Abstract:
A fluid distribution system has a microfluidic device that has a main channel with a plurality of branches extending therefrom. The main channel has a length. The main channel and the branches are coupled through a plurality of apertures with aperture diameters. The aperture diameters progressively increase along said length of the main channel to allow fluid to more evenly be distributed to the branches.

Description:
TECHNICAL FIELD 
     The present invention relates to microfluidic devices, and more particularly, to a method and apparatus for distributing fluid on 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 is tested by an agent to test a plurality of materials that differ perhaps only by a single amino acid or nucleotide base, or a different sequence of amino acids or nucleotides. 
     The processes described above have been improved by microfluidic chips which are able to separate materials in a micro channel and move the materials through the micro channel is possible. Moving the materials through micro channels 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. 
     In fluid delivery in microfluidic structures, it is important to distribute approximately the same fluid volume to each reaction well. By using certain fluids, however, even distribution to the various reaction wells is difficult to accomplish. This is especially true in pressure pumping. Pressure pumping uses pressurized fluid at the fluid input. The fluid under pressure is distributed along the channels and ultimately to reaction wells. One problem associated with pressure pumping is that fluid closer to the input is under higher pressure than the fluid further downstream due to the pressure losses associated with each of the branches. This in time allows the channels closer to the fluid input to fill more rapidly. 
     SUMMARY OF THE INVENTION 
     It is, therefore, one object of the invention to provide an improved fluid delivery mechanism to an array of reaction wells. It is a further object of the invention to provide a reliable method for delivering fluid to reaction wells. 
     It is another object of the present invention to create a relatively small device which can carry out hundreds and even thousands of chemical experiments simultaneously, create new compounds, and measure their reactivities. 
     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 without exposure to the atmosphere. 
     In one aspect of the invention, a fluid distribution system has a microfluidic device that has a main channel therein. The microfluidic device has a plurality of branches extending therefrom. The main channel has a length. The main channel and the branches are coupled through a plurality of apertures with aperture diameters. The apertures progressively increase along said length of the main channel. 
     One advantage of the invention is that small and controlled amounts of fluid may be delivered in an array structure with micro channels that have high pressure losses. 
    
    
     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 IF 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 schematic view of a fluid distribution system network formed according to the present invention. 
     FIG. 4 is a cross-sectional view along line  4 — 4  of FIG.  1 . 
     FIG. 5 is a cross-sectional view of an alternative embodiment of a fluid distribution network as shown in FIGS.  3  and  4 . 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
     Referring now to the drawings, like reference numerals are used to identify identical components in the various views. The present invention can be used particularly in the industrialization of drug discovery processes. The present invention increases speed and productivity while providing researchers with expended 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  12  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 on demands. 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 bead base separations. The versatility of the processor and its architecture make it available for use with synthesize work stations, genomic support stations, and analytical preparation systems. 
     A basic multiple fluid sample processor or microfluidic device  12  in accordance with the present invention is shown in FIGS. 1 and 2, with cross-sections of the layers being shown in FIGS. 4 and 5. The microfluidic device is illustrated as a three-layered structure in the embodiment illustrated. The microfluidic device  12  is also called a fluid assay layered device (FALD), or a fluidic array. 
     The microfluidic device  12  includes a top layer  7 , which is also called a reagent reservoir. The microfluidic device  12  also includes a middle layer or fluidic delivery layer  8 , as well as a bottom layer or well plate  9 . 
     The top layer  7  is also called a feed-through plate and serves as a cover for the microfluidic device  12 . Layer  7  contains a number of apertures  11  which are selectively positioned immediately above apertures  13  in layer  8 . Apertures  13  are connected by an elongated micro-channel  48  which in turn have a plurality of branches extending therefrom. As illustrated, layer  8  contains one layer, however, one skilled in the art would recognize that layer  8  may comprise several layers. 
     Well plate  9  has a plurality of wells  15  which are used to hold the reagents and other materials in order for them to react and synthesize. 
     The three layers  7 ,  8  and  9  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  7  can be bounded or fused to the center distribution plate  8  or layer. The bottom or well plate layer  9 , however, is detachably coupled to layer  8 . 
     The plates  7 ,  8  and  9  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, laser drilling or reactive ion etching. 
     Top plate  7  contains apertures positioned above the openings  13  located in the central plate. These apertures 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 repeated 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  12  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  7 ,  8  and  9  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  12  by being contained in one of the members of physically engaging sample multi-well plates, such as a top layer  7 , or other means of sample introduction can be utilized, such as through the edges of such layer. 
     Referring to FIG. 3, a microfluidic distribution system  10  is shown incorporated into a microfluidic device  12 . A fluid source  14  provides reagents to microfluidic device  12 . 
     Distribution system  10  has a fluid input  16  coupled to fluid source  14 . Fluid input  16  is coupled to a main channel  18 . Main channel  18  has a plurality of branches  20  extending therefrom. Main channel  18  is coupled to a fluid output  22  that directs fluid outside of microfluidic device  12 , which has not been diverted by one of the plurality of branches  20 . 
     Fluid source  14  is preferably a pressurized fluid source that provides pressurized fluid to main channel  18 . Various types of pressurized fluid sources  14  would be evident to those skilled in the art. Two examples of pressurized fluid sources are disclosed in my copending commonly assigned patent applications entitled “Fluid Delivery System For A Microfluidic Device Using A Pressure Pulse,” Ser. No. 09/351,206 filed Jul. 9, 1999, and “Fluid Delivery System For A Microfluidic Device Using Alternating Pressure Pulses,” Ser. No. 09/349,438 filed Jul. 9, 1999, the subject matter of such copending applications being incorporated herein by reference. 
     Referring now also to FIG. 4, microfluidic device  12  is preferably comprised of a plurality of adjacent layers. In the present example, a top layer  26 , a second layer  28 , a third layer  30 , a fourth layer  32 , and a well layer  34  are used. The composition of each layer may, for example, be glass, silicon, or another suitable material known to those in the art. Each layer may be bonded or glued together in a manner known to those skilled in the art. For example, the layers may be anodically bonded. 
     Branches  20  provide interconnections to well layer  34  through the various layers  26  through  32 . The various openings and channels forming branches  20  may be formed in a conventional manner, such as by etching or drilling. Drilling may be accomplished by laser or mechanical drilling. 
     Main channel  18  in the preferred embodiment is defined by third layer  30  and second layer  28 . A cell feed  36  is formed between top layer  26  and within second layer  28 . Cell feed  36  is coupled to main channel  18  through interlayer feed channel  38 . Interlayer feed channel  38 , as illustrated, is conical in shape. However, interlayer feed channel  38  may also be cylindrical in shape. Cell feed  36  has an extension  42  that extends to the edge of center layer  28  at the interface with third layer  30 . 
     An air fluid manifold  44  is formed in third layer  30 . Air fluid manifold  44  is fluidically coupled to extension  42 . The interface between air fluid manifold  44  and extension  42  forms a capillary break  46 . Fluid under pressure enters main channel  18  and fills cell feed  36  and extension  42  up to capillary break  46 . Capillary break  46  must be overcome with a higher pressure than the initial fill pressure. Once the higher pressure is applied, fluid flows through manifold  44 . Air fluid manifold  44  is coupled to the interface between third layer  30  and fourth layer  32  by a manifold channel  48 . Manifold channel  48  is fluidically coupled to a well feed  50  that extends through fourth layer  32 . In the preferred embodiment, a back flow valve  52  is formed at the interface between manifold channel  48  and well feed  50 . Back flow valve  52  is formed by providing a larger diameter manifold channel  48  at the entrance to well feed  50 . That is, the diameter of manifold channel  48  at fourth layer  32  is greater than the diameter of well feed  50 . 
     Well layer  34  has a well  54  formed therein. Well feed  50  is fluidically coupled to well  54 . Well layer  34  may be detachable from fourth layer  32 . 
     Referring now to FIG. 5, a similar structure to that of FIG. 4 is shown, except a silicon layer  56  is interposed between second layer  28  and third layer  30 . Silicon layer  56  may be doped to various levels to provide various electrical characteristics. 
     As is best shown in FIG. 3, the size of interlayer feed holes  40  varies as a function of the distance from fluid input. Preferably, the smallest diameter feed holes are located close to fluid input  16 . The diameter is steadily increased along the length of main channel  18  toward fluid input  22 . In one constructed device, main channel  18  had a 300 μm wide and 100 micrometers deep channel. Interlayer holes varied from 50 μm toward fluid input  16  and increased to a diameter of 150 μm. 
     In operation, pressurized fluid from fluid source  14  is introduced into main channel  18  at fluid input  16 . As the fluid passes the first interlayer feed hole  40 , fluid begins to fill interlayer feed channel  38  through interlayer feed hole  40 . Fluid then enters cell feed  36  and extension  42  up to the capillary break. Each branch along the main channel is filled in a similar manner and relatively simultaneously. By varying the size of interlayer feed hole  40 , the magnitude of the pressure loss associated with each branch may be somewhat balanced with the other feed holes. This allows each of the branches to be filled at the same rate. 
     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.