U.S. patent application number 15/529441 was filed with the patent office on 2017-11-16 for compact fluid analysis device and method to fabricate.
This patent application is currently assigned to IMEC VZW. The applicant listed for this patent is IMEC VZW. Invention is credited to Paolo Fiorini, Liesbet Lagae, Peter Peumans.
Application Number | 20170326552 15/529441 |
Document ID | / |
Family ID | 51947247 |
Filed Date | 2017-11-16 |
United States Patent
Application |
20170326552 |
Kind Code |
A1 |
Peumans; Peter ; et
al. |
November 16, 2017 |
Compact Fluid Analysis Device and Method to Fabricate
Abstract
The present disclosure relates to a fluid analyzing device that
includes a sensing device for analyzing a fluid sample. The sensing
device includes a microchip configured for sensing the fluid
sample, and a closed micro-fluidic component for propagating the
fluid sample to the microchip. The fluid sample can be provided to
the micro-fluidic component via an inlet of the fluid analyzing
device. And a vacuum compartment, which is air-tight connected to
the sensing device, can create in the micro-fluidic component a
suction force suitable for propagating the fluid sample through the
micro-fluidic component.
Inventors: |
Peumans; Peter;
(Herfelingen, BE) ; Lagae; Liesbet; (Leuven,
BE) ; Fiorini; Paolo; (Brussel, BE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
IMEC VZW |
Leuven |
|
BE |
|
|
Assignee: |
IMEC VZW
Leuven
BE
|
Family ID: |
51947247 |
Appl. No.: |
15/529441 |
Filed: |
November 24, 2015 |
PCT Filed: |
November 24, 2015 |
PCT NO: |
PCT/EP2015/077412 |
371 Date: |
May 24, 2017 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B01L 3/5027 20130101;
B01L 2400/049 20130101; B01L 3/502715 20130101; B01L 3/50273
20130101; A61B 5/157 20130101; A61B 5/150389 20130101; A61B
5/150022 20130101; B01L 2400/0406 20130101; B01L 2200/10 20130101;
A61B 5/150061 20130101; B01L 2300/041 20130101; B01L 2300/0654
20130101; A61B 5/151 20130101; A61B 2562/028 20130101; B01L 2300/18
20130101; B01L 2300/0816 20130101; B01L 2300/0672 20130101; B01L
2300/046 20130101 |
International
Class: |
B01L 3/00 20060101
B01L003/00; A61B 5/15 20060101 A61B005/15; B01L 3/00 20060101
B01L003/00; A61B 5/157 20060101 A61B005/157; A61B 5/15 20060101
A61B005/15; A61B 5/15 20060101 A61B005/15; A61B 5/151 20060101
A61B005/151 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 26, 2014 |
EP |
14194854.7 |
Claims
1. A fluid analyzing device comprising: a sensing device for
analyzing a fluid sample, the sensing device comprising: a
microchip configured for sensing the fluid sample; and a
micro-fluidic component for propagating the fluid sample to the
microchip; an inlet connected to the micro-fluidic component, for
providing the fluid sample to the micro-fluidic component, wherein
the micro-fluidic component, aside from its connection to the
inlet, a vacuum compartment air-tight connected to the sensing
device, wherein the vacuum compartment is adapted for creating a
suction force in the micro-fluidic component suitable for
propagating the fluid sample through the micro-fluidic component
when the fluid sample is provided in the micro-fluidic component,
and wherein the suction force is created by opening the vacuum
compartment.
2. The fluid analyzing device of claim 1, further comprising: a
package comprising the sensing device, the vacuum compartment, and
the inlet.
3. The fluid analyzing device of claim 1, wherein the vacuum
compartment comprises a sacrificial element adapted to open the
vacuum compartment towards the micro-fluidic component when the
sacrificial element is broken.
4. The fluid analyzing device of claim 3, further comprising a
movable structure for breaking the sacrificial element.
5. The fluid analyzing device of claim 4, wherein the movable
structure is a movable puncture device adapted to break the
sacrificial element when actuated.
6. The fluid analyzing device of claim 3, further comprising a
heating element positioned such that the sacrificial element is
broken by heating, thereby opening the vacuum compartment.
7. The fluid analyzing device of claim 6, wherein the heating
element is positioned in or on the sacrificial element.
8. The fluid analyzing device of claim 6, wherein the heating
element is positioned on a substrate comprising the micro-fluidic
component.
9. The fluid analyzing device of claim 3, wherein the sacrificial
element is solvent-dissolvable, wherein the fluid analyzing device
further comprises a solvent compartment containing a solvent, and
wherein the solvent compartment is configured to release the
solvent to the sacrificial element when the fluid sample is
provided in the micro-fluidic component, the releasing of the
solvent thereby opening the vacuum compartment.
10. The fluid analyzing device of claim 1, further comprising a
fluid detector positioned to detect the fluid sample when the fluid
sample is provided in the micro-fluidic component, and wherein the
vacuum compartment is configured to open when the fluid sample is
detected.
11. The fluid analyzing device of claim 1, wherein the sensing
device further comprises: a silicon fluidic substrate comprising
the micro-fluidic component embedded in the silicon fluidic
substrate, wherein the silicon fluidic substrate is fluidically
connected to the inlet, and wherein the microchip is adapted to act
as a lid attached to the silicon fluidic substrate, and wherein the
lid at least partly covers the silicon fluidic substrate and at
least partly closes the micro-fluidic component.
12. The fluid analyzing device of claim 11, wherein at least a part
of the lid is in contact with the fluid sample when the fluid
sample is propagated through the micro-fluidic component.
13. The fluid analyzing device of claim 11, wherein the lid
comprises a transistor layer, the transistor layer being
electrically connected to at least one electrical component, the
electrical component being at least one of: biosensing circuitry,
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.
14. A method for sensing a fluid sample, comprising: providing a
fluid analyzing device; providing a fluid sample to the
micro-fluidic component; propagating the fluid sample through the
micro-fluidic component by opening the vacuum compartment thereby
creating a pressure difference between the vacuum compartment and
the micro-fluidic component; and sensing the fluid sample using the
sensing device.
15. The method of claim 14, further comprising: detecting a fluid
sample being provided to the micro-fluidic component; and opening
the vacuum compartment when the fluid sample is detected.
16. A sensing device comprising: a fluidic substrate, the fluidic
substrate comprising a micro-fluidic component embedded in the
fluidic substrate, wherein the fluidic substrate is configured to
propagate a fluid sample via capillary force through the
micro-fluidic component; a means for providing a fluid sample,
wherein the means is connected to the micro-fluidic component; and
a lid attached to the fluidic substrate, wherein the lid at least
partly covers the fluidic substrate and at least partly closes the
micro-fluidic component.
17. The sensing device of claim 16, wherein the fluidic substrate
is a silicon fluidic substrate, and wherein the lid is a
Complementary Metal-Oxide Semiconductor (CMOS) chip.
18. The sensing device of claim 16, wherein the means for providing
a fluid sample is a needle fabricated from a semiconductor, wherein
the needle comprises an inner fluidic channel connected to the
micro-fluidic component, and wherein the needle is a protruding
portion of the fluidic substrate and positioned to penetrate skin
tissue when pressed against the skin tissue.
19. The sensing device of claim 16, wherein the fluidic substrate
further comprises at least one optical waveguide, wherein the at
least one optical waveguide allows for optical excitation and
sensing of the fluid sample when the fluid sample is present in the
sensing device.
20. The sensing device of claim 16, wherein the fluidic substrate
comprises at least one through-hole for application of a
biochemical reagent to at least one region of the micro-fluidic
component.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to medical devices for fluid
analysis. In particular, the present invention is related to
compact devices, e.g. medical devices, for the analysis of a fluid
sample. More in particular, the present invention is related to
fully integrated devices, such as lab-on-a-chip devices, for the
analysis of bodily fluid samples.
BACKGROUND OF THE INVENTION
[0002] Currently, state of the art point-of-care devices for the
analysis of blood exist. 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 state of the art
point of care devices is their cost to fabricate.
[0003] Other state of the art 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.
[0004] There is a need for a low-cost, easy to use, disposable,
compact device for the fully integrated analysis of a fluid
sample.
SUMMARY OF THE INVENTION
[0005] It is an object of embodiments of the present invention to
provide an easy to use device and method for analyzing a fluid
sample.
[0006] It is an advantage of embodiments of the present invention
that, at least for some actions, connecting of the device to a
separate fluid propagating element such as a pumping means can be
avoided.
[0007] It is an advantage of embodiments of the present invention
to provide compact devices for analyzing fluid samples as well as
corresponding methods for analyzing fluid samples.
[0008] It is an advantage of embodiments of the present invention
that low-cost devices for analyzing fluid samples can be provided,
whereby such low-cost devices can for example be disposable. This
objective is accomplished by a method and device according to
embodiments of the present invention.
[0009] According to an aspect of the invention, a fluid analyzing
device is presented. The fluid analyzing device comprises: a
sensing device for analyzing a fluid sample, the sensing device
comprising: a microchip configured for sensing the fluid sample and
a closed micro-fluidic component for propagating the fluid sample
to the microchip; a vacuum compartment air-tight connected to the
sensing device and adapted for creating a suction force in the
micro-fluidic component by opening the vacuum compartment, the
suction force being suitable for propagating the fluid sample
through the micro-fluidic component and an inlet for providing the
fluid sample to the micro-fluidic component. Hence, the
micro-fluidic component is closed, apart from the inlet for
providing the fluid sample. The sensing device may be defined as a
medical device suitable for performing an analysis of a fluid
sample, e.g. bodily fluid samples.
[0010] According to an embodiment of the invention, the vacuum
compartment encloses a volume at lower pressure than atmospheric
pressure, hence creating the suction force in the micro-fluidic
component by opening the vacuum compartment. Vacuum thereby means
that the pressure is lower than atmospheric pressure.
[0011] According to an embodiment of the invention, the fluid
analyzing device further comprises a package comprising: the
sensing device, the vacuum compartment and the inlet. The sensing
device and the vacuum compartment are encapsulated by the package.
The inlet is located in the package, e.g. in a wall of the package,
down to the micro-fluidic component such that a fluid sample may be
provided to the micro-fluidic component.
[0012] According to an embodiment of the invention, the vacuum
compartment comprises a sacrificial element adapted to open the
vacuum compartment towards the micro-fluidic component when the
element is destructed.
[0013] According to an embodiment of the invention, the fluid
analyzing device further comprises a movable structure for
destructing the sacrificial element. The movable structure may be
located in the package. Alternatively, it is part of the vacuum
compartment.
[0014] According to an embodiment of the invention, the movable
structure is a movable puncture device adapted to destruct the
sacrificial element when being actuated from outside the
package.
[0015] According to an embodiment of the invention, the sacrificial
element comprises a heating resistor positioned such that the
sacrificial element is destructed by heating
[0016] According to an embodiment of the invention, the heating
resistor is positioned in or on the sacrificial element. According
to an embodiment of the invention, the heating resistor is
positioned on a substrate comprising the micro-fluidic component.
The heating resistor may be contacting the sacrificial element.
[0017] According to an embodiment of the invention, the sacrificial
element is solvent-dissolvable. The fluid analyzing device further
comprises a solvent compartment containing a solvent. The solvent
compartment is configured to release the solvent to the sacrificial
element when the fluid sample is provided in the micro-fluidic
component. By dissolving the sacrificial element by the released
solvent, the vacuum compartment is opened.
[0018] According to an embodiment of the invention, the fluid
analyzing device further comprises a fluid detector positioned to
detect the fluid sample when provided in the micro-fluidic
component. When the fluid sample is detected, the vacuum
compartment is configured to open.
[0019] Optionally, the fluid analyzing device also may comprise
features of the sensing device described in the further aspect
below.
[0020] According to an aspect of the invention, a method for
sensing a fluid sample is presented, comprising: providing a fluid
analyzing device according to an embodiment as described above;
providing a fluid sample to the micro-fluidic component via the
inlet for providing the fluid sample to the micro-fluidic
component; thereafter propagating the fluid sample through the
micro-fluidic component by opening the vacuum compartment thereby
creating a pressure difference between the vacuum compartment and
the micro-fluidic component; and performing sensing on the fluid
sample using the sensing device.
[0021] According to an embodiment of the invention, the method for
sensing a fluid sample further comprises detecting a fluid sample
being provided to the micro-fluidic component, and wherein the
vacuum compartment is opened when the fluid sample is detected.
[0022] According to an aspect of the invention, the present
invention relates to a sensing device for analyzing a fluid sample.
The sensing device comprises: a fluidic substrate comprising a
micro-fluidic component embedded in the fluidic substrate,
configured to propagate a fluid sample via capillary force 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 thereby at least partly covering the fluidic
substrate and at least partly closing the micro-fluidic component.
The fluidic substrate is a silicon fluidic substrate and the lid is
a CMOS chip.
[0023] According to embodiments of the present invention, at least
a part of the lid is in contact with the fluid sample when the
fluid sample is present in the sensing device.
[0024] According to embodiments of the present invention, the lid
comprises a transistor layer, the transistor layer being
electrically connected at least one electrical component, the
electrical component being at least one of the following:
biosensing circuitry, 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, imaging
components, e.g. lensfree imaging components. These electrical
components may be present on the lid, hence on the microchip. In an
embodiment, the transistor layer and the electrical components are
integrated in a single microchip.
[0025] According to embodiments of the present invention, the means
for providing a fluid sample is a needle fabricated from a
semiconductor, e.g. silicon, and comprising an inner fluidic
channel connected to the micro-fluidic component. The needle is a
protruding portion of the fluidic substrate and positioned to
penetrate skin tissue when pressed against the skin tissue.
[0026] According to embodiments of the present invention, the
fluidic substrate comprises a cut-out and the needle is positioned
in the cut-out.
[0027] According to embodiments of the present invention, the
fluidic substrate comprises a protection structure for protecting
the needle, the protection structure being removably attached to
the fluidic substrate.
[0028] According to embodiments of the present invention, the means
for providing a fluid sample is an inlet. A sample drop may be
inserted into the microfluidic component by means of capillary
suction, or by other suitable means. The microfluidic component may
comprise different fluidic compartments, for instance for
multi-omic analysis. The different microfluidic compartments can
have the 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.
[0029] According to embodiments of the present invention, the
fluidic substrate 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 sensing device. The fluidic
substrate or the lid may also comprise filters for rejecting
optical excitation from emission to measure a fluorescent signal.
The fluidic substrate or the lid may comprise multispectral filters
for measuring fluorescent signals with multiple colors. The fluidic
substrate or the lid may comprise an optical waveguide and/or a
pinhole to irradiate the sample for performing lensfree
microscopy.
[0030] According to embodiments of the present invention, 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.
[0031] According to embodiments of the present invention, the lid
is bonded to the fluidic substrate using a lithographically
patterned polymer.
[0032] According to embodiments of the present invention, the
sensing device may further comprise metal contacts electrically
connected to the microchip for read-out of electrical signals
generated by the fluid and captured by measurement systems in the
lid. According to embodiments of the present invention, the lid of
the sensing device may further comprise CMOS active pixels for
readout of optical signals from the fluid.
[0033] According to embodiments of the present invention, 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.
[0034] According to embodiments of the present invention, the shape
of the sensing device allows insertion into a mobile communication
device.
[0035] According to an aspect, embodiments of the present invention
relate to a method for fabricating a sensing device for analyzing a
fluid sample. The method comprises: providing a fluidic substrate;
providing a lid; attaching the fluidic substrate to the lid thereby
at least partly close the fluidic substrate. The fluidic substrate
is a semiconductor fluidic substrate and the lid is CMOS chip. The
fluidic substrate is attached to the lid using a CMOS compatible
bonding process.
[0036] According to embodiments of the present invention, providing
a fluidic substrate may comprise: providing a semiconductor (e.g.
silicon) substrate, providing a mask layer, for instance an oxide
mask, patterning the mask layer so as to create fine structures in
the oxide mask layer; providing a protection layer to protect the
mask layer; patterning coarse structures; etching of the coarse
structures; growing oxide for protecting the coarse structures;
removing the protection layer and etch the fine structures; and,
removing the oxide.
[0037] According to embodiments of the present invention, providing
a fluidic substrate may comprise providing a semiconductor
substrate, providing a plurality of masks on top of one another and
using each mask for creating microfluidic structures of different
depths.
[0038] In accordance with particular embodiments of the present
invention, providing a fluidic substrate may comprise providing a
semiconductor, e.g. silicon, substrate, providing a first oxide
mask, patterning microfluidic structures, etching the substrate to
single depth, providing a second oxide mask, patterning
microfluidic structures, etching the substrate to a second depth,
and, if required, repeating these steps for creating multiple
depths of microfluidic structures.
[0039] According to particular embodiments, the fluidic substrate
and the lid of a sensing device according to embodiments of the
present invention may be integrated in 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. The advantage thereof
is that such system becomes more cost efficient.
[0040] According to embodiments of the present invention, 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.
[0041] According to an aspect of the invention, the present
invention provides the use of the sensing device as described in
the foregoing aspects to perform microscopy. Microscopy may be
implemented by using the lid for detecting lensfree images
according to the principles of digital holography.
[0042] The use of the sensing 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 CMOS lid is used to detect multiple signals from all assays.
Those signals can combine multiple DNA, RNA, small molecule, cell
signals from a same analyte.
[0043] In particular embodiments, the sensing device is used as a
single use disposable device for analysis of a small amount of
fluid.
[0044] According to an aspect of the invention, the data from the
microchip may be sent to a smart handheld device, for instance
using a wireless connection. The smart device can be used for
processing, visualizing and/or transferring the data.
[0045] In embodiments of the present invention, the combined data
gathered from a single same sample may be used in a software
algorithm for calculating a parameter indicative of disease or of
the wellbeing of an individual.
[0046] Particular and preferred aspects of the invention 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.
[0047] These and other aspects of the invention will be apparent
from and elucidated with reference to the embodiment(s) described
hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
[0048] FIG. 1 illustrates a 3D view of an embodiment of a fluidic
substrate which may be used in embodiments of the present
invention.
[0049] FIG. 2 illustrates a top view of a first embodiment of a
sensing device for analyzing a fluid sample according to
embodiments of the present invention.
[0050] FIG. 3 illustrates a top view of a fluidic substrate used in
the sensing device of FIG. 2.
[0051] FIG. 4 illustrates a side view of the sensing device of FIG.
2.
[0052] FIG. 5 illustrates a top view of a second embodiment of a
sensing device for analyzing a fluid sample according to
embodiments of the present invention, featuring a cut-out for a
needle.
[0053] FIG. 6 illustrates a top view of an embodiment of a fluidic
substrate featuring a cut-out for a needle, for use in the sensing
device of FIG. 5.
[0054] FIG. 7 illustrates a side view of the sensing device of FIG.
5.
[0055] FIG. 8 illustrates a top view of a third embodiment of a
sensing device for analyzing a fluid sample according to
embodiments of the present invention, featuring a protection
structure for a needle.
[0056] FIG. 9 illustrates a top view of an embodiment of a fluidic
substrate featuring a protection structure for a needle, for use in
the sensing device of FIG. 8.
[0057] FIG. 10 illustrates a side view of the sensing device of
FIG. 8
[0058] FIG. 11 to FIG. 17 illustrate a method to fabricate a
fluidic substrate for use in a sensing device according to
embodiments of the present invention.
[0059] FIG. 18 illustrates an embodiment of a CMOS chip for use in
a sensing device according to embodiments of the present
invention.
[0060] FIG. 19 illustrates the bonding of a CMOS chip with a
fluidic substrate, in accordance with embodiments of the present
invention.
[0061] FIG. 20 illustrates the bonding of a CMOS chip with a
fluidic substrate, in accordance with embodiments of the present
invention, wherein the CMOS chip comprises a silicon I/O
interconnect.
[0062] FIG. 21 illustrates an embodiment of a CMOS chip for use in
a sensing device according to embodiments of the present invention,
the CMOS chip comprising an I/O pad.
[0063] FIG. 22 illustrates an embodiment of a CMOS chip for use in
a sensing device according to embodiments of the present invention,
the CMOS chip comprising an I/O pad bonded to a fluidic substrate,
wherein a part of the CMOS chip overlaps the fluidic substrate.
[0064] FIG. 23 illustrates the bonding of a CMOS chip with a
fluidic substrate, in accordance with embodiments of the present
invention, wherein the CMOS chip comprises a through hole.
[0065] FIG. 24 illustrates the bonding of a CMOS chip with a
fluidic substrate, in accordance with embodiments of the present
invention, wherein the fluidic substrate comprises two through
holes.
[0066] FIG. 25 illustrates a 3D view of a sensing device according
to an embodiment of the present invention.
[0067] FIG. 26 illustrates a 3D view of a wireless stand-alone
sensing device according to an embodiment of the present invention.
FIG. 27 illustrates a top view of a part of a first embodiment of a
micro-fluidic component for use in a sensing device according to
embodiments of the present invention, the micro-fluidic component
comprising micro-pillars.
[0068] FIG. 28 illustrates a 3D view of a part of the micro-fluidic
component of FIG. 27.
[0069] FIG. 29 illustrates a top view of a part of a second
embodiment of a micro-fluidic component for use in a sensing device
according to embodiments of the present invention, the
micro-fluidic component comprising micro-pillars.
[0070] FIG. 30 illustrates a 3D view of a part of the micro-fluidic
component of FIG. 29.
[0071] FIG. 31 illustrates an embodiment of a sensing device
according to embodiments of the present invention in the shape of
an SD card.
[0072] FIG. 32 illustrates another embodiment of a sensing device
according to embodiments of the present invention in the shape of
an SD card.
[0073] FIG. 33 is a cross-sectional view of a sensing device
according to embodiments of the present invention, wherein a
plurality of functionalities are supported by a single CMOS
technology.
[0074] FIG. 34 illustrates an embodiment of a fluid analyzing
device.
[0075] FIG. 35 illustrates an embodiment of a fluid analyzing
device.
[0076] 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.
[0077] Any reference signs in the claims shall not be construed as
limiting the scope.
[0078] In the different drawings, the same reference signs refer to
the same or analogous elements.
DETAILED DESCRIPTION OF THE ILLUSTRATIVE EMBODIMENTS
[0079] 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 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 of the invention.
[0080] 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
invention described herein are capable of operation in other
sequences than described or illustrated herein.
[0081] 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 invention
described herein are capable of operation in other orientations
than described or illustrated herein.
[0082] It is to be noticed that the term "comprising", 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 "a device comprising means A and B"
should not be limited to devices consisting only of components A
and B. It means that with respect to the present invention, the
only relevant components of the device are A and B.
[0083] 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 phrases "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.
[0084] Similarly it should be appreciated that in the description
of exemplary embodiments of the invention, various features of the
invention 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 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.
[0085] 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 invention, 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.
[0086] 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 an
understanding of this description.
[0087] Where in embodiments of the present invention reference is
made to an "I/O pad" or an "I/O contact", reference is made to a
contact such as a metal contact allowing input and output of
electrical signals of a micro-chip.
[0088] Where in embodiments of the present invention reference is
made to "CMOS", reference is made to a Complementary Metal-Oxide
Semiconductor.
[0089] Throughout the description reference is made to "fluid
sample". This may refer to biological fluids including but not
limited to blood, serum, urine, gastric and digestive juices,
tears, saliva, stool, semen, and interstitial fluids derived from
tumorous tissues.
[0090] According to an aspect of the invention, a fluid analyzing
device 1 is presented. The fluid analyzing device comprises a
sensing device 100 which is adapted for analyzing a fluid sample.
The sensing device 100 comprises a closed micro-fluidic component 4
for propagating the fluid sample to a microchip 103 which is
present in the sensing device 100. The fluid analyzing device 1
further comprises an inlet for providing the fluid sample to the
micro-fluidic component 4. Further, the fluid analyzing device 1
comprises a vacuum compartment 6 which is air-tight connected or
attached to the micro-fluidic device 4. The micro-fluidic component
4 is embedded in a substrate (e.g. glass or silicon substrate) and
thus is closed, apart from the inlet, and apart from the location
where the vacuum compartment 6 is air tight connected to the
sensing device 100. By opening the vacuum compartment 6 at the side
attached to the sensing device 100, a suction force is created in
the micro-fluidic component 4 which allows a fluid sample present
in part of the micro-fluidic component 4 to be propagated through
the micro-fluidic component 4. By using a vacuum compartment to
create the suction force, a cheap, power-free and reliable way of
propagating the fluid sample is devised which makes it extremely
suitable for use in single usage, disposable medical devices. (In
this text and accompanying figures, the micro-fluidic component may
be referred to with reference number "4" or with reference number
"102").
[0091] According to an embodiment of the invention, the fluid
analyzing device 1 further comprises a package 2 comprising the
sensing device 100, the vacuum compartment 6 and the inlet 7. The
package 2 encapsulates the sensing device 100, the vacuum
compartment 6 and protects the fluid analyzing device 1 from the
environment. For example, the package may be dust, water or shock
proof. The package may be fabricated from a resilient material,
e.g. a plastic. The inlet 7 in the package 2 is fluidically
connected to the inlet of the micro-fluidic component 4. Via the
inlet 7 of the package 2, a fluid sample can be provided to the
micro-fluidic component 4. If the micro-fluidic component 4
comprises multiple inlets, the package 2 may also comprise multiple
corresponding inlets.
[0092] According to an embodiment of the invention, the
micro-fluidic component 4 is fluidically connected on one end with
the inlet 7 and fluidically connectable on the other end with the
vacuum compartment 6, by opening the vacuum compartment 6. In some
embodiments of the present invention, the vacuum compartment
pressure is lower than atmospheric pressure. When the vacuum
compartment 6 is opened, the pressure difference between the
micro-fluidic component 4 and the vacuum compartment 6 forces a
fluid sample which is provided at the inlet for the micro-fluidic
component 4 to propagate through the micro-fluidic component 4, at
least until the fluid sample reaches the microchip 103.
[0093] According to an embodiment of the invention, the vacuum
compartment 6 is part of the sensing device. For example, the
vacuum compartment may be a compartment located in the substrate
that also comprises the micro-fluidic component 4. In such an
embodiment, the compartment 6 may be a sealed cavity in the
substrate which can be connected to the micro-fluidic component 4
by breaking the seal which seals the cavity. The seal may be a
sacrificial element 8, such as a membrane, which can be destructed
by suitable means, such as dissolution, by heating or by applying a
force, for example an external pushing pressure.
[0094] According to an embodiment of the invention, for reducing
cost and to minimize the usage of substrate material, the vacuum
compartment 6 may be a separate component which is attached to the
sensing device 100.
[0095] According to an embodiment of the invention, the vacuum
compartment 6 may also be a part of the package 2, e.g. attached
inside the package. For example, the vacuum compartment is attached
to or is part of an inner wall of the package.
[0096] Different embodiments for the sacrificial element 8 may be
provided. According to embodiments of the invention, the vacuum
compartment 6 comprises a sacrificial element 8 which is adapted to
open the vacuum compartment 6 towards the micro-fluidic component
102 when the element 8 is destructed. The sacrificial element 8 is
located such that when the element is destructed, a suction force
in the micro-fluidic component 102 can be created while maintaining
the air-tight connection between the vacuum compartment 6 and the
sensing device 100. The sacrificial element 8 may be a membrane,
e.g. a sealing foil. The material and thickness of the sacrificial
element is selected such that its resistance is sufficiently high
thereby making it suitable for sealing the vacuum compartment
6.
[0097] According to an embodiment of the invention, the sacrificial
element 8 comprises a heating element, such as for example a
heating resistor, positioned such that the sacrificial element 8 is
destructed by heating when the heating element is electrically
driven, thereby opening the vacuum compartment 6. Other variations
of this method describing different method steps for the
destruction of the sacrificial element 8 also correspond with
embodiments of the present invention.
[0098] According to an embodiment of the invention, the heating
element is positioned in or on the sacrificial element 8. According
to an embodiment of the invention, the heating resistor is
positioned on the sensing device 100, for example on the substrate
which comprises the micro-fluidic component 4. The heating element
may be in direct contact with the sacrificial element 8. In such an
embodiment, the heating element is isolated from other parts of the
substrate to minimize heat transfer to other components on the
substrate. For example, the sensing device 100, e.g. the substrate
comprising the micro-fluidic component 102, may comprise trenches
located around the heat element to isolate the element from the
rest of the sensing device 100.
[0099] The cross-section of a device according to an embodiment of
the invention is illustrated in FIG. 34. A package 2 encapsulates a
sensing device 100. This package is not essential. The sensing
device 100 is fixed inside the package 2, e.g. via clamps. The
sensing device 100 is positioned inside the package 2 such that a
fluid sample introduced in the inlet 7 can enter the micro-fluidic
component 4, e.g. via an inlet of the micro-fluidic component 4. A
vacuum compartment 6 is attached to the sensing device 100.
[0100] A microchip 103 is part of the sensing device 100 and is
positioned such that it may perform direct sensing on a fluid
sample inside the micro-fluidic component 4. The inlet 7 is
connected to one end of the micro-fluidic component 4. The vacuum
compartment 6 is connected to the other end of the micro-fluidic
component 4. The micro-chip 103 is located along the micro-fluidic
component 4, positioned in between the inlet 7 and the vacuum
compartment 6 such that a fluid sample, introduced in the inlet 7
and propagated via a suction force created by opening the vacuum
compartment, passes through or into the micro-chip. In some
embodiments of the present invention, the microchip 103 may be
comprised in a side of the channel of the micro-fluidic component
4, or it may be comprised in the lid.
[0101] According to an embodiment of the invention, the package 2
or the vacuum compartment 6 may comprise a movable structure 5
suitable for destructing the sacrificial element 8. The movable
structure 5 may be a movable puncture device, positioned and
adapted to destruct the sacrificial element 8 when actuated from
outside the package 2 or from outside the vacuum compartment 6. The
moveable puncture device may be integrated in a wall of the vacuum
compartment 6 such that when the moveable puncture device is
actuated, the air tight connection to the sensing device 100 is
preserved. For preserving this air-tight connection, a diaphragm,
e.g. fabricated from an elastic material, may be used which allows
movement of the puncture device without causing a pressure loss in
the vacuum compartment 6. Alternatively, a mechanical structure may
be used which allows movement of the puncture device and which also
preserves the air-tight connection. The moveable puncture device
may comprise a needle which may be located inside the vacuum
compartment 6. Hence, by moving the puncture device, the needle can
be moved towards the sacrificial element 8 such that the
sacrificial element 8 can be punctured when applying enough
pressure on the moveable puncture device. The mechanical structure
may comprise a spring which causes the mechanical structure to
return to its initial position when the mechanical structure is not
actuated.
[0102] Such an embodiment is illustrated in FIG. 35. A package 2
encapsulates a sensing device 100. The sensing device 100 is fixed
inside the package 2, e.g. via clamps. The sensing device 100 is
positioned inside the package 2 such that a fluid sample introduced
in the inlet 7 can enter the micro-fluidic component 4. A vacuum
compartment 6 is attached to the sensing device 100. In between the
sensing device 100 and the vacuum compartment 6, a sealing layer 11
is present to bond the vacuum compartment 6 to the sensing device
100. The sealing layer may be a layer comprising a polymer. This
sealing layer is optional. The sealing layer may be a gasket. The
sealing layer is not present at the location where the vacuum
compartment can be opened by destructing the sacrificial element 8.
A microchip 103 is located in the sensing device 100 such that it
may perform direct sensing on a fluid sample inside the
micro-fluidic component 4. The inlet 7 is connected to one end of
the micro-fluidic component 4. The vacuum compartment 6 is
connected to the other end of the micro-fluidic component 4. The
micro-chip 103 is located along the micro-fluidic component 4, in
between the inlet 7 and the vacuum compartment 6 such that a fluid
sample introduced in the inlet 7 and propagated via a suction force
created by opening the vacuum compartment 6 passes the micro-chip
103 for sensing purposes. The vacuum compartment 6 can be opened by
actuating the moveable puncture device 6 from outside the package
2. When the puncture device 6 is pushed by a user, the puncture
device 6 approaches the sacrificial element 8 and eventually
punctures the sacrificial element 8 thereby opening the vacuum
compartment 6.
[0103] According to an embodiment of the invention, the sacrificial
element 8 is solvent-dissolvable. The fluid analyzing device 1
further comprises a solvent compartment containing a solvent. The
solvent compartment may be configured to release the solvent to the
element 8 when the fluid sample is provided in the micro-fluidic
component 4 thereby opening the vacuum compartment. The solvent
compartment may also be configured to release the solvent to the
element 8 by applying pressure to the vacuum compartment such that
the solvent compartment breaks and releases its content on the
sacrificial element 8. The solvent compartment may also be
configured to release the solvent to the element 8 when it is
electrically driven. For example, the fluid analyzing device 1 may
comprise a switch or a button which generates an electrical signal
to the element 8 causing the element 8 to break. The solvent
compartment is positioned close to the sacrificial element 8 such
that the sacrificial element 8 can be exposed to the solvent when
the solvent compartment is opened. The solvent compartment may
comprise a closed fluidic valve which can be opened when
electrically driven. The solvent may be acetone. The sacrificial
layer may be fabricated from a material dissolvable in acetone.
[0104] According to an embodiment of the invention, the fluid
analyzing device 1 further comprises a fluid detector 9 which is
positioned to detect the fluid sample when provided in the
micro-fluidic component 4. The vacuum compartment 6 may be
configured to open when the fluid sample is detected. The at least
one fluid detector may be one or more electrical element, e.g.
electrodes, configured to detect a fluid sample based on impedance
or capacitance measurements. The electrodes may be positioned
inside the inlet 7 of the package 2. The electrodes may be
positioned on the sensing device 100, e.g. on an inner wall of the
micro-fluidic component 4.
[0105] According to an embodiment of the invention, the fluid
analyzing device 1 further comprises an switch or a push-button for
activating the fluid analyzing device 1. The switch may be used to
electrically connect the fluid analyzing device 1 to an on-board
energy source, e.g. a battery. The switch may be adapted such that
the sacrificial element 8 is electrically driven when the switch is
actuated. When electrically driving the sacrificial element 8, the
vacuum compartment is opened. The switch may be adapted such that
the sacrificial element 8 of the solvent compartment is
electrically driven when the switch is actuated.
[0106] According to a method for operating the fluid analyzing
device 1, a fluid sample is provided to the micro-fluidic component
4. Thereafter, the switch is actuated which causes the vacuum
compartment to open thereby causing the fluid sample to propagate
through the micro-fluidic component 4. The switch may for example
act on a valve.
[0107] It will be understood that further features and advantages
may correspond with one or more features of the sensing device
described in further aspects below. Such one or more features may
be applied mutates mutandis in embodiments of the sensing device of
the present aspect
[0108] In an aspect of the invention, a method for sensing a fluid
sample is presented. The method comprises providing a fluid
analyzing device 1 according to an aspect of the invention. The
method comprises providing a fluid sample to the micro-fluidic
component 4; thereafter propagating the fluid sample through the
micro-fluidic component 4 by opening the vacuum compartment 6
thereby creating a pressure difference between the vacuum
compartment 6 and the micro-fluidic component 4; and performing
sensing on the fluid sample using the sensing device 100.
[0109] According to an embodiment of the invention, the method
further comprises detecting a fluid sample when it is provided to
the micro-fluidic component 4, and wherein the vacuum compartment 6
is opened, or configured to open, when the fluid sample is
detected.
[0110] An aspect of the invention relates to a sensing device 100
for analyzing a fluid sample, as for instance illustrated in FIGS.
25 and 26. The sensing device 100 comprises: an exemplary 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 the present example
illustrated by a plurality of microfluidic components such as a
sample pad 102a (=an inlet), a reagent storage 102b, a one-time
usage hermetic valve 102c, a first trigger valve 102d, a mixer
102e, a delay line 102f, a second trigger valve 102g, an a heater
102h and a wick 102i) embedded in the fluidic substrate 101
configured to propagate a fluid sample via capillary force through
the micro-fluidic component 102; and a means 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 embodiments of the
present invention, the fluidic substrate 101 is a silicon fluidic
substrate; and the lid 103 is a CMOS chip. The lid 103 functions as
a cover for the fluidic substrate 101 wherein the lid 103 fully or
partly closes the micro-fluidic component 102. FIG. 25 illustrates
an embodiment of the present invention wherein the lid 103 partly
covers the fluidic substrate 101. The lid 103 may fully or also
partially covering the fluidic substrate 101. When the means for
providing a fluid sample is an inlet 109 (as illustrated in FIG.
26), for instance a sample pad 102a, the lid 103 may partially
cover the fluidic substrate 101, allowing a user to access the
inlet 109 to deposit a fluid sample. When the fluid enters in
contact with a fluid detector, or by a switching action, the vacuum
chamber may open and suck the liquid into the micro-fluidic
channels of the micro-fluidic component 102.
[0111] As the fluidic substrate 101 may be a silicon substrate and
the lid 103 may comprise a CMOS chip 103, both can be manufactured
using mass production compatible silicon process technologies. As
an additional advantage, cheap CMOS packaging techniques may be
used to bond the silicon substrate to the CMOS chip. This reduces
the total cost of the sensing device and allows it to be used as a
disposable device and produced in high volume. Alternatively, the
fluidic substrate 101 is a glass substrate.
[0112] FIG. 1 illustrates a 3D view of an embodiment of a fluidic
substrate 101. A top view of an embodiment of the sensing device
100 is illustrated in FIG. 2, the fluidic substrate 101 and the lid
103 are attached to one another. A top view of an exemplary fluidic
substrate 101 used in the sensing device of FIG. 2 is illustrated
in FIG. 3. A side view of an embodiment of the sensing device 100
of FIG. 2 where the fluidic substrate 101 is attached to the lid
comprising a microchip 103 is illustrated in FIG. 4.
[0113] A sensing device 100 according to embodiments of the present
invention comprises a fluidic substrate 101 which is attached or
bonded to a lid 3. 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 optionally
comprise a plurality of micro-pillars or microstructures at regular
or irregular distances to allow filtering and separation, to act as
valves, to allow mixing of a fluid sample during capillary flow.
FIG. 27 illustrates a top view of a part of micro-fluidic component
102 comprising micro-pillars 270 to allow filtering and separation,
valving, mixing of a fluid sample during capillary flow. FIG. 28
illustrates a 3D view of the open micro-fluidic component 102 of
FIG. 27 comprising micro-pillars 270. The micro-pillars 270 in FIG.
27 and FIG. 28 are positioned as to form a gradient. This gradient
is advantageous to filter out larger particles in a first part of
the micro-fluidic component 102 and to filter out smaller particles
in a second part of the micro-fluidic component 102. FIG. 29 and
FIG. 30 illustrate another embodiment of a gradient of
micro-pillars 270 in the micro-fluidic component 102. The
micro-fluidic component 102 may be configured to create a capillary
action to propagate a fluid sample through the sensing device 101.
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. As an advantage, in embodiments of the present
invention, the sensing device 100 does not need additional active
components (e.g. an active pump) to propagate a fluid sample
through the sensing device 100. Thus, the complexity of the sensing
device 100 is reduced compared to prior art implementations, which
reduces fabrication cost and power consumption. As the costs to
fabricate are low, the sensing device may be used as a disposable
fluid analysis device.
[0114] It is an advantage of embodiments of the present invention
that precise control over the flow of a fluid sample in the
micro-fluidic component 102 may be achieved by e.g. correctly
dimensioning the micro-fluidic channels and/or micro-pillar sizes
and distances which are present in the micro-fluidic component 102.
Lithographic patterning may be used to fabricate the micro-fluidic
component 102 in the fluidic substrate 101. It is an advantage that
the lithographic patterning of micro-pillars and micro-fluidic
channels of the micro-fluidic component 102 allows to accurately
control the dimensions, size and shape of the micro-pillars and
micro-fluidic channels, thereby precisely controlling the capillary
flow. This precise control over the dimensions, achievable via
lithographic processes, presents an advantage in achieving more
reproducible lateral flow than the state of the art lateral flow
test strips, which are made from porous paper with uncontrolled
lateral flow. By varying the dimensions over the length of the
sensing device it is possible to slow down and/or to increase the
speed of the flow of a fluid sample where desired. 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 CMOS chip bonded
as a lid onto the fluidic substrate 101 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,
the implementation of capillary flow in silicon with controlled
lateral flow and with control over the temperature and flow rate
results in more accurate point of care test results.
[0115] According to some embodiments, a vacuum compartment for
sucking the fluid sample through the microfluidic component may be
provided. This may be provided alternative to or in addition to the
capillary system or pillar structures as described above. To use
the sensing device, a user may deposit a drop of fluid, e.g. a
bodily fluid such as blood or saliva on the inlet 109 of the
sensing device. When the fluid is to be introduced, the vacuum
compartment is opened and the underpressure induces propagation of
fluid, e.g. bodily fluid, through the micro-fluidic component 102.
The propagation may be further enhanced by capillary forces.
[0116] FIG. 26 illustrates an exploded view of a fluid analyzing
device 1 according to embodiments of the present invention,
comprising a fluidic substrate 101 comprising an inlet 109 and a
microfluidic component 102, a lid comprising a microchip 103 and a
package 110. The package 110 may comprise a base and a top which
can be assembled together to package the fluidic substrate 101 and
the lid, thus protecting these from environmental influences such
as dust. In some embodiments, the lid may be part of the top of the
package 110. The package may comprise a through-hole 260 for
depositing a fluid sample on an inlet 109 of the fluidic substrate
101. When all parts are assembled, the sensing device 100 may
function as a stand-alone wireless device for analyzing a fluid
sample. The microfluidic component 102 in FIGS. 25 and 26 may
comprise a microchip 103 and a vacuum compartment for creating a
negative pressure and bring fluids into the channels towards the
microchip, according to embodiments of the present invention.
[0117] In FIG. 1, a 3D view of an exemplary fluidic substrate
according to some embodiments of the present invention is
shown.
[0118] In embodiments of the present invention the fluidic
substrate 101 comprises a means for providing a fluid sample which
is connected to the micro-fluidic component 102.
[0119] The lid 103 functions as a cover for the fluidic substrate
101 wherein the lid 103 fully or partly closes the micro-fluidic
component 102. FIG. 25 illustrates an embodiment of the present
invention wherein the microchip 103, which may be part of a lid,
partly covers the fluidic substrate 101. The micro-fluidic
component 102 may be a micro-fluidic component 102 in the fluidic
substrate 101. According to alternative embodiments of the present
invention, the dimensions of the microchip 103 may be identical to
the dimensions of the fluidic substrate 101. The microchip 103 may
fully or also partially covering the fluidic substrate 101. When
the means for providing a fluid sample is an inlet 109 (as
illustrated in FIG. 26), for instance a sample pad 102a, the
microchip 103 may partially cover the fluidic substrate 101,
allowing a user to access the inlet 109 to deposit a fluid
sample.
[0120] According to embodiments of the present invention, the
sensing device 100 may further comprise one or more electrodes
which are placed on the micro-fluidic component 102 of the fluidic
substrate 101. These electrodes may be biocompatible electrodes.
The electrodes may be electrically connected to the lid 103
comprising a microchip 103 and are allowed to interact with a fluid
sample in the micro-fluidic component 102 of the sensing device 100
as they may be in direct contact with a fluid sample in the
micro-fluidic component 102. While the lid 103 itself may comprise
electrodes, it is advantageous to separate the electrodes from the
lid 103 to allow the lid 103 to be smaller, which reduces
costs.
[0121] According to embodiments of the present invention, the
micro-fluidic component 102 may comprise a capillary pump.
[0122] According to embodiments of the present invention, the means
for providing a fluid sample may be an integrated needle 104, for
instance fabricated from silicon, and comprising an inner fluidic
channel 105 connected to the micro-fluidic component 102. The
needle 104 may be a protruding portion of the fluidic substrate 101
and may be positioned so as to penetrate skin tissue when pressed
against that skin tissue.
[0123] The fluidic substrate 101 and the needle 104 may be
fabricated from a single piece of semiconductor This simplifies the
fabrication of the sensing device 100 according to embodiments of
the present invention, as separate steps to attach a needle 104 to
the fluidic substrate 101 are not required. Also, standard CMOS
processing techniques may be used to fabricate the needle 104.
Preferably the needle 104 is a sharp needle which allows skin
tissue to be penetrated. The fluidic substrate 101 and the needle
104 may be both fabricated from the same or different
semiconductors. For example, a needle fabricated from silicon has
the advantage of allowing the needle 104 to be very sharp, which
eases the penetration of the needle 104 in skin tissue. Further,
the strength of the silicon allows skin tissue to be firmly pressed
against the needle 104, allowing penetration of skin tissue without
bending or breaking the needle 104.
[0124] According to embodiments of the present invention, the
needle 104 may be positioned in a horizontal plane of the fluidic
substrate 101 wherein the needle 104 is positioned on a sidewall of
the fluidic substrate 101. The needle 104 may be a protruding
portion of a sidewall of the fluidic substrate 101. According to a
different embodiment, the needle 104 may be positioned on a
horizontal plane of the fluidic substrate 101 wherein the needle is
positioned perpendicular on a major surface of the fluidic
substrate 101. According to embodiments of the present invention,
the needle 104 may feature an open channel connected to the
micro-fluidic component 102, wherein, in use, the skin tissue
functions as a side-wall of the needle 104 when skin tissue is
penetrated.
[0125] The sensing device 100 according to embodiments of the
present invention may be used by pressing skin tissue of a user
against the needle 104. When sufficient force is used, the needle
104 penetrates the skin tissue, allowing blood to enter the inner
fluidic channel 105 of the needle 104. The needle 104 comprises a
tip which is open to allow a fluid sample to enter the inner
fluidic channel 105. When the needle is sharp with a small outer
diameter (preferably smaller than 200 um) the penetration of the
skin tissue will not cause any discomfort to the user. As the inner
fluidic channel 105 of the needle 104 is connected to the
micro-fluidic component 102 of the fluidic substrate 101, blood may
enter the micro-fluidic component 102. Due to capillary force and
the suction provided by the aperture of the vacuum compartment,
blood will propagate through the micro-fluidic component 102.
[0126] FIG. 1 illustrates an embodiment of the fluidic substrate
101 with an integrated needle 104 (as part of the fluidic substrate
101), the needle having an inner fluidic channel 105 connected to a
micro-fluidic component 102. The micro-fluidic component 102 may
comprise: a sample pad 102a (which may have the functions of an
inlet in some embodiments of the present invention), a reagent
storage 102b, a one-time usage hermetic valve 102c, a first trigger
valve 102d, a mixer 102e, a delay line 102f, a second trigger valve
102g, an heater 102h and a wick 102i. The lid 103 of FIG. 2 may
function as a cover to close some or all fluidic components.
[0127] According to embodiments of the present invention, the
fluidic substrate 101 may comprise a cut-out 106 wherein the needle
104 is positioned in the cut-out 106. The cut-out 106 is a removed
part of the fluidic substrate 101 to offer mechanical protection
for the needle 104 which resides in the cut-out 106.
[0128] FIG. 5 illustrates a top view of an embodiment of the
present invention wherein the lid comprising a microchip 103 is
bonded to the fluidic substrate 101. FIG. 6 illustrates a top view
of an exemplary fluidic substrate 101 of an embodiment of the
present invention. FIG. 7 illustrates a side view of an embodiment
of the present invention wherein the lid comprising a microchip 103
is bonded to the fluidic substrate 101.
[0129] As illustrated in FIGS. 5, 6 and 7, the needle 104 is
located in a cut-out 106 of the fluidic substrate 101. The cut-out
106 protects the needle 104 from breaking e.g. when the sensing
device 100 is inserted in a slot of an external device, e.g. a
mobile device such as a smartphone, for instance for readout. The
sidewall of the fluidic substrate 101 may feature the cut-out 106.
The needle 104 may be positioned in the cut-out 106 to allow a user
to penetrate skin tissue when pressed firmly against the cut-out
106. As a further advantage, during fabrication, the needle 104 may
be fabricated while fabricating the cut-out 106. As a result, less
material is wasted as only the material for the cut-out 106,
excluding the material for the needle 104, needs to be removed. The
cut-out 106 and needle 104 may be fabricated using standard
semiconductor processing techniques.
[0130] According to embodiments of the present invention shown in
FIGS. 8, 9 and 10, the fluidic substrate 101 may comprise a
protection structure 107 for protecting the needle 104, removably
attached to the fluidic substrate 101. According to embodiments of
the present invention, the protection structure 107 may be attached
to the fluidic substrate 101 via at least one anchoring mechanism
108. The protection structure 107 may be detached by breaking the
at least one anchoring mechanism 108. The protection structure 107
may be part of the fluidic substrate 101 wherein the anchoring
mechanism 108 may be 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 a sensing device 100. As can be
seen in FIG. 9 (illustrated is a top view of an exemplary
embodiment of a fluidic substrate 101 for use in a sensing device
according to embodiments of the present invention, for instance a
sensing device as illustrated in FIG. 8), the protection structure
107 is part of the fluidic substrate 101 and features two anchoring
mechanisms 108 which allow detaching of the protection structure
107 from the fluidic substrate 101. FIG. 10 illustrates a side view
of the sensing device 100 of FIG. 8 or 9.
[0131] According to embodiments of the present invention shown in
FIGS. 25 and 26, the means for providing a fluid sample may be an
inlet 109. The inlet 109 may be an indentation in the fluidic
substrate 101 which is connected to the micro-fluidic component 102
by a fluidic channel. To use the sensing device, a user may deposit
a drop of bodily fluid such as blood or saliva on the inlet 109 of
the sensing device. Due to capillary force, the bodily fluid will
propagate through the micro-fluidic component 102.
[0132] FIG. 26 illustrates a de-assembled sensing device 100
according to embodiments of the present invention, comprising a
fluidic substrate 101 comprising an inlet 109 and a microfluidic
component 102, a lid comprising a microchip 103 and an package 110.
The package 110 may comprise a base and a top which can be
assembled together to package the fluidic substrate 101 and the lid
comprising a microchip 103, thus protecting these from
environmental influences such as dust. The package may comprise a
through-hole 260 for depositing a fluid sample on an inlet 109 of
the fluidic substrate 101. When all parts are assembled, the
sensing device 100 may function as a stand-alone wireless device
for analyzing a fluid sample.
[0133] According to embodiments of the present invention, at least
a part of the microchip 103 may be in contact with the fluid sample
when the fluid sample is present in the sensing device 100. When
the microchip 103 is a CMOS chip, electronic circuitry present on a
surface of the chip may be in direct contact with the fluid sample
when the microchip 103 is functioning as a side-wall of a
micro-fluidic component 102 in the fluidic substrate 101. In this
case, the side of the chip comprising electronic circuitry may be
bonded to a micro-fluidic component 102 of the fluidic substrate
101 wherein the electronic circuitry is aligned with parts of the
micro-fluidic component 102 where interaction with a fluid sample
is desired. As an advantage, this may improve the interaction
between the electronic circuitry and the fluid sample.
[0134] According to embodiments of the present invention, the lid 3
may comprise bonding layers to enable bonding of the lid 103 to the
fluidic substrate 101.
[0135] According to embodiments of the present invention, a first
side of the fluidic substrate 101 comprising a micro-fluidic
component 102 may be bonded to a first side of the CMOS chip 103
comprising at least one electrical component.
[0136] According to an embodiment, the lid 3 may comprise a
microchip 103 comprising a transistor layer, the transistor layer
being electrically connected at least one electrical component, the
electrical component being at least one of the following:
biosensing circuitry, 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 or
temperature cycling and fluid sensors and electrodes for fluidic
viscosity control. The circuitry for wireless data communication
may comprise provisions for communication via a Bluetooth radio or
a WiFi module for wirelessly transmitting data from electronic
circuitry in the lid 3. As an advantage, the sensing device 100 may
communicate with an external device such as a mobile device which
may be used to further process the data.
[0137] According to FIGS. 18, 19, 21 and 22, the CMOS chip may
comprise a silicon substrate 111, a transistor layer 112, at least
one electrical component electrically connected to the transistor
layer 112 and at least one bonding layer 115. The at least one
electrical component may be biosensing circuitry, 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.
[0138] A particular embodiment of a microchip 103 according to
embodiments of the present invention is illustrated in FIG. 18. In
this embodiment, the CMOS chip 103 comprises a silicon substrate
111. Atop the silicon substrate 111 a transistor layer 112 may be
present. Atop the transistor layer 112 an interconnection layer 113
may be present. Atop the transistor layer 112, at least one
electrical component may be present electrically connected to the
transistor layer 112 via the interconnection layer 113. The
interconnection layer 113 may comprise a plurality of metal layers.
According to embodiments of the present invention, atop the
transistor layer 112, a bonding layer 115 and at least one
electrode 114 may be present. The electrode 114 may be electrically
connected to the transistor layer via the interconnection layer
113.
[0139] According to embodiments of the present invention, the at
least one electrical component may be a biocompatible electrode
which is fluid corrosion free and chemically inert. According to a
specific embodiment, the at least one electrode 114 is TiN
electrode.
[0140] According to embodiments of the present invention the
bonding layer 115 may be a layer which allows bonding of the CMOS
chip 103 to the fluidic substrate 101 at low temperatures and
voltages. This is advantageous as these conditions do not damage
the CMOS chip, neither do they damage reagents or for instance
proteins which may be provided on the microfluidic substrate 101.
According to a specific embodiment, the bonding layer 115 may be a
SiO2 or polymer layer.
[0141] FIG. 19 illustrates a sensing device 100 according to
embodiments of the present invention, wherein a CMOS chip 103 as
illustrated in FIG. 18 is bonded to a fluidic substrate 101. The
side of the CMOS chip 103 comprising the bonding layer 115 and the
electrode 114 is bonded to the side of the fluidic substrate 101
comprising a micro-fluidic component 102. This means that the CMOS
chip 103 as illustrated in FIG. 18 is flipped upside down with
respect to its position as illustrated in FIG. 18. The electrode
114 is thereby in direct contact with a fluid sample present in the
micro-fluidic component 102. The bonding layer 115 is used to
attach the CMOS chip 103 to the fluidic substrate 101.
[0142] According to embodiments of the present invention, the CMOS
chip 103 may comprise at least one silicon I/O connection 116, as
illustrated in FIG. 20. The silicon I/O connection 116 may be a
backside opening through the substrate 111 to access electrical
signals of the CMOS chip 103 in the transistor layer 112. Further,
in yet alternative embodiments, the silicon I/O connection 116 may
be a backside opening through both the substrate 111 and the
transistor layer 112 to access electrical signals of the CMOS chip
103 in the interconnection layer 113. FIG. 20 illustrates the
sensing device 100 wherein a CMOS chip 103 is bonded to a fluidic
substrate 101 and wherein the CMOS chip 103 features a silicon I/O
connection 116 through both the substrate 111 and the transistor
layer 112.
[0143] According to embodiments of the present invention, the
fluidic substrate may comprise an open micro-fluidic component 102
and the fluidic substrate may be covered partly by the CMOS chip
103. It is advantageous that a part of the micro-fluidic component
102 is not covered as this allows reagents to be applied/spotted on
specific open parts of the micro-fluidic component 102. In this
case, no extra through-holes are needed to apply reagents after
bonding of the fluidic substrate 101 to the CMOS chip 103. It is
also advantageous that the CMOS chip area is smaller, as the active
electronics is the more expensive part of the disposable.
[0144] According to embodiments of the present invention, the CMOS
chip 103 may further comprise at least one I/O pad 117. The at
least one I/O pad 117 may be located on the interconnection layer
113.
[0145] FIG. 21 illustrates an embodiment of a CMOS chip 103. The
CMOS chip 103 comprises a silicon substrate 111. Atop the silicon
substrate a transistor layer 112 is present. Atop the transistor
layer 112, an interconnection layer 113 is present. The
interconnection layer 113 may comprise a plurality of metal layers
to interconnect the transistor layer 112 with electrical
components. Atop the transistor layer 112, a bonding layer 115, an
I/O pad 117 and, in the embodiment illustrated, a plurality of
electrodes 114 are present. The electrodes 114 are electrically
connected to the transistor layer 112 via the interconnection layer
113. The I/O pad 117 is also electrically connected to the
transistor layer 112 via the interconnection layer 113.
[0146] According to embodiments of the present invention, a first
part of a first major surface of the CMOS chip 103 may cover the
fluidic substrate 101, a second part of the first major surface of
the CMOS chip 103 may not cover the fluidic substrate 101. In these
embodiments, the CMOS chip 103 may either be larger than the
fluidic substrate 101, or it may be laterally shifted with respect
to the fluidic substrate 101 so that a portion of the CMOS chip 103
forms an overhang with respect to the fluidic substrate 101. The
second part of the first major surface of the CMOS chip 103 may
comprise at least one I/O pad 117 to have access to the I/O pad
117.
[0147] FIG. 22 illustrates a CMOS chip 103 as illustrated in FIG.
21, bonded to a fluidic substrate 101. A first part of the CMOS
chip 103 at least partly, and in the embodiment illustrated fully
covers the fluidic substrate 101 wherein electrodes 114 are in
direct contact with a fluid sample when present in the
micro-fluidic component 102 of the sensing device 100. The bonding
layers 115 are used to bond a first part of the CMOS chip 103 to
the fluidic substrate 101. A second part of the CMOS chip 103 forms
an overhang which does not cover the fluidic substrate 101. The
second part comprises the I/O pad 117. As an advantage, this
overhang allows easy access to the I/O pad 117. This allows
standard I/O pad dimensions and packaging approaches to be used for
inserting the substrate in slots typically used for smartcards. It
is a further advantage that additional processing steps to
fabricate silicon I/O connections (e.g. a hole through the
substrate and transistor layer) to access electrical signals in the
CMOS chip 103 are not required.
[0148] According to embodiments of the present invention, the
fluidic substrate 101 further comprises at least one optical
waveguide to allow optical excitation and sensing of the fluid
sample when present in the sensing device 100.
[0149] According to embodiments of the present invention, the
fluidic substrate 101 or the microchip 103 comprises at least one
through-hole for application of a biochemical reagent to a region
of the micro-fluidic component 102 or to a region of the microchip
103. The through-holes in the fluidic substrate 101 or the
microchip 103 allow the application of biochemical reagents to
specific regions of the micro-fluidic component 102 or to specific
regions of the microchip 103. This is advantageous as it allows
reagents to be applied after attachment of the microchip 103 to the
fluidic substrate 101.
[0150] According to embodiments of the present invention, the CMOS
chip 103 may comprise at least one through-hole 118. When attached
to the fluidic substrate 101, the through hole 118 in the CMOS chip
103 allows reagent spotting on a specific location of the
micro-fluidic component 102 in the fluidic substrate 101 or on a
specific part of the CMOS chip 103. FIG. 23 illustrates such an
embodiment wherein the CMOS chip 103 comprises one through hole
118. In this embodiment, the CMOS chip further comprises a silicon
I/O connection 116. As illustrated, the CMOS chip 103 completely
covers a part of the fluidic substrate 101.
[0151] According to same or alternative embodiments of the present
invention, a first side of the fluidic substrate 101 comprises the
micro-fluidic component 102. The other side, opposite to the side
where the micro-fluidic component 102 is provided, may comprise a
at least one through hole 119. The through hole 119 allows reagent
spotting on a specific location of the micro-fluidic component 102
in the fluidic substrate 101 or on a specific part of the CMOS chip
103. FIG. 24 illustrates such an embodiment wherein the fluidic
substrate comprises two through holes 119. A part of the CMOS chip
103 covers the fluidic substrate 101, the part not covering the
fluidic substrate 101 but forming an overhang comprises an I/O pad
117.
[0152] According to embodiments of the present invention, the lid
comprising the microchip 103 may be bonded to the fluidic substrate
101 using a polymer, which may preferably be a lithographically
patterned polymer. The material for forming the bonding between the
microchip 103 and the fluidic substrate 101 should be suitable for
perform a Si--Si bonding, preferably at low temperature, for
instance room temperature. This is compatible with CMOS circuits
being present on the lid 103 and which should not be destroyed by
the bonding process, and with reagents being present on or in the
fluidic substrate 101, and which should also not be destroyed by
the bonding process. Suitable bonding materials for bonding the
microchip 103 to the fluidic substrate 101 are for instance
photopatternable PDMS, obtainable from Dow Corning; SU8, obtainable
from Micr Chem; or OSTE, obtainable from Mercene Labs. These
bonding materials all have room temperature as bonding
temperature.
[0153] According to another embodiment of the present invention,
the lid 103 is bonded to fluidic substrate 101 using a CMOS
compatible packaging technique. The use of CMOS packaging
techniques may be used when the fluidic substrate 101 is a
semiconductor substrate and the lid 103 is a microchip 103, e.g. a
CMOS chip.
[0154] According to embodiments of the present invention, the
device 100 may further comprise metal contacts electrically
connected to the microchip 103 for read-out of electrical signals
from the microchip 103. The metal contacts may be located on the
lid 3, electrically connected to electronic circuitry in the lid
103. The position and shape of the metal contacts may be selected
according to standards, allowing insertion of the sensing device in
standardized slots such as slots for memory cards (e.g.
CompactFlash, SmartMedia, MultiMedia Card or Secure Digital (SD)
memory cards) commonly used in communication devices such as mobile
devices. The insertion of the sensing device 100 in an mobile
device allows processing of the electrical signals from the
microchip 103 by a processor and/or other electronic components
present in the mobile device. For example, a processor of a
smartphone may be used to process electrical signals and/or to
display data. Further, the sensing device features a data
communication interface for sending data, e.g. via custom or
standard interfaces like wired interfaces such USB or via wireless
communication such NFC or Bluetooth, to a sensing device, personal
computer, a computing unit, smartphone. The sensing device may
function as a smartcard for use in communication devices, or as a
stand-alone system, or a system wherein a power interface such as a
battery powers electronic circuitry such as a micro-chip in the
sensing device. Alternatively, the sensing device may be powered
via a communication port of the sensing device.
[0155] FIG. 33 illustrates a sensing device 100 according to
embodiments of the present invention, where a fluidic substrate 101
and a microchip 103 are bonded to one another. The fluidic
substrate 101 comprises different microfluidic components for
multi-omic analysis, in the embodiment illustrated comprising a
plurality of chambers 330, 331, 332, 333 and microfluidic channels
(not illustrated). The chambers may have different depths,
depending on their function and the type of measurement being
performed. One or more chambers may act as vacuum compartments. The
chambers may be separated by valves that may be actuated in any
suitable way, for instance by fluidic forces or by electricity. The
membrane or valve separating the vacuum compartments from the
microfluidic channels may be opened by any suitable way as
discussed, such as mechanical action, seal breaking, valve opening,
heating, etc. Electrodes for actuation may be provided on the
fluidic substrate 101 or on the microchip 103. The CMOS chip
forming the lid 3 may thus incorporate different functionalities
(e.g. microscopic imager 334 comprising pixels, optical detectors
335, 336 comprising resonators and waveguides 339, and circuitry
337 for heating and/or sensing, filters for e.g. fluorescence,
etc). The CMOS microscopic imager 334 may comprise CMOS active
pixels for readout of optical signals from the fluid sample in the
microfluidic component 102. The CMOS optical detector 335 comprises
an optical resonator 338. A waveguide 339 may be present for
transporting measurement light from one location of the CMOS chip
103 to another location. The waveguide may for instance be used for
irradiating the sample for performing lensfree microscopy.
Furthermore, filters may be provided in the fluidic substrate 101
or in the microchip 103 for rejecting optical excitation from
emission, so as to enable measurement of a fluorescent signal. Also
multispectral filters may be provided in the fluidic substrate 101
or in the lid, for measurement fluorescent signals with multiple
colours.
[0156] This way, detection of different types of markers can be
performed within a single, preferably disposable, sensing device
according to embodiments of the present invention.
[0157] According to embodiments of the present invention, the shape
of the sensing device 100 allows insertion into a mobile
communication device. According to embodiments of the present
invention, the sensing device 100 has the shape/dimensions of a
memory card. It is an advantage of embodiments of the present
invention that the dimensions of the sensing device 100 may be
according to standards, e.g. according to standards of memory cards
used in mobile devices such as: CompactFlash, SmartMedia,
MultiMedia Card, Secure Digital memory cards or any other type. An
example of such embodiment can be seen in FIG. 31, in which a
needle 104 is present. Metal contacts of the SD card may allow
direct readout.
[0158] According to embodiments of the present invention, at least
a part of the fluidic substrate 101 and/or the lid 3 may be
fabricated from a transparent material to allow optical inspection
of a fluid sample when the fluid sample is present in the
micro-fluidic component 102. The part of the fluidic substrate 101
that is fabricated from a transparent material may be part of the
micro-fluidic component 102 of the sensing device 100. The
transparent part may be a side-wall of the micro-fluidic component
102 of the sensing device 100. The transparent material allows
optical inspection of a fluid sample in the sensing device 100. An
optical detector may be used to optically inspect a fluid sample,
in order for instance to detect an analyte. The optical detector
may be an image sensor which may be part of an external device or
may be integrated in the sensing device 100. The transparent
material may be a transparent oxide or polymer. For microscopy
purposes, a part of the lid 103 or a part of the fluidic substrate
101 may be transparent. For lens-free imaging purposes, a part of
the lid 103 and a part of the fluidic substrate 101 may be
transparent to enable working in transmission mode wherein a
radiation source may be used to radiate an object in a fluid sample
in the sensing device 100 through the transparent part of the lid
103 and a detector may be used to detect signals from the radiated
object through the transparent part of the fluidic substrate 101.
The signals may be diffraction patterns of a radiated object in the
fluid sample.
[0159] FIGS. 31 and 32 illustrate an embodiment of the present
invention wherein the sensing device 100 has the shape of an SD
card. Inside the cut-out 106 (which is always present according to
SD card standards), a needle 104 is present. At the other side of
the SD card, the metal contacts are present and electrically
connected to the microchip 103 to allow read-out of electrical
signals from the microchip 103 which may be further processed by
the device in which the SD card is inserted.
[0160] According to embodiments of the present invention, the lid 3
or the fluidic substrate 101 may further comprise a compartment for
powering the sensing device 100, such as a battery compartment (not
illustrated) which is electrically connected to the lid 3.
[0161] According to another aspect, the relates to a method to
fabricate a sensing device 100 as disclosed in other aspects of the
present invention. The method comprises: providing a fluidic
substrate 101; providing a lid 3; attaching the fluidic substrate
101 to the lid 3 to close the fluidic substrate 101 at least
partly; characterized in that: the fluidic substrate 101 is a
silicon fluidic substrate and the lid 3 comprises a CMOS chip; and
wherein the fluidic substrate 101 is attached to the lid 3 using a
CMOS compatible bonding process.
[0162] It is advantageous that the fluidic substrate 101 is bonded
to the lid 3 using a CMOS compatible bonding process. In state of
the art devices, bonding is performed using high
temperature/voltage bonding techniques. These bonding techniques
may damage electronic circuitry present in the CMOS chip and/or
reagents present in the microfluidic substrate 101. The use of a
CMOS compatible bonding enables bonding at lower
temperatures/voltages and therefore preserves the electronic
circuitry of the microchip 103 and the reagents present in the
microfluidic substrate 101. According to embodiments of the present
invention, the bonding may be performed via a wafer to wafer or die
to wafer bonding process such as direct oxide to oxide bonding or
bonding via a pattern-able polymer. Additionally, it can also be
advantageous to be able to perform the bonding at a low temperature
in case some reagents are already spotted on one of the substrates
during the fabrication flow.
[0163] The fluidic substrate 101 may be fabricated using a
combination of coarse and fine structures in a single piece of
silicon substrate by a combination of two hard masks, protection
and de-protection of layers, etching of coarse and etching of fine
structures. The fine structures may be structures configured to
enable a controlled capillary suction in the micro-fluidic
component 102 of the sensing device 100.
[0164] The fine structures may comprise micro-pillars 270 and/or
other microstructures. The coarse structures may be structures for
storing larger volumes of fluids e.g. reagent storage 102b for
storing reagents, or a wick 102i. It is an advantage to use silicon
since the very high anisotropic etching of silicon results in fine
structures with extremely high aspect ratios. The silicon
micro-pillars 270 typically have lateral dimensions from 1 um to 20
um with aspect ratios of 20-50. High aspect ratios are advantageous
in having a high surface to volume ratio, essential for capillary
flow. The high aspect ratio fine structures, combined with the
coarse structures allow to implement more complex capillary fluidic
functions in a more compact footprint than is achievable with any
other material. More complex functions include separation (e.g.
cells from molecules), mixing, valving, thermally controlled
reactions, . . . Moreover, silicon is an inert material with clear
advantages towards implementation of biochemical reactions. The
advantage of the extremely compact fully integrated disposable
device results from the advanced use of silicon for both the
fluidic substrate and the CMOS lid. The reduced footprint also
results in reduced cost of the entire sensing device.
[0165] According to embodiments of the present invention, providing
a fluidic substrate 101 comprises providing a silicon substrate
201, illustrated in FIG. 11, and patterning the silicon substrate
to form a micro-fluidic component 102 and a means for providing a
fluid sample in the sensing device 100, the micro-fluidic component
102 being configured to propagate a fluid sample via capillary
force through the sensing device 100.
[0166] According to embodiments of the present invention, providing
a fluidic substrate 101 comprises: providing a silicon substrate
201, providing an oxide mask 202, patterning the oxide mask 202 by
using a first patternable mask layer 210, so as to create fine
structures 203 in the oxide mask 202 (FIG. 12);
[0167] providing a protection layer 204 to protect the patterned
oxide mask; patterning coarse structures in a second patternable
mask layer 211 (FIG. 13); etching of the coarse structures 205 in
the silicon substrate 201 through the second mask layer 211 (FIG.
14); removing the second mask layer 211 and growing oxide 206 (FIG.
15) for protecting the coarse structures 205; removing the
protection layer 204 (FIG. 16) and etching the fine structures 203
using the oxide layer 206 as an etch mask (FIG. 16); removing the
oxide 206 (FIG. 17). The resulting structure is a microfluidic
substrate 101 which may be used in a sensing device according to
embodiments of an aspect of the present invention.
[0168] FIG. 11-17 illustrate how the fluidic substrate 101 may be
fabricated. According to embodiments of the present invention, the
fluidic substrate 101 may be fabricated by performing: [0169]
Patterning fine structures 203 comprising: providing a silicon
substrate 201, providing an oxide mask 202, patterning the oxide
mask 202 to create fine structures 203 in the oxide mask 202;
[0170] providing a protection layer 204 to protect the oxide 202;
[0171] performing lithography of coarse structures 205; [0172]
performing etching of the coarse structures 205; [0173] growing
oxide 206 for protecting the coarse structures 205 wherein the
protection layer 204 on the fine structures 203 prevents oxide
growth; [0174] removing the protection layer 204 and etch the fine
structures 203; [0175] removing the oxide 206.
[0176] According to embodiments of the present invention, the
protection layer 204 may be a nitride layer.
[0177] One or more of the coarse structures may be hermetically
closed with a sacrificial element (such as a membrane) under
pressure, thereby providing a vacuum chamber. A mechanism for
opening the chamber may optionally be provided in the manufacture
process of a device according to the present invention.
[0178] According to embodiments of the present invention, providing
the CMOS chip 103 comprises: providing a silicon substrate 111,
fabricating a transistor layer 112 atop the silicon substrate and
providing an interconnection layer 113 atop the transistor layer.
The interconnection layer may comprise at least one metal layer.
The CMOS chip 103 is fabricated using standard CMOS process
techniques.
[0179] Further, on top of standard CMOS process flows, additional
components may be deposited or patterned on the interconnection
layer 113 such as biocompatible electrodes, a bonding layer, I/O
pads or other components.
[0180] According to embodiments of the present invention, through
holes 109, 118 may be etched through the fluidic substrate 101 or
the CMOS chip 103 to enable fluidic access for applying of reagents
to the fluidic substrate 101 or CMOS chip 103. The through-holes in
the CMOS chip 103 may be fabricated whilst fabricating silicon I/O
interconnections 116 in the CMOS chip 103. The through-holes in the
fluidic substrate 101 may be fabricated by first thinning the
fluidic substrate 101 and then etching the through-holes.
[0181] According to embodiments of the present invention, the CMOS
chip 103 may be bonded to the fluidic substrate 101 using a die to
wafer or wafer to wafer bonding process.
[0182] To access electrical signals of the CMOS chip 103, silicon
I/O contacts 116 may be provided. According to embodiments of the
present invention, the contacts may be fabricated by thinning the
silicon substrate 111 of the CMOS chip 103 and performing a back
side etching on the silicon substrate 111 to gain access to a metal
layer of the interconnection layer 113.
[0183] Alternatively, a CMOS chip 103 comprising an I/O pad 117 at
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 wherein the first side of the CMOS chip 103 comprising the I/O
pad 117 does not cover the fluidic substrate 101. This is for
example illustrated in FIG. 22. The I/O pad 117 is accessible when
the CMOS chip 103 is bonded to the fluidic substrate 101. The I/O
pad 117 may be used as a metal contact on a memory card.
[0184] According to embodiments of the present invention, the CMOS
chip 103 is bonded to the fluidic substrate 101 while aligning at
least one electrical component on a first side of a CMOS chip 103
with the micro-fluidic component 102. For example, sensing and
actuating electrodes on the first side of the CMOS chip 103 are
aligned with a sensing or actuation side in the fluidic substrate
101. This allows direct contact of a fluid sample with electrical
components present on the CMOS chip 103 when a fluid sample is
present in the sensing device 100.
[0185] According to embodiments of the present invention, surfaces
of the fluidic substrate 101 and the lid 3 are partially or fully
coated to modify surface interactions with the fluid sample. The
surfaces may be inner surfaces of the micro-fluidic component 102
or a surface of the CMOS chip 103 that is bonded to the fluidic
substrate 101. In particular those parts of the surface of the CMOS
chip 103 that are in contact with a fluid sample present in the
micro-fluidic component 102. The coating may be a hydrophilic
coating.
[0186] The surfaces of the micro-fluidic component 102 and/or the
side of the CMOS chip 103 bonded to the fluidic substrate 101 can
be made hydrophilic in order to improve the wetting behavior of the
surfaces, thereby promoting capillary flow. The surfaces can also
be treated in order to avoid absorption or adhesion of biomolecules
on the walls. The coating can be done for example by vapor coating
with silanes. According to embodiments of the present invention the
coating may be performed locally on certain parts of the fluidic
substrate 101 (e.g. in some micro-fluidic channels) or on certain
parts of the CMOS chip 103.
[0187] According to embodiments of the present invention, at least
one through-hole is fabricated in the fluidic substrate 101 by
first etching the through-hole and then filling the through-holes
with a transparent oxide of polymer.
[0188] Embodiments of the present invention improve the
functionality, portability and manufacturability of compact
disposable point of care devices. A particular embodiment of the
present invention is a fully integrated silicon device with a
needle or an inlet for the intake of blood or any other body fluid.
The sensing device features a capillary fluidic system for the
propagation of a fluid sample through the sensing device via
capillary action. A capillary pump functioning as the wicking zone
of the capillary fluidic system may be used to propagate the fluid
sample in the sensing device. A sensor chip reading out signals
produced by biochemical sensing reactions inside the capillary
system may be used to add biosensing functionality to the sensing
device. Further, the sensing device features a data communication
interface for sending data to a personal computer, a computing
unit, smartphone or any other wireless communication sensing
device. The sensing device may function as a stand-alone system
wherein a power interface such as a battery powers electronic
circuitry such as a micro-chip in the sensing device.
Alternatively, the sensing device may be powered via a
communication port of the sensing device.
[0189] The sensing device may further comprise fluidic manipulation
structures including filtering, mixing, valves structures. A
protection structure with a cut off zone to protect and prevent
breaking the needle before usage may be present to avoiding
contamination before usage. Structures such as electrically
controllable fluidic manipulation structures including
electrowetting, electro and dielectrophoretic manipulation may be
present to interact with a fluid sample in the sensing device.
Electronic controllable heaters may be present for accurately
controlling the temperature of the chip or for thermal cycling
purposes.
[0190] Another exemplary embodiment of the present invention
includes a low cost and compact manner to fabricate all of the
above functions by providing a semiconductor substrate (e.g.
silicon substrate) which may comprise lithographically defined
channels, micro-pillars and microstructures of various shapes
fabricated by deep Reactive Ion Etching and designed to function as
a capillary fluidic platform. The silicon substrate may have a
provision for making a needle and a cut off zone for protecting the
needle. The silicon substrate can have different etch depths
allowing for precise control over the volume and capillary flow of
a fluid sample in the sensing device. The silicon substrate may be
closed by a CMOS substrate (=lid 103) comprising CMOS electronics
containing a transistor layer. The electronics may be designed to
provide functionality including sensing, actuating, signaling, data
processing and data communication and therefore replaces the point
of care instrument. Some of the electrodes may be in direct contact
with the fluid, these electrode may be protected in a fluid
compatible manner. The silicon substrate may be closed by the CMOS
substrate by bonding both substrates in a leakage free and
biocompatible manner. This can be done via a wafer to wafer or die
to wafer bonding process such as bonding via a patternable polymer.
The inner silicon substrate surfaces which may be in contact with
the body fluids may feature a hydrophilic layer via coating of the
inner channels. Additionally, through wafer holes may be fabricated
in the silicon substrate for supplying reagents after the sensing
device has been 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 the
through-holes in the last production step. The through holes may be
sealed when obtaining the sample via the inlet and propagating it
through the microfluidic component. The sensing device may be
manufactured using CMOS compatible processing steps which lower
production cost and enable the sensing device to be used as
disposable device.
[0191] Further, the sensing device may comprise components to
enable interfacing with standard user interfaces. For example, the
use of such a sensing device as a smartcard in wireless
communication devices inserted in slots typically foreseen for
smartcards. For example, the use of such a sensing device together
with a compact and cheap battery and low cost communication device
(e.g. Bluetooth, NFC). For example, the use of such a sensing
device together with a wired communication interface (e.g.
USB).
[0192] Embodiments of the present invention may be used to detect
DNA/RNA from body fluids and perform an analysis to detect:
mutations (ancestry, drug dosing, disease predisposition), miRNA
(marker for cancer and other diseases), pathogen DNA/RNA
(infectious diseases such as HepC, HIV, etc.), microbiome DNA.
Further, the sensing device may be used to detect proteins such as
biomarkers for a specific disease (cancer, Alzheimer's, infectious
diseases, heart disease, cancer etc.) Further, the sensing device
may be used to detect small molecules and metabolites to reveal
metabolic information (cholesterol). Further, the sensing device
may be used to detect biomarkers from exosomes. Further the sensing
device may be used to perform microscopy to perform a blood count,
analyze cells present in the blood (e.g. circulating tumour cells),
identify infectious agents (e.g. malaria) and to detect blood
disorders (e.g. sickle cell anemia).
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