Patent Document

TECHNICAL FIELD 
     The present invention relates to microfluidic devices, and more particularly, to a method and apparatus for distributing fluid within or from a microfluidic device. 
     BACKGROUND OF THE INVENTION 
     Methods of making a homologous series of compounds, or the testing of new potential drug compounds comprising a series of light compounds, has been a slow process because each member of a series or each potential drug must be made individually and tested individually. For example, a plurality of potential drug compounds that differ perhaps only by a single amino acid or nucleotide base, or a different sequence of amino acids or nucleotides are tested by an agent to determine their potential for being suitable drug candidates. 
     The processes described above have been improved by microfluidic chips which are able to separate materials in microchannels and move them through the microchannels. Moving the materials through microchannels is possible by use of various electro-kinetic processes such as electrophoresis or electro-osmosis. Fluids may be propelled through various small channels by the electro-osmotic forces. An electro-osmotic force is built up in the channel via surface charge buildup by means of an external voltage that can repel fluid and cause flow. 
     Other methods for moving materials through microchannels include, for example, pressure pumping. For this process, pressure heads are attached to the microfluidic chips and small bursts of pressured air or other gas, such as an inert gas; is directed into the microchannels. 
     Ultimately, the small volumes of liquids formed in the wells or reservoirs of a microfluidic device must be sampled and tested. Previous known methods for distributing and transporting fluids from the microfluidic devices include pressurizing the fluid to allow the fluid or a portion thereof to exit its chamber. One drawback to pressure pumping is that several parameters must be precisely controlled to expel a desired liquid amount. Such parameters include duration, the pulse magnitude, the channel dimension and solution viscosity. 
     SUMMARY OF THE INVENTION 
     It is, therefore, one object of the invention to provide an improved fluid dispensing system to dispense fluid from reaction wells. It is a further object of the invention to provide a controllable spray or stream of fluid for analysis. 
     It is yet another object of the present invention to provide a liquid handling drug discovery and diagnostic tool which increases the speed and productivity of discovering new drug candidates and does so on a miniaturized scale or platform that reduces cost and manual handling. It is still a further object of the present invention to provide a multiple fluid sample processor, system and method which is capable of conveying, transporting, and/or processing samples in a large multiplicity of sites. 
     In one aspect of the invention, a microfluidic fluid transportation system is coupled to a fluid pressure source. A microfluidic device has a fluid input coupled to the fluid pressure source, and a channel having an opening therein. The fluid pressure source pumps fluid into the channel to form a droplet at the opening having a predetermined volume. An electrical contact is proximate the opening and a power source is coupled to the contact. The power source selectively applies electrical power to the contact upon the formation of the droplet of a predetermined volume to form a fluid delivery. 
     In a further aspect of the invention, an inventive method is utilized which comprises forming a droplet having a predetermined volume of fluid at an outlet, generating a potential difference between the fluid and a target, releasing the fluid, and, directing the fluid at the target. 
     One advantage of the invention is that small and controlled amounts of fluid may be delivered or transported without the need to control many parameters. Another advantage of the invention is that the method for delivering fluid to microfluidic structures is applicable to structures having high integration densities and where viscous losses in micro channels are significant. 
     Other objects and features of the present invention will become apparent when viewed in light of the detailed description of the preferred embodiment when taken in conjunction with the attached drawings and appended claims. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 illustrates a multiple fluid sample processor according to the present invention; 
     FIG. 2 is an exploded view of the processor shown in FIG. 1; 
     FIG. 3 is a block diagram schematic view of a microfluidic fluid transportation system according to the present invention. 
     FIG. 4 is cross-sectional view of a well configured to transport liquid according to the present invention. 
     FIG. 5 is a top view of FIG.  4 . 
     FIG. 6 is a cross-sectional view of an alternative embodiment of a fluid transportation system having contacts in a different position and including a nozzle. 
     FIG. 7 is a cross-sectional view of a microfluidic device containing a fluid transportation system for moving fluid within a microfluidic device. 
     FIG. 8 is a side view of a droplet formation formed according to the process of the present invention. 
     FIG. 9 is a side view of a spray from an opening in a microfluidic device according to the present invention. 
     FIG. 10 is an alternative stream of fluid from a microfluidic device. 
     FIG. 11 is a cross-sectional view of a microfluidic device used for mixing two fluids. 
     FIG. 12 is a cross-sectional view of a microfluidic device with respect to a receiving plate. 
     FIG. 13 is a cross-sectional view of a microfluidic device having multiple openings. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
     Referring now to the drawings, like reference numerals are used to identify identical components in the various views. As illustrated below the present invention is particularly suited for use in connection with a microfluidic device. One skilled in the art, however, would recognize that the teachings of the present invention may be well suited for use in a variety of industries such as genomics, surface coating, apportionment, proteomics and inkjet applications. 
     The present invention can be used particularly in the industrialization of drug discovery processes including synthesis analysis and screening. The present invention increases speed and productivity while providing researchers with expanded capabilities and assuring quality. The invention provides substantial time and efficiency advantages over prior techniques. The invention provides miniaturized liquid handling systems which perform the biological, chemical and the analytical processes fundamental to life sciences, research and development. The invention can be utilized to perform thousands of reactions simultaneously in an integrated format, which substantially reduces the time, effort and expense required while improving the quality of the test results. 
     The processor in accordance with the present invention generally incorporates a modular configuration with distinct layers or plates. The processor or microfluidic device  10 , as shown in FIG. 1, is capable of conducting parallel synthesis of thousands of small molecule compounds through the precise delivery of reagents to discrete reaction sites. This helps create a significantly larger number and variety of small molecules more effectively and with fewer resources. 
     With the present invention, arrays of DNA can be synthesized and transported on demand. The processor can also be used for high volume of sample processing and testing, as well as the search for new molecular targets and determining expression levels and response to known drugs. The processor can incorporate multiple assay formats, such as receptor binding, antibody-antigen interactions, DNA/RNA amplification and detection, as well as magnetic deed base separations. The versatility of the processor and its architecture make it available for use with synthesis work stations, genomic support stations, and analytical preparation systems. 
     A basic multiple fluid sample processor or microfluidic device  10  in accordance with the present invention is shown in FIGS. 1 and 2. The microfluidic device is illustrated as a three-layered structure in the embodiment illustrated. The microfluidic device  10  is also called a fluid assay layered device (FALD), or a fluidic array. 
     The microfluidic device  10  includes a top layer  12 , which is also called a reagent reservoir. The microfluidic device  10  also includes a middle layer or fluidic delivery layer  14 , as well as a bottom layer or well plate  16 . 
     The top layer  12  is also called a feed-through plate and serves as a cover for the microfluidic device  10 . Layer  12  contains a number of apertures  18  which are selectively positioned immediately above apertures  20  in layer  14 . Apertures  20  are connected by an elongated micro-channels  22  which in turn have a plurality of branches extending therefrom. As illustrated, layer  14  comprises one layer, however, one skilled in the art would recognize that layer  14  may comprise several layers. 
     Well plate  16  has a plurality of wells  24  which are used to hold the reagents and other materials in order for them to react and synthesize. 
     The three layers  12 ,  14  and  16  are stacked together to form a modular configuration. They are also coupled together tightly to form a liquid-tight seal. If desired, the top layer  12  can be bounded or fused to the center distribution plate  14  or layer. The bottom or well plate layer  16 , however, is detachably coupled to layer  16 . 
     The plates  12 ,  14  and  16  may be made from any desirable material, such as glass, fused silica, quartz, or silicon wafer material. The reservoirs, micro-channels and reaction cells are controllably etched or otherwise formed onto the plates using traditional semi-conductor fabrication techniques with a suitable chemical etchant or laser drilling. 
     Top plate  12  contains apertures  18  positioned above the openings  20  located in central plate  14 . Apertures  18  provide the necessary openings for loading module to fill the reservoirs with a plurality of agents or other materials. 
     As will be further described below, a pressure pumping mechanism, is preferably used to assist in loading and distributing the reagents and other materials within the layers. 
     A typical need is for one of the sample plates to have each sample conveyed, transported and/or processed while eventually being delivered into the well plate. During this time, the samples are typically exposed to the atmosphere and can oxidize, evaporate or cross-contaminate to an undesirable extent. With the present invention, however, the multi-layered sample microfluidic device  10  with detachable well plates inhibits cross-contamination of the fluids used in the combinatorial process. 
     The detachable layers in accordance with the present invention are preferably of a common dimensionality for ease of being handled by robotic or other automation means. A common set of dimensions has been adopted by many manufacturers which match that of the 96-well plate known as a “micro titer” plate. 
     Preferably, the plates  12 ,  14  and  16  are connected to each other by an indexing means of detents, flanges or locating pins so they are closely aligned in the horizontal and vertical directions. While engaged in such manner, samples from one of the plates can be caused to be moved and transported to another plate. Means for transporting or moving the samples from one of the plates to the other can be by pumping, draining, or capillary action. While the samples are engaged, and as a result of the transport of the samples from one layer to the other, the samples may be processed, reacted, separated, or otherwise modified by chemical or physical means, and then finalized by optical, electrochemical, chemical, or other means. 
     Samples or fluids can be delivered to the microfluidic device  10  by being contained in one of the members of physically engaging sample multi-well plates, such as a top layer  12 , or other means of sample introduction can be utilized, such as through the edges of such layer. 
     Referring now to FIG. 3, a block diagram of a fluid transportation system  30  formed according to the present invention is illustrated. Fluid transportation system  30  controls the amount of fluid distributed from or within microfluidic device  10 . Fluid transportation system  30  is illustrated adjacent to a mass spectrometer  32  that is used for analyzing the composition of a fluid delivery  34  from microfluidic device  10 . Mass spectrometer  32  analyzes the composition of fluid delivery  34  in a well-known manner. 
     Microfluidic device  10  has a fluid input  36  which is coupled to a first fluid reservoir  38 . As will be further described below, a second fluid reservoir  40  may also be coupled in series with first fluid reservoir  38 . A pump  42  is used to move fluid from first reservoir  38  and second fluid reservoir  40  into fluid input  36 . 
     A power supply  44  is electrically coupled to buffer reservoir or pump  42  to an electrode  46  in microfluidic device  10  and mass spectrometer  32 . A controller  48  is coupled to power supply  44  and may be coupled to pump  42 . Controller  48  controls the coupling of power to electrode  46 , pump  42 , and mass spectrometer  32 . Controller  48  is preferably microprocessor based. Controller  48 , however, in its simplest form may comprise a number of switches. In the microprocessor form, controller  48  may include an internal timer. 
     A flow meter  50  may be positioned between fluid reservoir  38  and fluid input  36 . Flow meter  50  may provide feedback to controller  48  with regard to the amount of fluid transported to microfluidic device  10 . 
     Other feedback means to controller  48  may, for example, be timing for pump  42 . If pump flows at a certain rate when operated, the amount of fluid delivered to microfluidic device  10  may be determined by a timer. The timer may be incorporated within pump  42  or within controller  48  as described above. 
     In operation, controller  48  controls pump  42  to supply a predetermined amount of fluid from reservoirs  38  and  40 . As will be further described below, as a droplet of fluid forms at an opening of microfluidic device  10 , power supply  44  under the control of controller  48  applies power to contacts  46  and between a target  52 . A voltage potential difference exists between contact  46  and target  52  so that fluid delivery  34  is formed therebetween. 
     A first reservoir  38  and second reservoir  40  may be used to electrically isolate pump  42  from microfluidic device  10 . In this manner, second reservoir  40  provides isolation. Second reservoir  40  may be eliminated if another manner for electrical isolation is employed. In the illustration of FIG. 3, a single pump and a pair of series reservoirs  38 ,  40  are employed. However, it is likely that various numbers of pumps and reservoirs may be used to provide various reagents to microfluidic device  10 . 
     Referring now to FIGS. 4 and 5, a portion of a microfluidic device  10  is shown. The portion shown, may, for example, be a well plate  54  having a well  56 . A well plate  54  is described in FIGS. 1 and 2 as bottom layer  16 . Well  56  receives fluids from the other layers of microfluidic device  10 . Each fluid within each of the wells  56  of the device  10  must be analyzed. For many applications, it is desirable, however, to analyze only a small portion of the fluidic solution in well  56 . A sample outlet  58  is provided from well  56  through well plate  54 . An opening  60  is formed at sample outlet  60 . Sample outlet also has an entrance  62  adjacent to well  56 . To sample fluid from well  56 , fluid moves through entrance  62  through sample outlet  58  and through opening  60 . 
     Sample outlet  58  acts as a capillary channel from well  56 . A capillary barrier or “break”  64  is formed at opening  60  of sample outlet  58 . Capillary break  64  is formed by the surface tension of the fluid in sample outlet  58  when opening to a larger volume. Without a sufficiently high pressure or some other action, fluid within well  56  does not flow from sample outlet  58 . 
     An electrode  66  is positioned within sample outlet  58 . Electrode  66  is illustrated as a ring electrode positioned at opening  60 . The shape of electrode  66 , however, may vary depending on the application. Electrode  66  in any form should be capable of inducing a charge on fluid at outlet  58 . 
     Referring now to FIG. 6, electrode  66 ′ may be positioned at entrance  62  to sample outlet  58 . It has been experimentally found that the position of electrodes  66 ,  66 ′ in sample outlet  58  has little affect on the operation of fluid transportation system  30 . A nozzle  68  may also be used to extend sample outlet  58  at opening  60 . As shown, nozzle  68  forms a slight mesa that extends from the. bottom of well plate  54 . For most fluids, the formation of nozzle  68  has little affect on the operation of fluid transportation system  30 . 
     Referring now to FIG. 7, a three layer microfluidic device  10  is illustrated. Fluid transportation system may be incorporated within a microfluidic device  10  for providing fluid to various locations within microfluidic device. If accurate pumps or feedback systems are used, the amounts of fluid may be metered precisely. Microfluidic device may, for example, have a top layer  70 , a middle layer  72 , and a bottom layer  74 . Of course, the device illustrated in FIG. 7 is only a portion of a microfluidic device  10 . Microfluidic device  10  may, for example, have a number of layers incorporated therein. In the present example, a capillary channel  76  is formed between top layer  70  and middle layer  72 . Capillary channel  76  is ultimately coupled to a fluid reservoir such as that described above with respect to FIG.  3 . Capillary channel  76  may feed an intermediate well  78  within microfluidic device  10 . Electrodes  80  may be incorporated into microfluidic device to control the operation of fluid delivery as will be further described below. 
     Referring now to FIGS. 8 and 9, a droplet  82  is formed at opening  60  of sample outlet  58 . The volume of droplet  82  may be precisely controlled by pump  42  and controller  48  of FIG.  3 . Once a droplet  82  having a desired volume is formed, power supply provides a potential difference between contact  66  and target  52 . Depending on the viscosity of the fluid and other characteristics, when a sufficient potential difference is applied between contact  66  and target  52 , droplet  82  is formed into fluid delivery  34 . The type or fluid delivery  34  may include a cone  84  as illustrated in FIG. 9. A cone is formed by charged particles  86  of droplet  82 . 
     Referring now to FIG. 10, charged particles  86  may also form a stream between opening  60  and target  52 . A stream is formed when a relatively medium voltage potential is applied between electrode  66  and target  52 . The type of fluid delivery  34  obtained is dependent upon the voltage. For example, voltage in the range between 500 volts and 3 kilovolts may be used. 
     Referring now to FIG. 11, an alternative microfluidic device  10 ′ is illustrated having a first well  56 ′ and a second well  56 ″. Each well has a sample outlet  58 ′ and  58 ″. Wells  56 ′,  56 ″ may be coupled to the same fluids. In the preferred embodiment, however, wells  56 ′,  56 ″ are coupled to two different fluids. That is, wells  56 ′,  56 ″ may be coupled to two separate fluid reservoir/pump combinations. As described above, electrodes  66 ′ and  66 ″ are located within sample outlets  58 ′,  58 ″. When a droplet is formed in openings  60 ′ and  60 ″, and a voltage potential is applied between contact  60 ′,  60 ″ and target  52 , the droplets form fluid deliveries  34 ′,  34 ″. In this manner, a mixing region  90  is formed by the combination of the fluid deliveries  34 ′,  34 ″. Target  52  may be incorporated within a receiver plate or within a mass spectrometer. It is believed that mixing region  90  provides superior distribution of fluid deliveries  34 ′,  34 ″ for use with a mass spectrometer. 
     Referring now to FIG. 12, yet another alternative microfluidic device  10 ″ is illustrated. Microfluidic device  10 ″ has a well  56 ′″ having a capillary channel  92  extending therefrom. Capillary channel  92  has a sample outlet  58 ′″. Capillary channel  92  is also illustrative of the fact that well  56 ′″ may be located a distance from an opening  60 ′″ in sample outlet  58 ′″. A nozzle  68 ′″ may also be incorporated near opening  60 ′″. 
     When dispensing liquid from microfluidic device  10 ″, a receiver plate  94  may be positioned adjacent to microfluidic device  10 ″. Receiver plate  94  has a receiving well  96  that may be used to transport samples of the solution formed in well  56 ′″. Receiving well  96  may have an electrode  98  coupled thereto. Electrode  98  in combination with electrode  66 ′″ has an electrical potential difference. The potential difference allows fluid to be dispensed from sample outlet  58 ′″. 
     Referring now to FIG. 13, a microfluidic device  10 ′″ is illustrated similar to that of microfluidic device  10 ″ except having a multiple number of wells  56 A through  56 E. Wells  56 A through  56 E may each have different solutions therein. Microfluidic device  10 ′″ may be used for mixing or dispensing solutions from wells  56 A through  56 E. 
     In operation, when fluid is to be transferred within or from a microfluidic device, a droplet is formed at an opening. When a desired volume droplet is formed, a spray voltage is applied to an electrode within the fluid outlet. The application of voltage causes the droplet to be drawn towards an oppositely charged or grounded target. The particles of fluid or charge particles are attracted to the oppositely charged target. Charge particles may form a fluid delivery shaped as a cone or as a stream or as a number of droplets. Depending on the voltage, the characteristics of the fluid delivery may be changed. 
     One skilled in the art would recognize that a relatively low voltage may be maintained and when a fluid delivery is desired, the voltage may be increased to the desired level to obtain the desired fluid delivery characteristic. 
     While particular embodiments of the invention have been shown and described, numerous variations and alternate embodiments will occur to those skilled in the art. Accordingly, it is intended that the invention be limited only in terms of the appended claims.

Technology Category: 7