CN1317556C - Biomedical anodynia blood taking micro needle chip and method for making same - Google Patents

Biomedical anodynia blood taking micro needle chip and method for making same Download PDF

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Publication number
CN1317556C
CN1317556C CNB031375529A CN03137552A CN1317556C CN 1317556 C CN1317556 C CN 1317556C CN B031375529 A CNB031375529 A CN B031375529A CN 03137552 A CN03137552 A CN 03137552A CN 1317556 C CN1317556 C CN 1317556C
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chip
enzyme
silicon
micro
micropin
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CN1566939A (en
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周兆英
刘冉
王晓浩
叶雄英
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Tsinghua University
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Tsinghua University
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Abstract

The present invention discloses a micro-needle chip for blood collection without pain in biomedicine and a preparing method thereof, which relates to a blood collecting micro-needle with a biosensor and a preparing method thereof. The micro-needle chip is formed by that an upper sheet is bonded with a lower sheet, wherein a micro-pipeline is arranged in the middle of the upper sheet, a biosensor is arranged at one end of the lower sheet, the micro-needle comprises a needle head and a needle seat, and the biosensor comprises an enzyme electrode connected with the micro-pipeline and a metal electrode connected with the enzyme electrode. In the present invention, the structure of the micro-needle and the structure of the electrodes are realized through MEMS technology, and the blood collecting micro-needle chip is formed by solidified enzyme technology in biochemistry; blood is automatically collected under the capillary action, external mechanical force is not required completely, and the micro-needle has a small size and causes little damage to the skin so that blood collection without pain is realized; the volume of the micro-pipeline is used for realizing the quantitative collection of a trace amount of blood; the biosensor is integrated into the micro-pipeline so that sampling and sensing are integrated into one body; a blood sample after sampling directly comes into contact with enzyme and reacts with the enzyme so as to simplify operation steps and avoid sample exposure in the air. Consequently, the quality of detected blood is ensured.

Description

Biomedical painless blood sampling micropin chip and preparation method thereof
Technical field
The present invention relates to a kind of painless blood sampling micropin of MEMS (micro electro mechanical system) (MEMS) chip that has biology sensor and preparation method thereof, belong to biomedical detecting instrument field.
Background technology
Sampling is the first step that human body fluid (particularly whole blood) detects, and also is a very crucial step.The detection major part of a lot of diseases is by human body fluid (as blood) being carried out analyzing and testing, obtaining physiological parameter (as blood sugar, cholesterol, lactic acid etc.) and diagnose.The method of sampling has direct influence to the detection of blood, if the method for sampling is improper, the blood of extraction can't be used for detecting, and will influence the accuracy that detects when serious.
Blood sample generally is to obtain by venipuncture or by the pricking method of lancet adversary fingering row at present.For example, the diabetic can utilize the home test instrument to record blood sugar level by the finger sampling.These testing tools require to obtain the sample of bleeding and are placed in the instrument, calculate and demonstrate the blood sugar concentration of blood sample.In order to obtain this sample of bleeding, need to use lancing apparatus to come prick skin (being typically) at the finger place.And then extruding thorn tear, from the enough blood samples of surface extraction of finger; Blood sample is transferred on the testing tool again.The method of venipuncture is blood sample to be extracted in syringe or the bottle from vein by hypodermic needle, is sent in the testing tool again.In these two kinds of methods, blood sample is expelled in the sensing equipment, it or be loaded with the capsule of sensor, or the more ripe instrument of test usefulness in test strips (as the family expenses analysis of blood sugar) or the laboratory.
The deficiency of above-mentioned technology is that operation steps is more loaded down with trivial details, and blood sample is exposed in air; Existing in addition blood taking needle also can make the patient that pain is arranged.Pain is to aggravate along with the increase of the increase of the size of blood collection needles and blood sampling volume.The size of conventional lancet minimum is also in the submillimeter magnitude at present, not only damage biological tissue easily, and since blood sample to be sent to the efficient of sensing equipment very low, cause the actual blood sampling volume blood sample more required many than reality, therefore make the people can feel the tangible pain sensation, thus also caused a lot of people particularly children to the feared state of mind of blood testing.
In addition, the finger sampling can cause the change of analytical concentration in the process of skin surface extruding and extraction blood sample.Because the blood sample that obtains mixes interstitial fluid easily or exposes in the environment (air) around, also can influence the concentration of blood sample.In view of these reasons, the present method of finger sampling can not be used for test as contents such as parameter of vim and vigour.
Summary of the invention
At the deficiencies in the prior art and defective, the purpose of this invention is to provide the painless blood sampling micropin of a kind of biomedicine chip and preparation method thereof.Utilize MEMS (micro electro mechanical system) (MEMS) technology and biosensor technology to combine, realize sampling and be transmitted in one, the micro quantitative determination blood sampling, the step that simplifies the operation, and make blood sample not be exposed in the air; Cause wound little to biological tissue simultaneously, do not have pain.
Technical scheme of the present invention is as follows: the painless blood sampling micropin of a kind of biomedicine chip, it is characterized in that: this blood sampling micropin chip be by centre band microchannel last slice and following bonding of one end band biology sensor form, it comprises syringe needle and needle stand two parts; Described biology sensor comprises two enzyme electrodes that are arranged in the microchannel and two metal electrodes that link to each other with described enzyme electrode respectively.
Technical characterictic of the present invention also is: described two metal electrodes are connected as a single entity with the substrate of two enzyme electrodes respectively, and gold copper-base alloy is all adopted in the substrate of two enzyme electrodes; Described last slice and following sheet employing silicon chip.
The section of the microchannel described in the present invention is a triangle.
The present invention also provides the painless blood sampling micropin of a kind of described biomedicine chip production method, and this method comprises the steps:
1) thickness be 400 μ m-500 μ m on the two-sided growthing silica and the silicon nitride layer of silicon chip 1 and lower silicon slice 2;
2) at positive photoetching, whirl coating, the sputter gold of lower silicon slice 2, remove photoresist then, form the base material of biology sensor, and prepare for bonding technology;
3) carry out photoetching in the front of last silicon chip 1 and lower silicon slice 2 respectively;
4) the potassium hydroxide bulk silicon etching is carried out in the front of last silicon chip 1 and lower silicon slice 2, last silicon chip 1 forms the microneedle configuration that has open pipe;
5) to lower silicon slice 2 back side photoetching; Silicon dioxide and silicon nitride are removed in the positive back side of last silicon chip 1;
6) part of oil gidling on last silicon chip 1 and the lower silicon slice 2 is carried out gold silicon congruent melting bonding, it is combined closely, form whole micropin;
7) whole micropin is carried out the potassium hydroxide bulk silicon etching;
8) biology enzyme is mixed with solution with pure water;
9) micropin is immersed in the described enzyme solutions, utilizes the method for enzyme and the combination of gold electrode electrostatic force to adsorb, treat that enzyme solidifies after, utilize the unnecessary enzyme solutions of micro pipette sucking-off in pipeline again, airing micropin chip.
The present invention compared with prior art has the following advantages and the high-lighting effect:
1. utilize the micropin size of MEMS technology preparation small, very little to skin injury, have no side effect, realized painless blood sampling.Be specially adapted to frequently to carry out the diabetic of blood sugar test, the old man and the baby of skin fragility
2. whole micropin adopts silicon materials, low price, possess hydrophilic property, it is small-sized to add the sealing microchannel, after micropin thrusts skin, utilizes capillarity to take a blood sample automatically, fully without mechanical external force, whole process does not have the external force squeezes blood in addition, and blood sampling volume can quantitatively be taken a blood sample according to the size of microchannel, and the volume of control microchannel just can be realized the volume of required blood sample.
3. MEMS technology and biosensor technology combine, and integral biosensor in microchannel is realized the direct and enzyme contact reaction of sampling back blood sample, centralized procurement sample and sensing are in one, simplify operation steps, also avoided sample in air, to expose, guaranteed to detect the quality of blood.
4. have the interface that is connected with analyser, conveniently carry out the signal transmission.
Description of drawings
Fig. 1 is the general structure synoptic diagram of micropin chip provided by the invention.
Fig. 2 is the A-A cut-open view of Fig. 1.
Fig. 3 is the structural representation of micropin chip last slice.
Fig. 4 is the structural representation of sheet under the micropin chip.
Fig. 5 is the process chart of the present invention's preparation.
Embodiment
Describe concrete structure of the present invention and preferred embodiment in detail below in conjunction with accompanying drawing.
The painless blood sampling micropin of biomedicine provided by the present invention chip is to be formed by the last silicon chip 1 of centre band microchannel 3 and lower silicon slice 2 bondings of one end band biology sensor, comprises syringe needle 4 and needle stand 6 two parts.In needle stand 6, be provided with biology sensor.This biology sensor comprises the enzyme electrode that is arranged in the microchannel (working electrode 9 with to electrode 10) and the metal electrode 7,8 that links to each other with enzyme electrode; Metal electrode 7,8 links to each other with gold copper-base alloy substrate to electrode 10 with working electrode 9 respectively, plays the effect of conduction.The length of syringe needle 4 can be at 1~6mm, and width is about about 100 μ m; The width of microchannel 3, highly all about 20 μ m, the section of microchannel 3 is a triangle, is convenient to realize processing.The end of the syringe needle 4 of micropin chip has needle point 5, and during sampling, needle point 5 thrusts biological tissue's (not shown), from patient skin extraction blood.Utilize capillary force, blood sucks in the microchannel 3 automatically, directly with working electrode 9 with electrode 10 is contacted, with the curing enzyme reaction, produce little current signal, carry out signal by metal electrode 7,8 and transfer to outside analyser (not shown),, detect signal and analyze by signal Processing such as amplification filtering.
Fig. 5 is a manufacture craft process flow diagram of the present invention.The one, by the structure of MEMS technology realization micropin and electrode; The 2nd, utilize the curing zymotechnic in the biological chemistry, carry out enzyme and solidify, make enzyme attached on the electrode after graphical, concrete processing step is as follows:
1) at first two thickness be 400-500 μ m on the two-sided growthing silica (SiO of silicon chip 1 and lower silicon slice 2 2)/silicon nitride (Si 3N 4) layer;
2) to lower silicon slice 2 photoetching, whirl coating, sputter gold (Au), remove photoresist, form the substrate of biology sensor, for preparing with the bonding of last silicon chip 1;
3) last silicon chip 1 and lower silicon slice 2 are carried out photoetching;
4) last silicon chip 1 and lower silicon slice 2 are carried out potassium hydroxide (KOH) bulk silicon etching, on last silicon chip 1, become to have the microneedle configuration of open pipe;
5) to lower silicon slice 2 back side photoetching; Remove the silicon dioxide (SiO that goes up the silicon chip 1 positive back side 2) and silicon nitride (Si 3N 4) layer;
6) part of oil gidling on last silicon chip 1 and the lower silicon slice 2 is carried out gold silicon congruent melting bonding, silicon chip 1 and lower silicon slice 2 are combined closely, form and to have last slice and the three-dimensional microneedle configuration of following sheet;
7) micropin behind the para-linkage carries out the potassium hydroxide bulk silicon etching;
8) solidify enzyme: biology enzyme is prepared into enzyme solutions (can be different types of enzyme, for example solidify glucolase and be used for blood sugar test) by finite concentration with the pure water dilution;
9) without a point sample point sample, directly micropin is immersed in the enzyme solutions, utilize the method for enzyme and the combination of gold electrode electrostatic force to adsorb, through certain hour, treat to utilize the unnecessary enzyme solutions of micro pipette sucking-off in pipeline, airing micropin chip after enzyme solidifies.
Above-mentioned process is under the condition that satisfies micropin chip structure and function, has taken into full account the feasibility of technology, reduces processing step as far as possible, provides cost savings.Two silicon chips are processed simultaneously, have saved identical technological process; The sputter gold can be used as electrode simultaneously and uses in order to realize the better bonding of two silicon chips, forms gold electrode.
The purpose of bonding is to make to form combination closely between nonmetal silicon and the metallic gold, thereby makes two silicon chips form the spatial structure of a micropin, has realized the sealing of the microchannel 3 in the micropin.Last slice (go up silicon chip 1) of micropin formed the microneedle configuration that has open pipe by bulk silicon etching technology; Following sheet (lower silicon slice 2) mainly contains two effects: the one and last slice bonding, finish the sealing of microchannel 3, and realized the transmission of fluid; The 2nd, integral biosensor.Following sheet is a planar structure, and sputter patterned electrodes in the above is easy more than the surface of nonplanar structure, and more accurate.Working electrode 9 and to electrode 10 in microchannel 3, be substrate with the gold copper-base alloy, solidify enzyme and reaction of blood above and produce current signal.Whole process does not have the external force squeezes blood, does not expose in air yet, has guaranteed to detect the quality of blood.In addition, blood sampling volume has just obtained quantitatively according to the size of microchannel, and the volume of control microchannel just can be realized the volume of required blood sample.

Claims (5)

1. the painless blood sampling micropin of biomedicine chip is characterized in that: this blood sampling micropin chip be by centre band microchannel (3) last slice and following bonding of one end band biology sensor form, comprise syringe needle and needle stand two parts; Described biology sensor comprises two enzyme electrodes (9,10) that are arranged in the microchannel and two metal electrodes (7,8) that link to each other with described enzyme electrode respectively.
2. according to the painless blood sampling micropin of the described biomedicine of claim 1 chip, it is characterized in that: described two metal electrodes are connected as a single entity with the substrate of two enzyme electrodes respectively, and gold copper-base alloy is all adopted in the substrate of two enzyme electrodes.
3. according to claim 1 or the painless blood sampling micropin of 2 described biomedicines chip, it is characterized in that: described blood sampling micropin chip last slice and following sheet employing silicon chip.
4. according to the painless blood sampling micropin of the described biomedicine of claim 3 chip, it is characterized in that: the section of described microchannel (3) is a triangle.
5. the painless blood sampling micropin of biomedicine as claimed in claim 1 chip production method, this method comprises the steps:
1) thickness be 400 μ m-500 μ m on the two-sided growthing silica and the silicon nitride layer of silicon chip (1) and lower silicon slice (2);
2) at positive photoetching, whirl coating, the sputter gold of lower silicon slice (2), remove photoresist then, form the biosensor substrate material, and prepare for bonding technology;
3) carry out photoetching in the front of last silicon chip (1) and lower silicon slice (2) respectively;
4) the potassium hydroxide bulk silicon etching is carried out in the front of last silicon chip (1) and lower silicon slice (2), last silicon chip (1) forms the microneedle configuration that has open pipe;
5) to lower silicon slice (2) back side photoetching; The positive back side of silicon chip (1) be will go up and silicon dioxide and silicon nitride removed;
6) part of last silicon chip (1) and the last oil gidling of lower silicon slice (2) is carried out gold silicon congruent melting bonding, it is combined closely, form whole micropin;
7) whole micropin is carried out the potassium hydroxide bulk silicon etching;
8) biology enzyme is mixed with solution with pure water;
9) micropin is immersed in the described enzyme solutions, utilizes the method for enzyme and the combination of gold electrode electrostatic force to adsorb, treat that enzyme solidifies after, utilize the unnecessary enzyme solutions of micro pipette sucking-off in pipeline again, airing micropin chip.
CNB031375529A 2003-06-18 2003-06-18 Biomedical anodynia blood taking micro needle chip and method for making same Expired - Fee Related CN1317556C (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101905856A (en) * 2010-06-11 2010-12-08 北京大学 Method for preparing plane hollow microneedle for transdermal administration

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US7955271B2 (en) * 2006-10-13 2011-06-07 Roche Diagnostics Operations, Inc. Tape transport lance sampler
US7766846B2 (en) * 2008-01-28 2010-08-03 Roche Diagnostics Operations, Inc. Rapid blood expression and sampling
CN105748090A (en) * 2016-02-02 2016-07-13 上海交通大学 Minimally invasive sampling and injecting device based on MEMS microneedle
CN106860972B (en) * 2017-01-22 2022-10-21 杭州电子科技大学 Intelligent insulin pen
CN109730695A (en) * 2018-12-28 2019-05-10 浙江清华柔性电子技术研究院 Tissue fluid detection device

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JPH1028683A (en) * 1996-05-15 1998-02-03 Nok Corp Blood sugar value meter integrally incorporated with lancet
JPH11242011A (en) * 1998-02-26 1999-09-07 Kdk Corp Blood measurement device
CN1407871A (en) * 1999-12-13 2003-04-02 爱科来株式会社 Body fluid measuring apparatus with lancet and lancet holder used for the measuring apparatus

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Publication number Priority date Publication date Assignee Title
CN2031655U (en) * 1988-02-08 1989-02-01 山东医科大学 Multifunction composite type cardiac catheter
JPH1028683A (en) * 1996-05-15 1998-02-03 Nok Corp Blood sugar value meter integrally incorporated with lancet
JPH11242011A (en) * 1998-02-26 1999-09-07 Kdk Corp Blood measurement device
CN1407871A (en) * 1999-12-13 2003-04-02 爱科来株式会社 Body fluid measuring apparatus with lancet and lancet holder used for the measuring apparatus

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Title
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101905856A (en) * 2010-06-11 2010-12-08 北京大学 Method for preparing plane hollow microneedle for transdermal administration

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