CN104668002B - Compact fluid analysis device and manufacture method thereof - Google Patents
Compact fluid analysis device and manufacture method thereof Download PDFInfo
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- CN104668002B CN104668002B CN201410852370.8A CN201410852370A CN104668002B CN 104668002 B CN104668002 B CN 104668002B CN 201410852370 A CN201410852370 A CN 201410852370A CN 104668002 B CN104668002 B CN 104668002B
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Abstract
In first aspect, the present invention relates to the device for analysing fluid sample.Described device comprises: Flow Control substrate, comprising: be embedded in and be configured for the microfluidic components by capillary force, fluid sample being propagated through this device in Flow Control substrate; Be connected to the device for providing fluid sample of this microfluidic components; Be attached to this Flow Control substrate and cover this Flow Control substrate at least partly and the lid of closing this microfluidic components at least partly; Wherein this Flow Control substrate is silicon Flow Control substrate and wherein this lid is CMOS chip.In second aspect, various embodiments of the present invention relate to the method for the manufacture of such device.The method comprises: provide Flow Control substrate; Lid is provided; By CMOS compatible joining process, Flow Control substrate is attached to lid with at least part of closing flow control substrate.
Description
Technical field
The present invention relates to bioanalysis devices field.Specifically, the present invention relates to the compact device that fluid sample is analyzed.More specifically, the present invention relates to the laboratory device on the fully-integrated chip analyzed for fluid sample.
Background technology
Current, there is prior art real-time test (point-of-care) device being used for blood analysis.The shortcoming of these devices is that their size depends on the different assemblies performed needed for blood analysis.In these devices, outside pump is a part for real-time test instrument.In some devices, micropump is used to propagate the fluid passage of sample by device.The use of pump adds size and the expense of device, and this makes them be not suitable for use in disposable device.Current disposable device is inserted in expensive readout equipment usually, has the different electronics of multiple non-once or optical module to read the biochemical reaction occurred in disposable device.Another shortcoming of the real-time test device of prior art is their manufacturing expense.
Other prior art device is effluent test paper.Cellulose manufacture used usually by these test paper, and this does not allow the accurate control of the flowing to the fluid sample propagating through test paper.This makes the range of application of these devices narrow.
Need that the cost for the fully-integrated analysis of fluid sample is few, easy to use, disposable, compact device.
Summary of the invention
In first aspect, the present invention relates to the device for analysing fluid sample.Described device comprises: Flow Control substrate, comprising: be embedded in the microfluidic components in Flow Control substrate, is configured for propagate fluid sample by capillary force and pass through microfluidic components; And be connected to the device for providing fluid sample of microfluidic components; Be attached at least part of covering Flow Control substrate of Flow Control substrate and the lid of at least part of closedown microfluidic components.Flow Control substrate is silicon Flow Control substrate, and lid is CMOS chip.
According to each aspect of the present invention, when fluid sample is present in device, contacting with fluid sample at least partially of lid.
According to each aspect of the present invention, lid comprises transistor layer, this transistor layer is electrically connected at least one electronic building brick, this electronic building brick is following at least one: biological sensing circuit, for sense the electrode of object, the electrode for fluid actuated object, the circuit for data communication object, circuit for RFDC object, temperature sensor, for temperature controlled heater electrode, and the fluid sensor controlled for viscosity of fluid and electrode.
According to various embodiments of the present invention, for providing the device of fluid sample to be the integrated pin made with silicon, and comprise the Flow Control passage of the inside being connected to microfluidic components.This pin is the outstanding part of Flow Control substrate and is placed with the transdermal tissue when pressing skin histology.
According to various embodiments of the present invention, Flow Control substrate comprises otch, and pin is arranged in otch.
According to various embodiments of the present invention, Flow Control substrate comprises the operator guards for the protection of pin, and this operator guards is attached to Flow Control substrate removedly.
According to various embodiments of the present invention, be inlet for providing the device of fluid sample.Sample drop is inserted in microfluidic components by the mode of capillary attraction.Microfluidic components can comprise different Flow Control compartments, such as, analyze for organizing (muti-omic) more.Different micro-fluidic compartments can have the identical or different degree of depth.Different micro-fluidic compartments can by separating (such as by fluid force or pass through electric current) activates in any suitable manner valve (valve).Electrode for activating can be comprised on Flow Control substrate or lid.
According to various embodiments of the present invention, Flow Control substrate or lid also can comprise at least one optical waveguide to allow the optical excitation also senses flow sample body when fluid sample exists in device.Flow Control substrate or lid also can comprise filter, distribute measure fluorescence signal for refusing optical excitation.Flow Control substrate or lid can comprise multispectral section of filter for measuring the fluorescence signal with multiple color.Flow Control substrate or lid can comprise optical waveguide and/or aperture to irradiate sample for performing without lens microscopic method.
According to various embodiments of the present invention, Flow Control substrate or lid comprise at least one through hole for biochemical reagents being applied at least one region of microfluidic components or being applied at least one region of lid.
According to various embodiments of the present invention, the polymer that lid uses photoetching to form pattern is engaged to Flow Control substrate.
According to various embodiments of the present invention, this device also can comprise the metal contact being electrically connected to lid, is generated and the signal of telecommunication captured by the measuring system in lid by fluid for reading.According to various embodiments of the present invention, the lid of this device also can comprise CMOS active pixel, for the reading of the optical signal from fluid.
According to various embodiments of the present invention, manufacturing with transparent material, to allow the optical check of the fluid sample in microfluidic components at least partly of Flow Control substrate and/or lid.
According to various embodiments of the present invention, the shape of this device allows to be inserted in mobile communication equipment.
In second aspect, various embodiments of the present invention, relate to the method for the manufacture of the device for analysing fluid sample.The method comprises: provide Flow Control substrate; Lid is provided; This Flow Control substrate is attached to described lid to close this Flow Control substrate at least in part.Flow Control substrate is silicon Flow Control substrate, and lid is CMOS chip, and Flow Control substrate uses the compatible joining process of CMOS to be attached to lid.
According to various embodiments of the present invention, provide Flow Control substrate to comprise: to provide silicon substrate, provide mask layer, such as oxidation mask, patterned oxide mask to create fine structure in oxidation mask; There is provided protective layer to comprise oxidation mask; Patterning coarse-texture; Etch this coarse-texture; Generate oxide to protect this coarse-texture; Remove protective layer and etch fine structure; Remove oxide.
According to various embodiments of the present invention, provide Flow Control substrate to comprise and silicon substrate is provided, provide multiple mask in the mode of every one deck on the top of another layer, and use each mask to create the micro-fluidic structure of different depth.
According to each specific embodiment of the present invention, there is provided Flow Control substrate to comprise and silicon substrate is provided, there is provided the first oxide mask, patterning micro-fluidic structure, by this substrate etch to the single degree of depth, second oxide mask is provided, patterning micro-fluidic structure, by this substrate etch to second degree of depth, and, if necessary, repeat these steps to create multiple degree of depth of micro-fluidic structure.
According to each specific embodiment of the present invention, according to the part that the Flow Control substrate of the device of various embodiments of the present invention and lid can be larger Flow Control bags, it can be made up of different materials, such as polymer, and larger Flow Control structure, reagent, Flow Control and electrical interface can be comprised.Advantage is thus: such system becomes cost-effective more.
According to various embodiments of the present invention, the surface of Flow Control substrate and lid can partially or completely be applied to change the surface interaction of substrate and fluid sample.
In the third aspect, the invention provides the use of the device as described in a first aspect of the present invention and embodiment to perform microscopic method.Microscopic method can realize without lenticular image by using lid to detect according to the holographic principle of digitlization.
The use of device as described can perform organizes Epidemiological Analysis more, and wherein Flow Control substrate is used to perform multiple chemical examination in multiple passage and room, and CMOS lid is used to detect the multiple signals from whole chemical examinations.Those information may be combined with multiple DNA, RNA, Small molecular, cell signal from same analysis thing.
In each specific embodiment, device is used as the single single use device for analyzing a small amount of liquid.
In fourth aspect, the data from lid can such as use wireless connections to be sent to smart machine.Smart machine can be used to process, visual and/or transmission data.
In the various embodiments of the invention, can be used software algorithm from the data through combination of single same sample collection, to calculate the parameter be associated with the disease of individuality or kilter.
Set forth in appended independent sum dependent claims of the present invention concrete and preferred in.From dependent claims feature in due course can with the Feature Combination of independent claims, and can with the Feature Combination of other dependent claims, and not only as statement explicit in claim.
Embodiment by reference to the following description, these and other aspect of the present invention will be apparent and be illustrated.
Accompanying drawing is sketched
Fig. 1 shows the 3D view of an embodiment of the Flow Control substrate that can use in the various embodiments of the invention.
Fig. 2 shows the top view of the first embodiment of the device for analysing fluid sample according to various embodiments of the present invention.
Fig. 3 illustrates the top view of the Flow Control substrate used in the device of Fig. 2.
Fig. 4 illustrates the side view of device in Fig. 2.
Fig. 5 shows the top view of the second embodiment of the device for analysing fluid sample according to various embodiments of the present invention, carries out feature to the otch of pin.
Fig. 6 shows in the device of Fig. 5, the otch of pin is carried out to the top view of an embodiment of the Flow Control substrate of feature.
Fig. 7 illustrates the side view of the device of Fig. 5.
Fig. 8 shows the top view of the 3rd embodiment of the device for analysing fluid sample according to various embodiments of the present invention, to the operator guards feature of pin.
Fig. 9 shows in the device of Fig. 8, the operator guards of pin is carried out to the top view of an embodiment of the Flow Control substrate of feature.
Figure 10 illustrates the side view of the device of Fig. 8.
Figure 11-17 shows the method for the Flow Control substrate used in the device be manufactured on according to various embodiments of the present invention.
Figure 18 illustrates in the embodiment according to the CMOS chip used in the device of various embodiments of the present invention.
Figure 19 shows the joint of CMOS chip according to various embodiments of the present invention and Flow Control substrate.
Figure 20 shows the joint of CMOS chip according to various embodiments of the present invention and Flow Control substrate, and wherein CMOS chip comprises in silicon I/O and connecting.
Figure 21 shows in an embodiment according to the CMOS chip used in the device of various embodiments of the present invention, and CMOS chip comprises I/O pad.
Figure 22 shows in an embodiment according to the CMOS chip used in the device of various embodiments of the present invention, and CMOS chip comprises the I/O pad joining Flow Control substrate to, and wherein a part for CMOS chip covers on Flow Control substrate.
Figure 23 shows the joint of CMOS chip according to various embodiments of the present invention and Flow Control substrate, and wherein CMOS chip comprises through hole.
Figure 24 shows the joint of CMOS chip according to various embodiments of the present invention and Flow Control substrate, and wherein Flow Control substrate comprises two through holes.
Figure 25 shows the 3D view of device according to an embodiment of the invention.
Figure 26 shows the 3D view of wireless according to an embodiment of the invention individual devices.
Figure 27 shows the top view of the part in the first embodiment according to the microfluidic components used in the device of various embodiments of the present invention, and this microfluidic components comprises microtrabeculae.
Figure 28 shows the 3D view of a part for the microfluidic components of Figure 27.
Figure 29 shows the top view of the part in the second embodiment according to the microfluidic components used in the device of various embodiments of the present invention, and this microfluidic components comprises microtrabeculae.
Figure 30 shows the 3D view of a part for the microfluidic components of Figure 29.
Figure 31 shows an embodiment of the SD card shape of the device according to various embodiments of the present invention.
Figure 32 shows another embodiment of the SD card shape of the device according to various embodiments of the present invention.
Figure 33 is the sectional view of the device according to various embodiments of the present invention, and wherein multiple function is by single CMOS technology support.
Accompanying drawing is only illustrative rather than restrictive.In the accompanying drawings, for purposes of illustration, the size of some elements can be exaggerated and not to scale (NTS) draw.
Any Reference numeral in claims should not be interpreted as limited field.
In different figures, same reference numbers indicates same or similar element.
Detailed description of the invention
The present invention will be described for specific embodiment and with reference to certain figures, but the present invention is not limited thereto and only be defined by claims.Described accompanying drawing is just schematically with nonrestrictive.In the accompanying drawings, for purposes of illustration, the size of some elements can be exaggerated and not to scale (NTS) draw.Size and relative size also do not correspond to as putting into practice actual reproduction of the present invention.
In addition, in the specification and in the claims, term " first ", " second " etc. for distinguishing between analogous element, and might not be used for the order describing time sequencing, spatial order, ranking compositor or any other mode.Should be understood that the term so used is interchangeable in the appropriate case, and embodiments of the invention described herein can be different from other operation in tandem that is described herein or that illustrate.
In addition, the term in description and claims exists ... on ... under etc. be used to describe object, and not necessarily for describing relative position.Should be understood that the term so used is interchangeable in the appropriate case, and embodiments of the invention described herein can be different from other orientation that is described herein or that illustrate operation.
It should be noted that the term used in the claims " comprises " implication that should not be construed as limited to and hereinafter list; It does not get rid of other element or step.Therefore it should be read as specify described feature, integer, step or parts as the existence addressed, but do not get rid of existence or the interpolation of one or more further feature, integer, step or parts or its group.Therefore, the scope of word " a kind of device comprising device A and B " should not be defined to the device be only made up of assembly A and B.This means that this device unique associated component relevant with the present invention is A and B.
In the whole text, quoting of " embodiment " or " embodiment " is meaned that special characteristic, structure or the characteristic described in conjunction with this embodiment comprises at least one embodiment of the present invention at this description.Therefore, this description in the whole text in each position in the appearance of phrase " in one embodiment " or " in one embodiment " not necessarily all refer to same embodiment, but same embodiment can be referred to.In addition, in one or more embodiments, as those of ordinary skill in the art it is evident that according to present disclosure, special characteristic, structure or characteristic can combine in any suitable manner.
Similarly, should be understood that, in the description of example embodiment of the present invention, each feature of the present invention is incorporated into together sometimes in single embodiment, accompanying drawing and description thereof, so that present disclosure is linked to be entirety, and one or more aspects that help is understood in each inventive aspect.But method of the present disclosure is not to be read as the intention that reflection invention required for protection needs feature more more than the feature clearly stated in each claim.On the contrary, as appended claims reflect, each invention aspect is the feature fewer than all features of above disclosed single embodiment.Therefore, be included into clearly in this detailed description at this with the claim appended by describing in detail, wherein each claim is voluntarily as independent embodiment of the present invention.
In addition, although embodiments more described herein comprise some features included in other embodiments but other features not having other embodiments to comprise, but the combination of the feature of different embodiment intention falls within the scope of the invention, and forms different embodiment as understood by those skilled in the art.Such as, in the appended claims, any embodiment in embodiment required for protection all can use in any combination.
In description provided herein, set forth numerous detail.But, should be appreciated that and can implement various embodiments of the present invention when not having these details.In other example, be not shown specifically well-known method, structure and technology, in order to avoid obscure the understanding to this description.
When making the reference to " fluid sample " in the various embodiments of the invention, with reference to any human body fluids such as blood, urine, saliva.
When making the reference to " I/O pad " or " I/O contact " in the various embodiments of the invention, reference such as allows the metal contact of the input and output of the signal of telecommunication of microchip.
When making the reference to " CMOS " in the various embodiments of the invention, with reference to complementary metal oxide semiconductors (CMOS).
In a first aspect of the present invention, relate to the device 100 for analysing fluid sample as shown in figure 26.Described device 100 comprises: Flow Control substrate 101 also covers the lid 103 of substrate 101 at least in part with being attached to Flow Control substrate 101.Flow Control substrate 101 comprises the microfluidic components 102 be embedded in Flow Control substrate 101, is configured for and propagates fluid sample by microfluidic components 102 (microfluidic components 102 is illustrated by multiple microfluidic components such as such as sample pad 102a (=import), reagent storing device 102b, disposable seal valve 102c, the first trigger valve 102d, blender 102e, delay line 102f, the second trigger valve 102g, heater 102h and imbibition bar 102i) by capillary force; And be connected to the device for providing fluid sample of microfluidic components 102.Lid 103, by covering substrate 101 at least partly, closes microfluidic components 102 at least partly.In the various embodiments of the invention, Flow Control substrate 101 is silicon Flow Control substrates; And lid 103 is CMOS chips.
Because Flow Control substrate 101 is silicon substrate and lid 103 is CMOS chips, both all can use and generate compatible silicon treatment technology and manufacture on a large scale.As additional advantage, cheap CMOS mounting technology can be used to join silicon substrate to CMOS chip.Which reduce the total cost of device and allow it to be used as disposable device and a large amount of production.
Fig. 1 shows the 3D view of an embodiment of Flow Control substrate 101.
The top view of an embodiment of device 100 is shown in Figure 2, Flow Control substrate 101 and lid 103 mutually attached.The top view of the exemplary fluidic substrate 101 used in the device of Fig. 2 is shown in Figure 3.The side view (wherein Flow Control substrate 101 is attached to lid 103) of an embodiment of the device 100 of Fig. 2 is shown in Figure 4.
Comprise attached according to the device 100 of various embodiments of the present invention or join the Flow Control substrate 101 of lid 103 to.Flow Control substrate 101 comprises microfluidic components 102.Microfluidic components 102 can comprise interior company and propagate through the microfluidic channel of complete microfluidic components 102, microreactor or other micro-fluidic part/structure to allow fluid sample.Microfluidic components 102 can include multiple microtrabeculae or the micro-structural of rule or irregular distance, to allow to filter during capillary flow and separate, valve control (=as valve), mixed fluid sample.Figure 27 shows and comprises (in order to allow to filter during capillary flow and separation, valve control, mixed fluid sample) top view of part of the microfluidic components 102 opened of microtrabeculae 270.Figure 28 shows the 3D view comprising the microfluidic components 102 opened of microtrabeculae 270 of Figure 27.Microtrabeculae 270 in Figure 27 and 28 is placed to form gradient.This gradient is favourable for filtering out larger particles and filter out compared with granule in the Part II of microfluidic components 102 in the Part I of microfluidic components 102.Figure 29 and Figure 30 shows another embodiment of the gradient of the microtrabeculae 270 in microfluidic components 102.Microfluidic components 102 can be configured to cause capillarity to propagate fluid sample by device 100.Each size of microfluidic components 102 can be adapted to, and causes capillarity when existing with convenient fluid sample in microfluidic components 102.Such as, the size of the microtrabeculae 270 in microfluidic components 102 and distance therebetween can be configured to cause capillarity in microfluidic components 102.As advantage, in the various embodiments of the invention, device 100 does not need extra active block (such as active pump) to propagate fluid sample by device 100.Therefore, compared to the realization of prior art, the complexity of device 100 reduces, and which reduces manufacturing expense and energy consumption.Because manufacturing expense is cheap, device can be used as disposable fluid analysis device.
An advantage of the invention is, by such as correctly setting size and the distance of microfluidic channel and/or the microtrabeculae existed in microfluidic components 102, the precise controlling of the flowing of fluid sample in microfluidic components 102 can be obtained.Photoengraving pattern can be used to manufacture the microfluidic components 102 in Flow Control substrate 101.The microtrabeculae of microfluidic components 102 and the photoengraving pattern of microfluidic channel allow the size, the size and shape that control microtrabeculae and microfluidic channel exactly, thus accurately control capillary flow is an advantage.Accurately control to present advantage compared to prior art effluent test paper (being made up of the porous paper of uncontrolled effluent) in the reproducible effluent of acquisition by obtainable this for size of photoetching process.By changing the size in device length, to slow down when expecting and/or the flowing of accelerating fluid sample is possible.This allows the realization of biochemical reaction more complicated for the simple flow used in existing current immunity detecting test.With also add temperature control when needed in the combination joining the function realized in the CMOS chip on Flow Control substrate 101 as lid to, electronics Flow Control activates and valve control, integrated bio sense and read.Therefore, become the chemical examination of the complexity in an integrated wicking system that may realize from the fluid of health, comprise DNA/RNA chemical examination, protein, Small molecular and cell and combination thereof.In addition, in silicon there is controlled effluent and the realization with the capillary flow of the control to temperature and flow rate produces more accurate instant testing result.
In the various embodiments of the invention, Flow Control substrate 101 comprises the device for providing fluid sample being connected to microfluidic components 102.
Lid 103 is used as the covering of Flow Control substrate 101, and wherein lid 103 completely or partially closes microfluidic components 102.Figure 25 shows one embodiment of the present of invention, and wherein lid 103 part covers Flow Control substrate 101.Microfluidic components 102 can be the microfluidic components 102 opened in Flow Control substrate 101.According to alternative embodiment of the present invention, the size of lid 102 can with the consistent size of Flow Control substrate 101.Lid 103 can completely or or part covers Flow Control substrate 101.When for providing the device of fluid sample to be inlet 109 (as shown in figure 26) (such as sample pad 102a), lid 103 can partly cover Flow Control substrate 101, allows user to access inlet 109 to place fluid sample.
According to various embodiments of the present invention, device 100 also can comprise the one or more electrodes in the microfluidic components 102 that is placed on Flow Control substrate 101.These electrodes can be the electrodes of biocompatible.Electrode can be electrically connected to lid 103 and be allowed to mutual with the fluid sample in the microfluidic components 102 of device 100 (because they directly can contact the fluid sample in microfluidic components 102).When lid 103 self can comprise electrode, by electrode, from lid 103, separately to allow, lid 103 is less to have superiority with minimizing expense.
According to various embodiments of the present invention, microfluidic components 102 can comprise capillary pump.
According to various embodiments of the present invention, for providing the device of fluid sample can be such as with the integrated pin 104 that silicon is made, and comprise the Flow Control path 10 5 of the inside being connected to microfluidic components 102.Pin 104 can be the ledge of Flow Control substrate 101 and can be placed and make the transdermal tissue when pressing skin histology.
Flow Control substrate 101 and pin 104 can manufacture by single piece of silicon.According to various embodiments of the present invention, this simplify the manufacture of device 100, because do not need step separately that pin 104 is attached to Flow Control substrate 101.Equally, the CMOS treatment technology of standard can be used to manufacturing needles 104.Preferably pin 104 makes skin histology by the pin of point penetrated.Flow Control substrate 101 and pin 104 both can manufacture with silicon.As an advantage, the intensity of silicon allows pin 104 very sharp-pointed, this facilitate that pin 104 penetrating in skin histology.In addition, the intensity of silicon allows skin histology to be crushed on tightly on pin 104, thus allows penetrating of skin histology and the not bending or pin 104 that fractures.
According to various embodiments of the present invention, pin 104 can be arranged in the horizontal plane of Flow Control substrate 101, and wherein pin 104 is positioned on the sidewall of Flow Control substrate 101.Pin 104 can be the ledge of the sidewall of Flow Control substrate 101.According to different embodiments, pin 104 can be positioned on the horizontal plane of Flow Control substrate 101, and wherein pin is vertically placed on the first type surface of Flow Control substrate 101.According to various embodiments of the present invention, pin 104 can play the effect of the passage opened being connected to microfluidic components 102, and wherein in use, when skin histology is penetrated, skin histology is used as the sidewall of pin 104.
Device 100 according to various embodiments of the present invention uses by being pressed to pin 104 by the skin histology of user.When using enough power, pin 104 transdermal tissue, allows blood to enter the Flow Control path 10 5 of the inside of pin 104.Pin 104 has the needle point opened and enters inner Flow Control path 10 5 to allow fluid sample.When needle set has little external diameter (being preferably less than 200 μm) sharp-pointed, skin histology penetrate any discomfort that can not cause user.Flow Control path 10 5 along with the inside of pin 104 is connected to the microfluidic components 102 of Flow Control substrate 101, and blood can enter microfluidic components 102.Due to capillary force, blood will propagate through microfluidic components 102.
Fig. 1 shows the embodiment of the Flow Control substrate 101 with integrated pin 104 (part as Flow Control substrate 101), and this needle set has the Flow Control path 10 5 of the inside being connected to microfluidic components 102.Microfluidic components 102 can comprise: sample pad 102a (=inlet), reagent storing device 102b, disposable seal valve 102c, the first trigger valve 102d, blender 102e, delay line 102f, the second trigger valve 102g, heater 102h and imbibition bar 102i.As shown in Figure 1, the whole Flow Control assembly in Flow Control substrate 101 is opened.Lid 103 will close some or all Flow Control assemblies as covering.
According to various embodiments of the present invention, Flow Control substrate 101 can comprise otch 106, and wherein pin 104 is arranged in otch 106.Otch 106 is parts be removed of Flow Control substrate 101, to provide mechanical protection to the pin 104 be present in otch.
Fig. 5 shows the top view of one embodiment of the invention, and wherein lid 103 is engaged to Flow Control substrate 101.Fig. 6 shows the top view of the exemplary fluidic substrate 101 of one embodiment of the invention.Fig. 7 shows the side view of one embodiment of the invention, and wherein lid 103 is engaged to Flow Control substrate 101.
As shown in Fig. 5,6 and 7, pin 104 is arranged in the otch 106 of Flow Control substrate 101.Otch 106 protects pin 104 to avoid such as fractureing when device 100 inserts in the socket of external equipment (mobile device of such as smart phone, such as, for reading).The sidewall of Flow Control substrate 101 can play the effect of otch 106.Pin 104 can be arranged in otch 106 to allow user's transdermal tissue when firmly pressing to otch.As further advantage, in the fabrication process, pin 104 can be manufactured when manufacturing otch 106.As a result, less material is wasted, because be only used for the material of otch 106, does not comprise the material for pin 104, needs to be removed.Standard silicon treatment technology can be used to manufacture otch 106 and pin 104.
According to various embodiments of the present invention, Flow Control substrate 101 can comprise the operator guards 107 for the protection of pin 104, and this operator guards is attached to Flow Control substrate 101 removedly.According to various embodiments of the present invention, operator guards 107 is attached to Flow Control substrate 101 by least one anchoring mechanism 108.By disconnecting at least one anchoring mechanism 108, operator guards 107 can be separated.Operator guards 107 can be a part for Flow Control substrate 101, and wherein anchoring mechanism 108 is the grooves in Flow Control substrate 101, to allow to disconnect operator guards 107 at this groove.Fig. 8 is the top view of such embodiment of device 100.As visible in Fig. 9 top view of example embodiment for the Flow Control substrate 101 used in the device (such as shown in Figure 8 device) according to various embodiments of the present invention (shown be); operator guards 107 is parts of Flow Control substrate 101; and feature two anchoring mechanism 108, their allow operator guards 107 to be separated from Flow Control substrate 101.Figure 10 illustrates the side view of device 100 in Fig. 8.
According to various embodiments of the present invention, be inlet 109 for providing the device of fluid sample.Inlet 109 can be the breach in Flow Control substrate 101, and it passes through Flow Control expanding channels to microfluidic components 102.For using this device, the fluid of a health (such as blood or urine) can be placed on the inlet 109 of this device by user.Due to capillary force, the fluid of health will propagate through microfluidic components 102.
Figure 26 shows the device 100 according to various embodiments of the present invention taken apart, and it comprises the Flow Control substrate 101, lid 103 and the bag 110 that comprise inlet 109 and microfluidic components 102.Bag 110 can comprise base portion and top, and they can be assembled together and encase Flow Control substrate 101 and lid 103, thus protection Flow Control substrate 101 and lid 103 are from ambient influnence (as dust).Bag can comprise the through hole 260 for being put into by fluid sample on the inlet 109 of Flow Control substrate 101.When all part is assembled, device 100 can be used as the independent wireless device for analysing fluid sample.
According to each aspect of the present invention, when fluid sample is present in device 100, can contacting with fluid sample at least partially of lid 103.Because lid 103 is CMOS chips, when lid 103 is used as the sidewall of the microfluidic components 102 opened of Flow Control substrate 101, the electronic circuit be present on chip surface can directly contact with fluid sample.In this case, the side comprising electronic circuit of chip can be engaged to the microfluidic components 102 opened of Flow Control substrate 101, and wherein this electronic circuit is located to align with each several part of Flow Control assembly 102 with fluid sample interaction in expectation.As an advantage, this can improve the interaction between electronic circuit and fluid sample.
According to various embodiments of the present invention, lid 103 can comprise bonding layer to allow to join lid 103 to Flow Control substrate 101.
According to various embodiments of the present invention, first side comprising the microfluidic components 102 opened of Flow Control substrate 101 can be engaged to first side comprising at least one electronic building brick of CMOS chip 103.
According to an embodiment, lid 103 comprises transistor layer, this transistor layer is electrically connected at least one electronic building brick, this electronic building brick is following at least one: biological sensing circuit, for sensing the electrode of object, the electrode for fluid actuated object, the circuit for data communication object, circuit for RFDC object, temperature sensor, controlling for temperature or the heater electrode of temperature cycles, and the fluid sensor controlled for viscosity of fluid and electrode.Circuit for RFDC can comprise regulation for carrying out communicating via bluetooth radio or WiFi module wirelessly to send data from the electronic circuit in lid 103.As an advantage, device 100 can communicate with the external equipment of such as mobile device, and this external equipment can be used to process data further.
Lid 103 is CMOS chips.According to various embodiments of the present invention, CMOS chip comprises silicon substrate 111, transistor layer 112, is electrically connected at least one electronic building brick of this transistor layer 112, and at least one bonding layer 115.At least one electronic building brick can be biological sensing circuit, for sense the electrode of object, the electrode for fluid actuated object, the circuit for data communication object, circuit for RFDC object, temperature sensor, for temperature controlled heater electrode, and the fluid sensor controlled for viscosity of fluid and electrode.
A specific embodiment according to the lid 103 of various embodiments of the present invention illustrates at Figure 18.In this embodiment, CMOS chip 103 comprises silicon substrate 111.Transistor layer 112 can be there is on silicon substrate 111 pushes up.Interior interconnect layer 113 can be there is on transistor layer 112 pushes up.On the top of transistor layer 112, can there is at least one electronic building brick, it is electrically connected to transistor layer 112 by interior interconnect layer 113.Interior interconnect layer 113 can comprise multiple metal level.According to various embodiments of the present invention, on the top of transistor layer 112, bonding layer 115 and at least one electrode 114 can be there is.Electrode 114 can be electrically connected to transistor layer via interior interconnect layer 113.
According to various embodiments of the present invention, at least one electronic building brick can be can not by flow-induced corrosion and the electrode of chemically inert biocompatible.According to a specific embodiment, at least one electrode 114 is TiN electrodes.
According to various embodiments of the present invention, bonding layer 115 can be the layer allowing CMOS chip 103 to join to when low temperature and low-voltage Flow Control substrate 101.This is favourable, because these situations do not destroy CMOS chip, and the protein also not destroying reagent or such as can be provided on micro-fluidic substrate 101.According to a specific embodiment, bonding layer 115 can be SiO
2or polymeric layer.
Figure 19 shows the device 100 according to various embodiments of the present invention, and wherein CMOS chip 103 is as shown in figure 18 engaged to Flow Control substrate 101.The side comprising bonding layer 115 and electrode 114 of CMOS chip 103 is engaged to the side comprising the microfluidic components 102 opened of Flow Control substrate 101.This means that CMOS chip 103 has as shown in figure 18 turned over the position of Figure 18 up and down relative to it to come.Therefore electrode 114 directly contacts the fluid sample be present in microfluidic components 102.Bonding layer 115 is used to CMOS chip 103 to be attached to Flow Control substrate 101.
According to various embodiments of the present invention, CMOS chip 103 can comprise at least one silicon I/O and connect 116, as shown in figure 20.Silicon I/O connects the open-back that 116 can be Through-substrate 111, to access the signal of telecommunication of CMOS chip 103 in transistor layer 112.In addition, in an alternate embodiment, it can be Through-substrate 111 and the open-back both transistor layer 112 that silicon I/O connects 116, to access the signal of telecommunication of CMOS chip 103 in interior interconnect layer 113.Figure 20 shows device 100, and wherein CMOS chip 103 is engaged to Flow Control substrate 101, and wherein CMOS chip 103 feature Through-substrate 111 is connected 116 with the silicon I/O of both transistor layers 112.
According to various embodiments of the present invention, Flow Control substrate can comprise the microfluidic components 102 opened, and Flow Control substrate can part be covered by CMOS chip 103.It is favourable that a part for microfluidic components 102 is uncovered, and opens in part because this allows reagent to be applied in/to drop in the specific of microfluidic components 102.In the case, after joining Flow Control substrate 101 to CMOS chip 103, do not need extra through hole to apply reagent.CMOS chip area is less is also favourable, because active electronic instrument is a disposable more expensive part.
According to various embodiments of the present invention, CMOS chip 103 also can comprise at least one I/O pad 117.This at least one I/O pad 117 can be positioned in interconnect layer 113.
Figure 21 illustrates the embodiment of CMOS chip 103.CMOS chip 113 comprises silicon substrate 111.The top of silicon substrate exists transistor layer 112.Interconnect layer 113 in existing on transistor layer 112 pushes up.Interior interconnect layer 113 can comprise multiple metal level to connect in transistor layer 112 and electronic building brick.On the top of transistor layer 112, there is bonding layer 115, I/O pad 117, and multiple electrodes 114 in the embodiment shown.Electrode 114 is electrically connected to transistor layer 112 via interior interconnect layer 113.I/O pad 117 is also electrically connected to transistor layer 112 via interior interconnect layer 113.
According to various embodiments of the present invention, the Part II that the Part I of the first first type surface of CMOS chip 103 can cover the first first type surface of Flow Control substrate 101, CMOS chip 103 can not cover Flow Control substrate 101.In these embodiments, CMOS chip 103 or can be greater than Flow Control substrate 101, or it can be displaced sideways relative to Flow Control substrate 101, makes a part for CMOS chip 103 form overhang (overhang) relative to Flow Control substrate 101.The Part II of the first first type surface of CMOS chip 103 can comprise at least one I/O pad 117 to access I/O pad 117.
Figure 22 shows the CMOS chip 103 shown in the Figure 21 joining Flow Control substrate 101 to.The Part I indicating section ground of CMOS chip 103, and be illustrated as in this embodiment covering Flow Control substrate 101 completely, the wherein electrode 114 directly contacting with fluid sample when fluid sample is present in the microfluidic components 102 of device 100.Bonding layer 115 is used to join the Part I of CMOS chip 103 to Flow Control substrate 101.The Part II of CMOS chip 103 forms the overhang not covering Flow Control substrate 101.Part II comprises I/O pad 117.As an advantage, this overhang allows easily to access I/O pad 117.This allows to use standard I/O pad size and packing method, is generally used in the slot of smart card to be inserted by substrate.Further advantage is that the treatment step that do not need to add connects (such as by the hole of substrate and transistor layer) to access the signal of telecommunication in CMOS chip 103 to manufacture silicon I/O.
According to various embodiments of the present invention, Flow Control substrate 101 also comprises at least one optical waveguide to allow the optical excitation also senses flow sample body when fluid sample exists in device 100.
According to various embodiments of the present invention, Flow Control substrate 101 or lid 103 comprise at least one through hole for biochemical reagents being applied to a region of microfluidic components 102 or being applied to a region of lid 103.Through hole in Flow Control substrate 101 or lid 103 allows biochemical reagents be applied to the specific region of microfluidic components 102 or be applied to the specific region of lid 103.This is favourable, because it allows to apply reagent after lid 103 is attached to Flow Control substrate 101.
According to various embodiments of the present invention, CMOS chip 103 can comprise at least one through hole 118.When being attached to Flow Control substrate 101, on the ad-hoc location that the through hole 118 in CMOS chip 103 allows reagent to drop in the microfluidic components 102 in Flow Control substrate 101 or on the specific part of CMOS chip 103.Figure 23 shows such embodiment, and wherein CMOS chip 103 comprises a through hole 118.In this embodiment, CMOS chip also comprises silicon I/O and connects 116.As shown, CMOS chip 103 covers a part for Flow Control substrate 101 completely.
According to identical or alternative embodiment of the present invention, the first side of Flow Control substrate 101 comprises the microfluidic components 102 opened.Facing to the opposite side of that side that microfluidic components 102 is provided, at least one through hole 119 can be comprised.On the ad-hoc location that through hole 119 allows reagent to drop in the microfluidic components 102 of Flow Control substrate 101 or on the specific part of CMOS chip 102.Figure 24 shows such embodiment, and wherein Flow Control substrate comprises two through holes 119.The part covering Flow Control substrate 101 of CMOS chip 103, does not cover Flow Control substrate 101 but the part of formation overhang comprises I/O pad 117.
According to various embodiments of the present invention, polymer (being preferably the polymer that photoetching forms pattern) can be used to join lid 103 to Flow Control substrate 101.Material for the formation of the joint between lid 103 and Flow Control substrate 101 should be suitable for (such as, preferably at low temperature, room temperature) performs Si-Si joint.This with exist and lid 103 should not be engaged that to process the cmos circuit destroyed be compatible, and to process the reagent destroyed be compatible with being present in also should not be engaged on Flow Control substrate 101 or in Flow Control substrate.For lid 103 is joined to the suitable grafting material of Flow Control substrate 101 be such as can from DowCorning obtain can PDMS, the SU8 that can obtain from MicrChem of photo patterning or the OSTE that can obtain from MerceneLabs.These grafting materials all using room temperature as junction temperature.
According to another embodiment of the invention, CMOS compliant packet packing technique is used to join lid 103 to Flow Control substrate 101.When Flow Control substrate 101 is silicon substrate, lid 103 is CMOS chips, the purposes of CMOS packing technique can be used.
According to various embodiments of the present invention, device 100 also can comprise and is electrically connected to lid 103 to read the metal contact of the signal of telecommunication from lid 103.Metal contact can be positioned on lid 102, is electrically connected to the electronic circuit in lid 103.The position of metal contact and shape can be selected according to standard, device is allowed to insert standardized slot, such as: the slot of normally used storage card (such as, compact flash storage card, smart media storage card, multimedia storage card or secure digital (SD) storage card) in the communication equipment of such as mobile device.Device 100 is inserted mobile device to allow to process the signal of telecommunication from lid 103 by the processor existed in mobile device and/or other electronic building brick.Such as, the processor of smart mobile phone can be used to the process signal of telecommunication and/or display data.
According to various embodiments of the present invention, at least part of available transparent material manufacture of Flow Control substrate 101 and/or lid 103, allows fluid sample to carry out optical check during to be present in microfluidic components 102 at fluid sample.The part manufactured by transparent material of Flow Control substrate 101 can be the part of the microfluidic components 102 of device 100.Transparent part can be the sidewall of the microfluidic components 102 of device 100.Transparent material allows the optical check to the fluid sample in device 100.Fluorescence detector can be used to check fluid sample optically, so that such as detect analytes.Fluorescence detector can be imageing sensor, and it can be that the part of external equipment maybe can be integrated in device 100.Transparent material can be transparent oxide or polymer.In order to the object of microscopic method, a part for lid 103 or a part for Flow Control substrate 101 can be transparent.In order to the object without lens imaging, a part for lid 103 and a part for Flow Control substrate 101 can be transparent in allow to work in the transmission mode, wherein radiation source can be used with by the object in the fluid sample in the transparent part irradiation device 100 of lid 103, and detector can be used to detect by the transparent part of Flow Control substrate 101 signal from the object of institute's radiation.Signal can be the diffraction pattern of the institute's radiating object in fluid sample.
Figure 33 shows the device 100 according to various embodiments of the present invention, and wherein Flow Control substrate 101 and lid 103 are bonded with each other.Flow Control substrate 101 comprises the different microfluidic components for organizing Epidemiological Analysis more, comprises multiple room 330,331,332,333 and microfluidic channel (not shown) in an illustrated embodiment.Each room can have different depth, depends on their function and the type of performed measurement.Each room can by separating (such as by fluid force or pass through electric current) activates in any suitable manner valve.Electrode for activating can be provided on Flow Control substrate 101 or lid 103.The CMOS chip forming lid 103 can therefore in conjunction with difference in functionality, such as such as CMOS microcosmic imager 334, CMOS fluorescence detector 335,336, and the CMOS electronic circuit 337 for heating and/or sense.CMOS microcosmic imager 334 can comprise the CMOS active pixel for reading optical signalling from the fluid sample in microfluidic components 102.CMOS fluorescence detector 335 comprises optical resonantor 338.Waveguide 339 can be there is in order to will the location transmission of light from CMOS chip 103 be measured to another position.Waveguide can such as be used to irradiate sample to perform without lens microscopic method.In addition, filter can be provided in Flow Control substrate 101 or in lid 103 and distribute to refuse optical excitation, thus allows the measurement to fluorescence signal.Same multispectral filter can be provided in Flow Control substrate 101 or in lid, measures flow control signal for using multiple color.
In this way, according to various embodiments of the present invention, can single to the detection of dissimilar mark, preferably disposable, perform in detection means.
According to various embodiments of the present invention, the shape of this device 100 allows to be inserted in mobile communication equipment.According to various embodiments of the present invention, device 100 has the shape/size of storage card.This is an advantage of various embodiments of the present invention, the size of device 100 can according to standard, such as, according to the standard of the such as following storage card used in mobile device: compact flash storage card, smart media storage card, multimedia storage card, safety digital storage card or other type of storage card.
Figure 31 and 32 shows one embodiment of the present of invention, and wherein device 100 has the shape of SD card.Inner at otch 106 (always existing according to SD card standard), there is pin 104.At the opposite side of SD card, there is metal contact and be electrically connected to lid 103 to allow to read the signal of telecommunication from lid 103, the equipment that this signal of telecommunication can be inserted wherein by SD card further processes.
According to various embodiments of the present invention, lid 103 or Flow Control substrate 101 also can comprise the compartment for providing power supply to device 100 being electrically connected to lid 103, such as cell compartments (not shown).
In the second aspect of various embodiments of the present invention, relate to the method for the manufacture of device disclosed in a first aspect of the present invention.The method comprises: provide Flow Control substrate 101; Lid 103 is provided; Flow Control substrate 101 is attached to lid 103 with closing flow control substrate 101 at least in part; It is characterized in that: Flow Control substrate 101 is silicon Flow Control substrates, and lid 103 is CMOS chips; And wherein Flow Control substrate 101 uses cmos compatible joining process to be attached to lid 103.
It is favourable for using cmos compatible joining process to join Flow Control substrate 101 to lid 103.In the device of prior art, joint uses high temperature/high voltage joining technique to perform.These joining techniques may destroy the electronic circuit existed in CMOS chip and/or the reagent be present in micro-fluidic substrate 101.Use cmos compatible joint to allow to engage in lower temperature/low voltage, and therefore protective cover 103 electronic circuit and be present in reagent in micro-fluidic substrate 101.According to various embodiments of the present invention, engage and perform to wafer joining process (such as directly oxide engages to oxide or engages via patternable polymer) by wafer to wafer or tube core.In addition, it is favourable for can performing joint at low temperature, because some reagent have been dropped on one of substrate during manufacture stream.
Flow Control substrate 101 can use the combination of coarse-texture in single piece of silicon substrate and fine structure, is protected, the combination of etching coarse-texture and etching fine structure manufactures by the protection of two hard masks, layer and going.Fine structure can be the structure of the controlled capillary attraction be configured in the microfluidic components 102 allowing device 100.Fine structure can comprise microtrabeculae 270 and/or other micro-structural.Coarse-texture can be structure (such as storing the reagent storage 102b of reagent) or the imbibition bar 102i of fluid for storing more volume.The micro-fluidic material of silicon instead of more common such as glass or polymer is used to be an advantage, because the anisotropic etching of the not high of silicon causes fine structure to have extra high aspect ratio.This silicon microtrabeculae 270 has the lateral dimension from 1 μm to 20 μm usually, relative to the aspect ratio of 20-50.High aspect ratio has high surface to being favourable in volume ratio, and this is that capillary flow is required.High aspect ratio fine structure, with the combination of coarse-texture, allows to realize in compacter area coverage compared to by the obtainable more complicated capillary Flow Control function of other material any.More complicated function comprises separation (such as by cell from biomolecule partition), mixing, valve control, thermal control reaction ...In addition, silicon is the realization that has relative to biochemical reaction and explains the insertion material of true advantage.The advantage of fully-integrated disposable device compact is especially derived from the use of the advanced person of silicon on Flow Control substrate and CMOS lid.The area coverage reduced also causes the expense of the minimizing of whole device.
According to various embodiments of the present invention, there is provided Flow Control substrate 101 to comprise to provide silicon substrate 201 (shown in Figure 11) and patterned silicon substrate to form microfluidic components 102 and for providing the device of fluid sample, microfluidic components 102 is configured to, by capillary force, fluid sample is propagated through device 100 in device 100.
According to various embodiments of the present invention, Flow Control substrate 101 is provided to comprise: to provide silicon substrate 201, there is provided oxide mask 202, by using the first patternable mask layer 210 to carry out patterned oxide mask 202, to create fine structure 203 (Figure 12) in oxide mask 202; There is provided protective layer 204 to protect patterned oxide mask; Patterning coarse-texture (Figure 13) in the second patternable mask layer 211; In silicon substrate 201, coarse-texture 205 (Figure 14) is etched by the second mask layer 211; Remove the second mask layer 211 and generate oxide 206 (Figure 15) to protect coarse-texture 205; Remove protective layer 204 (Figure 16) and use oxide skin(coating) 206 as etching mask to etch fine structure 203 (Figure 16); Remove oxide 206 (Figure 17).The structure obtained is micro-fluidic substrate 101, and it can be used in the device of each embodiment according to a first aspect of the invention.
Figure 11-17 shows how to manufacture Flow Control substrate 101.According to various embodiments of the present invention, Flow Control substrate 101 is by performing following manufacture:
Patterning fine structure 203 comprises: provide silicon substrate 201, provides oxide mask 202, and patterned oxide mask 202 creates fine structure 203 in oxide mask 202;
There is provided protective layer 204 to protect oxide skin(coating) 202;
Perform the photoetching of coarse-texture 205;
Perform the etching of coarse-texture 205;
Generate oxide 206 for the protection of coarse-texture 205, the protective layer 204 wherein in fine structure 203 prevents oxide from generating;
Remove protective layer 204 and etch fine structure 203;
Remove oxide 206.
According to various embodiments of the present invention, protective layer 204 can be nitride layer.
According to various embodiments of the present invention, provide CMOS chip 103 to comprise: to provide silicon substrate 111, the top of silicon substrate manufactures transistor layer 112 and interior interconnect layer 113 is provided on the top of transistor layer.Interior interconnect layer can comprise at least one metal level.Standard CMOS treatment technology is used to manufacture CMOS chip 103.
In addition, on standard CMOS process stream, additional assembly, such as Biocompatible electrodes, bonding layer, I/O pad or other assembly, can be deployed or patterning in interior interconnect layer 113.
According to various embodiments of the present invention, through hole 109,118 can be accessed to allow fluid by the through Flow Control substrate 101 of etching or CMOS chip 103, thus reagent is applied to Flow Control substrate 101 or CMOS chip 103.Through hole in CMOS chip 103 can be manufactured, manufactures in silicon I/O simultaneously and connect 116 in CMOS chip 103.Through hole in Flow Control substrate 101 is by first making Flow Control substrate thinning and then etching vias manufactures.
According to various embodiments of the present invention, CMOS chip 103 can use tube core to the joining process of wafer or wafer to be engaged to Flow Control substrate 101.
In order to access the signal of telecommunication of CMOS chip 103, silicon I/O contact 116 can be provided.According to various embodiments of the present invention, contact manufactures with the access of the metal level obtaining internal interconnect layer 113 by making the silicon substrate 111 of CMOS chip 103 thinning and perform back side etch on silicon substrate 111.
Alternatively, the first side that may be provided in chip 103 comprises the CMOS chip 103 of I/O pad 117, and wherein the first side of CMOS chip 103 is engaged to Flow Control substrate 101 and the first side wherein comprising the CMOS chip 103 of I/O pad 117 does not cover Flow Control substrate 101.This is such as shown in Figure 22.When CMOS chip 103 is engaged to Flow Control substrate 101, I/O pad 117 is addressable.I/O pad 117 can be used as the metal contact on storage card.
According to various embodiments of the present invention, CMOS chip 103 is engaged to Flow Control substrate 101, is alignd by least one electronic building brick on the first side of CMOS chip 103 with microfluidic components 102 simultaneously.Such as, the sensing on the first side of CMOS chip 103 and activation electrodes are alignd with the sensing in Flow Control substrate 101 or actuating side.This allows when fluid sample is present in device 100, and fluid sample directly contacts with the electronic building brick be present on CMOS chip 103.
According to various embodiments of the present invention, the surface of Flow Control substrate 101 and lid 103 is applied to change the surface interaction with fluid sample partially or completely.Surface can be the inner surface of microfluidic components 102 or the surface being engaged to Flow Control substrate 101 of CMOS chip 103.Specifically, those parts on the surface of CMOS chip 103 contact with the fluid sample be present in microfluidic components 102.This coating can be hydrophilic coating.
The surface of microfluidic components 102 and/or that side joining Flow Control substrate 101 to of CMOS chip 103 can be made into hydrophilic, to improve the imbibition characteristic on surface, thus promote capillary flow.Surface also can be processed avoid the absorption of the biomolecule on wall or stick.Such as can carry out coating by using silane to carry out steam coating.According to various embodiments of the present invention, coating can on the specific part of Flow Control substrate 101 (such as in some microfluidic channels) or CMOS chip 103 specific part on locally perform.
According to various embodiments of the present invention, at least one through hole is by first etching vias and come to manufacture in Flow Control substrate 101 with the transparent oxide filling vias of polymer subsequently.
Various embodiments of the present invention improve the function of the disposable real-time test device of compact, portability and manufacturability.Specific embodiment of the present invention is pin with the import being used as blood or other body fluid or the fully-integrated silicon device of inlet.This device for feature, propagates through this device for fluid sample via capillarity with capillary flow Ore-controlling Role.Capillary pump as the imbibition district of capillary flow Ore-controlling Role can be used to propagate fluid sample in the devices.The sensor chip reading the signal produced by biochemical sensing reaction in wicking system can be used to add biological sensing function to device.In addition, device is feature for the data communication interface sending data to personal computer, computer unit, smart phone or other any Wireless Telecom Equipment.This device can be used as independent system, and wherein power supply interface (such as battery) is powered to electronic circuit (microchip in such as device).Alternatively, this device can be powered via the COM1 of device.
This device also comprises the Flow Control handle structure comprising filtration, mixing, valve control structure.Can exist there is the excision protection pin in district and the operator guards preventing pin from fractureing before use to prevent pollution before the use.Can exist such as electric controlled Flow Control handle structure structure (comprise electricity to infiltrate, electricity with the phoretic manipulation of dielectric) to carry out alternately with the fluid sample in device.Electricity controllable heater can exist, for the temperature of accurate control chip or for thermal cycle object.
Another example embodiment of the present invention comprises that letter is refined, low expense and compact mode manufactures whole above-mentioned functions by providing silicon substrate, the micro-structural of various shapes that this silicon substrate can be comprised lithographic definition passage, microtrabeculae and be manufactured by deep reaction ion(ic) etching, and be designed to be used as capillary Flow Control platform.Silicon substrate can have the regulation in manufacturing needles and the excision district for the protection of pin.Silicon substrate can have different etch depths to allow the accurate control to the capillary flow of the fluid sample in volume and device.The CMOS substrate (=lid 103) that silicon substrate can be included the CMOS electronic device comprising transistor layer is closed.This electronic device can be designed to provide comprise sensing, actuating, signalling, data processing and data communication function and therefore replace real-time test instrument.Some electrodes can direct contacting with fluid, these electrodes can fluid compatibility mode protected.By engaging silicon substrate and CMOS substrate with leakproof and bio-compatible mode, silicon substrate can be closed by CMOS substrate.This has come to wafer joining process (such as by the joint of patternable polymer) by wafer to wafer or tube core.Can with the inside surface of silicon of bioresorbable can with by the hydrophilic layer of the coating of inner passage for feature.In addition, can be manufactured in a silicon substrate by the hole of wafer, to supply reagent after device is engaged.For each analysis, different reagent can be supplied.As an advantage, by adding reagent simply by the through hole in last production stage, identity unit becomes configurable for various disease.CMOS compatible processing step can be used to manufacture device, and it reduces producing cost and allows device to be used as disposable device.
In addition, device can comprise the assembly allowing to carry out with standard user interface docking.Such as, such device is used as the smart card be inserted in the slot of prediction smart card usually in Wireless Telecom Equipment.Such as, such device uses together together with the communication equipment (such as, bluetooth, NFC) of compact and cheap battery and low expense.Such as, such device uses together with wired communication interface (such as USB).
Various embodiments of the present invention can be used to detect DNA/RNA from body fluid and execution analysis with detect: variation (blood lineage, drug dose, disease trend), miRNA (mark of cancer and Other diseases), pathogen DNA/RNA (communicable diseases of such as HepC, HIV etc.), microbial DNA.In addition, this device can be used to detect protein, the such as biomarker of specified disease (cancer, Alzheimer disease, communicable disease, heart disease, cancer etc.).In addition, this device can be used to detect Small molecular and metabolin to show metabolic information (cholesterol).In addition, this device can be used to detect the biomarker from allochthon.In addition, this device can be used to perform that microscopy counts to perform blood, the cell that exists in analyzing blood (such as, circulating tumor cell), mark infectiousness agent (such as, malaria) detect haematological disorders (such as, drepanocytemia).
Claims (19)
1. the device for analysing fluid sample (100), this device comprises:
Flow Control substrate (101), comprising:
Microfluidic components (102), described microfluidic components is embedded in described Flow Control substrate (101), is arranged to, by capillary force, fluid sample is propagated through described microfluidic components (102); And
Be connected to the device for providing fluid sample of described microfluidic components (102);
Be attached to described Flow Control substrate (101) and cover described Flow Control substrate (101) at least partly and the lid (103) of closing described microfluidic components (102) at least partly;
It is characterized in that:
Described Flow Control substrate (101) is silicon Flow Control substrate, and wherein said lid (103) is CMOS chip.
2. device (100) as claimed in claim 1, is characterized in that, when during described fluid sample is present in described device (100), and contacting with described fluid sample at least partially of described lid (103).
3. the device (100) as described in aforementioned any one claim, it is characterized in that, described lid (103) comprises transistor layer, this transistor layer is electrically connected at least one electronic building brick, this electronic building brick is following at least one: for sense object electrode, for the electrode of fluid actuated object, circuit for data communication object, temperature sensor, for temperature controlled heater electrode, and the fluid sensor controlled for viscosity of fluid and electrode.
4. device (100) as claimed in claim 3, it is characterized in that, the described electrode for sensing object is biological sensing circuit.
5. device (100) as claimed in claim 3, it is characterized in that, the described circuit for data communication object is the circuit for RFDC object.
6. device (100) as claimed in claim 1, it is characterized in that, described for providing the device of fluid sample to be the integrated pin (104) manufactured with silicon, and comprise the Flow Control passage (105) of the inside being connected to described microfluidic components (102), and wherein said pin (104) is the ledge of described Flow Control substrate (101) and is placed and makes the transdermal tissue when pressing skin histology.
7. device (100) as claimed in claim 6, it is characterized in that, described Flow Control substrate (101) comprises otch (106) and wherein said pin (104) is placed in described otch (106).
8. device (100) as claimed in claim 6; it is characterized in that; described Flow Control substrate (101) comprises the operator guards (107) for the protection of pin (104), and described operator guards is attached to described Flow Control substrate (101) removedly.
9. device (100) as claimed in claim 1, is characterized in that, described for providing the device of fluid sample to be inlet (109).
10. device (100) as claimed in claim 1, it is characterized in that, described Flow Control substrate (101) also comprises at least one optical waveguide to allow optical excitation and to sense described fluid sample when described fluid sample is present in described device (100).
11. devices (100) as claimed in claim 1, it is characterized in that, described Flow Control substrate (101) or described lid (103) comprise at least one through hole, for biochemical reagents being applied at least one region of described microfluidic components (102) or being applied at least one region of described lid (103).
12. devices (100) as claimed in claim 1, is characterized in that, the polymer that described lid (103) uses photoetching to form pattern is engaged to described Flow Control substrate (101).
13. devices (100) as claimed in claim 1, is characterized in that, also comprise and are electrically connected to described lid (103) for reading the metal contact of the signal of telecommunication from described lid (103).
14. devices (100) as claimed in claim 1, it is characterized in that, manufacturing with transparent material at least partly of described Flow Control substrate (101) and/or described lid (103), with allow when described fluid sample be present in described microfluidic components (102) middle time optical check to described fluid sample.
15. devices (100) as claimed in claim 1, it is characterized in that, the shape of described device (100) allows to be inserted in mobile communication equipment.
16. 1 kinds of methods for the manufacture of the device (100) for analysing fluid sample, described method comprises:
Flow Control substrate (101) is provided;
Lid (103) is provided;
Described Flow Control substrate (101) is attached to described lid (103) to close described Flow Control substrate (101) at least in part;
It is characterized in that:
Described Flow Control substrate (101) is silicon Flow Control substrate, and described lid (103) is CMOS chip; And
Wherein said Flow Control substrate (101) uses the compatible joining process of CMOS to be attached to described lid (103).
17. methods as claimed in claim 16, is characterized in that, provide Flow Control substrate (101) to comprise:
There is provided silicon substrate (201), provide oxide mask (202), oxide mask described in patterning (202) comes to create fine structure (203) in described oxide mask (202);
Protective layer (204) is provided to protect described oxide mask (202);
Patterning coarse-texture (205);
Etch described coarse-texture (205);
Generate oxide (206) for the protection of described coarse-texture (205);
Remove described protective layer (204) and etch described fine structure (203);
Remove described oxide (206).
18. methods as claimed in claim 16, is characterized in that, the surface of described Flow Control substrate (101) and described lid (103) is partially or completely applied to change the surface interaction of described substrate and described fluid sample.
19. use according to the arbitrary device of claim 1-15 to perform microscopic method.
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| CN101253404A (en) * | 2004-04-13 | 2008-08-27 | 哈佛大学 | Manipulation and/or detection of biological samples and other objects |
| CN101988897A (en) * | 2009-08-07 | 2011-03-23 | 中国科学院广州生物医药与健康研究院 | Liquid phase chip detector based on quantum dot |
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