Patent Grant
9110017
1. Technical Field
The presently disclosed subject matter relates generally to apparatuses and methods for manipulating droplets. More particularly, the presently the use of apparatuses comprising multiple arrays of electrodes disposed on a substrate wherein corresponding electrodes in each array are connected to a common electrical signal.
2. Background
Microfluidics is a rapidly advancing field which deals with the study of sub-microliter fluids. Microfluidic devices are increasingly finding application and acceptance in many fields of biology, chemistry, medicine, environmental monitoring, drug discovery, and consumer electronics. Miniaturization of traditional devices, particularly analytical devices, is expected to lead to many benefits including reduced consumption (and cost) of reagents and samples, higher throughput and automation, faster analysis times, and more reliable, inexpensive, and portable instrumentation. As more functionality becomes embedded within these devices, fully integrated micro-total-analysis systems (μTAS) or labs-on-a-chip are becoming a reality and increasingly important.
Lab-on-a-chip is an emerging paradigm which aims to miniaturize and integrate fluid-handling onto a chip. A lab-on-a-chip should enable fluid dispensing, transport, mixing, incubation, detection/separation, and waste disposal for it to be a truly self-contained unit. Microfluidic lab-on-a-chip systems can be broadly categorized into continuous-flow and discrete-flow systems. A continuous-flow system is self-descriptive and in discrete-flow systems the fluid is discretized into droplets. A common limitation of continuous flow systems is that fluid transport is physically confined to fixed channels, whereas droplet-based (or discrete-flow) systems can be either confined to physical channels or operate on planar and channel-less systems. The transport mechanisms generally used in continuous-flow systems are pressure-driven by external pumps or electrokinetically-driven by high-voltages. Continuous-flow systems can involve complex channeling and require large supporting instruments in the form of external valves or power supplies. In another approach to channel-based systems, centrifugal forces drive the fluids to flow uni-directionally in channels. The continuous-flow microfluidics paradigm has limitations in versatility, making it difficult to achieve high degrees of functional integration and control.
Discrete-flow or droplet-based microfluidic systems have been progressing steadily to fulfill the promise of the lab-on-a-chip concept to handle all steps of analysis, including sampling, sample preparation, sample-processing including transport, mixing, and incubation, detection, and waste handling. These steps have been designed to be performed on-chip without significant off-chip support systems. A few discrete-flow approaches have been recently developed for manipulating droplets based on multilayer soft lithography, hydrodynamic multiphase flows, continuous electrowetting, electrowetting-on-dielectric (EWOD), dielectrophoresis, electrostatics, and surface acoustic waves. Some of the above techniques manipulate droplets or slugs in physically confined channels while other techniques allow manipulation of droplets on planar surfaces without any physically defined channels. The channel-less droplet-based approaches have been referred to as “digital microfluidics” because the liquid is discretized and programmably manipulated.
Droplet-based protocols are very similar to bench-scale biochemical protocols which are also generally executed on discrete volumes of fluids. Therefore, established protocols can be easily adapted to digital microfluidic format. Some of the distinguishing features of digital microfluidic systems include: reconfigurability (droplet operations and pathways are selected through a software control panel to enable users to create any combination of microfluidic operations on-the-fly); software programmability also results in design flexibility where one generic microfluidic processor chip can be designed and reprogrammed for different applications; conditional execution steps can be implemented as each microfluidic operation can be performed under direct computer control to permit maximum operational flexibility; multidirectional droplet transport since the channels only exist in the virtual sense and can be instantly reconfigured through software; small droplet volumes (<1 μL); completely electronic operation without using external pumps or valves; simultaneous and independent control of many droplets; and channel-less operation (where no priming is required).
Many current lab-on-a-chip technologies (including both continuous-flow and discrete-flow devices) are relatively inflexible and designed to perform only a single assay or a small set of very similar assays. Due to the fixed layouts of current microfluidic chips, a new chip design is required for each application, making it expensive to develop new applications. Furthermore, many of these devices are fabricated using expensive microfabrication techniques derived from semiconductor integrated circuit manufacturing. As a result, applications for microfluidic devices are expanding relatively slowly due to the cost and effort required to develop new devices for each specific application. Although batch fabrication allows microfabricated devices to be inexpensive when mass-produced, the development of new devices can be prohibitively expensive and time consuming due to high prototyping costs and long turn-around time associated with standard semiconductor microfabrication techniques. In order to broaden the range of applications and impact of microfluidics in medicine, drug discovery, environmental and food monitoring, and other areas including consumer electronics, there is a long-felt need both for microfluidic approaches which provide more reconfigurable, flexible, integrated devices, as well as techniques for more inexpensively and rapidly developing and manufacturing these chips.
Over the past several years there have been advances utilizing different approaches to microfluidics based upon manipulation of individual nanoliter-sized droplets through direct electrical control. Examples of such systems can be found in U.S. Pat. No. 6,911,132 and U.S. Patent Application Publication No. 2004/0058450, both to Pamula et al. (and commonly assigned to the Assignee of the present subject matter), the disclosures of which are incorporated herein by reference. These techniques offer many advantages in the implementation of the digital microfluidics paradigm as described above but current fabrication techniques to produce these microfluidic chips still depend on rather complex and expensive manufacturing techniques. These microfluidic chips are currently produced in microfabrication foundries utilizing expensive processing steps based on semiconductor processing techniques routinely used in the integrated circuit (IC) fabrication industry. In addition to higher cost for semiconductor manufacturing techniques, semiconductor foundries are not easily accessible and typically do not offer fabrication or prototyping turn-around times of as quick as 24 hours. Microfluidic chips are generally fabricated using custom processes based on traditional semiconductor microfabrication procedures. Devices are fabricated on glass substrates through repeated steps of thin film deposition and patterning using standard photolithographic techniques. Typically, at least two metal layers (one for electrodes and one for wiring) are required in addition to two or three insulator layers, as well as layers for forming the standoff between the top and bottom plates. Due to the high cost of photomask fabrication and chip manufacturing, a single prototyping run producing up to 100 devices can cost as much as $10,000 and require three months to complete depending on the number of photolithographic levels. Furthermore, since the process flow is not standardized, device yields tend to be very low during the first several attempts to fabricate any new design.
The expense and time required for prototyping has been a serious impediment to the development and optimization of droplet-based microfluidics. Furthermore, the high chip costs and inability to rapidly customize or improve device designs is expected to dampen the commercial prospects of this versatile technology. In the short term, a more rapid, reliable and low cost fabrication technology is required to accelerate development and user acceptance of these devices. Since microfluidic structures tend to be relatively large and rarely test the limits of semiconductor manufacturing techniques, lower resolution, lower cost batch fabrication methods should be considered.
In particular, printed circuit board (PCB) technology offers many capabilities and materials similar to traditional semiconductor microfabrication though at much lower resolution. Layers of conductors and insulators are deposited and photolithographically patterned and stacked together to create intricate multi-level structures. For the fabrication of digital microfluidic systems, it is believed that PCB technology offers an excellent compromise in terms of resolution, availability, cost and ease of manufacture. It is further believed that an additional advantage of using a PCB as a substrate is that electronics for sensing, controlling or analyzing the device can be easily integrated at very low cost.
Typically, the copper line width and line spacing is measured in mils (25.4 μm) in a PCB process, which is orders of magnitude higher than the sub-micron features generally achieved in a semiconductor fab. Typically, PCB processing does not require an expensive ultra-clean environment as is required for semiconductor IC fabrication. The boards are also generally made out of reinforced plastic, glass fiber epoxy, TEFLON®, polyimide, etc. as compared to silicon or glass which are used as substrates for microfluidic devices microfabricated in a semiconductor fab. Also, in place of a semiconductor mask aligner, alignment can usually be performed manually for PCB processing. Inexpensive masks made out of transparencies or MYLAR sheets are used in place of expensive chrome-on glass photomasks used in semiconductor fabs. In PCB processing, via holes are drilled either mechanically or with a laser and then electroplated instead of etching and vapor deposition used in semiconductor processing which necessitates vacuum processing. Multiple wiring layers are generally obtained by bonding individually patterned single boards together as opposed to using a single substrate and building up the multiple layers or bonding wafers in a semiconductor fab. Broadly, these are the main differences between a PCB fabrication process and a semiconductor fabrication process even though high-end PCB processes are moving towards adopting some of the semiconductor processes (such as physical vapor deposition).
In today's highly competitive commercial environment, it is imperative that products reach the marketplace quickly and cost-effectively, particularly in consumer electronics and medical diagnostics businesses. The present subject matter is related to utilizing printed circuit board (PCB) manufacturing techniques which are widely available, reliable, inexpensive and well-defined. By fabricating reconfigurable microfluidic platforms with a reliable, easily accessible, and low-cost manufacturing technology, the development and acceptance of lab-on-a-chip devices for many potential applications in biomedicine and in other areas will be more widespread and rapid.
The attractiveness of PCB technology as an inexpensive, well-established, flexible and easily accessible manufacturing process for the development of microfluidic systems has already been recognized by researchers working with more traditional continuous-flow microfluidic systems. For example, researchers have previously demonstrated a number of continuous-flow microfluidic devices based on PCB technology including a bubble detector, a pH regulation system, a micropump, and a capacitive pressure sensor. More recently, PCB devices for the manipulation and analysis of single cells by dielectrophoresis have also been reported, as have hybrid approaches in which a PCB is used to monolithically integrate silicon-based microfluidic devices. However, there remains a long-felt need for an inexpensive, flexible, and reconfigurable system for discrete-flow manipulation of droplets.
In one embodiment, an apparatus for manipulating droplets is disclosed, the apparatus comprising a substrate, multiple arrays of electrodes disposed on the substrate, wherein corresponding electrodes in each array are connected to a common electrical signal, and a dielectric layer disposed on the substrate first side surface and patterned to cover the electrodes.
In another embodiment, an apparatus for manipulating droplets is disclosed, the apparatus comprising a substrate, a top plate arranged in a parallel orientation relative to the substrate and separated therefrom to define a gap between the top plate and the substrate, multiple arrays of electrodes disposed on the substrate, wherein corresponding electrodes in each array are connected to a common electrical signal, and a dielectric layer disposed on the substrate first side surface and patterned to cover the electrodes.
Methods for manipulating droplets are also disclosed. In one embodiment, a method of manipulating a droplet comprises providing an apparatus comprising a substrate, multiple arrays of electrodes disposed on the substrate, wherein corresponding electrodes in each array are connected to a common electrical signal, and a dielectric layer disposed on the substrate first side surface and patterned to cover the electrodes. The method also comprises providing a droplet on the substrate and activating electrodes of the multiple arrays of electrodes to cause the droplet to be manipulated.
In yet another embodiment, an apparatus for manipulating droplets is disclosed, the apparatus comprising a substrate, a top plate arranged in a parallel orientation relative to the substrate and separated therefrom to define a gap between the top plate and the substrate, multiple arrays of electrodes disposed on the substrate, wherein corresponding electrodes in each array are connected to a common electrical signal, and a dielectric layer disposed on the substrate first side surface and patterned to cover the electrodes.
A printed circuit board (PCB), also sometimes called a printed wiring board (PWB), is a substrate used to interconnect electronic components using conductive pads and traces patterned on the substrate. Typically, PCBs are made by adhering a layer of copper over the entire substrate, sometimes on both sides, (known as creating a “blank PCB”) then removing unwanted copper (e.g., by etching in an acid) after applying a temporary mask, leaving only the desired copper traces. Electrical connections (“vias”) between opposite sides of the substrate can be formed by drilling holes through the substrate either mechanically or with a laser and metallizing the interior of the drill hole to provide a continuous electrical connection between the two sides. Multilayer boards can be created by bonding together individually processed substrates. Electrode lines in the copper layer are usually defined by etching copper from a blank PCB in a subtractive process while some foundries use semi-additive and fully-additive processes where copper is built up on the substrate by electroplating or other techniques.
As discussed above, digital microfluidics is a microfluidic approach in which discrete droplets of fluid are electrically manipulated upon a substrate containing an array on electrodes. In a commonly used configuration, the droplets are sandwiched between two parallel plates where the top plate physically confines the droplets and the bottom plate contains an array of individually addressable drive or control electrodes (or elements) which are electrically insulated. Typically, one or more reference electrodes (or elements) are also required to control the electrical potential of the droplet. Reference electrodes may be either provided on the same substrate as the drive electrodes (co-planar) or on an opposite plate (bi-planar). The space between the two plates surrounding the droplet is generally open and may be filled with air or with an immiscible liquid to prevent evaporation. Examples of immiscible liquids that may be used with aqueous droplets include silicone oil, fluorosilicone oil or hydrocarbon oils. When the reference electrodes and drive electrodes are provided on the same substrate, the opposing plate does not serve as part of the electrical circuit, but serves only as a cover plate to physically contain the liquids and may not be required for operation of the device.
Droplet actuation is achieved by applying a potential between the reference electrode and one or more of the drive electrodes. The applied potential can be DC or AC and the reference electrodes need not be physically distinct from the drive electrodes. A droplet adjacent to an activated control electrode will become attracted towards that control electrode and move towards it. Control electrodes may be sequentially activated using user-defined patterns (possibly using an electrode selector) to transport droplets along arbitrary pathways defined by contiguous control electrodes. In addition to transport, other operations including merging, splitting, mixing, deforming and dispensing of droplets can be accomplished based on the design of the control electrodes and patterns of activation.
A digital microfluidic processor is essentially comprised of an array of control electrodes with one or more reference electrodes. A complete chip may include many other types of structures including channels, liquid reservoirs, top-plates, sensors, inlets, outlets, etc. The electrode array requires interconnections to electrically connect certain electrodes together and to connect electrodes to contact pads for connection to external circuitry. Previously, digital microfluidic chips were fabricated on glass or silicon substrates using thin-film deposition and photolithography techniques borrowed from semiconductor manufacturing. Multiple levels of electrical interconnect for wiring were built-up by depositing and patterning successive layers of conductors and insulators upon a single starting substrate. The present subject matter pertains to apparatuses and methods whereby digital microfluidic processors can be advantageously constructed in a standard PCB process as opposed to a custom glass or silicon based process.
The presently disclosed subject matter takes advantage of the ease with which multiple layers of conductors can be generated in a PCB process versus a glass or silicon based process. This is essentially the case because in PCB processing the metal layers are manufactured on separate substrates which are laminated together at the end rather than built up sequentially on a single substrate.
The PCB digital microfluidic chip as envisioned herein can have one or more wiring layers. The conductor wiring patterns are transferred onto the PCB substrate by subtractive plating, panel plating, pattern plating, or additive plating. When only one layer of wiring is used, all the electrodes for droplet manipulation and the pads for electrical input/output connections are made on a single-sided board which does not require any via holes. Generally, two or more wiring layers will be required for complex droplet handling operations which necessitate using multilayer boards. Multilayer boards are assembled by bonding several double-sided boards or by built-up/sequential boards which do not require mechanical drilling of holes (e.g., via holes are chemically etched or laser drilled and then electroless plated). By definition, double-sided boards have wiring on both sides of the boards which can be further classified into boards without through-hole metallization and boards with through-hole metallization. The boards with through-hole metallization are further classified into plated through-hole metallization and filled through-hole metallization. In plated through-hole metallization, the holes are metallized by copper plating (e.g., electroplating or electroless plating or a combination thereof) and in filled through-hole metallization, the holes can be filled with conductive pastes such as copper paste, silver paste, conductive epoxy, etc.
In digital microfluidic chips, through-holes (or via holes) are drilled through the center of the drive electrodes on one side of a multi-layer board to make electrical connections on the opposite side of the board. The foot print of a droplet is defined by the area of a drive electrode. In order to obtain small droplet volumes, the area of the drive electrodes need to be minimized. Since via holes are drilled through the drive electrodes, it is important to minimize the diameter of the via holes including the pad/land diameter. Therefore, via holes play an important role in defining the minimum volumes of droplets obtainable in a PCB process. The PCB industry is driving down the via hole sizes for a different reason which is to avoid blocking the wire routing channels and to maximize the PCB surface area available for traces. Many built-up processes use small vias which are formed by punching through using an excimer laser. There are a number of variations of the built-up processes used in the PCB industry including, but not limited to, Surface Laminar Circuits (SLC) where the vias are photoformed; DYCOstrate™ where the vias are dry-plasma etched in parallel; Film Redistribution Layer (FRL) where the outermost dielectric is photosensitive while inner layers constitute a regular multilayer board; Conductive Adhesive Bonded Flex (Z-Link); Built-up Structure System (IBSS) where the dielectric is photosensitive; Sequential Bonding Cores/Any-Layer Inner Via-hole (ALIVH) where a CO2 laser is used to drill the vias and the holes are then filled with silver paste; Carrier Formed Circuits where separate circuits are prepared on stainless steel carriers and then laminated onto an FR-4 prepreg; Roll Sheet Buildup where single-sided epoxy coated foils are laminated by rolling heat and pressure; and Sheet Buildup which is similar to roll sheet buildup but double sided or multilayer circuits are laminated. In one embodiment of using a built-up board (Z-Link) for digital microfluidic chips, multiple flex boards consisting of polyimide-backed copper foils can be laminated together and then onto a rigid board to form a multi-layer board. In this case, the holes in each flex layer can be punched, laser-drilled or plasma-drilled. The holes interconnecting various layers can then be filled by conductive adhesive.
With reference to
In each of the embodiments shown in
As discussed above, electrostatic microfluidic devices of the present subject matter include a substrate board 12 which can be fabricated on almost any board material commonly in use for the manufacture of PCBs. These materials include, but are not limited to, FR-2, FR-4, FR-5, polyimide, Kapton™, Rogers™, Duroid™, BT, cyanate esters and Polytetrafluoroethylene (PTFE). Rigid, rigid-flexible or flexible substrates can be used as base material 12 for the fabrication of these devices.
The outermost conductive copper layer of the PCB is patterned to form the drive electrodes required to manipulate liquid droplets by electric fields. Drive electrodes 16 may take a wide variety of shapes and forms depending on the particular application. For example, arrays of square-shaped electrodes, arrays of circular-shaped electrodes, arrays of hexagon-shaped electrodes, arrays of star-shaped and other interlocking or interdigitated electrode shapes, as well as elongated electrode structures can be used. Reference electrodes 18 can also be patterned in the same conductive layer or in a separate conductive layer on the same substrate (co-planar) or can be provided on a separate substrate (bi-planar).
In one embodiment as shown in
In another embodiment as shown in
In a further embodiment as shown in
In another embodiment as shown in
Because very little current is needed to charge drive electrodes 16 for electric field-based droplet manipulation, the conductive material forming the electrodes can be substantially more resistive than is typically acceptable for PCB applications. Thus, a wide range of different types of conductors, besides copper, may be used. This includes conductors which are typically considered unsuitable for forming pads and traces on PCBs. Similarly, the conductive layer may be substantially thinner than is typically favored for PCBs. Ideally, the conductive layer should be as thin as possible to minimize the topography of the conductive features which must be subsequently covered by the insulating layer. Additionally, minimization of the conductor thickness promotes planarity of the PCB surface which is desirable for consistent and reliable manipulation of droplets upon the surface. The conductor thickness may be minimized by using a starting substrate material with minimal conductor thickness (e.g., ¼ oz. or 5 μm layer of copper cladding) or by adding a polishing or etching step to reduce the conductor thickness prior to deposition of the insulator.
Conductive traces on PCB substrate 12 are used to make electrical connections to drive electrodes 16 and reference elements 18. Each drive electrode 16 or reference element 18 can be connected to one or more other drive electrodes 16 or reference elements 18, to other electronic components on the same PCB substrate 12, or to pads for external connection. In one arrangement, pads for external connection are provided along an edge of the PCB and the PCB is adapted for use in an edge-card connector socket 28 (see
As shown in
In order to establish electrical connections between electrodes and traces several approaches are available. In one approach, a wire or trace leads away from the electrode on the same side of the PCB, the wire can then be routed if necessary through the substrate at a via location remote from the electrode. In another approach, vias are made within the electrodes. In this case a means for filling or covering the drill hole may need to be provided to prevent liquid from entering or evaporating through the via drill hole. Via hole 24 may be plated shut using electroless or electroplating or may be filled or covered using a variety of techniques and a variety of materials (conductive epoxy, non-conductive epoxy, transparent epoxy, or any other material). After filling the via holes with any of these filler materials, the surface of the PCB can then be covered with copper by electroless or electroplating to completely obscure the via hole to the droplets moving on the surface.
In one approach, the hole is made small enough so that an insulator deposited in liquid form, such as a traditional liquid soldermask material, is prevented from penetrating the hole by viscous or surface tension effects, or it could be made large enough so that the liquid soldermask can enter the via hole thereby forming a soldermask-filled via hole 24′ (see
Referring further to
Soldermasks are available in two varieties: liquid photoimageable (LPI) or dry film soldermask (DFSS). LPI is not conformal. DFSS offers near vertical sidewalls and has been reported for fabricating electroplating molds, sealing of fluidic channels and as a mask for powderblasting of microchannels. However, DFSS has not been used to form liquid reservoirs or as a gasket material to provide a stand-off or seal between two parallel plates as is envisioned in the present subject matter.
In certain applications, soldermask materials may not exist with the desired combination of thermal, mechanical, electrical or optical properties. In these cases, the soldermask materials can be replaced with or combined with other types of insulator materials. For example, spin-on materials such as polyimide, dip or spin or spray or brush-coatable materials such as TEFLON® AF and Cytop™, vapor deposited or sputtered materials such as silicon dioxide, and polymers such as parylene may be applied to the PCB substrate.
As an alternative to soldermask for insulator 22, a thin layer of parylene could be deposited in a physical vapor deposition (PVD) process as a dielectric. Parylene is the generic name for a family of poly(para-xylylene) polymers which includes parylene C, D, and N. As used in this disclosure, parylene refers to any poly(para-xylylene) composition and mixtures thereof. A major advantage with parylene is that it can be deposited as a conformal layer and at a thickness much less than both LPI and DFSS. In PCB methods, LPI can be coated as thin as 0.5 mils (1 mil=25.4 μm) while pin-hole free parylene can be coated as thin as 0.5 μm. Such a thin insulator layer reduces the required potential for droplet actuation. In some applications, the dielectric will have to be patterned to expose the copper electrodes. Parylene can be patterned by reactive ion etching, plasma ashing, chemical etching, or by laser ablation. Alternatively, parylene can also be selectively deposited by masking the regions that need to be exposed by a tape (for example, 3M® Mask Plus II Water Soluble Wave Solder Tape No. 5414 which is used to mask gold fingers on PCBs during wave soldering). Other representative examples of materials that could be used as dielectrics include silicones, polyurethanes, acrylics, and other spin-coatable or depositable dielectrics.
Generally, it is desirable to minimize the thickness of insulator 22 in order to reduce the voltage required for actuation of the liquid.
It is also envisioned that additional layers of soldermask material may be deposited and patterned to create physical structures on the PCB surface such as wells and channels (not shown) for use in pooling or directing liquid flow.
In a further embodiment, a combination of subtractive and additive processes can be used to fabricate PCB droplet manipulation boards of the present subject matter. Subtractive processes can be used to fabricate a multilayer board that defines all the electrical routing and interconnections to the droplet control electrodes. A patternable dielectric layer can then be applied. Vias can be patterned in this dielectric by laser drilling or photomasking. In one embodiment, LPI can be used as a dielectric. The electrode pad exposed in the hole can be optionally plated to make it planar with the dielectric surface. At this point, an additive process can be used to define all electrodes using electroless copper deposition as a smaller line spacing could be obtained.
A finished device can include a combination of standard PCB processes and non-standard processes. For example, a one-step hydrophobic coating may be applied to a finished PCB to facilitate transport of droplets. Furthermore, the use of soldermask as a dielectric might be undesirable for certain applications, in which case uninsulated PCBs could subsequently be coated with specialty materials not available in a standard PCB process. However, in such cases, the use of a PCB as the starting substrate and PCB processes to form the conductive traces still provides many, if not most, of the benefits of a fully PCB-compatible process.
In one embodiment, all the conductor lines required for electrical routing can be fabricated on a multi-layer PCB. Some or all of the outer layer of copper can then be removed by polishing or chemical etching. This PCB, which contains all the electrical wiring required for droplet manipulations, can then serve as a substrate for further processing to pattern drive and reference electrodes with finer line spacing. In order to obtain fine line spacing, the control electrodes may be patterned using semiconductor processing techniques including thin film deposition and photolithography.
In an embodiment where reference electrodes 18 are also patterned in the same layer as drive electrodes 16 (see, for example,
In one embodiment, after all the copper electrodes are formed as described hereinabove, the LPI coating can then be used as an inter-level dielectric and another copper layer can be patterned over the LPI to serve as reference electrodes. The dielectric can also be a thin (2 mil or less) prepreg PCB board in a typical multilayer construction or it could be a flex board with copper features to serve as reference electrodes on the outermost layer. The copper layer just beneath this outermost copper layer has copper features that define the drive electrodes.
In a further embodiment, it is envisioned that the PCB of the present subject matter may also consist of electronic components in the areas which are not used for liquid handling. The electronic components can include microcontrollers, relays, high voltage multiplexers, voltage converters (DC-DC to step up the voltage, DC-AC, AC-DC, etc.), electro-optical elements such as LEDs, photodiodes, photo-multiplier tubes (PMT), heating elements, thermistors, resistance temperature devices (RTDs), and other electrodes for electrochemical measurements. Copper traces can also be used for impedance measurements of the droplets. Resistive heating elements are realized by meandering copper traces and the resistive heating characteristics will be dependent on the dimensions of the copper lines. In one embodiment, a PCB containing an optical detector, such as a PMT or a photodiode, can be used as a parallel plate to form a sandwich with the droplet manipulation PCB board. In another embodiment, gold coated electrodes obtained in a standard PCB process can be used for electrochemical measurements.
Mechanically drilled holes on a PCB are used typically for affixing or securing the board to another surface. It is further envisioned in the PCB microfluidic chip of the present subject matter that these drill holes can be used to serve as fluidic input/output ports for the addition and removal of liquids to or from the surface of the PCB substrate. It is further envisioned that these drill holes can be mated with a source of liquid including, but not limited to, flexible tubing, syringes, pipettes, glass capillary tubes, intra-venous line, or microdialysis lumen. The liquid in these tubes can be driven by pressure or any other means. A continuous flow of liquid from the tubing can be interfaced to the PCB through these drill holes which can be discretized into droplets either directly from the flow or through an intermediate reservoir on the PCB.
For instance, in one embodiment, metallized drill holes (see, for example, drill holes 32 in
Generally, droplets moved on apparatuses of the present subject matter are manipulated within a horizontal plane in a sandwich structure with one or both of the plates comprising PCBs. In a further embodiment, the holes drilled on a PCB could be used to extract droplets out of the sandwich structure in a vertical plane. Droplets can be extracted through the holes in a variety of ways. In one method that exploits the pressure difference between a droplet confined in a sandwich structure and a large hole, droplets could be passively pushed through a hole with a diameter larger than the radius of the droplet by just positioning underneath the hole. Droplets could also be extracted by electrical means where another plate is added to the sandwich structure and the droplets can be pulled out of one sandwich structure into the newly-formed sandwich structure by applying an electric potential. In this case, to simplify the extraction process, a sandwich structure can be formed between a coplanar PCB substrate and another substrate with electrodes. While both these plates form a parallel-plate arrangement, the droplets will be touching only the coplanar PCB substrate and will move vertically onto the other substrate when an electric potential is applied on the other substrate to electrostatically pull the droplet out of plane. Droplet could also be moved vertically with gravity for stamping onto another plate. Applications for such vertical actuation of droplets include DNA or protein stamping applications. Droplets extracted from such holes can also be used to increase the path length for absorbance measurements and to transport into another sandwich structure to enable transport in another layer.
A number of biochemical reactions can be performed through the manipulation of liquids on PCB substrates as disclosed in the present subject matter. As disclosed herein, the present subject matter provides an apparatus for detecting a target analyte in sample solutions by optical and electrical means of detection. The sample solution may comprise any number of items, including, but not limited to, bodily fluids (including, but not limited to, blood, sweat, tears, urine, plasma, serum, lymph, saliva, anal and vaginal secretions, semen, of virtually any organism, with mammalian samples being preferred and human samples being particularly preferred); food and environmental samples (including, but not limited to, air, agricultural, water, and soil samples); biological warfare agent samples; research samples; purified samples, such as purified genomic DNA, RNA, proteins, cells, etc.; and raw samples (bacteria, virus, fungus, etc). The types of assays that can be performed on the PCB substrate as disclosed herein include enzymatic assays, DNA amplification isothermally or by thermocycling, immunoassays, including sandwich and homogeneous arrangements, and cell-based assays with optical and electrical means of detection. The analytes measured in the physiological samples includes metabolites, electrolytes, gases, proteins, hormones, cytokines, peptides, DNA, and RNA.
In one embodiment, a human physiological sample can be input into a reservoir on the PCB. The reservoir could be defined by the dry film soldermask. The sample can then be dispensed into droplets which will be mixed with the appropriate reagent droplets provided on the PCB or input onto the PCB. Some of the enzymatic assays can then be monitored optically (e.g., by absorbance, reflectometry, fluorescence, and luminescence). In the case of absorbance, the via holes can be filled with an optically transparent material so that the light can pass through a droplet positioned on one of these via holes for absorbance measurements.
In another embodiment, biochemical samples can also be synthesized on a PCB substrate using droplet manipulation techniques described herein. For example, on the PCB, a number of protein droplets can be dispensed from a reservoir and mixed with different reagents and incubated to automate finding conditions to crystallize a protein.
In a further embodiment, copper traces with thickness on the same order as the droplet height can be used so that the droplet is contained between the traces lying on the same substrate and covered with an insulator. The droplet is actuated through electric fields applied primarily in the plane of the substrate rather than perpendicular to it. Unlike the coplanar arrangement, where the droplet sits on the coplanar drive and reference electrodes and parallel-plate arrangement, where the droplet is sandwiched between the drive electrodes on a substrate and a common reference electrode on a parallel substrate, in this structure a droplet is sandwiched between the coplanar drive and reference electrodes.
While general embodiments and processes of the present subject matter have been discussed hereinabove, more specific embodiments of fabrication of an apparatus to manipulate micro-volume liquid samples wherein the apparatus comprises a printed circuit board substrate will now be discussed.
In a preferred embodiment, a FR-4 substrate is laminated with a ¼ Oz (˜9 μm) copper foil on both sides. 8 mil via holes are drilled through the substrate. These via holes are then electroplated with copper and filled with soldermask or an epoxy. Preferably, the via holes are button-plated to a thickness of about 5 μm where the via holes are specifically plated while the rest of the board is covered by a mask. The buttons are mechanically planarized and then the via holes are filled with soldermask or a non-conductive epoxy. After processing the via holes, a flash plating step is performed to a thickness of less than 5 μm. In case unfilled via holes are required, another step of drilling can be performed to obtain unfilled holes and plating is performed if necessary. At this stage, the designed electrode pattern is transferred onto the copper with a minimum line spacing of 2 mils by etching it through a mask. LPI is patterned and coated to a thickness of about 0.5 mils. Finally, a dry film soldermask is laminated and patterned to form the physical structures (e.g., wells and/or channels) to hold liquids and also to serve as a stand off material. In other embodiments, the stand off layer can also be obtained by using one of more LPI soldermask coatings or by laminating and etching a copper foil.
Experiments were conducted wherein a two-layer single-board design for an electric field-mediated droplet manipulator as disclosed herein was submitted to a commercially available electronics PCB manufacturer and tested. The design consisted of arrays of different control electrode shapes for transport and mixing of liquid droplets as well as specialized electrode shapes for dispensing of droplets from a larger liquid volume. The electrodes were connected to contact pads by conductive traces patterned in the same layer of copper on the surface of the PCB. Where necessary, the traces were routed between the two sides of the board using conventional vias at remote locations from the control electrodes. Several different chip designs and interconnection schemes were tested.
Some chips contained multiple copies of a single linear array of electrodes where the corresponding elements in each copy of the array were connected to the same electrical signal—thus multiple identical arrays could be controlled simultaneously. Other chips contained an electrode “bus” or conveyor structure where every fourth electrode in a contiguous line of control electrodes was connected to the same control signal. The use of such a structure allows arbitrarily long transport pathways to be controlled using a fixed number of control signals. Multiple droplets can be switched onto or off of the bus and synchronously transported. The contact pads were arranged along the side of the PCB and were designed to be contacted either using a standard edgecard connector or a standard SOIC test clip.
The arrays of control electrodes were designed with a pitch of either 1.0 mm or 1.5 mm and a nominal 2 mil spacing between adjacent electrodes. The substrate material was FR-4 with ¼ oz. copper cladding. The copper was patterned to form the control electrodes, traces and contact pads. The nominal minimum linewidth/spacing of the process used was 2 mil/2 mil, which was the spacing used between adjacent electrodes as well as the trace width between the control electrodes and contact pads. A liquid photoimageable soldermask material, CARAPACE® EMP 110 (available from Electra Polymers & Chemicals, Ltd.) was used as the electrode insulator. The nominal thickness of the soldermask insulator was 0.6 mil. After the PCBs were received from the manufacturer a thin hydrophobic coating of TEFLON® AF was applied to the top surface of the chip. TEFLON® AF was applied by spin-coating a 1% solution in FC-75 at 3000 rpm for 20 seconds onto the PCB surface, followed by a 30 minute cure at 150° C.
The PCBs were assembled as a sandwich with an indium-tin-oxide coated glass top-plate. The top-plate was also coated with a thin layer of TEFLON® AF so that all interior surfaces in contact with the droplet were hydrophobic. The conductive indium-tin-oxide film on the top-plate was used as the reference electrode. The PCB and top-plate were separated by a gap of approximately 0.8 mm. One or more droplets of electrolyte (0.1 M KCl) were injected into the sandwich structure and deposited on a control electrode. The volume of the droplet was sufficient to cover a single electrode and was approximately 2.2 μL for the 1.5 mm pitch electrodes and 1.1 μL for the 1 mm electrodes. The remaining volume between the two plates was filled either with air or with low viscosity (1 cSt.) silicone oil.
Referring to
For each electrode size and shape the maximum rate at which droplets could be transported between adjacent control electrodes was determined as a function of the applied voltage, as shown in
As expected, beyond the initial threshold voltage, the speed of transport and consequently the maximum speed at which the droplet could be switched increased with voltage. The range of voltage tested was from roughly 0-200 V for the 1.5 mm electrodes and 0-100 V for the 1.0 mm electrodes, and droplet transport rates up to 24 Hz were observed. The resulting test curves exhibited an expected general shape—the higher the voltage applied the higher the possible transfer frequency. However, the curves for the 1.5 mm electrodes (
As shown graphically in
With reference to the graph shown in
The minimum actuation voltages required to successfully transport droplets were measured for each system at switching frequencies ranging from 1 to 32 Hz. As shown graphically in
Referring to
The references listed below are incorporated herein by reference to the extent that they supplement, explain, provide a background for or teach methodology, techniques and/or processes employed herein. All cited patent documents and publications referred to in this application are herein expressly incorporated by reference.
The foregoing detailed description of embodiments refers to the accompanying drawings, which illustrate specific embodiments of the invention. Other embodiments having different structures and operations do not depart from the scope of the present invention. The term “the invention” or the like is used with reference to certain specific examples of the many alternative aspects or embodiments of the applicants' invention set forth in this specification, and neither its use nor its absence is intended to limit the scope of the applicants' invention or the scope of the claims. This specification is divided into sections for the convenience of the reader only. Headings should not be construed as limiting of the scope of the invention. The definitions are intended as a part of the description of the invention. It will be understood that various details of the present invention may be changed without departing from the scope of the present invention. Furthermore, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation.
This application is a continuation of U.S. patent application Ser. No. 13/737,433, entitled “Apparatuses and Methods for Manipulating Droplets,” filed on Jan. 9, 2013, the application of which is a continuation of U.S. patent application Ser. No. 12/576,794 filed Oct. 9, 2009 (now U.S. Pat. No. 8,388,909 issued Mar. 5, 2013), the application of which is a continuation of Ser. No. 11/343,284 filed Jan. 30, 2006 (now U.S. Pat. No. 8,349,276 issued Jan. 8, 2013) which claims priority to U.S. Provisional Patent Application No. 60/648,051 filed Jan. 28, 2005. U.S. patent application Ser. No. 12/576,794 is also a continuation-in-part of U.S. patent application Ser. No. 11/965,152 filed Dec. 27, 2007 (now U.S. Pat. No. 8,221,605 issued Jul. 17, 2012) the application of which is a continuation of U.S. patent application Ser. No. 11/077,569 filed Mar. 10, 2005 (now U.S. Pat. No. 7,569,129 issued Aug. 4, 2009), the application of which is a divisional of U.S. patent application Ser. No. 10/253,368 filed Sep. 24, 2002 (now U.S. Pat. No. 6,911,132 issued Jun. 28, 2005).). The entire disclosures of the aforementioned patent applications and the other patents and patent applications discussed herein are incorporated herein by reference in their entirety.
| Number | Name | Date | Kind |
|---|---|---|---|
| 3687834 | Candor | Aug 1972 | A |
| 3734622 | Adler | May 1973 | A |
| 3746911 | Nathanson et al. | Jul 1973 | A |
| 3756693 | Ota | Sep 1973 | A |
| 3795605 | Candor | Mar 1974 | A |
| 3872480 | Engelbrecht | Mar 1975 | A |
| 3930982 | Batha et al. | Jan 1976 | A |
| 3934180 | Kiess et al. | Jan 1976 | A |
| 4057482 | Candor | Nov 1977 | A |
| 4390403 | Batchelder | Jun 1983 | A |
| 4418346 | Batchelder | Nov 1983 | A |
| 4430645 | Eskandry et al. | Feb 1984 | A |
| 4467325 | Lustig | Aug 1984 | A |
| 4569575 | Le Pesant et al. | Feb 1986 | A |
| 4582391 | Legrand | Apr 1986 | A |
| 4636785 | Le Pesant | Jan 1987 | A |
| 4701021 | Le Pesant et al. | Oct 1987 | A |
| 4742345 | Di Santo et al. | May 1988 | A |
| 4818052 | Le Pesant et al. | Apr 1989 | A |
| 4863849 | Melamede | Sep 1989 | A |
| 4908112 | Pace | Mar 1990 | A |
| 4911782 | Brown | Mar 1990 | A |
| 5001594 | Bobbio | Mar 1991 | A |
| 5038852 | Johnson et al. | Aug 1991 | A |
| 5176203 | Larzul | Jan 1993 | A |
| 5180480 | Manz | Jan 1993 | A |
| 5181016 | Lee | Jan 1993 | A |
| 5192659 | Simons | Mar 1993 | A |
| 5194862 | Edwards | Mar 1993 | A |
| 5240994 | Brink et al. | Aug 1993 | A |
| 5276125 | Pedain et al. | Jan 1994 | A |
| 5296114 | Manz | Mar 1994 | A |
| 5454472 | Benecke et al. | Oct 1995 | A |
| 5468374 | Knoll | Nov 1995 | A |
| 5472577 | Porter et al. | Dec 1995 | A |
| 5486337 | Ohkawa et al. | Jan 1996 | A |
| 5495077 | Miller et al. | Feb 1996 | A |
| 5525493 | Hornes et al. | Jun 1996 | A |
| 5571410 | Swedberg et al. | Nov 1996 | A |
| 5603351 | Cherukuri et al. | Feb 1997 | A |
| 5605662 | Heller et al. | Feb 1997 | A |
| 5632876 | Zanzucchi et al. | May 1997 | A |
| 5632957 | Heller et al. | May 1997 | A |
| 5635671 | Freyman et al. | Jun 1997 | A |
| 5720923 | Haff et al. | Feb 1998 | A |
| 5731792 | Sheridon | Mar 1998 | A |
| 5757345 | Sheridon | May 1998 | A |
| 5770391 | Foote et al. | Jun 1998 | A |
| 5770457 | Stocker et al. | Jun 1998 | A |
| 5777391 | Nakamura et al. | Jul 1998 | A |
| 5795457 | Pethig et al. | Aug 1998 | A |
| 5808593 | Sheridon | Sep 1998 | A |
| 5814200 | Pethig et al. | Sep 1998 | A |
| 5846396 | Zanzucchi et al. | Dec 1998 | A |
| 5849486 | Heller et al. | Dec 1998 | A |
| 5851769 | Gray et al. | Dec 1998 | A |
| 5858195 | Ramsey | Jan 1999 | A |
| 5871908 | Henco et al. | Feb 1999 | A |
| 5876675 | Kennedy | Mar 1999 | A |
| 5888370 | Becker et al. | Mar 1999 | A |
| 5911533 | Fassler et al. | Jun 1999 | A |
| 5921678 | Desai et al. | Jul 1999 | A |
| 5929960 | West et al. | Jul 1999 | A |
| 5948227 | Dubrow | Sep 1999 | A |
| 5948328 | Fiedler et al. | Sep 1999 | A |
| 5956005 | Sheridon | Sep 1999 | A |
| 5958694 | Nikiforov | Sep 1999 | A |
| 5980719 | Cherukuri et al. | Nov 1999 | A |
| 5989402 | Chow et al. | Nov 1999 | A |
| 5992820 | Fare et al. | Nov 1999 | A |
| 5993630 | Becker et al. | Nov 1999 | A |
| 5993632 | Becker et al. | Nov 1999 | A |
| 5994056 | Higuchi | Nov 1999 | A |
| 6001229 | Ramsey | Dec 1999 | A |
| 6010607 | Ramsey | Jan 2000 | A |
| 6010608 | Ramsey | Jan 2000 | A |
| 6017696 | Heller | Jan 2000 | A |
| 6022463 | Leader et al. | Feb 2000 | A |
| 6033546 | Ramsey | Mar 2000 | A |
| 6042710 | Dubrow | Mar 2000 | A |
| 6043878 | Gratzl et al. | Mar 2000 | A |
| 6048498 | Kennedy | Apr 2000 | A |
| 6056861 | Fuhr et al. | May 2000 | A |
| 6057149 | Burns et al. | May 2000 | A |
| 6063339 | Tisone et al. | May 2000 | A |
| 6068752 | Dubrow et al. | May 2000 | A |
| 6068818 | Ackley et al. | May 2000 | A |
| 6071394 | Cheng et al. | Jun 2000 | A |
| 6086243 | Paul et al. | Jul 2000 | A |
| 6086740 | Kennedy | Jul 2000 | A |
| 6093296 | Soane et al. | Jul 2000 | A |
| 6099803 | Ackley et al. | Aug 2000 | A |
| 6106685 | McBride et al. | Aug 2000 | A |
| 6107044 | Nikiforov | Aug 2000 | A |
| 6109717 | Kane et al. | Aug 2000 | A |
| 6110426 | Shalon et al. | Aug 2000 | A |
| 6123798 | Gandhi et al. | Sep 2000 | A |
| 6124851 | Jacobson | Sep 2000 | A |
| 6126800 | Caillat et al. | Oct 2000 | A |
| 6130098 | Handique et al. | Oct 2000 | A |
| 6136171 | Frazier et al. | Oct 2000 | A |
| 6136212 | Mastrangelo et al. | Oct 2000 | A |
| 6148508 | Wolk | Nov 2000 | A |
| 6153073 | Dubrow et al. | Nov 2000 | A |
| 6154226 | York et al. | Nov 2000 | A |
| 6156181 | Parce et al. | Dec 2000 | A |
| 6167910 | Chow | Jan 2001 | B1 |
| 6169394 | Frazier et al. | Jan 2001 | B1 |
| 6170981 | Regnier et al. | Jan 2001 | B1 |
| 6171785 | Higuchi | Jan 2001 | B1 |
| 6174675 | Chow et al. | Jan 2001 | B1 |
| 6176990 | Yager et al. | Jan 2001 | B1 |
| 6210891 | Nyren et al. | Apr 2001 | B1 |
| 6211477 | Cardott et al. | Apr 2001 | B1 |
| 6213151 | Jacobson et al. | Apr 2001 | B1 |
| 6225059 | Ackley et al. | May 2001 | B1 |
| 6231177 | Cherukuri et al. | May 2001 | B1 |
| 6235471 | Knapp et al. | May 2001 | B1 |
| 6251343 | Dubrow et al. | Jun 2001 | B1 |
| 6251595 | Gordon et al. | Jun 2001 | B1 |
| 6258568 | Nyren | Jul 2001 | B1 |
| 6261430 | Yager et al. | Jul 2001 | B1 |
| 6274089 | Chow et al. | Aug 2001 | B1 |
| 6280590 | Cheng et al. | Aug 2001 | B1 |
| 6294063 | Becker et al. | Sep 2001 | B1 |
| 6318970 | Backhouse | Nov 2001 | B1 |
| 6319668 | Nova et al. | Nov 2001 | B1 |
| 6342142 | Ramsey | Jan 2002 | B1 |
| 6352838 | Krulevitch et al. | Mar 2002 | B1 |
| 6355198 | Kim et al. | Mar 2002 | B1 |
| 6379929 | Burns et al. | Apr 2002 | B1 |
| 6409698 | Robinson et al. | Jun 2002 | B1 |
| 6432290 | Harrison et al. | Aug 2002 | B1 |
| 6473492 | Prins et al. | Oct 2002 | B2 |
| 6482306 | Yager et al. | Nov 2002 | B1 |
| 6485913 | Becker et al. | Nov 2002 | B1 |
| 6491803 | Shen et al. | Dec 2002 | B1 |
| 6492122 | Weidenhammer et al. | Dec 2002 | B2 |
| 6538823 | Kroupenkine et al. | Mar 2003 | B2 |
| 6545815 | Kroupenkine et al. | Apr 2003 | B2 |
| 6565727 | Shenderov | May 2003 | B1 |
| 6586233 | Benett et al. | Jul 2003 | B2 |
| 6596238 | Belder et al. | Jul 2003 | B1 |
| 6600888 | Mishra et al. | Jul 2003 | B2 |
| 6602400 | Choong et al. | Aug 2003 | B1 |
| 6605453 | Ozkan et al. | Aug 2003 | B2 |
| 6613560 | Tso et al. | Sep 2003 | B1 |
| 6629826 | Yoon et al. | Oct 2003 | B2 |
| 6661563 | Hayashi et al. | Dec 2003 | B2 |
| 6665127 | Bao et al. | Dec 2003 | B2 |
| 6673225 | Arnold | Jan 2004 | B1 |
| 6681788 | Parce et al. | Jan 2004 | B2 |
| 6692700 | Handique | Feb 2004 | B2 |
| 6761962 | Bentsen et al. | Jul 2004 | B2 |
| 6767706 | Quake et al. | Jul 2004 | B2 |
| 6773566 | Shenderov | Aug 2004 | B2 |
| 6790011 | Le Pesant et al. | Sep 2004 | B1 |
| 6790330 | Gascoyne et al. | Sep 2004 | B2 |
| 6814934 | Higuchi | Nov 2004 | B1 |
| 6828100 | Ronaghi | Dec 2004 | B1 |
| 6841128 | Kambara et al. | Jan 2005 | B2 |
| 6866762 | Gascoyne et al. | Mar 2005 | B2 |
| 6887362 | Huang et al. | May 2005 | B2 |
| 6893547 | Gascoyne et al. | May 2005 | B2 |
| 6896855 | Kohler et al. | May 2005 | B1 |
| 6897848 | Sheridon | May 2005 | B2 |
| 6911132 | Pamula et al. | Jun 2005 | B2 |
| 6924792 | Jessop | Aug 2005 | B1 |
| 6949176 | Vacca et al. | Sep 2005 | B2 |
| 6958132 | Chiou et al. | Oct 2005 | B2 |
| 6960437 | Enzelberger et al. | Nov 2005 | B2 |
| 6977033 | Becker et al. | Dec 2005 | B2 |
| 6989086 | Cheng et al. | Jan 2006 | B2 |
| 6989234 | Kolar et al. | Jan 2006 | B2 |
| 7014747 | Cummings et al. | Mar 2006 | B2 |
| 7033473 | Gascoyne et al. | Apr 2006 | B2 |
| 7052244 | Fouillet et al. | May 2006 | B2 |
| 7078168 | Sylvan | Jul 2006 | B2 |
| 7081192 | Wang et al. | Jul 2006 | B1 |
| 7147763 | Elrod et al. | Dec 2006 | B2 |
| 7163612 | Sterling et al. | Jan 2007 | B2 |
| 7167156 | Glass | Jan 2007 | B1 |
| 7183509 | Beerling | Feb 2007 | B2 |
| 7189359 | Yuan et al. | Mar 2007 | B2 |
| 7189560 | Kim et al. | Mar 2007 | B2 |
| 7211223 | Fouillet et al. | May 2007 | B2 |
| 7255780 | Shenderov | Aug 2007 | B2 |
| 7328979 | Decre et al. | Feb 2008 | B2 |
| 7329545 | Pamula et al. | Feb 2008 | B2 |
| 7338760 | Gong et al. | Mar 2008 | B2 |
| 7439014 | Pamula et al. | Oct 2008 | B2 |
| 7458661 | Kim et al. | Dec 2008 | B2 |
| 7531072 | Roux et al. | May 2009 | B2 |
| 7547380 | Velev | Jun 2009 | B2 |
| 7569129 | Pamula et al. | Aug 2009 | B2 |
| 7604718 | Zhang et al. | Oct 2009 | B2 |
| 7641779 | Becker et al. | Jan 2010 | B2 |
| 7687280 | Woudenberg et al. | Mar 2010 | B2 |
| 7699969 | Manaresi et al. | Apr 2010 | B2 |
| 7727466 | Meathrel et al. | Jun 2010 | B2 |
| 7833711 | Woudenberg et al. | Nov 2010 | B2 |
| 7833719 | O'Keefe et al. | Nov 2010 | B2 |
| 7888108 | Woudenberg et al. | Feb 2011 | B2 |
| 7919330 | De Guzman et al. | Apr 2011 | B2 |
| 7922886 | Fouillet et al. | Apr 2011 | B2 |
| 7943030 | Shenderov | May 2011 | B2 |
| 7989056 | Plissonier et al. | Aug 2011 | B2 |
| 8048628 | Pollack et al. | Nov 2011 | B2 |
| 8147668 | Pollack et al. | Apr 2012 | B2 |
| 8221605 | Pollack et al. | Jul 2012 | B2 |
| 8287711 | Pollack et al. | Oct 2012 | B2 |
| 8304253 | Yi et al. | Nov 2012 | B2 |
| 8313698 | Pollack et al. | Nov 2012 | B2 |
| 8349276 | Pamula et al. | Jan 2013 | B2 |
| 8388909 | Pollack et al. | Mar 2013 | B2 |
| 8394249 | Pollack et al. | Mar 2013 | B2 |
| 8906627 | Pollack et al. | Dec 2014 | B2 |
| 20010045359 | Cheng et al. | Nov 2001 | A1 |
| 20010055242 | Deshmukh et al. | Dec 2001 | A1 |
| 20020005354 | Spence et al. | Jan 2002 | A1 |
| 20020036139 | Becker et al. | Mar 2002 | A1 |
| 20020043463 | Shenderov | Apr 2002 | A1 |
| 20020045394 | Noda et al. | Apr 2002 | A1 |
| 20020058332 | Quake et al. | May 2002 | A1 |
| 20020063060 | Gascoyne et al. | May 2002 | A1 |
| 20020088712 | Miles | Jul 2002 | A1 |
| 20020093651 | Roe | Jul 2002 | A1 |
| 20020098124 | Bentsen et al. | Jul 2002 | A1 |
| 20020100612 | Crockett et al. | Aug 2002 | A1 |
| 20020125134 | Santiago et al. | Sep 2002 | A1 |
| 20020125135 | Derand et al. | Sep 2002 | A1 |
| 20020128546 | Silver | Sep 2002 | A1 |
| 20020143437 | Handique et al. | Oct 2002 | A1 |
| 20020168671 | Burns et al. | Nov 2002 | A1 |
| 20020172969 | Burns et al. | Nov 2002 | A1 |
| 20030006141 | Gerlach et al. | Jan 2003 | A1 |
| 20030012483 | Ticknor et al. | Jan 2003 | A1 |
| 20030012699 | Moore et al. | Jan 2003 | A1 |
| 20030049632 | Edman et al. | Mar 2003 | A1 |
| 20030082081 | Fouillet et al. | May 2003 | A1 |
| 20030103021 | Young et al. | Jun 2003 | A1 |
| 20030119057 | Gascoyne et al. | Jun 2003 | A1 |
| 20030121788 | Gascoyne et al. | Jul 2003 | A1 |
| 20030164295 | Sterling | Sep 2003 | A1 |
| 20030175947 | Liu et al. | Sep 2003 | A1 |
| 20030175990 | Hayenga et al. | Sep 2003 | A1 |
| 20030183525 | Elrod et al. | Oct 2003 | A1 |
| 20030205632 | Kim et al. | Nov 2003 | A1 |
| 20030206351 | Kroupenkine | Nov 2003 | A1 |
| 20030224528 | Chiou et al. | Dec 2003 | A1 |
| 20030227100 | Chandross et al. | Dec 2003 | A1 |
| 20040007377 | Fouillet et al. | Jan 2004 | A1 |
| 20040031688 | Shenderov | Feb 2004 | A1 |
| 20040042721 | Kroupenkine et al. | Mar 2004 | A1 |
| 20040053290 | Terbrueggen et al. | Mar 2004 | A1 |
| 20040055536 | Kolar et al. | Mar 2004 | A1 |
| 20040055891 | Pamula et al. | Mar 2004 | A1 |
| 20040058450 | Pamula et al. | Mar 2004 | A1 |
| 20040091392 | McBride et al. | May 2004 | A1 |
| 20040136876 | Fouillet et al. | Jul 2004 | A1 |
| 20040141884 | Unno et al. | Jul 2004 | A1 |
| 20040144651 | Huang et al. | Jul 2004 | A1 |
| 20040180346 | Anderson et al. | Sep 2004 | A1 |
| 20040211659 | Velev | Oct 2004 | A1 |
| 20040211669 | Cummings et al. | Oct 2004 | A1 |
| 20040231987 | Sterling et al. | Nov 2004 | A1 |
| 20050001329 | Matsuki et al. | Jan 2005 | A1 |
| 20050038329 | Morris et al. | Feb 2005 | A1 |
| 20050048581 | Chiu et al. | Mar 2005 | A1 |
| 20050056569 | Yuan et al. | Mar 2005 | A1 |
| 20050064423 | Higuchi et al. | Mar 2005 | A1 |
| 20050100675 | Mao et al. | May 2005 | A1 |
| 20050106742 | Wahl | May 2005 | A1 |
| 20050142037 | Reihs | Jun 2005 | A1 |
| 20050148042 | Prestwich et al. | Jul 2005 | A1 |
| 20050158755 | Lee et al. | Jul 2005 | A1 |
| 20050179746 | Roux et al. | Aug 2005 | A1 |
| 20050199796 | Currell | Sep 2005 | A1 |
| 20050227264 | Nobile et al. | Oct 2005 | A1 |
| 20050272159 | Ismagilov et al. | Dec 2005 | A1 |
| 20050287572 | Mathies et al. | Dec 2005 | A1 |
| 20060021875 | Griffith et al. | Feb 2006 | A1 |
| 20060054503 | Pamula et al. | Mar 2006 | A1 |
| 20060068450 | Combette et al. | Mar 2006 | A1 |
| 20060102477 | Vann et al. | May 2006 | A1 |
| 20060114296 | Gascoyne et al. | Jun 2006 | A1 |
| 20060132543 | Elrod et al. | Jun 2006 | A1 |
| 20060164490 | Kim et al. | Jul 2006 | A1 |
| 20060166261 | Higuchi et al. | Jul 2006 | A1 |
| 20060166262 | Higuchi et al. | Jul 2006 | A1 |
| 20060172336 | Higuchi et al. | Aug 2006 | A1 |
| 20060186048 | Tan | Aug 2006 | A1 |
| 20060194331 | Pamula et al. | Aug 2006 | A1 |
| 20070023292 | Kim et al. | Feb 2007 | A1 |
| 20070037294 | Pamula et al. | Feb 2007 | A1 |
| 20070045117 | Pamula et al. | Mar 2007 | A1 |
| 20070064990 | Roth | Mar 2007 | A1 |
| 20070086927 | Natarajan et al. | Apr 2007 | A1 |
| 20070141593 | Lee et al. | Jun 2007 | A1 |
| 20070267294 | Shenderov | Nov 2007 | A1 |
| 20080003588 | Hasson et al. | Jan 2008 | A1 |
| 20080105549 | Pamela et al. | May 2008 | A1 |
| 20080124252 | Marchand et al. | May 2008 | A1 |
| 20080138815 | Brown et al. | Jun 2008 | A1 |
| 20080142376 | Fouillet et al. | Jun 2008 | A1 |
| 20080151240 | Roth | Jun 2008 | A1 |
| 20080153091 | Brown et al. | Jun 2008 | A1 |
| 20080160525 | Brown et al. | Jul 2008 | A1 |
| 20080169184 | Brown et al. | Jul 2008 | A1 |
| 20080171324 | Brown et al. | Jul 2008 | A1 |
| 20080171325 | Brown et al. | Jul 2008 | A1 |
| 20080171326 | Brown et al. | Jul 2008 | A1 |
| 20080171327 | Brown et al. | Jul 2008 | A1 |
| 20080171382 | Brown et al. | Jul 2008 | A1 |
| 20080213766 | Brown et al. | Sep 2008 | A1 |
| 20080247920 | Pollack et al. | Oct 2008 | A1 |
| 20080264797 | Pamula et al. | Oct 2008 | A1 |
| 20080274513 | Shenderov et al. | Nov 2008 | A1 |
| 20080302431 | Marchand et al. | Dec 2008 | A1 |
| 20090014394 | Yi et al. | Jan 2009 | A1 |
| 20090042319 | De Guzman et al. | Feb 2009 | A1 |
| 20090134027 | Jary | May 2009 | A1 |
| 20090142564 | Plissonnier et al. | Jun 2009 | A1 |
| 20090145485 | Smith et al. | Jun 2009 | A1 |
| 20090145576 | Wyrick et al. | Jun 2009 | A1 |
| 20090146380 | Votaw et al. | Jun 2009 | A1 |
| 20090192044 | Fouillet | Jul 2009 | A1 |
| 20090260988 | Pamula et al. | Oct 2009 | A1 |
| 20090280251 | De Guzman et al. | Nov 2009 | A1 |
| 20100025242 | Pamula et al. | Feb 2010 | A1 |
| 20110003281 | Woudenberg et al. | Jan 2011 | A1 |
| 20110065590 | Hunter | Mar 2011 | A1 |
| 20110209998 | Shenderov | Sep 2011 | A1 |
| 20120132528 | Shenderov et al. | May 2012 | A1 |
| Number | Date | Country |
|---|---|---|
| 1211160 | Mar 1999 | CN |
| 1456030 | Nov 2003 | CN |
| 3808942 | Sep 1989 | DE |
| 10162188 | Jun 2003 | DE |
| 0558233 | Oct 1995 | EP |
| 1283662 | Feb 2003 | EP |
| 1990-088615 | Dec 1991 | JP |
| 1996-008283 | Jul 1997 | JP |
| 2000068263 | Mar 2000 | JP |
| 2003194845 | Jul 2003 | JP |
| 2004-500033 | Jan 2004 | JP |
| 2004158744 | Jun 2004 | JP |
| 2005-19686 | Jan 2005 | JP |
| 2006317364 | Nov 2006 | JP |
| 2006329899 | Dec 2006 | JP |
| 2006329904 | Dec 2006 | JP |
| 9015881 | Dec 1990 | WO |
| 9523020 | Aug 1995 | WO |
| 9604547 | Feb 1996 | WO |
| 9822625 | May 1998 | WO |
| 9915876 | Apr 1999 | WO |
| 9917093 | Apr 1999 | WO |
| 9954730 | Oct 1999 | WO |
| 0047322 | Aug 2000 | WO |
| 0069565 | Nov 2000 | WO |
| 0073655 | Dec 2000 | WO |
| 0107665 | Feb 2001 | WO |
| 03049184 | Jun 2003 | WO |
| 03069380 | Aug 2003 | WO |
| 2004021385 | Mar 2004 | WO |
| 2004027490 | Apr 2004 | WO |
| 2004029585 | Apr 2004 | WO |
| 2004030820 | Apr 2004 | WO |
| 2004073863 | Sep 2004 | WO |
| 2005047696 | May 2005 | WO |
| 2005069015 | Jul 2005 | WO |
| 2006013303 | Feb 2006 | WO |
| 2006026351 | Mar 2006 | WO |
| 2006070162 | Jul 2006 | WO |
| 2006081558 | Aug 2006 | WO |
| 2006124458 | Nov 2006 | WO |
| 2006127451 | Nov 2006 | WO |
| 2006129486 | Dec 2006 | WO |
| 2006132211 | Dec 2006 | WO |
| 2006138543 | Dec 2006 | WO |
| 2007003720 | Jan 2007 | WO |
| 2007048111 | Apr 2007 | WO |
| Entry |
|---|
| Chakrabarty et al., “Design Automation Challenges for Microfluidics-Based Biochips”, DTIP of MEMS & MOEMS, Montreux, Switzerland, Jun. 1-3, 2005. |
| Chakrabarty et al., “Design Automation for Microfluidics-Based Biochips”, ACM Journal on Engineering Technologies in Computing Systems , 1(3), Oct. 2005, 186-223. |
| Chakrabarty, “Design, Testing, and Applications of Digital Microfluidics-Based Biochips”, Proceedings of the 18th International Conf. on VLSI held jointly with 4th International Conf. on Embedded Systems Design (VLSID'05), IEEE, Jan. 3-7, 2005. |
| Chen et al., “Development of Mesoscale Actuator Device with Micro Interlocking Mechanism”, J. Intelligent Material Systems and Structures, vol. 9, No. 4, Jun. 1998, pp. 449-457. |
| Chen et al., “Mesoscale Actuator Device with Micro Interlocking Mechanism”, Proc. IEEE Micro Electro Mechanical Systems Workshop, Heidelberg, Germany, Jan. 1998, pp. 384-389. |
| Chen et al., “Mesoscale Actuator Device: Micro Interlocking Mechanism to Transfer Macro Load”, Sensors and Actuators, vol. 73, Issues 1-2, Mar. 1999, pp. 30-36. |
| Dewey, “Towards a Visual Modeling Approach to Designing Microelectromechanical System Transducers”, Journal of Micromechanics and Microengineering, vol. 9, Dec. 1999, 332-340. |
| Dewey et al., “Visual modeling and design of microelectromechanical system tansducers”, Microelectronics Journal, vol. 32, Apr. 2001, 373-381. |
| Fair et al., “A Micro-Watt Metal-Insulator-Solution-Transport (MIST) Device for Scalable Digital Bio-Microfluidic Systems”, IEEE IEDM Technical Digest, 2001, 16.4.1-4. |
| Fair et al., “Advances in droplet-based bio lab-on-a-chip”, BioChips 2003, Boston, 2003. |
| Fair et al., “Bead-Based and Solution-Based Assays Performed on a Digital Microfluidic Platform”, Biomedical Engineering Society (BMES) Fall Meeting, Baltimore, MD, Oct. 1, 2005. |
| Fair et al., “Chemical and biological pathogen detection in a digital microfluidic platform”, DARPA Workshop on Microfluidic Analyzers for DoD and National Security Applications, Keystone, CO, 2006. |
| Fair, “Droplet-based microfluidic Genome sequencing”, NHGRI PI's meeting, Boston, 2005. |
| Fair et al., “Electrowetting-based On-Chip Sample Processing for Integrated Microfluidics”, IEEE Inter. Electron Devices Meeting (IEDM), 2003, 32.5.1-32.5.4. |
| Fair et al., “Integrated chemical/biochemical sample collection, pre-concentration, and analysis on a digital microfluidic lab-on-a-chip platform”, Lab-on-a-Chip: Platforms, Devices, and Applications, Conf. 5591, SPIE Optics East, Philadelphia, Oct. 25-28, 2004. |
| Fouillet et al., “Design and Validation of a Complex Generic Fluidic Microprocessor Based on EWOD Droplet for Biological Applications”, 9th International Conference on Miniaturized Systems for Chem and Life Sciences, Boston, MA, Oct. 9-13, 2005, 58-60. |
| Jun et al., “Valveless Pumping using Traversing Vapor Bubbles in Microchannels”, J. Applied Physics, vol. 83, No. 11, Jun. 1998, pp. 5658-5664. |
| Kim et al., “MEMS Devices Based on the Use of Surface Tension”, Proc. Int. Semiconductor Device Research Symposium (ISDRS'99), Charlottesville, VA, Dec. 1999, pp. 481-484. |
| Kim, “Microelectromechanical Systems (MEMS) at the UCLA Micromanufacturing Lab”, Dig. Papers, Int. Microprocesses and Nanotechnology Conf. (MNC'98), Kyungju, Korea, Jul. 1998, pp. 54-55. |
| Kim et al., “Micromachines Driven by Surface Tension”, AIAA 99-3800, 30th AIAA Fluid Dynamics Conference, Norfolk, VA, (Invited lecture), Jun. 1999, pp. 1-6. |
| Lee et al., “Microactuation by Continuous Electrowetting Phenomenon and Silicon Deep Rie Process”, Proc. MEMS (DSC—vol. 66) ASME Int. Mechanical Engineering Congress and Exposition, Anaheim, CA, Nov. 1998, 475-480. |
| Lee et al., “Liquid Micromotor Driven by Continuous Electrowetting”, Proc. IEEE Micro Electro Mechanical Systems Workshop, Heidelberg, Germany, Jan. 1998, pp. 538-543. |
| Lee et al., “Theory and Modeling of Continuous Electrowetting Microactuation”, Proc. MEMS (MEMS—vol. 1), ASME Int. Mechanical Engineering Congress and Exposition, Nashville, TN, Nov. 1999, pp. 397-403. |
| Paik et al., “Adaptive hot-spot cooling of integrated circuits using digital microfluidics”, Proceedings ASME International Mechanical Engineering Congress and Exposition, Orlando, Florida, USA. IMECE2005-81081, Nov. 5-11, 2005, 1-6. |
| Paik et al., “Coplanar Digital Microfluidics Using Standard Printed Circuit Board Processes”, 9th International Conference on Miniaturized Systems for Chemistry and Life Sciences (MicroTAS), Boston, MA; Poster, 2005. |
| Paik et al., “Coplanar Digital Microfluidics Using Standard Printed Circuit Board Processes”, 9th Int'l Conf. on Miniaturized Systems for Chemistry and Life Sciences, Boston, MA, Oct. 9-13, 2005, 566-68. |
| Paik et al., “Droplet-Based Hot Spot Cooling Using Topless Digital Microfluidics on a Printed Circuit Board”, Int'l Workshops on Thermal Investigations of ICs and Systems (THERMINIC), 2005, 278-83. |
| Paik et al., “Electrowetting-based droplet mixers for microfluidic systems”, Lab on a Chip (LOC), vol. 3. (more mixing videos available, along with the article, at LOC's website), 2003, 28-33. |
| Paik et al., “Rapid Droplet Mixers for Digital Microfluidic Systems”, Masters Thesis, Duke Graduate School., 2002, 1-82. |
| Paik et al., “Rapid droplet mixers for digital microfluidic systems”, Lab on a Chip, vol. 3. (More mixing videos available, along with the article, at LOC's website.), 2003, 253-259. |
| Paik et al., “Thermal effects on Droplet Transport in Digital Microfluids with Application to Chip Cooling Processing for Integrated Microfluidics”, International Conference on Thermal, Mechanics, and Thermomechanical Phenomena in Electronic Systems (ITherm), 2004, 649-654. |
| Pamula, “A digital microfluidic platform for multiplexed explosive detection”, Chapter 18, Electronics Noses and Sensors for the Detection of Explosives, Eds., J.W. Gardner and J. Yinon, Kluwer Academic Publishers, 2004. |
| Pamula et al., “A droplet-based lab-on-a-chip for colorimetric detection of nitroaromatic explosives”, Proceedings of Micro Electro Mechanical Systems, 2005, 722-725. |
| Pamula et al., “Cooling of integrated circuits using droplet-based microfluidics”, Proc. ACM Great Lakes Symposium on VLSI, Apr. 2003, 84-87. |
| Pamula et al., “Digital Microfluidics Platform for Lab-on-a-chip applications”, Duke University Annual Post Doctoral Research Day, 2002. |
| Pamula et al., “Microfluidic electrowetting-based droplet mixing”, IEEE, 2002, 8-10. |
| Pollack, et al., “Electrowetting-Based Actuation of Droplets for Integrated Microfluidics”, Lab on a Chip (LOC), vol. 2, 2002, 96-101. |
| Pollack et al., “Electrowetting-based actuation of liquid droplets for microfluidic applications”, Appl. Phys. Letters, vol. 77, No. 11, Sep. 11, 2000, 1725-1726. |
| Pollack, “Electrowetting-based Microactuation of Droplets for Digital Microfluidics”, PhD Thesis, Department of Electrical and Computer Engineering, Duke University, 2001. |
| Pollack et al., “Electrowetting-Based Microfluidics for High-Throughput Screening”, smallTalk 2001 Conference Program Abstract, San Diego, Aug. 27-31, 2001, 149. |
| Pollack et al., “Investigation of electrowetting-based microfluidics for real-time PCR applications”, Proc. 7th Int'l Conference on Micro Total Analysis Systems (mTAS), Squaw Valley, CA, Oct. 5-9, 2003, 619-622. |
| Ren et al., “Automated electrowetting-based droplet dispensing with good reproducibility”, Proc. Micro Total Analysis Systems (mTAS), 7th Int. Conf.on Miniaturized Chem and Biochem Analysis Systems, Squaw Valley, CA, Oct. 5-9, 2003, 993-996. |
| Ren et al., “Automated on-chip droplet dispensing with volume control by electro-wetting actuation and capacitance metering”, Sensors and Actuators B: Chemical, vol. 98, Mar. 2004, 319-327. |
| Ren et al., “Design and testing of an interpolating mixing architecture for electrowetting-based droplet-on-chip chemical dilution”, Transducers, 12th International Conference on Solid-State Sensors, Actuators and Microsystems, 2003, 619-622. |
| Ren et al., “Dynamics of electro-wetting droplet transport”, Sensors and Actuators B (Chemical), vol. B87, No. 1, Nov. 15, 2002, 201-206. |
| Ren et al., “Micro/Nano Liter Droplet Formation and Dispensing by Capacitance Metering and Electrowetting Actuation”, IEEE-NANO, 2002, 369-372. |
| Sherman et al., “Flow Control by Using High-Aspect-Ratio, In-Plane Microactuators”, Sensors and Actuators, vol. 73, 1999, pp. 169-175. |
| Sherman et al., “In-Plane Microactuator for Fluid Control Application”, Proc. IEEE Micro Electro Mechanical Systems Workshop, Heidelberg, Germany, Jan. 1998, pp. 454-459. |
| Srinivasan et al., “3-D imaging of moving droplets for microfluidics using optical coherence tomography”, Proc. 7th International Conference on Micro Total Analysis Systems (mTAS), Squaw Valley, CA, Oct. 5-9, 2003, 1303-1306. |
| Srinivasan et al., “A digital microfluidic biosensor for multianalyte detection”, Proc. IEEE 16th Annual Int'l Conf. on Micro Electro Mechanical Systems Conference, 2003, 327-330. |
| Srinivasan, “A Digital Microfluidic Lab-on-a-Chip for Clinical Diagnostic Applications”, Ph.D. thesis, Dept of Electrical and Computer Engineering, Duke University, 2005. |
| Srinivasan et al., “An integrated digital microfluidic lab-on-a-chip for clinical diagnostics on human physiological fluids”, Lab on a Chip, vol. 4, 2004, 310-315. |
| Srinivasan et al., “Clinical diagnostics on human whole blood, plasma, serum, urine, saliva, sweat and tears on a digital microfluidic platform”, Proc. 7th International Conference on Micro Total Analysis Systems (mTAS), Squaw Valley, CA, Oct. 5-9, 2003, 1287-1290. |
| Srinivasan et al., “Droplet-based microfluidic lab-on-a-chip for glucose detection”, Analytica Chimica Acta, vol. 507, No. 1, 2004, 145-150. |
| Srinivasan et al., “Protein Stamping for MALDI Mass Spectrometry Using an Electrowetting-based Microfluidic Platform”, Lab-on-a-Chip: Platforms, Devices, and Applications, Conf. 5591, SPIE Optics East, Philadelphia, Oct. 25-28, 2004. |
| Srinivasan et al., “Scalable Macromodels for Microelectromechanical Systems”, Technical Proc. 2001 Int. Conf. on Modeling and Simulation of Microsystems, 2001, 72-75. |
| Su et al., “Yield Enhancement of Digital Microfluidics-Based Biochips Using Space Redundancy and Local Reconfiguration”, Proc. Design, Automation and Test in Europe (DATE) Conf., IEEE, 2005, 1196-1201. |
| Sudarsan et al., “Printed circuit technology for fabrication of plastic based microfluidic devices”, Analytical Chemistry vol. 76, No. 11, Jun. 1, 2004, Previously published on-line, May 2004, 3229-3235. |
| Wang et al., “Droplet-based micro oscillating-flow PCR chip”, J. Micromechanics and Microengineering, vol. 15, 2005, 1369-1377. |
| Weaver, “Application of Magnetic Microspheres for Pyrosequencing on a Digital Microfluidic Platform”, Department of Electrical and Computer Engineering, Duke University, 2005. |
| Yao et al., “Spot Cooling Using Thermoelectric Microcooler”, Proc. 18th Int. Thermoelectric Conf, Baltimore, VA, pp. 256-259, Aug. 1999. |
| Yi et al., “EWOD Actuation with Electrode-Free Cover Plate”, Digest of Tech. papers,l3th International Conference on Solid-State Sensors, Actuators and Microsystems (Transducers '05), Seoul, Korea, Jun. 5-9, 2005, 89-92. |
| Yi et al., “Geometric surface modification of nozzles for complete transfer of liquid drops”, Solid-State Sensor, Actuator and Microsystems Workshop, Hilton Head Island, South Carolina, Jun. 6-10, 2004, 164-167. |
| Yi, “Soft Printing of Biological Liquids for Micro-arrays: Concept, Principle, Fabrication, and Demonstration”, Ph.D. dissertation, UCLA, 2004. |
| Yi et al., “Soft Printing of Droplets Digitized by Electrowetting”, Transducers 12th Int'l Conf. on Solid State Sensors, Actuators and Microsystems, Boston, Jun. 8-12, 2003, 1804-1807. |
| Yi et al., “Soft Printing of Droplets Pre-Metered by Electrowetting”, Sensors and Actuators A: Physical, vol. 114, Jan. 2004, 347-354. |
| Zeng et al., “Actuation and Control of Droplets by Using Electrowetting-on-Dielectric”, Chin. Phys. Lett., vol. 21(9), 2004, 1851-1854. |
| Washizu, “Electrostatic Actuation of Liquid Droplets for Micro-Reactor Applications”, IEEE Industry Applications Society Annual Meeting, pp. 1867-1873, Oct. 5-9, 1997. |
| Washizu, “Electrostatic Actuation of Liquid Droplets for Microreaction Applications,”, IEEE Transactions on Industry Applications, 34(4), 1998, pp. 732-737. |
| Torkkeli, “Droplet microfluidics on a planar surface,” Doctoral Dissertation, Department of Electrical Engineering, Helsinki University of Technology (Oct. 3, 2003). |
| PCT International Search Report for PCT/US03/12754 dated Sep. 1, 2004. |
| Office Action dated Jun. 2, 2004 from co-pending U.S. Appl. No. 10/253,368. |
| Response to Office Action dated Nov. 5, 2004 from co-pending U.S. Appl. No. 10/253,368. |
| Cho et al., “Towards Digital Microfluidic Circuits: Creating, Transporting, Cutting and Merging Liquid Droplets by Electrowetting-Based Actuation,” Proc. IEEE/Micro Electro Mechanical Systems Conference, pp. 32-35, 2002. |
| Cho et al., Proceedings of 2001 ASME International Mechanical Engineering Congress and Exposition, Nov. 2001, pp. 1-7. |
| Choi et al., “An Active Micro Mixer Using Electrohdrodynamic (EHD) Convection”, Technical Digest of Solid-State Sensor and Actuator Workshop, Hilton Head Island, SC, pp. 52-55, 2000. |
| Gong et al., “Portable digital microfluidics platform with active but disposable Lab-On-Chip,” Micro Electro Mechanical Systems, 17th IEEE International Conference on (MEMS), Maastricht, Netherlands, Jan. 25-29, 2004; Piscataway, NJ, IEEE, Jan. 25, 2004, pp. 355-358. |
| Gong et al., “Two-Dimensional Digital Microfluidic System by Multi-Layer Printed Circuit Board,” IEEE, pp. 726-729, 2005. |
| Kim et al., “U.S. Appl. No. 10/343,261 Electrowetting-Driven Micropumping,” UCLA Invention Report, Amendment, Declaration including Invention Report, Petition for Extension of Time, and Authorization to Charge Deposit, submitted to USPTO on Feb. 4, 2005. |
| Kim, “Micropumping by electrowetting”, Proceedings of the 2001 ASME International Mechanical Engeering Congress & Exposition, Interlaken, New York, Nov. 11-16, 2001. |
| Yamaguchi et al., “High-Throughput Method for N-Terminal Sequencing of Proteins by MALDI Mass Spectrometry,” Analytical Chemistry, vol. 77, No. 2, pp. 645-651 (Jan. 15, 2005). |
| Seyrat and Hayes, “Amorphous fluoropolymers as insulators for reversible low-voltage electrowetting,” Journal of Applied Physics, vol. 90 (3): pp. 1383-1386, Aug. 1, 2001. |
| Wego et al., “A self-filling micropump based on PCB technology,” Sensors and Actuators A-Physical, vol. 88, No. 3, pp. 220-226 (Mar. 5, 2001). |
| Wego et al. “Fluidic Microsystems Based on Printed Circuit Board Technology,” J. Micromech, Microeng. vol. 11, pp. 528-531 (2001). |
| Wego et al. “Investigations on Thermo-Pneumatic Volume Acutators Based on PCB Technology,” Sensors and Actuators A 93, pp. 95-102 (2001). |
| Wheeler et al., “Digital microfluidics with in-line sample purification for proteomics analyses with MALDI-MS,” Analytical Chemistry, vol. 77, No. 2, pp. 534-540 (Jan. 15, 2005). |
| Wheeler et al., “Electrowetting-on-dielectric for analysis of peptides and proteins by matrix assisted laser desorption/ionization mass spectrometry,” Solid-State Sensor, Actuator and Microsystems Workshop publication, pp. 402-403, Jun. 6-10, 2004. |
| Altomare et al. “Levitation and Movement of Human Tumor Cells Using a Printer Circuit Board Device on Software-Controlled Dielectrophoresis,” Biotechnology and Bioengineering, vol. 82 pp. 474-479 (2003). |
| Berge et al. “Variable Focal Lens Controlled by an External Voltage: An Application of Electrowetting,” The European Physical Journal E, pp. 159-163 (2000). |
| Berge, “Electrocapillarity & wetting of insulator films by water,” C. R. Acad. Sci. Paris, 317(11), pp. 157-163, 1993. |
| Jobst et al. “Mass Producible Miniaturized Flow Through a Device With a Biosensor Array,” Sensors and Actuators B 43, pp. 121-125 (1997). |
| Laritz et al. “A Microfluidic pH-Regulation System Based on Printed Circuit Board Technology,” Sensors and Actuators, vol. 84, pp. 230-235 (2000). |
| Li et al. “PDMS-Based Microfluidic Device with Multi-Height Structures Fabricated by Single-Step Photolithography Using Printed Circuit Board as Masters,” Analyst vol. 128, pp. 1137-1142 (2003). |
| Li et al., “Development of PDMS-based Microfluidic Device for Cell-based Assays,” Chemical Journal of Chinese Universities, vol. 25, No. 1, pp. 4-6 (2004). |
| Medoro et al. “A Lab-on-a-Chip for Cell Detection and Manipulation,” IEEE Sensors Journal, vol. 3, No. 3, Jun. 2003, pp. 317-325. |
| Merkel et al. “A New Technology for Fluidic Microsystems Based on PCB Technology,” Sensors and Actuators, vol. 77 pp. 98-105 (1999). |
| Merkel et al. “Electric Fields in Fluidic Channels and Sensor Applications with Capacitance,” Sensors and Actuators, vol. 80, pp. 1-7 (2000). |
| Nguyen et al. “Miniature Valveless Pumps Based on Printed Circuit Board Technique,” Sensors and Actuators A 88, pp. 104-111 (2001). |
| Pamula et al., Microfluidic electrowetting-based droplet mixing. Proceedings, MEMS Conference Berkeley, Aug. 2001; pp. 8-10. |
| Prins et al. “Fluid Control in Multichannel Structures by Electrocapillary Pressure,” Science vol. 291, pp. 277-280, Jan. 12, 2001. |
| Schwartz et al. “Droplet-Based Chemistry on a Programmable Micro-Chip,” Lab on a Chip, vol. 4, pp. 11-17 (2002). |
| Schwartz, “Dielectrophoretic Approaches to Sample Preparation and Analysis,” The University of Texas, Dissertation, Dec. 2001. |
| Tan et al. “Design of Microfluidic Channel Geometries for the Control of Droplet Volume, Chemical Concentration, and Sorting,” Lab Chip, vol. 4, pp. 292-2988 (2004). |
| Tice et al. “Effects of Viscosity on Droplet Formation and Mixing in Microfluidic Channels,” Analytica Chimica Acta 507, pp. 73-77 (2004). |
| Unger et al. “Monolithic Microfabricated Valves and Pumps by Multilayer Soft Lithography,” Science vol. 288, pp. 113-116, Apr. 17, 2000. |
| “Chip mixes droplets faster”, MIT Technology Review, Oct. 2003. |
| “Chip Juggles Droplets”, Technology Research News, Sep. 4-11, 2002. |
| “Laboratory on a Chip”, Popular Mechanics, Mar. 2002. |
| “Lab-on-a-Chip Technology May Present New ESD Challenges”, Electrostatic Discharge Journal, Mar. 2002. |
| “Making materials fit the future: accommodating relentless technological requirements means researchers must recreate and reconfigure materials, frequently challenging established laws of physics, while keeping an eye on Moore's law”, R&D Magazine, Dec. 2001. |
| Agah, “DNA Analysis Chip by Electrowetting Actuation,” Stanford Nanofabrication Facility, p. 9, 2002. |
| Armani et al., “Control of Microfluidic Systems: Two Examples, Results, and Challenges,” International Journal of Robust and Nonlinear Control, vol. 15, Issue 16, pp. 785-803, Sep. 15, 2005. |
| Bhansali et al., “Resolving chemical/bio-compatibility issues in microfluidic MEMS systems,” SPIE Conference on Microfluidic Devices and Systems II, vol. 3877, Santa Clara, CA, pp. 101-109 (1999). |
| Cooney et al., “isothermal DNA Amplification Reaction on an Electrowetting Microchip,” Keck Graduate Institute online poster publication (http://microfluidics.kgi.edu/publications/ACS-sandiego-poster-2004.pdf), 2004. |
| Huang et al., “MEMS-based sample preparation for molecular diagnostics”, Analytical and Bioanalytical Chemistry, vol. 372, pp. 49-65 (2002). |
| Shen et al., “A microchip-based PCR device using flexible printed circuit technology,” Sensors and Actuators, vol. 105, pp. 251-258, 2005. |
| Su et al., “Testing of droplet-based microelectrofluidic systems”, Proc. IEEE International Test Conference, pp. 1192-1200, 2003. |
| Taniguchi et al., “Chemical reactions in microdroplets by electrostatic manipulation of droplets in liquid media,” Lab on a Chip, vol. 2, No. 2, pp. 19-23 (2002). |
| Verpoorte, “Beads and chips: new recipes for analysis,” Lab on a Chip (LOC), vol. 3, pp. 60N-68N, 2003. |
| Vinet, F., et al., “Microarrays and microfluidic devices: miniaturized systems for biological analysis,” Microelectronic Engineering 61-62 (2002) 41-47. |
| Vivek et al., “Novel Acoustic-Wave Micromixer,” IEEE International Micro Electro Mechanical Systems Conference, Miyazaki, Japan, pp. 668-673, Jan. 23-27, 2000. |
| Voldman, “An Integrated Liquid Mixer/Valve”, Journal of Microelectromechanical Systems, vol. 9, No. 3, pp. 295-302, Sep. 2000. |
| Zhang et al., “Behavioral modeling and performance evaluation of microelectrofluidics-based PCR systems using SystemC”, IEEE Transactions on Computer-Aided Design of Integrated Circuits & Systems, vol. 23 (6): pp. 843-858, Jun. 2004. |
| Zou et al., “Micro-assembled multi-chamber thermal cycler for low-cost reaction chip thermal multiplexing,” Sensors and Actuators, vol. 102, pp. 114-121, 2002. |
| Ding, “System level architectural optimization of semi-reconfigurable microfluidic system,” M.S. Thesis, Duke University Dept of Electrical Engineering, 2000. |
| Ding et al., “Reconfigurable Microfluidic System Architecture Based on Two-Dimensional Electrowetting Arrays,” Proc. International Conference on Modeling and Simulation of Microsystems (Mar. 19-21, 2001), pp. 181-185. |
| Moon et al., “Low voltage electrowetting-on-dielectric,” Journal of Applied Physics, vol. 92 (7): pp. 4080-4087, Oct. 1, 2002. |
| Cheuk-Wing et al., Development of PDMS-based Microfluid Device for Cell-based Assays; Applied Research Centre for Genomic Technology, and Department of Biology and Chemistry, Chemical Journal of Chinese Universities, vol. 25, 2004, pp. 4-6. |
| Colgate and Matsumoto, “An Investigation of Electrowetting-based Microactuation,” Journal of Vacuum Science & Technology A—Vacuume Surfaces and Films, V. 8 (4): pp. 3625-3633, Jul.-Aug. 1990. |
| Fan et al., “EWOD Driving of Droplet on NxM Grid Using Single-Layer Electrode Patterns,” Solid-State Sensor, Actuator and Microsystems Workshop, Hilton Head Island, South Carolina, pp. 134-137, Jun. 2-6, 2002. |
| Fan, “Digital Microfluidics by Cross-Reference EWOD Actuation: Principle, Device, and System,” PhD Dissertation, University of California Dept. of Mechanical Engineering, 2003. |
| Terry et al., “A Gas Chromatographic Air Analyzer Fabricated on a Silicon Wafer,” IEEE Transactions on Electron Devices, vol. ED-26, 1979, pp. 1880-1886. |
| Tuckerman and Pease, “High-Performance Heat Sinking for VLSI,” IEEE Electron Device Letters, 1981, pp. 126-129. |
| Batchelder, “Dielectrophoretic manipulator,” Review of Scientific Instruments, vol. 54, 1983, pp. 300-302. |
| Manz et al., “Miniaturized Total Chemical Analysis Systems: a Novel Concept for Chemical Sensing,” Sensors and Actuators B: Chemical, 1990, pp. 244-248. |
| Welters et al., “Fast Electrically Switchable Capillary Effects,” Langmuir, vol. 14, Mar. 1998, pp. 1535-1538. |
| McDonald et al., “Fabrication of Microfluidic systems in poly (dimethylsiloxane),” Electrophoresis, vol. 21, 2000, pp. 27-40. |
| Locascio et al. “Polymer microfluidic devices,” Talanta, vol. 56, Feb. 2002, pp. 267-287. |
| Garrell et al., “Preventing Biomolecular Adsorption in Electrowetting-Based Biofluidic Chips,” Analytical Chemistry, vol. 75, Oct. 2003, pp. 5097-5102. |
| Chiou et al., “Light actuation of liquid by optoelectrowetting,” Sensors and Actuators A: Physical, vol. 104, May 2003, pp. 222-228. |
| Squires and Quake, “Microfluidics: Fluid physics at the nanoliter scale,” Reviews of Modern Physics, vol. 77, Oct. 2005, pp. 977-1-26. |
| Guttenberg et al., “Planar chip devices for PCR and hybridization with surface acoustic wave pump.,” Lab on a chip, vol. 5, Mar. 2005, pp. 12617-12622. |
| Madou et al., “Lab on a CD,” Annual Review of Biomedical Engineering, vol. 8, pp. 601-628, 2006. |
| Fowler, “Lab-on-a-Chip Technology May Present New ESD Challenges”, Electrostatic Discharge (ESD) Journal, Mar. 2002. |
| Fowler et al., “Enhancement of Mixing by Droplet-Based Microfluidics”, IEEE, pp. 97-100, 2002. |
| Lee and Kim, “Surface-tension-driven microactuation based on continuous electrowetting,” Journal of Microelectromechanical Systems, vol. 9 (2): pp. 171-180, Jun. 2000. |
| Lee et al., “Chaotic Mixing in Electrokinetically and Pressure Driven Micro Flows”, Rhw 14.sup.th IEEE Workshop on MEMS, Jan. 2001. |
| Lee et al., Addressable micro liquid handling by electric control of surface tension. Proceedings IEEE Conference on Micro Electro Mechanical Systems (MEMS 2001) Interlaken, Switzerland, Jan. 2001, pp. 499-502. |
| Lee, dissertation, Microactuation by continuous electrowetting and electroweeting: theory, fabrication and demonstration, UCLA 2000. |
| Aldrich et al., “PathoFinder: Microscale PCR Based Virus Detection,” Yale Department of Engineering Design Course Report, Dec. 2003. |
| Atencia and Beebe, “Controlled microfluidic interfaces,” Nature, vol. 437, pp. 648-655, Sep. 2005. |
| Bertsch, “3D Micromixers—Downscaling Large Scale Industrial Static Mixers”, IEEE, pp. 507-510, 2001. |
| Branebjerg et al., “Fast mixing by lamination”, in Proc. of the 9th IEEE Micro Electro Mechanical Systems Workshop, eds. M. G. Allen and M. L. Reed (San Diego, Calif.) pp. 441-446, 1996. |
| Burns et al., “An Integrated Nanoliter DNA Analysis Device”, Science, vol. 282, pp. 484-487, 1998. |
| Deruijter et al., “Droplet Spreading: Partial Wetting Regime Revisited”, Langmuir, vol. 15, pp. 2209-2216, 1999. |
| Dussan, “Immiscible Liquid Displacement in a Capillary Tube: The Moving Contact Line”, AlChe Journal, vol. 23, No. 1, pp. 131-133, Jan. 1977. |
| Dussan, “On the Spreading of Liquids on Solid Surfaces: Static and Dynamic Contact Lines”, Ann. Rev. Fluid Mech., vol. 11, pp. 371-400, 1979. |
| Dussan et al., “On the Motion of a Fluid-Fluid Interface Along a Solid Surface”, J. Fluid Mech., vol. 65, pp. 71-95, 1974. |
| Evans et al., “Planar Laminar Mixer”, Proceeding of the IEEE 10th Annual Workshop of MEMS (MEMS '97), Nagoya, Japan, pp. 96-101, Jan. 1997. |
| Hosokawa et al., “Droplet-Based Nano/Picoliter Mixer using Hydrophobic Microcapillary Vent”, Twelfth IEEE International Conference on Micro Electro Mechanical Systems, IEEE, pp. 388-393, Jan. 1999. |
| Hosokawa et al., “Handling of Picoliter Liquid Samples in a Poly (dimethysiloxane)-Based Microfluidic Device”, Anal. Chem., vol. 71, pp. 4781-4785, 1999. |
| Huh et al., Hydrodynamic Model of Steady Movement of a Solid/Liquid/Fluid Contact Line, Journal of Colloid and Interface Science, vol. 35, No. 1, pp. 85-101, Jan. 1971. |
| Jones et al., “Dielectrophoretic liquid actuation and nanodroplet formation,” J. Appl. Phys., vol. 89, No. 2, pp. 1441-1448 (Jan. 2001). |
| Kamper et al., “Microfluidic Components for Biological and Chemical Microreactors”, IEEE, pp. 338-343, 1997. |
| Koch et al., “Two Simple Micromixers Based on Silicon”, J. Micromech. Microeng. vol. 8, pp. 123-126, Jun. 1998. |
| Koch et al., “Improved Characterization Technique for Micromixers”, J. Micromech.Microeng. vol. 9, pp. 156-158, 1998. |
| Krog et al., “Experiments and Simulations on a Micro-Mixer Fabricated using a Planar Silicon/Glass Technology”, Microelectromechanical Systems (MEMS) DSC—vol. 59, ASME, pp. 177-182, 1996. |
| Lehmann et al., “Droplet-Based DNA Purification in a Magnetic Lab-on-a-Chip,” Angewandte Chemie, vol. 45, pp. 3062-3067, 2006. |
| Liu et al., “Passive Mixing in a Three Dimensional Serpentine Microchannel”, Journal of Microelectromechanical Systems, vol. 9, No. 2, pp. 190-197, 2000. |
| Miyake et al., “Micro Mixer with Fast Diffusion”, IEEE, pp. 248253, 1993. |
| Moesner et al., Devices for particle handling by an AC electric field. Proceedings IEEE Micro Electro Mechanical Systems, Amsterdam, Jan. 1995. UCLA 2000. |
| Mugele et al., “Electrowetting: from basics to applications,” Journal of Physics: Condensed Matter, 17, pp. R705-R774 (Jul. 2005). |
| Pamme, “Magnetism and microfluidics,” Lab on a Chip (LOC), vol. 6, pp. 24-38, 2006. |
| Saeki et al., “Electrowetting on Dielectrics (EWOD): Reducing Voltage Requirements for Microfluidics”, Polymeric Materials: Sci. Engr., vol. 85, pp. 12-13, 2001. |
| Schwesinger et al., “A Modular Microfluid System with an Integrated Micromixer”, J. Micromech.Microeng. vol. 6, IOP Publishing Ltd., pp. 99-102, Mar. 1996. |
| Schwesinger et al., “A Static Micromixer Built Up in Silicon”, Proc. SPIE vol. 2642, pp. 150-155, Sep. 1995. |
| Veenstra et al. “Characterization method for a new diffusion mixer applicable in micro flow injection analysis systems”, Journal of Micromechanics and Microengineering, 9, (2), pp. 199-202, 1999. |
| Kuzmin et al., Mol Gen Mikrobiol Virusol, 1991, vol. 8, pp. 6-8. |
| Yang et al., “Ultrasonic Micromixer for Microfluidic Systems”, MEMS'2000, pp. 80-85. |
| Yang et al., “Micromixer Incorporated with Piezoelectrially Driven Valveless Micropump”, Total Analysis Systems'98, Kluwer Acad. Pub, Dordrecht, Boston and London, pp. 177-180, 1998. |
| Poliski, “Making materials fit the future: accommodating relentless technological requirements means researchers must recreate and reconfigure materials, frequently challenging established laws of physics, while keeping an eye on Moore's law”, R&D Magazine, Dec. 2001. |
| Number | Date | Country | |
|---|---|---|---|
| 20150060284 A1 | Mar 2015 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60648051 | Jan 2005 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10253368 | Sep 2002 | US |
| Child | 11077569 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 13737433 | Jan 2013 | US |
| Child | 14538322 | US | |
| Parent | 12576794 | Oct 2009 | US |
| Child | 13737433 | US | |
| Parent | 11343284 | Jan 2006 | US |
| Child | 12576794 | US | |
| Parent | 11077569 | Mar 2005 | US |
| Child | 11965152 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11965152 | Dec 2007 | US |
| Child | 12576794 | US |
