CN1996014B - Array micro-fluidic chip device for use in drug metabolism screening - Google Patents
Array micro-fluidic chip device for use in drug metabolism screening Download PDFInfo
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- CN1996014B CN1996014B CN2006101194404A CN200610119440A CN1996014B CN 1996014 B CN1996014 B CN 1996014B CN 2006101194404 A CN2006101194404 A CN 2006101194404A CN 200610119440 A CN200610119440 A CN 200610119440A CN 1996014 B CN1996014 B CN 1996014B
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Abstract
The matrix microflow control chip for medicine metabolism screening comprises sample incoming interface and micro flow control chip, with the former made of top and bottom covers, with several sample intake ducts on the top cover, the integral micro flow control chip having several storage fluid entering pool at one side, several liquid output pool, with the micro flow control chip having several micro channel buried with active protein or contained with active protein, one end of the micro channel connected with one end of the liquid storage entering pool, the other end connected with one end of the liquid storage pool, the micro flow control chip fixed between the top and bottom covers of the sample intake interface and allowing the sample intake channel interior connected with the other end of the liquid entering pool. It is convenient, simple in operation, good in stability and high in analysis flux.
Description
Technical field
The present invention relates to drug metabolism screening, a kind of specifically device that adopts array micro-fluidic chip to carry out drug metabolism screening.
Background technology
Drug metabolism screening research is significant at aspects such as new drug development design, toxicologic studies.Commitment at new drug development, the research of drug metabolism screening can be estimated the drug metabolism feature of new drug material standed for, so that seek more outstanding material standed for, therefrom provide the structural modification mentality of designing for new drug development, help to obtain medicine safely and effectively, reduce the mortality of drug candidate.Drug metabolism study relates to the generation of metabolic product, the aspects such as definite and metabolic process stability of metabolic pathway.Adopt external metabolism research method, can get rid of the body intrinsic factor disturbs, the Direct observation enzyme is to the selectivity metabolism of substrate, for bulk testing provides reliable theoretical foundation, big and the medicine that lacks sensitive detection means of particularly low, toxicity for the internal metabolism conversion ratio, the good especially research means of external metabolism research.
At present, traditional external drug metabolism screening method mainly contains hepatomicrosome incubated in vitro method, liver cell incubated in vitro method, exsomatize liver perfusion method, hepatic tissue histotomy etc., these methods exist that analysis speed is slow, reagent and the sample consumption is big, serviceable life short or hatching after shortcomings such as product is not easily separated.Along with pharmaceutical chemical development, new chemical monomer amount is increasing, presses for a kind of external fast and effectively drug metabolism screening technology.
The drug metabolism screening that appears as of micro-fluidic chip has brought new life, carries out drug metabolism screening and be the significant innovation to the drug metabolism screening technology on micro-fluidic chip.Micro-fluidic chip is the lab-on-a-chip based on microfluidic control, and its final goal is that elementary cells such as sampling, enrichment, reaction, separation, detection are integrated on more than one square centimeters the chip.On the other hand, immobilization albumen and solution mutually albumen compare and have long, advantage such as stability is high, reusable, be easy to separate with reaction product of life-span.The various fixed protein process is arranged at present, comprise investment, absorption method, covalent bond method, wherein the activity that provides of investment is the highest.Therefore, technical matters to be solved by this invention integrates micro-fluidic chip technology, embedding activated protein technology and drug metabolism screening technology exactly, with activated protein or contain the material of activated protein such as cytochrome enzyme, hepatomicrosome, liver cell etc. are embedded in the microchannel, make a kind of device of drug metabolism screening fast and effectively, to satisfy pharmaceutical chemical fast development.
Summary of the invention
The object of the present invention is to provide a kind of easy to make, simple to operate, good stability, analysis throughput height, the economic and practical array micro-fluidic chip device that is used for drug metabolism screening.
Technical scheme of the present invention is as follows: a kind of array micro-fluidic chip device that is used for drug metabolism screening, comprise a sample introduction interface, and form by upper cover plate and lower cover slip, be provided with a plurality of sample introduction siphunculus in this upper cover plate; An and micro-fluidic chip, the one side is provided with a plurality of liquid storages and goes into the pond, the other end is provided with a plurality of liquid storages and goes out the pond, also be provided with a plurality of microchannels in this micro-fluidic chip, be embedded with activated protein in it or contain active proteic substance, an end of this microchannel is gone into Chi Yiduan with this liquid storage and is connected, and the other end goes out Chi Yiduan with this liquid storage and is connected, this micro-fluidic chip is installed with between the upper and lower cover plate of sample introduction interface, and makes corresponding the communicating of the other end that the inner and this liquid storage of this sample introduction siphunculus are gone into the pond; The microchannel of this micro-fluidic chip is shape or twist linearly.
According to embodiments of the invention, this micro-fluidic chip is formed by the cast of material monolithics such as the dimethyl silicone polymer (PDMS) or the hydrosol; Embedding activated protein or the material that contains active proteic substance are collosol and gel; Liquid storage goes out the pond and is substituted by corresponding stainless steel microtubule in this micro-fluidic chip, and this stainless steel microtubule is terminal to be connected the quartz that draws and receive shower nozzle; The internal diameter of this stainless steel microtubule, external diameter are respectively 50-100 μ m, 200-400 μ m; The internal diameter of the sample introduction siphunculus in the sample introduction interface, external diameter are respectively 50-100 μ m, 200-400 μ m; The outer end of this sample introduction siphunculus can link to each other with a peristaltic pump, to realize auto injection; Go into also to be provided with an O shape circle that is used for sealing between the pond at the sample introduction siphunculus of sample introduction interface and the liquid storage of chip; The upper and lower cover plate of this sample introduction interface is regulated fixing by the screw that is located at its both sides with screw.
Advantage of the present invention is:
1. device is made simply, and is easy to operate, but auto injection and online, offline inspection;
2. chip is the integration chip, and without sealing-in, mechanical voltage endurance capability is strong;
3. the bio-compatibility of chip is good, stability is high, can repeat repeatedly to use;
4. sample and reagent consumption are little;
5. reaction velocity is fast, and reaction product is easy to separate.
Description of drawings
Fig. 1-3 is the schematic top plan view of three kinds of array micro-fluidic chips of apparatus of the present invention.
Fig. 4 is apparatus of the present invention diagrammatic cross-section.
Fig. 5 is the testing result figure after metabolic response takes place on this device chip substrate.
Embodiment
Consult Fig. 4, apparatus of the present invention comprise and are used for introducing the sample introduction interface of sample and are used for for sample aitiogenic micro-fluidic chip 1.The sample introduction interface comprises upper cover plate 6, lower cover slip 7, and available for example organic glass is made, and the correspondence position on upper and lower cover plate 6,7 both sides sets up two screws separately so that make upper and lower cover plate 6,7 relative fixed by 9 adjustings of two screws.In addition, be provided with a plurality of through holes on upper cover plate 6, it is corresponding that its position and number and the chip liquid storage that hereinafter will describe in detail are gone into pond 3, and what the quantity of through hole showed in Fig. 4 is four, but also can be more as five or fewer as two.In addition, in these through holes, be installed with the sample introduction siphunculus of making of stainless steel or other suitable material 10 respectively, its inside and outside footpath is respectively 50-100 μ m, 200-400 μ m, and being fixed with the O type circle 8 that seals in periphery, sample introduction siphunculus 10 lower end, its size is gone into the big or small corresponding of pond 3 with the chip liquid storage.The other end of sample introduction siphunculus 10 can be connected with peristaltic pump (figure does not show), so that the automatic introducing of sample to be analyzed.
The micro-fluidic chip 1 of apparatus of the present invention adopts integrated poured method to make by dimethyl silicone polymer (PDMS), and Fig. 1-3 has provided its structural representation.As seen from the figure, be provided with four microchannels 2 that are array-like in the micro-fluidic chip 1, alinement shape (Fig. 1) or spirality (Fig. 2), the number of array-like microchannel 2 can be greater or less than four, as 2-5.Obviously, helical microchannel 2, thus the effective length that can increase passage makes example reaction more abundant.By figure also as can be known, an end of every microchannel 2 is gone into pond 3 with a liquid storage and is linked to each other, thereby realizes sample feeding by above-mentioned sample introduction interface.The other end of microchannel 2 is connected with liquid storage and goes out pond (Fig. 1,2) or stainless steel microtubule 4 (Fig. 3), be used for storing or the acceptable response product, reaction product is carried out offline inspection by detecting devices such as mass spectrum or laser-induced fluorescence (LIF), if the quartz that will draw receive end that shower nozzle 5 is bonded in this microtubule 4 then can with the online detection of electro spraying ionization-mass spectrometry realization response product.In the present embodiment, liquid storage is gone into pond 3 and is cylindrical shape, and column diameter is about 0.3cm, and volume is about 20 μ L.Among the present invention, the internal diameter of microchannel 2 is 50-100 μ m; The internal diameter of stainless steel microtubule 4, external diameter are respectively 50-100 μ m, 200-400 μ m.In addition, in this array-like microchannel 2, the employing sol-gal process is embedded with activated protein or contains the material of activated protein.
As shown in Figure 4, above-mentioned micro-fluidic chip 1 be fixedly arranged in the sample introduction interface on, lower cover slip 6, between 7, and, the O shape circle 8 that the position of this chip 1 should make its liquid storage go into pond 3 and sample introduction interface aligns, therefore, sample introduction siphunculus 10 1 ends of sample introduction interface are just gone into pond 3 with the liquid storage of chip 1 and are connected, and because its other end can be connected with peristaltic pump, so utilizing peristaltic pump sample can be gone into pond 3 by sample introduction siphunculus 10 via the liquid storage of chip 1 is incorporated in the microchannel 2, and there be embedded with activated protein or contain the substance reaction of activated protein, then be stored in the liquid storage that links to each other with microchannel 2 other ends through the product of reaction and go out in the pond to be detected or directly carry out online detection.
Because cytochrome enzyme Cyp4503A4, Cyp4502C9, Cyp4502D6 account for 50% of people liver Cyp450s total amount altogether, about 80% medicine is by these enzymes metabolisms, so the research of relevant Cyp450s is especially important.In view of this, as an example, the present invention utilizes silicasol that hepatomicrosome Cyp3A4 is embedded in chip 1 microchannel 2, used chip 1, the size of microchannel 2 is respectively 7.8cm * 2.8cm * 0.4cm, 80 μ m i.d. * 5.0cm, sample Verapamil solution is introduced in chip 1 microchannel 2, Verapamil reacts with hepatomicrosome Cyp3A4 in microchannel 2, collect metabolic product, utilize Mass Spectrometer Method, testing result as shown in Figure 5, wherein 11 is substrate Verapamils through being embedded with the metabolite spectrum chromatographic peak that is produced behind the Cyp3A4 hepatomicrosome microchannel, the 12nd, and the substrate Verapamil is through being embedded with behind the Cyp3A4 hepatomicrosome microchannel the not Verapamil mass spectrum chromatographic peak of complete reaction.
Though the present invention discloses as above with preferred embodiment; right its is not in order to limiting the present invention, anyly has the knack of this skill person, without departing from the spirit and scope of the invention; when can doing a little change and retouching, so the present invention's protection domain defines when looking appended claim scope.
Claims (4)
1. array micro-fluidic chip device that is used for drug metabolism screening comprises:
One sample introduction interface, be made up of upper cover plate and lower cover slip, be provided with a plurality of sample introduction siphunculus in this upper cover plate, the internal diameter of described sample introduction siphunculus, external diameter are respectively 50-100 μ m, 200-400 μ m, and the outer end of described sample introduction siphunculus links to each other with a peristaltic pump, to realize auto injection; And
One micro-fluidic chip, by integrated poured the forming of dimethyl silicone polymer (PDMS), the one side is provided with a plurality of liquid storages and goes into the pond, the other end is provided with a plurality of liquid storages and goes out the pond, also be provided with a plurality of microchannels in this micro-fluidic chip, activated protein is arranged or contain active proteic substance with sol-gel embedding in it, one end of this microchannel is gone into Chi Yiduan with this liquid storage and is connected, the other end goes out Chi Yiduan with this liquid storage and is connected, this micro-fluidic chip is installed with between the upper and lower cover plate of sample introduction interface, and makes corresponding the communicating of the other end that the inner and this liquid storage of this sample introduction siphunculus are gone into the pond;
Wherein: go into also to be provided with an O shape circle that is used for sealing between the pond at the sample introduction siphunculus of sample introduction interface and the liquid storage of chip.
2. the array micro-fluidic chip device that is used for drug metabolism screening according to claim 1, it is characterized in that, liquid storage goes out the pond and is substituted by corresponding stainless steel microtubule in this micro-fluidic chip, this stainless steel microtubule is terminal to be connected the quartz that draws and receives shower nozzle, wherein, the internal diameter of described stainless steel microtubule, external diameter are respectively 50-100 μ m, 200-400 μ m.
3. the array micro-fluidic chip device that is used for drug metabolism screening according to claim 1 is characterized in that, the upper and lower cover plate of this sample introduction interface is regulated fixing by the screw that is located at its both sides with screw.
4. the array micro-fluidic chip device that is used for drug metabolism screening according to claim 1 is characterized in that, the microchannel of this micro-fluidic chip is shape or twist linearly.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN2006101194404A CN1996014B (en) | 2006-12-12 | 2006-12-12 | Array micro-fluidic chip device for use in drug metabolism screening |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2006101194404A CN1996014B (en) | 2006-12-12 | 2006-12-12 | Array micro-fluidic chip device for use in drug metabolism screening |
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| CN1996014A CN1996014A (en) | 2007-07-11 |
| CN1996014B true CN1996014B (en) | 2011-06-01 |
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| CN2006101194404A Expired - Fee Related CN1996014B (en) | 2006-12-12 | 2006-12-12 | Array micro-fluidic chip device for use in drug metabolism screening |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101376908B (en) * | 2007-08-29 | 2012-01-25 | 中国科学院大连化学物理研究所 | Method for studying medicament metabolism based on molecule and cell level |
| CN101709261B (en) * | 2009-12-11 | 2013-06-19 | 香港城市大学深圳研究院 | Microfluidic microbead array chip and application thereof in virus analysis |
| CN102921481A (en) * | 2012-10-31 | 2013-02-13 | 太原理工大学 | Microfluid array device |
| CN106925359A (en) * | 2017-04-21 | 2017-07-07 | 苏州汶颢微流控技术股份有限公司 | Micro grade is than loading micro-fluidic chip system and upper quadrat method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1469123A (en) * | 2002-07-18 | 2004-01-21 | 中国科学院大连化学物理研究所 | Microflow control chip for protein analysis and its application in protein analysis |
| CN1616967A (en) * | 2003-11-11 | 2005-05-18 | 中国科学院大连化学物理研究所 | Micro fluid control chip for immunilogical analysis and its use in immunilogical analysis |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1469123A (en) * | 2002-07-18 | 2004-01-21 | 中国科学院大连化学物理研究所 | Microflow control chip for protein analysis and its application in protein analysis |
| CN1616967A (en) * | 2003-11-11 | 2005-05-18 | 中国科学院大连化学物理研究所 | Micro fluid control chip for immunilogical analysis and its use in immunilogical analysis |
Non-Patent Citations (3)
| Title |
|---|
| Huiling Wu et al.Microfluidic enzymatic-reactors for peptide mapping: strategy, characterization, and performance.《Lab Chip》.2004,(第4期),第588–597页. * |
| 方肇伦等.微流控芯片发展与展望.《现代科学仪器》.2001,(第4期),第3-6页. * |
| 田玉平等.用于蛋白质酶解的一体化PDMS微流控芯片.《化学世界》.2005,(第10期),第590-592页. * |
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Granted publication date: 20110601 Termination date: 20131212 |