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Method and apparatus for delivery of submicroliter volumes onto a substrateRelated Patent Categories: Chemistry: Analytical And Immunological Testing, Including Sample Preparation, Volumetric Liquid TransferMethod and apparatus for delivery of submicroliter volumes onto a substrate description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060024841, Method and apparatus for delivery of submicroliter volumes onto a substrate. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATIONS [0001] Benefit of priority under 35 U.S.C. .sctn.119(e) to U.S. provisional application Ser. No. 60/244,404, filed Oct. 30, 2000, to Chao Lin et al., entitled "METHOD AND APPARATUS FOR DELIVERY OF SUBMICROLITER VOLUMES ONTO A SUBSTRATE" is claimed herein. The subject matter of the provisional application is incorporated by reference in its entirety. BACKGROUND [0002] 1. Field of the Invention [0003] The invention relates to sample dispensing systems and, more particularly, to the delivery of liquid samples onto substrate, such as a microarray, for laboratory analysis. [0004] 2. Description of the Background Art [0005] Genetic sequencing efforts, such as the Human Genome project, have produced vast amounts of information for basic genetic research that have proven useful in developing advances in health care and drug research. These advances are possible because of improvements in engineering and instrumentation that provide advanced tools for the biotechnology community to continue with basic genetic research. With these advances, scientists can move from basic genomic discoveries to associating specific phenotypes and diseases, and can thereby better identify targets for drug development. [0006] Nucleic acid sequencing and diagnostic methods often analyze samples deposited onto target locations on substrates microarrays, such has microplates, silicon chips and other such supports capable of retaining biological molecules or samples at discrete loci. Microarrays have been used to execute tests on large batches of genetic samples to generate phenotype associations and improve interpretation of the large data sets that result from such tests. A typical microarray, referred to as a chip, includes a substrate, such as a silicon or silicon-coated substrate, on which a large number of reactive points receive samples for testing. Microarray chips provide a technology that permits operators to increase sample throughput, allowing the screening of large numbers of samples and reducing reagent costs by using submicroliter sample volumes. Preparation of such arrays employs a variety of methodologies, including printed arrays and spotted arrays, with a wide variety of substrate surfaces and different modes of quantification. The resulting microarrays are used as substrates for a variety of biochemical applications. [0007] Among the ways for delivery of multiple samples to loci on microarray surfaces are solid pins. The solid pins typically are dipped into a liquid sample, which coats the tip of each pin, holding a sample droplet by surface tension. The coated pins are then touched to a target surface on a microarray substrate, so that the sample is transferred to the target by contact printing. The size and taper of the pin tool tip can affect the volume of liquid sample that is picked up during dipping. The amount of liquid sample transferred on contact will vary with the surface tension of the liquid. Pin tools also can be problematic for high throughput systems because the pins may have to be changed if different sample volumes are desired, or if the nature of the liquid sample is changed to avoid sample contamination. In addition, pin tools cannot be used in situations where contact dispensing where there is a risk of damage to a fragile preloaded sample, such as for mass spectrometric analyses in which samples are deposited on loci that have preloaded material, such as matrix material for matrix-assisted laser desorption (MALDI). [0008] Some mass spectrometry formats, such as MALDI formats, combine the sample to be tested with a matrix material, such as an inorganic acid, which when dried forms a crystal structure. Matrix material can be preloaded on a mass spectrometry substrate and the sample can be added at a later time, using an appropriate liquid dispensing apparatus. When a sample target is preloaded or prespotted with the porous matrix material required for mass spectrometry, direct contact by the solid pin with the matrix material can crush the material. [0009] Other liquid samples dispensing apparatus rely on piezoelectric mechanisms, sometimes using quill-type pin tools that hold the samples in a cut-out at the lower tool tip. Such piezoelectric delivery systems are susceptible to dispensing satellite droplets on a target location because of surface tension effects. Piezoelectric systems also may be prone to variations in voltage and frequency among different tips, which results in variation between the volume of liquid sample dispensed from different individual tips. [0010] From the discussion above, it is apparent that there is a need for a dispensing systems that can accurately deposit precise amounts of liquid sample on target locations on a substrate, with a high throughput rate, without risk of cross contamination of samples or damage to the deposited material. Therefore, it is an object herein to provide apparatus, methods and substrates for fulfilling these and other needs. SUMMARY OF THE INVENTION [0011] A delivery system for delivery of precise amounts small volumes, particularly submicroliter and smaller volumes is provided. Also provided are pin tools for use in the system and substrates for retaining samples, particularly substrates for use in the systems provided herein. [0012] One delivery system with pin tool as constructed as provided herein, accurately delivers small volumes, typically submicroliter or nanoliter or picoliter volumes, of liquid samples onto a substrates, such as a microarray substrate, at high throughput rates by dipping a slotted pin tool (a pin tool having one or more pins with slotted ends) having an open tip into a sample reservoir or well containing a liquid sample to be delivered onto the substrate, thereby drawing a volume of liquid sample up into the pin tool. The slotted pin tool is then moved toward the substrate at a predetermined rate and then is halted, thereby expelling the liquid sample from the slotted pin tool onto the reaction location of the substrate. Thus, the sample fluid is expelled from the slotted pin tool by the force of momentum. The volume of liquid sample expelled is proportional to the momentum of the moving pin tool (i.e., the amount delivered is proportional to the velocity of the pin tool as it contacts the surface or to the velocity of the liquid in a pin when movement of the pin tool is halted). Hence volume delivered is a function of the speed of moving the pin tool toward the microarray, which provides a way to accurately control and deliver desired sample volumes. For each pin tool size there is a range of volumes in which the amount of volume delivered is a linearly of the velocity of the pin tool. Sample volume delivered is not dependent on tip surface areal, thereby providing for flexibility in use since it is not necessary to change pins to dispense different volumes. [0013] The system uses the slotted pin tool provided herein. The pin tool has a slot that is sufficiently large to contain the volume of sample liquid desired for delivery. The slotted pin tool and system are provided herein. In one aspect, the pin tool slot may be sized to fit around target locations, such as loci on which material has been deposited on a substrate, such as a microarray substrate, to prevent contact between the pin tool and the material. The slotted pins can be mounted in a holding block so as to move up and down in the block; the positions of each pin in the block are selected to match the target loci on the substrate. The slotted pins in the pin tool have a substantially cylindrical tip having a lateral slot forming a cavity with a width of greater than at least about 10, 30, 50, 75 or 100 .mu.m, and can be of a size up to about 300 .mu.m or 500 .mu.m or 1000 .mu.m and having a height of at least about, 25, 50 .mu.m, 100 .mu.m or greater. The selected size is a function of the delivered volume of liquid. Such pins can deliver samples of as low or lower about 1 nanoliter and higher, and can be as low as about 3-10 picoliters. [0014] For example, a pin tool provided herein with a 300 .mu.m slot permits delivery of volumes of as low as about 1 nanoliter to 30 nanoliters. For this pin tool and for delivery of volumes in this range the volume delivered is linearly related to the velocity of the tool prior to halting it. Varying the size of the slot permits greater variation in volume delivered. [0015] The particular geometry of the slot in the pin tool is selected as a function of the size of the loci on the target array. In some embodiments, system is designed so that the pin tool halts prior to contacting the surface. In other embodiments it contacts the surface. For embodiments in which the halting of the movement of the pin tool results from or includes contact with the substrate, the slots fit around each locus. [0016] Generally the sample selected to be delivered, when intended for mass spectrometric analysis by MALDI, results in a spot on the substrate surface that is at least the size of the laser spot but can be smaller or larger as desired. A typical laser spot is about 30-50 .mu.m. Delivery of about 5 nanoliters results in a spot of about 100 .mu.m. The precise size of the spot varies depending upon the surface on which it is delivered. [0017] To move the pin tool towards the substrate, the holding block can be moved toward the substrate, such as a microarray substrate, until the slotted pins on the tool make contact with the microarray, whereupon the pin tool tips fit around the loci, such as spots of matrix material, without contacting any deposited material on the surface. The pin tool then moves upward in the pin tool holding block, which is then moved away from the microarray. Because it is designed to fit around each locus, the pin tool does not contact any material, such as matrix material for MALDI, cells, protein crystals or other materials, on the substrate. In this way, the dispensing system accurately deposits precise amounts of liquid sample on target locations, such as on a microarray substrate, with a high throughput rate, without contacting or damaging any material, such as matrix material, deposited on a substrate. [0018] A microarray substrate that can be used with the system is also provided. This microarray is constructed using photolithographic techniques and hydrophobic materials. Target locations on the microarray are defined with the application of photoresist materials and photolithographic deposition to create an array of locations on the chip that are less hydrophobic than the surrounding areas. The differential hydrophobicity confines the droplets to a desired locus. The microarrays can contain any desired number of loci from 1 to 1000, to 2000 or more, and typically have 96-, 384-, 1536-loci. Higher densities are also contemplated. The pins in the pin tools are in a pattern that matches a selected array. [0019] By virtue of the pin tool design herein, it is possible to transfer the sample to a pre-determined locus on a substrate that already has pre-deposited material, such as matrix, cells, such as bacterial or mammalian cells, protein crystals and other materials sensitive to contact. Since the instant tools provided herein rely on inertial forces for delivery, delivery of liquids is primarily dependent upon the momentum of the liquid in the slotted tool, not on the relative surface tensions of the pin and the substrate for the liquid. As one result, the pin tools provided herein permit accurate and controlled delivery of defined volumes by selection of the velocity of the tool at impact or as it reaches it the substrate and is stopped prior to contact. [0020] Substrates that contain two materials, a photoresist material treated to render it resistant to chemical treatments such as silation used mass spectrometry and other synthetic procedures, and a second more hydrophobic material are provided. Unlike most substrates that employ photolithographic methods, the photoresist is not removed from the surface, but includes the target loci of the surface. This is achieved by baking the substrate. Hence a substrate that contains photoresist material as the target loci are provided. [0021] Also provided are combinations of pin tools that contain slotted pins and substrates, where the number and arrangement of pins and size of the slots is designed to match the arrayed loci and, preferably, the slots are of a size that is greater than each locus, or each locus with loaded or preloaded material, such as matrix material. Continue reading about Method and apparatus for delivery of submicroliter volumes onto a substrate... Full patent description for Method and apparatus for delivery of submicroliter volumes onto a substrate Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Method and apparatus for delivery of submicroliter volumes onto a substrate patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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