HK40018494B - Digital microfluidic devices including dual substrates with thin-film transistors and capacitive sensing - Google Patents

Description

Digital microfluidic device including dual substrates with thin film transistors and capacitive sensing

RELATED APPLICATIONS

This application claims priority from U.S. provisional patent application No. 62/573,846 filed on 18/10/2017. All patents and patent applications cited in this specification are herein incorporated by reference in their entirety.

Background

Digital microfluidic devices use independent electrodes to propel, break up and combine droplets in a confined environment, providing a "lab-on-a-chip". The digital microfluidic device is alternatively referred to as an electrowetting on dielectric device, or "EWoD", to further distinguish the method from competing microfluidic systems that rely on electrophoretic flow and/or micropumps. Wheeler in "Digital Microfluidics (Digital Microfluidics)," analytic chemistry annual reviewAnnu.Rev.Anal.Chem.)A 2012 review of electrowetting technology is provided in 2012,5:413-40, which is incorporated herein by reference in its entirety. This technique allows sample preparation, assay, and synthetic chemistry to be performed using both small amounts of sample and small amounts of reagents. In recent years, controlled droplet operations in microfluidic cells (cells) using electrowetting have become commercially viable; and there are now products from large life science companies such as Oxford Nanopore.

Most literature reports on EWoD involve so-called "passive matrix" devices (also called "segmented" devices), whereby ten to twenty electrodes are driven directly with a controller. Although segmented devices are easy to manufacture, the number of electrodes is limited by space and drive constraints. Therefore, it is impossible to perform parallel measurement, reaction, and the like on a large scale in a passive matrix device. In contrast, an "active matrix" device (also known as an active matrix EWoD, also known as AM-EWoD) may have thousands, hundreds of thousands or even millions of addressable electrodes. The electrodes are typically switched by Thin Film Transistors (TFTs) and the droplet movement is programmable so that the AM-EWoD array can be used as a general purpose device that provides great freedom to control multiple droplets and perform simultaneous analytical processes.

Due to the limited requirements on electric field leakage, most advanced AM-EWoD devices are composed of polycrystalline silicon (also known as polysilicon (poly-Si)), also known as poly-Si (poly-Si). However, polysilicon is much more expensive to manufacture than amorphous silicon, the type used in mass-produced active matrix TFTs for the LCD display industry. The polysilicon fabrication process is more expensive because of the unique processing and fabrication steps used to process polysilicon. There are also fewer facilities in the world that are configured to manufacture equipment from poly-Si. However, due to the improved functionality of polysilicon, Sharp Corporation has been able to implement AM-EWoD devices including propulsion, sensing, and heating capabilities on a single active matrix. See, for example, U.S. patent nos. 8,419,273, 8,547,111, 8,654,571, 8,828,336, 9,458,543, which are all incorporated herein by reference in their entirety. An example of a complex poly-Si AM-EWoD is shown in FIG. 1.

Although poly-Si manufacturing technology allows for the implementation of sophisticated AM-EWoD devices, the cost of poly-Si device preparation, combined with the lack of globally suitable manufacturing facilities, has hindered the widespread application of AM-EWoD technology. A different design is needed that can take advantage of existing amorphous silicon manufacturing capabilities. Such devices can be prepared at relatively low cost and in large quantities, making them suitable for general diagnostic tests such as immunoassays.

Summary of The Invention

The present invention addresses the shortcomings of the prior art by providing an alternative structure for AM-EWoD that is well suitedAnd is suitable for the structure made of amorphous silicon substrate. In one example, the present disclosure provides a digital microfluidic device comprising a first substrate, a second substrate, a spacer, and a first controller and a second controller. The first substrate includes a first plurality of electrodes coupled to the first set of thin film transistors and includes a first dielectric layer covering both the first plurality of electrodes and the first set of thin film transistors. The second substrate includes a second plurality of electrodes coupled to the second set of thin film transistors and includes a second dielectric layer covering the second plurality of electrodes and the second set of thin film transistors. The spacer separates the first substrate and the second substrate and creates a microfluidic region between the first substrate and the second substrate. The first controller is operably coupled to the first set of thin film transistors and configured to provide a push-in voltage to at least a portion of the first plurality of electrodes, and the second controller is operably coupled to the second set of thin film transistors and configured to determine a capacitance between at least one of the second plurality of electrodes and a drive electrode. In some embodiments, the first dielectric layer is hydrophobic, and in other embodiments, the second dielectric layer is hydrophobic. In a preferred embodiment, the first plurality of electrodes is arranged in an array, for example at least 25 electrodes per linear cm. In some embodiments, the second plurality of electrodes are interdigitated with the drive electrodes. The second plurality of electrodes has a width of 0.01 to 5 mm. In some embodiments, a signal source is coupled to the drive electrode and configured to provide a time-varying voltage to the drive electrode. In some embodiments, the second substrate comprises at least one light-transmissive region, which may, for example, have an area of at least 10mm ² . The digital microfluidic device may be constructed of amorphous silicon or polycrystalline silicon.

In some embodiments, the second plurality of electrodes is arranged at a first density and a second density, and the first density comprises per 100mm ² At least three times the second density. The first density of the second plurality of electrodes comprises 20 to 200 electrodes per linear centimeter. A second density package of the second plurality of electrodesIncluding 1 to 15 electrodes per linear cm. An area of the device corresponding to the first density is less than an area of the device corresponding to the second density. An area of the apparatus corresponding to the second density is at least three times an area of the apparatus corresponding to the first density. The digital microfluidic device will have two regions of different electrode density, namely a high density (also referred to as "high resolution") region and a low density (also referred to as "low resolution") region for the sensor electrode side. Such a design would allow a user to perform particle interrogation (i.e., capacitive sensing) to determine the composition or size in one part of the device and then simply monitor the location or presence of particles in another part of the device. In general, this configuration simplifies the manufacture of the device, while also simplifying the data processing associated with the sensing function.

Brief Description of Drawings

FIG. 1 illustrates a prior art EWoD device that includes both propulsion and sensing on the same active matrix;

FIG. 2 depicts the movement of an aqueous phase droplet between adjacent electrodes by providing different charge states on the adjacent electrodes;

FIG. 3 illustrates a TFT structure for a plurality of push electrodes of the EWoD device of the present invention;

FIG. 4 is a schematic view of a portion of a first substrate including a push electrode, a thin film transistor, a storage capacitor, a dielectric layer, and a hydrophobic layer;

FIG. 5 is a schematic view of a portion of a second substrate including sense electrodes, drive electrodes, thin film transistors, dielectric layers, and a hydrophobic layer;

FIG. 6 shows a TFT structure for sense and drive electrodes configured for capacitive sensing and evaluation of microfluidic droplets;

FIG. 7 illustrates an embodiment in which the sense electrodes and drive electrodes are interdigitated as part of a second substrate;

fig. 8 illustrates a top view of a digital microfluidic device in which sensing electrodes are arranged with varying high and low density regions. The electrode arrangement shown in fig. 8 provides the necessary functions for many analytical functions (droplet sizing and movement tracking) while reducing the complexity and manufacturing cost of the device;

fig. 9 illustrates an alternative embodiment comprising light transmissive regions in which droplets can be interrogated by electromagnetic radiation, i.e. light. It should be understood that both the probe light and the generated signal may enter/exit through the same light-transmissive region;

FIG. 10 shows an alternative arrangement of sense electrodes with varying high and low density regions;

FIG. 11 shows an alternative arrangement of sense electrodes with varying high and low density regions;

FIG. 12 shows an alternative arrangement including elongate sensing electrodes arranged with varying high and low density regions;

fig. 13 shows an alternative arrangement including elongate sensing electrodes arranged with varying high and low density regions.

Detailed description of the invention

As indicated above, the present invention provides an active matrix dielectric electrowetting (AM-EWoD) device comprising a dual substrate with a Thin Film Transistor (TFT) and capacitive sensing. As depicted herein, the "bottom" substrate includes a plurality of electrodes to push various droplets through the microfluidic region. The "top" substrate includes a plurality of electrodes to provide signals and detect the presence and/or size and/or composition of a droplet with capacitive sensing. The use of "top" and "bottom" is only a convention, as the positions of the two substrates can be switched, and the device can be oriented in a variety of ways, for example, the top and bottom plates can be substantially parallel, while the entire device is oriented so that the substrates are perpendicular to the work surface (as opposed to parallel to the work surface as shown). The top or bottom substrate may include additional functions such as resistive heating and/or temperature sensing. Because the devices include TFT-based sensors, these devices have much higher sensitivity and resolution than known passive devices. In addition, because both electrodes required for capacitive sensing are on the same substrate, the top and bottom electrodes need not be aligned, and the sensing pixels can have different sizes or configurations compared to the push electrodes. In addition, the design can be implemented with amorphous silicon, thereby reducing manufacturing costs to the point where the device can be discarded after use. Amorphous Si TFTs may also be used for the bottom plate to benefit from their higher operating voltage and poly-Si TFTs on the top plate for higher sensitivity sensing.

The basic operation of the EWoD device is illustrated in the cross-sectional view of fig. 2. The EWoD 200 includes a cell (cell) filled with oil 202 and at least one water droplet 204. The cell gap typically ranges from 50 to 200 μm, but the gap may be larger. In a basic configuration, as shown in fig. 2, a plurality of push electrodes 205 are disposed on one substrate, and a single top electrode 206 is disposed on the opposite surface. The cell additionally comprises a hydrophobic coating 207 on the surface contacting the oil layer, and a dielectric layer 208 between the push electrode 205 and the hydrophobic coating 207. (the upper substrate may also include a dielectric layer, but is not shown in FIG. 2). The hydrophobic layer prevents the droplet from wetting the surface. When no voltage difference is applied between adjacent electrodes, the droplet will remain spherical to minimize contact with the hydrophobic surfaces (oil and hydrophobic layer). Because the droplets do not wet the surface, they are less likely to contaminate the surface or interact with other droplets, except when such behavior is desired.

Although it is possible to have a single layer for both dielectric and hydrophobic functions, such layers typically require a thick inorganic layer (to prevent pinholes), which has a resulting low dielectric constant and therefore requires more than 100V for droplet movement. For low voltage driving it is desirable to have a thin inorganic layer to achieve high capacitance and no pinholes, on top of a thin organic hydrophobic layer. By this combination, electrowetting operations can be performed with voltages in the range of +/-10 to +/-50V, which is in the range that conventional TFT arrays can provide.

When a voltage difference is applied between adjacent electrodes, the voltage on one electrode attracts the opposite charge in the droplet at the dielectric-droplet interface, and the droplet moves towards that electrode, as shown in fig. 2. The voltage required for acceptable droplet propulsion depends on the properties of the dielectric layer and the hydrophobic layer. Alternating current drive is used to reduce degradation of the droplets, dielectric and electrodes by various electrochemical actions. The operating frequency for EWoD may be in the range of 100Hz to 1MHz, but a lower frequency of 1kHz or less is preferably used for TFTs with limited operating speed.

As shown in fig. 2, top electrode 206 is a single conductive layer typically set to zero volts or a common voltage Value (VCOM) to account for offset voltages on the push electrode 205 due to capacitive kickback of the TFT used to switch the voltage on the electrode (see fig. 3). The top electrode may also apply a square wave to increase the voltage across the liquid. Such an arrangement allows a lower push voltage for the TFT connected push electrode 205, since the top plate voltage 206 is additional to the voltage provided by the TFT.

As shown in fig. 3, the active matrix of push electrodes may be arranged to be driven by data lines and gate (select) lines, much like the active matrix in a liquid crystal display. The gate (select) lines are scanned to address one line at a time while the data lines carry the voltage to be transmitted to the push electrodes for electrowetting operations. If no movement is required, or if the droplet is intended to move away from the push electrode, 0V is applied to the (non-target) push electrode. If the droplet is intended to move towards the push electrode, an AC voltage is applied to the (target) push electrode.

Fig. 4 shows the structure of the push-in electrode of an amorphous silicon, TFT switch. The dielectric 408 must be sufficiently thin and have a dielectric constant compatible with low voltage AC driving, such as is available from conventional image controllers for LCD displays. For example, the dielectric layer may comprise about 20-40nm SiO top overcoated with 200-400nm plasma deposited silicon nitride ₂ And (3) a layer. Alternatively, the dielectric may comprise atomic layer deposited Al 2 to 100nm thick, preferably 20 to 60nm thick ₂ O ₃ . The TFT is constructed by creating alternating layers of differently doped amorphous silicon structures along various electrode lines using methods known to those skilled in the art. Hydrophobic layer 407 may be formed of a material such asAF (Sigma-Aldrich, Milwaukee, Wis.) and FlurorPel from Cytonix (Beltsville, Md.) ^TM The material of the coating is configured such that the material may be spin coated on the dielectric layer 408.

In the present invention, a second substrate with TFT functionality is constructed to provide capacitive sensing capability and the two layers are separated by a spacer that creates a microfluidic region between the two layers. Capacitive sensing of droplets uses two electrodes as shown in fig. 6. Typically, an AC signal is applied to drive electrodes 506, whereby the AC signal creates a capacitively coupled voltage on nearby sense electrodes 505. The capacitively coupled signal is measured by an external circuit, and a change in the signal is indicative of the material between the drive electrode 506 and the sense electrode 505. For example, due to the difference in relative dielectric constant between materials, the coupling voltage will be significantly different depending on whether oil 202 or water 204 droplets are between the electrodes. (relative permittivity ε of silicon oil _r 2.5, relative dielectric constant ε of ethanol _r 24, relative dielectric constant ε of water _r ＝80。)

Fig. 5 shows the structure of an amorphous silicon sensing layer comprising a sensing electrode 505 and a driving electrode 506 of a TFT switch. The AC signal for the drive electrodes runs horizontally and only one line is activated at a time to minimize capacitive coupling with the sense lines and the "off" sense electrodes. TFTs are not perfectly switched and have some small conductance even in the "off" state. This means that a large number of off lines may have a similar signal to one "on" pixel. For this reason, it is desirable to minimize the capacitive signal from the ac voltage above and below the driven row by having the ac voltage only on the driven row.

As shown in FIG. 6, the sense electrodes and drive electrodes create coplanar gap cells. One major advantage is that the two plates do not need to be precisely aligned, or even have the same pixel pitch, thus simplifying the manufacture of the two plate system. Additional details of capacitive sensing of droplets using interdigitated gap cells can be found, for example, in "lab-on-a-chip devicesCapacitance changes caused by Microfluidic Two-Phase Flow across an Insulated Interdigital electrode (capacitive Two-Phase Flow across an Insulated Interdigital electrode) "T.Dong, CBarbosa,sensor (Sensors)15, 2694-. The circuitry for detecting the capacitance signal may include various electronic components including amplifiers, multiplexing switches. Advanced designs may include amorphous Si TFT arrays coupled to multi-channel charge sensors such as those used for digital X-ray imaging. See "Front-end electronics for imaging detectors", g.de Geronimo et al,nuclear instrumentation and method in physical research A(Nuclear Instruments and Methods in Physics Research A)471 page 192-.

In some embodiments, it is not necessary to provide multiple independent drive electrodes for the AC signal. As shown in fig. 7, the drive electrodes may be arranged adjacent to, but interdigitated with, the sense electrodes. (all electrodes shown in FIG. 7 are in the same metal layer, but are shown in different colors to indicate their function.) in FIG. 7, an AC signal is provided to a single drive electrode that is horizontally across the surface, while the various sense electrodes are "read" across the array. Typically, only one sensor line is activated at a time to minimize capacitive coupling between the AC signals from the drive and sense electrodes in the "off" mode. Without such a row-by-row readout, the signals from multiple sense electrodes in an "empty" state (e.g., coupled to oil) would appear to be larger than appropriate, reducing the signal-to-noise ratio of the correct sense electrodes. In alternative embodiments, the top substrate may include drive electrodes, sense electrodes, and a ground grid. As described above, the drive and sense electrodes can be used for drop sensing, while the ground grid provides an electrode surface area opposite the push electrode that has a low impedance to electrical ground.

The present invention will use circuitry coupled to the top drive and sense electrodes to provide capacitive sensing, allowing the device to track the position of a droplet manipulated by the device. However, the signal from capacitive sensing of a droplet on a small sensing electrode is also relatively small, so one hundred to three hundred rows of sensor electrodes may be required to obtain an acceptable signal-to-noise ratio. Providing such a high density of sensing electrodes across the entire device would be expensive and unnecessary. Thus, for larger arrays (such as for combinatorial chemistry), it is preferable to have a small local area with a high density of sensing pixels on the top plate for particle size measurement, and a lower density elsewhere for motion sensing.

As shown in fig. 8, AM-EWoD devices with different densities of sensing electrodes may be produced at various locations on the top plate. In the embodiment of FIG. 8, there is a high resolution area of 200dpi on the array for drop size measurement, and a resolution area of 10dpi to track drop movement. In fig. 8, the sensor would be 181.61mm wide for 100 measurement lines. If the TFT EWoD advancing substrate under the sense plate had a uniform resolution of 200dpi (electrodes per inch), then there would be 1430 rows of advancing electrodes to control the movement, mixing, etc. of the droplets. In contrast, a device limited to one hundred sense lines with a resolution of 180dpi across the entire device would be only 14.1 millimeters wide, resulting in only 111 lines of push electrodes; may be too small for complex analysis. Thus, by providing different densities, larger devices can be made with all the required sensing capabilities. In general, the low resolution area will comprise 1 to 15 electrodes per linear cm, while the high resolution area will comprise 20 to 200 electrodes per linear cm. Generally, the total area (length x width) of the sensing electrodes with a lower density (also referred to as "low resolution") is larger than the total area of the sensing electrodes with a higher density (also referred to as "high resolution"). For example, the low resolution area may be three times or more larger than the high resolution area as compared to the high resolution area. For example, the low resolution area may be five times or more larger. For example, the low resolution area may be ten times or more larger than the high resolution area.

An additional benefit of using different densities of sensing electrodes is that portions of the top plate may be provided with transparent or otherwise light transmissive regions to allow further interrogation of the droplets. For example, the fluorescent label may be observed by illuminating the droplet with a light source through the top substrate and then observing the resulting fluorescence through the top substrate using a detector and optionally a color filter. In other embodiments, light may pass through both the top and bottom substrates to allow absorption measurements at IR, UV or visible wavelengths. Alternatively, attenuated (frustrated) total internal reflection spectroscopy may be used to detect the content and/or location of droplets in the system.

One embodiment of such a system is shown in fig. 9, where the gap 910 between the sensing electrodes 905 is of the order of 2mm, allowing light 915 to pass from the objective lens 920 to illuminate the passing droplet 930. In one embodiment, droplet 930 contains fluorescent molecules, and the resulting fluorescent signal is collected back through objective lens 920 and separated using a dichroic filter (not shown) for detection with a detector (not shown). Thus, the design allows for different types of information to be collected about the droplet as it moves through the system, such as capacitance and spectral information.

As discussed with respect to fig. 8, the simplest way to implement low resolution sensing would be to have the same sensing pixel design as the high resolution area, but with a large space around the sensing pixels. This concept is illustrated in a different embodiment of fig. 10. With the design of fig. 10, it will be possible for a droplet to pass between low resolution sensing pixels, but a droplet control algorithm can be programmed to ensure that the droplet passes regularly through the sensing pixels, allowing the size and composition of the droplet to be monitored. As shown in fig. 10, the uniform distribution of low resolution pixels allows for a significant increase in the area available for sensing, while allowing the use of commercially available drivers. Alternatively, the number of sensing pixels on any one vertical sensing line may be constant while the sensing pixels are staggered, as shown in fig. 11. Other patterns, such as pseudo-random patterns, may also be employed to maximize interaction with the droplets while reducing the actual number of sensing TFTs that must be fabricated and subsequently addressed.

Different shapes of electrodes may also be used to create the low resolution sensing area and the high resolution sensing area, as shown in fig. 12 and 13. Fig. 12 shows square pixels in the high resolution sensing region and larger rectangular sensing pixels in the low resolution sensing region. This design would be effective for sensing up and down movements along the array, i.e. from one elongate electrode to another. This same technique can be implemented to fabricate both horizontally and vertically elongated electrodes, which would provide drop tracking with lower resolution. FIG. 13 shows a low resolution area with vertical rectangular sensing pixels and horizontal rectangular sensing pixels to detect vertical and horizontal movement of a droplet. Other geometric designs, such as a spiral, may also be used to facilitate position sensing with fewer electrodes and fewer TFTs. As shown in fig. 12 and 13, droplets can be easily moved from a low density region where droplet generation, fragmentation or mixing occurs to a high density region where the size and composition of those droplets can be evaluated.

From the foregoing, it will be seen that the present invention can provide low cost lab-on-a-chip functionality. In particular, by using the described structure, electrowetting can be produced on a dielectric system using amorphous silicon fabrication facilities and lower cost drive electronics. The present invention effectively utilizes the available surfaces on both the top and bottom of the EWoD device, but does not require alignment of the electrodes on the top and bottom surfaces.

It will be apparent to those skilled in the art that many changes and modifications can be made to the specific embodiments of the invention described above without departing from the scope of the invention. Accordingly, the entire foregoing description is to be construed in an illustrative and not a restrictive sense.

Claims (17)

1. A digital microfluidic device, comprising:

a first substrate comprising a plurality of push electrodes coupled to a first set of thin film transistors and comprising a first dielectric layer covering both the plurality of push electrodes and the first set of thin film transistors;

a second substrate including a plurality of sensing electrodes and driving electrodes coupled to a second set of thin film transistors, and including a second dielectric layer covering the plurality of sensing electrodes, the second set of thin film transistors, and the driving electrodes;

a spacer separating the first substrate and the second substrate and creating a microfluidic region between the first substrate and the second substrate;

a first controller operably coupled to the first set of thin film transistors and configured to provide a propel voltage to at least a portion of the plurality of propel electrodes, wherein application of an AC signal to the propel electrodes moves fluid of a microfluidic region; and

a second controller operatively coupled to the second set of thin film transistors and configured to determine a capacitance between at least one of the plurality of sense electrodes and the drive electrode, wherein application of an AC signal to the drive electrode generates a capacitively coupled voltage on nearby sense electrodes.

2. The digital microfluidic device according to claim 1 wherein said first dielectric layer is hydrophobic.

3. The digital microfluidic device according to claim 1 wherein said second dielectric layer is hydrophobic.

4. The digital microfluidic device according to claim 1 further comprising a first hydrophobic layer covering said first dielectric layer and a second hydrophobic layer covering said second dielectric layer.

5. The digital microfluidic device according to claim 1 wherein said first plurality of thin film transistors or said second plurality of thin film transistors comprise amorphous silicon.

6. The digital microfluidic device according to claim 1 wherein said plurality of push electrodes are arranged in an array.

7. The digital microfluidic device according to claim 6 wherein said array of a plurality of push electrodes comprises at least 25 electrodes per linear centimeter.

8. The digital microfluidic device according to claim 1 wherein each of said plurality of sensing electrodes is interdigitated with said drive electrode.

9. The digital microfluidic device according to claim 8 further comprising a signal source coupled to said drive electrodes and configured to provide a time-varying voltage to said drive electrodes.

10. The digital microfluidic device according to claim 8 wherein said plurality of sensing electrodes have a width of 0.01 to 5 mm.

11. The digital microfluidic device according to claim 1 wherein said second substrate comprises at least one light transmissive region.

12. The digital microfluidic device according to claim 11 wherein said optically transparent region has an area of at least 10mm ² 。

13. The digital microfluidic device according to claim 1 wherein said plurality of sensing electrodes are arranged at a first density and a second density, and said first density comprises per 100mm ² At least three times the second density.

14. The digital microfluidic device according to claim 13 wherein said first density comprises 20 to 200 electrodes per linear centimeter.

15. The digital microfluidic device according to claim 13 wherein said second density comprises 1 to 15 electrodes per linear cm.

16. The digital microfluidic device according to claim 13 wherein the area of said device corresponding to said first density is smaller than the area of said device corresponding to said second density.

17. The digital microfluidic device according to claim 16 wherein the area of said device corresponding to said second density is at least three times the area of said device corresponding to said first density.