WO2017022815A1 - 重合体組成物、物品、メディカルデバイス、物品の製造方法および細胞塊の製造方法 - Google Patents
重合体組成物、物品、メディカルデバイス、物品の製造方法および細胞塊の製造方法 Download PDFInfo
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- A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- C08F216/12—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical by an ether radical
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- C09D133/00—Coating compositions based on homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Coating compositions based on derivatives of such polymers
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- C09D4/00—Coating compositions, e.g. paints, varnishes or lacquers, based on organic non-macromolecular compounds having at least one polymerisable carbon-to-carbon unsaturated bond ; Coating compositions, based on monomers of macromolecular compounds of groups C09D183/00 - C09D183/16
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- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
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- C09D133/00—Coating compositions based on homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Coating compositions based on derivatives of such polymers
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- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/0018—Culture media for cell or tissue culture
Definitions
- the present invention (I) relates to a composition for a medical device, a medical device and a method for producing the same, and in particular, a composition for a medical device capable of imparting excellent lubricity to the surface of the medical device, a medical device having a lubricating surface, and the medical device
- the present invention relates to a device manufacturing method.
- the present invention (II) relates to a cell adhesion inhibitor, a cell culture device, a method for producing the device, and a method for producing a cell mass.
- the present invention (III) relates to a composition for treating a silicone substrate, a silicone substrate, a silicone substrate having a microchannel, and a method for producing a silicone substrate.
- a medical device having a portion that comes into contact with a living body such as a catheter, a tube, an endoscope, an insertion instrument, etc.
- a surface having lubricity is required.
- the conventional surface generally has low lubricity when contacting with a living tissue or the like and poor hydrophilicity, which may cause problems such as deterioration of the medical device due to friction and inflammation of the living body.
- Patent Documents 1 and 2 a method has been proposed in which a functional group is generated on the device surface by performing treatment with ozone or plasma treatment on the device surface and then a hydrophilic polymer is graft-polymerized on the device.
- Patent Documents 1 and 2 a method of coating the surface of a medical device using a urethane resin having a hydrophilic portion has been proposed.
- Adherent cells such as macrophages and fibroblasts are called anchorage-dependent cells because they become active and proliferate only when attached to adherends. This cell adhesion is triggered through a family of proteins (adhesion molecules and proteins) such as vitronectin and fibronectin found in the extracellular matrix. This cell adhesion is a problem in various fields including medical treatment.
- fibroblasts added to the medium adhere to the tissue culture plate via extracellular matrix proteins.
- bacterial cells adhere to the catheter wall.
- platelets adhere to the tip of the catheter. The surface is covered.
- the co-polymer of 2-methacryloyloxyethyl phosphorylcholine and methacrylate ester does not easily cause platelet adhesion, aggregation, and plasma protein adhesion.
- Patent Document 4 the co-polymer of 2-methacryloyloxyethyl phosphorylcholine and methacrylate ester does not easily cause platelet adhesion, aggregation, and plasma protein adhesion.
- Patent Document 5 a copolymer of 2-methacryloyloxyethyl phosphorylcholine and n-butyl (meth) acrylate, methyl (meth) acrylate or styrene is described (Patent Document 5).
- Non-Patent Document 1 Conventionally, as a method for forming a cell mass, a hanging drop method, a swirl culture method, a methylcellulose method, a three-dimensional sphere method, and the like are known.
- microchannel devices have been used for the synthesis, analysis, extraction, separation, etc. of substances due to many advantages such as small variety and variety, high efficiency, and low environmental impact.
- a material for the base material of such a device glass and resin are known.
- a silicone rubber substrate is useful because it is easy to finely process and is excellent in light transmittance and chemical resistance.
- the device is usually provided with a micro flow channel of 0.1 ⁇ m to 1 mm, and movement, reaction, or measurement of liquid, fine particles, gel-like substance, etc. is performed in the flow channel.
- a biological sample such as a blood sample
- measurement and detection of a biological sample can be easily performed in a short time.
- the micro-channel device since the micro-channel device has a narrow channel, there is a problem that the flow velocity tends to decrease when a biological sample or the like adheres to the inner surface of the channel. In addition to the narrowing of the flow path due to the sample components adhering to the inner surface of the flow path, the influence of the loss of reagents and the like on the measured value cannot be ignored. Furthermore, since the silicone rubber base material has low affinity for water, when a liquid containing water is flowed through the flow path, there is a possibility that a desired operation cannot be performed accurately due to poor flowability. Accordingly, it is necessary to attach the sample component to the inner surface of the flow path and to make the flow path surface hydrophilic.
- the end surface is hydrophilic on the metal layer surface of the microchannel. It has been proposed to form a sulfur compound layer having a functional group (Patent Document 6). Further, surface modification of the inner wall of the microchannel with a fluorine-based resin (Patent Document 7) and surface coating treatment with a polymer having polyethylene glycol, eval, poval, or phosphorylcholine group (Patent Document 8) have been proposed. Yes.
- Japanese Patent No. 3131950 JP-A-5-168695 Japanese National Patent Publication No. 11-506375 Japanese Patent No. 2890316 Japanese Patent No. 3434891 JP 2001-252896 A JP 2005-125280 A JP 2008-82961 A
- Patent Documents 1 and 2 are not preferable because they have side effects such as poor durability and reduced mechanical properties of the substrate. Further, the method described in Patent Document 3 has a problem that the peel resistance to the substrate and the lubricity when wet are not sufficient.
- the present invention (I) provides a composition capable of producing a medical device having a surface having sufficient lubricity and excellent durability, a medical device having a modified surface, and a modified surface. It is an object of the present invention to provide a method for manufacturing a medical device.
- Patent Documents 4 to 5 do not always have a sufficient cell adhesion preventing effect.
- Non-Patent Document 1 such studies on various anchorage-dependent cells are still insufficient, and equipment that can form a cell mass almost universally on a fairly wide range of anchorage-dependent cells has not yet been found. It has not been issued.
- the present invention (II) provides a cell adhesion inhibitor having a low cytotoxicity and an excellent cell adhesion prevention effect and equipment having these effects, and also easily produces a cell mass. It is an object of the present invention to provide a culture device and method capable of performing the above.
- the present invention (III) has been made in view of the above problems, and can easily form a silicone substrate having a hydrophilic property and a surface to which a sample component does not easily adhere, and a silicone substrate having a microchannel. It is an object of the present invention to provide a composition and a method for producing the substrate.
- the inventors of the present invention have a composition comprising a polymer having a hydrophilic repeating unit and a repeating unit having a polyoxyalkylene group in a side chain and a specific group at the end of the side chain. According to the present invention, the present inventors have found that the above problems can be solved and completed the present invention.
- a composition for a medical device comprising a polymer having the following repeating unit (A) and the following repeating unit (B).
- the repeating unit (A-1) having a repeating unit (A) having a polyoxyalkylene group in the side chain and having a side chain terminal consisting of a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, side A repeating unit (A-2) having an ammonioalkylphosphate group at the chain end, a repeating unit (A-3) having an amide group at the side chain, and a repeating unit having a heterocycle containing nitrogen and oxygen at the side chain end (A -4), a repeating unit having a lactam in the side chain (A-5), a repeating unit having a betaine group at the end of the side chain (A-6), an anionic repeating unit (A-7), and a cationic repeating
- the repeating unit (A) is a repeating unit (A-1) represented by the following formula (1), a repeating unit (A-2) represented by the following formula (2), or the following formula (3).
- the composition for medical devices according to [1] or [2].
- R 1 represents an alkylene group having 2 to 4 carbon atoms
- R 2 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms
- R 3 represents a hydrogen atom or a methyl group.
- R 4 represents —O—, * — (C ⁇ O) —O—, * — (C ⁇ O) —NR 5 —, * —NR 5 — (C ⁇ O) —
- R 5 represents hydrogen, Represents an atom or an organic group having 1 to 10 carbon atoms, * represents a position bonded to the carbon atom to which R 3 in Formula (1) is bonded) or a phenylene group, and n represents an average value 2 to 100 are indicated.
- R 6 represents a hydrogen atom or a methyl group
- R 7 represents an alkylene group having 2 to 4 carbon atoms
- R 8 represents an alkylene group having 1 to 10 carbon atoms
- R 9 , R 10 and R 11 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms
- q represents an average value of 1 to 10.
- R 12 represents a hydrogen atom or a methyl group
- R 13 and R 14 each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a hydroxyalkyl group.
- R 15 represents a hydrogen atom or a methyl group
- R 16 and R 17 each independently represents an alkylene group having 1 to 3 carbon atoms.
- R 18 represents an alkylene group having 1 to 5 carbon atoms.
- Y represents — (C ⁇ O) O ⁇ , — (O ⁇ S ⁇ O) O ⁇ , —O (O ⁇ S ⁇ O) O ⁇ , — (S ⁇ O) O ⁇ .
- -O (S O) O -
- -OP ( O) (oR 24) O -
- -OP ( O) (R 24) O -
- -P ( O) (oR 24) O - or —P ( ⁇ O) (R 24 ) O 2 —
- R 19 represents a hydrogen atom or a methyl group
- R 20 represents 1 carbon atom.
- R 21 and R 22 each independently represents a hydrocarbon group having 1 to 10 carbon atoms
- R 23 represents a divalent organic group having 1 to 10 carbon atoms. Show. ]
- R 25 represents a hydrogen atom or a methyl group
- R 26 represents —O—, * — (C ⁇ O) —O—, * — (C ⁇ O) —NR 31 —, * —NR 31 — (C ⁇ O) —
- R 31 represents a hydrogen atom or an organic group having 1 to 10 carbon atoms
- * represents a bond to the carbon atom to which R 25 in Formula (8) is bonded.
- R 27 represents a divalent organic group having 1 to 10 carbon atoms
- R 28 , R 29 and R 30 each independently represents a carbon atom having 1 to 10 carbon atoms. Indicates a hydrogen group.
- composition for a medical device according to any one of [1] to [3], wherein the repeating unit (B) is a repeating unit derived from a monomer having an ethylenically unsaturated bond.
- composition for a medical device according to any one of [1] to [4], wherein the repeating unit (B) is represented by the following formula (b2).
- R 32 represents an alkylene group having 2 to 4 carbon atoms
- R 33 represents an alkyl group having 5 to 30 carbon atoms, an alkanoyl group having 5 to 30 carbon atoms, or an alkyl group having 6 to 30 carbon atoms.
- R 34 represents a hydrogen atom or a methyl group
- R 35 represents —O—, ** — (C ⁇ O) —O—, ** — (C ⁇ O) —NR 36 —, **-NR 36 — (C ⁇ O) —
- R 36 represents a hydrogen atom or an organic group having 1 to 10 carbon atoms, and ** represents a carbon atom to which R 34 in formula (b2) is bonded.
- a phenylene group, and m is an average value of 2 to 100.
- the polymer is selected from a repeating unit (C-1) represented by the following formula (c1) and a repeating unit (C-2) having a group represented by the following formula (c2) at the side chain end.
- C-1 represented by the following formula (c1)
- C-2 having a group represented by the following formula (c2) at the side chain end.
- R 37 represents a hydrogen atom or a methyl group
- R 39 represents a hydrocarbon group having 4 to 30 carbon atoms, and represents a phenylene group.
- R 41 represents a divalent organic group having 1 to 10 carbon atoms
- R 42 and R 43 each independently represents an organic group having 1 to 10 carbon atoms
- R 44 , R 45 and R 46 are each independently —OSi (R 49 ) 3 (R 49 is independently a hydrogen atom or an organic group having 1 to 8 carbon atoms) or an organic group having 1 to 10 carbon atoms.
- R represents an average value of 0 to 200.
- composition for a medical device according to any one of [1] to [6], wherein the polymer is water-soluble.
- a medical device having a polymer having the following repeating unit (A) and the following repeating unit (B) on at least a part of the surface.
- a medical device having a crosslinked product of a polymer having the following repeating unit (A) and the following repeating unit (B) on at least a part of the substrate surface.
- A hydrophilic repeating unit (B) having a polyoxyalkylene group in the side chain, the side chain terminal of which is an alkyl group having 5 to 30 carbon atoms, an alkanoyl group having 5 to 30 carbon atoms, or a group having 6 to 30 carbon atoms
- a method for producing a medical device comprising a step of providing a polymer having the following repeating unit (A) and the following repeating unit (B) on at least a part of the surface of the medical device.
- the cell adhesion inhibitor according to [11] which is one or more selected from units (A-8).
- the repeating unit (A) is a repeating unit (A-1) represented by the formula (1), a repeating unit (A-2) represented by the formula (2), or the formula (3).
- the polymer is selected from the repeating unit (C-1) represented by the formula (c1) and the repeating unit (C-2) having a group represented by the formula (c2) at a side chain end.
- the cell adhesion inhibitor according to any one of [11] to [15], further comprising one or more repeating units (C).
- a cell culture device having a polymer having the following repeating unit (A) and the following repeating unit (B) on at least a part of its surface.
- a method for producing a cell culture device comprising a step of providing a polymer having the following repeating unit (A) and the following repeating unit (B) on at least a part of the surface.
- [20] A method for producing a cell mass, wherein cells are cultured with the cell culture equipment according to [18] to form a cell mass.
- a composition for treating a silicone substrate comprising a polymer having the following repeating unit (A) and the following repeating unit (B).
- the repeating unit (A) is a repeating unit (A-1) represented by the formula (1), a repeating unit (A-2) represented by the formula (2), or the formula (3).
- A-1 The composition for treating a silicone substrate according to [22].
- composition for treating a silicone substrate according to any one of [21] to [23], wherein the repeating unit (B) is a repeating unit derived from a monomer having an ethylenically unsaturated bond.
- composition for treating a silicone substrate according to any one of [21] to [24], wherein the repeating unit (B) is represented by the formula (b2).
- the polymer is selected from the repeating unit (C-1) represented by the formula (c1) and the repeating unit (C-2) having a group represented by the formula (c2) at the end of the side chain.
- composition for treating a silicone substrate according to any one of [21] to [26], wherein the polymer is water-soluble.
- a silicone substrate having a microchannel wherein a polymer having the following repeating unit (A) and the following repeating unit (B) is present on at least a part of the substrate surface.
- a method for producing a silicone substrate comprising a step of providing a polymer having the following repeating unit (A) and the following repeating unit (B) on at least a part of the silicone substrate.
- a medical device having excellent lubricity and excellent durability can be easily provided.
- the cell adhesion inhibitor of the present invention (II) has low cytotoxicity and exhibits an excellent cell adhesion prevention effect. Therefore, according to the present invention (II), it is possible to provide a device and an apparatus having a modified surface, in which cells are hard to die and cells are difficult to adhere, and these effects last for a long time. A culture device can be provided. Furthermore, according to the present invention (II), a cell mass can be easily produced.
- the silicone substrate treating composition of the present invention (III) excellent hydrophilicity and sample component adhesion prevention, in particular, biological sample adhesion prevention effect can be imparted to the silicone substrate.
- the polymer contained in the composition exhibits high adsorptivity to the silicone base material and is difficult to peel off, so that the effect can be maintained for a long time. Therefore, the composition for treating a silicone substrate of the present invention (III) is useful as a coating composition for a silicone substrate.
- a silicone substrate that is difficult to adsorb sample components, particularly a biological sample, and that is excellent in sustainability of the effect can be easily produced.
- the polymer composition according to the present invention includes a polymer having the following repeating unit (A) and the following repeating unit (B), a composition for a medical device, and cell adhesion One composition selected from the group consisting of an inhibitor and a composition for treating a silicone substrate.
- a composition composed of only the polymer is also referred to as a composition.
- the present invention (I) relates to a composition for a medical device, and the composition imparts lubricity to the medical device and imparts excellent durability.
- the reason why such an effect is obtained is not necessarily clear, but the polymer is adsorbed on the wall surface of the medical device by the repeating unit (B), and further, the repeating unit (B) and the repeating unit (C),
- the repeating unit (A) and the repeating unit (B) hydrophilize the wall surface and form a thick hydrophilic layer, thereby exhibiting lubricity.
- the present invention (I) not only lubricity but also adsorption of biological substances such as proteins, lipids and nucleic acids can be suppressed.
- the composition for a medical device has the effects described above depending on the specific polymer. Therefore, the polymer can be used as it is as a composition for a medical device, or can be used as a raw material for producing a composition for a medical device.
- the present invention (II) relates to a cell adhesion inhibitor, and such a cell adhesion inhibitor has low cytotoxicity and exhibits an excellent cell adhesion prevention effect. Further, even when the polymer is present on the surface of the cell culture equipment, the cytotoxicity is low, and the polymer provided on the surface of the equipment is not easily peeled off from the equipment. Even so, the cytotoxicity is low. For this reason, the said cell adhesion inhibitor can be used suitably for the apparatus used for cell culture.
- the polymer is adsorbed on the wall surface of the instrument or device by the repeating unit (B), and further, the repeating unit (B) and the repeating unit (C).
- the repeating unit (A) and the repeating unit (B) hydrophilize the wall surface, further prevent adsorption of proteins, lipids, etc., and suppress cell adhesion.
- the polymer can be used as it is as a cell adhesion inhibitor, and can also be used as a material for producing a cell adhesion inhibitor.
- a cell adhesion inhibitor not only cell adhesion but also adsorption of biological substances such as proteins, lipids, and nucleic acids can be suppressed.
- prevention of cell adhesion refers to prevention of adhesion between adherent cells such as anchorage-dependent cells and various (equipment) surfaces that come into contact with such cells.
- Examples of the cells include anchorage-dependent cells and floating cells (for example, blood cells such as leukocytes, erythrocytes, and platelets).
- anchorage-dependent cells include cancer cells such as HeLa cells and F9 cells; fibroblasts such as 3T3 cells; stem cells such as ES cells, iPS cells and mesenchymal stem cells; kidney cells such as HEK293 cells; NT2 cells and the like Neurons; endothelial cells such as UV 2 cells and HMEC-1 cells; cardiomyocytes such as H9c2 cells; epithelial cells such as Caco-2 cells and the like.
- the present invention (III) relates to a composition for treating a silicone substrate.
- the polymer has the following repeating unit (A) and the following repeating unit (B).
- the repeating unit (A) is a hydrophilic repeating unit and is not particularly limited as long as it is a repeating unit other than the repeating unit (B), but has a polyoxyalkylene group in the side chain, and the side chain terminal is a hydrogen atom.
- a repeating unit (A-1) composed of an alkyl group having 1 to 4 carbon atoms, a repeating unit (A-2) having an ammonioalkylphosphate group at the end of the side chain, and a repeating unit having an amide group in the side chain ( A-3), a repeating unit having a heterocycle containing nitrogen and oxygen at the end of the side chain (A-4), a repeating unit having a lactam at the side chain (A-5), a repeating unit having a betaine group at the end of the side chain
- One or more selected from the unit (A-6), the anionic repeating unit (A-7), and the cationic repeating unit (A-8) are preferable.
- a medical device with excellent lubricity can be easily obtained, Since it is possible to easily obtain an instrument or device having a hydrophilic surface, it is possible to easily obtain an instrument or device excellent in cell adhesion prevention, A silicone base material excellent in surface hydrophilicity and sample components, particularly, biological sample adhesion prevention properties can be easily obtained.
- the hydrophilic repeating unit means a repeating unit having a property of having a strong affinity for water.
- a homopolymer having a number average molecular weight of about 10,000 according to the measurement method of the example
- the repeating unit is said to be hydrophilic.
- the repeating unit (A-1) has a polyoxyalkylene group in the side chain, and the side chain terminal is composed of a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
- a repeating unit having a structure represented by the following formula (1 ′) at the side chain end is preferable.
- Examples of the repeating unit having the structure represented by the formula (1 ′) at the end of the side chain include known repeating units. Among them, (meth) acrylate-based repeating units, (meth) acrylamide-based repeating units, styrene-based units These repeating units are preferred. Among these, the repeating unit represented by the following formula (1) is preferable.
- R 1 represents an alkylene group having 2 to 4 carbon atoms
- R 2 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms
- n is an average value of 2 to 100 Indicates.
- R 1 , R 2 and n are as defined in the formula (1 ′), R 3 represents a hydrogen atom or a methyl group, and R 4 represents —O—, * — (C ⁇ O) —O—, * — (C ⁇ O) —NR 5 —, * —NR 5 — (C ⁇ O) — (R 5 represents a hydrogen atom or an organic group having 1 to 10 carbon atoms; Represents a position bonded to the carbon atom to which R 3 in Formula (1) is bonded) or a phenylene group.
- R 1 s may be the same or different, and the plurality of R 1 contained in the repeating unit may be the same or different.
- the other symbols in each structural unit may have the same or different groups having the same symbol contained in the repeating unit. That is, for example, a plurality of R 2 contained in the repeating unit may be the same or different.
- the number of carbon atoms of the alkylene group represented by R 1 is preferably 2 or 3, and more preferably 2.
- the alkylene group represented by R 1 may be linear or branched, and specifically includes ethane-1,2-diyl group, propane-1,2-diyl group, propane-1,3-diyl. Group, propane-2,2-diyl group, butane-1,2-diyl group, butane-1,3-diyl group, butane-1,4-diyl group and the like.
- an ethane-1,2-diyl group is preferable from the viewpoints of availability, lubricity imparting performance, and hydrophilization performance.
- the number of carbon atoms of the alkyl group in R 2 is preferably 1 to 3, more preferably 1 or 2, and even more preferably 1 from the viewpoints of availability, lubricity imparting performance, and hydrophilic performance. It is. Further, the alkyl group represented by R 2 may be linear or branched, and specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl. Group and tert-butyl group. Among such R 2 , a hydrogen atom or an alkyl group having 1 to 3 carbon atoms is preferable from the viewpoint of easy availability, lubricity imparting performance, and hydrophilization performance. An alkyl group is more preferable, a hydrogen atom or a methyl group is more preferable, and a methyl group is particularly preferable.
- Examples of the phenylene group for R 4 include a 1,2-phenylene group, a 1,3-phenylene group, and a 1,4-phenylene group.
- the carbon number of the organic group in R 5 is preferably 1-6.
- Examples of the organic group include a hydrocarbon group.
- Such a hydrocarbon group is a concept including an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, and an aromatic hydrocarbon group.
- the aliphatic hydrocarbon group in R 5 may be linear or branched, and specifically includes a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group.
- Alkyl groups such as tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group and decyl group.
- Alicyclic hydrocarbon groups are roughly classified into monocyclic alicyclic hydrocarbon groups and bridged ring hydrocarbon groups.
- Examples of the monocyclic alicyclic hydrocarbon group include cycloalkyl groups such as a cyclopropyl group and a cyclohexyl group.
- Examples of the bridged ring hydrocarbon group include an isobornyl group.
- aromatic hydrocarbon group examples include aryl groups such as a phenyl group.
- R 4 * — (C ⁇ O) —O— or a phenylene group is preferable, and * — (C ⁇ O) —O— is particularly preferable from the viewpoint of excellent lubricity imparting performance and hydrophilicity performance. .
- n is preferably an average value of 4 to 90, more preferably an average value of 8 to 90, still more preferably an average value of 8 to 60, still more preferably an average value of 8 to 40, Particularly preferred is an average value of 9 to 25.
- Each “average value” in this specification can be measured by NMR.
- 1 H-NMR is measured, and an alkylene group having 2 to 4 carbon atoms in R 1 and a terminal methyl group of an alkyl group having 1 to 4 carbon atoms in R 2 are obtained.
- the average value of n can be calculated by comparing the integrated values of the respective proton peaks.
- Examples of the monomer for deriving such a repeating unit (A-1) include polyethylene glycol (meth) acrylate, polypropylenelene glycol (meth) acrylate, polyethylene glycol polypropylene glycol (meth) acrylate, polyethylene glycol polytetramethylene glycol (meth). Acrylate, polypropylene glycol polytetramethylene glycol (meth) acrylate, methoxypolyethylene glycol (meth) acrylate, ethoxypolyethylene glycol (meth) acrylate, etc. Among these, polyethylene glycol (meth) acrylate, methoxypolyethylene glycol (meth) Acrylate is preferred.
- Examples of the repeating unit (A-1) include repeating units obtained by using these alone or in combination of two or more.
- the repeating unit (A-2) is a repeating unit having an ammonioalkyl phosphate group at the end of the side chain.
- the repeating unit (A-2) a repeating unit represented by the following formula (2) is preferable.
- R 6 represents a hydrogen atom or a methyl group
- R 7 represents an alkylene group having 2 to 4 carbon atoms
- R 8 represents an alkylene group having 1 to 10 carbon atoms
- R 9 , R 10 and R 11 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms
- q represents an average value of 1 to 10.
- the number of carbon atoms of the alkylene group for R 7 is preferably 2 or 3, and more preferably 2.
- the alkylene group for R 7 may be linear or branched, and examples include the same groups as those exemplified for R 1 . Among these, an ethane-1,2-diyl group is preferable from the viewpoints of availability, lubricity imparting performance, and hydrophilization performance. In the case where R 7 is more, R 7 may be the same or different.
- the number of carbon atoms of the alkylene group in R 8 is preferably 1 to 6, more preferably 1 to 4, still more preferably 2 or 3, and particularly preferably 2.
- the alkylene group for R 8 may be linear or branched, and preferred specific examples include the same groups as the alkylene group for R 7 .
- R 9 , R 10 and R 11 are preferably each independently a hydrocarbon group having 1 to 8 carbon atoms.
- the carbon number of such a hydrocarbon group is preferably 1 to 4, more preferably 1 or 2, and particularly preferably 1.
- the hydrocarbon group include an alkyl group; an aryl group such as a phenyl group; an aralkyl group such as a benzyl group; and an alkyl group is preferable.
- the alkyl group may be linear or branched, and preferred specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- A butyl group is mentioned.
- Q is preferably an average value of 1 to 7, more preferably an average value of 1 to 4, and particularly preferably 1.
- the repeating unit (A-2) includes alkali metal ions such as sodium ions and potassium ions, alkaline earth metal ions such as calcium ions and magnesium ions, counter ions such as ammonium ions, hydrogen ions and hydroxide ions. You may have.
- Examples of the monomer for deriving such a repeating unit (A-2) include 2- (meth) acryloyloxyethyl-2 ′-(trimethylammonio) ethyl phosphate (2- (meth) acryloyloxyethyl phosphorylcholine), 3- (Meth) acryloyloxypropyl-2 '-(trimethylammonio) ethyl phosphate, 4- (meth) acryloyloxybutyl-2'-(trimethylammonio) ethyl phosphate, 2- (meth) acryloyloxyethoxyethyl-2 ' -(Trimethylammonio) ethyl phosphate, 2- (meth) acryloyloxydiethoxyethyl-2 '-(trimethylammonio) ethyl phosphate, 2- (meth) acryloyloxyethyl-2'-(triethylammonio) ethyl
- the repeating unit (A-3) is a repeating unit having an amide group in the side chain.
- the repeating unit (A-3) a repeating unit represented by the following formula (3) is preferable.
- R 12 represents a hydrogen atom or a methyl group
- R 13 and R 14 each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a hydroxyalkyl group.
- the number of carbon atoms of the alkyl group in R 13 and R 14 is preferably 1 to 3.
- the alkyl group may be linear or branched, and preferred specific examples include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group.
- the number of carbon atoms of the hydroxyalkyl group in R 13 and R 14 is preferably 1 to 6, more preferably 1 to 3.
- the alkyl group contained in the hydroxyalkyl group may be linear or branched, and preferred specific examples of the hydroxyalkyl group include a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, and a hydroxyisopropyl group.
- the substitution position of the hydroxy group in the hydroxyalkyl group is arbitrary.
- Examples of the monomer for deriving such a repeating unit (A-3) include dimethyl (meth) acrylamide, diethyl (meth) acrylamide, N-isopropyl (meth) acrylamide, N- (hydroxymethyl) (meth) acrylamide, N- (2-hydroxyethyl) (meth) acrylamide and the like.
- the repeating unit (A-3) a repeating unit obtained by using these alone or in combination of two or more thereof can be mentioned.
- the repeating unit (A-4) is a repeating unit having a heterocycle containing nitrogen and oxygen at the end of the side chain.
- the repeating unit (A-4) a repeating unit represented by the following formula (4) is preferable.
- R 15 represents a hydrogen atom or a methyl group
- R 16 and R 17 each independently represents an alkylene group having 1 to 3 carbon atoms.
- the number of carbon atoms of the alkylene group in R 16 and R 17 is preferably 1 to 2.
- the alkylene group may be linear or branched, but is preferably linear.
- Preferable specific examples include methane-1,1-diyl group and ethane-1,2-diyl group.
- Examples of such a monomer that induces the repeating unit (A-4) include 4- (meth) acryloylmorpholine.
- Examples of the repeating unit (A-4) include repeating units obtained by using the above monomers alone or in combination of two or more thereof.
- the repeating unit (A-5) is a repeating unit having a lactam in the side chain.
- a repeating unit represented by the following formula (5) is preferable.
- R 18 represents an alkylene group having 1 to 5 carbon atoms.
- the number of carbon atoms of the alkylene group for R 18 is preferably 3 to 5.
- the alkylene group may be linear or branched, but is preferably linear.
- Preferable specific examples include a propane-1,3-diyl group, a butane-1,4-diyl group, and a pentane-1,5-diyl group.
- Examples of the monomer for deriving such a repeating unit (A-5) include 1-vinyl-2-pyrrolidone and N-vinyl- ⁇ -caprolactam.
- Examples of the repeating unit (A-5) include repeating units obtained by using these alone or in combination of two or more thereof.
- the repeating unit (A-6) is a repeating unit having a betaine group at the end of the side chain.
- the repeating unit (A-6) a repeating unit represented by the following formula (6) is preferable.
- Y represents — (C ⁇ O) O ⁇ , — (O ⁇ S ⁇ O) O ⁇ , —O (O ⁇ S ⁇ O) O ⁇ , — (S ⁇ O) O ⁇ .
- -O (S O) O -
- -OP ( O) (oR 24) O -
- -OP ( O) (R 24) O -
- -P ( O) (oR 24) O - or —P ( ⁇ O) (R 24 ) O 2 —
- R 19 represents a hydrogen atom or a methyl group
- R 20 represents 1 carbon atom.
- R 21 and R 22 each independently represents a hydrocarbon group having 1 to 10 carbon atoms
- R 23 represents a divalent organic group having 1 to 10 carbon atoms. Show. ]
- Y is preferably — (C ⁇ O) O 2 — .
- alkyl group for R 24 include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group.
- the carbon number of the divalent organic group in R 20 and R 23 is preferably 1-8, more preferably 1-6.
- the divalent organic group is preferably a divalent hydrocarbon group, and more preferably a divalent aliphatic hydrocarbon group.
- the divalent aliphatic hydrocarbon group may be linear or branched.
- an alkanediyl group is preferable.
- methane-1,1-diyl group ethane-1,2-diyl group
- propane-1,1-diyl group propane-1,2-diyl group
- propane-1,3-diyl group propane-2
- 2-diyl group butane-1,4-diyl group
- pentane-1,5-diyl group and hexane-1,6-diyl group.
- the carbon number of the hydrocarbon group in R 21 and R 22 is preferably 1 to 6, more preferably 1 to 4.
- Examples of the hydrocarbon group for R 21 and R 22 include an alkyl group; an aryl group such as a phenyl group; an aralkyl group such as a benzyl group; an alkyl group is preferred.
- the alkyl group may be linear or branched, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. It is done.
- the repeating unit (A-6) includes an alkali metal ion such as sodium ion and potassium ion, an alkaline earth metal ion such as calcium ion and magnesium ion, a counter ion such as ammonium ion, hydrogen ion and hydroxide ion. You may have.
- alkali metal ion such as sodium ion and potassium ion
- alkaline earth metal ion such as calcium ion and magnesium ion
- a counter ion such as ammonium ion
- hydrogen ion and hydroxide ion You may have.
- repeating unit (A-6) As the monomer for deriving such a repeating unit (A-6), N- (meth) acryloyloxyethyl-N, N-dimethylammonium- ⁇ -N-methylcarboxybetaine, N- (meth) acryloyloxyethyl- And (meth) acrylate monomers such as N, N-dimethylammonium- ⁇ -N-propylsulfobetaine.
- Examples of the repeating unit (A-6) include repeating units obtained by using these alone or in combination of two or more thereof.
- the repeating unit (A-7) is an anionic repeating unit.
- the repeating unit (A-7) a repeating unit having an acidic group can be mentioned.
- the repeating unit (A-7) is preferably a unit derived from a monomer containing an ethylenically unsaturated bond from the viewpoints of easy introduction and excellent safety.
- Examples of the acidic group include a carboxy group, a sulfo group, a phosphoric acid group, or a salt group thereof, and may include one or two or more of these.
- Examples of the salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salt; organic ammonium salt and the like.
- Monomers for deriving the repeating unit (A-7) include unsaturated dicarboxylic acids such as fumaric acid, maleic acid and itaconic acid or salts thereof; unsaturated carboxylic acids such as (meth) acrylic acid or salts thereof; ethylenesulfonic acid , Sulfo group-containing polymerizable unsaturated monomers such as allyl sulfonic acid, methallyl sulfonic acid, 2-sulfoethyl (meth) acrylate, 2-acrylamido-2-methylpropane sulfonic acid, or salts thereof; 2- (meth) acryloyloxyethyl And phosphoric acid group-containing polymerizable unsaturated monomers such as acid phosphate and 2- (meth) acryloyloxypropyl acid phosphate, or salts thereof.
- unsaturated dicarboxylic acids such as fumaric acid, maleic acid and itaconic acid or salts thereof
- the repeating unit (A-7) is a hydrolyzate of an acrylate ester; a hydrolyzate of an acid anhydride of an unsaturated dicarboxylic acid such as maleic anhydride or itaconic anhydride; glycidyl methacrylate or (4-vinylbenzyl) It can also be obtained using an adduct of an acidic group-containing thiol to an epoxy group such as glycidyl ether. Among these, (meth) acrylic acid is preferable from the viewpoint of easy introduction and excellent reactivity.
- the repeating unit (A-7) a repeating unit obtained by using these alone or in combination of two or more thereof can be mentioned.
- the repeating unit (A-8) is a cationic repeating unit.
- the repeating unit (A-8) a repeating unit represented by the following formula (8) is preferable.
- R 25 represents a hydrogen atom or a methyl group
- R 26 represents —O—, * — (C ⁇ O) —O—, * — (C ⁇ O) —NR 31 —, * —NR 31 — (C ⁇ O) —
- R 31 represents a hydrogen atom or an organic group having 1 to 10 carbon atoms
- * represents a bond to the carbon atom to which R 25 in Formula (8) is bonded.
- R 27 represents a divalent organic group having 1 to 10 carbon atoms
- R 28 , R 29 and R 30 each independently represents a carbon atom having 1 to 10 carbon atoms. Indicates a hydrogen group.
- Examples of the phenylene group for R 26 include a 1,2-phenylene group, a 1,3-phenylene group, and a 1,4-phenylene group.
- the carbon number of the organic group in R 31 is preferably 1-6.
- Examples of the organic group include a hydrocarbon group. Examples of such hydrocarbon groups include the same groups as those exemplified for R 5 .
- the carbon number of the divalent organic group in R 27 is preferably 1 to 8, more preferably 1 to 6.
- the divalent organic group is preferably a divalent hydrocarbon group, and more preferably a divalent aliphatic hydrocarbon group.
- the divalent aliphatic hydrocarbon group may be linear or branched. Examples of the divalent aliphatic hydrocarbon group include the same groups as those exemplified for R 20 and R 23 .
- the carbon number of the hydrocarbon group in R 28 , R 29 and R 30 is preferably 1 to 6, more preferably 1 to 4.
- Examples of the hydrocarbon group for R 28 , R 29 and R 30 include the same groups as those exemplified as the hydrocarbon group for R 9 , R 10 and R 11 .
- the repeating unit (A-8) may have a counter ion.
- Counter ions include halogen ions such as chlorine ion, bromine ion and iodine ion; hydrogen sulfate ion; alkyl sulfate ion such as methyl sulfate ion and ethyl sulfate ion; alkyl sulfonate ion; dodecylbenzene sulfonate ion and paratoluene sulfonate Examples thereof include aryl sulfonate ions such as ions; alkenyl sulfonate ions such as sodium 2-methyl-2-propene-1-sulfonate; carboxylate ions such as acetate ions.
- the monomer for deriving the repeating unit (A-8) include (meth) acrylates and (meth) acrylamides.
- monomer species of (meth) acrylates include ((meth) acryloyloxyethyl) trimethylammonium chloride ((meth) acryloyloxy C 1-10 alkyl) tri-C 1-10 alkylammonium chloride, ((meth) acryloyl) ((Meth) acryloyloxy C 1-10 alkyl) diC 1-10 alkyl C 6-10 aralkylammonium chloride such as oxyethyl) dimethylbenzylammonium chloride.
- Examples of monomer species of (meth) acrylamides include (3- (meth) acrylamide C 1-10 alkyl) tri-C 1-10 alkyl ammonium chloride such as (3- (meth) acrylamidopropyl) trimethylammonium chloride, (3- And (3- (meth) acrylamide C 1-10 alkyl) diC 1-10 alkyl C 6-10 aralkyl ammonium chloride such as (meth) acrylamidopropyl) dimethylbenzylammonium chloride.
- (3- (meth) acrylamidopropyl) trimethylammonium chloride is preferable from the viewpoint of easy introduction and excellent reactivity.
- Examples of the repeating unit (A-8) include repeating units obtained by using these alone or in combination of two or more thereof.
- the repeating unit (A-1) is preferable from the viewpoint of excellent lubricity imparting performance, hydrophilization performance, cell adhesion prevention performance, and biological sample adhesion prevention performance.
- the repeating unit (A-2), the repeating unit (A-3), the repeating unit (A-4), and the repeating unit (A-6) are preferable.
- the repeating unit (A-1) and the repeating unit (A-2) are preferable.
- the repeating unit (A-3) and the repeating unit (A-6) are more preferable.
- repeating unit (A) As the repeating unit (A), the following (i) to (ii) are preferable from the viewpoint of better lubricity, hydrophilization performance, cell adhesion prevention performance and biological sample adhesion prevention performance, and (ii) Is particularly preferred.
- the total content of the repeating unit (A) is preferably 2.5 to 95% by mass, more preferably 5 to 95% by mass, and further preferably 20 to 95% by mass with respect to all the repeating units of the polymer. 30 to 95% by mass is more preferable, and 40 to 90% by mass is particularly preferable.
- the content of the repeating unit (A) can be measured by 1 H-NMR, 13 C-NMR or the like.
- the repeating unit (B) has a polyoxyalkylene group in the side chain, and the end of the side chain is an alkyl group having 5 to 30 carbon atoms, an alkanoyl group having 5 to 30 carbon atoms, or an aryl group having 6 to 30 carbon atoms.
- the polymer is a repeating unit constituted, and the polymer may have one or more repeating units corresponding to the repeating unit (B).
- the adhesion of the polymer to a medical device, a device, an apparatus, and a silicone substrate is increased, and the interaction with the repeating unit (A) is increased.
- Medical devices with excellent lubricity medical devices with excellent durability (continuity of lubricity), especially medical devices with excellent durability of lubricity even under friction that may occur when using medical devices, can be easily obtained, Instruments and devices excellent in surface hydrophilicity and cell adhesion prevention effect, and further, cell culture equipment excellent in durability of this effect can be easily obtained, A silicone base material excellent in surface hydrophilicity and sample components, particularly a biological sample adhesion preventing property, and a silicone base material excellent in sustainability of this effect can be easily obtained.
- Such a repeating unit (B) is preferably a repeating unit derived from a monomer having an ethylenically unsaturated bond from the viewpoint of easiness of synthesis and the like, and has a structure represented by the following formula (b1).
- a repeating unit at the chain end is preferred.
- Examples of the repeating unit having a structure represented by the formula (b1) at the end of the side chain include known repeating units. Among them, a (meth) acrylate-based repeating unit, a (meth) acrylamide-based repeating unit, a styrene-based repeating unit, and the like. Repeating units are preferred. Among these, the repeating unit represented by the following formula (b2) is preferable.
- R 32 represents an alkylene group having 2 to 4 carbon atoms
- R 33 represents an alkyl group having 5 to 30 carbon atoms, an alkanoyl group having 5 to 30 carbon atoms, or an alkyl group having 6 to 30 carbon atoms.
- m represents an average value of 2 to 100.
- R 32 , R 33 and m are as defined in the formula (b1), R 34 represents a hydrogen atom or a methyl group, and R 35 represents —O—, **-(C ⁇ O) —O—, **-(C ⁇ O) —NR 36 —, **-NR 36 — (C ⁇ O) — (R 36 represents a hydrogen atom or an organic group having 1 to 10 carbon atoms) , ** represents a position bonded to the carbon atom to which R 34 in formula (b2) is bonded) or a phenylene group.
- the number of carbon atoms of the alkylene group in R 32 is preferably 2 or 3, and more preferably 2.
- the alkylene group represented by R 32 may be linear or branched, and specifically includes an ethane-1,2-diyl group, a propane-1,2-diyl group, a propane-1,3-diyl group, Examples include propane-2,2-diyl group, butane-1,2-diyl group, butane-1,3-diyl group, butane-1,4-diyl group. Among these, an ethane-1,2-diyl group is preferable from the viewpoint of availability.
- the m R 32 may be the same or different.
- the number of carbon atoms of the alkyl group and alkanoyl group in R 33 is preferably 6 to 25, more preferably 7 to 20, still more preferably 8 to 18, and still more preferably from the viewpoint of availability. 9 to 18, particularly preferably 10 to 18.
- the alkyl group in R 33 may be linear or branched, and specific examples include 2-ethylhexyl group, octyl group, decyl group, lauryl group, palmityl group, stearyl group and the like. Among these, 2-ethylhexyl group, lauryl group and stearyl group are preferable, and lauryl group and stearyl group are more preferable. Further, examples of the alkanoyl group for R 33 include a 2-ethylhexanoyl group, a lauroyl group, and a stearoyl group.
- the carbon number of the aryl group in R 33 is preferably 6-12. Specific examples include a phenyl group.
- the aryl group may have an alkyl group having 1 to 24 carbon atoms as a substituent. Such an alkyl group preferably has 3 to 24 carbon atoms, more preferably 5 to 16 carbon atoms.
- the substituted position and the number of substitution of such a substituted alkyl group are arbitrary, the suitable number of substitution is 1 or 2.
- An example of such an aryl group having an alkyl group having 1 to 24 carbon atoms as a substituent is a nonylphenyl group.
- an alkyl group having 5 to 30 carbon atoms and an aryl group having 6 to 30 carbon atoms are preferable, and an alkyl group having 5 to 30 carbon atoms is more preferable from the viewpoint of availability.
- Examples of the phenylene group for R 35 include a 1,2-phenylene group, a 1,3-phenylene group, and a 1,4-phenylene group.
- the carbon number of the organic group in R 36 is preferably 1-6.
- Examples of the organic group include a hydrocarbon group. Examples of such a hydrocarbon group include the same groups as the hydrocarbon group exemplified for R 5 .
- R 35 **-(C ⁇ O) —O— or a phenylene group is preferable, and **-(C ⁇ O) —O— is particularly preferable.
- M is preferably an average value of 2 to 90, more preferably an average value of 4 to 90, still more preferably an average value of 9 to 60, and particularly preferably an average value of 10 to 40.
- Examples of the monomer for deriving such a repeating unit (B) include 2-ethylhexyl polyethylene glycol (meth) acrylate, lauroxy polyethylene glycol (meth) acrylate, stearoxy polyethylene glycol (meth) acrylate, and phenoxy polyethylene glycol (meth) acrylate. , Phenoxypolypropylene glycol (meth) acrylate, nonylphenoxypolypropylene glycol (meth) acrylate, 2-ethylhexyl polyethylene glycol polypropylenelene glycol (meth) acrylate, nonylphenoxypolyethylene glycol polypropylenelene glycol (meth) acrylate, and the like. , Lauroxy polyethylene glycol (meth) acrylate, stearoxy Polyethylene glycol (meth) acrylate.
- Examples of the repeating unit (B) include repeating units obtained by using these alone or in combination of two or more thereof.
- the total content of the repeating unit (B) is preferably 2.5 to 95% by mass, more preferably 2.5 to 80% by mass, and more preferably 5 to 70% by mass with respect to all the repeating units of the polymer. Is more preferable, and 5 to 60% by mass is particularly preferable.
- the hydrophilization performance and the cell adhesion prevention performance are excellent from the viewpoints of providing lubricity and exfoliation resistance to a medical device. Excellent sample adhesion prevention performance.
- what is necessary is just to measure content of a repeating unit (B) similarly to content of a repeating unit (A).
- the polymer is selected from a repeating unit (C-1) represented by the following formula (c1) and a repeating unit (C-2) having a group represented by the following formula (c2) at the end of the side chain. It is preferable to contain a repeating unit (C) of more than seeds.
- a repeating unit (C) By providing the polymer with such a repeating unit (C), The peel resistance of the polymer to the medical device is further enhanced, and the lubricity imparting effect is further improved.
- the adsorption power of the polymer to the equipment is further strengthened, and the hydrophilization performance and cell adhesion prevention performance are further improved.
- the adsorptive power of the polymer to the silicone substrate is further increased, and the hydrophilization performance and biological sample adhesion prevention performance are further improved.
- the repeating unit (C-1) is a repeating unit represented by the following formula (c1).
- R 37 represents a hydrogen atom or a methyl group
- R 39 represents a hydrocarbon group having 4 to 30 carbon atoms, and represents a phenylene group.
- Examples of the phenylene group for R 38 include a 1,2-phenylene group, a 1,3-phenylene group, and a 1,4-phenylene group.
- the carbon number of the organic group in R 40 is preferably 1-6.
- the organic group include a hydrocarbon group.
- Examples of such a hydrocarbon group include the same groups as the hydrocarbon group exemplified for R 5 .
- the hydrocarbon group for R 39 may be either linear or branched, and may contain a ring structure, but is preferably an alkyl group.
- the number of carbon atoms of the hydrocarbon group in R 39 is preferably 6 to 24 from the viewpoints of excellent lubricity, peeling resistance to medical devices, hydrophilicity, cell adhesion prevention and biological sample adhesion prevention. More preferably, it is 8 to 18, more preferably 8 to 14, and particularly preferably 10 to 14.
- Examples of the alkyl group include 2-ethylhexyl group, octyl group, decyl group, lauryl group, palmityl group, stearyl group and the like.
- 2-ethylhexyl group, lauryl group, and stearyl group are preferable, and 2-ethylhexyl group and lauryl group are more preferable from the viewpoints of availability, antifouling property, and the like.
- Examples of the monomer for deriving such a repeating unit (C-1) include 2-ethylhexyl (meth) acrylate, lauryl (meth) acrylate, stearyl (meth) acrylate, N-dodecyl (meth) acrylamide and the like.
- Examples of the repeating unit (C-1) include repeating units obtained by using these alone or in combination of two or more thereof.
- the repeating unit (C-2) is a repeating unit having a group represented by the following formula (c2) at the end of the side chain.
- Examples of the repeating unit having a group represented by the formula (c2) at the side chain terminal include known repeating units. Among them, a (meth) acrylate-based repeating unit, a (meth) acrylamide-based repeating unit, a styrene-based repeating unit, and the like. Repeating units are preferred. Among these, the repeating unit represented by the following formula (c3) is preferable.
- R 41 represents a divalent organic group having 1 to 10 carbon atoms
- R 42 and R 43 each independently represents an organic group having 1 to 10 carbon atoms
- R 44 , R 45 and R 46 are each independently —OSi (R 49 ) 3 (R 49 is independently a hydrogen atom or an organic group having 1 to 8 carbon atoms) or an organic group having 1 to 10 carbon atoms.
- R represents an average value of 0 to 200.
- R 47 represents a hydrogen atom or a methyl group
- R 48 represents —O—, * — (C ⁇ O) —O—, * — (C ⁇ O) —NR 50 —, * —NR 50 — (C ⁇ O) —
- R 50 represents a hydrogen atom or an organic group having 1 to 10 carbon atoms, and * represents a bond to the carbon atom to which R 47 in formula (c3) is bonded.
- R 50 represents a hydrogen atom or an organic group having 1 to 10 carbon atoms
- * represents a bond to the carbon atom to which R 47 in formula (c3) is bonded.
- other symbols are the same as those in formula (c2).
- the number of carbon atoms of the divalent organic group in R 41 is preferably 2 to 8, more preferably 2 to 6, and still more preferably 2 to 4.
- Examples of the divalent organic group include a divalent hydrocarbon group.
- the divalent hydrocarbon group is preferably a divalent aliphatic hydrocarbon group, which may be linear or branched, and more preferably an alkanediyl group. Specific examples of such alkanediyl groups include ethane-1,2-diyl group, propane-1,2-diyl group, propane-1,3-diyl group, propane-2,2-diyl group, butane. Examples include -1,2-diyl group, butane-1,3-diyl group, and butane-1,4-diyl group.
- the carbon number of the organic group in R 42 and R 43 is preferably 1 to 6, more preferably 1 to 4, and further preferably 1 or 2.
- Examples of the organic group include a hydrocarbon group.
- the hydrocarbon group may be linear or branched, but is preferably an alkyl group. Specific examples of such an alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, and tert-butyl group.
- R 42 may be the same or different
- R 43 may be the same or different.
- the carbon number of the organic group in R 44 , R 45 and R 46 is preferably 1 to 6, more preferably 1 to 4, and still more preferably 1 or 2. Further, examples of the organic group for R 44 , R 45 , R 46 and R 49 include the same groups as the organic groups for R 42 and R 43 .
- R 44 , R 45, and R 46 are preferably —OSi (R 49 ) 3 from the viewpoints of providing lubricity, exfoliation resistance to a medical device, and excellent hydrophilization performance.
- R 49 an organic group having 1 to 8 carbon atoms is preferable from the viewpoints of providing lubricity, exfoliation resistance to a medical device, and excellent hydrophilization performance, and the carbon number is more preferably 1 Is 6, more preferably 1 to 4, and particularly preferably 1 or 2.
- r is preferably an average value of 0 to 100, more preferably an average value of 0 to 50, and an average value of 0 to 25. Is more preferable, and an average value of 0 to 10 is particularly preferable.
- R 48 is the same as R 38 and R 50 is the same as R 40 .
- Examples of the monomer for deriving such a repeating unit (C-2) include 3- [tris (trimethylsiloxy) silyl] propyl (meth) acrylate, 3- [bis (trimethylsiloxy) (methyl) (meth) acrylate. Silyl] propyl, silicone (meth) acrylate (X-22-2475 (manufactured by Shin-Etsu Silicone), FM-0711 (manufactured by JNC), etc.) and the like.
- Examples of the repeating unit (C-2) include repeating units obtained by using these alone or in combination of two or more thereof.
- repeating units (C-1) to (C-2) from the viewpoint of excellent lubricity imparting performance, peel resistance to medical devices, hydrophilization performance, cell adhesion prevention performance and biological sample adhesion prevention performance, etc.
- R 38 is ***-(C ⁇ O) —NH— and a repeating unit represented by the formula (c3) are preferable.
- the total content of the repeating unit (C) is the total repeating unit of the polymer from the viewpoints of excellent lubricity, peeling resistance to medical devices, hydrophilization performance, cell adhesion prevention performance and biological sample adhesion prevention performance. Is preferably 40% by mass or less, more preferably 0.1 to 30% by mass, still more preferably 0.5 to 20% by mass, and particularly preferably 1.0 to 10% by mass. In addition, what is necessary is just to measure content of a repeating unit (C) similarly to content of a repeating unit (A).
- the polymer used in the present invention (I) may be crosslinked using a crosslinking agent.
- the repeating units (A) to (C) do not have a reactive functional group that reacts with a crosslinking agent, or when the reactivity is weak and the crosslinking reaction does not proceed sufficiently
- the polymer used in the present invention (I) Contains a repeating unit (D) having a reactive functional group in the side chain as another repeating unit other than the repeating units (A) to (C), as long as the effects of the present invention (I) are not impaired. May be.
- the polymer comprises a repeating unit (D) and the polymer is cross-linked on the medical device, so that the peel resistance of the polymer (cross-linked product) to the medical device is further enhanced and excellent lubricity. The imparting effect lasts longer.
- the reactive functional group is not particularly limited, but a carboxy group or a hydroxy group that can be contained in the repeating units (A) to (C) when the reactive functional group contained in the repeating unit (D) is crosslinked. It is preferable to select a reactive functional group having a high selectivity such that functional groups such as these do not react simultaneously.
- a preferred reactive functional group depends on what is selected as the repeating units (A) to (C). For example, an epoxy group, a carboxyl group, a hydroxyl group, an acid anhydride group, a ketone group, an aldehyde group, An isocyanate group, an ethylenically unsaturated group, etc. are mentioned. Among these, as a reactive functional group, an epoxy group, a ketone group, and an ethylenically unsaturated group are preferable from the viewpoint of ease of introduction and reactivity.
- the repeating unit (D) can be introduced using a monomer having the reactive functional group. These reactive functional groups may be present alone or in combination of two or more in the monomer.
- the monomer for deriving the repeating unit (D) include monomers having an epoxy group in the molecule such as glycidyl (meth) acrylate, methyl glycidyl methacrylate, and allyl glycidyl ether; maleic anhydride, itaconic anhydride , Monomers having acid anhydride groups such as citraconic anhydride in the molecule; monomers having ketone groups in the molecule such as diacetone acrylamide and acetoacetoxyethyl (meth) acrylate; (meth) acrylaldehyde, croton Monomers having an aldehyde group in the molecule such as aldehyde, acrolein, methacrolein; (meth) acryloyloxymethyl isocyanate, (meth) acryloyloxyethyl isocyanate, (meth) acryloyloxypropyl isocyanate, (meth) acryloloxy
- the repeating unit (D) can be introduced alone or in combination of two or more.
- glycidyl (meth) acrylate, diacetone acrylamide, and acetoacetoxyethyl methacrylate are preferable from the viewpoint of ease of introduction and reactivity.
- the mass ratio of the repeating unit (A) and the repeating unit (B) contained in the polymer [(A) :( B)] includes lubricity imparting performance, resistance to peeling against medical devices, hydrophilization performance, cells From the standpoint of excellent adhesion prevention performance and biological sample adhesion prevention performance, 20:80 to 95: 5 is preferable, 30:70 to 95: 5 is more preferable, 40:60 to 95: 5 is still more preferable, and 50: 50 to 95: 5 is more preferable, and 55:45 to 95: 5 is particularly preferable.
- the mass ratio [((A) + (B)) :( C)] is as follows: lubricity imparting performance, peel resistance to medical devices, hydrophilization performance, cell 60:40 to 99: 1 is preferable, and 70:30 to 99: 1 is preferable from the viewpoint of obtaining a cell culture device or a silicone base material having excellent adhesion prevention performance and biological sample adhesion prevention performance and excellent transparency. More preferably, 75:25 to 99: 1 is still more preferable, 80:20 to 99: 1 is still more preferable, and 85:15 to 99: 1 is particularly preferable.
- the mass ratio [(A) :( B)] is in the range of the mass ratio [(A) :( B)], and the mass ratio [((A) + (B)) :( C)]. Is in the range of the mass ratio [((A) + (B)) :( C)].
- the ratio of the repeating unit (A), the repeating unit (B), the repeating unit (C), and the repeating unit (D) is not particularly limited.
- the mass ratio ((A) + (B) + (C)) :( D) is preferably 50:50 to 99: 1, more preferably 80 : 20 to 99: 1, more preferably 90:10 to 98: 2.
- the polymer may be a copolymer, and may be a block copolymer, a random copolymer, or an alternating copolymer.
- the lower limit of the weight average molecular weight (Mw) of the polymer is preferably 3,000, more preferably 5,000, still more preferably 8,000, particularly preferably 10,000, and the upper limit thereof is preferably 10 million. More preferably, it is 5 million, more preferably 3 million, particularly preferably 2 million.
- Mw weight average molecular weight
- lubricity imparting effect, cell adhesion prevention performance, biological sample adhesion prevention performance, peeling resistance to medical devices, adsorption to equipment, adsorption to silicone substrate and handling Improves.
- the lower limit of the number average molecular weight (Mn) of the polymer is preferably 2,000, more preferably 3,000, still more preferably 5,000, more preferably 8,000, particularly preferably 10,000, and the upper limit thereof. Is preferably 10 million, more preferably 5 million, still more preferably 3 million, more preferably 2 million, and particularly preferably 500,000.
- the molecular weight distribution (Mw / Mn) is preferably 1 to 10, more preferably 1 to 7, and particularly preferably 1 to 5. In addition, what is necessary is just to measure the said weight average molecular weight, number average molecular weight, and molecular weight distribution according to the method as described in the Example mentioned later.
- the polymer is preferably water-soluble. Because the polymer is water soluble, Without sacrificing the characteristics of the medical device, it is possible to easily produce a medical device with excellent lubricity, Without damaging the characteristics of the equipment, it is possible to easily produce cell culture equipment and the like having excellent surface hydrophilicity and cell adhesion prevention, Without impairing the properties of the silicone substrate, it is possible to easily produce a silicone substrate that is excellent in surface hydrophilicity and biological sample adhesion prevention.
- the water-soluble polymer means a visually transparent solution when the polymer is added to water (25 ° C.) and mixed so that the polymer concentration is 0.5% by mass. It means that it is obtained.
- the polymer is, for example, mixed with monomers that induce each repeating unit, and the mixture is dissolved in a solvent such as water, acetonitrile, or t-butyl alcohol, if necessary, and a polymerization initiator is added to perform radical polymerization. Can be obtained.
- the polymerization initiator used for carrying out the radical polymerization is not particularly limited as long as it is a normal radical polymerization initiator.
- the amount of the polymerization initiator charged is preferably 0.001 to 10 parts by mass, more preferably 0.01 to 5 parts by mass with respect to 100 parts by mass of the monomer component.
- the polymerization temperature is preferably 20 to 100 ° C., and the polymerization time is preferably 0.5 to 48 hours.
- the medical device composition and the silicone substrate treating composition are not particularly limited as long as they contain the polymer, but usually contain other components other than the polymer such as a solvent. Moreover, the said cell adhesion inhibitor will not be restrict
- the content of the polymer in the composition is preferably 0.001 to 20% by mass, more preferably 0.01 to 10% by mass, and still more preferably 0.01 to 5% by mass.
- the content of the polymer is in the above range, It is easy to obtain a medical device that is excellent in lubricity and maintains its effect. Cell culture equipment with excellent hydrophilization performance and cell adhesion prevention performance and low cytotoxicity can be easily obtained. It is excellent in hydrophilization performance and biological sample adhesion prevention, and furthermore, a silicone substrate, particularly a silicone substrate having a microchannel can be easily treated.
- Examples of the other components include solvents, surfactants, isotonic agents, chelating agents, pH adjusters, buffers, thickeners, stabilizers, proteolytic enzymes, pharmacologically active ingredients, physiologically active ingredients, Various additives described in Pharmaceutical Additives Encyclopedia 2007 (edited by Japan Pharmaceutical Additives Association) may be included as long as the effects of the present invention are not impaired. These may contain 1 type independently and may contain 2 or more types.
- the solvent examples include water; various buffer aqueous solutions such as phosphate buffer, glycine buffer, Good buffer, Tris buffer, and ammonia buffer.
- the surfactant examples include amphoteric surfactants such as alkyldiaminoethylglycine or a salt thereof (for example, hydrochloride); cationic surfactants such as benzalkonium chloride and benzethonium chloride; alkylbenzene sulfonate and alkyl sulfate And anionic surfactants such as salts, polyoxyethylene alkyl sulfates, aliphatic ⁇ -sulfomethyl esters and ⁇ -olefin sulfonic acids.
- amphoteric surfactants such as alkyldiaminoethylglycine or a salt thereof (for example, hydrochloride)
- cationic surfactants such as benzalkonium chloride and benzethonium chloride
- anionic surfactants such as salts, polyoxyethylene alkyl sulfates,
- tonicity agent examples include disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate.
- chelating agent examples include salts of ethylenediaminetetraacetic acid such as ethylenediaminetetraacetic acid (EDTA), ethylenediaminetetraacetic acid.2 sodium (EDTA.2Na), ethylenediaminetetraacetic acid.3 sodium (EDTA.3Na), citric acid, and gluconic acid. , Tartaric acid, salts thereof (for example, sodium salt) and the like.
- EDTA ethylenediaminetetraacetic acid
- EDTA.2Na ethylenediaminetetraacetic acid.2 sodium
- EDTA.3Na ethylenediaminetetraacetic acid.3 sodium
- citric acid and gluconic acid.
- Tartaric acid Tartaric acid, salts thereof (for example, sodium salt) and the like.
- Examples of the pH adjuster include hydrochloric acid, boric acid, epsilon-aminocaproic acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, borax, and triethanol.
- Examples include amine, monoethanolamine, diisopropanolamine, sulfuric acid, phosphoric acid, polyphosphoric acid, propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, gluconolactone, and ammonium acetate.
- the pH adjuster may be used by adjusting so that the pH value of the solution is about 4.0 to 9.0, preferably about 6.0 to 8.0, and more preferably around 7.0.
- buffer examples include citric acid, malic acid, lactic acid, ascorbic acid, maleic acid, gluconic acid, phosphoric acid, boric acid, oxycarboxylic acid, glycine, glutamic acid and other amino acids, tris (hydroxymethyl) aminomethane (Tris) And acids such as salts thereof (for example, sodium salts), good buffer containing taurine and derivatives thereof, and hydroxyalkylamines such as bis (2-hydroxyethyl) iminotris (hydroxymethyl) methane (Bis-tris). .
- thickener and stabilizer examples include synthetic organic polymer compounds such as polyvinyl alcohol, poly-N-vinyl pyrrolidone, polyethylene glycol, polypropylene glycol and polyacrylamide, and celluloses such as hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Derivatives, starch derivatives such as sodium carboxymethyl starch and hydroxyethyl starch, chondroitin sulfate, hyaluronate and the like.
- proteolytic enzymes examples include proteases derived from living bodies such as papain, bromelain, ficin, trypsin, chymotrypsin, pancreatin and the like.
- the composition for a medical device is a polyfunctional compound capable of reacting with a functional group contained in the repeating units (A) to (C) or a reactive functional group of the repeating unit (D).
- the crosslinking agent and polymerization initiator may be included.
- the polyfunctional compound include polyols, polyfunctional amines, polyfunctional thiols, polyfunctional isocyanates, hydrazide compounds, and polyfunctional ethylenically unsaturated compounds. Of these, one type may be used alone, or two or more types may be used.
- polyol examples include divalent alcohols having 2 to 20 carbon atoms (aliphatic diols such as ethylene glycol, propylene glycol, 1,3- or 1,4-butanediol, 1,6-hexanediol, and neopentyl.
- divalent alcohols having 2 to 20 carbon atoms aliphatic diols such as ethylene glycol, propylene glycol, 1,3- or 1,4-butanediol, 1,6-hexanediol, and neopentyl.
- Alkylene glycols such as glycol] alicyclic diols (eg, cycloalkylene glycols such as cyclohexanediol and cyclohexanedimethanol)); trihydric alcohols having 3 to 20 carbon atoms (aliphatic triols such as glycerin, trimethylolpropane, Alkanetriols such as trimethylolethane and hexanetriol); polyhydric alcohols having 4 to 8 or more carbon atoms having 5 to 20 carbon atoms (aliphatic polyols, such as pentaerythritol, sorbitol, mannitol, sorbitan, diglycerin, dipe Data alkane polyols erythritol, etc.], an intramolecular or intermolecular dehydration products of alkane triol or alkane polyols, sugars and their derivatives [e.g. sucrose, glucose, mannose, fructose
- polyfunctional amine examples include ethylenediamine, propylenediamine, hexamethylenediamine, dialkylenetriamine, trialkylenetetramine, tetraalkylenepentamine, pentaalkylenehexamine, and hexaalkyleneheptamine.
- polyfunctional thiol examples include ethylenedithiol, 1,6-hexanedithiol, and 3,6-dioxa-1,8-octanedithiol.
- polyfunctional isocyanate examples include 1,6-hexamethylene diisocyanate, 2,2,4-trimethylhexamethylene diisocyanate, lysine diisocyanate, isophorone diisocyanate, 4,4′-dicyclohexylmethane diisocyanate, 1,4-cyclohexane diisocyanate, Mention may be made of norbornane diisocyanate, 1,3- or 1,4-phenylene diisocyanate, 2,4- or 2,6-tolylene diisocyanate, 2,4′- or 4,4′-diphenylmethane diisocyanate.
- hydrazide compound examples include oxalic acid dihydrazide, malonic acid dihydrazide, succinic acid dihydrazide, glutaric acid dihydrazide, adipic acid dihydrazide, sebacic acid dihydrazide, phthalic acid dihydrazide, isophthalic acid dihydrazide, terephthalic acid dihydrazide, maleic acid dihydrazide Dihydrazide, itaconic acid dihydrazide, citric acid trihydrazide, nitriloacetic acid trihydrazide, cyclohexanetricarboxylic acid trihydrazide, ethylenediaminetetraacetic acid tetrahydrazide, ethylene-1,2-dihydrazine, propylene-1,2-dihydrazine, propylene-1, 3-dihydrazine, butylene-1,2-dihydrazine, butylene-1,3-dihydra
- polyfunctional ethylenically unsaturated compound examples include ethylene glycol di (meth) acrylate, diethylene glycol di (meth) acrylate, triethylene glycol di (meth) acrylate, polyethylene glycol di (meth) acrylate, and 1,3-butylene.
- a polymerization initiator When a compound having an ethylenically unsaturated group is contained in the medical device composition, a polymerization initiator may be used, and a known photopolymerization initiator or thermal polymerization initiator is used as the polymerization initiator. can do.
- a polymerization initiator may be used individually by 1 type, and may use 2 or more types.
- photopolymerization initiator examples include thioxanthone compounds, acetophenone compounds, benzyl compounds, biimidazole compounds, triazine compounds, O-acyloxime compounds, onium salt compounds, benzoin compounds, benzophenone compounds, ⁇ -diketone compounds, polynuclear quinone compounds, A diazo compound, an imide sulfonate compound, etc. can be mentioned.
- thermal polymerization initiator examples include the same initiators as the radical polymerization initiator that may be used when the polymer is synthesized.
- the medical device is not particularly limited as long as it is a medical device, and specific examples include, for example, a blood bag, a urine collection bag, a blood transfusion set, a suture, a drain tube, various catheters, a blood access, a blood circuit, an artificial blood vessel, Examples include artificial kidneys, heart-lung machines, artificial valves, plasma exchange membranes, various adsorbents, CAPD, IABP, pacemakers, artificial joints, artificial bone heads, dental materials, and various shunts.
- the material and shape of the medical device are not particularly limited.
- the material include polyolefin, modified polyolefin, polyether, polyurethane, polyamide, polyimide, polyethylene terephthalate, polyester, polytetrafluoroethylene, polyvinyl chloride, and copolymers thereof. And various polymer materials such as metals, ceramics, carbon, and composite materials thereof.
- the shape is not particularly limited, and any shape such as smooth or porous may be used.
- the silicone substrate to be treated with the silicone substrate treating composition is not particularly limited as long as it is a substrate containing a silicone resin.
- Specific examples of such a silicone substrate include a silicone-containing medical device, a silicone substrate having a microchannel, and preferably a silicone-containing microchannel device.
- the medical device refers to a medical structure used in a living body, and such a structure is used by being implanted in the body, and is used in the body (without being implanted). It is divided roughly into.
- the size and length of the medical device are not particularly limited, and include a device having a fine circuit and a device that detects a small amount of sample.
- a function assisting device for supplementing the function of a living body having a disease such as a cardiac pacemaker
- a device for detecting an abnormality of the living body such as an implantable biochip
- Medical devices such as implants, bone anchors, sutures, and artificial blood vessels can be mentioned. Examples of structures used in the body (not implanted) include catheters and gastrocameras.
- microchannel device examples include a microreaction device (specifically, a microreactor and a microplant), a microanalysis device such as an integrated nucleic acid analysis device, a microelectrophoresis device, and a microchromatography device; Micro devices for sample preparation such as liquid chromatography; physicochemical processing devices used for extraction, membrane separation, dialysis, etc .; environmental analysis chip, clinical analysis chip, gene analysis chip (DNA chip), protein analysis chip (proteome chip) And microchannel chips such as sugar chain chips, chromatographic chips, cell analysis chips, and pharmaceutical screening chips. Among these, a microchannel chip is preferable.
- the microchannel is a portion through which a small amount of sample (preferably a liquid sample) flows, and the width and depth of the channel are not particularly limited, but both are usually about 0.1 ⁇ m to 1 mm, The thickness is preferably 10 ⁇ m to 800 ⁇ m. Note that the channel width and depth of the microchannel may be the same over the entire length of the channel, or may be partially different in size and shape.
- the silicone substrate may be subjected to plasma treatment, UV ozone treatment, internal infiltrant treatment, and the like. Since the silicone base material subjected to these treatments has a hydrophilic surface, it may be difficult for the polymer to be adsorbed, but the polymer used in the present invention is a silicone base material subjected to such plasma treatment or the like. It is also adsorbed to give excellent hydrophilicity and biological sample adsorption suppression effect.
- the article in the present invention is selected from the group consisting of a medical device, a cell culture device, and a silicone base material, and has a polymer having the following repeating unit (A) and the following repeating unit (B) on at least a part of the surface.
- a medical device having a polymer or a crosslinked product of the polymer on the surface (hereinafter also referred to as “target object 1”) has the polymer or a crosslinked product thereof on at least a part of the surface of the medical device.
- the object to be treated 1 has excellent lubricity because it has the polymer or a crosslinked product thereof on the surface.
- the object to be treated 1 can be manufactured by including a step of providing the polymer on at least a part of the surface of a medical device, specifically, a step of coating.
- the object to be processed 1 may be manufactured by including a step of providing a crosslinked product of the polymer on at least a part of the surface of the medical device, specifically, a step of coating, It is possible to produce a polymer (crosslinked body) with respect to the medical device by performing a step of providing the polymer on at least a part of the surface of the medical device (eg, coating) and then including a step of crosslinking the polymer. Peeling resistance is further enhanced, and an excellent lubricity-imparting effect is preferred for a longer period.
- the coating may use the composition for a medical device or may use only the polymer, but since the object 1 can be easily obtained, the composition for a medical device is used. Is preferred.
- the medical device before the treatment may be subjected to a surface treatment in advance by plasma treatment, UV ozone treatment, or the like.
- the coating may be performed by a known method, and specific examples include spray coating, dip coating, flow coating, brush coating, and sponge coating.
- the medical device can be coated by simply immersing the medical device in the medical device composition or the like and bringing the polymer or a cross-linked product thereof into contact with the medical device.
- heating the medical device composition and the medical device in contact with each other is excellent in lubricity, and in particular, the object to be treated 1 exhibiting these effects over a long period of time can be easily and easily obtained. It is preferable because it can be manufactured at low cost.
- the temperature is preferably 30 to 150 ° C., more preferably 30 to 135 ° C., and further preferably 35 to 135 ° C., and the time is preferably 20 minutes to 72 hours, more preferably 20 minutes. ⁇ 24 hours.
- the heating conditions may be determined according to the medical device or polymer to be used, and if the temperature is low, the heating time may be selected according to the heating temperature, such as lengthening the time, or the heating time may be The heating temperature may be selected accordingly.
- the heating condition may be carried out in any of the following normal pressure conditions and sterilization conditions, or in combination.
- the normal pressure is preferably 30 to 80 ° C. for 30 minutes to 72 hours under normal pressure, more preferably 35 to 70 ° C. for 1 hour to 24 hours, and normal pressure 35 to 60 ° C. for 1 hour to 24 hours. Time is more preferred.
- the heating under the sterilization condition may be performed when the medical device is sterilized by autoclave, and the preferable sterilization condition in this case is in the range of 115 ° C. for 30 minutes to 135 ° C. for 20 minutes. More preferred sterilization conditions range from 120 ° C. for 30 minutes to 135 ° C. for 20 minutes.
- the autoclave sterilization in this specification refers to the high-pressure steam method described in the 16th revision Japanese Pharmacopoeia, and can be performed under the same conditions as described in the same method or under longer conditions.
- the step of crosslinking the polymer can be performed by a known method.
- the strength and durability of the coating layer can be greatly improved by heat treatment or light treatment.
- it can also harden
- the polymer contains a repeating unit (D) having a ketone group
- a composition containing the polymer and a dihydrazide compound such as adipic acid dihydrazide as the polyfunctional compound is prepared, and a medical device is prepared. It is immersed in an object, taken out, and then heated and dried to form a covalent bond between the ketone group and the hydrazide group, and the polymer is strongly medically treated without damaging the physical properties provided by the polymer. It can be immobilized on the device surface.
- the hydrazide reaction is preferably carried out in the range of 10 to 100% of the total amount of ketone groups in the composition by the hydrazide group of the polyfunctional compound.
- the polymer contains a repeating unit (D) having an epoxy group
- the polymer and the polyfunctional compound such as a dithiol compound such as 3,6-dioxa-1,8-octanedithiol or ethylenediamine
- a composition containing a diamine compound is prepared, a medical device is immersed in the composition, taken out, and then heated to form a covalent bond between the epoxy group and the thiol group or amino group. It is possible to achieve the same effect as described above.
- the object to be treated 1 may be manufactured in the same manner as a normal surface treatment method except for the above-described process. For example, after performing the above-described process, a washing or drying process may be performed as necessary.
- the cell culture device of the present invention has the polymer on at least a part of its surface. Specifically, the polymer is applied to at least a part. Moreover, it is preferable that the surface is hydrophilically modified by forming a hydrophilic layer on the surface of the device and has a cell adhesion preventing effect.
- the cell culture device can be produced by a method including a step of providing the polymer on at least a part of the surface of the device, specifically, a method including a step of coating at least a part of the surface of the device. What is necessary is just to manufacture similarly to the manufacturing method of a normal cell culture equipment except this coating.
- the cell adhesion inhibitor may be used, or only the polymer may be used. However, since the cell culture equipment can be easily obtained, it is preferable to use the cell adhesion inhibitor.
- Examples of the equipment include a flask, a flask for tissue culture, a dish, a petri dish, a dish for tissue culture, a multi-dish, a microplate, a microwell plate, a micropore, a multiplate, a multiwell plate, a chamber slide, a petri dish, and a tube. , Tray, culture bag, roller bottle.
- the coating may be performed by a known method, and specific examples include the same methods as those described in the column of medical devices.
- the coating can be performed by immersing the device in the cell adhesion inhibitor and bringing the polymer into contact with the device.
- heating the cell adhesion inhibitor in contact with the equipment is excellent in hydrophilicity and cell adhesion prevention, and in particular, a cell culture equipment that exhibits these effects over a long period of time. It is preferable because it can be produced simply and at low cost.
- the conditions for the heating include the same conditions as those described in the column of medical device, and the preferred ranges are also the same.
- the cell culture device may be produced in the same manner as a normal surface treatment method except for the step of providing the polymer. For example, after performing the step, a washing or drying step may be performed as necessary. Alternatively, plasma treatment, UV ozone treatment, or the like may be performed before the step of providing the polymer. Moreover, you may pass through the process hardened
- the method for producing a cell mass in the present invention is characterized by culturing cells with the cell culture equipment. Since the polymer is provided on the surface of the cell culture equipment, cell adhesion to the equipment is suppressed. Then, by culturing the cells in this equipment, adhesion occurs only between the cells, and a cell mass can be obtained. In particular, since the cell culture equipment has low cytotoxicity, the production of the cell mass is hardly inhibited, and the cell mass can be easily obtained.
- the time to obtain the cell mass is preferably within 24 hours, more preferably within 12 hours.
- culture conditions suitable for the cells to be used may be appropriately employed.
- the silicone base material having a polymer on the surface and the silicone base material having a micro-channel are each made of the polymer. And at least a part of the surface of the silicone substrate having a silicone substrate and a microchannel. Since the object to be treated 2 has the polymer on the surface thereof, it has excellent hydrophilicity and sample components, particularly a biological sample adsorption inhibiting effect.
- the silicone base material which has a microchannel the surface of a base material, the surface in a microchannel, etc. are mentioned with a base material surface. That is, the silicone substrate having a microchannel having a polymer on the surface may have the polymer on the surface of the substrate, or may have the polymer on the surface of the microchannel. However, since the effect of the present invention is more exerted, it is preferable to have the polymer at least on the surface of the microchannel.
- the to-be-processed object 2 is manufactured by including the step of providing the polymer on at least a part of the surface of the silicone substrate or the silicone substrate having microchannels, specifically, the step of coating. be able to.
- the coating the composition for treating a silicone substrate may be used, or only the polymer may be used. However, since the article to be treated 2 can be easily obtained, the silicone substrate is used. It is preferable to use a treatment composition.
- the coating may be performed by a known method, and specific examples include the same methods as those described in the column of medical devices.
- the desired object 2 can be obtained easily and inexpensively.
- the coating of the microchannel is preferably performed on substantially the entire surface (including the entire surface) of the channel.
- heating in a state where the composition for treating a silicone substrate and the substrate are in contact with each other is excellent in hydrophilicity and sample components, particularly in preventing biological sample adhesion. Since the to-be-processed object 2 exhibited over a long term can be manufactured simply and at low cost, it is preferable.
- the conditions for the heating include the same conditions as those described in the column of medical device, and the preferred ranges are also the same.
- ⁇ NMR spectrum> The structure (content of repeating units) of the copolymer obtained below was measured based on 1 H-NMR spectrum.
- the 1 H-NMR spectrum was measured with a model AVANCE 500 (500 MHz) manufactured by BRUKER using d 6 -DMSO as a solvent and an internal standard substance.
- the content of repeating units derived from MPEGM is 85% by mass
- the content of repeating units derived from GLBT is 2.5% by mass
- the repeating units derived from LPEGM The content of was 12.5% by mass.
- the obtained copolymer (N-1) had a weight average molecular weight of 235,000, a number average molecular weight of 58,000, and a molecular weight distribution of 4.1.
- Synthesis Example 2 Synthesis of Copolymer (N-2) Acryloylmorpholine (ACMO (manufactured by KJ Chemicals), hereinafter referred to as “ACM”) 8.5 g, GLBT 0.25 g, LPEGM 1.25 g, AIBN0 0.1 g, 27 g of pure water and 63 g of acetonitrile were placed in a flask and mixed. Nitrogen was blown into this, the temperature was raised to 60 ° C., polymerized for 4 hours, and then cooled to room temperature. The resulting solution was dialyzed against pure water to obtain an aqueous solution of copolymer (N-2).
- ACM Acryloylmorpholine
- the content of the repeating unit derived from ACM is 85% by mass
- the content of the repeating unit derived from GLBT is 2.5% by mass
- the repeating unit derived from LPEGM The content of was 12.5% by mass.
- the obtained copolymer (N-2) had a weight average molecular weight of 455000, a number average molecular weight of 137,000, and a molecular weight distribution of 3.3.
- the content of the repeating unit derived from DMA is 85% by mass
- the content of the repeating unit derived from GLBT is 2.5% by mass
- the repeating unit derived from LPEGM The content of was 12.5% by mass.
- the obtained copolymer (N-3) had a weight average molecular weight of 499000, a number average molecular weight of 125,000, and a molecular weight distribution of 4.0.
- Synthesis Example 4 Synthesis of Copolymer (N-4) N-vinylpyrrolidone (Wako Pure Chemical Industries, Ltd., hereinafter referred to as “NVP”) 8.5 g, GLBT 0.25 g, and LPEGM 1.25 g Then, 0.1 g of AIBN, 27 g of pure water and 63 g of acetonitrile were placed in a flask and mixed. Nitrogen was blown into this, the temperature was raised to 60 ° C., polymerized for 4 hours, and then cooled to room temperature. The resulting solution was dialyzed against pure water to obtain an aqueous solution of copolymer (N-4).
- NRP N-vinylpyrrolidone
- the content of repeating units derived from NVP is 85% by mass
- the content of repeating units derived from GLBT is 2.5% by mass
- the repeating units derived from LPEGM The content of was 12.5% by mass.
- the obtained copolymer (N-4) had a weight average molecular weight of 208,000, a number average molecular weight of 43,000, and a molecular weight distribution of 4.8.
- the content of the repeating unit derived from DMA is 85% by mass
- the content of the repeating unit derived from MPC is 2.5% by mass
- the repeating unit derived from LPEGM The content of was 12.5% by mass.
- the obtained copolymer (N-5) had a weight average molecular weight of 494000, a number average molecular weight of 153,000, and a molecular weight distribution of 3.2.
- the content of repeating units derived from DMA is 85% by mass
- the content of repeating units derived from AA is 2.5% by mass
- the repeating units derived from LPEGM The content of was 12.5% by mass.
- the obtained copolymer (N-6) had a weight average molecular weight of 436000, a number average molecular weight of 103,000, and a molecular weight distribution of 4.2.
- Synthesis Example 7 Synthesis of Copolymer (N-7) DMA 8.5 g and dimethylaminopropylacrylamide methyl chloride quaternary salt (DMAPAA-Q (manufactured by KJ Chemicals), hereinafter referred to as “QA”) 25 g, LPEGM 1.25 g, AIBN 0.1 g, pure water 27 g and acetonitrile 63 g were placed in a flask and mixed. Nitrogen was blown into this, the temperature was raised to 60 ° C., polymerized for 4 hours, and then cooled to room temperature. The resulting solution was dialyzed against pure water to obtain an aqueous solution of copolymer (N-7).
- QA dimethylaminopropylacrylamide methyl chloride quaternary salt
- the content of the repeating unit derived from DMA is 85% by mass
- the content of the repeating unit derived from QA is 2.5% by mass
- the repeating unit derived from LPEGM The content of was 12.5% by mass.
- the obtained copolymer (N-7) had a weight average molecular weight of 549000, a number average molecular weight of 172,000, and a molecular weight distribution of 3.2.
- the content of the repeating unit derived from MPC was 87.5% by mass, and the content of the repeating unit derived from LPEGM was 12.5% by mass.
- the obtained copolymer (N-8) had a weight average molecular weight of 153,000, a number average molecular weight of 39000, and a molecular weight distribution of 3.9.
- the content of repeating units derived from GLBT was 87.5% by mass
- the content of repeating units derived from LPEGM was 12.5% by mass.
- the obtained copolymer (N-9) had a weight average molecular weight of 197,000, a number average molecular weight of 44,000, and a molecular weight distribution of 4.5.
- the content of repeating units derived from DMA is 85% by mass
- the content of repeating units derived from GLBT is 2.5% by mass
- the repeating units derived from SPEGM The content of was 12.5% by mass.
- the obtained copolymer (N-10) had a weight average molecular weight of 484,000, a number average molecular weight of 122,000, and a molecular weight distribution of 4.0.
- MIBK methyl isobutyl ketone
- acetone made by Wako Pure Chemical Industries
- DIPE diisopropyl ether
- the content of repeating units derived from DMA is 85% by mass
- the content of repeating units derived from GLBT is 2.5% by mass
- the repeating units derived from LPEGM was 10% by mass
- the content of the EHA-derived repeating unit was 2.5% by mass.
- the obtained copolymer (N-11) had a weight average molecular weight of 513,000, a number average molecular weight of 145000, and a molecular weight distribution of 3.5.
- the content of the repeating unit derived from DMA is 85% by mass
- the content of the repeating unit derived from GLBT is 2.5% by mass
- the repeating unit derived from LPEGM The content of LMA was 10% by mass
- the content of repeating units derived from LMA was 2.5% by mass.
- the obtained copolymer (N-12) had a weight average molecular weight of 465,000, a number average molecular weight of 119000, and a molecular weight distribution of 3.9.
- Synthesis Example 13 Synthesis of Copolymer (N-13) 8.5 g of DMA, 0.25 g of GLBT, 1.0 g of LPEGM, dodecylacrylamide (manufactured by Tokyo Chemical Industry Co., Ltd., hereinafter referred to as “DDAA”) 0 .25 g, AIBN 0.1 g, 27 g of pure water and 63 g of acetonitrile were placed in a flask and mixed. Nitrogen was blown into this, the temperature was raised to 60 ° C., polymerized for 4 hours, and then cooled to room temperature.
- DDAA dodecylacrylamide
- the content of the repeating unit derived from DMA is 85% by mass
- the content of the repeating unit derived from GLBT is 2.5% by mass
- the repeating unit derived from LPEGM was 10% by mass
- the content of the repeating unit derived from DDAA was 2.5% by mass.
- the obtained copolymer (N-13) had a weight average molecular weight of 497,000, a number average molecular weight of 130,000, and a molecular weight distribution of 3.8.
- the content of repeating units derived from DMA is 85% by mass
- the content of repeating units derived from GLBT is 2.5% by mass
- the repeating units derived from LPEGM The content of the repeating unit derived from SiMA was 2.5% by mass.
- the obtained copolymer (N-14) had a weight average molecular weight of 462,000, a number average molecular weight of 108,000, and a molecular weight distribution of 4.3.
- the content of repeating units derived from DMA is 85% by mass
- the content of repeating units derived from GLBT is 2.5% by mass
- the repeating units derived from LPEGM The content of the repeating unit derived from DMSMA was 2.5% by mass.
- the obtained copolymer (N-15) had a weight average molecular weight of 497,000, a number average molecular weight of 103,000, and a molecular weight distribution of 4.8.
- Synthesis Example 16 Synthesis of Copolymer (N-16) 7.75 g of DMA, 0.5 g of GLBT, 1.0 g of LPEGM, 0.25 g of DDAA, diacetone acrylamide (manufactured by Nippon Kasei Co., Ltd.), hereinafter “DAAM” 0.5 g, 0.1 g of AIBN, 27 g of pure water and 63 g of acetonitrile were placed in a flask and mixed. Nitrogen was blown into this, the temperature was raised to 60 ° C., polymerized for 4 hours, and then cooled to room temperature.
- DAAM diacetone acrylamide
- the content of the repeating unit derived from DMA is 77.5% by mass
- the content of the repeating unit derived from GLBT is 5% by mass
- the repeating unit derived from LPEGM was 10% by mass
- the content of the repeating unit derived from DDAA was 2.5% by mass
- the content of the repeating unit derived from DAAM was 5% by mass.
- the obtained copolymer (N-16) had a weight average molecular weight of 408,000, a number average molecular weight of 106,000, and a molecular weight distribution of 3.8.
- the content of the repeating unit derived from DMA is 85% by mass
- the content of the repeating unit derived from GLBT is 2.5% by mass
- the repeating unit derived from EHA The content of was 12.5% by mass.
- the obtained copolymer (N-17) had a weight average molecular weight of 354000, a number average molecular weight of 83,000, and a molecular weight distribution of 4.3.
- the content of the repeating unit derived from DMA is 85% by mass
- the content of the repeating unit derived from GLBT is 2.5% by mass
- the repeating unit derived from LMA The content of was 12.5% by mass.
- the obtained copolymer (N-18) had a weight average molecular weight of 438,000, a number average molecular weight of 101,000, and a molecular weight distribution of 4.3.
- the content of the repeating unit derived from DMA is 85% by mass
- the content of the repeating unit derived from GLBT is 2.5% by mass
- the repeating unit derived from DDAA The content of was 12.5% by mass.
- the obtained copolymer (N-19) had a weight average molecular weight of 406000, a number average molecular weight of 81,000, and a molecular weight distribution of 5.0.
- the content of the repeating unit derived from DMA is 85% by mass
- the content of the repeating unit derived from GLBT is 2.5% by mass
- the repeating unit derived from SiMA The content of was 12.5% by mass.
- the obtained copolymer (N-20) had a weight average molecular weight of 360,000, a number average molecular weight of 95,000, and a molecular weight distribution of 3.8.
- the content of the repeating unit derived from DMA is 85% by mass
- the content of the repeating unit derived from GLBT is 2.5% by mass
- the repeating unit derived from DMSMA The content of was 12.5% by mass.
- the obtained copolymer (N-21) had a weight average molecular weight of 325,000, a number average molecular weight of 77,000, and a molecular weight distribution of 4.2.
- copolymers (N-1) to (N-21) obtained in each synthesis example and reference example were mixed with purified water at 25 ° C. so that the concentration of each copolymer was 0.5% by mass. did. Copolymers (N-1) to (N-17), (N-19) and (N-20) were dissolved in purified water.
- Example 1-1 Using the aqueous solution of copolymer (N-1) obtained in Synthesis Example 1, a 0.5% by mass aqueous solution was prepared. A urethane substrate was immersed in the aqueous solution and allowed to stand at 35 ° C. for 2 hours. Thereafter, the base material was washed with pure water three times to remove the unadsorbed polymer, thereby obtaining a urethane base material coated with the copolymer (N-1).
- Examples 1-2 to 1-16 and Comparative Examples 1-1 to 1-3 instead of the aqueous solution of copolymer (N-1), the same procedure as in Example 1-1 was performed except that the one obtained in Synthesis Examples 2 to 16, Reference Example 1, Reference Example 3 or Reference Example 4 was used. Then, a urethane substrate coated with each copolymer was obtained.
- Example 1-17 Using the copolymer (N-16) obtained in Synthesis Example 16, a 0.5% by mass aqueous solution was prepared. Further, 1/10 mass of adipic acid dihydrazide of the copolymer was added and dissolved in the aqueous solution. A urethane substrate was immersed in the aqueous solution and allowed to stand at 35 ° C. for 2 hours, then taken out from the aqueous solution, and dried by heating in an oven set at 60 ° C. for 4 hours or more. Thereafter, the base material was washed with pure water three times to obtain a urethane base material cross-linked with the copolymer (N-16).
- Examples 1-18 to 1-33 and Comparative Examples 1-4 to 1-6 In Examples 1-1 to 1-16 and Comparative Examples 1-1 to 1-3, a nylon base coated with each copolymer was similarly used except that the urethane base was changed to a nylon base. The material was obtained.
- Example 1-34 A nylon substrate cross-linked with the copolymer (N-16) was obtained in the same manner as in Example 1-17, except that the urethane substrate was changed to a nylon substrate.
- Examples 2-1 to 2-15 and Comparative Examples 2-1 to 2-3 Using each copolymer (aqueous solution) of Synthesis Examples 1 to 15 and Reference Example 1, Reference Example 3 or Reference Example 4, it was prepared using pure water so as to have a polymer concentration as shown in Table 5. Compositions of 2-1 to 2-15 and Comparative Examples 2-1 to 2-3 were obtained. The following tests were conducted using the composition. The test results are shown in Table 5 or 6. The control in Table 5 shows the results of testing in the same manner as described above except that pure water was used instead of the composition.
- FBS fetal bovine serum
- HeLa cells human cervical cancer cells
- FBS fetal bovine serum
- HeLa cells human cervical cancer cells
- the cells were cultured for 4 hours under the conditions of 2 . Thereafter, the medium was changed and the cells were further cultured for 44 hours (37 ° C., 5% CO 2 conditions). Then, the state of the cells was observed with an inverted microscope, and the number of cells was counted with a hemocytometer.
- the average value of adherent cell density was calculated according to the following formula.
- Adherent cell density (%) [(number of adherent cells) / (number of cells at confluence)] ⁇ 100
- Adherent cell density is 40% or more ⁇ Adherent cell density is 10% or more and less than 40% ⁇ Adherent cell density is less than 10%
- Test Example 2 Cell adhesion test (2) Adherent cell density was evaluated in the same manner as in Test Example 1 except that HeLa cells were changed to 3T3 cells (mouse fibroblasts). The test results are shown in Table 5.
- Test Example 4 Measurement of antibody adsorption amount 1 mL of the composition of each Example or Comparative Example was added to a 96-well plate made of polystyrene, allowed to stand for 4 hours while heated to 35 ° C, and then washed three times with pure water. The unadsorbed polymer was removed. Next, 1 mL of an aqueous solution of horseradish peroxidase-labeled mouse IgG antibody (AP124P: manufactured by Millipore) was filled in the 96-well plate, incubated at room temperature for 1 hour, and then washed three times with phosphate buffered saline (PBS).
- PBS phosphate buffered saline
- the absorbance of light at a wavelength of 450 nm is measured by coloring the antibody using TMB (3,3 ′, 5,5′-tetramethylbenzidine) / hydrogen peroxide solution / sulfuric acid, and the antibody is measured from the absorbance by a calibration curve method. The amount of adsorption was calculated.
- the precultured HeLa cell medium was replaced with the above-mentioned copolymer-containing medium, and cultured for 24 hours at 37 ° C. and 5% CO 2 .
- what was cultured like the above except having changed the copolymer aqueous solution into the pure water was set as control.
- MTT assay MTT Cell Proliferation Assay Kit 10009365: manufactured by Cayman Chemical Company
- Table 6 The test results are shown in Table 6.
- surface shows a relative value when control is set to 100%, and when this figure is 80% or more, it shows that there is no toxicity, and it shows that the toxicity of a copolymer is so high that this figure is low. .
- Examples 3-1 to 3-15 and Comparative Examples 3-1 to 3-3 Using each of the copolymers (aqueous solutions) of Synthesis Examples 1 to 15 and Reference Example 1, Reference Example 3 or Reference Example 4, preparation was performed using pure water so that the polymer concentrations as shown in Table 7 were obtained. Treatment compositions of 3-1 to 3-15 and Comparative Examples 3-1 to 3-3 were obtained. The following tests were conducted using the treatment composition. The test results are shown in Table 7. In addition, the control in a table
- the washed silicone rubber sheet is transferred to a well of a polystyrene 96-well plate, and the absorbance of light at a wavelength of 450 nm is measured by coloring the antibody using TMB / hydrogen peroxide solution / sulfuric acid. A calibration curve is obtained from this absorbance. The amount of antibody adsorption was calculated by the method.
- Blood feeding test Example 3 shown in Table 7 below in the flow path of a standard chip (made by Fluidware Technologies) made of PDMS (polydimethylsiloxane) having a flow path with a width of 200 ⁇ m and a height of 50 ⁇ m. -3, the treatment composition of Example 3-13, Comparative Example 3-2 or Comparative Example 3-3 was poured and left to stand at a temperature of 35 ° C. for 4 hours, and then 3 times with pure water and with PBS. Washed three times to remove unadsorbed polymer.
- PDMS polydimethylsiloxane
- the blood sample is fed at a constant pressure at an inlet speed of 2 ⁇ L / min for 6 minutes, and the amount of blood sample that has flowed out from the outlet of the flow channel for 1 minute immediately after the feeding, and 5 minutes to 6 minutes after the start of liquid feeding. The amount of the blood sample that flowed out from the outlet of the flow channel was measured.
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Abstract
Description
また、タンパク質吸着防止剤として、2-メタクリロイルオキシエチルホスホリルコリンと、(メタ)アクリル酸n-ブチル、(メタ)アクリル酸メチルまたはスチレンとの共重合体等が記載されている(特許文献5)。
また、非特許文献1に関し、種々の足場依存性細胞についての、このような研究は未だ不十分であり、かなり広範な足場依存性細胞について、ほぼ普遍的に細胞塊を形成できる器材は未だ見出されていない。
本発明(III)は、前記課題に鑑みてなされたものであり、親水性および試料成分が付着しにくい表面を有するシリコーン基材、マイクロ流路を有するシリコーン基材を容易に形成することができる組成物ならびに該基材の製造方法を提供することを課題とする。
[1] 下記繰り返し単位(A)と下記繰り返し単位(B)とを有する重合体を含む、メディカルデバイス用組成物。
(A)親水性繰り返し単位
(B)側鎖にポリオキシアルキレン基を有し、その側鎖末端が炭素数5~30のアルキル基、炭素数5~30のアルカノイル基または炭素数6~30のアリール基で構成される繰り返し単位
(A)親水性繰り返し単位
(B)側鎖にポリオキシアルキレン基を有し、その側鎖末端が炭素数5~30のアルキル基、炭素数5~30のアルカノイル基または炭素数6~30のアリール基で構成される繰り返し単位
(A)親水性繰り返し単位
(B)側鎖にポリオキシアルキレン基を有し、その側鎖末端が炭素数5~30のアルキル基、炭素数5~30のアルカノイル基または炭素数6~30のアリール基で構成される繰り返し単位
(A)親水性繰り返し単位
(B)側鎖にポリオキシアルキレン基を有し、その側鎖末端が炭素数5~30のアルキル基、炭素数5~30のアルカノイル基または炭素数6~30のアリール基で構成される繰り返し単位
[11] 下記繰り返し単位(A)と下記繰り返し単位(B)とを有する重合体を含む細胞接着防止剤
(A)親水性繰り返し単位
(B)側鎖にポリオキシアルキレン基を有し、その側鎖末端が炭素数5~30のアルキル基、炭素数5~30のアルカノイル基または炭素数6~30のアリール基で構成される繰り返し単位
(A)親水性繰り返し単位
(B)側鎖にポリオキシアルキレン基を有し、その側鎖末端が炭素数5~30のアルキル基、炭素数5~30のアルカノイル基または炭素数6~30のアリール基で構成される繰り返し単位
(A)親水性繰り返し単位
(B)側鎖にポリオキシアルキレン基を有し、その側鎖末端が炭素数5~30のアルキル基、炭素数5~30のアルカノイル基または炭素数6~30のアリール基で構成される繰り返し単位
[21] 下記繰り返し単位(A)と下記繰り返し単位(B)とを有する重合体を含むシリコーン基材処理用組成物。
(A)親水性繰り返し単位
(B)側鎖にポリオキシアルキレン基を有し、その側鎖末端が炭素数5~30のアルキル基、炭素数5~30のアルカノイル基または炭素数6~30のアリール基で構成される繰り返し単位
(A)親水性繰り返し単位
(B)側鎖にポリオキシアルキレン基を有し、その側鎖末端が炭素数5~30のアルキル基、炭素数5~30のアルカノイル基または炭素数6~30のアリール基で構成される繰り返し単位
(A)親水性繰り返し単位
(B)側鎖にポリオキシアルキレン基を有し、その側鎖末端が炭素数5~30のアルキル基、炭素数5~30のアルカノイル基または炭素数6~30のアリール基で構成される繰り返し単位
(A)親水性繰り返し単位
(B)側鎖にポリオキシアルキレン基を有し、その側鎖末端が炭素数5~30のアルキル基、炭素数5~30のアルカノイル基または炭素数6~30のアリール基で構成される繰り返し単位
さらに、本発明(II)によれば、細胞塊を容易に製造することができる。
従って、本発明(III)のシリコーン基材処理用組成物は、シリコーン基材のコーティング用組成物として有用である。
また、本発明(III)のシリコーン基材の製造方法によれば、試料成分、特に生体試料が吸着しにくく、しかもその効果の持続性に優れるシリコーン基材を簡便に製造できる。
本発明に係る重合体組成物(以下「本組成物」ともいう。)は、下記繰り返し単位(A)と下記繰り返し単位(B)とを有する重合体を含む、メディカルデバイス用組成物、細胞接着防止剤およびシリコーン基材処理用組成物からなる群より選ばれる1種の組成物である。
なお、本発明では、前記重合体のみからなる場合も組成物という。
このような効果が奏される理由は必ずしも明らかではないが、繰り返し単位(B)、さらには、繰り返し単位(B)および繰り返し単位(C)によって、重合体が、メディカルデバイスの壁面に吸着し、その一方で、繰り返し単位(A)および繰り返し単位(B)によって、前記壁面が親水化され、厚い親水性の層が形成されることで、潤滑性を発現することができるものと推察される。
更に、本発明(I)によれば、潤滑性のみならずタンパク質、脂質、核酸等生体物質の吸着の抑制もできる。
また、前記重合体は、細胞培養器材表面に存在していても、細胞毒性が低く、また、器材表面に設けられた前記重合体は、容易に該器材から剥離するものではないが、たとえ剥離したとしても、細胞毒性が低い。このため、前記細胞接着防止剤は、細胞培養に用いる器材に好適に用いることができる。
従って、前記重合体は、細胞接着防止剤としてそのまま用いることができ、また、細胞接着防止剤を製造するための素材として使用することができる。更に、斯かる細胞接着防止剤によれば、細胞接着のみならずタンパク質、脂質、核酸等生体物質の吸着も抑制できる。
前記重合体は、下記繰り返し単位(A)と、下記繰り返し単位(B)とを有する。
(A)親水性繰り返し単位
(B)側鎖にポリオキシアルキレン基を有し、その側鎖末端が炭素数5~30のアルキル基、炭素数5~30のアルカノイル基または炭素数6~30のアリール基で構成される繰り返し単位
繰り返し単位(A)は、親水性繰り返し単位であり、前記繰り返し単位(B)以外の繰り返し単位であれば特に制限されないが、側鎖にポリオキシアルキレン基を有し、その側鎖末端が水素原子または炭素数1~4のアルキル基で構成される繰り返し単位(A-1)、側鎖末端にアンモニオアルキルホスフェート基を有する繰り返し単位(A-2)、側鎖にアミド基を有する繰り返し単位(A-3)、側鎖末端に窒素および酸素を含むヘテロ環を有する繰り返し単位(A-4)、側鎖にラクタムを有する繰り返し単位(A-5)、側鎖末端にベタイン性基を有する繰り返し単位(A-6)、アニオン性繰り返し単位(A-7)、ならびに、カチオン性繰り返し単位(A-8)から選ばれる1種以上であることが好ましい。
潤滑性に優れるメディカルデバイスを容易に得ることができ、
親水性表面を有する器具や装置を容易に得ることができるため、細胞の接着防止性に優れる器具や装置を容易に得ることができ、
表面親水性および試料成分、特に生体試料付着防止性に優れるシリコーン基材を容易に得ることができる。
繰り返し単位(A-1)は、側鎖にポリオキシアルキレン基を有し、その側鎖末端が水素原子または炭素数1~4のアルキル基で構成されるものである。
繰り返し単位(A-1)としては、下記式(1')で表される構造を側鎖末端に有する繰り返し単位が好ましい。式(1')で表される構造を側鎖末端に有する繰り返し単位としては公知の繰り返し単位が挙げられ、中でも、(メタ)アクリレート系の繰り返し単位、(メタ)アクリルアミド系の繰り返し単位、スチレン系の繰り返し単位等が好ましい。これらの中でも、下記式(1)で表される繰り返し単位が好ましい。
また、R1で示されるアルキレン基は直鎖状でも分岐鎖状でもよく、具体的には、エタン-1,2-ジイル基、プロパン-1,2-ジイル基、プロパン-1,3-ジイル基、プロパン-2,2-ジイル基、ブタン-1,2-ジイル基、ブタン-1,3-ジイル基、ブタン-1,4-ジイル基等が挙げられる。これらの中でも、入手容易性、潤滑性付与性能、親水化性能に優れる等の観点から、エタン-1,2-ジイル基が好ましい。
斯様なR2の中でも、入手容易性、潤滑性付与性能、親水化性能に優れる等の観点から、水素原子または炭素数1~3のアルキル基が好ましく、水素原子または炭素数1もしくは2のアルキル基がより好ましく、水素原子またはメチル基が更に好ましく、メチル基が特に好ましい。
繰り返し単位(A-1)としては、これらを単独でまたは2種以上を用いて得られた繰り返し単位が挙げられる。
繰り返し単位(A-2)は、側鎖末端にアンモニオアルキルホスフェート基を有する繰り返し単位である。繰り返し単位(A-2)としては、下記式(2)で表される繰り返し単位が好ましい。
R7におけるアルキレン基は直鎖状でも分岐鎖状でもよく、R1で例示した基と同様の基等が挙げられる。これらの中でも、入手容易性、潤滑性付与性能、親水化性能に優れる等の観点から、エタン-1,2-ジイル基が好ましい。
なお、R7が複数ある場合、R7は同一でも異なっていてもよい。
R8におけるアルキレン基は直鎖状でも分岐鎖状でもよく、好適な具体例としては、R7におけるアルキレン基と同様の基が挙げられる。
該炭化水素基としては、アルキル基;フェニル基等のアリール基;ベンジル基等のアラルキル基などが挙げられるが、アルキル基が好ましい。
このアルキル基は直鎖状でも分岐鎖状でもよく、好適な具体例としては、メチル基、エチル基、n-プロピル基、イソプロピル基、n-ブチル基、イソブチル基、sec-ブチル基、tert-ブチル基が挙げられる。
繰り返し単位(A-2)としては、これらを単独でまたは2種以上を用いて得られた繰り返し単位が挙げられる。
繰り返し単位(A-3)は、側鎖にアミド基を有する繰り返し単位である。繰り返し単位(A-3)としては、下記式(3)で表される繰り返し単位が好ましい。
また、該アルキル基は直鎖状でも分岐鎖状でもよく、好適な具体例としては、メチル基、エチル基、n-プロピル基、イソプロピル基が挙げられる。
繰り返し単位(A-3)としては、これらを単独でまたは2種以上を用いて得られた繰り返し単位が挙げられる。
繰り返し単位(A-4)は、側鎖末端に窒素および酸素を含むヘテロ環を有する繰り返し単位である。繰り返し単位(A-4)としては、下記式(4)で表される繰り返し単位が好ましい。
また、該アルキレン基は直鎖状でも分岐鎖状でもよいが、直鎖状が好ましい。好適な具体例としては、メタン-1,1-ジイル基、エタン-1,2-ジイル基が挙げられる。
繰り返し単位(A-4)としては、前記モノマーを単独でまたは2種以上を用いて得られた繰り返し単位が挙げられる。
繰り返し単位(A-5)は、側鎖にラクタムを有する繰り返し単位である。繰り返し単位(A-5)としては、下記式(5)で表される繰り返し単位が好ましい。
また、該アルキレン基は直鎖状でも分岐鎖状でもよいが、直鎖状が好ましい。好適な具体例としては、プロパン-1,3-ジイル基、ブタン-1,4-ジイル基、ペンタン-1,5-ジイル基が挙げられる。
繰り返し単位(A-5)としては、これらを単独でまたは2種以上を用いて得られた繰り返し単位が挙げられる。
繰り返し単位(A-6)は、側鎖末端にベタイン性基を有する繰り返し単位である。繰り返し単位(A-6)としては、下記式(6)で表される繰り返し単位が好ましい。
また、2価の有機基としては、2価の炭化水素基が好ましく、2価の脂肪族炭化水素基がより好ましい。当該2価の脂肪族炭化水素基は、直鎖状でも分岐鎖状でもよい。また、2価の脂肪族炭化水素基としては、アルカンジイル基が好ましい。例えば、メタン-1,1-ジイル基、エタン-1,2-ジイル基、プロパン-1,1-ジイル基、プロパン-1,2-ジイル基、プロパン-1,3-ジイル基、プロパン-2,2-ジイル基、ブタン-1,4-ジイル基、ペンタン-1,5-ジイル基、ヘキサン-1,6-ジイル基が挙げられる。
R21およびR22における炭化水素基としては、アルキル基;フェニル基等のアリール基;ベンジル基等のアラルキル基などが挙げられるが、アルキル基が好ましい。当該アルキル基は、直鎖状でも分岐鎖状でもよく、例えば、メチル基、エチル基、n-プロピル基、イソプロピル基、n-ブチル基、イソブチル基、sec-ブチル基、tert-ブチル基が挙げられる。
繰り返し単位(A-6)としては、これらを単独でまたは2種以上用いて得られた繰り返し単位が挙げられる。
繰り返し単位(A-7)は、アニオン性繰り返し単位である。
繰り返し単位(A-7)としては、酸性基を有する繰り返し単位が挙げられる。
また、繰り返し単位(A-7)としては、導入の容易さ、安全性に優れる等の観点から、エチレン性不飽和結合を含有するモノマーに由来する単位が好ましい。
これらの中でも、導入の容易さ、反応性に優れる等の観点から、(メタ)アクリル酸が好ましい。
繰り返し単位(A-7)は、これらを単独でまたは2種以上用いて得られた繰り返し単位が挙げられる。
繰り返し単位(A-8)は、カチオン性繰り返し単位である。繰り返し単位(A-8)としては、下記式(8)で表される繰り返し単位が好ましい。
該2価の有機基としては、2価の炭化水素基が好ましく、2価の脂肪族炭化水素基がより好ましい。当該2価の脂肪族炭化水素基は、直鎖状でも分岐鎖状でもよい。2価の脂肪族炭化水素基としては、R20およびR23で例示した基と同様の基等が挙げられる。
R28、R29及びR30における炭化水素基としては、R9、R10およびR11における炭化水素基として例示した基と同様の基等が挙げられる。
(メタ)アクリレート類のモノマー種としては、((メタ)アクリロイルオキシエチル)トリメチルアンモニウムクロライド等の((メタ)アクリロイルオキシC1-10アルキル)トリC1-10アルキルアンモニウムクロライド、((メタ)アクリロイルオキシエチル)ジメチルベンジルアンモニウムクロライド等の((メタ)アクリロイルオキシC1-10アルキル)ジC1-10アルキルC6-10アラルキルアンモニウムクロライドが挙げられる。(メタ)アクリルアミド類のモノマー種としては、(3-(メタ)アクリルアミドプロピル)トリメチルアンモニウムクロリド等の(3-(メタ)アクリルアミドC1-10アルキル)トリC1-10アルキルアンモニウムクロリド、(3-(メタ)アクリルアミドプロピル)ジメチルベンジルアンモニウムクロリド等の(3-(メタ)アクリルアミドC1-10アルキル)ジC1-10アルキルC6-10アラルキルアンモニウムクロリド等が挙げられる。これらの中でも、導入の容易さ、反応性に優れる等の観点から、(3-(メタ)アクリルアミドプロピル)トリメチルアンモニウムクロリドが好ましい。
繰り返し単位(A-8)としては、これらを単独でまたは2種以上を用いて得られた繰り返し単位が挙げられる。
(ii)繰り返し単位(A-1)および(A-3)から選ばれる1種以上と、繰り返し単位(A-2)および(A-6)から選ばれる1種以上との組み合わせ、好ましくは繰り返し単位(A-3)と、繰り返し単位(A-2)および(A-6)から選ばれる1種以上との組み合わせ
繰り返し単位(A)の合計含有量が前記範囲にあると、メディカルデバイスへの潤滑性付与性能により優れ、器材への親水化性能および細胞接着防止性能により優れ、シリコーン基材への親水化性能および生体試料付着防止性能により優れる。
なお、繰り返し単位(A)の含有量は1H-NMR、13C-NMR等により測定可能である。
繰り返し単位(B)は、側鎖にポリオキシアルキレン基を有し、その側鎖末端が炭素数5~30のアルキル基、炭素数5~30のアルカノイル基または炭素数6~30のアリール基で構成される繰り返し単位であり、重合体は、繰り返し単位(B)に該当する繰り返し単位を1種または2種以上有していてよい。
潤滑性に優れるメディカルデバイス、耐久性(潤滑性の持続性)に優れるメディカルデバイス、特に、メディカルデバイスの使用時に生じ得る摩擦下でも潤滑性の持続性に優れるメディカルデバイスを容易に得ることができ、
表面親水性および細胞接着防止効果に優れる器具および装置、さらにこの効果の持続性に優れる細胞培養器材を容易に得ることができ、
表面親水性および試料成分、特に生体試料付着防止性に優れるシリコーン基材、さらにこの効果の持続性に優れるシリコーン基材を容易に得ることができる。従って、本組成物を、マイクロ流路表面の処理に用いた場合であっても、該流路を通過するガスや液体等により、重合体の剥落が起こりにくく、所望の効果が長期にわたって発揮されるマイクロ流路を有するシリコーン基材を得ることができる。
R32で示されるアルキレン基は直鎖状でも分岐鎖状でもよく、具体的には、エタン-1,2-ジイル基、プロパン-1,2-ジイル基、プロパン-1,3-ジイル基、プロパン-2,2-ジイル基、ブタン-1,2-ジイル基、ブタン-1,3-ジイル基、ブタン-1,4-ジイル基等が挙げられる。これらの中でも、入手容易性等の観点から、エタン-1,2-ジイル基が好ましい。
なお、m個のR32は同一でも異なっていてもよい。
R33におけるアルキル基は直鎖状でも分岐鎖状でもよく、具体的には、2-エチルヘキシル基、オクチル基、デシル基、ラウリル基、パルミチル基、ステアリル基等が挙げられる。これらの中でも、2-エチルヘキシル基、ラウリル基、ステアリル基が好ましく、ラウリル基、ステアリル基がより好ましい。
また、R33におけるアルカノイル基としては、2-エチルヘキサノイル基、ラウロイル基、ステアロイル基が挙げられる。
また、該アリール基は、炭素数1~24のアルキル基を置換基として有していてもよい。斯かるアルキル基の炭素数としては、3~24が好ましく、5~16がより好ましい。なお、斯かる置換アルキル基の置換位置および置換個数は任意であるが、好適な置換個数は1または2個である。
また、斯様な炭素数1~24のアルキル基を置換基として有するアリール基としては、ノニルフェニル基が挙げられる。
また、R36における有機基の炭素数は、好ましくは1~6である。該有機基としては、炭化水素基が挙げられる。斯かる炭化水素基としては、R5で例示した炭化水素基と同様の基等が挙げられる。
R35の中では、**-(C=O)-O-またはフェニレン基が好ましく、**-(C=O)-O-が特に好ましい。
繰り返し単位(B)としては、これらを単独でまたは2種以上を用いて得られた繰り返し単位が挙げられる。
繰り返し単位(B)の合計含有量が前記範囲にあると、潤滑性付与性能およびメディカルデバイスに対する耐剥離性により優れなどの観点から、親水化性能および細胞接着防止性能により優れ、親水化性能および生体試料付着防止性能により優れる。
なお、繰り返し単位(B)の含有量は、繰り返し単位(A)の含有量と同様にして測定すればよい。
前記重合体としては、下記式(c1)で表される繰り返し単位(C-1)および下記式(c2)で表される基を側鎖末端に有する繰り返し単位(C-2)から選ばれる1種以上の繰り返し単位(C)を含有することが好ましい。
前記重合体が、斯様な繰り返し単位(C)を備えることにより、
重合体のメディカルデバイスに対する耐剥離性が更に強くなり、潤滑性付与効果がより向上し、
重合体の器材への吸着力が更に強くなり、親水化性能および細胞接着防止性能がより向上し、
重合体のシリコーン基材への吸着力が更に強くなり、親水化性能および生体試料付着防止性能がより向上する。
繰り返し単位(C-1)は、下記式(c1)で表される繰り返し単位である。
R39における炭化水素基の炭素数は、潤滑性付与性能、メディカルデバイスに対する耐剥離性、親水化性能、細胞接着防止性能および生体試料付着防止性能に優れる等の観点から、好ましくは6~24であり、より好ましくは8~18であり、更に好ましくは8~14であり、特に好ましくは10~14である。
前記アルキル基としては、例えば、2-エチルヘキシル基、オクチル基、デシル基、ラウリル基、パルミチル基、ステアリル基等が挙げられる。これらの中でも、入手容易性、防汚性付与効果等の観点から、2-エチルヘキシル基、ラウリル基、ステアリル基が好ましく、2-エチルヘキシル基、ラウリル基がより好ましい。
繰り返し単位(C-1)としては、これらを単独でまたは2種以上を用いて得られた繰り返し単位が挙げられる。
繰り返し単位(C-2)は、下記式(c2)で表される基を側鎖末端に有する繰り返し単位である。式(c2)で表される基を側鎖末端に有する繰り返し単位としては公知の繰り返し単位が挙げられ、中でも、(メタ)アクリレート系の繰り返し単位、(メタ)アクリルアミド系の繰り返し単位、スチレン系の繰り返し単位等が好ましい。これらの中でも、下記式(c3)で表される繰り返し単位が好ましい。
該2価の有機基としては、2価の炭化水素基が挙げられる。2価の炭化水素基は、好ましくは2価の脂肪族炭化水素基であり、直鎖状でも分岐鎖状でもよいが、より好ましくはアルカンジイル基である。斯かるアルカンジイル基の好適な具体例としては、エタン-1,2-ジイル基、プロパン-1,2-ジイル基、プロパン-1,3-ジイル基、プロパン-2,2-ジイル基、ブタン-1,2-ジイル基、ブタン-1,3-ジイル基、ブタン-1,4-ジイル基が挙げられる。
該有機基としては、炭化水素基が挙げられる。炭化水素基は直鎖状でも分岐鎖状でもよいが、好ましくはアルキル基である。斯かるアルキル基の具体例としては、メチル基、エチル基、n-プロピル基、イソプロピル基、n-ブチル基、イソブチル基、sec-ブチル基、tert-ブチル基が挙げられる。
なお、R42およびR43が複数ある場合、R42は同一でも異なっていてもよく、R43も同一でも異なっていてもよい。
繰り返し単位(C-2)としては、これらを単独でまたは2種以上を用いて得られた繰り返し単位が挙げられる。
なお、繰り返し単位(C)の含有量は、繰り返し単位(A)の含有量と同様にして測定すればよい。
本発明(I)で用いる重合体は、架橋剤を用いて架橋させてもよい。前記繰り返し単位(A)~(C)に架橋剤と反応する反応性官能基がない場合、または、反応性が弱く架橋反応が十分に進まない場合には、本発明(I)で用いる重合体は、本発明(I)の効果を損なわない範囲で、前記繰り返し単位(A)~(C)以外の他の繰り返し単位として、側鎖に反応性官能基を有する繰り返し単位(D)を含有してもよい。
前記重合体が、繰り返し単位(D)を備え、かつ、メディカルデバイス上で前記重合体を架橋させることで、重合体(架橋体)のメディカルデバイスに対する耐剥離性が更に強くなり、優れた潤滑性付与効果がより長期間持続する。
これらの中でも、導入の容易さ、反応性の観点から、グリシジル(メタ)アクリレート、ジアセトンアクリルアミド、アセトアセトキシエチルメタクリレートが好ましい。
前記重合体に含まれる繰り返し単位(A)と繰り返し単位(B)との質量比〔(A):(B)〕としては、潤滑性付与性能、メディカルデバイスに対する耐剥離性、親水化性能、細胞接着防止性能および生体試料付着防止性能に優れる等の観点から、20:80~95:5が好ましく、30:70~95:5がより好ましく、40:60~95:5が更に好ましく、50:50~95:5が更に好ましく、55:45~95:5が特に好ましい。
また、質量比〔(A):(B)〕が前記質量比〔(A):(B)〕の範囲であり、かつ、質量比〔((A)+(B)):(C)〕が前記質量比〔((A)+(B)):(C)〕の範囲であることが特に好ましい。
また、分子量分布(Mw/Mn)としては、1~10が好ましく、1~7がより好ましく、1~5が特に好ましい。
なお、前記重量平均分子量、数平均分子量および分子量分布は、後述する実施例に記載の方法に従い測定すればよい。
メディカルデバイスの特性を損なうことなく、潤滑性に優れるメディカルデバイスを容易に製造することができ、
器材の特性を損なうことなく、表面親水性および細胞接着防止性に優れる細胞培養器材等を容易に製造することができ、
シリコーン基材の特性を損なうことなく、表面親水性および生体試料付着防止性に優れるシリコーン基材を容易に製造することができる。
なお、本明細書において、水溶性の重合体とは、重合体濃度が0.5質量%となるように重合体を水(25℃)に添加、混合したときに、目視で透明な溶液が得られることをいう。
前記メディカルデバイス用組成物およびシリコーン基材処理用組成物は、前記重合体を含有すれば特に制限されないが、通常、溶剤等の前記重合体以外の他の成分を含む。また、前記細胞接着防止剤は、前記重合体を含有すれば特に制限されず、溶剤等の前記重合体以外の他の成分を本発明の効果を損なわない範囲で含んでいてもよい。
これらの本組成物は、常法に従い製造することができる。
重合体の含有量が前記範囲にあると、
潤滑性に優れ、さらにその効果が持続するメディカルデバイスを容易に得ることができ、
親水化性能および細胞接着防止性能に優れ、さらに、細胞毒性が低い細胞培養器材を容易に得ることができ、
親水化性能および生体試料付着防止性に優れ、さらに、シリコーン基材、特に、マイクロ流路を有するシリコーン基材を容易に処理できる。
pH調整剤は、前記溶液のpH値が、4.0~9.0程度、好ましくは6.0~8.0程度、より好ましくは7.0付近になるように調整して用いればよい。
該多官能化合物としては、例えば、ポリオール、多官能アミン、多官能チオール、多官能イソシアネート、ヒドラジド化合物、多官能エチレン性不飽和化合物が挙げられる。これらのうち1種を単独で使用してもよく、また2種以上を使用してもよい。
重合開始剤は、1種を単独で使用してもよく、また2種以上を使用してもよい。
具体的には、2,2-ジエトキシアセトフェノン、4'-イソプロピル-2-ヒドロキシ-2-メチル-プロピオフェノン、2-ヒドロキシ-2-メチル-プロピオフェノン、p-ジメチルアミノアセトン、p-tert-ブチルジクロロアセトフェノン、p-tert-ブチルトリクロロアセトフェノン、p-アジドベンザルアセトフェノン、ベンジル、ベンジルジメチルケタール、ベンジル-β-メトキシエチルアセタール、1-ヒドロキシシクロヘキシルフェニルケトン、ベンゾイン、ベンゾインメチルエーテル、ベンゾインエチルエーテル、ベンゾイン-n-プロピルエーテル、ベンゾインイソプロピルエーテル、ベンゾイン-n-ブチルエーテル、ベンゾインイソブチルエーテル、ベンゾフェノン、o-ベンゾイル安息香酸メチル、ミヒラーズケトン、4,4’-ビスジエチルアミノベンゾフェノン、4,4’-ジクロロベンゾフェノン、チオキサントン、2-メチルチオキサントン、2-エチルチオキサントン、2-イソプロピルチオキサントン、4-イソプロピルチオキサントン、2-クロロチオキサントン、2,4-ジエチルチオキサントン等が挙げられる。
前記メディカルデバイスは、医療用器材であれば特に制限されず、具体例としては、例えば、血液バッグ、採尿バッグ、輸血セット、縫合糸、ドレーンチューブ、各種カテーテル、ブラッドアクセス、血液回路、人工血管、人工腎臓、人工心肺、人工弁、血漿交換膜、各種吸着体、CAPD、IABP、ペースメーカー、人工関節、人工骨頭、歯科材料、各種シャントが挙げられる。
前記シリコーン基材処理用組成物で処理されるシリコーン基材としては、シリコーン系樹脂を含む基材であれば特に制限されない。このようなシリコーン基材としては、具体的には、例えば、シリコーン含有医療用デバイス、マイクロ流路を有するシリコーン基材、好ましくはシリコーン含有マイクロ流路デバイスが挙げられる。
体内へ埋め込んで使用する構造体としては、例えば、心臓ペースメーカー等の疾患が生じている生体の機能を補うための機能補助装置;埋入型バイオチップ等の生体の異常を検出するための装置;インプラント、骨固定材、縫合糸、人工血管等の医療用器具が挙げられる。
また、体内で(埋め込まずに)使用する構造体としては、カテーテル、胃カメラ等が挙げられる。
なお、マイクロ流路の流路幅や深さは、流路全長にわたって同じであってもよく、部分的に異なる大きさや形状であってもよい。
本発明における物品は、メディカルデバイス、細胞培養器材およびシリコーン基材からなる群より選ばれ、下記繰り返し単位(A)と下記繰り返し単位(B)とを有する重合体を表面の少なくとも一部に有する。
(A)親水性繰り返し単位
(B)側鎖にポリオキシアルキレン基を有し、その側鎖末端が炭素数5~30のアルキル基、炭素数5~30のアルカノイル基または炭素数6~30のアリール基で構成される繰り返し単位
本発明における、表面に重合体または重合体の架橋物を有するメディカルデバイス(以下「被処理物1」ともいう。)は、前記重合体またはその架橋物をメディカルデバイス表面の少なくとも一部に有する。
前記被処理物1は、その表面に前記重合体またはその架橋物を有するため、優れた潤滑性を有する。
なお、本明細書におけるオートクレーブ滅菌とは、第十六改正日本薬局方に記載の高圧蒸気法を指し、同方に記載の通例と同様、またはさらに長時間の条件で行うことができる。
本発明の細胞培養器材は、前記重合体を表面の少なくとも一部に有するものである。具体的には、上記重合体が少なくとも一部に塗布されたものである。
また、器材表面に親水層が形成されることによって、表面が親水的に改質され、細胞接着防止効果を有する器材であることが好ましい。
前記細胞培養器材は、前記重合体を、器材表面の少なくとも一部に設ける工程を含む方法、具体的には、器材表面の少なくとも一部にコーティングする工程を含む方法により製造できる。該コーティング以外は通常の細胞培養器材の製法と同様にして製造すればよい。該コーティングは、前記細胞接着防止剤を用いてもよいし、前記重合体のみを用いてもよいが、容易に細胞培養器材を得ることができることから、前記細胞接着防止剤を用いることが好ましい。
また、架橋剤や架橋モノマーを使用して硬化する工程を経てもよい。
本発明における細胞塊の作成方法は、前記細胞培養器材で細胞を培養することを特徴とする。
前記細胞培養器材の表面には重合体が設けられているため、器材への細胞接着が抑制される。そして、この器材中で細胞を培養することにより、細胞間のみで接着が生じ、細胞塊を得ることができる。特に、前記細胞培養器材は、細胞毒性が低いため、細胞塊の作成が阻害され難く、容易に細胞塊を得ることができる。細胞塊を得るまでの時間は、好ましくは24時間以内、より好ましくは12時間以内が望ましい。
本発明における、表面に重合体を有するシリコーン基材およびマイクロ流路を有するシリコーン基材(以下これらをまとめて「被処理物2」ともいう。)は、それぞれ、前記重合体を基材、つまり、シリコーン基材およびマイクロ流路を有するシリコーン基材表面の少なくとも一部に有する。
前記被処理物2は、その表面に前記重合体を有するため、優れた親水性および試料成分、特に生体試料吸着抑制効果を有する。
なお、マイクロ流路のコーティングは、流路の略全面(全面を含む)に行うことが好ましい。
また、架橋剤や架橋モノマーを使用して硬化する工程を経てもよい。
重量平均分子量(Mw)および数平均分子量(Mn)は、東ソー社製 TSKgel α-Mカラムを用い、流量:0.5ミリリットル/分、溶出溶媒:N-メチル-2-ピロリドン溶媒(H3PO4:0.016M、LiBr:0.030M)、カラム温度:40℃の分析条件で、ポリスチレンを標準とするゲルパーミエーションクロマトグラフィー(GPC)により測定した。
以下で得られた共重合体の構造(繰り返し単位の含有量)は、1H-NMRスペクトルに基づいて測定した。
1H-NMRスペクトルは、溶媒および内部標準物質としてd6-DMSOを用いて、BRUKER製モデルAVANCE500(500MHz)により測定した。
メトキシポリエチレングリコール(23)モノメタクリレート(M-230G(新中村化学社製)、以下「MPEGM」と称する。なお、「ポリエチレングリコール(23)」は、「(OC2H4)23」を意味する。以下同様の表現は同様の意味を有する。)8.5gと、N-メタクリロイルオキシエチル-N,N-ジメチルアンモニウム-α-N-メチルカルボキシベタイン(GLBT(大阪有機化学工業社製)、以下「GLBT」と称する。)0.25gと、ラウロキシポリエチレングリコール(30)モノメタクリレート(PLE-1300(日油社製)、以下「LPEGM」と称する。)1.25gと、重合開始剤として2,2'-アゾビス(イソブチロニトリル)((和光純薬工業社製)、以下「AIBN」と称する。)0.1gと、溶媒として純水27gおよびアセトニトリル63gとをフラスコに入れ、混合した。これに窒素を吹き込み、60℃まで昇温し、4時間重合させ、その後室温まで冷却した。得られた溶液を純水で透析することで、共重合体(N-1)の水溶液を得た。
また、得られた共重合体(N-1)の重量平均分子量は235000であり、数平均分子量は58000であり、分子量分布は4.1であった。
アクリロイルモルホリン(ACMO(KJケミカルズ社製)、以下「ACM」と称する。)8.5gと、GLBT0.25gと、LPEGM1.25gと、AIBN0.1gと、純水27gおよびアセトニトリル63gとをフラスコに入れ、混合した。これに窒素を吹き込み、60℃まで昇温し、4時間重合させ、その後室温まで冷却した。得られた溶液を純水で透析することで、共重合体(N-2)の水溶液を得た。
また、得られた共重合体(N-2)の重量平均分子量は455000であり、数平均分子量は137000であり、分子量分布は3.3であった。
ジメチルアクリルアミド(DMAA(KJケミカルズ社製)、以下「DMA」と称する。)8.5gと、GLBT0.25gと、LPEGM1.25gと、AIBN0.1gと、純水27gおよびアセトニトリル63gとをフラスコに入れ、混合した。これに窒素を吹き込み、60℃まで昇温し、4時間重合させ、その後室温まで冷却した。得られた溶液を純水で透析することで、共重合体(N-3)の水溶液を得た。
また、得られた共重合体(N-3)の重量平均分子量は499000であり、数平均分子量は125000であり、分子量分布は4.0であった。
N-ビニルピロリドン((和光純薬工業社製)、以下「NVP」と称する。)8.5gと、GLBT0.25gと、LPEGM1.25gと、AIBN0.1gと、純水27gおよびアセトニトリル63gとをフラスコに入れ、混合した。これに窒素を吹き込み、60℃まで昇温し、4時間重合させ、その後室温まで冷却した。得られた溶液を純水で透析することで、共重合体(N-4)の水溶液を得た。
また、得られた共重合体(N-4)の重量平均分子量は208000であり、数平均分子量は43000であり、分子量分布は4.8であった。
DMA8.5gと、2-メタクリロイルオキシエチルホスホリルコリン((東京化成工業社製)、以下「MPC」と称す)0.25gと、LPEGM1.25gと、AIBN0.1gと、純水27gおよびアセトニトリル63gとをフラスコに入れ、混合した。これに窒素を吹き込み、60℃まで昇温し、4時間重合させ、その後室温まで冷却した。得られた溶液を純水で透析することで、共重合体(N-5)の水溶液を得た。
また、得られた共重合体(N-5)の重量平均分子量は494000であり、数平均分子量は153000であり、分子量分布は3.2であった。
DMA8.5gと、アクリル酸((日本触媒社製)、以下「AA」と称す。)0.25gと、LPEGM1.25gと、AIBN0.1gと、純水27gおよびアセトニトリル63gとをフラスコに入れ、混合した。これに窒素を吹き込み、60℃まで昇温し、4時間重合させ、その後室温まで冷却した。得られた溶液に炭酸水素ナトリウム0.31gを加えて溶解させた後、純水で透析することで、共重合体(N-6)の水溶液を得た。
また、得られた共重合体(N-6)の重量平均分子量は436000であり、数平均分子量は103000であり、分子量分布は4.2であった。
DMA8.5gと、ジメチルアミノプロピルアクリルアミド塩化メチル4級塩(DMAPAA-Q(KJケミカルズ社製)、以下「QA」と称す。)0.25gと、LPEGM1.25gと、AIBN0.1gと、純水27gおよびアセトニトリル63gとをフラスコに入れ、混合した。これに窒素を吹き込み、60℃まで昇温し、4時間重合させ、その後室温まで冷却した。得られた溶液を純水で透析することで、共重合体(N-7)の水溶液を得た。
また、得られた共重合体(N-7)の重量平均分子量は549000であり、数平均分子量は172000であり、分子量分布は3.2であった。
MPC8.75gと、LPEGM1.25gと、AIBN0.1gと、t-ブタノール((和光純薬工業社製)、以下「TBA」と称す。)90gとをフラスコに入れ、混合した。これに窒素を吹き込み、60℃まで昇温し、4時間重合させ、その後室温まで冷却した。得られた溶液を純水で透析することで、共重合体(N-8)の水溶液を得た。
また、得られた共重合体(N-8)の重量平均分子量は153000であり、数平均分子量は39000であり、分子量分布は3.9であった。
GLBT8.75gと、LPEGM1.25gと、AIBN0.1gと、TBA90gとをフラスコに入れ、混合した。これに窒素を吹き込み、60℃まで昇温し、4時間重合させ、その後室温まで冷却した。得られた溶液を純水で透析することで、共重合体(N-9)の水溶液を得た。
また、得られた共重合体(N-9)の重量平均分子量は197000であり、数平均分子量は44000であり、分子量分布は4.5であった。
DMA8.5gと、GLBT0.25gと、ステアロキシポリエチレングリコール(30)モノメタクリレート(PSE-1300(日油社製)、以下「SPEGM」と称する。)1.25gと、AIBN0.1gと、純水27gおよびアセトニトリル63gとをフラスコに入れ、混合した。これに窒素を吹き込み、60℃まで昇温し、4時間重合させ、その後室温まで冷却した。得られた溶液を純水で透析することで、共重合体(N-10)の水溶液を得た。
また、得られた共重合体(N-10)の重量平均分子量は484000であり、数平均分子量は122000であり、分子量分布は4.0であった。
DMA8.5gと、GLBT0.25gと、LPEGM1.0gと、2-エチルヘキシルアクリレート((東京化成工業社製)、以下「EHA」と称す。)0.25gと、AIBN0.1gと、純水27gおよびアセトニトリル63gとをフラスコに入れ、混合した。これに窒素を吹き込み、60℃まで昇温し、4時間重合させ、その後室温まで冷却した。
また、得られた共重合体(N-11)の重量平均分子量は513000であり、数平均分子量は145000であり、分子量分布は3.5であった。
DMA8.5gと、GLBT0.25gと、LPEGM1.0gと、ラウリルメタクリレート(ライトエステルL(共栄社化学社製)、以下「LMA」と称す。)0.25gと、AIBN0.1gと、TBA90gとをフラスコに入れ、混合した。これに窒素を吹き込み、60℃まで昇温し、4時間重合させ、その後室温まで冷却した。
また、得られた共重合体(N-12)の重量平均分子量は465000であり、数平均分子量は119000であり、分子量分布は3.9であった。
DMA8.5gと、GLBT0.25gと、LPEGM1.0gと、ドデシルアクリルアミド((東京化成工業社製)、以下「DDAA」と称す。)0.25gと、AIBN0.1gと、純水27gとアセトニトリル63gとをフラスコに入れ、混合した。これに窒素を吹き込み、60℃まで昇温し、4時間重合させ、その後室温まで冷却した。
また、得られた共重合体(N-13)の重量平均分子量は497000であり、数平均分子量は130000であり、分子量分布は3.8であった。
DMA8.5gと、GLBT0.25gと、LPEGM1.0gと、下記式(X)で示されるシリコーンメタクリレート((東京化成工業社製)、以下「SiMA」と称す。)0.25gと、AIBN0.1gと、純水27gおよびアセトニトリル63gとをフラスコに入れ、混合した。これに窒素を吹き込み、60℃まで昇温し、4時間重合させ、その後室温まで冷却した。
また、得られた共重合体(N-14)の重量平均分子量は462000であり、数平均分子量は108000であり、分子量分布は4.3であった。
DMA8.5gと、GLBT0.25gと、LPEGM1.0gと、シリコーンメタクリレート(サイラプレーンFM-0711(JNC社製)、以下「DMSMA」と称す。)0.25gと、AIBN0.1gと、純水27gおよびアセトニトリル63gとをフラスコに入れ、混合した。これに窒素を吹き込み、60℃まで昇温し、4時間重合させ、その後室温まで冷却した。
また、得られた共重合体(N-15)の重量平均分子量は497000であり、数平均分子量は103000であり、分子量分布は4.8であった。
DMA7.75gと、GLBT0.5gと、LPEGM1.0gと、DDAA0.25gと、ジアセトンアクリルアミド((日本化成社製)、以下「DAAM」と称す。)0.5gと、AIBN0.1gと、純水27gおよびアセトニトリル63gとをフラスコに入れ、混合した。これに窒素を吹き込み、60℃まで昇温し、4時間重合させ、その後室温まで冷却した。
また、得られた共重合体(N-16)の重量平均分子量は408000であり、数平均分子量は106000であり、分子量分布は3.8であった。
DMA8.5gと、GLBT0.25gと、EHA1.25gと、AIBN0.1gと、純水27gおよびアセトニトリル63gとをフラスコに入れ、混合した。これに窒素を吹き込み、60℃まで昇温し、4時間重合させ、その後室温まで冷却した。得られた溶液を純水で透析することで、共重合体(N-17)の水溶液を得た。
また、得られた共重合体(N-17)の重量平均分子量は354000であり、数平均分子量は83000であり、分子量分布は4.3であった。
DMA8.5gと、GLBT0.25gと、LMA1.25gと、AIBN0.1gと、純水27gおよびアセトニトリル63gとをフラスコに入れ、混合した。これに窒素を吹き込み、60℃まで昇温し、4時間重合させ、その後室温まで冷却した。得られた溶液を純水で再沈殿し、乾燥することで、共重合体(N-18)を得た。
また、得られた共重合体(N-18)の重量平均分子量は438000であり、数平均分子量は101000であり、分子量分布は4.3であった。
DMA8.5gと、GLBT0.25gと、DDAA1.25gと、AIBN0.1gと、純水27gおよびアセトニトリル63gとをフラスコに入れ、混合した。これに窒素を吹き込み、60℃まで昇温し、4時間重合させ、その後室温まで冷却した。得られた溶液を純水で再沈殿し、乾燥することで、共重合体(N-19)を得た。
また、得られた共重合体(N-19)の重量平均分子量は406000であり、数平均分子量は81000であり、分子量分布は5.0であった。
DMA8.5gと、GLBT0.25gと、SiMA1.25gと、AIBN0.1gと、純水27gおよびアセトニトリル63gとをフラスコに入れ、混合した。これに窒素を吹き込み、60℃まで昇温し、4時間重合させ、その後室温まで冷却した。得られた溶液を純水で再沈殿し、乾燥することで、共重合体(N-20)を得た。
また、得られた共重合体(N-20)の重量平均分子量は360000であり、数平均分子量は95000であり、分子量分布は3.8であった。
DMA8.5gと、GLBT0.25gと、DMSMA1.25gと、AIBN0.1gと、純水27gおよびアセトニトリル63gとをフラスコに入れ、混合した。これに窒素を吹き込み、60℃まで昇温し、4時間重合させ、その後室温まで冷却した。得られた溶液を純水で再沈殿し、乾燥することで、共重合体(N-21)を得た。
また、得られた共重合体(N-21)の重量平均分子量は325000であり、数平均分子量は77000であり、分子量分布は4.2であった。
合成例1で得られた共重合体(N-1)の水溶液を用い、0.5質量%の水溶液を調製した。ウレタン製の基材をその水溶液に浸漬して35℃で2時間静置した。その後、基材を純水で3回洗浄し、未吸着ポリマーを除去することで、共重合体(N-1)でコーティングされたウレタン製基材を得た。
共重合体(N-1)の水溶液の代わりに、合成例2~16、参考例1、参考例3または参考例4で得られたものを用いた以外は実施例1-1と同様にして、各共重合体でコーティングされたウレタン製基材を得た。
合成例16で得られた共重合体(N-16)を用い、0.5質量%の水溶液を調製した。さらに、該水溶液に共重合体の10分の1質量のアジピン酸ジヒドラジドを添加、溶解させた。ウレタン製の基材をその水溶液に浸漬して35℃で2時間静置後、該水溶液から取り出し、60℃に設定したオーブンで4時間以上、加熱乾燥した。その後、基材を純水で3回洗浄し、共重合体(N-16)で架橋コーティングされたウレタン製基材を得た。
実施例1-1~1-16および比較例1-1~1-3において、ウレタン製基材からナイロン製基材に変更した以外は同様にして、各共重合体でコーティングされたナイロン製基材を得た。
実施例1-17において、ウレタン製基材をナイロン製基材に変更した以外は同様にして、共重合体(N-16)で架橋コーティングされたナイロン製基材を得た。
実施例1-1~1-34および比較例1-1~1-6の各基材について、各基材表面の水分を拭き取った後、接触角計DM-701(協和界面科学社製)を用いて液滴法による接触角を測定した。液滴は2μLの生理食塩水を用いた。試験結果を表3および4に示す。
なお、以下の試験において、コントロールとして、各合成例および参考例で得られた共重合体でコーティングされていない基材を用いた。
実施例1-1~1-34および比較例1-1~1-6の各基材について、自動摩擦摩耗解析装置TS501(協和界面科学社製)を用いて摩擦係数を測定した。
固定した基材の上に200μLの生理食塩水を添加し、点接触子を、100gf荷重、速度8mm/s、20mm幅で動かした。点接触子を動かして1往復目の摩擦係数を測定し、同様にして、2~5往復目のそれぞれの摩擦係数を測定した。なお、これらの摩擦係数は、基材上の同一箇所で行ったものである。前記1~5回目往復時のそれぞれの摩擦係数の平均値を初期摩擦係数とし、結果を表3および4の初期摩擦係数に示す。
実施例1-1~1-34および比較例1-1~1-6の各基材について、試験例2と同様の条件で、点接触子を動かした。点接触子を動かして101往復目の摩擦係数を測定し、同様にして、102~105往復目のそれぞれの摩擦係数を測定した後、これらの平均値(100往復後の摩擦係数)を算出した。なお、これらの摩擦係数は、基材上の同一箇所で行ったものである。試験例2の試験結果と、この100往復後の摩擦係数の結果とを比較し、以下のように耐久性を評価した。試験結果を表3および4に示す。
○ ; 摩擦係数の変化は認められない
△ ; 摩擦係数が上昇した(コーティング前の状態の摩擦係数未満)
× ; 摩擦係数がほぼコーティング前の状態と同等以上まで上昇した
合成例1~15および参考例1、参考例3または参考例4の各共重合体(水溶液)を用い、表5に記載の通りのポリマー濃度となるよう純水を用いて調製し、実施例2-1~2-15および比較例2-1~2-3の組成物を得た。
該組成物を用いて、以下の試験を行った。試験結果を表5または6に示す。なお、表5中のコントロールは、前記組成物の代わりに純水を用いた以外は前記と同様に試験した結果を示す。
表面がポリスチレンで構成されている6ウェルプレートのウェルに、以下の表5に示す実施例2-1~2-15および比較例2-1~2-3の組成物を2mLずつ加え、35℃に加熱した状態で2時間静置した後、純水で3回洗浄することで未吸着ポリマーを除去した。
その後培地交換し、更に44時間培養(37℃、5%CO2条件)した後、細胞の状態を倒立顕微鏡にて観察し、細胞数を血球計算盤にて計数した。
下記式に従って接着細胞密度の平均値を算出した。なお、評価はn=3で実施し、接着細胞密度は下記評価基準で評価した。
接着細胞密度(%)=〔(接着細胞数)/(コンフルエント時の細胞数)〕×100
ランク 細胞凝集
× 接着細胞密度が40%以上
△ 接着細胞密度が10%以上40%未満
○ 接着細胞密度が10%未満
HeLa細胞を3T3細胞(マウス線維芽細胞)に変更した以外は試験例1と同様にして接着細胞密度を評価した。試験結果を表5に示す。
HeLa細胞をUV♀2細胞(マウス内皮細胞)に変更した以外は試験例1と同様にして接着細胞密度を評価した。試験結果を表5に示す。
ポリスチレン製96穴プレートに各実施例または比較例の組成物1mLを加え、35℃に加熱した状態で4時間静置した後、純水で3回洗浄することで未吸着ポリマーを除去した。次いで、西洋ワサビパーオキシダーゼ標識マウスIgG抗体(AP124P:ミリポア社製)水溶液1mLを前記96穴プレートに満たし、室温で1時間インキュベートした後、リン酸緩衝生理食塩水(PBS)で3回洗浄し、TMB(3,3',5,5'-テトラメチルベンジジン)/過酸化水素水/硫酸を用いて抗体を発色させることで波長450nmの光の吸光度を測定し、この吸光度から検量線法により抗体吸着量を算出した。
細胞培養用に親水化処理された市販の48ウェルプレート(IWAKI社製)のウェルに、2×104cell/mLに調製したHeLa細胞を含む液体培地(10体積%FBS)を200μLずつ添加し、37℃、5%CO2の条件で12時間前培養した。
一方、表6に示す実施例2-16、実施例2-17、比較例2-4、比較例2-5の各共重合体をそれぞれ0.10質量%含み、かつ共重合体水溶液が10質量%となるよう共重合体含有培地を調製した。
次いで、前培養したHeLa細胞の培地を前記共重合体含有培地に交換し、37℃、5%CO2の条件で24時間培養した。なお、共重合体水溶液を純水に変更した以外は上記と同様にして培養したものをコントロールとした。
なお、表中の数値は、コントロールを100%とした時の相対値を示し、この数値が80%以上では毒性が無いことを示し、この数値が低いほど共重合体の毒性が高いことを示す。
HeLa細胞を3T3細胞に変更した以外は試験例5と同様にして細胞毒性を確認した。試験結果を表6に示す。
HeLa細胞をUV♀2細胞に変更した以外は試験例5と同様にして細胞毒性を確認した。試験結果を表6に示す。
U底の96ウェルプレートに各実施例または比較例の組成物180μLずつを添加し、37℃に加熱した状態で2時間静置した後、PBSで3回洗浄することで未吸着ポリマーを除去した。
次いで、2.5×104cell/mLのHT29細胞(ヒト大腸がん細胞)を含む液体培地(10体積%FBS)100μLをウェルに添加した。播種した細胞を37℃、5%CO2の条件で16時間培養したのち、光学顕微鏡によって細胞の様子を観察した。細胞がウェルの底面に接着している場合、ウェル全体に細胞が散らばっている状態が観察される。一方で、細胞がウェルに接着していない場合は、細胞がU底付近の中心に集まり、細胞塊が形成される。本試験はn=3で実施し、その細胞凝集のランクを平均値で評価した。細胞凝集は下記の評価基準で評価した。
ランク 細胞凝集
1 ウェル全体に細胞が散らばっている
2 ウェルの中心に細胞が集まる傾向が見られる
3 ウェルの中心に細胞が集まり細胞塊となっている
合成例1~15および参考例1、参考例3または参考例4の各共重合体(水溶液)を用い、表7に記載の通りのポリマー濃度となるよう純水を用いて調製し、実施例3-1~3-15および比較例3-1~3-3の処理用組成物を得た。
該処理用組成物を用いて、以下の試験を行った。試験結果を表7に示す。なお、表中のコントロールは、処理用組成物の代わりに純水を用いた以外は前記と同様に試験した結果を示す。
まず、10×5mmに切り出した、厚さ0.5mmのシリコーンゴムシート(SR-50、タイガースポリマー社製)を用意した。
次いで、前記シリコーンゴムシートを、各実施例または比較例の処理用組成物1mL中にそれぞれ浸漬し、35℃に加熱した状態で4時間静置した後、純水で3回洗浄することで未吸着ポリマーを除去した。次いで、各シート表面の水分を拭き取った後、接触角計DM-701(協和界面科学社製)を用いて気泡法による気泡の接触角(25℃)を測定した。気泡法による測定結果は、濡れた状態での表面親水性を示し、親水性が高ければ値は高くなる。
φ6mmに切り出した、厚さ0.5mmのシリコーンゴムシート(SR-50、タイガースポリマー社製)を用意した。
該シリコーンゴムシートを各実施例または比較例の処理用組成物1mL中にそれぞれ浸漬し、35℃に加熱した状態で4時間静置した後、純水で3回洗浄することで未吸着ポリマーを除去した。次いで、処理済みの各シリコーンゴムシートを西洋ワサビパーオキシダーゼ標識マウスIgG抗体(AP124P:ミリポア社製)水溶液1mL中にそれぞれ浸漬し、室温で1時間静置した後、PBSで3回洗浄した。該洗浄後のシリコーンゴムシートをポリスチレン製96穴プレートのウェルに移し、TMB/過酸化水素水/硫酸を用いて抗体を発色させることで波長450nmの光の吸光度を測定し、この吸光度から検量線法により抗体吸着量を算出した。
幅200μm、高さ50μmの流路を有するPDMS(ポリジメチルシロキサン)製標準チップ(フルイドウェアテクノロジーズ社製)の流路中に、下記表7に示す実施例3-3、実施例3-13、比較例3-2または比較例3-3の処理用組成物を流し込み、35℃に加熱した状態で4時間静置した後、純水で3回、PBSで3回洗浄し、未吸着ポリマーを除去した。
次いで、血液検体を一定圧力下、2μL/minの入口スピードで6分間送液し、送液直後から1分間の間に流路出口から流出した血液検体量と、送液開始後5分から6分間の間に流路出口から流出した血液検体量とをそれぞれ計測した。
Claims (13)
- 下記繰り返し単位(A)と下記繰り返し単位(B)とを有する重合体を含む、メディカルデバイス用組成物、細胞接着防止剤およびシリコーン基材処理用組成物からなる群より選ばれる1種の重合体組成物。
(A)親水性繰り返し単位
(B)側鎖にポリオキシアルキレン基を有し、その側鎖末端が炭素数5~30のアルキル基、炭素数5~30のアルカノイル基または炭素数6~30のアリール基で構成される繰り返し単位 - 繰り返し単位(A)が、側鎖にポリオキシアルキレン基を有し、その側鎖末端が水素原子または炭素数1~4のアルキル基で構成される繰り返し単位(A-1)、側鎖末端にアンモニオアルキルホスフェート基を有する繰り返し単位(A-2)、側鎖にアミド基を有する繰り返し単位(A-3)、側鎖末端に窒素および酸素を含むヘテロ環を有する繰り返し単位(A-4)、側鎖にラクタムを有する繰り返し単位(A-5)、側鎖末端にベタイン性基を有する繰り返し単位(A-6)、アニオン性繰り返し単位(A-7)、ならびに、カチオン性繰り返し単位(A-8)から選ばれる1種以上である、請求項1に記載の重合体組成物。
- 前記繰り返し単位(A)が、下記式(1)で表される繰り返し単位(A-1)、下記式(2)で表される繰り返し単位(A-2)、下記式(3)で表される繰り返し単位(A-3)、下記式(4)で表される繰り返し単位(A-4)、下記式(5)で表される繰り返し単位(A-5)、下記式(6)で表される繰り返し単位(A-6)、アニオン性繰り返し単位(A-7)、および、下記式(8)で表される繰り返し単位(A-8)から選ばれる1種以上である、請求項1または2に記載の重合体組成物。
- 前記繰り返し単位(B)がエチレン性不飽和結合を有するモノマーに由来する繰り返し単位である、請求項1~3いずれか1項に記載の重合体組成物。
- 前記重合体が、下記式(c1)で表される繰り返し単位(C-1)および下記式(c2)で表される基を側鎖末端に有する繰り返し単位(C-2)から選ばれる1種以上の繰り返し単位(C)を更に有する、請求項1~5のいずれか1項に記載の重合体組成物。
- 前記重合体が水溶性である、請求項1~6のいずれか1項に記載の重合体組成物。
- 下記繰り返し単位(A)と下記繰り返し単位(B)とを有する重合体を表面の少なくとも一部に有する、メディカルデバイス、細胞培養器材およびシリコーン基材からなる群より選ばれる1種の物品。
(A)親水性繰り返し単位
(B)側鎖にポリオキシアルキレン基を有し、その側鎖末端が炭素数5~30のアルキル基、炭素数5~30のアルカノイル基または炭素数6~30のアリール基で構成される繰り返し単位 - 前記シリコーン基材がマイクロ流路を有するシリコーン基材である、請求項8に記載の物品。
- 下記繰り返し単位(A)と下記繰り返し単位(B)とを有する重合体の架橋物を基材表面の少なくとも一部に有する、メディカルデバイス。
(A)親水性繰り返し単位
(B)側鎖にポリオキシアルキレン基を有し、その側鎖末端が炭素数5~30のアルキル基、炭素数5~30のアルカノイル基または炭素数6~30のアリール基で構成される繰り返し単位 - 下記繰り返し単位(A)と下記繰り返し単位(B)とを有する重合体を、少なくとも一部の表面に設ける工程を含む、メディカルデバイス、細胞培養器材およびシリコーン基材からなる群より選ばれる1種の物品の製造方法。
(A)親水性繰り返し単位
(B)側鎖にポリオキシアルキレン基を有し、その側鎖末端が炭素数5~30のアルキル基、炭素数5~30のアルカノイル基または炭素数6~30のアリール基で構成される繰り返し単位 - 前記シリコーン基材がマイクロ流路を有するシリコーン基材である、請求項11に記載の製造方法。
- 請求項8に記載の物品が細胞培養器材であり、該細胞培養器材で細胞を培養し、細胞塊を形成する、細胞塊の製造方法。
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