CN104668002B - Compact fluid analysis device and manufacture method thereof - Google Patents

Abstract

In a first aspect, the invention relates to a device for analyzing a fluid sample. The device includes: a fluidic substrate, including: a microfluidic component embedded in the fluidic substrate and configured to propagate a fluid sample through the device through capillary force; a microfluidic component connected to the microfluidic component for providing A device for a fluid sample; a cover attached to the fluidic substrate at least partially covering the fluidic substrate and at least partially closing the microfluidic assembly; wherein the fluidic substrate is a silicon fluidic substrate and wherein the cover is CMOS chips. In a second aspect, embodiments of the invention relate to methods for fabricating such devices. The method includes: providing a fluidic substrate; providing a cover; and attaching the fluidic substrate to the cover by a CMOS compatible bonding process to at least partially close the fluidic substrate.

Description

Compact fluid analysis device and method of manufacturing the same

technical field

The invention relates to the field of biological analysis devices. In particular, the present invention relates to compact devices for analysis of fluid samples. More specifically, the present invention relates to a fully integrated lab-on-a-chip device for fluid sample analysis.

Background technique

Currently, there are prior art point-of-care devices for blood analysis. The disadvantage of these devices is that their size depends on the different components required to perform blood analysis. In these devices, the external pump is part of the point-of-care instrument. In some devices, micropumps are used to propagate the sample through the fluidic channels of the device. The use of pumps adds to the size and expense of the devices, which makes them unsuitable for use as disposables. Current disposables are typically inserted into expensive readout instruments with multiple, non-disposable, different electronic or optical components to read out the biochemical reactions that occur in the disposable. Another disadvantage of prior art point-of-care devices is their manufacturing expense.

Other prior art devices are lateral flow test strips. These dipsticks are usually manufactured from cellulose, which does not allow precise control over the flow of the fluid sample propagating through the dipstick. This narrows the range of applications of these devices.

Inexpensive, easy-to-use, disposable, compact devices for fully integrated analysis of fluid samples are desired.

Contents of the invention

In a first aspect, the invention relates to a device for analyzing a fluid sample. The device includes: a fluidic substrate, including: a microfluidic component embedded in the fluidic substrate, configured to spread a fluid sample through the microfluidic component by capillary force; and a microfluidic component connected to the microfluidic component. A device for providing a fluid sample; a cover attached to the fluidic substrate at least partially covering the fluidic substrate and at least partially closing the microfluidic assembly. The fluidic substrate is a silicon fluidic substrate, while the lid is a CMOS chip.

According to aspects of the invention, at least a portion of the cover is in contact with the fluid sample when the fluid sample is present in the device.

According to aspects of the invention, the cover includes a transistor layer electrically connected to at least one electronic component, the electronic component being at least one of: biosensing circuitry, electrodes for sensing purposes, electrodes for fluid manipulation purposes Electrodes, circuits for data communication purposes, circuits for wireless data communication purposes, temperature sensors, heater electrodes for temperature control, and fluid sensors and electrodes for fluid viscosity control.

According to various embodiments of the present invention, the means for providing a fluid sample is an integrated needle made of silicon and includes a fluidic channel connected to the interior of the microfluidic assembly. The needles are protruding portions of the fluidic substrate and are positioned to penetrate the skin tissue when pressed against the skin tissue.

According to various embodiments of the invention, the fluidic substrate includes cutouts, and the needles are located in the cutouts.

According to various embodiments of the invention, the fluidic substrate includes a protective structure for protecting the needles, the protective structure being removably attached to the fluidic substrate.

According to various embodiments of the invention, the means for providing a fluid sample is an injection port. The sample droplet can be inserted into the microfluidic assembly by means of capillary suction. A microfluidic assembly may comprise different fluidic compartments, eg, for muti-omic analysis. Different microfluidic compartments can have the same or different depths. The different microfluidic compartments may be separated by valves that can be actuated in any suitable way, eg by fluid force or by electric current. Electrodes for actuation may be included on the fluidic substrate or on the cover.

According to various embodiments of the present invention, the fluidic substrate or cover may further comprise at least one optical waveguide to allow optical excitation and sensing of a fluid sample when present within the device. The fluidic substrate or cover may also include a filter for rejecting light excitation emission to measure the fluorescence signal. Fluidic substrates or covers can include multispectral filters for measuring fluorescent signals with multiple colors. The fluidic substrate or cover may include optical waveguides and/or apertures to illuminate samples for performing lensless microscopy methods.

According to various embodiments of the present invention, the fluidic substrate or the cover comprises at least one through hole for applying a biochemical reagent to at least one area of the microfluidic assembly or to at least one area of the cover.

According to various embodiments of the invention, the lid is bonded to the fluidic substrate using photolithographically patterned polymer.

According to various embodiments of the invention, the device may also include metal contacts electrically connected to the cover for reading out electrical signals generated by the fluid and captured by the measurement system in the cover. According to various embodiments of the invention, the cover of the device may also include CMOS active pixels for readout of optical signals from the fluid.

According to various embodiments of the invention, at least part of the fluidic substrate and/or cover is fabricated from a transparent material to allow optical inspection of the fluidic sample in the microfluidic assembly.

According to embodiments of the invention, the shape of the device allows insertion into a mobile communication device.

In a second aspect, embodiments of the invention relate to a method for manufacturing a device for analyzing a fluid sample. The method includes: providing a fluidic substrate; providing a cover; attaching the fluidic substrate to the cover to at least partially close the fluidic substrate. The fluidic substrate is a silicon fluidic substrate, while the lid is a CMOS chip, and the fluidic substrate is attached to the lid using a CMOS compatible bonding process.

According to various embodiments of the present invention, providing a fluidic substrate may include: providing a silicon substrate, providing a mask layer, such as an oxide mask, patterning the oxide mask to create fine structures in the oxide mask; providing a protective layer to An oxide mask is included; patterning the coarse structure; etching the coarse structure; generating an oxide to protect the coarse structure; removing the protective layer and etching the fine structure; removing the oxide.

According to various embodiments of the invention, providing a fluidic substrate may include providing a silicon substrate, providing a plurality of masks with each layer on top of another, and using each mask to create a Microfluidic structures.

According to certain embodiments of the invention, providing a fluidic substrate may include providing a silicon substrate, providing a first oxide mask, patterning the microfluidic structure, etching the substrate to a single depth, providing a second oxide mask, pattern the microfluidic structure, etch the substrate to a second depth, and, if necessary, repeat these steps to create multiple depths of microfluidic structures.

According to certain embodiments of the present invention, the fluidic substrate and cover of devices according to various embodiments of the present invention may be part of a larger fluidic pack, which may be made of different materials, such as polymers, and may include Larger fluidic structures, reagents, fluidics and electrical interfaces. The advantage hereby is that such a system becomes more cost-effective.

According to various embodiments of the present invention, the surfaces of the fluidic substrate and cover may be partially or fully coated to alter the surface interaction of the substrate with the fluid sample.

In a third aspect, the invention provides the use of a device as described in the first aspect of the invention and embodiments thereof to perform a microscopic method. The microscopic method can be implemented according to the principle of digital holography by using a cover to detect a lensless image.

Use of the device as described can perform multi-omics analysis where a fluidic substrate is used to perform multiple assays in multiple channels and chambers, and a CMOS cover is used to detect multiple signals from all assays. That information can combine multiple DNA, RNA, small molecule, cellular signals from the same analyte.

In particular embodiments, the device is used as a single single-use device for analyzing small volumes of liquid.

In a fourth aspect, data from the cover may be sent to the smart device, for example using a wireless connection. Smart devices can be used to process, visualize and/or communicate data.

In various embodiments of the invention, the combined data collected from the single same sample can be used in software algorithms to calculate parameters associated with the disease or well-being of the individual.

Particular and preferred aspects of the invention are set out in the appended independent and dependent claims. Features from dependent claims may, where appropriate, be combined with features of the independent claim, and with features of other dependent claims, not only as explicitly stated in the claims.

These and other aspects of the invention will be apparent from and elucidated with reference to the embodiments described hereinafter.

Brief description of the drawings

Figure 1 shows a 3D view of one embodiment of a fluidic substrate that may be used in various embodiments of the present invention.

Fig. 2 shows a top view of a first embodiment of a device for analyzing a fluid sample according to embodiments of the invention.

FIG. 3 shows a top view of a fluidic substrate used in the device of FIG. 2 .

FIG. 4 shows a side view of the device in FIG. 2 .

Fig. 5 shows a top view of a second embodiment of a device for analyzing a fluid sample according to embodiments of the present invention, with a close-up of the cutout of the needle.

FIG. 6 shows a top view of one embodiment of a fluidic substrate for use in the device of FIG. 5 , close-up of the needle cutouts.

FIG. 7 shows a side view of the device of FIG. 5 .

Fig. 8 shows a top view of a third embodiment of a device for analyzing a fluid sample according to various embodiments of the present invention, with a close-up of the needle protection structure.

FIG. 9 shows a top view of one embodiment of a fluidic substrate for use in the device of FIG. 8 , close-up of the needle protection structure.

FIG. 10 shows a side view of the device of FIG. 8 .

11-17 illustrate methods of fabricating fluidic substrates for use in devices according to various embodiments of the invention.

Figure 18 shows an embodiment of a CMOS chip used in a device according to various embodiments of the invention.

FIG. 19 illustrates the bonding of a CMOS chip to a fluidic substrate according to various embodiments of the present invention.

Figure 20 illustrates the bonding of a CMOS chip including silicon I/O interconnects to a fluidic substrate according to various embodiments of the invention.

Figure 21 shows one embodiment of a CMOS chip including I/O pads for use in devices according to embodiments of the invention.

Figure 22 shows one embodiment of a CMOS chip for use in devices according to embodiments of the invention, the CMOS chip comprising I/O pads bonded to a fluidic substrate, wherein a portion of the CMOS chip covers the fluidic substrate on the bottom.

FIG. 23 illustrates the bonding of a CMOS chip to a fluidic substrate, wherein the CMOS chip includes vias, according to various embodiments of the present invention.

FIG. 24 shows the bonding of a CMOS chip and a fluidic substrate according to various embodiments of the present invention, wherein the fluidic substrate includes two through holes.

Figure 25 shows a 3D view of a device according to an embodiment of the invention.

Figure 26 shows a 3D view of a wireless standalone device according to an embodiment of the present invention.

Figure 27 shows a top view of a portion of a first embodiment of a microfluidic assembly comprising micropillars for use in devices according to embodiments of the invention.

FIG. 28 shows a 3D view of a portion of the microfluidic assembly of FIG. 27 .

Figure 29 shows a top view of a portion of a second embodiment of a microfluidic assembly comprising micropillars for use in devices according to embodiments of the invention.

FIG. 30 shows a 3D view of a portion of the microfluidic assembly of FIG. 29 .

Figure 31 shows one embodiment of an SD card form factor of a device according to various embodiments of the invention.

Figure 32 shows another embodiment of a device in SD card form according to embodiments of the invention.

Figure 33 is a cross-sectional view of a device according to various embodiments of the invention, wherein multiple functions are supported by a single CMOS technology.

The drawings are illustrative only and non-limiting. In the drawings, the size of some of the elements may be exaggerated and not drawn on scale for illustrative purposes.

Any reference signs in the claims should not be construed as limiting the scope.

In the different drawings, the same reference signs indicate the same or similar elements.

detailed description

The present invention will be described with respect to particular embodiments and with reference to certain drawings but the invention is not limited thereto but only by the claims. The drawings described are only schematic and non-limiting. In the drawings, the size of some of the elements may be exaggerated and not drawn on scale for illustrative purposes. The dimensions and relative dimensions do not correspond to actual reproductions for the practice of the invention.

Furthermore, in the specification and claims, the terms "first", "second", etc. are used to distinguish between similar elements, and not necessarily to describe a temporal order, spatial order, hierarchical ordering, or any other the order of the methods. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein.

Furthermore, the terms above, below, etc. in the specification and claims are used for descriptive purposes and not necessarily to describe relative positions. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other orientations than described or illustrated herein.

It should be noted that the term "comprising", used in the claims, should not be interpreted as limited to the meanings listed below; it does not exclude other elements or steps. It should therefore be read as specifying the presence of said features, integers, steps or components as stated, but not excluding the presence or addition of one or more other features, integers, steps or components or groups thereof. Therefore, the scope of the expression "a device comprising means A and B" should not be limited to a device consisting of components A and B only. This means that the only relevant components of this device that are relevant to the invention are A and B.

Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to one of ordinary skill in the art from this disclosure, in one or more embodiments.

Similarly, it is to be understood that, in the description of example embodiments of the invention, various features of the invention are sometimes grouped together in a single embodiment, drawings and description thereof, so as to tie the disclosure together, and aid in the understanding of one or more of the various inventive aspects. This method of disclosure, however, is not to be interpreted as reflecting an intention that the claimed invention requires more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive aspects lie in less than all features of a single foregoing disclosed embodiment. Thus, the claims following the Detailed Description are hereby expressly incorporated into this Detailed Description, with each claim standing on its own as a separate embodiment of this invention.

Furthermore, although some embodiments described herein include some features included in other embodiments but not others, combinations of features from different embodiments are intended to be within the scope of the invention and form Different embodiments as understood by those skilled in the art. For example, in the appended claims, any of the claimed embodiments may be used in any combination.

In the description provided herein, numerous specific details are set forth. However, it is understood that embodiments of the invention may be practiced without these specific details. In other instances, well-known methods, structures and techniques have not been shown in detail in order not to obscure the understanding of this description.

Where reference is made to a "fluid sample" in various embodiments of the invention, reference is made to any bodily fluid such as blood, urine, saliva.

When reference is made to "I/O pads" or "I/O contacts" in various embodiments of the present invention, reference is made to metal contacts such as metal contacts that allow input and output of electrical signals of a microchip.

Where references to "CMOS" are made in the various embodiments of the present invention, reference is made to complementary metal oxide semiconductors.

In a first aspect the invention relates to a device 100 for analyzing a fluid sample as shown in FIG. 26 . The device 100 includes: a fluidic substrate 101 and a cover 103 attached to the fluidic substrate 101 and at least partially covering the substrate 101 . The fluidic substrate 101 includes a microfluidic component 102 embedded in the fluidic substrate 101, configured to spread a fluid sample through the microfluidic component 102 by capillary force (the microfluidic component 102 is composed of a sample pad 102a ( = inlet), reagent storage 102b, single-use sealing valve 102c, first trigger valve 102d, mixer 102e, delay line 102f, second trigger valve 102g, heater 102h, and wicking strip 102i, etc. Components are shown); and a device connected to the microfluidic component 102 for providing a fluid sample. The cover 103 at least partially closes the microfluidic assembly 102 by at least partially covering the substrate 101 . In various embodiments of the present invention, the fluidic substrate 101 is a silicon fluidic substrate; and the cover 103 is a CMOS chip.

Since the fluidic substrate 101 is a silicon substrate and the lid 103 is a CMOS chip, both can be fabricated using mass production compatible silicon processing techniques. As an added advantage, inexpensive CMOS assembly techniques can be used to bond the silicon substrate to the CMOS chip. This reduces the overall cost of the device and allows it to be used as a disposable device and mass produced.

FIG. 1 shows a 3D view of one embodiment of a fluidic substrate 101 .

A top view of one embodiment of a device 100 is shown in FIG. 2 with a fluidic substrate 101 and a lid 103 attached to each other. A top view of an exemplary fluidic substrate 101 used in the device of FIG. 2 is shown in FIG. 3 . A side view of one embodiment of the device 100 of FIG. 2 with the fluidic substrate 101 attached to the lid 103 is shown in FIG. 4 .

A device 100 according to various embodiments of the invention includes a fluidic substrate 101 attached or bonded to a cover 103 . The fluidic substrate 101 includes a microfluidic component 102 . Microfluidic assembly 102 may include microfluidic channels, microreactors, or other microfluidic parts/structures interconnected to allow fluidic samples to propagate through the complete microfluidic assembly 102 . The microfluidic assembly 102 may comprise a plurality of micropillars or microstructures at regular or irregular distances to allow filtering and separation, valving (= acting as a valve), mixing of fluid samples during capillary flow. 27 shows a top view of a portion of an open microfluidic assembly 102 including micropillars 270 (to allow filtration and separation, valving, mixing of fluid samples during capillary flow). FIG. 28 shows a 3D view of the opened microfluidic assembly 102 of FIG. 27 including micropillars 270 . The micropillars 270 in Figures 27 and 28 are positioned to form a gradient. This gradient is advantageous for filtering out larger particles in the first portion of the microfluidic assembly 102 and filtering out smaller particles in the second portion of the microfluidic assembly 102 . 29 and 30 illustrate another embodiment of the gradient of the microcolumn 270 in the microfluidic assembly 102. Microfluidic assembly 102 may be configured to induce capillary action to propagate a fluid sample through device 100 . The dimensions of the microfluidic assembly 102 can be adapted to induce capillary action in the microfluidic assembly 102 when a fluid sample is present. For example, the size and distance between micropillars 270 in microfluidic assembly 102 can be configured to induce capillary action in microfluidic assembly 102 . As an advantage, in various embodiments of the invention, the device 100 does not require additional active components (eg, active pumps) to propagate the fluid sample through the device 100 . Thus, the complexity of device 100 is reduced compared to prior art implementations, which reduces manufacturing costs and energy consumption. Due to the low manufacturing cost, the device can be used as a disposable fluid analysis device.

An advantage of the present invention is that by, for example, correctly setting the dimensions and distances of the microfluidic channels and/or microcolumns present in the microfluidic assembly 102, the flow of fluid samples in the microfluidic assembly 102 can be controlled precisely. Fine control. The photolithographic pattern can be used to fabricate the microfluidic component 102 in the fluidic substrate 101 . The photolithographic patterning of the micropillars and microfluidic channels of the microfluidic assembly 102 allows for precise control of the size, size and shape of the micropillars and microfluidic channels, thus precisely controlling capillary flow is an advantage. This precise control of dimensions achievable by the photolithographic process presents an advantage in obtaining reproducible lateral flow over prior art lateral flow test papers (made from porous paper with uncontrolled lateral flow) . By varying the dimensions along the length of the device, it is possible to slow down and/or speed up the flow of the fluid sample as desired. This allows the realization of more complex biochemical reactions relative to the simple flow used in existing lateral flow immunoassay tests. The combination with the functions implemented in the CMOS chip bonded as a lid onto the fluidic substrate 101 also adds temperature control, electrofluidic actuation and valve control, integrated biosensing and readout if required. Thus, it becomes possible to realize complex assays, including DNA/RNA assays, proteins, small molecules and cells, and combinations thereof, in an integrated capillary system starting from the fluids of the body. Furthermore, the implementation of capillary flow in silicon with controlled side flow and with control over temperature and flow rate yields more accurate immediate detection results.

In various embodiments of the present invention, the fluidic substrate 101 includes a device connected to the microfluidic component 102 for providing a fluid sample.

The cover 103 serves as a cover for the fluidic substrate 101 , wherein the cover 103 completely or partially closes the microfluidic assembly 102 . FIG. 25 shows an embodiment of the present invention, wherein the cover 103 partially covers the fluidic substrate 101 . The microfluidic component 102 may be an open microfluidic component 102 in the fluidic substrate 101 . According to an alternative embodiment of the present invention, the size of the cover 102 may coincide with the size of the fluidic substrate 101 . The cover 103 may completely or partially cover the fluidic substrate 101 . When the device for providing the fluid sample is an injection port 109 (as shown in FIG. 26 ) such as a sample pad 102a, the cover 103 can partially cover the fluidic substrate 101, allowing the user to access the injection port 109 to place the fluid sample.

According to various embodiments of the present invention, the device 100 may further include one or more electrodes placed on the microfluidic component 102 on the fluidic substrate 101 . These electrodes may be biocompatible electrodes. The electrodes can be electrically connected to the cover 103 and allowed to interact with the fluid sample in the microfluidic assembly 102 of the device 100 (since they can directly contact the fluid sample in the microfluidic assembly 102). While the cover 103 may itself include electrodes, it may be advantageous to separate the electrodes from the cover 103 to allow the cover 103 to be smaller to reduce costs.

According to various embodiments of the invention, the microfluidic assembly 102 may include a capillary pump.

According to various embodiments of the present invention, the means for providing a fluid sample may be, for example, an integrated needle 104 made of silicon and comprising a fluidic channel 105 connected to the interior of the microfluidic assembly 102 . The needles 104 may be protruding portions of the fluidic substrate 101 and may be positioned so as to penetrate the skin tissue when pressed against the skin tissue.

Fluidic substrate 101 and needles 104 can be fabricated from a single piece of silicon. According to various embodiments of the invention, this simplifies the fabrication of the device 100 since no separate step is required to attach the needles 104 to the fluidic substrate 101 . Likewise, standard CMOS processing techniques can be used to fabricate needles 104 . Preferably needle 104 is a sharp needle that allows skin tissue to be penetrated. Both the fluidic substrate 101 and the needle 104 can be fabricated from silicon. As an advantage, the strength of silicon allows the needles 104 to be very sharp, which facilitates the penetration of the needles 104 in skin tissue. In addition, the strength of silicon allows the skin tissue to be pressed tightly against the needle 104 , allowing penetration of the skin tissue without bending or breaking the needle 104 .

According to various embodiments of the present invention, the needles 104 may be located in the horizontal plane of the fluidic substrate 101 , wherein the needles 104 are located on the sidewall of the fluidic substrate 101 . The needles 104 may be protruding portions of the sidewall of the fluidic substrate 101 . According to different embodiments, the needles 104 may be located on the horizontal plane of the fluidic substrate 101 , wherein the needles are vertically placed on the main surface of the fluidic substrate 101 . According to various embodiments of the invention, the needle 104 may function as an open channel connected to the microfluidic assembly 102, wherein in use, the skin tissue acts as a side wall of the needle 104 when it is penetrated.

The device 100 according to various embodiments of the invention may be used by pressing the user's skin tissue against the needle 104 . When sufficient force is applied, the needle 104 penetrates the skin tissue, allowing blood to enter the fluidic channel 105 inside the needle 104 . Needle 104 has an open tip to allow a fluid sample to enter internal fluidic channel 105 . When the needle is sharp with a small outer diameter (preferably less than 200 μm), the penetration of the skin tissue will not cause any discomfort to the user. With the internal fluidic channel 105 of the needle 104 connected to the microfluidic component 102 of the fluidic substrate 101 , blood can enter the microfluidic component 102 . Blood will travel through the microfluidic assembly 102 due to capillary forces.

FIG. 1 shows an embodiment of a fluidic substrate 101 with integrated needles 104 (as part of the fluidic substrate 101 ) with fluidic channels 105 connected to the interior of the microfluidic assembly 102 . The microfluidic assembly 102 may comprise: a sample pad 102a (=injection port), a reagent reservoir 102b, a single-use sealing valve 102c, a first trigger valve 102d, a mixer 102e, a delay line 102f, a second trigger valve 102g, a heating Device 102h and imbibition bar 102i. As shown in FIG. 1 , all the fluidic components in the fluidic substrate 101 are opened. Lid 103 will serve as a cover to close off some or all of the fluidic components.

According to various embodiments of the present invention, the fluidic substrate 101 may include a cutout 106 , wherein the needle 104 is located in the cutout 106 . The cutouts 106 are portions of the fluidic substrate 101 that are removed to provide mechanical protection to the needles 104 present in the cutouts.

FIG. 5 shows a top view of an embodiment of the present invention where a lid 103 is bonded to a fluidic substrate 101 . FIG. 6 shows a top view of an exemplary fluidic substrate 101 according to an embodiment of the present invention. FIG. 7 shows a side view of an embodiment of the present invention where a cover 103 is bonded to a fluidic substrate 101 .

As shown in FIGS. 5 , 6 and 7 , needles 104 are located in cutouts 106 of fluidic substrate 101 . The cutouts 106 protect the pins 104 from breaking, for example, when the device 100 is inserted into a socket of an external device, such as a mobile device such as a smartphone, for example for readout. The sidewall of the fluidic substrate 101 may function as the cutout 106 . Needle 104 may be positioned in incision 106 to allow the user to penetrate skin tissue while pressing firmly against the incision. As a further advantage, during the manufacturing process, the needle 104 can be manufactured when the incision 106 is made. As a result, less material is wasted, since only the material for the incision 106 , not including the material for the needle 104 , needs to be removed. Slits 106 and needles 104 can be fabricated using standard silicon processing techniques.

According to various embodiments of the present invention, the fluidic substrate 101 may include a protective structure 107 for protecting the needles 104 , the protective structure being removably attached to the fluidic substrate 101 . According to various embodiments of the invention, the protective structure 107 may be attached to the fluidic substrate 101 by at least one anchoring mechanism 108 . By breaking at least one anchoring mechanism 108, the protective structure 107 can be detached. The protection structure 107 may be part of the fluidic substrate 101, wherein the anchoring mechanism 108 is a groove in the fluidic substrate 101 to allow breaking of the protection structure 107 at the groove. FIG. 8 is a top view of such an embodiment of device 100 . As can be seen in FIG. 9 (shown is a top view of an example embodiment of a fluidic substrate 101 for use in devices according to embodiments of the invention, such as the device shown in FIG. 8 ), a protective structure 107 is part of the fluidic substrate 101 and features two anchoring mechanisms 108 that allow the protection structure 107 to be detached from the fluidic substrate 101 . FIG. 10 shows a side view of device 100 in FIG. 8 .

According to various embodiments of the invention, the means for providing a fluid sample is an injection port 109 . The injection port 109 may be a gap in the fluidic substrate 101, and it is connected to the microfluidic component 102 through a fluidic channel. To use the device, a user places a drop of bodily fluid, such as blood or urine, on the infusion port 109 of the device. Fluids of the body will travel through the microfluidic assembly 102 due to capillary forces.

FIG. 26 shows a device 100 disassembled according to various embodiments of the present invention, which includes a fluidic substrate 101 including an injection port 109 and a microfluidic assembly 102 , a cover 103 and a bag 110 . Pack 110 may include a base and a top that may fit together to enclose fluidic substrate 101 and cover 103, thereby protecting fluidic substrate 101 and cover 103 from environmental influences such as dust. The pack may include a through hole 260 for placing a fluid sample onto the injection port 109 of the fluidic substrate 101 . When all parts are assembled, the device 100 can be used as a single wireless device for analyzing fluid samples.

According to aspects of the invention, at least a portion of the cover 103 may be in contact with the fluid sample when the fluid sample is present in the device 100 . Since the cover 103 is a CMOS chip, when the cover 103 is used as a side wall of the opened microfluidic assembly 102 of the fluidic substrate 101, the electronic circuits present on the surface of the chip can directly contact the fluid sample. In this case, the side of the chip that includes the electronic circuitry may be bonded to the open microfluidic assembly 102 of the fluidic substrate 101, wherein the electronic circuitry interacts with portions of the fluidic assembly 102 where interaction with the fluid sample is desired. align. As an advantage, this improves the interaction between the electronic circuit and the fluid sample.

According to various embodiments of the invention, the cover 103 may include a bonding layer to allow bonding of the cover 103 to the fluidic substrate 101 .

According to various embodiments of the present invention, the first side of the fluidic substrate 101 including the opened microfluidic component 102 may be bonded to the first side of the CMOS chip 103 including at least one electronic component.

According to one embodiment, the cover 103 includes a transistor layer electrically connected to at least one electronic component, the electronic component being at least one of: bio-sensing circuitry, electrodes for sensing purposes, electrodes for fluid manipulation purposes , circuits for data communication purposes, circuits for wireless data communication purposes, temperature sensors, heater electrodes for temperature control or temperature cycling, and fluid sensors and electrodes for fluid viscosity control. The circuitry for wireless data communication may include provisions for communicating via a Bluetooth radio or a WiFi module to wirelessly send data from the electronic circuitry in the cover 103 . As an advantage, device 100 can communicate with external devices, such as mobile devices, which can be used for further processing of data.

The cover 103 is a CMOS chip. According to various embodiments of the present invention, a CMOS chip includes a silicon substrate 111 , a transistor layer 112 , at least one electronic component electrically connected to the transistor layer 112 , and at least one bonding layer 115 . The at least one electronic component may be a biosensing circuit, an electrode for sensing purposes, an electrode for fluid manipulation purposes, a circuit for data communication purposes, a circuit for wireless data communication purposes, a temperature sensor, a temperature sensor for temperature heater electrodes for control, and fluid sensors and electrodes for fluid viscosity control.

One particular embodiment of a cover 103 according to embodiments of the invention is shown in FIG. 18 . In this embodiment, the CMOS chip 103 includes a silicon substrate 111 . On top of the silicon substrate 111 there may be a transistor layer 112 . On top of the transistor layer 112 there may be an interconnect layer 113 . On top of transistor layer 112 there may be at least one electronic component electrically connected to transistor layer 112 through interconnect layer 113 . The interconnect layer 113 may include multiple metal layers. On top of the transistor layer 112 there may be a bonding layer 115 and at least one electrode 114 according to various embodiments of the invention. The electrode 114 may be electrically connected to the transistor layer via the interconnect layer 113 .

According to various embodiments of the invention, at least one electronic component may be a biocompatible electrode that is not corroded by the fluid and is chemically inert. According to a particular embodiment, at least one electrode 114 is a TiN electrode.

According to various embodiments of the present invention, the bonding layer 115 may be a layer that allows bonding the CMOS chip 103 to the fluidic substrate 101 at low temperature and low voltage. This is advantageous because these situations do not damage the CMOS chip, nor reagents or eg proteins that may be provided on the microfluidic substrate 101 . According to a particular embodiment, bonding layer 115 may be a SiO ₂ or polymer layer.

FIG. 19 shows a device 100 according to various embodiments of the present invention, wherein a CMOS chip 103 as shown in FIG. 18 is bonded to a fluidic substrate 101 . The side of the CMOS chip 103 including the bonding layer 115 and the electrodes 114 is bonded to the side of the fluidic substrate 101 including the opened microfluidic assembly 102 . This means that the CMOS chip 103 shown in FIG. 18 is turned upside down relative to its position in FIG. 18 . The electrodes 114 are thus in direct contact with the fluid sample present in the microfluidic assembly 102 . The bonding layer 115 is used to attach the CMOS chip 103 to the fluidic substrate 101 .

According to various embodiments of the invention, the CMOS chip 103 may include at least one silicon I/O connection 116, as shown in FIG. 20 . The silicon I/O connection 116 may be a rear opening through the substrate 111 to access electrical signals of the CMOS chip 103 in the transistor layer 112 . Furthermore, in an alternative embodiment, the silicon I/O connection 116 may be a rear opening through both the substrate 111 and the transistor layer 112 to access electrical signals of the CMOS chip 103 in the interconnect layer 113 . FIG. 20 shows device 100 where CMOS chip 103 is bonded to fluidic substrate 101 and where CMOS chip 103 features silicon I/O connections 116 through both substrate 111 and transistor layer 112 .

According to various embodiments of the present invention, the fluidic substrate may include an open microfluidic component 102 , and the fluidic substrate may be partially covered by the CMOS chip 103 . It is advantageous that a portion of the microfluidic assembly 102 is not covered, as this allows reagents to be applied/dropped on specific open portions of the microfluidic assembly 102 . In this case, after bonding the fluidic substrate 101 to the CMOS chip 103, no additional via holes are required to apply reagents. The smaller area of the CMOS chip is also advantageous because the active electronics are a more expensive part of the disposable.

According to various embodiments of the present invention, the CMOS chip 103 may further include at least one I/O pad 117 . The at least one I/O pad 117 can be located on the interconnect layer 113 .

FIG. 21 shows an embodiment of a CMOS chip 103 . The CMOS chip 113 includes a silicon substrate 111 . On top of the silicon substrate there is a transistor layer 112 . On top of the transistor layer 112 there is an interconnect layer 113 . The interconnect layer 113 may include multiple metal layers to interconnect the transistor layer 112 with electronic components. On top of the transistor layer 112, there is a bonding layer 115, an I/O pad 117, and in the embodiment shown a plurality of electrodes 114. The electrode 114 is electrically connected to the transistor layer 112 via the interconnection layer 113 . I/O pad 117 is also electrically connected to transistor layer 112 via interconnect layer 113 .

According to various embodiments of the present invention, the first part of the first main surface of the CMOS chip 103 may cover the fluidic substrate 101 , and the second part of the first main surface of the CMOS chip 103 may not cover the fluidic substrate 101 . In these embodiments, the CMOS chip 103 can either be larger than the fluidic substrate 101 or it can be moved laterally relative to the fluidic substrate 101 such that a portion of the CMOS chip 103 forms an overhang relative to the fluidic substrate 101 (overhang). A second portion of the first main surface of the CMOS chip 103 may include at least one I/O pad 117 to access the I/O pad 117 .

FIG. 22 shows the CMOS chip 103 shown in FIG. 21 bonded to the fluidic substrate 101 . The first part of the CMOS chip 103 indicates partially, and in this embodiment is shown completely covering the fluidic substrate 101 , where the electrodes 114 directly contact the fluidic sample when it is present in the microfluidic assembly 102 of the device 100 . The bonding layer 115 is used to bond the first part of the CMOS chip 103 to the fluidic substrate 101 . The second part of the CMOS chip 103 forms an overhang that does not cover the fluidic substrate 101 . The second part includes I/O pads 117 . As an advantage, the overhang allows easy access to the I/O pad 117 . This allows the use of standard I/O pad sizes and packaging methods to insert the substrate into the socket typically used for smart cards. A further advantage is that no additional processing steps are required to make silicon I/O connections (such as holes through the substrate and transistor layers) to access electrical signals in the CMOS chip 103 .

According to various embodiments of the present invention, the fluidic substrate 101 also includes at least one optical waveguide to allow optical excitation and sensing of a fluid sample when present within the device 100 .

According to various embodiments of the present invention, the fluidic substrate 101 or the cover 103 includes at least one through hole for applying a biochemical reagent to a region of the microfluidic assembly 102 or to a region of the cover 103 . Through holes in the fluidic substrate 101 or the cover 103 allow biochemical reagents to be applied to specific areas of the microfluidic assembly 102 or to specific areas of the cover 103 . This is advantageous because it allows reagents to be applied after the lid 103 is attached to the fluidic substrate 101 .

According to various embodiments of the present invention, the CMOS chip 103 may include at least one via 118 . When attached to the fluidic substrate 101 , the through holes 118 in the CMOS chip 103 allow reagent droplets to be dropped on specific locations of the microfluidic component 102 in the fluidic substrate 101 or on specific portions of the CMOS chip 103 . FIG. 23 shows an embodiment in which the CMOS chip 103 includes a via 118 . In this embodiment, the CMOS chip also includes silicon I/O connections 116 . As shown, the CMOS chip 103 completely covers a portion of the fluidic substrate 101 .

According to the same or an alternative embodiment of the invention, the first side of the fluidic substrate 101 comprises an open microfluidic assembly 102 . The other side opposite to the side where the microfluidic assembly 102 is provided may include at least one through hole 119 . The through holes 119 allow reagents to be dropped on a specific position of the microfluidic component 102 of the fluidic substrate 101 or a specific part of the CMOS chip 102 . FIG. 24 shows an embodiment in which the fluidic substrate includes two vias 119 . A part of the CMOS chip 103 covers the fluidic substrate 101 , and a part that does not cover the fluidic substrate 101 but forms an overhang includes an I/O pad 117 .

According to various embodiments of the invention, the lid 103 may be bonded to the fluidic substrate 101 using a polymer, preferably a photolithographically patterned polymer. The material used to form the bond between the lid 103 and the fluidic substrate 101 should be suitable (preferably at low temperature, eg room temperature) to perform Si-Si bonding. This is compatible with the presence of CMOS circuitry on the lid 103 that should not be damaged by the bonding process, and with reagents present on or in the fluidic substrate 101 that should also not be damaged by the bonding process of. Suitable bonding materials for bonding the lid 103 to the fluidic substrate 101 are, for example, photopatternable PDMS available from Dow Corning, SU8 available from MicrChem, or OSTE available from MerceneLabs. All of these bonding materials use room temperature as the bonding temperature.

According to another embodiment of the present invention, the lid 103 is bonded to the fluidic substrate 101 using CMOS compatible packaging techniques. The use of CMOS packaging technology can be used when the fluidic substrate 101 is a silicon substrate and the cover 103 is a CMOS chip.

According to various embodiments of the present invention, the device 100 may further include metal contacts electrically connected to the cover 103 to read out electrical signals from the cover 103 . Metal contacts may be located on cover 102 electrically connected to electronic circuitry in cover 103 . The position and shape of the metal contacts can be selected according to standards, allowing the device to be plugged into standardized slots, such as: memory cards commonly used in communication devices such as mobile devices (e.g., Compact Flash memory cards, SmartMedia memory cards, Multimedia memory card or Secure Digital (SD) memory card). Plugging device 100 into the mobile device allows electrical signals from cover 103 to be processed by processors and/or other electronic components present in the mobile device. For example, a smartphone's processor may be used to process electrical signals and/or display data.

According to various embodiments of the invention, at least part of the fluidic substrate 101 and/or cover 103 may be fabricated from a transparent material to allow optical inspection of the fluid sample while it is present in the microfluidic assembly 102 . That portion of the fluidic substrate 101 made of transparent material may be part of the microfluidic component 102 of the device 100 . The transparent portion may be a sidewall of the microfluidic component 102 of the device 100 . Transparent materials allow optical inspection of fluid samples in device 100 . Optical detectors may be used to optically examine fluid samples, for example to detect analytes. The optical detector can be an image sensor, which can be part of an external device or can be integrated in device 100 . Transparent materials can be transparent oxides or polymers. A portion of the cover 103 or a portion of the fluidic substrate 101 may be transparent for microscopy purposes. For lensless imaging purposes, a portion of the cover 103 and a portion of the fluidic substrate 101 may be transparent to allow operation in a transmission mode, where a radiation source may be used to irradiate a fluid sample in the device 100 through the transparent portion of the cover 103 objects in the fluidic substrate 101 , while detectors can be used to detect signals from irradiated objects through the transparent portion of the fluidic substrate 101 . The signal may be a diffraction pattern of an irradiated object in the fluid sample.

Fig. 33 shows a device 100 according to various embodiments of the invention, wherein a fluidic substrate 101 and a cover 103 are bonded to each other. Fluidic substrate 101 includes various microfluidic components for multi-omics analysis, including in the illustrated embodiment multiple chambers 330, 331, 332, 333 and microfluidic channels (not shown). The chambers can have different depths, depending on their function and the type of measurements performed. The chambers may be separated by valves actuatable in any suitable manner, eg by fluid force or by electrical current. Electrodes for actuation may be provided on the fluidic substrate 101 or on the cover 103 . The CMOS chip forming the lid 103 may thus incorporate different functions, such as for example a CMOS microscopic imager 334, CMOS optical detectors 335, 336, and CMOS electronics 337 for heating and/or sensing. The CMOS microscopic imager 334 may include CMOS active pixels for reading out optical signals from a fluid sample in the microfluidic assembly 102 . The CMOS optical detector 335 includes an optical resonator 338 . A waveguide 339 may be present to transport measurement light from one location of the CMOS chip 103 to another. The waveguide can be used, for example, to illuminate a sample to perform lens-less microscopy. In addition, filters may be provided in the fluidic substrate 101 or in the cover 103 to reject light excitation emission, thereby allowing the measurement of fluorescent signals. Also a multispectral filter can be provided in the fluidic substrate 101 or in the cover for measuring the fluidic signal using multiple colors.

In this way, according to various embodiments of the invention, the detection of different types of labels can be performed in a single, preferably disposable, detection device.

According to embodiments of the invention, the shape of the device 100 allows insertion into a mobile communication device. According to various embodiments of the invention, device 100 has the shape/dimensions of a memory card. It is an advantage of various embodiments of the present invention that the device 100 can be sized according to standards, for example, according to the standards of memory cards used in mobile devices such as: Compact Flash memory cards, smart media memory cards, multimedia memory cards, security Digital memory card or other type of memory card.

Figures 31 and 32 show an embodiment of the invention in which the device 100 has the shape of an SD card. Inside the cutout 106 (always present according to the SD card standard), there is a needle 104 . On the other side of the SD card, there are metal contacts and are electrically connected to the cover 103 to allow electrical signals to be read out from the cover 103, which can be further processed by the device into which the SD card is inserted.

According to various embodiments of the present invention, the cover 103 or the fluidic substrate 101 may further include a compartment, such as a battery compartment (not shown), electrically connected to the cover 103 for providing power to the device 100 .

In a second aspect embodiments of the invention relate to methods for fabricating the device disclosed in the first aspect of the invention. The method includes: providing a flow control substrate 101; providing a cover 103; attaching the flow control substrate 101 to the cover 103 to at least partially close the flow control substrate 101; characterized in that: the flow control substrate 101 is a silicon flow control substrate, while the cover 103 is a CMOS chip; and wherein the fluidic substrate 101 is attached to the cover 103 using a CMOS compatible bonding process.

It is advantageous to use a CMOS compatible bonding process to bond the fluidic substrate 101 to the lid 103 . In prior art devices, bonding is performed using high temperature/high voltage bonding techniques. These bonding techniques may damage the electronic circuits present in the CMOS chip and/or the reagents present in the microfluidic substrate 101 . Using CMOS compatible bonding allows bonding at lower temperature/lower voltage and thus protects the electronic circuitry of the cover 103 and the reagents present in the microfluidic substrate 101 . According to various embodiments of the invention, bonding may be performed by a wafer-to-wafer or die-to-wafer bonding process, such as direct oxide-to-oxide bonding or via patternable polymer bonding. Furthermore, it is advantageous to be able to perform bonding at low temperatures, since some reagents are already dripped onto one of the substrates during the fabrication flow.

The fluidic substrate 101 can be fabricated using a combination of coarse and fine structures in a monolithic silicon substrate, through a combination of two hard masks, protection and deprotection of layers, etching of coarse structures and etching of fine structures. The fine structure may be a structure configured to allow controlled capillary suction in the microfluidic assembly 102 of the device 100 . Fine structures may include micropillars 270 and/or other microstructures. The coarse structure may be a structure for storing a larger volume of fluid (such as reagent storage 102b for storing reagents) or a wicking strip 102i. Using silicon rather than more common microfluidic materials such as glass or polymers is an advantage because the non-highly anisotropic etching of silicon results in fine structures with particularly high aspect ratios. The silicon micropillars 270 typically have lateral dimensions from 1 μm to 20 μm, relative to an aspect ratio of 20-50. A high aspect ratio is advantageous in having a high surface to volume ratio, which is necessary for capillary flow. High aspect ratio fine structures, in combination with coarse structures, allow for more complex capillary fluidic functions in a more compact footprint than can be achieved by any other material. More complex functions include separation (e.g. separating cells from molecules), mixing, valve control, thermally controlled reactions...  Furthermore, silicon is an intercalation material with definite advantages with respect to the realization of biochemical reactions. The advantage of a particularly compact fully integrated disposable device derives from the advanced use of silicon both on the fluidic substrate and on the CMOS lid. The reduced footprint also results in reduced cost of the overall device.

According to various embodiments of the present invention, providing a fluidic substrate 101 includes providing a silicon substrate 201 (shown in FIG. 11 ) and patterning the silicon substrate to form a microfluidic component 102 in the device 100 and a device for providing a fluid sample. The device, microfluidic assembly 102 is configured to propagate a fluid sample through device 100 by capillary force.

According to various embodiments of the present invention, providing the fluidic substrate 101 includes: providing a silicon substrate 201, providing an oxide mask 202, and patterning the oxide mask 202 by using a first patternable mask layer 210, so that Fine structure 203 is created in oxide mask 202 (FIG. 12); protective layer 204 is provided to protect the patterned oxide mask; coarse structure is patterned in second patternable mask layer 211 (FIG. 13) ; Etch the coarse structure 205 in the silicon substrate 201 through the second mask layer 211 ( FIG. 14 ); remove the second mask layer 211 and generate an oxide 206 ( FIG. 15 ) to protect the coarse structure 205 ; remove the protective layer 204 (FIG. 16) and etch the fine structure 203 (FIG. 16) using the oxide layer 206 as an etch mask; remove the oxide 206 (FIG. 17). The resulting structure is a microfluidic substrate 101, which can be used in devices according to various embodiments of the first aspect of the invention.

11-17 illustrate how the fluidic substrate 101 is fabricated. According to various embodiments of the present invention, the fluidic substrate 101 can be manufactured by performing the following:

Patterning the fine structure 203 includes: providing a silicon substrate 201, providing an oxide mask 202, and patterning the oxide mask 202 to create a fine structure 203 in the oxide mask 202;

providing a protective layer 204 to protect the oxide layer 202;

performing photolithography of the coarse structure 205;

performing etching of the coarse structure 205;

Oxide generation 206 is used to protect the coarse structure 205, wherein the protective layer 204 on the fine structure 203 prevents oxide generation;

removing the protection layer 204 and etching the fine structure 203;

Oxide 206 is removed.

According to various embodiments of the present invention, the protection layer 204 may be a nitride layer.

According to various embodiments of the present invention, providing a CMOS chip 103 includes providing a silicon substrate 111, fabricating a transistor layer 112 on top of the silicon substrate and providing an interconnect layer 113 on top of the transistor layer. The interconnection layer may include at least one metal layer. CMOS chip 103 is fabricated using standard CMOS processing techniques.

Additionally, additional components, such as biocompatible electrodes, bonding layers, I/O pads, or other components, may be deployed or patterned onto the interconnect layer 113 on top of standard CMOS processing flow.

According to various embodiments of the present invention, vias 109 , 118 may be etched through fluidic substrate 101 or CMOS chip 103 to allow fluidic access to apply reagents to fluidic substrate 101 or CMOS chip 103 . Vias in the CMOS chip 103 may be fabricated while silicon I/O interconnects 116 are fabricated in the CMOS chip 103 . The vias in the fluidic substrate 101 can be fabricated by first thinning the fluidic substrate and then etching the vias.

According to various embodiments of the invention, the CMOS chip 103 may be bonded to the fluidic substrate 101 using a die-to-wafer or wafer-to-wafer bonding process.

In order to access the electrical signals of the CMOS chip 103, silicon I/O contacts 116 may be provided. According to embodiments of the invention, the contacts may be fabricated by thinning the silicon substrate 111 of the CMOS chip 103 and performing a backside etch on the silicon substrate 111 to gain access to the metal layers of the interconnect layer 113 .

Alternatively, a CMOS chip 103 containing I/O pads 117 on a first side of the chip 103 may be provided, wherein the first side of the CMOS chip 103 is bonded to the fluidic substrate 101 and contains a CMOS chip of the I/O pads 117 therein. The first side of the chip 103 does not cover the fluidic substrate 101 . This is shown, for example, in FIG. 22 . The I/O pads 117 are accessible when the CMOS chip 103 is bonded to the fluidic substrate 101 . I/O pads 117 may be used as metal contacts on the memory card.

According to various embodiments of the present invention, the CMOS chip 103 is bonded to the fluidic substrate 101 while at least one electronic component on the first side of the CMOS chip 103 is aligned with the microfluidic component 102 . For example, the sensing and actuation electrodes on the first side of the CMOS chip 103 are aligned with the sensing or actuation side in the fluidic substrate 101 . This allows the fluid sample to be in direct contact with the electronic components present on the CMOS chip 103 while the fluid sample is present in the device 100 .

According to various embodiments of the invention, the surfaces of the fluidic substrate 101 and cover 103 are partially or fully coated to alter the surface interaction with the fluid sample. The surface may be the inner surface of the microfluidic component 102 or the surface of the CMOS chip 103 bonded to the fluidic substrate 101 . In particular, those parts of the surface of the CMOS chip 103 are in contact with the fluid sample present in the microfluidic assembly 102 . The coating can be a hydrophilic coating.

The surface of the microfluidic component 102 and/or the side of the CMOS chip 103 bonded to the fluidic substrate 101 can be made hydrophilic to improve the wetting properties of the surface, thereby enhancing capillary flow. The surface can also be treated to avoid absorption or adhesion of biomolecules on the wall. Coating can be accomplished, for example, by vapor coating with silanes. According to various embodiments of the present invention, the coating can be performed locally on a specific portion of the fluidic substrate 101 (for example in some microfluidic channels) or on a specific portion of the CMOS chip 103 .

According to various embodiments of the invention, at least one via is fabricated in the fluidic substrate 101 by first etching the via and then filling the via with a transparent oxide of a polymer.

Embodiments of the present invention improve the functionality, portability, and manufacturability of compact, single-use point-of-care testing devices. A particular embodiment of the invention is a fully integrated silicon device with a needle or infusion port used as an inlet for blood or other bodily fluids. The device features a capillary fluidic system for a fluid sample to propagate through the device via capillary action. A capillary pump serving as the imbibition region of the capillary fluidic system can be used to spread the fluid sample in the device. Sensor chips that read signals generated by biochemical sensing reactions within capillary systems can be used to add biosensing functionality to devices. Furthermore, the device features a data communication interface for sending data to a personal computer, computer unit, smartphone or any other wireless communication device. The device can be used as a stand-alone system where a power interface (such as a battery) supplies power to an electronic circuit (such as a microchip in the device). Alternatively, the device may be powered via the communication port of the device.

The device also includes a fluidic control structure including filtering, mixing, and valve control structures. There may be a protective needle with a cut-out area and a protective structure that prevents the needle from snapping off before use to prevent contamination before use. Structures such as electrically controllable fluidic manipulation structures (including electrowetting, electrical and dielectric interatomic-induced conductivity manipulation) may exist to interact with fluid samples in the device. Electrically controllable heaters may be present for precise control of the temperature of the chip or for thermal cycling purposes.

Another exemplary embodiment of the present invention includes manufacturing all of the above functions in a compact, low-cost and compact manner by providing a silicon substrate that may include photolithographically defined channels, micropillars, and pass-through depth reactive ions. Microstructures of various shapes were etched and designed to serve as capillary fluidic platforms. The silicon substrate may have provisions for fabricating the needles as well as cut-out areas for protecting the needles. The silicon substrate can have different etch depths to allow precise control over the volume and capillary flow of fluid samples in the device. The silicon substrate can be closed by a CMOS substrate (=lid 103 ) comprising CMOS electronics comprising transistor layers. The electronics can be designed to provide functions including sensing, actuation, signaling, data processing and data communication and thus replace point-of-care instruments. Some electrodes may be in direct contact with the fluid and these electrodes may be protected in a fluid compatible manner. By bonding both the silicon substrate and the CMOS substrate in a leak-proof and biocompatible manner, the silicon substrate can be closed by the CMOS substrate. This can be done through a wafer-to-wafer or die-to-wafer bonding process, such as bonding through a patternable polymer. The internal silicon substrate surface that may come into contact with bodily fluids may be characterized by a hydrophilic layer applied to the internal channels. Additionally, through-wafer holes can be fabricated in the silicon substrate to supply reagents after the devices are bonded. For each analysis, different reagents can be supplied. As an advantage, the same device becomes configurable for different diseases by simply adding reagents through through-holes in the final production step. The devices can be fabricated using CMOS compatible processing steps, which reduces production costs and allows the devices to be used as disposable devices.

Additionally, the device may include components that allow interfacing with standard user interfaces. For example, such a device is used as a smart card in a wireless communication device that is inserted into a slot where a smart card is usually foreseen. For example, such devices are used in conjunction with compact and cheap batteries and low-cost communication devices (eg, Bluetooth, NFC). For example, such devices are used with wired communication interfaces such as USB.

Embodiments of the invention can be used to detect DNA/RNA from bodily fluids and perform analysis to detect: variants (ancestry, drug dosage, disease trends), miRNAs (markers of cancer and other diseases), pathogenic DNA/RNA (such as Infectious diseases such as HepC, HIV, etc.), microbial DNA. Furthermore, the device can be used to detect proteins, such as biomarkers of specific diseases (cancer, Alzheimer's disease, infectious diseases, heart disease, cancer, etc.). Furthermore, the device can be used to detect small molecules and metabolites to reveal metabolic information (cholesterol). Additionally, the device can be used to detect biomarkers from exosomes. Additionally, the device can be used to perform microscopy methods to perform blood counts, analyze cells present in blood (e.g., circulating tumor cells), identify infectious agents (e.g., malaria), and detect blood disorders (e.g., sickle cell blood disease).

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.