U.S. patent application number 12/293581 was filed with the patent office on 2010-06-24 for microelectronic device with heating electrodes.
This patent application is currently assigned to KONINKLIJKE PHILIPS ELECTRONICS N.V.. Invention is credited to David Andrew Fish, Murray Fulton Gillies, Mark Thomas Johnson, Marc Wilhelmus Gijsbert Ponjee.
Application Number | 20100156444 12/293581 |
Document ID | / |
Family ID | 38080858 |
Filed Date | 2010-06-24 |
United States Patent
Application |
20100156444 |
Kind Code |
A1 |
Ponjee; Marc Wilhelmus Gijsbert ;
et al. |
June 24, 2010 |
MICROELECTRONIC DEVICE WITH HEATING ELECTRODES
Abstract
The invention relates to different designs of a microelectronic
device comprising heating electrodes (HE) and field electrodes (FE)
that have effect in the same sub-region of a sample chamber. By
applying appropriate voltages to the field electrodes (FE), an
electrical field (E) can be generated in the sample chamber. By
applying appropriate currents to the heating electrodes (HE), the
sample chamber can be heated according to a desired temperature
profile. The heating electrodes (HE) may optionally be operated as
field electrodes such that they generate an electrical field in the
sample chamber, too.
Inventors: |
Ponjee; Marc Wilhelmus
Gijsbert; (Eindhoven, NL) ; Gillies; Murray
Fulton; (Eindhoven, NL) ; Johnson; Mark Thomas;
(Eindhoven, NL) ; Fish; David Andrew; (Haywards
Heath, GB) |
Correspondence
Address: |
PHILIPS INTELLECTUAL PROPERTY & STANDARDS
P.O. BOX 3001
BRIARCLIFF MANOR
NY
10510
US
|
Assignee: |
KONINKLIJKE PHILIPS ELECTRONICS
N.V.
EINDHOVEN
NL
|
Family ID: |
38080858 |
Appl. No.: |
12/293581 |
Filed: |
March 19, 2007 |
PCT Filed: |
March 19, 2007 |
PCT NO: |
PCT/IB07/50943 |
371 Date: |
September 19, 2008 |
Current U.S.
Class: |
324/703 |
Current CPC
Class: |
B01L 2400/0406 20130101;
B01L 3/5027 20130101; B01L 3/502792 20130101; B01L 7/52 20130101;
B01L 2300/1883 20130101; B01L 2300/0816 20130101; B01L 2300/0819
20130101; B01L 2300/0645 20130101; B01L 2200/147 20130101; B01L
2400/0442 20130101; B01L 2300/1827 20130101; B01L 2400/0448
20130101; B01L 2400/0415 20130101; B01L 3/50273 20130101 |
Class at
Publication: |
324/703 |
International
Class: |
G01R 27/08 20060101
G01R027/08 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 21, 2006 |
EP |
06111438.5 |
Mar 21, 2006 |
EP |
06111439.3 |
Mar 21, 2006 |
EP |
06111442.7 |
Claims
1. A microelectronic device for manipulating a sample, comprising:
a) a sample chamber; b) at least one heating electrode for
exchanging heat with at least a sub-region of the sample chamber
when being driven with electrical energy; c) at least one field
electrode for generating an electrical field in said sub-region of
the sample chamber when an electrical potential is applied to it;
d) a control unit for selectively driving the electrodes.
2. The microelectronic device according to claim 1, characterized
in that the heating electrode is disposed in a first layer, called
"heating layer", and the field electrode is disposed in a second
layer, called "field layer", said layers being arranged one upon
the other adjacent to the sample chamber.
3. The microelectronic device according to claim 2, characterized
in that the field layer is disposed between the sample chamber and
the heating layer.
4. The microelectronic device according to claim 2, characterized
in that the heating layer and the field layer each comprise a
plurality of heating electrodes and field electrodes, respectively,
wherein the electrodes of different layers are preferably aligned
with respect to each other.
5. The microelectronic device according to claim 4, characterized
in that the field electrodes are at least partially disposed above
gaps between the heating electrodes.
6. The microelectronic device according to claim 4, characterized
in that the field electrodes are at least partially disposed above
the heating electrodes.
7. The microelectronic device according to claim 4, characterized
in that the field electrodes are at least partially arranged at an
angle, preferably a right angle, to the heating electrodes.
8. The microelectronic device according to claim 1, characterized
in that it comprises an array of heating electrodes.
9. The microelectronic device according to claim 8, characterized
in that the control unit is located outside the array and connected
to the heating electrodes by power lines for selectively carrying
electrical energy.
10. The microelectronic device according to claim 9, characterized
in that the control unit comprises a de-multiplexer for coupling it
to the power lines.
11. The microelectronic device according to claim 8, characterized
in that each heating electrode is associated with a local driving
unit.
12. The microelectronic device according to claim 11, characterized
in that all local driving units are coupled to a common power line
and that all heating elements are coupled to another common power
line.
13. The microelectronic device according to claim 8, characterized
in that a part of the control unit is located outside the array and
connected to local driving units, which are located at and coupled
to the heating electrodes, via control lines for carrying control
signals.
14. The microelectronic device according to claim 13, characterized
in that control signals are pulse-width modulated, pulse-amplitude
modulated, and/or pulse frequency modulated.
15. The microelectronic device according to claim 13, characterized
in that the local driving units comprise a memory for storing the
information of the control signals.
16. The microelectronic device according to claim 1, characterized
in that the field electrode is a bi-functional electrode, which can
by definition also be operated like a heating electrode.
17. The microelectronic device according to claim 16, characterized
in that it comprises several field electrodes which all are
bi-functional electrodes.
18. The microelectronic device according to claim 16, characterized
in that the control unit is adapted to drive the bi-functional
electrode simultaneously and/or sequentially like a field electrode
and like a heating electrode.
19. The microelectronic device according to claim 16, characterized
in that the bi-functional electrode is connected with one pole to a
first potential and, via a switch controlled by the control unit,
with its second pole to a distinct second potential.
20. The microelectronic device according to claim 1, characterized
in that it comprises at least two field electrodes which commonly
generate an electrical field in said sub-region of the sample
chamber when an electrical voltage is applied between them.
21-48. (canceled)
Description
FIELD OF THE INVENTION
[0001] The invention relates to a microelectronic device for
manipulating a sample, comprising a sample chamber and at least one
heating or mixing electrode. Moreover, it relates to the use of
such a microelectronic device as a biosensor.
[0002] Biosensors often need a well controlled temperature to
operate, for example because many biomolecules are only stable in a
small temperature window (usually around 37.degree. C.) or become
de-activated when temperatures are outside of this temperature
window. Temperature regulation is especially of high importance for
hybridization assays. In these assays temperature is often used to
regulate stringency of the binding of a DNA strand to its
complementary strand. A high stringency is required when for
instance single point mutations are of interest. Melting
temperature ranges (i.e. denaturing of DNA strands) for single
point mutation hybridizations can differ by less than 5.degree. C.
as compared to the wild types. A control over stringency during
hybridization can give extra flexibility to especially
multi-parameter testing of DNA hybridization, for example on a DNA
micro-array. In these assays one also wants to ramp up temperature
in a well controlled way to distinguish between mutations in a
multiplexed format.
[0003] In the U.S. Pat. No. 6,864,140 B2, some of the
aforementioned problems are addressed by local heating elements in
the form of a thin film transistor formed on polycrystalline
silicon on a substrate adjacent to a sample chamber where
(bio-)chemical reactions take place. A further manipulation of the
sample in the sample chamber is however not possible with this
known device. Moreover, the U.S. Pat. No. 6,876,048 B2 discloses a
microelectronic biosensor in which a microchip with an array of
sensor elements is disposed on a membrane with heating elements.
The membrane allows to control the temperature in an adjacent
sample chamber in the same way for all sensor elements.
BACKGROUND OF THE INVENTION
[0004] Based on this situation it was an object of the present
invention to provide means for a more versatile manipulation of a
sample in a microelectronic device.
[0005] This objective is achieved by a microelectronic device
according to claim 1 and a use according to claim 48. Preferred
embodiments are disclosed in the dependent claims.
[0006] The microelectronic device according to a first aspect of
the present invention is intended for the manipulation of a sample,
particularly a liquid or gaseous chemical substance like a
biological body fluid which may contain particles. The term
"manipulation" shall denote any interaction with said sample, for
example measuring characteristic quantities of the sample,
investigating its properties, processing it mechanically or
chemically or the like. The microelectronic device comprises the
following components:
a) A sample chamber in which the sample to be manipulated can be
provided. The sample chamber is typically an empty cavity or a
cavity filled with some substance like a gel that may absorb a
sample substance; it may be an open cavity, a closed cavity, or a
cavity connected to other cavities by fluid connection channels. b)
At least one heating electrode for exchanging heat with at least a
sub-region of the sample chamber when being driven with electrical
energy. As the name "heating electrode" indicates, the electrode
preferably converts electrical energy into heat that is transported
into the sample chamber. It is however also possible that the
heating electrode absorbs heat from the sample chamber and
transfers it to somewhere else under consumption of electrical
energy. c) At least one field electrode for generating an
electrical field in said sub-region of the sample chamber when an
electrical potential is applied to said field electrode. d) A
control unit for selectively driving the heating electrode and the
field electrode, i.e. for supplying electrical energy to the
heating electrode and for applying a potential to the field
electrode.
[0007] It should be noted that the existence of an "electrical
field in a sub-region of the sample chamber" or a "heat exchange
with a sub-region of the sample chamber" is assumed if such a
field/exchange is strong enough in the sub-region to provoke
desired/observable reactions of the sample to be manipulated. This
definition shall exclude small "parasitic" electrical fields and
thermal effects that are inevitably associated with any (moving)
electrical charge in the electrodes. Typically, a heat flow in the
sense of the present invention is larger than 0.01 W/cm.sup.2 and
will have a duration in excess of 1 millisecond, and the strength
of electrical fields in the sense of the present invention is
larger than 1000 V/m.
[0008] The aforementioned microelectronic device has the advantage
that the same sub-region of the sample chamber can be
temperature-controlled via the heating electrode and subjected to
an electrical field by which a sample in said sub-region can be
manipulated in desired ways (e.g. inducing flow of a fluid and/or
movement of particles).
A. Electrode Layers
[0009] In the following, embodiments of the microelectronic device
according to the first aspect of the invention are described that
are all based on an arrangement of the electrodes in layers.
[0010] More particularly, in these embodiments the heating
electrode is disposed in a first layer, which will be called
"heating layer" in the following, and the field electrode is
disposed in a second layer, which will be called "field layer" in
the following, wherein said layers are arranged one upon the other
and adjacent to the sample chamber. The arrangement of the heating
and the field electrodes in different, stacked layers has the
advantage that each type of electrode can be designed in its
optimal layout, for example with optimal distances between
neighboring electrodes. The layers are geometrically
two-dimensional and may be planar or optionally have a
three-dimensional shape.
[0011] In the aforementioned embodiment, the field layer is
preferably disposed between the sample chamber and the heating
layer. Thus it will be as close as possible to the sample chamber,
which guarantees that a maximal strength/gradient of the electrical
field can be achieved there.
[0012] In another embodiment, the heating layer comprises a
plurality of heating electrodes and the field layer comprises a
plurality of field electrodes, wherein the electrodes of these
different two layers are preferably aligned with respect to each
other. Due to said alignment, the heating and the field electrodes
interact similarly at different locations, thus providing
uniform/periodic conditions across the area of the layers.
[0013] The aforementioned alignment may optionally comprise the
situation that the field electrodes are at least partially disposed
above the gaps between the heating electrodes. Here and in the
following, the term "above" relates to an arbitrarily chosen
orientation in which the field layer is vertically above the
heating layer. Moreover, the term "partially" means that this
positioning above the gaps may only be true for some (but not for
all) field electrodes and/or that this condition holds only for a
part of a field electrode but not the whole electrode.
[0014] Another kind of alignment may comprise the situation that
the field electrodes are at least partially disposed above the
heating electrodes. This design may be combined with the
aforementioned design if for example some field electrodes are
located above gaps and some above heating electrodes, or if a part
of a field electrode is located above a gap and the rest above a
heating electrode.
[0015] While the aforementioned two embodiments imply that the
field electrodes run at least partially parallel to the heating
electrodes, another embodiment comprises that the field electrodes
are at least partially arranged at an angle to the heating
electrodes. Preferably said angle is a right angle of 90.degree.,
i.e. the field electrodes run orthogonally to the heating
electrodes.
B. Array of Heating Electrodes
[0016] In the following, embodiments of the microelectronic device
according to the first aspect of the invention will be discussed
that are based on the existence of an array of heating electrodes.
It should be noted that analog embodiments can be realized mutatis
mutandis with an array of field electrodes. In the most general
sense, an "array of heating electrodes" simply denotes an arbitrary
three-dimensional arrangement of a plurality of heating electrodes.
Typically such an array is however two-dimensional and preferably
planar, and the heating electrodes are arranged in a regular
pattern, for example a grid or matrix pattern.
[0017] According to a preferred embodiment of the aforementioned
microelectronic device, the control unit is located outside the
array of heating electrodes and connected to the heating electrodes
by power lines that can selectively carry electrical energy to (or
from) the heating electrodes. As the amount or rate of transferred
electrical energy determines the extent to which heat is exchanged
with the sample chamber, the control unit has to allocate the
transferred electrical energy appropriately in order to achieve a
desired temperature profile in the sample chamber. The heating
array can be kept most simple in this approach because the heating
electrodes just have to convert electrical energy into heat without
further processing. The control unit is preferably adapted to drive
the heating electrodes such that a desired spatial and/or temporal
temperature profile is achieved in the sample chamber. This allows
to provide optimal (particularly non-uniform and/or dynamic)
conditions for the manipulation of e.g. a sensitive biological
sample.
[0018] In a further development of the aforementioned embodiment,
the control unit comprises a de-multiplexer for coupling the
control unit to the power lines. This allows to use one circuit for
providing several power lines (subsequently) with electrical
power.
[0019] In another realization of a microelectronic device with an
array of heating electrodes, each heating electrode is associated
with a local driving unit. Such local driving units can take over
certain control tasks and thus relieve the control unit and in
addition can increase the efficiency of the array by avoiding
leakage of driving currents between e.g. an external current source
and an array of heating electrodes.
[0020] According to a further development of the aforementioned
embodiment, said driving units are coupled to a common power supply
line, and the heating electrodes are coupled to another common
power supply line (e.g. ground). In this case the local driving
unit determines the amount of electrical energy or power that is
taken from the common power supply lines. This simplifies the
design insofar as properly allocated amounts of electrical energy
do not have to be transported through the whole array to a certain
heating electrode.
[0021] In another embodiment of the microelectronic device with an
array of heating electrodes, which may advantageously be combined
with the aforementioned design, a part of the control unit is
located outside the array of heating electrodes and connected via
control lines for carrying control signals to local driving units
(which constitute the residual part of the control unit). Said
local driving units are located at the heating electrodes and
coupled to them. In this case the mentioned outside part of the
control unit can determine how much electrical energy or power a
certain heating electrode shall receive; this energy/power needs
however not to be transferred directly from the outside control
unit to the heating electrode. Instead, only the associated
information has to be transferred via control signals to the local
driving units, which may then extract the needed energy/power from
common power supply lines.
[0022] In another realization of the aforementioned embodiment, the
control signals are pulse-width modulated (PWM). With such PWM
signals, the local driving units can be switched off or on with
selectable rate and duty cycle, wherein these parameters determine
the average power extraction from common power supply lines. The
individual characteristics of the local driving units are then less
critical as only an on/off behavior is required. It is also
possible to drive the heaters or field electrodes with pulse
amplitude modulation (PAM), pulse frequency modulation (PFM) or a
combination of modulation techniques.
[0023] In a further development of the aforementioned embodiments,
the local driving units comprise a memory for storing information
of control signals transmitted by the outside part of the control
unit. Such a memory may for example be realized by a capacitor that
stores the voltage of the control signals. The memory allows to
continue a commanded operation of a heating electrode while the
associated control line is disconnected again from the driving unit
and used to control other driving units.
C. Bi-Functional Electrode
[0024] In the following, embodiments of the microelectronic device
according to the first aspect of the invention will be discussed
that are based on field electrodes that can also be operated as
heating electrode. Due to this fact, such field electrodes will be
called "bi-functional electrodes" in the following.
[0025] Such a microelectronic device may comprise several
bi-functional electrodes. Preferably, all electrodes of the
microelectronic device are bi-functional electrodes, i.e. they may
be used for the generation of electrical fields as well as for a
heat exchange with the sample chamber.
[0026] The bi-functional electrode may by definition be operated as
a field electrode for generating an electrical field and as a
heating electrode for exchanging heat with the sample chamber. It
may particularly fulfill these two functions subsequently.
According to a preferred embodiment, the control unit is however
adapted to drive the bi-functional electrode simultaneously as a
field electrode and a heating electrode; the bi-functional
electrode will then at the same time generate an electrical field
and exchange heat with the sample chamber. Of course a mixed
operation is also possible in which the bi-functional electrode may
at times be operated exclusively as field electrode, exclusively as
heating electrode, or simultaneously as field and heating
electrode.
[0027] There are many different ways to realize a bi-functional
electrode. In a particular simple design, the bi-functional
electrode is connected with one pole to a first electrical
potential and, via a switch that is controlled by the control unit,
with its second pole to a distinct second electrical potential
(wherein an electrode is in general assumed to have two poles or
ends for connecting it to different electrical potentials). When
the switch is opened, the electrode floats at the first potential;
when the switch is closed, a current according to the difference
between the first and second potential will flow through the
electrode.
D. Miscellaneous Embodiments
[0028] In the following, several further particular embodiments of
the present invention will be described that can be realized in
connection with microelectronic devices according to the first
aspect of the invention.
[0029] Thus the microelectronic device may comprise at least two
field electrodes which commonly generate an electrical field in the
sub-region of the sample chamber when an electrical voltage is
applied between them. Using cooperating pairs of two field
electrodes allows a very precise control of the generated
electrical field.
[0030] It was already mentioned that the heating electrode is in
most cases capable of generating heat. In an optional embodiment,
the heating electrode may however also be adapted to remove heat
from the sample chamber. Such a removal may for example be achieved
by coupling the heating electrode to a heat sink or by cooling it
with a fan. In these cases, the heating electrode may internally
still generate heat, which is however less than the heat that it is
absorbed by the heat sink, thus resulting in a net absorption of
heat.
[0031] The heating electrode may particularly be realized by a
resistive strip, a transparent electrode, a Peltier element, a
radiofrequency heating electrode, or a radiative heating (IR)
element. All these elements can convert electrical energy into
heat, wherein the Peltier element can additionally absorb heat and
thus provide a cooling function.
[0032] The microelectronic device may optionally comprise at least
one temperature sensor which makes it possible to monitor the
temperature in the sample chamber. Preferably, the microfluidic
device comprises a plurality of temperature sensors. In another
preferred embodiment, said temperature sensor is comprised in the
heating layer. In a particular embodiment, the heating electrode
may be operated as a temperature sensor, which allows to measure
temperature without additional hardware.
[0033] In cases in which a temperature sensor is available, the
control unit is preferably coupled to said temperature sensor and
adapted to control the heating electrodes in a closed loop
according to a predetermined (temporal and/or spatial) temperature
profile in the sample chamber. This allows to provide robustly
optimal conditions for the manipulation of e.g. a sensitive
biological sample.
[0034] The microelectronic device may further comprise a
micromechanical device or an electrical device, for example a pump
or a valve, for controlling the flow of a fluid and/or the movement
of particles in the sample chamber. Controlling the flow of a
sample or of particles is a very important capability for a
versatile manipulation of samples in a microfluidic device.
[0035] In a particular embodiment, the heating electrode may be
adapted to create flow in a fluid in the sample chamber by a
thermo-capillary effect. Thus its heating capability can be
exploited for moving the sample.
[0036] Moreover, the field electrodes can be used to generate
movement of particles or liquid via AC or DC electro-osmosis,
electrophoresis, dielectrophoresis, electrohydrodynamics and/or a
combination of these effects. In the case of dielectrophoresis real
bio-particles in the sample maybe too small for manipulation and
therefore larger diameter particles with the desired electrical
properties may be added to the liquid to facilitate mixing.
[0037] The microelectronic device may optionally comprise a sensor
element, preferably an optical, magnetic or electrical sensor
element for sensing properties of a sample in the sample chamber. A
microelectronic device with magnetic sensor elements is for example
described in the WO 2005/010543 A1 and WO 2005/010542 A2. Said
device is used as a microfluidic biosensor for the detection of
biological molecules labeled with magnetic beads. It is provided
with an array of sensor units comprising wires for the generation
of a magnetic field and Giant Magneto Resistance devices (GMRs) for
the detection of stray fields generated by magnetized beads.
[0038] According to a preferred embodiment of the invention, the
microelectronic device comprises a "heating array" of several
heating electrodes and a "sensing array" of several sensor elements
(including the aforementioned sensor elements and/or temperature
sensors mentioned above), wherein the heating electrodes are
aligned with respect to the sensor elements. This "alignment" means
that there is a fixed (translation-invariant) relation between the
positions of the heating electrodes in the heating array and the
sensor elements in the sensing array; the heating and sensor
elements may for example be arranged in pairs, or each heating
electrode may be associated with a group of several sensor elements
(or vice versa). The alignment has the advantage that the heating
and sensor elements interact similarly at different locations. Thus
uniform/periodic conditions are provided across the arrays.
[0039] A preferred kind of alignment between the sensor and the
heating electrodes is achieved if the patterns of their arrangement
in the sensing array and the heating array, respectively, are
identical. In this case, each sensor element is associated with
just one heating electrode.
[0040] In an alternative embodiment, more than one heating
electrode is associated to each sensor element. This allows to
create a spatially non-uniform heating profile, which can result in
either a spatially non-uniform or a spatially uniform temperature
profile in the region of one sensor element and thus an even better
temperature control. Preferably, there is additionally an alignment
of the above mentioned kind between heating electrodes and sensor
elements.
[0041] If it is necessary or desired to have sub-regions of
different temperature in the sample chamber, this may optionally be
achieved by dividing the sample chamber with a heat insulation into
at least two compartments.
[0042] Between the sample chamber and the field electrodes, a
partially electrical isolating layer and/or a biocompatible layer
may be disposed. Such a layer may be a hydrogel material such as
polyacrylamide or polyimide.
[0043] Between the field and heater electrode layers an isolating
layer may be disposed. Such a layer may for example consist of
polyimide, silicon dioxide SiO.sub.2 or the photoresist SU8.
[0044] It was already mentioned that the heating electrodes and
field electrodes may be arranged in separate layers at one side of
the sample chamber. The heating electrode(s) and field electrode(s)
may however also be disposed on vertically opposing sides of the
sample chamber (including the case that there are additionally some
heating electrodes and field electrodes which are located at the
same side of the sample chamber).
[0045] The microelectronic device may particularly comprise a
plurality of field electrodes that are arranged parallel to each
other in a layer and that are connected to the control unit at
alternating ends. This means that one field electrode is connected
at its left end to the control unit, the next at its right end, the
next but one again at its left end and so on. This alternating
scheme provides at both sides a maximum of space to make the
connections.
[0046] The heating electrode and/or the field electrode may be
straight or non-straight (i.e. curved or bent). Examples of these
designs will be discussed with respect to the Figures in more
detail.
[0047] The electrodes may further be rectangular, tapered and/or
asymmetric in their shape and/or in their cross section. Tapered
field electrodes may for example be advantageous with respect to
the concentration of electric field lines.
[0048] Furthermore, the heating electrode and/or the field
electrode may consist of several parallel leads. These leads are
preferably connected at one end, thus forming a common pole of the
electrode.
[0049] Moreover, the field electrodes may optionally be arranged as
a quadrupole. Such a design may be advantageous for concentrating
particles at a certain focus-location of a sample.
[0050] The distance between neighboring field electrodes is
preferably less than 50 .mu.m, most preferably less than 10 .mu.m.
These distances allow to generate electrical fields of high
strength and gradient.
[0051] Moreover, the microelectronic device may comprise several
heating electrodes arranged in parallel, wherein the distance
between neighboring heating electrodes is larger than 50 .mu.m,
preferably larger than 100 .mu.m.
[0052] In a further embodiment of the invention, the control unit
is adapted to drive the heating electrode with an alternating
current of selectable intensity and/or frequency. The electrical
fields associated with such an operation of the heating electrodes
may in certain cases, for example in cases of dielectrophoresis,
generate a motion in the sample if they have an appropriate
intensity and frequency. On the other hand, the intensity and
frequency of the alternating current determines the average rate of
heat production. Thus it is possible to execute the heating and the
manipulation function of such an electrode simply by changing the
intensity and/or frequency of the applied current appropriately. In
particular at the cross-over frequency the dielectrophoretic force
is zero and so no particle movement will be induced. In essence
only heating will occur when this frequency of field is applied.
This is of particular interest if mixing particles have been added
as they have a well defined diameter and electrical properties and
thus also a well defined zero frequency.
[0053] The heating electrode(s) and/or field electrode(s) may
preferably be realized in thin film electronics.
[0054] In the following, some preferred embodiments will be
described which are based on a microelectronic device that
comprises a "heating array" with a plurality of heating electrodes
and/or a "field array" with a plurality of field electrodes,
wherein said arrays may optionally be merged.
[0055] When realizing such a device, a large area electronics (LAE)
matrix approach, preferably an active matrix approach may be used
in order to contact the electrodes. The technique of LAE, and
specifically active matrix technology using for example thin film
transistors (TFTs) is applied for example in the production of flat
panel displays such as LCDs, OLED and electrophoretic displays.
[0056] In the aforementioned embodiment, a line-at-a-time
addressing approach may be used to address the electrodes by the
control unit.
[0057] According to a further development of the microelectronic
device with arrays of heating and/or field electrodes, the
interface between the sample chamber and said arrays is chemically
coated in a pattern that corresponds to the patterns of the
electrodes. Thus the effect of the electrodes can be combined with
chemical effects.
[0058] In the aforementioned embodiment, binding molecules may for
example be attached to the interface at locations where a sample
substance can be trapped by electrical fields of the field
electrodes. Thus the field electrodes can assist the process of
binding a sample to the interface for further analysis. There
afterwards the polarity of the force can be reversed to remove
non-bonded material.
[0059] In another embodiment of the microelectronic device with
arrays of field and/or heating electrodes, each heating electrode
and/or field electrode is locally associated to an addressing
element, a driving unit, a memory unit and/or a frequency
oscillator. The oscillator may particularly be a tunable
oscillator, preferably a relaxation oscillator or a ring
oscillator.
[0060] The invention further relates to the use of the
microelectronic devices described above for molecular diagnostics,
biological sample analysis, or chemical sample analysis, food
analysis, and/or forensic analysis. Molecular diagnostics may for
example be accomplished with the help of magnetic beads or
fluorescent particles that are directly or indirectly attached to
target molecules.
BRIEF DESCRIPTION OF THE DRAWINGS
[0061] These and other aspects of the invention will be apparent
from and elucidated with reference to the embodiment(s) described
hereinafter. These embodiments will be described by way of example
with the help of the accompanying drawings in which:
[0062] FIG. 1 shows schematically a section through a
microelectronic device with stacked layers of heating electrodes
and field electrodes;
[0063] FIGS. 2 and 3 show a microelectronic device like that of
FIG. 1 when additional electrical fields are generated by
bi-functional heating electrodes;
[0064] FIG. 4 shows a variant of the device of FIG. 1, wherein a
counter electrode is located at the opposite side of the sample
chamber;
[0065] FIGS. 5-7 show different designs of the sample chamber with
a substrate and electrodes on both sides;
[0066] FIGS. 8 and 9 show schematically views of a substrate with
two vertically stacked electrode layers that are aligned with
respect to each other;
[0067] FIGS. 10 and 11 show alternative approaches for connecting
electrodes in large area electronics by VIAs;
[0068] FIG. 12 shows schematically a top view of a patterned layer
of bi-functional electrodes;
[0069] FIG. 13 shows two alternative circuits for applying
alternatively current or voltage to a bi-functional electrode;
[0070] FIG. 14 shows schematically an active matrix heater array
with the heater driver circuitry outside the array;
[0071] FIG. 15 shows a variant of FIG. 14 in which a single heater
driver is connected via a de-multiplexer to the array of heating
electrodes;
[0072] FIG. 16 shows schematically the circuit of an active matrix
heater system with local driving units;
[0073] FIG. 17 shows the design of FIG. 16 with an additional
memory element;
[0074] FIG. 18 shows an active matrix system with a local
oscillator;
[0075] FIGS. 19 to 26 show different designs concerning the local
oscillator of FIG. 18.
[0076] Like reference numbers/characters in the Figures refer to
identical or similar components.
DESCRIPTION OF THE EMBODIMENT
[0077] Biochips for (bio)chemical analysis, such as molecular
diagnostics, will become an important tool for a variety of
medical, forensic and food applications. In general, biochips
comprise a biosensor in most of which target molecules (e.g.
proteins, DNA) are immobilized on biochemical surfaces with
capturing molecules and subsequently detected using for instance
optical, magnetic or electrical detection schemes. Examples of
magnetic biochips are described in the WO 2003/054566, WO
2003/054523, WO 2005/010542 A2, WO 2005/010543 A1, and WO
2005/038911 A1, which are incorporated into the present application
by reference.
[0078] The binding-kinetics of the target molecules to the
biochemical surface determine the speed and specificity of the
biosensor. For low concentrations (pMol) of large biomolecules the
binding-kinetics are diffusion limited, and with that the speed of
high-sensitivity biosensors is limited. Electrical manipulation and
local fluid control offer the ability to influence the
binding-kinetics of molecules to a surface, and allow to increase
the speed of measurement. It will become essential if reduced
concentrations of biomarkers are to be measured. It is even
conceivable to improve on the specificity of the binding by
"pulling" the target molecules from the surface in a controlled way
(stringency test) to remove specifically the weakly bound
(a-specifically adsorbed) molecules.
[0079] A more defined way to improve the specificity of a biosensor
is by control of the temperature, which is often used during a
hybridization assay to regulate stringency of the binding of a
target biomolecule to a functionalized surface, e.g. the binding of
a DNA strand to its complementary strand. A high stringency is
required when for instance single point mutations are of interest.
Besides being of high importance for hybridization assays,
temperature control of a biosensor is needed in general. In the
literature the use of resistive electrodes for heating elements and
temperature sensing elements in integrated biomedical devices has
therefore been reported. More generally, the ability to control
temperature AND fluids on a biochip is essential. Besides general
temperature or flow management, the ability to control fluid
convection locally in combination with temperature control offers
options to enhance dissolution of reagents, to enhance mixing of
(bio)chemicals and to enhance temperature uniformity.
[0080] In order to optimize the performance of a biosensor,
elements to control the temperature as well as means for electrical
fluid actuation and electrical manipulation of biomolecules need to
be integrated in the biosensor. It is therefore proposed here to
incorporate a temperature processing array in a biosensor and to
combine it with mixing or pumping elements. Electrode arrays used
for electrical particle/fluid manipulation however have typically a
spacing between the electrodes smaller than 100 .mu.m (high field
strengths and field gradients are desired), often in the range of
10 .mu.m, which leaves little lateral space for integration of
temperature control elements (e.g. heaters, sensors). Hence, the
problem to be solved is that electrodes for temperature control and
electrodes for electrical particle or fluid manipulation cannot
generally be deposited next to one another and therefore cannot be
patterned from a single conductive/resistive layer.
1) Vertically Stacked Electrode Arrays
[0081] In a first series of embodiments it is proposed to use at
least two vertically stacked arrays of electrodes for temperature
control and electrical manipulation of fluids/biomolecules. FIG. 1
shows schematically the general setup. The heating elements or
"heating electrodes" HE consist of resistive electrodes and are
preferably located in the patterned electrode layer closest to the
substrate SU carrying the electrodes. In addition, the "field
electrodes" FE used for electrical manipulation of
fluids/biomolecules are preferably positioned closest to the sample
chamber SC, which is advantageous with respect to the ability to
obtain high electric fields E and high gradients in electric fields
in the sample. In a preferred embodiment, at least one temperature
sensing element, consisting of a resistive electrode, is
incorporated in at least one of the patterned electrode layers. The
heating electrodes HE and field electrodes FE are coupled to a
control unit CU that supplies them with appropriate voltages and/or
currents.
[0082] An electrically insulating layer is present between the
first and second electrode layer. A preferred technology to realize
this structure is the well known "field shielded pixel" active
matrix technology used for the fabrication of (reflective and
transflective) LCDs, where a tough (polymeric) layer of several
microns in thickness is used to separate the second metal layer
from the first layer (which is generally deposited directly onto
the substrate).
[0083] Besides being electrically insulating, the aforementioned
layer may comprise a biocompatible topcoat. Also the field
electrode layer may be covered with a partially electrically
insulating layer and/or a biocompatible topcoat (e.g. polyimide,
porous SiO.sub.2, polyacrylamide). Both electrode layers may also
comprise a native oxide on top of the electrodes. Additional
biocompatible and/or insulating layers may be deposited on top of
the stack of electrode layers.
[0084] In another embodiment, heating electrodes in the first
patterned layer are sequentially used for heating and to guard the
electric field created with the field electrodes FE in the second
patterned layer. Due to their double function for heating and field
generation, these electrodes are denoted with the reference sign
FHE in FIGS. 2-4 (the heating electrodes HE shown in the other
Figures may in general also be bi-functional FHE electrodes). The
field generation of the FHE electrodes is advantageous as it
provides an additional parameter to obtain the desired electrical
field, which is particularly of relevance for the electrical
manipulation of fluids/biomolecules. For instance, by setting the
electrodes in the first and second layer at the same potential a
more homogeneous in-plane electric field can be created (FIG. 2).
On the other hand, by applying a different potential to the
electrodes in the first and second layer, a vertical component of
the electric field can be tuned (FIG. 3). In an additional
embodiment, the electrodes FHE that are used for
heating/temperature sensing AND manipulation are connected to a
floating current source or can be disconnected from a current
source while being connected to a voltage source.
[0085] Although the electric field may be directed in a better
direction using the heating layer electrodes in addition to the
field layer electrodes, the presence of the field layer (or
additional layers) electrodes may reduce the intensity of the field
lines that will pass through from the heating electrode. An
alternative set of embodiments to reduce this effect will be to
provide the field electrodes at a much smaller pitch (say 10 .mu.m)
than the heating electrodes (say 100 .mu.m)--heat will spread in
any case.
[0086] The use of the first and second layer of patterned
electrodes to tune the desired electrical field strength and
gradients can be expanded to multiple electrode layers. In
addition, an (patterned) electrode layer used for heating may also
be present on another substrate above the first mentioned
substrate.
[0087] FIGS. 4-7 show a schematic representation of a sample
chamber or flow channel SC enclosed by multiple substrates, of
which one substrate carries at least one electrode and the other
substrate carries at least two patterned electrode layers. Such a
structure is particularly suited to manipulate biomolecules
perpendicular to the substrates, in addition to manipulation
in-plane with the substrate (FIG. 4). It should be understood that
this part of the invention is not limited to the shown embodiments
but can be generally applied to a wide variety of
configurations.
[0088] The field and heating electrode layers are preferably
aligned with respect to one another. FIGS. 8 and 9 show several
specific embodiments of alignment. In these Figures it is assumed
that electrodes HE (or FHE) used for heating are located in the
first patterned electrode layer and electrodes FE used for
electrical manipulation of fluids/biomolecules are located in the
second patterned electrode layer. As will be appreciated by an
expert in the field, the invention is not limited to the shown
embodiments. The invention also applies to non-straight electrode
configurations, such as quadrupoles or multipoles. Besides
illustrating several ways of alignment, FIGS. 8 and 9 also
illustrate how the individual electrodes of each of the layers can
be contacted without shorts. For clarity, it is noted that heating
elements HE (or FHE) and temperature sensing elements TS require at
least two contacts as a current must flow through the electrodes.
An electrode FE used for electrical manipulation of
fluids/biomolecules requires at least one contact to bring the
electrode to a certain electrical potential.
[0089] FIG. 8 shows schematic views a) to f) of a substrate with
two vertically stacked patterned electrode layers that are aligned
with respect to one another in a cross section (top of each drawing
a-f) and a top view (bottom of each drawing a-f). More
particularly, the individual drawings show:
a) and c): field electrodes FE in the second layer are positioned
parallel to and in between the heating electrodes HE of the first
layer with contacts to one side. The contacts of the field layer
electrodes are positioned in between the contacts of the heating
electrodes in the first layer. In drawing c), each field electrode
FE consists of several parallel leads. b), d), and e): field
electrodes FE in the second layer are positioned parallel to and in
between the heating electrodes HE of the first layer with contacts
to two opposite sides. The contacts of the field layer electrodes
are positioned in between the contacts of the heating electrodes in
the first layer. In drawings d) and e), each field electrode FE
consist of several parallel leads. In drawing d), the electrodes FE
are contacted in an alternating fashion from both sides, while in
e) they run only to the middle of the array and thus have to be
contacted at both sides. f): field electrodes FE in the second
layer are positioned orthogonal to the heating electrodes HE of the
first layer. The contacts of the field layer electrodes are
positioned in between the contacts of the heating electrodes in the
first layer.
[0090] FIG. 9 shows similarly schematic top views of a substrate
with two vertically stacked patterned electrode layers that are
aligned with respect to one another:
a), b): field electrodes FE in the second layer are positioned
parallel and on top of the heating electrodes HE of the first layer
with contacts to one side. The contacts of the field layer
electrodes are positioned in between the contacts of the heating
electrodes in the first layer. In drawing b), each field electrode
FE consists of several parallel leads. c), d): field electrodes FE
in second layer are positioned parallel and on top of the heating
electrodes HE of the first layer with contacts to two opposite
sides. The contacts of the field layer electrodes are positioned in
between the contacts of the heating electrodes in the first layer.
In drawing c), the electrodes FE are contacted in an alternating
fashion from both sides, while in d) they run only to the middle of
the array and thus have to be contacted at both sides. e): field
electrodes FE in the second layer are positioned parallel and in an
alternating way on top of and in between the heating electrodes HE
of the first layer with contacts to two opposite sides. The
contacts of the field layer electrodes are positioned in between
the contacts of the heating electrodes in the first layer. f):
field electrodes FE in the second layer are positioned in between
the heating electrodes HE of the first layer with contacts to two
opposite sides. Opposing electrodes in the field layer are
displaced with respect to one another. The heating electrodes HE in
the first layer are non-straight. The contacts of the field layer
electrodes are positioned in between the contacts of the heating
electrodes in the first layer.
[0091] In general terms, FIGS. 8 and 9 show that electrodes in the
field and heating layer may be non-straight in order to be able to
position the contacts of the individual electrodes next to one
another on the same edge. Moreover, it is shown that electrodes may
also be non-straight to diverge towards a different edge (e.g. FIG.
90. Optionally the non-straight lengths of the FE electrodes can be
covered with an insulator to prevent them creating inhomogeneous
fields in the sample space.
[0092] Besides the shown square-like shaped electrodes, various
patterns may be used, such as sharpened and asymmetric electrodes,
and quadrupoles. These structures are in particular advantageous
for electrical manipulation of fluids/biomolceules.
[0093] The resistive heating elements may also be used to create a
fluid flow using the so-called thermo-capillary effect. The fluid
flow will drag with it the particles contained in the fluid. In
combination with the electrical manipulation of biomolecules this
can be advantageous. For instance, in case particles are trapped
with the electrodes used for electrical manipulation, the heating
elements can create a fluid flow and with that supply new
particles. In a similar manner, a convectional flow could be
introduced into the cell.
[0094] The field electrodes may be used to create a fluid flow,
too. This can be achieved by moving the liquid via AC or DC
electro-osmosis, electrophoresis, dielectrophoresis,
electrohydrodynamics and/or a combination of these effects.
[0095] In another preferred embodiment, a large area electronics
(LAE) matrix approach, even more preferably an active matrix
approach (e.g. low temperature poly silicon (LTPS), amorphous-Si),
is used to contact the electrodes in the first and second patterned
layer. This is advantageous as it reduces the number of required
input/output contacts to the outside world. Large area electronics,
and specifically active matrix technology using for example Thin
Film Transistors (TFT), is commonly used in the field of flat panel
displays for the drive of many display effects e.g. LCD, OLED and
Electrophoretic. The (metal) electrodes used for heating and/or
manipulation may be additionally deposited on top of a backplane
containing the active matrix electronics. In another embodiment,
the metal layers used to built the active matrix components (e.g.
TFTs, diodes) are also used to make one or both of the electrode
layers for temperature control and/or electrical manipulation of
biomolecules/fluid.
[0096] Conductive paths (vias) are needed between the active
components (TFTs, diodes, capacitors) and the electrodes in the
first and second layer. This is shown in FIGS. 10 and 11. The vias
VIA1, VIA2 may be made from the same metal layer as deposited to
make part of the active matrix components of (e.g. TFT, diode). In
case the electrodes in the first and second layer are not aligned
above one another, the application of vias is straightforward.
[0097] FIG. 10 shows particularly the case that electrodes in the
first and second layer are aligned above one another. A via VIA1
can then be applied to connect a field electrode FE in the second
layer through a hole in the heating electrode HE in the first layer
with its field-control circuit FC that is located in the LAE
backplane. The heating electrode HE in the first layer can be
directly connected to its heating-control circuit HE in the LAE
backplane by a via VIA2.
[0098] The aforementioned design is however undesirable if the
electrode HE in the first layer is used for heating as the presence
of the hole will locally increase the resistance and therefore the
temperature. The electrode with the hole for the via can be made
slightly wider to compensate for the increase in resistance of the
hole. This, however, may result in unwanted current profiles and
therefore temperature gradients. As shown in FIG. 11, the via VIA1
to the field electrode FE in the second layer may in that case be
applied around the heating electrode HE. This may however be
undesirable when the field electrodes in the second layer are used
to electrically manipulate the fluids/biomolecules as the contact
between via and electrode will disturb the electrical field (e.g.
in a sense broaden the electrode). The problem becomes more severe
when the number of field electrodes FE in the second electrode
layer becomes larger. When a certain voltage (amplitude, phase,
frequency) is applied to multiple electrodes at the same moment, a
possible solution is to attach only one via to a multiplicity of
closely spaced comb like electrodes (not shown).
[0099] Whilst FIGS. 10 and 11 show the positioning of the
electronics HC, FC in the LAE backplane underneath the electrode
layers, the invention is not limited to such a configuration. The
electronics may also be placed next to the electrodes, or in
another place where there is sufficient space and use fan in
connections to the heaters, sensors and manipulation
electrodes.
2) Single Electrode Layer for Temperature Control and Electrical
Manipulation of Fluids/Biomolecules
[0100] In a second series of embodiments it is proposed to use a
single patterned layer of electrodes FHE for both temperature
control and electrical manipulation of fluids/biomolecules by
sequential application of a voltage across a (resistive) electrode
FHE (i.e. for heating and temperature sensing, FIG. 12a) and
between the electrodes FHE (i.e. for electrical manipulation of
fluids/biomolecules, FIG. 12b). The patterned electrode layer may
be covered with a (partially) electrically insulating layer (e.g.
SU-8, polyimide, SiO.sub.2, native metallic oxide) and/or with a
biocompatible layer (e.g. SU-8). Each electrode FHE has at least
two contacts. At least two contacts are used in case the
(resistive) electrode is used for heating or temperature sensing
(FIG. 12a). In case the electrode is used for electrical
manipulation of fluids/biomolecules (FIG. 12b), (distinct) voltages
V1, V2, V3, V4 are applied via at least one contact. Applying these
voltages via more than one contact (shown for the rightmost
electrode in FIG. 12b) may be advantageous in order to reduce the
time it takes to put the complete electrode at the desired
potential.
[0101] A single electrode can be regarded as a resistor.
Alternating use of the same electrode for heating/temperature
sensing and electric manipulation of fluids/biomolecules requires
switching of the electric circuit connected to the electrode
between applying a current through the electrode and a potential to
the electrode. FIG. 13 shows two concepts to realize this. Both AC
and DC signals may be applied. FIG. 13a shows the use of one
voltage source V1 with a switch T1 (e.g. transistor) between the
electrode FHE (resistor) and ground GR. When the switch is closed,
a current will flow through the electrode. When the switch is open,
the electrode is driven to the voltage of the source. The TFT
switch can also be used as a current source for heating. FIG. 13b
shows the use of two voltage sources; one V1 for heating and one V2
for manipulation. The switches T2, T3, T4 provide the necessary
voltages to the electrode FHE (resistor). The voltage sources can
be AC or DC. In the AC case the gates of the switches will need to
be held at voltages beyond the range of the AC field. The sources
may be applied from a connection to the outside.
[0102] In another embodiment, the same electrode is SIMULTANEOUSLY
used for temperature control (heating, sensing) and manipulation of
biomolecules/fluid. In the case of e.g. DEP (dielectrophoresis)
motion, the high frequencies will or can be used to cause a heating
effect. It would therefore be possible to additionally drive the
single electrode to realize the following functionality:
[0103] DEP only, no heating: Use either low intensity or low duty
cycle AC signal;
[0104] Heating only (no net particle movement)--high intensity AC
at two frequencies for mutually compensating +DEP and -DEP;
temperature control via duty cycle;
[0105] DEP at cross over frequency so only heating occurs. This is
most applicable for systems with well-defined particles such as
mixer particles or magnetic particles of a well-defined
diameter.
[0106] Motion+heating: high intensity AC at required frequency.
[0107] The use of a single patterned electrode layer for
temperature control and electrical manipulation of
fluids/biomolecules already reduces the number of required I/O pins
to the outside world. Preferably, the electrode array is realized
using thin film electronics. In order to reduce the number of
required I/O pins further and/or to integrate electronic circuits
on the substrate, the array may be realized in the form of a matrix
array, especially an active matrix array (e.g. LTPS, amorphous
Si).
[0108] The (metal) electrodes used for heating and/or manipulation
may be deposited on top of a backplane containing the active matrix
electronics. In another embodiment, the metal layers used to build
the active matrix components (e.g. TFTs, diodes) are also used to
make the electrodes layer for temperature control and/or electrical
manipulation of biomolecules/fluids.
[0109] Conductive paths (vias) are needed between the active
components (e.g. TFTs, diodes) and the electrodes. The application
of vias is straightforward. To be able to sequentially apply a
voltage across an electrode or in between electrodes, electronic
circuits may be integrated in the LAE backplane.
3) Hybridization Spots Deposited in Alignment with Electrodes
[0110] In a third series of embodiments it is proposed to align
hybridization spots, typically consisting of probe molecules (e.g.
single DNA strands, anti-ligands) immobilized on a surface, with
the electrodes used for temperature control and electrical
manipulation of fluid and biomolecules.
[0111] Generally, hybridization spots are deposited on the surface
after the electrodes have been fabricated. For instance, ink-jet
printing may be used to deposit DNA capturing probes. Hybridization
spots can be deposited on certain positions relative to the
electrodes, e.g. at trapping sites of biomolecules, and/or above
temperature controlled areas. Alternatively self-assembling capture
molecules can be grown on certain surfaces (e.g. Au)
[0112] Depending on the electrode structure and applied (AC, DC)
voltages biomolecules can be trapped. For example, an electrode
structure like that of FIG. 12 can be used to electrically smear
out the various particles present in a sample using the
frequency-dependent dielectrophoretic force.
[0113] The presence of hybridization spots at electrical trapping
sites provides a way to keep biomolecules trapped while the
voltages on the electrodes are altered. By switching voltages
and/or frequencies one can switch between a negative and a positive
dielectric force on a biomolecule (e.g. pull/push), which provides
a simple electrical method to control the stringency of the binding
and flush away any non-bonded material. Similarly, the combination
of electrical and biochemical trapping is advantageous in case a
single electrode layer is used for temperature control and
electrical manipulation. First the electrodes can be used to trap
biomolecules. Then, when the biomolecules are held on position with
the hybridization spots, the same electrodes can be used to control
the temperature, for instance to control the stringency of the
binding.
4) Various Designs of Microfluidic Biosensors
[0114] As was already mentioned, the performance of a biosensor can
considerably be improved by incorporating a programmable
temperature processing array into the sensor module. The
temperature processing array can be used to either maintain a
constant temperature across the entire sensor area, or
alternatively to create a defined temperature profile if the
biosensor is also configured in the form of an array and different
portions of the biosensor operate optimally at different
temperatures. In all cases, the temperature processing array
comprises a multiplicity of individually addressable and drivable
heating elements, and may optionally comprise additional elements
such as temperature sensors, mixing or pumping elements, and even
the sensing element itself (e.g. a photosensor). Preferably, the
temperature processing array is realized using thin film
electronics, and optionally the array may be realized in the form
of a matrix array, especially an active matrix array. Whilst the
invention is not limited to any particular type of biosensor, it
can be advantageously applied to biosensors based upon optical
(e.g. fluorescence), magnetic or electrical (e.g capacitive,
inductive . . . ) sensing principles. In the following, various
designs of such biosensors will be described in more detail.
[0115] Each individual heating element HE, FHE may comprise any of
the well known concepts for heat generation, for example a
resistive strip, Peltier element, radio frequency heating element,
radiative heating element (such as an Infra-red source or diode)
etc. Each heating element is individually drivable, whereby a
multiplicity of temperature profiles may be created.
[0116] To enhance temperature control, in particular thermal
cycling, means may be provided to cool a biosensors during
operation, such as active cooling elements (e.g. thin film Peltier
elements), thermal conductive layers in thermal contact with a heat
sink or cold mass and a fan.
5) Active Matrix Arrays of Heating Elements
[0117] As was already pointed out several times, the array of
heating terminals may be realized in the form of a matrix device,
preferably an active matrix device (alternatively being driven in a
multiplexed manner). In an active matrix or a multiplexed device,
it is possible to re-direct a driving signal from one driver to a
multiplicity of heaters, without requiring that each heater is
connected to the outside world by two contact terminals.
[0118] In the embodiment shown in FIG. 14, an active matrix is used
as a distribution network to route the electrical signals required
for the heaters from a central driver CU via individual power lines
iPL to the heater elements HE. In this example, the heaters HE are
provided as a regular array of identical units, whereby the heaters
are connected to the driver CU via the transistors T1 of the active
matrix. The gates of the transistors are connected to a select
driver (in all cases a standard shift register gate driver as used
for an Active Matrix Liquid Crystal Display AMLCD), whilst the
source is connected to the heater driver, for example a set of
voltage or current drivers. The operation of this array is as
follows:
[0119] To activate a given heater element HE, the transistors T1 in
the entire row of compartments incorporating the required heater
are switched into the conducting state (by e.g. applying a positive
voltage to the gates from the select driver).
[0120] The signal (voltage or current) on the individual power line
iPL in the column where the heater is situated is set to its
desired value. This signal is passed through the conducting TFT to
the heater element, resulting in a local temperature increase.
[0121] The driving signal in all other columns is held at a voltage
or current, which will not cause heating (this will typically be 0V
or 0 A).
[0122] After the temperature increase has been realized, the
transistors in the line are again set to the non-conducting state,
preventing further heater activation.
[0123] As such, the matrix preferably operates using a
"line-at-a-time" addressing principle, in contrast to the usual
random access approach taken by CMOS based devices.
[0124] It is also possible to activate more than one heater HE in a
given row simultaneously by applying a signal to more than one
column in the array. It is possible to sequentially activate
heaters in different rows by activating another line (using the
gate driver) and applying a signal to one or more columns in the
array.
[0125] Whilst in the embodiment of FIG. 14 a driver is considered
that is capable of providing (if required) individual signals to
all columns of the array simultaneously, it would also be feasible
to consider a more simple driver with a function of a
de-multiplexer. This is shown in FIG. 15, wherein only a single
output driver SD is required to generate the heating signal (e.g. a
voltage or a current). The function of the de-multiplex circuit DX
is simply to route the heater signal to one of the columns, whereby
only the heater is activated in the selected row in that column.
Alternatively, the dc-multiplexer DX could be directly attached to
a plurality of heating elements (corresponding to the case of only
one row in FIG. 15). The function of the de-multiplex circuit is
then simply to route the heater signal to one of its outputs,
whereby only the desired heater is activated.
[0126] A problem with the simple approach of individually driving
each heating element through two contact terminals is that an
external driver is required to provide the electrical signals for
each heater (i.e. a current source for a resistive heater). As a
consequence, each driver can only activate a single heater at a
time, which means that heaters attached to the same driver must be
activated sequentially. This makes it difficult to maintain steady
state temperature profiles. Furthermore, if a driving current is
required, it is not always possible to bring the current from the
driver to the heater without a loss of current, due to leakage
effects.
[0127] For this reason, it may be preferred to use the active
matrix technology to create an integrated local heater driver per
heating element. FIG. 16 illustrates such a local driver CU2 which
forms one part of the control unit for the whole array; the other
part CU1 of said control unit is located outside the array of
heating electrodes HE (note that only one heating electrode HE of
the whole array is shown in FIG. 16). Now every heater element HE
comprises not only a select transistor T1, but also a local current
source. Whilst there are many methods to realize such a local
current source, the most simple embodiment requires the addition of
just a second transistor T2, the current flowing through this
transistor being defined by the voltage at the gate. Now, the
programming of the release signal is simply to provide a specified
voltage from the external voltage driver CU1 via individual control
lines iCL and the select transistor T1 to the gate of the current
source transistor T2, which then takes the required power from a
common power line cPL.
[0128] In a further embodiment shown in FIG. 17, the local driver
CU2 can be provided with a local memory function, whereby it
becomes possible to extend the drive signal beyond the time that
the compartment is addressed. In many cases, the memory element
could be a simple capacitor C1. For example, in the case of a
current signal, the extra capacitor C1 is situated to store the
voltage on the gate of the current source transistor T2 and
maintain the heater current whilst e.g. another line of heater
elements is being addressed. Adding the memory allows the heating
signal to be applied for a longer period of time, whereby the
temperature profile can be better controlled.
[0129] Whilst all the above embodiments consider the use of thin
film electronics (and active matrix approaches) to activate the
heating elements, in the most simple embodiment, the individual
heating elements may all be individually driven, for example in the
case of a resistive heating element by passing a defined current
through the element via the two contact terminals. Whilst this is
an effective solution for a relatively small number of heating
elements, one problem with such an approach is that at least one
additional contact terminal is required for each additional heating
element which is to be individually driven. As a consequence, if a
larger number of heating elements is required (to create more
complex or more uniform temperature profiles), the number of
contact terminals may become prohibitively large, making the device
unacceptably large and cumbersome. It would also be possible to
implement several of the embodiments using other active matrix thin
film switching technologies such as diodes and MIM
(metal-insulator-metal) devices.
6) Driving Circuits with Oscillators for Biomolecule/Fluid
Manipulation
[0130] While it is possible to simply incorporate a switch at the
heating electrode HE that is to be switched, it is often beneficial
to incorporate a frequency oscillator on the glass at each heating
electrode HE. This is especially true for trapping of biomolecules
as high frequencies (>1 MHz) are often necessary for small
particle confinement and with local frequency oscillators the line
capacitance is no longer relevant (thus allowing higher frequencies
and significantly reducing power dissipation). In addition, it
makes it possible to use higher resistance transparent electrodes
like transparent oxides, as again the RC delay and power is
low.
[0131] According to the schematic design shown in FIG. 18, each
field electrode used for particle manipulation will be associated
with an active matrix circuit which comprises an addressing
element, a memory function, an oscillating element, optionally a
driving function, and one or more electrodes. Of these functions,
the addressing element may be a simple switch, or a more
complicated switch in case the same electrode is used for
temperature control and biomolecule/fluid actuation (see above),
and the memory function may be a storage capacitor.
[0132] There are many methods of producing a tunable oscillator.
One class of oscillators, known as relaxation oscillators, is
frequency tunable by altering the current supplied to the
integrated electronics; an example of this class of oscillators is
shown in FIG. 20. Here, the rate at which the data current fills
the switching capacitor C determines the oscillation frequency. An
advantage of this oscillator embodiment is that all TFTs have the
same polarity, which makes the circuit also implementable in a-Si
technology.
[0133] In this class of oscillators, the current required to set
the oscillator frequency could be directly supplied by the data
driving circuits and mirrored onto the pixel using the circuits
shown in FIGS. 20 and 21. The operation of the circuit in FIG. 20
is as follows:
[0134] SAMPLE: close S1 and S2; a current I.sub.1 flows in T1 and a
current I.sub.2 (=kI.sub.1) flows in T2 and the oscillator.
[0135] HOLD: open S1 and S2; the current I.sub.2 continues to flow
in T2 and the oscillator.
The operation of the circuit in FIG. 21 is as follows: 1. Close T1
and T2, current I.sub.1 flows in T4.
2. Open T1 and T2.
[0136] 3. Close T3, current I.sub.1 now flows in T4 and
oscillator.
[0137] While FIG. 20 shows a traditional current mirror circuit, in
FIG. 21 the current mirror uses the same transistor T4 for sampling
the data driver current and driving the oscillator. This single TFT
current mirror circuit has the advantage that it is self
compensating, and corrects for any variations in the TFT
characteristics (such as mobility and threshold voltage). This is
important if p-Si TFTs are being used, as here considerable
mobility (5-10%) and threshold voltage (+/-1V) variations are
found. Any non-uniformity in drive current will be reflected in an
equivalent shift in the oscillator frequency.
[0138] Alternatively, the data could be addressed in the form of a
voltage, and the voltage converted to the required current at a
pixel level, using the current source circuits shown in FIGS. 22
and 23. In these circuits, the data voltage is applied to the gate
of the current source TFT, and its transconductance characteristic
is used to define the current (the current increases as the
source-gate voltage gets larger). FIG. 23 shows an improved version
of the basic circuit, which is much less sensitive to horizontal
cross talk (a decrease in output current when moving across the
substrate due to voltage drops along the power line).
[0139] If both n-type and p-type transistors are available (for
example p-Si technology, or CMOS technology), it is possible to
produce oscillators with less TFTs. This is advantageous for the
open space (aperture) on the substrate which can be used for rear
illumination and detection. Examples of such oscillators can be
found in electronics reference books.
[0140] Relaxation oscillators of the type shown in FIG. 21 usually
have the characteristic that the amplitude of the output signal
changes with the output frequency. For many applications it will be
necessary to either ensure a constant amplitude output voltage or,
more generally, to ensure that the output voltage is variable,
independent of the frequency. Both of these situations can be
achieved by using output buffers, and these form preferred
embodiments of the invention. An example of an implementation of
the relaxation oscillator of FIG. 19 with a constant output voltage
buffer is given in FIG. 24. In this Figure, the actual
implementation of the circuit in p-Si is given (i.e. current
sources and resistances are defined by TFTs). The circuit
components are furthermore dimensioned to provide oscillation in
the 300 Hz-10 kHz bandwidth though the choice of other components
would allow other bandwidths. An example of a pixel circuit where
the frequency and amplitude of the output voltage are independently
variable is shown in FIG. 25. This pixel circuit will require two
data signals, one for the frequency (current) and one for the pixel
voltage (voltage).
[0141] A further class of oscillator circuit which can be
implemented in a local tunable oscillator pixel circuit is a ring
oscillator. An example of this class of oscillator is shown in FIG.
26. In this example, the frequency and amplitude of the output
voltage are independently variable. Again, the circuit components
are dimensioned to provide oscillation in the 300 Hz-10 kHz
bandwidth as was required for display application. By choosing
other components this bandwidth can be altered.
[0142] In most cases, the output of the oscillator (a voltage) will
directly be used to drive the electrode. In some cases, the
electrode will require an oscillating output current. This can
again be achieved by converting the oscillating output voltage to a
current by using (for example) the transconductance characteristics
of a current source TFT, as already shown in FIGS. 22 and 23.
[0143] In the above description of the drawings, reference is made
to transistors in general. In practice, the temperature controlled
cell-array is suited to be manufactured using Low Temperature
Poly-Silicon (LTPS) Thin Film Transistors (TFT). Therefore, in a
preferred embodiment, the transistors referred to above may be
TFTs. In particular, the array may be manufactured on a large area
glass substrate using LTPS technology, since LTPS is particularly
cost effective when used for large areas.
[0144] Further, although the present invention has been described
with regard to low temperature poly-Si (LTPS) based active matrix
device, amorphous-Si thin film transistor (TFT), microcrystalline
or nano-crystalline Si, high temperature poly SiTFT, other
anorganic TFTs based upon e.g. CdSe, SnO or organic TFTs may be
used as well. Similarly, MIM, i.e. metal-insulator-metal devices or
diode devices, for example using the double diode with reset (D2R)
active matrix addressing methods, as known in the art, may be used
to develop the invention disclosed herein as well.
[0145] A programmable temperature processing array as it was
described in numerous embodiments above would be an extremely
important component of a range of devices aimed at medical and
health and wellness products. A main application is to use a
temperature processing array in a biochip, such as underneath a
biosensor or underneath reaction chambers, where controlled heating
provides functional capabilities, such as mixing, thermal
denaturation of proteins and nucleic acids, enhanced diffusion
rates, modification of surface binding coefficients, etc. A
specific application is DNA amplification using PCR that requires
reproducible and accurate multiplexed (i.e. parallel and
independent) temperature control of the array elements. Other
applications could be for actuating MEMS related devices for
pressure actuation, thermally driven fluid pumping etc.
[0146] Finally it is pointed out that in the present application
the term "comprising" does not exclude other elements or steps,
that "a" or "an" does not exclude a plurality, and that a single
processor or other unit may fulfill the functions of several means.
The invention resides in each and every novel characteristic
feature and each and every combination of characteristic features.
Moreover, reference signs in the claims shall not be construed as
limiting their scope.
* * * * *