 to 40 mol% of the composition.
- the material for dual ion charge-deviating blood cell screening has a negative charge deviation range of 15% to 59%, and the material for screening the double-ion charge-displacement blood cell has no activation effect on platelets.
- the charge deviation range is such that when the sum of the diionic structural unit and the negatively charged structural unit is 100 mol%, the molar ratio of the diionic structural unit is 51 to 80 mol%, and the molar ratio of the negatively charged structural unit is 49 to 20 mol% of the composition.
- the material for dual ion charge-deviating blood cell screening has a negative charge deviation range of 60% to 90%, and the material for screening the double-ion charge-displacement blood cell has an activation effect on platelets.
- the charge deviation range is such that when the sum of the diionic structural unit and the negatively charged structural unit is 100 mol%, the molar ratio of the diionic structural unit is 30 to 50 mol%, and the molar ratio of the negatively charged structural unit is 70 to 50% by mole.
- the material for double ion charge-deviating blood cell screening has a positive charge deviation ranging from 5% to 35%, and a white blood cell-containing sample passes through the double-ion charge-displacement blood cell screening material, and the white blood cell in the sample is The double ion charge-displacement blood cell screening material is filtered.
- the charge deviation range is such that when the sum of the diionic structural unit and the positively charged structural unit is 100 mol%, the molar ratio of the diionic structural unit is 70 to 90 mol%, and the molar ratio of the positively charged structural unit is 30 to It is composed of 10 mol%.
- a material for screening a double ion charge deviation type blood cell is a copolymer composed of a positively-charged structural unit and a negatively-charged structural unit, wherein the positively-charged structural unit and the The distance of the negatively charged structural unit is a length of 1 to 5 carbon-carbon bonds, and the positively-charged structural unit and the negatively-charged structural unit are randomly arranged to form a double ion charge deviation.
- This embodiment differs from the first embodiment in that the present embodiment uses only the positively charged structural unit and the negatively charged structural unit to constitute the copolymer of the present invention by the distance between the positively charged structural unit and the negatively charged structural unit. 1 to 5
- the length of the carbon-carbon bond for example, the selection of a specific group, the positively charged structural unit and the negatively charged structural unit are randomly arranged to constitute a double ion charge deviation.
- the positively charged structural unit is a group derived from one or more of the following groups:
- the negatively charged structural unit is a group derived from one or more of the following groups:
- the material for dual ion charge-deviating blood cell screening has a positive charge deviation range of 15% to 65%, and the material for screening the double-ion charge-displacement blood cell has an activation effect on platelets.
- the material for dual ion charge-deviating blood cell screening has a negative charge deviation range of 50% to 80%, and the material for screening the double-ion charge-displacement blood cell has no activation effect on platelets.
- the material for dual ion charge-deviating blood cell screening has a positive charge deviation ranging from 20% to 70%, and a white blood cell-containing sample passes through the double-ion charge-displacement blood cell screening material, and the white blood cell in the sample is The double ion charge-displacement blood cell screening material is filtered. More preferably, when the total of the positively-charged structural unit and the negatively-charged structural unit is 100% by mole, the molar ratio of the positively-charged structural unit is 80% by mole, and the molar ratio of the negatively-charged structural unit is 20% by mole.
- a method of removing white blood cells from a blood sample the method of removing white blood cells from a blood sample by making a blood sample through a double ion charge deviation type blood cell screening material.
- the above method further comprises performing a fixing procedure for bonding the double ion charge-deviating blood cell screening material to the surface of a substrate, and the filter material prepared by the substrate can be more easily combined with other medical accessories. Assemble.
- the double ion charge-deviating blood cell screening material is a copolymer composed of a dual ion structural unit and a charged structural unit, wherein the dual ion structural unit includes at least one positively charged group and one With a negatively charged group, the distance between the positively charged group and the negatively charged group is 1 to 5 carbon-carbon bonds, and the charged structural unit and the double-ionic structural unit are randomly arranged to form a double ion charge deviation .
- the double ion charge-displacement blood cell screening material is a copolymer composed of a positively-charged structural unit and a negatively-charged structural unit, wherein the positively-charged structural unit and the negatively-charged structural unit are Distance is The length of the 1 to 5 carbon-carbon bonds, the positively-charged structural unit and the negatively-charged structural unit are randomly arranged to form a double ion charge deviation.
- the method for removing white blood cells from a blood sample further comprises a fixing process for bonding the double ion charge-deviating blood cell screening material to a surface of the substrate, and containing the filter made of the substrate.
- the material can be assembled more easily with other medical tubing, and the leukocyte removal rate of the filter is also greater than 95%.
- the immobilization procedure is a plasma induced surface grafting reaction or a physically induced surface bridging graft.
- the substrate comprises polypropylene fibers and polyester fibers.
- the substrate is polypropylene fibers.
- the filter material made by the above fixed procedure is a film.
- the blood sample comprises whole blood, red blood cell thick liquid or platelet thick liquid.
- the filter material In order to effectively remove white blood cells from blood samples and meet industry regulatory requirements, the filter material must have a leukocyte removal rate greater than 95%.
- the combination and the molar ratio of the positively charged structural unit or the negatively charged structural unit can enable the filter medium to have white blood cells.
- the removal rate is greater than 95%.
- the diionic structural unit is a diionic sulfobetaine; Zwitterionic sulfobetaine
- the diionic sulfobetaine is 2-(Methacryloyloxyethyl) dimethyl (3-sulfopropyl)-ammonium hydroxide (sulfobetaine methacrylate, SBMA)
- the negatively charged structural unit is a group derived from one or more of the following groups:
- the material for double ion charge-deviating blood cell screening is 60% by mole of [2-(Methacryloyloxy)ethyl]trimethylammonium; [TMA) And a copolymer composed of 40 mol% of 3-sulfopropylmethacrylate having a white blood cell removal rate of 97% or more.
- the material for double ion charge-deviating blood cell screening is 70 mol% of [2-(Methacryloyloxy)ethyl]trimethylammonium; [TMA) And a copolymer composed of 30 mol% of 3-sulfopropyl methacrylate, which has a leukocyte removal rate of 95% or more.
- the material for double ion charge-deviating blood cell screening is 80% by mole of [2-(Methacryloyloxy)ethyl]trimethylammonium; (TMA) And a copolymer composed of 20 mol% of 3-sulfopropyl methacrylate having a white blood cell removal rate of 99.9% or more.
- the material for dual ion charge-deviating blood cell screening is 30 mol% of [2-(methacryloyloxy)ethyl]trimethylammonium; [2-(Methacryloyloxy)ethyl]trimethylammonium; TMA And a copolymer of 70% by mole of methacrylic acid thiocarbamate (SBMA) (3-(sulfopropyl)ethyl]dimethyl (3-sulfopropyl)-ammonium hydroxide Has a white blood cell removal rate of more than 99%.
- SBMA methacrylic acid thiocarbamate
- Embodiment 1 is a diagrammatic representation of Embodiment 1:
- the synthetic double ion charge-displacement blood cell screening material is a copolymer I: SAmTMAn composed of a positively charged structural unit (TMA) and a negatively charged structural unit (SA) (where m and n represent the molar ratios of SA and TMA, respectively, for example SA8TMA2 indicates that the molar ratio of SA to TMA is 8:2, and the same expression is used hereinafter.
- TMA [2-(Methacryloyloxy)ethyl]trimethylammonium chloride solution
- SA 3-Sulfopropyl methacrylate potassium salt
- the raw material of the monomer unit that is, the mixture of TMA and SA
- NMBA N, N-Methylenebisacryl amide, 96%, manufactured by ACROS Co.
- the initiator APS (1 wt%) was added at room temperature (25 °C)
- the monomer and the cross-linking agent are subjected to radical polymerization, and finally the catalyst TEMED (N, N, N', N'-Teramethylethylenediamine, 99%) (1% by weight) is added to accelerate the polymerization reaction, and the mixed solution is taken out and placed.
- TEMED N, N, N', N'-Teramethylethylenediamine, 99%
- the reaction is completed to form the copolymer I.
- the copolymer II was taken out and immersed in deionized water and stored in a refrigerator at 4 ° C, and washed three times with deionized water every 24 hours to ensure that the copolymer I was stored in a clean environment.
- the double ion charge deviation and the diiodomethane contact angle of each copolymer I are shown in Table 1.
- the diiodomethane contact angle was measured by diiodomethane as a test liquid, and dropped onto the surface of the copolymer I to be tested, and the contact angle with the surface of the copolymer I was observed.
- figure 1 A bar graph showing the difference in the double ion charge of the material for the double ion charge-deviating blood cell screening (copolymer I) and the results of the adsorption test of platelets, red blood cells and white blood cells according to the first embodiment of the present invention.
- Embodiment 2 is a diagrammatic representation of Embodiment 1:
- the synthetic double ion charge-biased blood cell screening material is a double ion structural unit (SBMA) and a charged structural unit (positively structured structural unit (TMA) or negatively charged structural unit (SA)) composed of copolymer II: SpTMAq (wherein p and q represent the molar ratio of S and TMA, respectively, for example, S8TMA2 indicates that the molar ratio of SBMA and TMA is 8:2, and the same expression is used below) or SpSAr (where p and r respectively represent the molar ratio of S and SA). For example, S8SA2 indicates that the molar ratio of SBMA and SA is 8:2, and the same expression is used hereinafter.
- SBMA double ion structural unit
- TMA positively structured structural unit
- SA negatively charged structural unit
- SBMA (2-(Methacryloyloxy)ethyl]dimethyl(3-sulfopropyl)-ammoniumhydroxide) is mixed with TMA ([2-(Methacryloyloxy)ethyl]trimethylammonium chloride solution) or SA (3-Sulfo propyl methacrylate potassium salt) according to different ratios.
- the monomer unit raw material that is, the mixture of SBMA and TMA or SA
- the cross-linking agent NMBA 8wt%) and mix and stir until uniform
- the starting agent ammonium persulfate APS (1wt %)
- the monomer and the cross-linking agent are subjected to radical polymerization at room temperature (25 ° C)
- the catalyst TEMED (1 wt%) is added to accelerate the polymerization reaction, and the mixed solution is taken out and placed in the module for preparing the copolymer II. In the reaction, the reaction is completed to form the copolymer II.
- Fig. 2 is a bar graph showing the results of the double ion charge deviation and the results of platelet, red blood cell and white blood cell adsorption experiments of the material for the double ion charge deviation type blood cell screening (copolymer II) according to the second embodiment of the present invention.
- the water gel (copolymer I or II) to be tested was placed in a 24-well culture dish, and 1 mL of PBS was added to each well plate, and then placed in an oven at 37 ° C for one hour.
- PBS platelet-rich human plasma solution
- the platelets attached to the surface of the water gel were fixed, and 1 mL of a 2.5 vol% glutaraldehyde solution was added to the 24-well culture dish, and the solution was placed in a refrigerator at 4 ° C for 24 hours, and then the glutaraldehyde solution was further added. After taking out, it was repeatedly washed with PBS, and the water gel was dried by a freeze dryer. After the dry operation, the water glue is fixed on the stage by using a carbon tape, and a conductive metal is plated on the surface by a plasma technique, and the platelet is attached to the surface of the water gel by scanning electron microscopy (SEM). Type.
- SEM scanning electron microscopy
- the red blood cell adsorption experiment is to place the water gel (copolymer I or II) to be tested in a 24-well culture dish, add 1 mL of PBS to each well plate, and place it in an oven at 37 ° C for one hour.
- the PBS was taken out and 1 mL of a red blood cell thick solution was added to the water gel to be tested, and placed in an oven at 37 ° C for 2 hours.
- 1 mL of a 2.5 vol% glutaraldehyde solution was added and left to stand in a refrigerator at 4 ° C for 24 hours.
- a conjugated-focus laser scanning electron microscope (CLSM) was used to observe the image of red blood cells attached to the surface of the water gel.
- the water gel (copolymer I or II) to be tested was placed in a 24-well culture dish, and 1 mL of PBS was added to each well plate, and then placed in an oven at 37 ° C for one hour. The PBS was taken out and 1 mL of a white blood cell thick solution was added to the water gel to be tested, and placed in an oven at 37 ° C for 2 hours. After the white blood cell thick liquid was aspirated and washed with PBS to remove unadsorbed blood cells, 1 mL of a 2.5 vol% glutaraldehyde solution was added, and the mixture was allowed to stand in a refrigerator at 4 ° C for 24 hours. Finally, a conjugated-focus laser scanning electron microscope (CLSM) was used to observe the condition in which white blood cells were attached to the surface of the water gel.
- CLSM conjugated-focus laser scanning electron microscope
- the desired blood cell screening characteristics can be obtained by controlling the double ion charge deviation.
- Table 3 shows the different diionic charge deviation ranges.
- the materials have different hemocytic screening characteristics.
- the TMA and SA are plasma-induced surface grafting techniques to prepare PP fiber films with different SA-TMA bias ranges (pore 30um). , fiber diameter 2um, thickness 0.5mm), a modified film with a diameter of 2.5cm was placed in the holder, and 5cc of human red blood cell thick liquid was filtered by means of pressure.
- the filtration effect was measured by a blood analyzer (LH780- LH 780 Hematology Analyzer, Beckman Coulter Co.) tested the filtered blood cell content.
- a blood analyzer LH780- LH 780 Hematology Analyzer, Beckman Coulter Co.
- Table 3 when the red blood cell thick liquid was filtered by the double ion charge-displacement blood cell screening material SA2TMA8, the white blood cell removal rate was 99.98%, and the platelet recovery rate was 3.825%, which was extremely useful for red blood cell recovery of the red blood cell thick liquid.
- the platelet recovery rate was 99.1%, and the white blood cell removal rate was 99.15%. Platelet recovery in platelet concentrates is extremely useful.
- the material for screening double-ion charge-deviating blood cells can be utilized as a material for blood cell screening, and by controlling the distance, distribution, and ratio between charged groups having different charges, the material itself has Porous, self-contained is a filter material for blood cell screening, and there is no treatment for surface modification of materials, which meets the needs of various blood cell separations, but can also be combined with fiber materials such as PP (polypropylene) fiber or PET. Use as a blood cell screening application.
- PP polypropylene
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Abstract
一种双离子电荷偏差型血球筛选用材料和一种从血液样品中移除白血球的方法，其双离子电荷偏差型血球筛选用材料是双离子构造单元以及带电荷构造单元所构成的共聚物，其中双离子构造单元至少包括一个带正电基团与一个带负电基团，该带正电基团与该带负电基团的距离为1-5个碳碳键的长度，该带电荷构造单元与该双离子构造单元无规则排列而构成一双离子电荷偏差。
Description
本发明涉及一种双离子电荷偏差型材料和一种从血液样品中移除白血球的方法，特别是涉及一种双离子电荷偏差型血球筛选用材料和一种使血液样品通过由一种双离子电荷偏差型血球筛选用材料所制成的滤材，以从该血液样品中移除白血球的方法。
通常，白血球例如可借由含有纤维材料的过滤器从血液中滤除，再者由于血小板及白血球带负电，滤材表面一般处理成为带正电荷，除利用滤材的海绵结构(多孔隙)外，利用带正电的滤材表面吸附带负电的血小板及白血球。此外，为了避免凝血或活化血小板，在血液样品中需要添加抗凝血剂，或者滤材表面需要进一步进行表面处理，以防止凝血。美国专利第5,407,581号揭露处理血液的表面带负电的滤材，使用PET(聚对苯二甲酸乙二酯)制纤维材料作为基材，再于其表面接枝带电荷的聚合物，以使滤材表面带少许负电荷，因为带正电荷的表面，容易造成缓激肽(bradykinin)的浓度增加，易引发输血时的过敏反应。然而，作为血球筛选用材料，需要考虑选择性、不引起凝血、过敏反应等，文献(美国专利第5,407,581号)中，虽然揭露使用带正电荷、带负电荷的化合物，可得到带正电的表面、带负电的表面或电中性的表面，表面整体电荷表现，包括3种(正电、负电或电中性)，然而血液对材料的反应，不是只有3种，再者电中性还包括无电荷或电荷平衡，电荷平衡时电荷分布亦会影响血液对材料的反应。因此，血球筛选用材料的发展，仍为一重要课题。
发明内容
鉴于上述发明背景，为了符合产业上的要求，本发明的目的之一在于提供一种双离子电荷偏差型血球筛选用材料，对血小板、红血球及白血球具有不同的选择性。
本发明的另一目的，是在于提供一种双离子电荷偏差型血球筛选用材料，借由控制带有不同电荷的带电基团之间的距离、分布以及比例，即制造具有特定的双离子电荷偏差范围的材料，以达到血球筛选的效果。
再者，本发明的再一目的，是在于提供一种双离子电荷偏差型血球筛选用材料，从血液样品分离白血球时，不引起凝血反应，不会造成滤材的堵塞。
本发明的又一目的，在于提供一种从血液样品中移除白血球的方法，借由使一血液样品通过本发明所提供的一种双离子电荷偏差型血球筛选用材料所制成的一滤材，以达到从该血液样品中移除白血球的目的。
为了达到上述目的，根据本发明一实施例，提供一种双离子电荷偏差型血球筛选用材料，其是双离子构造单元以及带电荷构造单元所构成的共聚物，其中双离子构造单元至少包括一个带正电基团与一个带负电基团，该带正电基团与该带负电基团的距离为1～5个碳碳键的长度，该带电荷构造单元与该双离子构造单元无规则排列而构成一双离子电荷偏差。
于一实施例，上述双离子构造单元是衍生自下列群组之一或以上的基团：
双离子磷基甜菜碱；Zwitterionic phosphobetain
(R1＝H or CH3；R2＝O or NH；m＝1～5；n＝1～5)
双离子磺基甜菜碱；Zwitterionic sulfobetain
(R1，＝H or CH3；R2＝O or NH；m＝1～5；n＝1～5)
双离子羧基甜菜碱；Zwitterionic carboxybetain
(R1，＝H or CH3；R2＝O or NH；m＝1～5；n＝1～5)。
具体地，例如下述式所示的磷基甜菜碱甲基丙烯酸酯
(2-methacryloyloxyethyl phosphorylcholine(phophobetaine methacrylate；PBMA))
下述式所示的磺基甜菜碱甲基丙烯酸酯
([2-(Methacryloyloxy)ethyl]dimethyl(3-sulfopropyl)-ammonium hydroxide(sulfobetaine methacrylate，SBMA))
下述式所示的羧基甜菜碱甲基丙烯酸酯
(2-Carboxy-N，N-dimethyl-N-(2′-(methacryloyloxy)ethyl)ethanamin-ium inner salt(carboxybetaine methacrylate，CBMA))
上述双离子构造单元是衍生自磺基甜菜碱甲基丙烯酸酯(Sulfobetaine methacrylate)较理想。
于一实施例，上述带电荷构造单元包括带正电荷构造单元以及带负电荷构造单元之一或两者。
于一实施例，上述带正电荷构造单元是衍生自下列群组之一或以上的基团：
一级胺基单体
(R1，＝H or CH3；R2＝O or NH；m＝1～5)
二级胺基单体
(R1，＝H or CH3；R2＝O or NH；R3＝CH3 or CH(CH3)2；m＝1～5)
三级胺基单体
(R1，＝H or CH3；R2＝O or NH；m＝1～5)
四级胺基单体
(R1，＝H or CH3；R2＝O or NH；m＝1～5)。
具体地，例如具有下述式的甲基丙烯酸2-胺基乙酯(2-aminoethyl methacrylate)
具有下述式的甲基丙烯酸二甲基胺基乙酯(dimethylaminoethyl methacrylate)
[2-(甲基丙烯酰氧基)乙基]三甲基铵([2-(Methacryloyloxy)ethyl]trimethylammonium；TMA)
于一实施例，上述带负电荷构造单元是衍生自下列群组之一或以上的基团：
硫基单体
羧基单体
具体地，例如具有下述式的甲基丙烯酸3-磺基丙酯(3-sulfopropyl methacrylate)
具有下述式的甲基丙烯酸2-羧基乙酯(2-Carboxyethyl acrylate)
于一实施例，双离子电荷偏差型血球筛选用材料具有正的电荷偏差范围为5％～34％，该双离子电荷偏差型血球筛选用材料对血小板无活化效果。上述电荷偏差范围，是对双离子构造单元以及带正电荷构造单元的总和为100摩尔％时，双离子构造单元的摩尔比例为70～90摩尔％，带正电荷构造单元的摩尔比例为30～10摩尔％所构成。
于一实施例，双离子电荷偏差型血球筛选用材料具有正的电荷偏差范围为35％～75％，该双离子电荷偏差型血球筛选用材料对血小板具有活化效果。上述电荷偏差范围是对双离子构造单元及带正电荷构造单元的总和为100摩尔％时，双离子构造单元的摩尔比为30～60摩尔％，带正电荷构造单元的摩尔比例为70～40摩尔％所构成。
于一实施例，双离子电荷偏差型血球筛选用材料具有负的电荷偏差范围为15％～59％，该双离子电荷偏差型血球筛选用材料对血小板无活化效果。上述电荷偏差范围是对双离子构造单元及带负电荷构造单元的总和为100摩尔％时，双离子构造单元的摩尔比例为51～80摩尔％，带负电荷构造单元的摩尔比例为49～20摩尔％所构成。
于一实施例，双离子电荷偏差型血球筛选用材料具有负的电荷偏差范围为60％～90％，该双离子电荷偏差型血球筛选用材料对血小板具有活化效果。上述电荷偏差范围，是对双离子构造单元以及带负电荷构造单元的总和为100摩尔％时，双离子构造单元的摩尔比例为30～50摩尔％，带负电荷构造单元的摩尔比例为70～50摩尔％所构成。
于一实施例，双离子电荷偏差型血球筛选用材料具有正的电荷偏差范围为5％～35％，一含有白血球的样品通过该双离子电荷偏差型血球筛选用材料后，样品中的白血球被该双离子电荷偏差型血球筛选用材料过滤。上述电荷偏差范围，是对双离子构造单
元以及带正电荷构造单元的总和为100摩尔％时，双离子构造单元的摩尔比例为70～90摩尔％，带正电荷构造单元的摩尔比例为30～10摩尔％所构成。
于一实施例，上述双离子构造单元中，该带正电基团与该带负电基团的距离为2～4个碳碳键的长度较理想。
再者，根据本发明另一实施例，提供一种双离子电荷偏差型血球筛选用材料，其是带正电构造单元以及带负电构造单元所构成的共聚物，其中该带正电构造单元与该带负电构造单元的距离为1～5个碳碳键的长度，该带正电构造单元以及该带负电构造单元无规则排列而构成一双离子电荷偏差。
于一实施例，上述带正电构造单元，是衍生自下列群组之一或以上的基团：
一级胺基单体
(R1，＝H or CH3；R2＝O or NH；m＝1～5)、
二级胺基单体
(R1，＝H or CH3；R2＝O or NH；R3＝CH3 or CH(CH3)2；m＝1～5)、
三级胺基单体
(R1，＝H or CH3；R2＝O or NH；m＝1～5)、
四级胺基单体
(R1，＝H or CH3；R2＝O or NH；m＝1～5)。
具有下述式的甲基丙烯酸2-胺基乙酯(2-aminoethyl methacrylate)
具有下述式的甲基丙烯酸二甲基胺基乙酯(dimethylaminoethyl methacrylate)
[2-(甲基丙烯酰氧基)乙基]三甲基铵([2-(Methacryloyloxy)ethyl]trimethylammonium；TMA)
于一实施例，上述带负电构造单元，是衍生自下列群组之一或以上的基团：
硫基单体
例：3-sulfopropyl methacrylate(SA)
羧基单体
例：2-Carboxyethyl acrylate
于一实施例，双离子电荷偏差型血球筛选用材料具有正的电荷偏差范围为15％～65％，该双离子电荷偏差型血球筛选用材料对血小板具有活化效果。
于一实施例，双离子电荷偏差型血球筛选用材料具有负的电荷偏差范围为50％～80％，该双离子电荷偏差型血球筛选用材料对血小板无活化效果。
于一实施例，双离子电荷偏差型血球筛选用材料具有正的电荷偏差范围为20％～70％，一含有白血球的样品通过该双离子电荷偏差型血球筛选用材料后，样品中的白血球被该双离子电荷偏差型血球筛选用材料过滤。
根据本发明的又一实施例，提供一种从血液样品中移除白血球的方法，该从血液样品中移除白血球的方法是使一血液样品通过一双离子电荷偏差型血球筛选用材料所制成的一滤材，其中，该滤材的白血球移除率大于95％。上述的方法更包含进行一固定程序，使该双离子电荷偏差型血球筛选用材料键结在一基材的表面，含有该基材所制成的滤材能更简易地和其他的医材配件进行组装，因此能更广泛的将本发明所述的从血液样品中移除白血球的方法应用在相关的产业领域。
于一实施例，所述的双离子电荷偏差型血球筛选用材料，其是双离子构造单元以及带电荷构造单元所构成的共聚物，其中双离子构造单元至少包括一个带正电基团与一个带负电基团，该带正电基团与该带负电基团的距离为1～5个碳碳键的长度，该带电荷
构造单元与该双离子构造单元无规则排列而构成一双离子电荷偏差。
于一实施例，所述的双离子电荷偏差型血球筛选用材料，其是带正电构造单元以及带负电构造单元所构成的共聚物，其中该带正电构造单元与该带负电构造单元的距离为1～5个碳碳键的长度，该带正电构造单元以及该带负电构造单元无规则排列而构成一双离子电荷偏差。
本发明所述的从血液样品中移除白血球的方法更包含一固定程序，使上述的双离子电荷偏差型血球筛选用材料键结在一基材的表面上，含有该基材所制成的滤材能更简易的和其他的医材管件进行组装，且该滤材的白血球移除率亦大于95％。
于一实施例，该固定程序是电浆诱导表面接枝反应或是物理诱导表面架桥接枝。
于一实施例，该基材包含聚丙烯纤维和聚酯纤维，优选地，所述的基材是聚丙烯纤维。
于一实施例，借由上述的固定程序所制成的滤材是一薄膜。
于一实施例，所述的血液样品包含全血、红血球浓厚液和血小板浓厚液。
为了有效地从血液样品中移除白血球和符合产业法规上的要求，所述的滤材的白血球移除率必须大于95％。借由调整改变构成该滤材的双离子电荷偏差型血球筛选用材料中的双离子构造单元，带正电构造单元或带负电构造单元的组合和摩尔比例，能使所述的滤材具有白血球移除率大于95％的效果。
于一实施例，上述双离子构造单元是双离子磺基甜菜碱；Zwitterionic sulfobetaine
(R1，＝H or CH3；R2＝O or NH；m＝1～5；n＝1～5)
优选地，所述的双离子磺基甜菜碱是磺基甜菜碱甲基丙烯酸酯[2-(Methacryloyloxy)ethyl]dimethyl(3-sulfopropyl)-ammonium hydroxide(sulfobetaine methacrylate，SBMA)
于一实施例，上述带正电构造单元是[2-(甲基丙烯酰氧基)乙基]三甲基铵([2-(Methacryloyloxy)ethyl]trimethylammonium；TMA)
于一实施例，上述带负电构造单元，是衍生自下列群组之一或以上的基团：
硫基单体
例：甲基丙烯酸3-磺基丙酯3-sulfopropyl methacrylate(SA)
于一实施例，双离子电荷偏差型血球筛选用材料是60摩尔％的[2-(甲基丙烯酰氧基)乙基]三甲基铵([2-(Methacryloyloxy)ethyl]trimethylammonium；TMA)和40摩尔％的甲基丙烯酸3-磺基丙酯(3-sulfopropyl methacrylate)所构成的共聚物，该共聚物所制成的滤材具有97％以上的白血球移除率。
于一实施例，双离子电荷偏差型血球筛选用材料是70摩尔％的[2-(甲基丙烯酰氧基)乙基]三甲基铵([2-(Methacryloyloxy)ethyl]trimethylammonium；TMA)和30摩尔％的甲基丙烯酸3-磺基丙酯(3-sulfopropyl methacrylate)所构成的共聚物，该共聚物所制成的滤材具有95％以上的白血球移除率。
于一实施例，双离子电荷偏差型血球筛选用材料是80摩尔％的[2-(甲基丙烯酰氧基)乙基]三甲基铵([2-(Methacryloyloxy)ethyl]trimethylammonium；TMA)和20摩尔％的甲基丙烯酸3-磺基丙酯(3-sulfopropyl methacrylate)所构成的共聚物，该共聚物所制成的滤材具有99.9％以上的白血球移除率。
于另一实施例，双离子电荷偏差型血球筛选用材料是30摩尔％的[2-(甲基丙烯酰氧基)乙基]三甲基铵([2-(Methacryloyloxy)ethyl]trimethylammonium；TMA)和70摩尔％的甲基丙烯酰氧基硫代甜菜碱SBMA(2-(Methacryloyloxy)ethyl]dimethyl(3-sulfopropyl)-ammonium hydroxide)所构成的共聚物，该共聚物所制成的滤材具有99％以上的白血球移除率。
借由上述技术方案，本发明至少具有下列优点及有益效果：根据本发明的双离子电荷偏差型血球筛选用材料，可利用作为血球筛选用材料，借由控制带有不同电荷的带电基团之间的距离、分布以及比例，符合各种血球分离的需求。再者，根据本发明提供的一種從血液樣品中移除白血球的方法，该方法的白血球移除率大於95％，可有效率地达到从血液样品中移除白血球的目的。
上述说明仅是本发明技术方案的概述，为了能够更清楚了解本发明的技术手段，而可依照说明书的内容予以实施，并且为了让本发明的上述和其他目的、特征和优点能够更明显易懂，以下特举较佳实施例，并配合附图，详细说明如下。
附图的简要说明
图1表示依据本发明实施例一的双离子电荷偏差型血球筛选用材料(共聚物I)的双离子电荷偏差与血小板、红血球及白血球吸附实验结果的条形图。
图2表示依据本发明实施例二的双离子电荷偏差型血球筛选用材料(共聚物II)的双离子电荷偏差与血小板、红血球及白血球吸附实验结果的条形图。
实现发明的最佳方式
有关本发明的前述及其它技术内容、特点与功效，在以下配合参考图式的一较佳实施例的详细说明中，将可清楚的呈现。为了能彻底地了解本发明，将在下列的描述中提出详尽的步骤及其组成。显然地，本发明的施行并未限定于该领域技术人员所熟习的特殊细节。另一方面，众所周知的组成或步骤并未描述于细节中，以避免造成本发明不必要的限制。本发明的较佳实施例会详细描述如下，然而除了这些详细描述之外，本发明还可以广泛地施行在其它的实施例中，且本发明的范围不受限定，其以权利要求书的范围为准。
在血液处理的应用，现有技术(美国专利第5,407,581号)中，虽揭露有关带电荷基团作为血液处理的滤材，特别是带些微负电荷的滤材表面，适合应用于对于血液处理，不会产生过敏反应。然而，本发明人等发现滤材表面的整体电荷表现(带正电、带负电或电中性)并非影响滤材对各种血球的选择性的主要因素，亦即各种血球对滤材表面(带正电、带负电或电中性的表面)不是只有3种选择性，再者，上述文献中，仍利用PET(聚对苯二甲酸乙二酯)等多孔性纤维材料作为滤材的基材，再对纤维材料进行接枝聚合物等的表面改质处理，得到带些微负电荷的滤材表面，达到不会产生过敏反应的效果。
然而，根据本发明的双离子电荷偏差型血球筛选用材料，没有使用例如PET等纤维材料作为血球筛选用滤材的基材，材料本身具有多孔性，自体即为血球筛选用滤材，亦没有进行材料的表面改质处理等处理。但是，本发明的双离子电荷偏差型血球筛选用材料，可与PP(聚丙烯)纤维或PET等的纤维材料结合，利用作为血球筛选的用途。
根据本发明第一实施例，揭露一种双离子电荷偏差型血球筛选用材料，其是双离子构造单元以及带电荷构造单元所构成的共聚物，其中双离子构造单元至少包括一个带正电基团与一个带负电基团，该带正电基团与该带负电基团的距离为1～5个碳碳键的长度，该带电荷构造单元与该双离子构造单元无规则排列而构成一双离子电荷偏差。
上述双离子构造单元在本发明的双离子电荷偏差型血球筛选用材料中，除一般现有习知的抗生物分子沾黏的效果外，借由正负电荷的基团的添加，具有提供双离子电荷偏差的特性，由于电中性表面包括完全不具有带电荷基团的表面以及具有带电荷基团的表面，再者带电荷基团的表面，其特性会随带正电基团与带负电基团的距离而异。所以，上述双离子构造单元至少包括一个带正电基团与一个带负电基团，该带正电基团与该带负电基团的距离为1～5个碳碳键的长度较理想，2～4个碳碳键的长度更理想。
于一实施例，上述双离子构造单元是衍生自下列群组之一或以上的基团：
双离子磷基甜菜碱；Zwitterionic phosphobetain
(R1，＝H or CH3；R2＝O or NH；m＝1～5；n＝1～5)
例：磷基甜菜碱甲基丙烯酸酯
2-methacryloyloxyethyl phosphorylcholine(phophobetaine methacrylate；PBMA)
双离子磺基甜菜碱；Zwitterionic sulfobetain
(R1，＝H or CH3；R2＝O or NH；m＝1～5；n＝1～5)
例：磺基甜菜碱甲基丙烯酸酯
[2-(Methacryloyloxy)ethyl]dimethyl(3-sulfopropyl)-ammonium hydroxide(sulfobetaine methacrylate，SBMA)
双离子羧基甜菜碱；Zwitterionic carboxybetain
(R1，＝H or CH3；R2＝O or NH；m＝1～5；n＝1～5)
例：羧基甜菜碱甲基丙烯酸酯
2-Carboxy-N，N-dimethyl-N-(2′-(methacryloyloxy)ethyl)ethanamin-ium inner salt(carboxybetaine methacrylate，CBMA)
于一实施例，上述带电荷构造单元包括带正电荷构造单元以及带负电荷构造单元之一或两者。
于一实施例，上述带正电荷构造单元是衍生自下列群组之一或以上的基团：
一级胺基单体
(R1，＝H or CH3；R2＝O or NH；m＝1～5)
例：2-aminoethyl methacrylate
二级胺基单体
(R1，＝H or CH3；R2＝O or NH；R3＝CH3 or CH(CH3)2；m＝1～5)
三级胺基单体
(R1，＝H or CH3；R2＝O or NH；m＝1～5)
例：dimethylaminoethyl methacrylate
四级胺基单体
(R1，＝H or CH3；R2＝O or NH；m＝1～5)
例：[2-(Methacryloyloxy)ethyl]trimethylammonium(TMA)
于一实施例，上述带负电荷构造单元是衍生自下列群组之一或以上的基团：
硫基单体
例：3-sulfopropyl methacrylate(SA)
羧基单体
例：2-Carboxyethyl acrylate
于一实施例，双离子电荷偏差型血球筛选用材料具有正的电荷偏差范围为5％～34％，该双离子电荷偏差型血球筛选用材料对血小板无活化效果。上述电荷偏差范围，是对双离子构造单元以及带正电荷构造单元的总和为100摩尔％时，双离子构造单元的摩尔比例为70～90摩尔％，带正电荷构造单元的摩尔比例为30～10摩尔％所构成。
上述电荷偏差范围，于双离子电荷偏差型血球筛选用材料为正电荷离子单体(例如TMA)与负电荷离子单体(例如SA)所构成的情况，定义为根据X射线光电子图谱(XPS)中，波峰位置399eV为正电荷离子单体(TMA)上的四级氮基团(N+)所贡献的信号，由波峰位置168eV为负电荷离子单体(SA)上的硫元素(SO3-)贡献的信号，分别将两者信号进行分峰且计算波峰下的积分面积，利用面积的比例为正负电荷单体于双离子电荷偏差型血球筛选用材料中所占的含量。
于一实施例，双离子电荷偏差型血球筛选用材料具有正的电荷偏差范围为35％～75％，该双离子电荷偏差型血球筛选用材料对血小板具有活化效果。上述电荷偏差范围，是对双离子构造单元以及带正电荷构造单元的总和为100摩尔％时，双离子构造单元的摩尔比例为30～60摩尔％，带正电荷构造单元的摩尔比例为70～40摩尔％所构成。
于一实施例，双离子电荷偏差型血球筛选用材料具有负的电荷偏差范围为15％～59％，该双离子电荷偏差型血球筛选用材料对血小板无活化效果。上述电荷偏差范围，是对双离子构造单元以及带负电荷构造单元的总和为100摩尔％时，双离子构造单元的摩尔比例为51～80摩尔％，带负电荷构造单元的摩尔比例为49～20摩尔％所构成。
于一实施例，双离子电荷偏差型血球筛选用材料具有负的电荷偏差范围为60％～90％，该双离子电荷偏差型血球筛选用材料对血小板具有活化效果。上述电荷偏差范围，是对双离子构造单元以及带负电荷构造单元的总和为100摩尔％时，双离子构造单元的摩尔比例为30～50摩尔％，带负电荷构造单元的摩尔比例为70～50摩尔％所构成。
于一实施例，双离子电荷偏差型血球筛选用材料具有正的电荷偏差范围为5％～35％，一含有白血球的样品通过该双离子电荷偏差型血球筛选用材料后，样品中的白血球被该双离子电荷偏差型血球筛选用材料过滤。上述电荷偏差范围，是对双离子构造单元以及带正电荷构造单元的总和为100摩尔％时，双离子构造单元的摩尔比例为70～90摩尔％，带正电荷构造单元的摩尔比例为30～10摩尔％所构成。
再者，根据本发明第二实施例，一种双离子电荷偏差型血球筛选用材料，其是带正电构造单元以及带负电构造单元所构成的共聚物，其中该带正电构造单元与该带负电构造单元的距离为1～5个碳碳键的长度，该带正电构造单元以及该带负电构造单元无规则排列而构成一双离子电荷偏差。
本实施例与第一实施例不同之处，在于本实施例仅使用带正电构造单元以及带负电构造单元构成本发明的共聚物，借由使带正电构造单元与带负电构造单元的距离为1～5
个碳碳键的长度，例如选择特定的基团，带正电构造单元以及带负电构造单元无规则排列而构成一双离子电荷偏差。
于一实施例，上述带正电构造单元，是衍生自下列群组之一或以上的基团：
一级胺基单体
(R1，＝H or CH3；R2＝O or NH；m＝1～5)
例：2-aminoethyl methacrylate
二级胺基单体
(R1，＝H or CH3；R2＝O or NH；R3＝CH3 or CH(CH3)2；m＝1～5。
三级胺基单体
(R1，＝H or CH3；R2＝O or NH；m＝1～5)
例：dimethylaminoethyl methaerylate
四级胺基单体
(R1，＝H or CH3；R2＝O or NH；m＝1～5)
例：[2-(Methacryloyloxy)ethyl]trimethylammonium(TMA)
于一实施例，上述带负电构造单元，是衍生自下列群组之一或以上的基团：
硫基单体
例：3-sulfopropyl methacrylate
羧基单体
例：2-Carboxyethyl acrylate
于一实施例，双离子电荷偏差型血球筛选用材料具有正的电荷偏差范围为15％～65％，该双离子电荷偏差型血球筛选用材料对血小板具有活化效果。
于一实施例，双离子电荷偏差型血球筛选用材料具有负的电荷偏差范围为50％～80％，该双离子电荷偏差型血球筛选用材料对血小板无活化效果。
于一实施例，双离子电荷偏差型血球筛选用材料具有正的电荷偏差范围为20％～70％，一含有白血球的样品通过该双离子电荷偏差型血球筛选用材料后，样品中的白血球被该双离子电荷偏差型血球筛选用材料过滤。更理想为对带正电构造单元以及带负电构造单元的总和为100摩尔％时，带正电构造单元的摩尔比例为80摩尔％，带负电构造单元的摩尔比例为20摩尔％。
根据本发明的又一实施例，提供一种从血液样品中移除白血球的方法，该从血液样品中移除白血球的方法是使一血液样品通过一双离子电荷偏差型血球筛选用材料所制成的一滤材，其中，该滤材的白血球移除率大于95％。上述的方法更包含进行一固定程序，使该双离子电荷偏差型血球筛选用材料键结在一基材的表面，含有该基材所制成的滤材能更简易地和其他的医材配件进行组装。
于一实施例，所述的双离子电荷偏差型血球筛选用材料，其是双离子构造单元以及带电荷构造单元所构成的共聚物，其中双离子构造单元至少包括一个带正电基团与一个带负电基团，该带正电基团与该带负电基团的距离为1～5个碳碳键的长度，该带电荷构造单元与该双离子构造单元无规则排列而构成一双离子电荷偏差。
于一实施例，所述的双离子电荷偏差型血球筛选用材料，其是带正电构造单元以及带负电构造单元所构成的共聚物，其中该带正电构造单元与该带负电构造单元的距离为
1～5个碳碳键的长度，该带正电构造单元以及该带负电构造单元无规则排列而构成一双离子电荷偏差。
所述的从血液样品中移除白血球的方法更包含一固定程序，使所述的双离子电荷偏差型血球筛选用材料键结在一基材的表面上，含有该基材所制成的滤材能更简易地和其他的医材管件进行组装，且该滤材的白血球移除率亦大于95％。
于一实施例，该固定程序是电浆诱导表面接枝反应或是物理诱导表面架桥接枝。
于一实施例，该基材包含聚丙烯纤维和聚酯纤维，优选地，所述的基材是聚丙烯纤维。
于一实施例，借由上述的固定程序所制成的滤材是一薄膜。
于一实施例，所述的血液样品包含全血，红血球浓厚液或血小板浓厚液。
为了有效地从血液样品中移除白血球和符合产业法规上的要求，所述的滤材的白血球移除率必须大于95％。借由调整改变构成该滤材的双离子电荷偏差型血球筛选用材料中的双离子构造单元，带正电构造单元或带负电构造单元的组合和摩尔比例，能使所述的滤材具有白血球移除率大于95％的效果。
于一实施例，上述双离子构造单元是双离子磺基甜菜碱；Zwitterionic sulfobetaine
(R1，＝H or CH3；R2＝O or NH；m＝1～5；n＝1～5)
优选地，该双离子磺基甜菜碱是磺基甜菜碱甲基丙烯酸酯[2-(Methacryloyloxy)ethyl]dimethyl(3-sulfopropyl)-ammonium hydroxide(sulfobetaine methacrylate，SBMA)
于一实施例，上述带负电构造单元，是衍生自下列群组之一或以上的基团：
硫基单体
例：甲基丙烯酸3-磺基丙酯3-sulfopropyl methacrylate(SA)
于一实施例，双离子电荷偏差型血球筛选用材料是60摩尔％的[2-(甲基丙烯酰氧基)乙基]三甲基铵([2-(Methacryloyloxy)ethyl]trimethylammonium；TMA)和40摩尔％的甲基丙烯酸3-磺基丙酯(3-sulfopropylmethacrylate)所构成的共聚物，该共聚物所制成的滤材具有97％以上的白血球移除率。
于一实施例，双离子电荷偏差型血球筛选用材料是70摩尔％的[2-(甲基丙烯酰氧基)乙基]三甲基铵([2-(Methacryloyloxy)ethyl]trimethylammonium；TMA)和30摩尔％的甲基丙烯酸3-磺基丙酯(3-sulfopropyl methacrylate)所构成的共聚物，该共聚物所制成的滤材具有95％以上的白血球移除率。
于一实施例，双离子电荷偏差型血球筛选用材料是80摩尔％的[2-(甲基丙烯酰氧基)乙基]三甲基铵([2-(Methacryloyloxy)ethyl]trimethylammonium；TMA)和20摩尔％的甲基丙烯酸3-磺基丙酯(3-sulfopropyl methacrylate)所构成的共聚物，该共聚物所制成的滤材具有99.9％以上的白血球移除率。
于另一实施例，双离子电荷偏差型血球筛选用材料是30摩尔％的[2-(甲基丙烯酰氧基)乙基]三甲基铵([2-(Methacryloyloxy)ethyl]trimethylammonium；TMA)和70摩尔％的甲基丙烯酰氧基硫代甜菜碱SBMA(2-(Methacryloyloxy)ethyl]dimethyl(3-sulfopropyl)-ammonium hydroxide)所构成的共聚物，该共聚物所制成的滤材具有99％以上的白血球移除率。
实施例一：
合成双离子电荷偏差型血球筛选用材料为带正电构造单元(TMA)以及带负电构造单元(SA)所构成的共聚物I：SAmTMAn(其中m及n分别表示SA及TMA的摩尔比例，例如SA8TMA2表示SA及TMA的摩尔比例为8∶2，以下亦使用相同的表示方式)。
依据不同比例将TMA([2-(Methacryloyloxy)ethyl]trimethylammonium chloride solution)与SA(3-Sulfopropyl methacrylate potassium salt)混合且搅拌均匀，接着使单体单元的原料(亦即TMA与SA的混合物)为90wt％，加入交联剂NMBA(N，N-Methylenebisacryl amide，96％，ACROS Co.制)(8wt％)混合搅拌直至均匀后，将起始剂APS(1wt％)加入，于室温下(25℃)使单体与交联剂产生自由基聚合反应，最后再加入催化剂TEMED(N，N，N’，N’-Teramethylethylenediamine，99％)(1wt％)加速聚合反应，将混合溶液取出置入于制备共聚物I的模块中，待反应完全以形成共聚物I。反应时间两小时后，将共聚物II取出并浸入去离子水中且于4℃冰箱中保存，每间隔24小时利用去离子水清洗三次，以确保共聚物I存放于干净的环境。各共聚物I的双离子电荷偏差、二碘甲烷接触角表示于表1。二碘甲烷接触角是以二碘甲烷为测试液体，滴至待测共聚物I的表面，观察其与共聚物I表面的接触角度。当接触角度越大时，表示共聚物I表面较为亲水性；反之，当接触角度变小时，则表示共聚物I表面较呈现疏水性。图1
表示依据本发明实施例一的双离子电荷偏差型血球筛选用材料(共聚物I)的双离子电荷偏差与血小板、红血球及白血球吸附实验结果的条形图。
实施例二：
合成双离子电荷偏差型血球筛选用材料为双离子构造单元(SBMA)以及带电荷构造单元(带正电构造单元(TMA)或带负电构造单元(SA))所构成的共聚物II：SpTMAq(其中p及q分别表示S及TMA的摩尔比例，例如S8TMA2表示SBMA及TMA的摩尔比例为8∶2，以下亦使用相同的表示方式)或SpSAr(其中p及r分别表示S及SA的摩尔比例，例如S8SA2表示SBMA及SA的摩尔比例为8∶2，以下亦使用相同的表示方式)。
依据不同比例将SBMA(2-(Methacryloyloxy)ethyl]dimethyl(3-sulfopropyl)-ammoniumhydroxide)与TMA([2-(Methacryloyloxy)ethyl]trimethylammonium chloride solution)或SA(3-Sulfo propyl methacrylate potassium salt)混合且搅拌均匀，接着使单体单元的原料(亦即SBMA与TMA或SA的混合物)为90wt％，加入交联剂NMBA(8wt％)混合搅拌直至均匀后，将起始剂过硫酸铵APS(1wt％)加入，于室温下(25℃)使单体与交联剂产生自由基聚合反应，最后再加入催化剂TEMED(1wt％)加速聚合反应，将混合溶液取出置入于制备共聚物II的模块中，待反应完全以形成共聚物II。反应时间两小时后，将共聚物II取出并浸入去离子水中且于4℃冰箱中保存，每间隔24小时利用去离子水清洗三次，以确保共聚物II存放于干净的环境。各共聚物II的双离子电荷偏差、二碘甲烷接触角表示于表2。图2表示依据本发明实施例二的双离子电荷偏差型血球筛选用材料(共聚物II)的双离子电荷偏差与血小板、红血球及白血球吸附实验结果的条形图。
血小板吸附实验，是将待测水胶(共聚物I或II)置于24孔培养盘，每格孔盘中加入1mL的PBS后放置37℃烘箱静置一小时。取出PBS溶液，为了消除抗凝血剂反应且利于血小板活化，首先需添加1mM Mg2+和2.5mM Ca2+于含富有血小板的人体血浆溶液(Platelet Rich Plasma，PRP)中。于每格孔盘中加入1mL PRP，于37℃下反应2小时后，以PBS清洗5次，将水胶表面未贴附的血小板洗涤。接着将贴附于水胶表面上的血小板进行固定，于24孔培养盘中分别加入1mL浓度为2.5vol％戊二醛溶液，并静置于4℃冰箱内24小时，再将戊二醛溶液取出后以PBS反复清洗，以冷冻干燥机干燥水胶。待干操后，利用碳胶带将水胶固定于载台上，经由电浆技术于表面上镀一层具导电性的金属，再利用扫描式电子显微镜(SEM)观察血小板贴附于水胶表面的型态。
红血球吸附实验，是将待测水胶(共聚物I或II)置于24孔培养盘，每格孔盘中加入1mL的PBS后放置37℃烘箱静置一小时。取出PBS并于待测水胶中加入1mL的红血球浓厚液，置于37℃内烘箱2小时。将红血球浓厚液吸出并以PBS冲洗清除未吸附的血球后，加入1mL的2.5vol％戊二醛溶液，并静置于4℃冰箱内24小时。最后以共轭焦雷射扫描式电子显微镜(CLSM)进行红血球贴附于水胶表面的影像观察。
白血球吸附实验，是将待测水胶(共聚物I或II)置于24孔培养盘，每格孔盘中加入1mL的PBS后放置37℃烘箱静置一小时。取出PBS并于待测水胶中加入1mL的白血球浓厚液，置于37℃内烘箱2小时。将白血球浓厚液吸出并以PBS冲洗清除未吸附的血球后，加入1mL的2.5vol％戊二醛溶液，并静置于4℃冰箱内24小时。最后以共轭焦雷射扫描式电子显微镜(CLSM)观察白血球贴附于水胶表面的情形。
由上述血小板、红血球及白血球吸附实验结果，可得知合成本发明的双离子电荷偏差型血球筛选用材料时，借由控制双离子电荷偏差，可得到所需的血球筛选特性。表3显示不同的双离子电荷偏差范围，材料具有不同的血球筛选特性，其是将TMA与SA利用电浆诱导表面接枝技术，制备出具有不同SA-TMA bias range的PP fiber薄膜(pore 30um，fiber diameter 2um，thickness 0.5mm)，在支架中放置直径2.5cm的改质完后的薄膜，利用加压的方式过滤5cc人体红血球浓厚液，过滤效果利用血液分析仪(LH780-
LH 780 Hematology Analyzer，Beckman Coulter Co.)检测其过滤的血球含量。表3中，双离子电荷偏差型血球筛选用材料SA2TMA8，进行红血球浓厚液的过滤时，可得到白血球移除率为99.98％，血小板回收率为3.825％，在红血球浓厚液的红血球回收极为有用。
此外，使用双离子电荷偏差型血球筛选用材料S7TMA3(图2中白血球吸附率最大的样品)，进行血小板浓厚液的过滤时，可得到血小板回收率为99.1％，白血球移除率为99.15％，在血小板浓厚液的血小板回收极为有用。
上述实施例仅提供作为例示，在不脱离本发明的意图及范围下可进行各种变形或变更。
综上所述，根据本发明的双离子电荷偏差型血球筛选用材料，可利用作为血球筛选用材料，借由控制带有不同电荷的带电基团之间的距离、分布以及比例，材料本身具有多孔性，自体即为血球筛选用滤材，亦没有进行材料的表面改质处理等处理，符合各种血球分离的需求，但亦可与PP(聚丙烯)纤维或PET等的纤维材料结合，利用作为血球筛选的用途。
以上虽以特定实施例说明本发明，但并不因此限定本发明的范围，只要不脱离本发明的要旨，熟悉本技艺者了解在不脱离本发明的意图及范围下可进行各种变形或变更。另外本发明的任一实施例或申请专利范围不须达成本发明所揭露的全部目的或优点或特点。
[根据细则91更正 07.12.2015]
表1
表1
[根据细则91更正 07.12.2015]
表２
表２
[根据细则91更正 07.12.2015]
表３
表３
Claims (38)
- 一种双离子电荷偏差型血球筛选用材料，其特征在于其是双离子构造单元以及带电荷构造单元所构成的共聚物，其中双离子构造单元至少包括一个带正电基团与一个带负电基团，该带正电基团与该带负电基团的距离为1～5个碳碳键的长度，该带电荷构造单元与该双离子构造单元无规则排列而构成一双离子电荷偏差。
- 根据权利要求1所述的双离子电荷偏差型血球筛选用材料，其特征在于该双离子构造单元是衍生自下列群组之一或以上的基团：具有下述通式的双离子磷基甜菜碱
(R1＝H or CH3；R2＝O or NH；m＝1～5；n＝1～5)、具有下述通式的双离子磺基甜菜碱
(R1＝H or CH3；R2＝O or NH；m＝1～5；n＝1～5)以及具有下述通式的双离子羧基甜菜碱
(R1，＝H or CH3；R2＝O or NH；m＝1～5；n＝1～5)。 - 根据权利要求1所述的双离子电荷偏差型血球筛选用材料，其特征在于该带电荷构造单元包括带正电荷构造单元以及带负电荷构造单元之一或两者。
- 根据权利要求3所述的双离子电荷偏差型血球筛选用材料，其特征在于该带正电荷构造单元是衍生自下列群组之一或以上的基团：具有下述通式的一级胺基单体
(R1＝H or CH3；R2＝O or NH；m＝1～5)、具有下述通式的二级胺基单体
(R1＝H or CH3；R2＝O or NH；R3＝CH3 or CH(CH3)2；m＝1～5)、具有下述通式的三级胺基单体
(R1，＝H or CH3；R2＝O or NH；m＝1～5)以及具有下述通式的四级胺基单体
(R1＝H or CH3；R2＝O or NH；m＝1～5)。 - 根据权利要求3所述的双离子电荷偏差型血球筛选用材料，其特征在于该带负电荷构造单元是衍生自下列群组之一或以上的基团：具有下述通式的硫基单体
(R1＝H or CH3；R2＝O or NH；m＝1～5)以及具有下述通式的羧基单体
(R1＝H or CH3；R2＝O or NH；m＝1～5)。 - 根据权利要求3所述的双离子电荷偏差型血球筛选用材料，其特征在于双离子电荷偏差型血球筛选用材料具有正的电荷偏差范围为5％～34％，该双离子电荷偏差型血球筛选用材料对血小板无活化效果。
- 根据权利要求6所述的双离子电荷偏差型血球筛选用材料，其特征在于对双离子构造单元以及带正电荷构造单元的总和为100摩尔％时，双离子构造单元的摩尔比例为70～90摩尔％，带正电荷构造单元的摩尔比例为30～10摩尔％。
- 根据权利要求3所述的双离子电荷偏差型血球筛选用材料，其特征在于双离子电荷偏差型血球筛选用材料具有正的电荷偏差范围为35％～75％，该双离子电荷偏差型血球筛选用材料对血小板具有活化效果。
- 根据权利要求8所述的双离子电荷偏差型血球筛选用材料，其特征在于对双离子构造单元以及带正电荷构造单元的总和为100摩尔％时，双离子构造单元的摩尔比例为30～60摩尔％，带正电荷构造单元的摩尔比例为70～40摩尔％。
- 根据权利要求3所述的双离子电荷偏差型血球筛选用材料，其特征在于双离子电荷偏差型血球筛选用材料具有负的电荷偏差范围为15％～59％，该双离子电荷偏差型血球筛选用材料对血小板无活化效果。
- 根据权利要求10所述的双离子电荷偏差型血球筛选用材料，其特征在于对双离子构造单元以及带负电荷构造单元的总和为100摩尔％时，双离子构造单元的摩尔比例为51～80摩尔％，带负电荷构造单元的摩尔比例为49～20摩尔％。
- 根据权利要求3所述的双离子电荷偏差型血球筛选用材料，其特征在于双离子电荷偏差型血球筛选用材料具有负的电荷偏差范围为60％～90％，该双离子电荷偏差型血球筛选用材料对血小板具有活化效果。
- 根据权利要求12所述的双离子电荷偏差型血球筛选用材料，其特征在于对双离子构造单元以及带负电荷构造单元的总和为100摩尔％时，双离子构造单元的摩尔比例为30～50摩尔％，带负电荷构造单元的摩尔比例为70～50摩尔％。
- 根据权利要求3所述的双离子电荷偏差型血球筛选用材料，其特征在于双离子电荷偏差型血球筛选用材料具有正的电荷偏差范围为5％～35％，一含有白血球的样品通过该双离子电荷偏差型血球筛选用材料后，样品中的白血球被该双离子电荷偏差型血球筛选用材料过滤捕捉，可達到單位樣品體積中90％以上的白血球捕捉移除率。
- 根据权利要求14所述的双离子电荷偏差型血球筛选用材料，其特征在于对双离子构造单元以及带正电荷构造单元的总和为100摩尔％时，双离子构造单元的摩尔比例为70～90摩尔％，带正电荷构造单元的摩尔比例为30～10摩尔％。
- 根据权利要求1所述的双离子电荷偏差型血球筛选用材料，其特征在于该双离子构造单元中，该带正电基团与该带负电基团的距离为2～4个碳碳键的长度。
- 一种双离子电荷偏差型血球筛选用材料，其特征在于其是带正电构造单元以及带负电构造单元所构成的共聚物，其中该带正电构造单元以及该带负电构造单元无规则排列而构成一双离子电荷偏差。
- 根据权利要求17所述的双离子电荷偏差型血球筛选用材料，其特征在于该带正电荷构造单元是衍生自下列群组之一或两者以上的基团：具有下述通式的一级胺基单体
(R1＝H or CH3；R2＝O or NH；m＝1～5)、具有下述通式的二级胺基单体
(R1＝H or CH3；R2＝O or NH；R3＝CH3 or CH(CH3)2；m＝1～5)、具有下述通式的三级胺基单体
(R1，＝H or CH3；R2＝O or NH；m＝1～5)以及具有下述通式的四级胺基单体
(R1＝H or CH3；R2＝O or NH；m＝1～5)。 - 根据权利要求17所述的双离子电荷偏差型血球筛选用材料，其特征在于该带负电荷构造单元是衍生自下列群组之一或以上的基团：具有下述通式的硫基单体
(R1＝H or CH3；R2＝O or NH；m＝1～5)以及具有下述通式的羧基单体
(R1＝H or CH3；R2＝O or NH；m＝1～5)。 - 根据权利要求17所述的双离子电荷偏差型血球筛选用材料，其特征在于双离子电荷偏差型血球筛选用材料具有正的电荷偏差范围为15％～65％，该双离子电荷偏差型血球筛选用材料对血小板具有活化效果。
- 根据权利要求17所述的双离子电荷偏差型血球筛选用材料，其特征在于双离子电荷偏差型血球筛选用材料具有负的电荷偏差范围为50％～80％，该双离子电荷偏差型血球筛选用材料对血小板无活化效果。
- 根据权利要求17所述的双离子电荷偏差型血球筛选用材料，其特征在于双离子电荷偏差型血球筛选用材料具有正的电荷偏差范围为20％～70％，一含有白血球的样品通过该双离子电荷偏差型血球筛选用材料后，样品中的白血球被该双离子电荷偏差型血球筛选用材料过滤捕捉，可達到單位樣品體積中90％以上的白血球捕捉移除率。
- 根据权利要求1或17所述的双离子电荷偏差型血球筛选用材料，其特征在于其是接枝于聚丙烯纤维，利用作为血球筛选。
- 根据权利要求1所述的双离子电荷偏差型血球筛选用材料，其特征在于该双离子构造单元是衍生自磺基甜菜碱甲基丙烯酸酯。
- 根据权利要求17所述的双离子电荷偏差型血球筛选用材料，其特征在于对带正电构造单元以及带负电构造单元的总和为100摩尔％时，带正电构造单元的摩尔比例为80摩尔％，带负电构造单元的摩尔比例为20摩尔％。
- 根据权利要求1所述的双离子电荷偏差型血球筛选用材料，其特征在于对双离子构造单元以及带正电荷构造单元的总和为100摩尔％时，双离子构造单元的摩尔比例为70摩尔％，带正电荷构造单元的摩尔比例为30摩尔％。
- 根据权利要求1所述的双离子电荷偏差型血球筛选用材料，其特征在于该双离子构造单元衍生自下述式所示的磷基甜菜碱甲基丙烯酸酯
下述式所示的磺基甜菜碱甲基丙烯酸酯
下述式所示的羧基甜菜碱甲基丙烯酸酯
- 根据权利要求3所述的双离子电荷偏差型血球筛选用材料，其特征在于该带正电荷构造单元衍生自具有下述式的甲基丙烯酸2-胺基乙酯
具有下述式的甲基丙烯酸二甲基胺基乙酯
[2-(甲基丙烯酰氧基)乙基]三甲基铵
- 根据权利要求3所述的双离子电荷偏差型血球筛选用材料，其特征在于该带负电荷构造单元是衍生自具有下述式的甲基丙烯酸3-磺基丙酯
具有下述式的甲基丙烯酸2-羧基乙酯
- 一种从血液样品中移除白血球的方法，其特征在于所述的从血液样品中移除白血球的方法是使一血液样品通过如权利要求1或17所述的双离子电荷偏差型血球筛选用材料所制成的一滤材，其中，该滤材的白血球移除率大于95％。
- 根据权利要求30所述的从血液样品中移除白血球的方法，其特征在于所述的从血液样品中移除白血球的方法更包含一固定程序，使如权利要求1或17所述的双离子电荷偏差型血球筛选用材料键结在一基材的表面。
- 根据权利要求31所述的从血液样品中移除白血球的方法，其特征在于所述的固定程序是选自电浆诱导表面接枝反应或物理诱导表面架桥接枝。
- 根据权利要求31所述的从血液样品中移除白血球的方法，其特征在于所述的基材包含聚丙烯纤维和聚酯纤维。
- 根据权利要求30所述的从血液样品中移除白血球的方法，其特征在于所述的血液样品包含全血，红血球浓厚液和血小板浓厚液。
- 根据权利要求30所述的从血液样品中移除白血球的方法，其特征在于所述的如权利要求1的双离子电荷偏差型血球筛选用材料是30摩尔％的[2-(甲基丙烯酰氧基)乙基]三甲基铵和70摩尔％的甲基丙烯酰氧基硫代甜菜碱所构成的共聚物，该共聚物所制成的滤材具有99％以上的白血球移除率。
- 根据权利要求30所述的从血液样品中移除白血球的方法，其特征在于所述的如权利要求17的双离子电荷偏差型血球筛选用材料是60摩尔％的[2-(甲基丙烯酰氧基)乙基]三甲基铵和40摩尔％的甲基丙烯酸3-磺基丙酯所构成的共聚物，该共聚物所制成的滤材具有97％以上的白血球移除率。
- 根据权利要求30所述的从血液样品中移除白血球的方法，其特征在于所述的如权利要求17的双离子电荷偏差型血球筛选用材料是70摩尔％的[2-(甲基丙烯酰氧基)乙基]三甲基铵和30摩尔％的甲基丙烯酸3-磺基丙酯所构成的共聚物，该共聚物所制成的滤材具有95％以上的白血球移除率。
- 根据权利要求30所述的从血液样品中移除白血球的方法，其特征在于所述的如权利要求17的双离子电荷偏差型血球筛选用材料是80摩尔％的[2-(甲基丙烯酰氧基)乙基]三甲基铵和20摩尔％的甲基丙烯酸3-磺基丙酯所构成的共聚物，该共聚物所制成的滤材具有99.9％以上的白血球移除率。
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| CN1735636A (zh) * | 2002-11-07 | 2006-02-15 | 罗地亚化学公司 | 具有两性或两性离子部分的可控结构共聚物 |
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| JP3176753B2 (ja) * | 1992-03-17 | 2001-06-18 | 旭メディカル株式会社 | 血液処理用の吸着材 |
| JP2006505686A (ja) * | 2002-11-07 | 2006-02-16 | ロディア・シミ | 両性又は双極性イオン性部分を含む制御された構造のコポリマー |
| GB0418123D0 (en) * | 2004-08-13 | 2004-09-15 | Asahi Chemical Ind | Polymers useful as medical materials |
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2015
- 2015-03-20 JP JP2017507052A patent/JP6457627B2/ja active Active
- 2015-03-20 WO PCT/CN2015/000192 patent/WO2016149851A1/zh active Application Filing
- 2015-03-20 EP EP15797831.3A patent/EP3095502B1/en active Active
- 2015-03-20 US US14/889,711 patent/US20170096637A1/en not_active Abandoned
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| US5407581A (en) | 1992-03-17 | 1995-04-18 | Asahi Medical Co., Ltd. | Filter medium having a limited surface negative charge for treating a blood material |
| CN1735636A (zh) * | 2002-11-07 | 2006-02-15 | 罗地亚化学公司 | 具有两性或两性离子部分的可控结构共聚物 |
| US20090259015A1 (en) * | 2006-08-07 | 2009-10-15 | Washington, University Of | Mixed charge copolymers and hydrogels |
| CN102905730A (zh) * | 2009-11-06 | 2013-01-30 | 华盛顿大学商业中心 | 两性离子聚合物生物缀合物以及相关的方法 |
| CN102397724A (zh) * | 2010-09-16 | 2012-04-04 | 私立中原大学 | 白血球过滤材料及其过滤方法 |
| US9034932B1 (en) * | 2013-11-14 | 2015-05-19 | Chung Yuan Christian University | Zwitterionic-bias material for blood cell selection |
| CN104623978A (zh) * | 2013-11-14 | 2015-05-20 | 中原大学 | 双离子电荷偏差型血球筛选用材料及从血液样品中移除白血球的方法 |
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Also Published As
| Publication number | Publication date |
|---|---|
| US20170096637A1 (en) | 2017-04-06 |
| EP3095502A4 (en) | 2017-07-05 |
| EP3095502B1 (en) | 2021-01-20 |
| EP3095502A1 (en) | 2016-11-23 |
| JP6457627B2 (ja) | 2019-01-23 |
| JP2017526427A (ja) | 2017-09-14 |
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