ABSTRACT
Abstract
The present disclosure relates to devices and methods for analyzing a fluid sample. An example device comprises a fluidic substrate comprising a micro-fluidic component embedded therein, for propagating a fluid sample; a needle or inlet for providing the fluid sample which is fluidically connected to the micro-fluidic component; a lid attached to the fluidic substrate thereby at least partly covering the fluidic substrate and at least partly closing the micro-fluidic component; wherein the fluidic substrate is a glass fluidic substrate and wherein the lid is a microchip. The present disclosure also relates to a method for fabricating a fluid analysis device. The method comprises providing a fluidic substrate; providing a lid; attaching the lid to the fluidic substrate to close the fluidic substrate at least partly.
Description
CROSS-REFERENCE TO RELATED APPLICATION
The present application is a national stage entry of PCT/EP2015/077855 filed Nov. 26, 2015, which claims priority to European Patent Application No. 14194864.6 filed Nov. 26, 2014, the contents of which are hereby incorporated by reference.
FIELD OF THE DISCLOSURE
The present disclosure relates to the field of biological analysis devices. In particular, the present disclosure is related to compact medical devices for the analysis of a fluid sample. More in particular, the present disclosure is related to fully integrated lab-on-a-chip devices for the analysis of fluid samples.
BACKGROUND
Currently, conventional point-of-care devices exist for the analysis of blood. A disadvantage of these devices is their size which depends on the different components needed to perform analysis of blood. In these devices, external pumps are part of the point of care instrument. In some devices, miniature scale pumps are used to propagate a sample through the fluidic channels of the device. The use of pumps increases the size and cost of the device which makes them less suitable for usage as a disposable device. Current disposable devices are typically inserted in expensive read-out instruments; with many non-disposable different electronic or optical components to read out the biochemical reactions taking place in the disposable. Another disadvantage of conventional point of care devices is their cost to fabricate.
Other conventional devices are lateral flow test strips. These test strips are usually fabricated from cellulose which does not allow a precise control of the flow of a fluid sample propagating through the test strips. This narrows the scope of application of these devices.
SUMMARY
The embodiments described herein provide devices for the analysis of a fluid sample. This is accomplished by a device according to the present disclosure, and a method for fabricating such device.
In a first aspect, the present disclosure relates to a device for analyzing a fluid sample. The device comprises: a fluidic substrate comprising: a micro-fluidic component embedded in the fluidic substrate configured to propagate a fluid sample through the micro-fluidic component; and a means for providing a fluid sample connected to the micro-fluidic component; a lid attached to the fluidic substrate at least partly covering the fluidic substrate and at least partly closing the micro-fluidic component. The lid is a microchip, e.g. a CMOS chip.
According to some embodiments, the fluidic substrate is a glass substrate.
The embodiments described herein allow for a low-cost, easy to use, disposable, compact device to be provided for the fully integrated analysis of a fluid sample.
The embodiments described herein allow for mass production technologies to be used to manufacture the device as the fluidic substrate is a glass substrate and the lid a microchip. The embodiments described herein improve the functionality, portability and manufacturability of compact disposable point of care devices.
The embodiments described herein allow for the glass to be used as a material for the fluidic substrate which is an inert material with advantages towards implementation of biochemical reactions.
As the fluidic substrate is a glass substrate and the lid is a microchip, it is an advantage that both and thus the device can be manufactured using mass production process technologies. As an additional advantage, cheap packaging techniques may be used to attach (e.g. bond) the glass substrate to the microchip. This reduces the total cost of the device and allows it to be used as a disposable device and produced in high volume.
According to some embodiments, the fluidic substrate is a glass silicon substrate.
According to some embodiments, the fluidic substrate is configured to propagate a fluid sample through the micro-fluidic component via capillary force.
According to some embodiments, the fluidic substrate comprises a vacuum compartment which is connectable to the micro-fluidic component and which is adapted for creating a suction force in the micro-fluidic component when the vacuum compartment is opened, thereby propagating a fluid sample through the micro-fluidic component.
The embodiments described herein allow for the device to not need additional active components (e.g. an active pump) to propagate a fluid sample through the device. Thus, the complexity of the device is reduced compared to conventional implementations, which reduces fabrication cost and power consumption. As the costs to fabricate are low, the device may be used as a disposable fluid analysis device.
According to some embodiments, at least a part of the lid is in direct contact with the fluid sample when the fluid sample is present in the device. According to some embodiments, the lid comprises a transistor layer, the transistor layer being electrically connected to at least one electrical component, the electrical component comprising or being at least one of the following: biosensing circuitry, biosensing circuitry for fluorescent detection, biosensing circuitry for lens-free detection of particles, electrodes for sensing purposes, electrodes for fluid manipulation purposes, circuitry for data communication purposes, circuitry for wireless data communication purposes, temperature sensors, heater electrodes for temperature control and fluid sensors and electrodes for fluidic viscosity control.
According to some embodiments, the means for providing a fluid sample is needle integrated in the fluidic substrate, fabricated from glass and comprising an inner fluidic channel connected to the micro-fluidic component. The needle is a protruding portion of the fluidic substrate and is positioned to penetrate skin tissue when pressed against the skin tissue.
The embodiments described herein allow for when the fluidic substrate and the needle are fabricated from a single piece of glass, the fabrication of the device is simplified, as separate additional steps to attach a needle to the fluidic substrate become obsolete. In addition, the strength of the glass allows the needle to be very sharp which eases the penetration of the needle in skin tissue of the user. Further, the strength of the glass allows the skin tissue to be firmly pressed against the needle allowing penetration of skin tissue without bending or breaking of the needle.
In some embodiments, the needle is sharp with a small outer diameter, possibly smaller than 200 μm, resulting in the penetration of the skin not causing any discomfort, or only limited discomfort, to the user.
According to alternative embodiments, the means for providing a fluid sample is a system comprising a portion having sharp objects. The portion can be actuated by the user towards the skin of the user. The sharp objects are positioned such that they puncture the skin when the portion is actuated. This way a blood sample from the user can be obtained. Further, the system comprises a fluidic channel adapted for sucking the obtained blood sample, e.g. via capillary force. The fluidic channel is in fluidic connection with the fluidic substrate such that the fluid sample can be provided to the fluidic substrate.
According to some embodiments, the fluidic substrate comprises a cut-out and the needle is positioned in the cut-out.
The embodiments described herein allow for the needle to be fabricated as a consequence of fabricating the cut-out. As a result, less material is wasted as only the material for the cut-out is wasted, excluding the material needed for the needle. In addition, the cut-out and needle can be fabricated using standard micromachining processing techniques.
According to some embodiments of, the fluidic substrate comprises a protection structure for protecting the needle, removably attached to the fluidic substrate.
According to some embodiments, the means for providing a fluid sample is an inlet. A sample drop may be inserted into the microfluidic component by means of: 1) capillary suction, for example generated by a capillary pump; or 2) a suction force created in the micro-fluidic component by a vacuum compartment which is opened when the fluid sample is provided. The microfluidic component may comprise different fluidic compartments, e.g. micro-fluidic channels, for instance for multi-omic analysis. The different microfluidic compartments can have same or different depths. The different microfluidic compartments may be separated by valves that may be actuated in any suitable way, for instance by fluidic forces or by electricity. Electrodes for actuation may be contained on the fluidic substrate or on the lid.
According to some embodiments, the fluidic substrate and/or the lid may further comprise at least one optical waveguide to allow optical excitation and sensing of the fluid sample when present in the device. The fluidic substrate and/or the lid may also comprise filters for rejecting optical excitation from emission to measure a fluorescent signal. The fluidic substrate and/or the lid may comprise filters, for instance multispectral filters for measuring fluorescent signals with multiple colors. The fluidic substrate and/or the lid may comprise an optical waveguide and/or a pinhole to irradiate the sample for performing lens-free microscopy.
According to some embodiments, the fluidic substrate and/or the lid comprises at least one through-hole for application of a biochemical reagent to at least one region of the micro-fluidic component or to at least one region of the lid.
According to some embodiments, the lid is attached, for example bonded or clamped, to the fluidic substrate using a lithographically patterned polymer.
According to some embodiments, when the lid is bonded to the fluidic substrate using a bonding layer, the bonding layer enables bonding at low temperatures and voltages. These conditions do not damage the lid, neither do they damage reagents or for example proteins which may be provided on or in the fluidic substrate.
According to some embodiments, the device may further comprise metal contacts electrically connected to the lid for read-out of electrical signals generated by the fluid and captured by measurement systems in the lid. According to some embodiments, the lid of the device may further comprise active pixels, e.g. CMOS pixels, for readout of optical signals from the fluid.
According to some embodiments, at least part of the fluidic substrate and/or the lid is fabricated from a transparent material to allow optical inspection of a fluid sample in the micro-fluidic component.
According to some embodiments, the shape of the device allows insertion into a mobile communication device.
The embodiments described herein allow for the shape or dimensions of the device to be chosen according to standards, e.g. according to standards of memory cards used in mobile devices such as for example: CompactFlash, SmartMedia, MultiMedia Card, Secure Digital memory cards or any other type.
In a second aspect, embodiments of the present disclosure relate to a method for fabricating a device for analyzing a fluid sample. The method comprises: providing a fluidic substrate; providing a lid; attaching the fluidic substrate to the lid to close the fluidic substrate at least partly. The fluidic substrate is a glass fluidic substrate and the lid is microchip. The fluidic substrate may be attached to the lid using a semiconductor bonding process, e.g. a CMOS compatible bonding process.
According to some embodiments, providing a fluidic substrate may comprise: providing a glass substrate, providing a mask layer on the glass substrate, patterning the mask layer so as to create fine structures in the mask layer; providing a first protection layer to protect the patterned mask layer; patterning coarse structures; etching of the coarse structures; growing a second protection layer for protecting coarse structures in a second patternable mask layer; etching the coarse structures in the glass substrate through the second patterned mask layer; growing a second protection layer for protecting the etched coarse structures; removing the first protection layer and etching the fine structures using the second protection layer as an etch mask; and removing the second protection layer.
The embodiments described herein allow for the dimensions of the fine and coarse structures to be precisely controlled. For example e.g. correctly dimensioning the microfluidic channels and/or micro-pillar sizes and distances which are present in the micro-fluidic component.
Moreover, some embodiments enable fine structures with a high aspect ratio. As a result, these embodiments provide a precise control over the flow of a fluid sample in the micro-fluid component may be achieved. In addition, this allows implementation of more complex biochemical reactions than the simple flow used in existing lateral flow immunoassay tests. The combination with the functions implemented in the microchip bonded or clamped as a lid onto the fluidic substrate further adds temperature control, electrical fluid actuation and valving, integrated biosensing and read out where needed. Therefore it becomes possible to implement complex assays, including DNA/RNA assays, proteins, small molecules and cells and combinations thereof in one integrated capillary system starting from body fluids. Moreover, controlled lateral flow and control over the temperature and flow rate results in more accurate point of care test results.
According to some embodiments, providing a fluidic substrate may comprise providing a glass substrate, providing a plurality of masks on top of one another and using each mask for creating microfluidic structures of different depths.
In accordance with particular embodiments of the present disclosure, providing a fluidic substrate may comprise providing a glass substrate, providing a first mask, patterning microfluidic structures, etching the substrate to single depth, providing a second mask, patterning microfluidic structures, etching the substrate to a second depth, and, if required, repeating these steps for creating multiple depths of microfluidic structures.
According to particular embodiments, the fluidic substrate and the lid of a device according to embodiments of the present disclosure may be part of a larger fluidic package, which may be made from different materials like for instance polymers, and which may contain larger fluidic structures, reagents, fluidic and electrical interfaces. This allows the system to become more cost efficient.
According to some embodiments, surfaces of the fluidic substrate and the lid may be partially or fully coated to modify surface interactions of the substrate with the fluid sample.
In a third aspect, the present disclosure provides the use of a device as described in the first aspect of the present disclosure and its embodiments, to perform microscopy. Microscopy may be implemented by using the lid for detecting lens-free images according to the principles of digital holography.
According to a fourth aspect of the disclosure, a packaged device is presented. The package encapsulates the device described in embodiments of the first aspect of the disclosure. According to an example embodiment, the package further comprises a sealed fluidic compartment adapted to be fluidically connected to the micro-fluidic component when opened. According to an example embodiment, the package further comprises electronic circuitry electrically connected to the micro-chip of the device.
The use of the device as described may perform multi-omic analysis in which the
CROSS-REFERENCE TO RELATED APPLICATION
The present application is a national stage entry of PCT/EP2015/077855 filed Nov. 26, 2015, which claims priority to European Patent Application No. 14194864.6 filed Nov. 26, 2014, the contents of which are hereby incorporated by reference.
FIELD OF THE DISCLOSURE
The present disclosure relates to the field of biological analysis devices. In particular, the present disclosure is related to compact medical devices for the analysis of a fluid sample. More in particular, the present disclosure is related to fully integrated lab-on-a-chip devices for the analysis of fluid samples.
BACKGROUND
Currently, conventional point-of-care devices exist for the analysis of blood. A disadvantage of these devices is their size which depends on the different components needed to perform analysis of blood. In these devices, external pumps are part of the point of care instrument. In some devices, miniature scale pumps are used to propagate a sample through the fluidic channels of the device. The use of pumps increases the size and cost of the device which makes them less suitable for usage as a disposable device. Current disposable devices are typically inserted in expensive read-out instruments; with many non-disposable different electronic or optical components to read out the biochemical reactions taking place in the disposable. Another disadvantage of conventional point of care devices is their cost to fabricate.
Other conventional devices are lateral flow test strips. These test strips are usually fabricated from cellulose which does not allow a precise control of the flow of a fluid sample propagating through the test strips. This narrows the scope of application of these devices.
SUMMARY
The embodiments described herein provide devices for the analysis of a fluid sample. This is accomplished by a device according to the present disclosure, and a method for fabricating such device.
In a first aspect, the present disclosure relates to a device for analyzing a fluid sample. The device comprises: a fluidic substrate comprising: a micro-fluidic component embedded in the fluidic substrate configured to propagate a fluid sample through the micro-fluidic component; and a means for providing a fluid sample connected to the micro-fluidic component; a lid attached to the fluidic substrate at least partly covering the fluidic substrate and at least partly closing the micro-fluidic component. The lid is a microchip, e.g. a CMOS chip.
According to some embodiments, the fluidic substrate is a glass substrate.
The embodiments described herein allow for a low-cost, easy to use, disposable, compact device to be provided for the fully integrated analysis of a fluid sample.
The embodiments described herein allow for mass production technologies to be used to manufacture the device as the fluidic substrate is a glass substrate and the lid a microchip. The embodiments described herein improve the functionality, portability and manufacturability of compact disposable point of care devices.
The embodiments described herein allow for the glass to be used as a material for the fluidic substrate which is an inert material with advantages towards implementation of biochemical reactions.
As the fluidic substrate is a glass substrate and the lid is a microchip, it is an advantage that both and thus the device can be manufactured using mass production process technologies. As an additional advantage, cheap packaging techniques may be used to attach (e.g. bond) the glass substrate to the microchip. This reduces the total cost of the device and allows it to be used as a disposable device and produced in high volume.
According to some embodiments, the fluidic substrate is a glass silicon substrate.
According to some embodiments, the fluidic substrate is configured to propagate a fluid sample through the micro-fluidic component via capillary force.
According to some embodiments, the fluidic substrate comprises a vacuum compartment which is connectable to the micro-fluidic component and which is adapted for creating a suction force in the micro-fluidic component when the vacuum compartment is opened, thereby propagating a fluid sample through the micro-fluidic component.
The embodiments described herein allow for the device to not need additional active components (e.g. an active pump) to propagate a fluid sample through the device. Thus, the complexity of the device is reduced compared to conventional implementations, which reduces fabrication cost and power consumption. As the costs to fabricate are low, the device may be used as a disposable fluid analysis device.
According to some embodiments, at least a part of the lid is in direct contact with the fluid sample when the fluid sample is present in the device. According to some embodiments, the lid comprises a transistor layer, the transistor layer being electrically connected to at least one electrical component, the electrical component comprising or being at least one of the following: biosensing circuitry, biosensing circuitry for fluorescent detection, biosensing circuitry for lens-free detection of particles, electrodes for sensing purposes, electrodes for fluid manipulation purposes, circuitry for data communication purposes, circuitry for wireless data communication purposes, temperature sensors, heater electrodes for temperature control and fluid sensors and electrodes for fluidic viscosity control.
According to some embodiments, the means for providing a fluid sample is needle integrated in the fluidic substrate, fabricated from glass and comprising an inner fluidic channel connected to the micro-fluidic component. The needle is a protruding portion of the fluidic substrate and is positioned to penetrate skin tissue when pressed against the skin tissue.
The embodiments described herein allow for when the fluidic substrate and the needle are fabricated from a single piece of glass, the fabrication of the device is simplified, as separate additional steps to attach a needle to the fluidic substrate become obsolete. In addition, the strength of the glass allows the needle to be very sharp which eases the penetration of the needle in skin tissue of the user. Further, the strength of the glass allows the skin tissue to be firmly pressed against the needle allowing penetration of skin tissue without bending or breaking of the needle.
In some embodiments, the needle is sharp with a small outer diameter, possibly smaller than 200 μm, resulting in the penetration of the skin not causing any discomfort, or only limited discomfort, to the user.
According to alternative embodiments, the means for providing a fluid sample is a system comprising a portion having sharp objects. The portion can be actuated by the user towards the skin of the user. The sharp objects are positioned such that they puncture the skin when the portion is actuated. This way a blood sample from the user can be obtained. Further, the system comprises a fluidic channel adapted for sucking the obtained blood sample, e.g. via capillary force. The fluidic channel is in fluidic connection with the fluidic substrate such that the fluid sample can be provided to the fluidic substrate.
According to some embodiments, the fluidic substrate comprises a cut-out and the needle is positioned in the cut-out.
The embodiments described herein allow for the needle to be fabricated as a consequence of fabricating the cut-out. As a result, less material is wasted as only the material for the cut-out is wasted, excluding the material needed for the needle. In addition, the cut-out and needle can be fabricated using standard micromachining processing techniques.
According to some embodiments of, the fluidic substrate comprises a protection structure for protecting the needle, removably attached to the fluidic substrate.
According to some embodiments, the means for providing a fluid sample is an inlet. A sample drop may be inserted into the microfluidic component by means of: 1) capillary suction, for example generated by a capillary pump; or 2) a suction force created in the micro-fluidic component by a vacuum compartment which is opened when the fluid sample is provided. The microfluidic component may comprise different fluidic compartments, e.g. micro-fluidic channels, for instance for multi-omic analysis. The different microfluidic compartments can have same or different depths. The different microfluidic compartments may be separated by valves that may be actuated in any suitable way, for instance by fluidic forces or by electricity. Electrodes for actuation may be contained on the fluidic substrate or on the lid.
According to some embodiments, the fluidic substrate and/or the lid may further comprise at least one optical waveguide to allow optical excitation and sensing of the fluid sample when present in the device. The fluidic substrate and/or the lid may also comprise filters for rejecting optical excitation from emission to measure a fluorescent signal. The fluidic substrate and/or the lid may comprise filters, for instance multispectral filters for measuring fluorescent signals with multiple colors. The fluidic substrate and/or the lid may comprise an optical waveguide and/or a pinhole to irradiate the sample for performing lens-free microscopy.
According to some embodiments, the fluidic substrate and/or the lid comprises at least one through-hole for application of a biochemical reagent to at least one region of the micro-fluidic component or to at least one region of the lid.
According to some embodiments, the lid is attached, for example bonded or clamped, to the fluidic substrate using a lithographically patterned polymer.
According to some embodiments, when the lid is bonded to the fluidic substrate using a bonding layer, the bonding layer enables bonding at low temperatures and voltages. These conditions do not damage the lid, neither do they damage reagents or for example proteins which may be provided on or in the fluidic substrate.
According to some embodiments, the device may further comprise metal contacts electrically connected to the lid for read-out of electrical signals generated by the fluid and captured by measurement systems in the lid. According to some embodiments, the lid of the device may further comprise active pixels, e.g. CMOS pixels, for readout of optical signals from the fluid.
According to some embodiments, at least part of the fluidic substrate and/or the lid is fabricated from a transparent material to allow optical inspection of a fluid sample in the micro-fluidic component.
According to some embodiments, the shape of the device allows insertion into a mobile communication device.
The embodiments described herein allow for the shape or dimensions of the device to be chosen according to standards, e.g. according to standards of memory cards used in mobile devices such as for example: CompactFlash, SmartMedia, MultiMedia Card, Secure Digital memory cards or any other type.
In a second aspect, embodiments of the present disclosure relate to a method for fabricating a device for analyzing a fluid sample. The method comprises: providing a fluidic substrate; providing a lid; attaching the fluidic substrate to the lid to close the fluidic substrate at least partly. The fluidic substrate is a glass fluidic substrate and the lid is microchip. The fluidic substrate may be attached to the lid using a semiconductor bonding process, e.g. a CMOS compatible bonding process.
According to some embodiments, providing a fluidic substrate may comprise: providing a glass substrate, providing a mask layer on the glass substrate, patterning the mask layer so as to create fine structures in the mask layer; providing a first protection layer to protect the patterned mask layer; patterning coarse structures; etching of the coarse structures; growing a second protection layer for protecting coarse structures in a second patternable mask layer; etching the coarse structures in the glass substrate through the second patterned mask layer; growing a second protection layer for protecting the etched coarse structures; removing the first protection layer and etching the fine structures using the second protection layer as an etch mask; and removing the second protection layer.
The embodiments described herein allow for the dimensions of the fine and coarse structures to be precisely controlled. For example e.g. correctly dimensioning the microfluidic channels and/or micro-pillar sizes and distances which are present in the micro-fluidic component.
Moreover, some embodiments enable fine structures with a high aspect ratio. As a result, these embodiments provide a precise control over the flow of a fluid sample in the micro-fluid component may be achieved. In addition, this allows implementation of more complex biochemical reactions than the simple flow used in existing lateral flow immunoassay tests. The combination with the functions implemented in the microchip bonded or clamped as a lid onto the fluidic substrate further adds temperature control, electrical fluid actuation and valving, integrated biosensing and read out where needed. Therefore it becomes possible to implement complex assays, including DNA/RNA assays, proteins, small molecules and cells and combinations thereof in one integrated capillary system starting from body fluids. Moreover, controlled lateral flow and control over the temperature and flow rate results in more accurate point of care test results.
According to some embodiments, providing a fluidic substrate may comprise providing a glass substrate, providing a plurality of masks on top of one another and using each mask for creating microfluidic structures of different depths.
In accordance with particular embodiments of the present disclosure, providing a fluidic substrate may comprise providing a glass substrate, providing a first mask, patterning microfluidic structures, etching the substrate to single depth, providing a second mask, patterning microfluidic structures, etching the substrate to a second depth, and, if required, repeating these steps for creating multiple depths of microfluidic structures.
According to particular embodiments, the fluidic substrate and the lid of a device according to embodiments of the present disclosure may be part of a larger fluidic package, which may be made from different materials like for instance polymers, and which may contain larger fluidic structures, reagents, fluidic and electrical interfaces. This allows the system to become more cost efficient.
According to some embodiments, surfaces of the fluidic substrate and the lid may be partially or fully coated to modify surface interactions of the substrate with the fluid sample.
In a third aspect, the present disclosure provides the use of a device as described in the first aspect of the present disclosure and its embodiments, to perform microscopy. Microscopy may be implemented by using the lid for detecting lens-free images according to the principles of digital holography.
According to a fourth aspect of the disclosure, a packaged device is presented. The package encapsulates the device described in embodiments of the first aspect of the disclosure. According to an example embodiment, the package further comprises a sealed fluidic compartment adapted to be fluidically connected to the micro-fluidic component when opened. According to an example embodiment, the package further comprises electronic circuitry electrically connected to the micro-chip of the device.
The use of the device as described may perform multi-omic analysis in which the fluidic substrate is used for performing multiple assays in multiple channels and chambers, and the lid comprising the microchip is used to detect multiple signals from all assays. Those signals can combine multiple DNA, RNA, small molecule, cell signals from a same analyte.
In particular embodiments, the device is used as a single use disposable device for analysis of a small amount of fluid.
In a fifth aspect, the data from the lid may be sent to a smart device such as for instance a smart handheld device, e.g. a smartphone, for instance using a wireless connection. The smart device can be used for processing, visualizing and/or transferring the data.
In some embodiments, the combined data gathered from a single same sample may be used in a software algorithm for calculating a parameter correlating to disease or wellbeing of an individual.
Some aspects of the disclosure are set out in the accompanying independent and dependent claims. Features from the dependent claims may be combined with features of the independent claims and with features of other dependent claims as appropriate and not merely as explicitly set out in the claims.
These and other aspects of the disclosure will be apparent from and elucidated with reference to the embodiment(s) described hereinafter.
BRIEF DESCRIPTION OF THE FIGURES
The above, as well as additional, features will be better understood through the following illustrative and non-limiting detailed description of example embodiments, with reference to the appended drawings.
FIG. 1 illustrates a schematic 3D view of a fluidic substrate, according to an example embodiment.
FIG. 2 schematically illustrates a top view of a device for analyzing a fluid sample, according to an example embodiment.
FIG. 3 schematically illustrates a top view of a fluidic substrate without a lid used in the device of FIG. 2 .
FIG. 4 schematically illustrates a side view of the device of FIG. 2 .
FIG. 5 schematically illustrates a top view of a device for analyzing a fluid sample, featuring a cut-out for a needle, according to an example embodiment.
FIG. 6 schematically illustrates a top view of a fluidic substrate featuring a cut-out for a needle without a lid, for use in the device of FIG. 5 , according to an example embodiment.
FIG. 7 schematically illustrates a side view of the device of FIG. 5 , according to an example embodiment.
FIG. 8 schematically illustrates a top view of a device for analyzing a fluid sample, featuring a protection structure for a needle, according to an example embodiment.
FIG. 9 schematically illustrates a top view of a fluidic substrate featuring a protection structure for a needle, for use in the device of FIG. 8 without a lid, according to an example embodiment.
FIG. 10 schematically illustrates a side view of the device of FIG. 8 , according to an example embodiment.
FIG. 11 - FIG. 17 schematically illustrate method steps of a method to fabricate a fluidic substrate for use in a device, according to an example embodiment.
FIG. 18 schematically illustrates a microchip for use in a device, according to an example embodiment.
FIG. 19 schematically illustrates the bonding of a microchip with a fluidic substrate, according to an example embodiment.
FIG. 20 schematically illustrates the bonding of a microchip with a fluidic substrate, wherein the microchip comprises a silicon I/O interconnect, according to an example embodiment.
FIG. 21 schematically illustrates a microchip for use in a device, the microchip comprising an I/O pad, according to an example embodiment.
FIG. 22 schematically illustrates a microchip for use in a device, the microchip comprising an I/O pad bonded or clamped to a fluidic substrate, wherein a part of the microchip overlaps the fluidic substrate and a part forms an overhang with respect to the fluidic substrate, according to an example embodiment.
FIG. 23 schematically illustrates the bonding of a microchip with a fluidic substrate, wherein the microchip comprises a through hole, according to an example embodiment.
FIG. 24 schematically illustrates the bonding of a microchip with a fluidic substrate, wherein the fluidic substrate comprises two through holes, according to an example embodiment.
FIG. 25 schematically illustrates a 3D view of a device, according to an example embodiment.
FIG. 26 schematically illustrates a 3D view of a wireless stand-alone device, according to an example embodiment.
FIG. 27 schematically illustrates a top view of a part of a first embodiment of a micro-fluidic component, the micro-fluidic component comprising micro-pillars, according to an example embodiment.
FIG. 28 schematically illustrates a 3D view of a part of the micro-fluidic component of FIG. 27 , according to an example embodiment.
FIG. 29 schematically illustrates a top view of a part of a micro-fluidic component for use in a device, the micro-fluidic component comprising micro-pillars, according to an example embodiment.
FIG. 30 schematically illustrates a 3D view of a part of the micro-fluidic component of FIG. 29 , according to an example embodiment.
FIG. 31 illustrates a device in the shape of an SD card, according to an example embodiment.
FIG. 32 illustrates a device the shape of an SD card, according to an example embodiment.
FIG. 33 is a schematic cross-sectional view of a device, wherein a plurality of functionalities are supported by a single semiconductor technology, according to an example embodiment.
The drawings are only schematic and are 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 shall not be construed as limiting the scope.
In the different drawings, the same reference signs refer to the same or analogous elements.
All the figures are schematic, not necessarily to scale, and generally only show parts which are necessary to elucidate example embodiments, wherein other parts may be omitted or merely suggested.
DETAILED DESCRIPTION
Example embodiments will now be described more fully hereinafter with reference to the accompanying drawings. That which is encompassed by the claims may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided by way of example. Furthermore, like numbers refer to the same or similar elements or components throughout.
The present disclosure will be described with respect to particular embodiments and with reference to certain drawings but the disclosure is not limited thereto but only by the claims. The drawings described are only schematic and are 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 the relative dimensions do not correspond to actual reductions to practice.
Furthermore, the terms first, second and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequence, either temporally, spatially, in ranking or in any other manner. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the disclosure described herein are capable of operation in other sequences than described or illustrated herein.
Moreover, the terms top, under and the like in the description and the claims are used for descriptive purposes and not necessarily for describing relative positions. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the disclosure described herein are capable of operation in other orientations than described or illustrated herein.
It is to be noticed that the term âcomprisingâ, used in the claims, should not be interpreted as being restricted to the means listed thereafter; it does not exclude other elements or steps. It is thus to be interpreted as specifying the presence of the stated features, integers, steps or components as referred to, but does not preclude the presence or addition of one or more other features, integers, steps or components, or groups thereof. Thus, the scope of the expression âa device comprising means A and Bâ should not be limited to devices consisting only of components A and B. It means that with respect to the present disclosure, the only relevant components of the device are A and B.
Reference throughout this specification to âone embodimentâ or âan embodimentâ means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, appearances of the phrases âin one embodimentâ or âin an embodimentâ 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 should be appreciated that in the description of example embodiments, various features are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure and aiding in the understanding of one or more of the various aspects. This method of disclosure, however, is not to be interpreted as reflecting an intention that the claimed embodiments require more features than are expressly recited in each claim. Rather, as the following claims reflect, 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 disclosure.
Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the disclosure, and form different embodiments, as would be understood by those in the art. For example, in the following claims, any of the claimed embodiments can be used in any combination.
In the description provided herein, numerous specific details are set forth. However, it is understood that some embodiments 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 an understanding of this description.
In some embodiments, where reference is made to a âfluid sampleâ, reference is made to any human or animal body fluid such as blood, urine, saliva.
In some embodiments, where reference is made to an âI/O padâ or an âI/O contactâ, reference is made to a contact such as a metal contact allowing input and output of electrical signals of a micro-chip.
In some embodiments, where reference is made to âCMOSâ, reference is made to a Complementary Metal-Oxide Semiconductor.
In some embodiments, where reference is made to âglassâ reference is made to a non-crystalline amorphous solid at the atomic scale that exhibits a glass transition when heated towards the liquid state. In some embodiments, âglassâ may refer to silicate glasses, like for example quartz, boro-silicate glass, etc. An advantage of silicate glasses is their optical transparency. Glass in addition can transmit, reflect and refract light; moreover these qualities may be enhanced by cutting and polishing. Glass substrates used in some embodiments may be colored, for instance by adding metallic salts, and may also be painted. Although brittle, silicate glass is extremely durable, can be formed or molded into any shape, and is a sterile product. As a result, several material properties of glass and reproducible electro-osmotic flow properties make it a very attractive material for use in microfluidic systems.
In some embodiments, where reference is made to âmicro-fluidicâ reference is made to fluidic devices having device sizes typically below 1 mm.
In some embodiments, where reference is made to âlab-on-a-chip deviceâ, reference is made to devices that integrate one or more laboratory function on a single chip.
Throughout the description reference may be made to âparticlesâ. This may refer to particles of biological nature, for example cells or biomolecules. In a first aspect the present disclosure relates to a device 100 for analyzing a fluid sample, as for instance illustrated in FIG. 26 . The device 100 may be defined as a medical device. In some embodiments, the device 100 comprises: a fluidic substrate 101 and a lid 103 attached to the fluidic substrate 101 at least partly covering the substrate 101 .
The fluidic substrate 101 comprises a micro-fluidic component 102 . In some embodiments, a micro-fluidic component 102 may comprise, as schematically illustrated in a detailed 3D drawing in FIG. 1 , a plurality of microfluidic components such as an inlet, the inlet comprising a sample pad 102 a , a reagent storage 102 b , a hermetic valve 102 c , whereby the hermetic valve is suited for one-time usage, a first trigger valve 102 d , a mixer 102 e , a delay line 102 f , a second trigger valve 102 g , an heater 102 h and a wick 102 i . The microfluidic component is embedded in the fluidic substrate 101 and configured to propagate a fluid sample through the micro-fluidic component 102 ; and a means 109 for providing a fluid sample connected to the micro-fluidic component 102 . The lid 103 , by at least partly covering the substrate 101 , at least partly closes the micro-fluidic component 102 . In some embodiments, the fluidic substrate 101 is a glass fluidic substrate; and the lid 103 is a microchip, e.g. a CMOS chip.
In embodiments where the fluidic substrate 101 is a glass substrate and the lid 103 is a microchip, both can be manufactured using mass production process technologies, like for example CMOS compatible processing techniques. Cheap packaging techniques may be used to attach, e.g. bond, the glass substrate to the lid, e.g. microchip. This may reduce the total cost of the device and allow it to be used as a disposable device and produced in high volume.
According to an example embodiment, the lid, e.g. microchip, 103 at least partly closes or covers the fluidic substrate 101 . Other parts of the fluidic substrate 101 may be closed or covered by other means. For example, the other parts of the fluidic substrate 101 may be closed by a printed circuit board (PCB) 120 which is electrically connected to the lid, e.g. microchip 103 (which is illustrated in FIG. 26 and described further below). Further, other parts of the fluidic substrate 101 may be closed by a package which encapsulates the device 100 . Due to capillary forces present in the micro-fluidic component 102 , some parts of the micro-fluidic component 102 may remain open. For example, like in embodiments where the entire or complete micro-fluidic component 102 is open except for the lid, e.g. microchip, 103 covering a part such that it may be in direct contact with a fluid sample in the micro-fluidic component 102 .
A top view of an embodiment of a device 100 is schematically illustrated in FIG. 2 , whereby the fluidic substrate 101 and the lid 103 are attached to one another. In FIG. 2 the fluidic substrate 101 further may comprise a means for providing a fluid sample 104 . A top view of an exemplary fluidic substrate 101 used in the device of FIG. 2 is schematically illustrated in FIG. 3 . A side view of an embodiment of the device 100 of FIG. 2 where the fluidic substrate 101 is attached to the lid 103 is schematically illustrated in FIG. 4 .
A device 100 comprises a fluidic substrate 101 which is attached, for example bonded or clamped, to a lid 103 , whereby the lid 103 at least partially covers the fluidic substrate 101 . The fluidic substrate 101 comprises a micro-fluidic component 102 . The micro-fluidic component 102 may comprise micro-fluidic channels, micro-reactors or other micro-fluidic parts/structures which are interconnected to allow a fluid sample to propagate through the complete micro-fluidic component 102 . The micro-fluidic component 102 may comprise a plurality of micro-pillars or microstructures at regular or irregular distances to allow at least one of the following functionalities: filtering and separation, valve functionality or âvalvingâ, mixing of a fluid sample during propagation through the micro-fluidic component. FIG. 27 schematically illustrates a top view of a part of an open micro-fluidic component 102 comprising a pillar array, the pillar array comprising micro-pillars 270 to allow filtering and separation, valving, mixing of a fluid sample during propagation through the micro-fluidic component. FIG. 28 schematically illustrates a 3D view of the open micro-fluidic component 102 embodiment of FIG. 27 comprising micro-pillars 270 . The micro-pillars 270 in FIG. 27 and FIG. 28 are positioned in such a way as to enable or form a gradient for the to-be-examined fluid sample. This gradient allows the filtering out of larger particles in a first part of the micro-fluidic component 102 and the filtering out of smaller particles in a second part of the micro-fluidic component 102 . FIG. 29 and FIG. 30 schematically illustrate another embodiment of a gradient of micro-pillars 270 in the micro-fluidic component 102 . FIGS. 27-30 illustrate micro-pillars having a cylindrical shape; however, the present disclosure is not limited thereto.
According to some embodiments, the micro-fluidic component 102 may be configured to create a capillary action to propagate a fluid sample through the device 100 . The dimensions of the micro-fluidic component 102 may be adapted to create a capillary action in the micro-fluidic component 102 when a fluid sample is present. For example, dimensions and distance between micro-pillars 270 in the micro-fluidic component 102 may be configured to create a capillary action in the micro-fluidic component 102 . The device 100 might not need additional active components (e.g. an active separate pump) to propagate a fluid sample through the device 100 . Thus, the complexity of the device 100 is reduced compared to conventional implementations, which further reduces fabrication cost and power consumption. As the costs to fabricate are low, the device may be used as a disposable fluid analysis device.
According to some embodiments, the fluidic substrate 101 may comprise a vacuum element or compartment which is connectable to the micro-fluidic component 102 . When a fluid sample is provided to the micro-fluidic component 102 , an air-tight connection between the vacuum compartment and the micro-fluidic component can be realized. By connecting the vacuum compartment to the micro-fluidic component, hence by opening the vacuum compartment, a suction force is generated in the micro-fluidic component 102 thereby realizing propagation of a fluid sample through the micro-fluidic component 102 .
The air-tight connection between the vacuum compartment and the micro-fluidic component may be realized by for example opening an air-tight valve which is present between the vacuum compartment and the micro-fluidic component. The air-tight valve seals the vacuum compartment as long as it is closed.
Alternatively, the air-tight connection between the vacuum compartment and the micro-fluidic component may be realized by removing an element which is present between the vacuum compartment and the micro-fluidic component. The element seals the vacuum compartment from the micro-fluidic component as long as it is present. The element may be removed by supplying a voltage or a current pulse to the element. The element may be a membrane comprising a resistor configured to destruct the membrane when a voltage or current pulse is supplied to the resistor. The resistor may be positioned in or on the membrane. The resistor may also be positioned on the fluidic substrate 101 such that the membrane may be destroyed when the resistor is powered. Trenches in the fluidic substrate 101 may be present around the resistor for reducing heat dissipation in the fluidic substrate 101 . The element may also comprise a meltable material which may be melted at a suitable temperature depending on the material used, by a heating element positioned near the element, e.g. on the fluidic substrate. By melting the material, the compartment is opened towards the micro-fluidic component.
Some embodiments allow for precise control over the flow of a fluid sample in the <figure-callout id="102" label="micro-fluidic component" filenames="US11241687-20220208-D00002.png,US11241687-20220208-D00003.pn
CLAIMS
Claims ( 20 )
The invention claimed is:
1. A device comprising:
a fluidic substrate comprising:
a micro-fluidic component comprising a micro-fluidic compartment embedded in the fluidic substrate comprising fine structures and coarse structures etched therein, wherein the fine structures comprise an aspect ratio of at least 20, and wherein the fine structures comprise a plurality of micro-pillars configured to propagate a fluid sample;
a needle or an inlet for providing the fluid sample connected to the micro-fluidic component; and
one or more filters configured to reject optical excitation from an emission generated by the fluid sample in response to the optical excitation; and
a lid attached to the fluidic substrate thereby at least partly covering the fluidic substrate and at least partly closing the micro-fluidic component, wherein the fluidic substrate is a glass fluidic substrate, wherein the lid is a microchip, and wherein the lid comprises at least one optical waveguide to allow optical excitation and sensing of the fluid sample when present in the device.
2. The device according to claim 1 , wherein the fluidic substrate is configured to propagate the fluid sample through the micro-fluidic component via capillary force.
3. The device according to claim 1 , wherein the fluidic substrate comprises a vacuum compartment connectable to the micro-fluidic component and the vacuum compartment is adapted for creating a suction force in the micro-fluidic component when the vacuum compartment which is connected to the micro-fluidic component is opened, thereby propagating the fluid sample through the micro-fluidic component.
4. The device according to claim 1 , wherein at least a part of the lid is in direct contact with the fluid sample when the fluid sample is present in the device.
5. The device according to claim 1 , wherein the lid comprises a transistor layer, the transistor layer being electrically connected to at least one electrical component present in the lid, the electrical component being at least one of the following:
biosensing circuitry, biosensing circuitry for fluorescent detection, biosensing circuitry for lens-free detection of particles, electrodes for sensing purposes, electrodes for fluid manipulation purposes, circuitry for data communication purposes, circuitry for wireless data communication purposes, temperature sensors, heater electrodes for temperature control and fluid sensors and electrodes for fluidic viscosity control.
6. The device according to claim 1 , wherein the needle is integrated with the fluidic substrate, the needle being fabricated from glass and comprising an inner fluidic channel connected to the micro-fluidic component and wherein the needle is a protruding portion of a horizontal plane of the fluidic substrate and positioned to penetrate skin tissue when pressed against the skin tissue, wherein the fluidic substrate and the needle are fabricated from a single piece of glass.
7. The device according to claim 1 , wherein the fluidic substrate or the lid comprises at least one through-hole for application of a biochemical reagent to at least one region of the micro-fluidic component or to at least one region of the lid.
8. The device according to claim 1 , wherein the lid is bonded to the fluidic substrate using a lithographically patterned polymer.
9. The device according to claim 1 , further comprising metal contacts electrically connected to the lid for read-out of electrical signals from the lid.
10. The device according to claim 1 , wherein at least part of the fluidic substrate or the lid is fabricated from a transparent material to allow optical inspection of the fluid sample when the fluid sample is present in the micro-fluidic component.
11. A method for fabricating the device of claim 1 for analyzing a fluid sample, the method comprising:
providing the fluidic substrate;
providing the lid; and
attaching the lid to the fluidic substrate to close the fluidic substrate at least partly, wherein the fluidic substrate is the glass fluidic substrate and the lid is the microchip.
12. The method according to claim 11 wherein providing a fluidic substrate comprises:
providing a glass substrate, providing a mask on the glass substrate, patterning the mask to create fine structures in the mask;
providing a first protection layer to protect the patterned mask;
patterning coarse structures in a second patternable mask;
etching of the coarse structures in the glass substrate through the second patterned mask;
growing a second protection layer for protecting the etched coarse structures;
removing the first protection layer and etching the fine structures using the second protection layer as an etch mask; and
removing the second protection layer.
13. The method according to claim 11 , wherein surfaces of the fluidic substrate and the lid are partially or fully coated to modify surface interactions of the fluidic substrate with the fluid sample.
14. The method according claim 11 , for fabricating a device for analyzing a fluid sample, the device comprising:
a fluidic substrate comprising a micro-fluidic component embedded in the fluidic substrate configured to propagate a fluid sample, and a needle or inlet for providing a fluid sample connected to the micro-fluidic component; and
a lid attached to the fluidic substrate thereby at least partly covering the fluidic substrate and at least partly closing the micro-fluidic component, wherein the fluidic substrate is a glass fluidic substrate and wherein the lid is a microchip.
15. A packaged device, comprising a package encapsulating a device for analyzing a fluid sample, the device comprising:
a fluidic substrate comprising a micro-fluidic component embedded in the fluidic substrate comprising fine structures and coarse structures etched therein, wherein the fine structures comprise an aspect ratio of at least 20, and wherein the fine structures comprise a plurality of micro-pillars configured to propagate a fluid sample;
a needle or inlet for providing a fluid sample connected to the micro-fluidic component;
one or more filters configured to reject optical excitation from an emission generated by the fluid sample in response to the optical excitation; and
a lid attached to the fluidic substrate thereby at least partly covering the fluidic substrate and at least partly closing the micro-fluidic component, wherein the fluidic substrate is a glass fluidic substrate, wherein the lid is a microchip, and wherein the lid comprises at least one optical waveguide to allow optical excitation and sensing of the fluid sample when present in the device.
16. The packaged device according to claim 15 , further comprising a sealed fluidic compartment adapted to be fluidically connected to the micro-fluidic component, when opened.
17. The packaged device according to claim 15 , further comprising electronic circuitry electrically connected to the microchip of the device.
18. The device according to claim 1 , wherein the lid further comprises a radiation source coupled to the at least one optical waveguide and configured to generate the excitation.
19. The device according to claim 1 , wherein the at least one optical waveguide is further configured to receive an emission generated by the fluid sample in response to the optical excitation, and wherein the at least one optical waveguide further comprises a detector coupled to the at least one optical waveguide and configured to receive the emission and to generate an image based on the emission.
20. The device according to claim 1 , wherein the one or more filters or the lid comprises a multispectral filter.
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