US20010008615A1 - Systems and methods for preparing and analyzing low volume analyte array elements - Google Patents
Systems and methods for preparing and analyzing low volume analyte array elements Download PDFInfo
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- US20010008615A1 US20010008615A1 US09/371,150 US37115099A US2001008615A1 US 20010008615 A1 US20010008615 A1 US 20010008615A1 US 37115099 A US37115099 A US 37115099A US 2001008615 A1 US2001008615 A1 US 2001008615A1
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- B01L3/0241—Drop counters; Drop formers
- B01L3/0268—Drop counters; Drop formers using pulse dispensing or spraying, eg. inkjet type, piezo actuated ejection of droplets from capillaries
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
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- C07F9/24—Esteramides
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Definitions
- the invention relates to systems and methods for preparing a sample for analysis, and more specifically to systems and methods for dispensing low volumes of fluid material onto a substrate surface for generating an array of samples for diagnostic analysis.
- genomic DNA includes both coding and non-coding sequences (e.g., exons and introns).
- traditional techniques for analyzing chemical structures such as the manual pipeting of source material to create samples for analysis, are of little value.
- scientist have developed parallel processing protocols for DNA diagnostics.
- nucleic acid sequences can be identified by hybridization with a probe which is complementary to the sequence to be identified.
- the nucleic acid fragment is labeled with a sensitive reporter function that can be radioactive, fluorescent, or chemiluminescent.
- a sensitive reporter function can be radioactive, fluorescent, or chemiluminescent.
- Radioactive labels can be hazardous and the signals they produce decay over time.
- Nonisotopic (e.g. fluorescent) labels suffer from a lack of sensitivity and fading of the signal with high intensity lasers are employed during the identification process.
- labeling is a laborious and time consuming error prone procedure.
- Serial and parallel dispensing tools that can be employed to generate multi-element arrays of sample material on a substrate surface are provided.
- the substrates surfaces can be flat or geometrically altered to include wells of receiving material.
- a tool that allows the parallel development of a sample array is provided.
- the tool can be understood as an assembly of vesicle elements, or pins, wherein each of the pins can include a narrow interior chamber suitable for holding nano liter volumes of fluid.
- Each of the pins can fit inside a housing that itself has in interior chamber.
- the interior housing can be connected to a pressure source that will control the pressure within the interior housing chamber to regulate the flow of fluid through the interior chamber of the pins.
- the invention provides a tool that includes a jet assembly that can include a capillary pin having an interior chamber, and a transducer element mounted to the pin and capable of driving fluid through the interior chamber of the pin to eject fluid from the pin.
- the tool can dispense a spot of fluid to a substrate surface by spraying the fluid from the pin.
- the transducer can cause a drop of fluid to extend from the capillary so that fluid can be passed to the substrate by contacting the drop to the surface of the substrate.
- the tool can form an array of sample material by dispensing sample material in a series of steps, while moving the pin to different locations above the substrate surface to form the sample array.
- the invention then passes the prepared sample arrays to a plate assembly that disposes the sample arrays for analysis by mass spectrometry.
- a mass spectrometer is provided that generates a set of spectra signal which can be understood as indicative of the composition of the sample material under analysis.
- a dispensing apparatus for dispensing defined volumes of fluid, including nano and sub-nano volumes of fluid, in chemical or biological procedures onto the surface of a substrate.
- the apparatus provided herein can include a housing having a plurality of sides and a bottom portion having formed therein a plurality of apertures, the walls and bottom portion of the housing defining an interior volume; one or more fluid transmitting vesicles, or pins, mounted within the apertures, having a nanovolume sized fluid holding chamber for holding nanovolumes of fluid, the fluid holding chamber being disposed in fluid communication with the interior volume of the housing, and a dispensing element that is in communication with the interior volume of the housing for selectively dispensing nanovolumes of fluid form the nanovolume sized fluid transmitting vesicles when the fluid is loaded with the fluid holding chambers of the vesicles.
- this allows the dispensing element to dispense nanovolumes of the fluid onto the surface of the substrate when the apparatus is disposed over and in registration
- the fluid transmitting vesicle has an open proximal end and a distal tip portion that extends beyond the housing bottom portion when mounted within the apertures.
- the open proximal end can dispose the fluid holding chamber in fluid communication with the interior volume when mounted with the apertures.
- the plurality of fluid transmitting vesicles are removably and replaceably mounted within the apertures of the housing, or alternatively can include a glue seal for fixedly mounting the vesicles within the housing.
- the fluid holding chamber includes a narrow bore dimensionally adapted for being filled with the fluid through capillary action, and can be sized to fill substantially completely with the fluid through capillary action.
- the plurality of fluid transmitting vesicles comprise an array of fluid delivering needles, which can be formed of metal, glass, silica, polymeric material, or any other suitable material.
- the housing can include a top portion, and mechanical biasing elements for mechanically biasing the plurality of fluid transmitting vesicles into sealing contact with the housing bottom portion.
- each fluid transmitting vesicle has a proximal end portion that includes a flange, and further includes a seal element disposed between the flange and an inner surface of the housing bottom portion for forming a seal between the interior volume and an external environment.
- the biasing elements can be mechanical and can include a plurality of spring elements each of which are coupled at one end to the proximal end of each the plurality of fluid transmitting vesicles, and at another end to an inner surface of the housing top portion. The springs can apply a mechanical biasing force to the vesicle proximal end to form the seal.
- the housing further includes a top portion, and securing element for securing the housing top portion to the housing bottom portion.
- the securing element can comprise a plurality of fastener- receiving apertures formed within one of the top and bottom portions of the housing, and a plurality of fasteners for mounting within the apertures for securing together the housing top and bottom portions.
- the dispensing element can comprise a pressure source fluidly coupled to the interior volume of the housing for disposing the interior volume at a selected pressure condition.
- the dispensing element can include a pressure controller than can vary the pressure source to dispose the interior volume of the housing at varying pressure conditions. This allows the controller varying element to dispose the interior volume at a selected pressure condition sufficient to offset the capillary action to fill the fluid holding chamber of each vesicle to a predetermined height corresponding to a predetermined fluid amount.
- the controller can further include a fluid selection element for selectively discharging a selected nanovolume fluid amount from the chamber of each the vesicle.
- the apparatus includes a pressure controller that operates under the controller of a computer program operating on a data processing system to provide variable control over the pressure applied to the interior chamber of the housing.
- the fluid transmitting vesicle can have a proximal end that opens onto the interior volume of the housing, and the fluid holding chamber of the vesicles are sized to substantially completely fill with the fluid through capillary action without forming a meniscus at the proximal open end.
- the apparatus can have plural vesicles, wherein a first portion of the plural vesicles include fluid holding chambers of a first size and a second portion including fluid holding chambers of a second size, whereby plural fluid volumes can be dispensed.
- the apparatus can include, a fluid selection element that has a pressure source coupled to the housing and in communication with the interior volume for disposing the interior volume at a selected pressure condition, and an adjustment element that couples to the pressure source for varying the pressure within the interior volume of the housing to apply a positive pressure in the fluid chamber of each the fluid transmitting vesicle to vary the amount of fluid dispensed therefrom.
- the selection element and adjustment element can be computer programs operating on a data processing system that directs the operation of a pressure controller connected to the interior chamber.
- an apparatus for dispensing a fluid in chemical or biological procedures into one or more wells of a multi-well substrate can include a housing having a plurality of sides and a bottom portion having formed therein a plurality of apertures, the walls and bottom portion defining an interior volume, a plurality of fluid transmitting vesicles, mounted within the apertures, having a fluid holding chamber disposed in communication with the interior volume of the housing, and a fluid selection and dispensing means in communication with the interior volume of the housing for variably selecting am amount of the fluid loaded within the fluid holding chambers of the vesicles to be dispensed from a single set of the plurality of fluid transmitting vesicles. Accordingly, the dispensing means dispenses a selected amount of the fluid into the wells of the multi-well substrate when the apparatus is disposed over and in registration with the substrate.
- a fluid dispensing apparatus for dispensing fluid in chemical or biological procedures into one or more wells of a multi-well substrate, that includes a housing having a plurality of sides and top and bottom portions, the bottom portion having formed therein a plurality of apertures, the walls and top and bottom portions of the housing defining an interior volume, a plurality of fluid transmitting vesicles, mounted within the apertures, having a fluid holding chamber sized to hold nanovolumes of the fluid, the fluid holding chamber being disposed in fluid communication with the volume of the housing, and mechanical biasing element for mechanically biasing the plurality of fluid transmitting vesicles into sealing contact with the housing bottom portion is provided.
- FIG. 1 illustrates one system provided herein for preparing arrays of a sample material for analysis
- FIG. 2 illustrates a pin assembly suitable for use with the system depicted in FIG. 1 for implementing a parallel process of dispensing material to a surface of a substrate;
- FIG. 3 depicts a bottom portion of the assembly shown in FIG. 2;
- FIG. 4 depicts an alternative view of the bottom portion of the pin assembly depicted in FIG. 2;
- FIGS. 5 A- 5 D depict one method provided herein for preparing an array of sample material
- FIGS. 6 A- 6 B depict an alternative assembly for dispensing material to the surface of a substrate.
- FIG. 7 depicts one embodiment of a substrate having wells etched therein that are suitable for receiving material for analysis.
- FIG. 8 depicts one example of spectra obtained from a linear time of flight mass spectrometer instrument and representative of the material composition of the sample material on the surface of the substrate depicted in FIG. 7;
- FIG. 9 depicts molecular weights determined for the sample material having spectra identified in FIG. 8.
- FIG. 1 illustrates one system provided herein for preparing arrays of sample material for analysis by a diagnostic tool.
- FIG. 1 depicts a system that includes a data processor 12 , a motion controller 14 , a robotic arm assembly 1 6 , a monitor element 18 A, a central processing unit 18 B, a microliter plate of source material 20 , a stage housing 22 , a robotic arm 24 , a stage 26 , a pressure controller 28 , a conduit 30 , a mounting assembly 32 , a pin assembly 38 , and substrate elements 34 .
- the robotic assembly 16 can include a moveable mount element 40 and a horizontal slide groove 42 .
- the robotic arm 24 can optionally pivot about a pin 36 to increase the travel range of the arm 24 so that arm 24 can disposes the pin assembly 38 above the source plate 20 .
- the data processor 12 depicted in FIG. 1 can be a conventional digital data processing system such as an IBM PC compatible computer system that is suitable for processing data and for executing program instructions that will provide information for controlling the movement and operation of the robotic assembly 16 .
- the data processor unit 12 can be any type of system suitable for processing a program of instructions signals that will operate the robotic assembly that is integrated into the robotic housing 16 .
- the data processor 12 can be a micro-controlled assembly that is integrated into robotic housing 16 .
- the system 10 need not be programmable and can be a singleboard computer having a firmware memory for storing instructions for operating the robotic assembly 16 .
- controller 14 that electronically couples between the data processor 12 and the robotic assembly 16 .
- the depicted controller 14 is a motion controller that drives the motor elements of the robotic assembly 16 for positioning the robotic arm 24 at a selected location. Additionally, the controller 14 can provide instructions to the robotic assembly 16 to direct the pressure controller 28 to control the volume of fluid ejected from the individual pin elements of the depicted pin assembly 38 .
- the design and construction of the depicted motion controller 14 follows from principles well known in the art of electrical engineering, and any controller element suitable for driving the robotic assembly 16 can be used.
- the robotic assembly 16 depicted in FIG. 1 electronically couples to the controller 14 .
- the depicted robotic assembly 16 is a gantry system that includes an XY table for moving the robotic arm about a XY plane, and further includes a Z axis actuator for moving the robotic arm orthogonally to that XY plane.
- the robotic assembly 16 depicted in FIG. 1 includes an arm 24 that mounts to the XY stage which moves the arm within a plane defined by the XY access.
- the XY table is mounted to the Z actuator to move the entire table along the Z axis orthogonal to the XY plane.
- the robotic assembly provides three degrees of freedom that allows the pin assembly 38 to be disposed to any location above the substrates 34 and the source plate 20 which are shown in FIG. 1 as sitting on the stage 26 mounted to the robotic assembly 16 .
- the depicted robotic assembly 16 follows from principles well known in the art of electrical engineering and is just one example of a robotic assembly suitable for moving a pin assembly to locations adjacent a substrate and source plate such as the depicted substrate 34 . Accordingly, it will be apparent to one of skill in the art that alternative robotic systems can be used.
- FIG. 1 depicts an embodiment of a robotic assembly 16 that includes a pressure controller 28 that connects via a conduit 30 to the mount 32 that connects to the pin assembly 38 .
- the mount 32 has an interior channel for fluidicly coupling the conduit 30 to the pin assembly 38 .
- the pressure controller 28 is fluidicly coupled by the conduit 30 and the mount 32 to the pin assembly 38 .
- the controller 1 4 can send signals to the pressure controller 28 to control selectively a fluid pressure delivered to the pin assembly 38 .
- FIG. 2 depicts one embodiment of a pin assembly 50 suitable for practice with the system depicted in FIG. 1 which includes the pressure controller 28 .
- the pin assembly 50 includes a housing formed from an upper portion 52 and a lower portion 54 that are joined together by the crews 56 A and 56 B to define an interior chamber volume 58 .
- FIG. 2 further depicts that to fluidicly seal the interior chamber volume 58 the housing can include a seal element depicted in FIG. 2 as an O-ring gasket 60 that sites between the upper block and the lower block 54 and surrounds completely the perimeter of the interior chamber volume 58 .
- FIG. 1 depicts one embodiment of a pin assembly 50 suitable for practice with the system depicted in FIG. 1 which includes the pressure controller 28 .
- the pin assembly 50 includes a housing formed from an upper portion 52 and a lower portion 54 that are joined together by the crews 56 A and 56 B to define an interior chamber volume 58 .
- FIG. 2 further depicts that to fluidicly seal the interior chamber volume 58 the housing can include
- the pin assembly 50 includes a plurality of vesicles 62 A- 62 D, each of which include an axial bore extending therethrough to form the depicted holding chambers 64 A- 64 D.
- Each of the depicted vesicles extends through a respective aperture 68 A- 68 D disposed within the lower block 54 of the housing.
- each of the vesicles 62 A- 62 D has an upper flange portion that sits against a seal element 70 A- 70 D to form a fluid-tight seal between the vesicle and the lower block 54 to prevent fluid from passing through the apertures 68 A- 68 D.
- the depicted pin assembly 50 further includes a set of biasing elements 74 A- 74 D depicted in FIG. 2 as springs which, in the depicted embodiments, are in a compressed state to force the flange element of the vesicles 62 A- 62 D against their respective seal elements 70 A- 70 D. As shown in FIG.
- the biasing elements 74 A- 74 D extend between the vesicles and the upper block 52 .
- Each of the springs 74 A- 74 D can be fixedly mounted to a mounting pad 76 A- 76 D where the spring elements can attach to the upper block 52 .
- the upper block 52 further includes an aperture 78 depicted in FIG. 2 as a centrally disposed aperture that includes a threaded bore for receiving a swagelok 80 that can be rotatably mounted within the aperture 78 .
- the swagelok 80 attaches by a conduit to a valve 82 than can connect the swagelok 80 to a conduit 84 that can be coupled to a pressure source, or alternatively can couple the swagelok 80 to a conduit 86 that provides for venting of the interior chamber 58 .
- a central bore 88 extends through the swagelok 80 and couples to the tubing element which further connects to the valve 82 to thereby fluidicly and selectively couple the interior chamber volume 58 to either a pressure source, or a venting outlet.
- the pin assembly 50 described above and depicted in FIG. 2 disposed above a substrate element 90 that includes a plurality of wells 92 that are etched into the upper surface of the substrate 90 .
- the pitch of the vesicles 62 A- 62 D is such that each vesicle is spaced from the adjacent vesicles by a distance that is an integral multiple of the pitch distance between wells 92 etched into the upper surface of the substrate 90 .
- this spacing facilitates the parallel dispensing of fluid, such that fluid can be dispensed into a plurality of wells in a single operation.
- Each of the vesicles can be made from stainless steel, silica, polymeric material or any other material suitable for holding fluid sample.
- 16 vesicles are employed in the assembly, which are made of hardened beryllium copper, gold plated over nickel plate. They are 43.2 mm long and the shaft of the vesicle is graduated to 0.46 mm outer diameter with a concave tip.
- Such a pin was chosen since the pointing accuracy (distance between the center of adjacent tips) can be approximately 501 micrometers.
- any suitable pin style can be employed for-the device, including but not limited to flat, star-shaped, concave, pointed solid, pointed semi-hollow, angled on one or both sides, or other such geometries.
- FIG. 3 shows from a side perspective the lower block 54 of the pin assembly 50 depicted in FIG. 2.
- FIG. 3 shows approximate dimensions for one pin assembly suited for use in the methods and with the apparatus provided herein.
- the lower block 54 has a bottom plate 98 and a surrounding shoulder 100 .
- the bottom plate 98 is approximately 3 mm in thickness and the shoulder 100 is approximately 5 mm in thickness.
- FIG. 4 shows from an overhead perspective the general structure and dimensions for one lower block 54 suitable for use with the pin assembly for use with the pin assembly 50 shown in FIG. 2.
- the lower block 54 includes a four-by-four matrix of apertures 68 to provide 16 apertures each suitable for receiving a vesicle.
- the spacing between the aperture 68 is typically an integral multiple of the distance between wells on a substrate surface as well as the wells of a source plate. Accordingly, a pin assembly having the lower block 54 as depicted in FIG. 4 can dispense fluid in up to 16 wells simultaneously.
- FIG. 4 shows from an overhead perspective the general structure and dimensions for one lower block 54 suitable for use with the pin assembly for use with the pin assembly 50 shown in FIG. 2.
- the lower block 54 includes a four-by-four matrix of apertures 68 to provide 16 apertures each suitable for receiving a vesicle.
- the spacing between the aperture 68 is typically an integral multiple of the distance between wells on a substrate surface as well as the wells of a
- each side of block 54 is generally 22 mm in length and the pitch between aperture 68 is approximately 4.5 mm.
- Such a pitch is suitable for use with a substrate where fluid is to be dispensed at locations approximately 500 ⁇ m apart, as exemplified by the substrate 90 of FIG. 2.
- the lower block 54 can include an optional O-ring groove 94 adapted for receiving an O-ring seal element, such as the seal element 60 depicted in FIG. 2. It is understood that such a groove element 94 can enhance and improve the fluid seal formed by the seal element 60 .
- the pinblock can be manufactured of stainless steel as this material can be drilled accurately to about +25 ⁇ m, but a variety of probe materials can also be used, such as G10 laminate, PMMA or other suitable material.
- the pin block can contain any number of apertures and is shown with 16 receptacles which hold the 16 pins in place. To increase the pointing accuracy of each pin, an optional alignment place can be placed below the block so that about 6 mm of the pin tip is left exposed to enable dipping into the wells of a microtiter plate.
- the layout of the probes in the depicted tool is designed to coordinate with a 384-well microtiter plate, thus the center-to-center spacing of the probes in 4.5 mm.
- the robotic assembly 16 employs a pin tool assembly 38 that is configured similarly as the pin tool assembly 50 depicted in FIG. 2.
- the pressure controller 28 selectively controls the pressure within chamber 58 .
- a control program operates on the data processor 12 to control the robotic assembly 16 in a way that the assembly 16 prints an array of elements on the substrates 34 .
- the program can direct the robotic assembly 16 to move the pin assembly 38 to be disposed above the source plate 20 .
- the robotic assembly 16 will then dip the pin assembly into the source plate 20 which can be a 384 well DNA source plate.
- the pin assembly can include 16 different pins such that the pin assembly 50 will dip 16 pins into different 16 wells of the 384 well DNA source plate 20 .
- the data processor 12 will direct the motion controller 14 to operate the robotic assembly 16 to move the pin assembly to a position above the surface of the substrate 34 .
- the substrate 34 can be any substrate suitable for receiving a sample of material and can be formed of silicon, plastic, metal, or any other such suitable material.
- the substrate will have a flat surface, but can alternatively include a pitted surface, a surface etched with wells or any other suitable surface typography.
- the program operating on data processor 12 can then direct the robotic assembly, through the motion controller 14 , to direct the pressure controller 28 to generate a positive pressure within the interior chamber volume 58 .
- the positive interior pressure will force fluid from the holding chambers of vesicles 62 to eject fluid from the vesicles and into a respective well 92 of the substrate 90 .
- the program operating on data processor 12 can also direct the controller 14 to control the pressure controller 28 to control filling the holding chambers with source material from the source plate 20 .
- the pressure controller 28 can generate a negative pressure within the interior chamber volume 58 of the pin assembly. This will cause fluid to be drawn up into the holding chambers of the vesicles 62 A- 62 D.
- the pressure controller 28 can regulate the pressure either by open-loop or closed-loop control to avoid having fluid overdrawn through the holding chambers and spilled into the interior chamber volume 58 . Loop control systems for controlling pressure are well known in the art and any suitable controller can be employed. Such spillage could cause cross-contamination, particularly if the source material drawn from the source plate 20 varies from well to well.
- each of the holding chambers 64 A- 64 D is sufficiently small to allow the chambers to be filled by capillary action.
- the pin assembly can include an array of narrow bore needles, such as stainless steel needles, that extend through the apertures of the lower block 54 . The needles that are dipped into source solutions will be filled by capillary action.
- the volume of fluid held by each vesicle can be controlled by selecting the dimensions of the interior bore. It is understood that at room temperature water will fill a 15 cm length of 100 ⁇ m radius capillary. Thus, a short bore nanoliter volume needle will fill to full capacity, but should not overflow because the capillary force is understood to be too small to form a meniscus at the top of the needle orifice. This prevents cross-contamination due to spillage.
- the vesicles of the pin assembly can be provided with different sized interior chambers for holding and dispensing different volumes of fluid.
- a small positive pressure can be provided within the interior chamber volume 58 by the pressure controller 28 .
- the downward force created by the positive pressure can be used to counter the upward capillary force. In this way, the volume of fluid that is drawn by capillary force into the holding chambers of the vesicles can be controlled.
- FIG. 5B shows that fluid within the holding chambers of the needle can be dispensed by a small positive pressure introduced through the central bore 88 extending through a swagelok 80 .
- a small positive pressure introduced through the central bore 88 extending through a swagelok 80 .
- fluid can be ejected either as a spray or by droplet formation at the needle tip. It is understood that the rate of dispensing, droplet versus spray, depends in part upon the pressure applied by the pressure controller 28 . In one practice, pressure is applied in the range of between 10 and 1,000 Torr of atmospheric pressure.
- the data processor 12 can run a computer program that controls and regulates the volume of fluid dispensed.
- the program can direct the controller 28 to eject a defined volume of fluid, either by generating a spray or by forming a drop that sits at the end of the vesicle, and can be contacted with the substrate surface for dispensing the fluid thereto.
- FIGS. 5C and 5D show the earlier steps shown in FIGS. 5 A- 5 B can again be performed, this time at a position on the substrate surface that is offset from the earlier position.
- the pin tool is offset by a distance equal to the distance between two wells 92 .
- other offset printing techniques can be employed.
- deposition of sample material onto substrate surface can include techniques that employ pin tool assemblies that have solid pin elements extending from a block wherein a robotic assembly dips the solid pin elements of the pin assembly into a source of sample material to wet the distal ends of the pins with the sample materials. Subsequently the robotic assembly can move the pin assembly to a location above the substrate and then lower the pin assembly against the surface of the substrate to contact the individual wetted pins against the surface for spotting material of the substrate surface.
- FIG. 6A depicts a jet printing device 110 which includes a capillary element 112 , a transducer element 114 and orifice (not shown) 118 , a fluid conduit 122 , and a mount 124 connecting to a robotic arm assembly, such as the robotic arm 24 depicted in FIG. 1.
- the jet assembly 110 is suitable for ejecting from the orifice 118 a series of drops 120 of a sample material for dispensing sample material onto the surface 128 .
- the capillary 112 of the jet assembly 110 can be a glass capillary, a plastic capillary, or any other suitable housing that can carry a fluid sample and that will allow the fluid sample to be ejected by the action of a transducer element, such as the transducer element 114 .
- the transducer element 114 depicted in FIG. 6A is a piezo electric transducer element which forms around the parameter of the capillary 112 and can transform an electrical pulse received from the pulse generator within a robotic assembly 16 to cause fluid to eject from the orifice 118 of the capillary 112 .
- One such jet assembly having a piezoelectric transducer element is manufactured by MicroFab Technology, Inc., of Germany.
- any jet assembly that is suitable for dispensing defined and controlled the volumes of fluid can be used, including those that use piezoelectric transducers, electric transducers, electrorestrictive transducers, magnetorestrictive transducers, electromechanical transducers, or any other suitable transducer element.
- the capillary 112 has a fluid conduit 122 for receiving fluid material.
- fluid can be drawn into the capillary by action of a vacuum pressure that will draw fluid through the orifice 118 when the orifice 118 is submerged in a source of fluid material.
- Other embodiments of the jet assembly 110 can be employed.
- FIG. 6B illustrates a further alternative assembly suitable for use herein, and suitable for being carried on the robotic arm of a robotic assembly, such as the assembly 1 6 depicted in FIG. 1.
- FIG. 6B illustrates four jet assemblies connected together, 130 A- 130 D. Similar to the pin assembly in FIG. 2, the jet assembly depicted in FIG. 6B can be employed for the parallel dispensing of fluid material. It will be understood by the skilled artisan in the art of electrical engineering, that each of the jet assemblies 130 A- 130 D can be operated independently of the others, for allowing the selective dispensing of fluid from select ones of the jet assemblies. Moreover, each of the jet assemblies 130 A- 130 D can be independently controlled to select the volume of fluid that is dispensed from each respected one of the assembly 130 A- 130 D. Other modifications and alterations can be made to the assembly depicted in FIG. 6B.
- sample arrays can be formed on a substrate surface according to any of the techniques discussed above.
- the sample arrays are then analyzed by mass spectrometry to collect spectra data that is representative of the composition of the samples in the array.
- mass spectrometry provides processes that allow for rapidly dispensing definite and controlled volumes of analyte material.
- these processes allow for dispensing sub to low nanoliter volumes of fluid.
- These low volume deposition techniques generate sample arrays well suited for analysis by mass spectrometry. For example, the low volumes yield reproducibility of spot characteristics, such as evaporation rates and reduced dependence on atmospheric conditions such as ambient temperature and light.
- the arrays can be prepared by loading oligonucleotides (0.1-50 ng/lll) of different sequences or concentrations into the wells of a 96 well microtiter source plate 20 ; the first well can be reserved for holding a matrix solution.
- a substrate 34 such as a pitted silicon chip substrate, can be placed on the stage 26 of the robotics assembly 16 and can be aligned manually to orient the matrix of wells about a set of reference axes.
- the control program executing on the data processor 12 can receive the coordinates of the first well of the source plate 20 .
- the robotic arm 24 can dip the pin assembly 38 into source plate 20 such that each of the 16 pins is dipped into one of the wells.
- Each vesicle can fill by capillary action so that the full volume of the holding chamber contains fluid.
- the program executing on the data processor 12 can direct the pressure controller to fill the interior chamber 58 of the pin assembly 38 with a positive bias pressure that will counteract, in part, the force of the capillary action to limit or reduce the volume of fluid that is drawn into the holding chamber.
- the pin assembly 38 can be dipped into the same 16 wells of the source plate 20 and spotted on a second target substrate. This cycle can be repeated on as many target substrates as desired.
- the robotic arm 24 can dip the pin assembly 38 in a washing solution, and then dip the pin assembly into 16 different wells of the source plate 20 , and spot onto the substrate target offset a distance from the initial set of 16 spots. Again this can be repeated for as many target substrates as desired.
- any process suitable for forming arrays can be used with the methods herein.
- oligonucleotides of different sequences or concentrations can be loaded into the wells of up to three different 384-well microtiter source plates; one set of 16 wells can be reserved for matrix solution. The wells of two plates are filled with washing solution. Five microtiter plates can be loaded onto the stage of the robotic assembly 16 .
- a plurality of target substrates can be placed abutting an optional set of banking or registration pins disposed on the stage 26 and provided for aligning the target substrates along a set of reference axes. If the matrix and oligonucleotide are not pre-mixed, the pin assembly can be employed to first spot matrix solution on all desired target substrates.
- oligonucleotide solution can be spotted in the same pattern as the matrix material to re-dissolve the matrix.
- a sample array can be made by placing the oligonucleotide solution on the wafer first, followed by the matrix solution, or by pre-mixing the matrix and oligonucleotide solutions.
- sample loaded substrates can be placed onto a MALDI-TOF source plate and held there with a set of beveled screw mounted polycarbonate supports.
- the plate can be transferred on the end of a probe to be held onto a 1 ⁇ m resolution, 1′′ travel xy stage (Newport) in the source region of a time-of-flight mass spectrometer.
- any suitable mass spectrometry tool can be employed in the methods and with the apparatus and systems provided herein.
- Preferred mass spectrometer formats include, but are not limited to, ionization (I) techniques including but not limited to matrix assisted laser desorption (MALDI), continuous or pulsed electrospray (ESI) and related methods (e.g. lonspray or Thermospray), or massive cluster impact (MCI); those ion sources can be matched with detection formats including linear or non-linear reflectron time-of-flight (TOF), single or multiple quadruple, single or multiple magnetic sector, Fourier Transform ion cyclotron resonance (FTICR), ion trap, and combinations thereof (e.g., ion-trap/time-of-flight).
- I ionization
- MALDI matrix assisted laser desorption
- ESI continuous or pulsed electrospray
- MCI massive cluster impact
- detection formats including linear or non-linear reflectron time-of-flight (TOF), single or multiple quadruple, single or multiple magnetic sector, Fourier Transform ion cyclotron
- MALDI matrix/wavelength combinations
- ESI solvent combinations
- Subattomole levels of protein have been detected for example, using ESI (Valaskovic, G. A. et al., (1996) Science 273: 1199-1202) or MALDI (Li, L. et al., (1996) J. Am. Chem. Soc 118: 1662-1663) mass spectrometry.
- nucleic acid refers to oligonucleotides or polynucleotides such as deoxyribonucleic acid DNA) and ribonucleic acid (RNA) as well as analogs of either RNA or DNA, for example made from nucleotide analog, any of which are in single or double stranded form, Nucleic acid molecules can by synthetic or can be isolated from a particular biological sample using any of a number or procedures which are well-known in the art, the particular isolation procedure chosen being appropriate for the particular biological sample.
- freeze-thaw and alkaline lysis procedures can be useful for obtaining nucleic acid molecules from solid materials; heat and alkaline lysis procedures can be useful for obtaining nucleic acid molecules for urine; and proteinase K extraction can be used to obtain nucleic acid from blood (Rolff, A. et al. PCR: Clinical Diagnostics and Research, Springer (1994)).
- protein protein
- polypeptide peptide
- sample shall refer to a composition containing a material to be detected.
- the sample is a “biological sample” (i.e., any material obtained from a living source (e.g. human, animal, plant, bacteria, fungi, protist, virus).
- the biological sample can be in any form, including solid materials (e.g. tissue, cell pellets and biopsies) and biological fluids (e.g. urine, blood, saliva, amniotic fluid and mouth wash (containing buccal cells)).
- solid materials e.g. tissue, cell pellets and biopsies
- biological fluids e.g. urine, blood, saliva, amniotic fluid and mouth wash (containing buccal cells).
- solid materials are mixed with a fluid.
- Substrate shall mean an insoluble support onto which a sample is deposited.
- appropriate substrates include beads (e.g., silica gel, controlled pore glass, magnetic, Sephadex/Sepharose, cellulose), capillaries, flat supports such as glass fiber filters, glass surfaces, metal surfaces (steel, gold, silver, aluminum, copper and silicon), plastic materials including multiwell plates or membranes (e.g., of polyethylene, polypropylene, polyamide, polyvinylidenedifluoride), pins (e.g., arrays of pins suitable for combinatorial synthesis or analysis or beads in pits of flat surfaces such as wafers (e.g., silicon wafers) with or without plates.
- beads e.g., silica gel, controlled pore glass, magnetic, Sephadex/Sepharose, cellulose
- capillaries flat supports such as glass fiber filters, glass surfaces, metal surfaces (steel, gold, silver, aluminum, copper and silicon), plastic materials including multiwell plates or membranes (e.g
- Robot-driven serial and parallel pL-nL dispensing tools were used to generate 10-10 3 element DNA arrays on ⁇ 1′′ square chips with flat or geometrically altered (e.g. with wells) surfaces for matrix assisted laser desorption ionization mass spectrometry analysis.
- a ‘piezoelectric pipette’ 70 ⁇ m id capillary
- probes from 384 well microtiter plate are dispensed 1 6 at a time into chip wells or onto flat surfaces using an array of spring loaded pins which transfer-20 nL to the chip by surface contact; MS analysis of array elements deposited with the parallel method are comparable in terms of sensitivity and resolution to those made with the serial method.
- the experimental system built on a system purchased from Microdrop GmbH, Norderstedt Germany and includes a piezoelectric element driver which sends a pulsed signal to a piezoelectric element bonded to and surrounding a glass capillary which holds the solution to be dispensed; a pressure transducer to load (by negative pressure) or empty (by positive pressure) the capillary; a robotic xyz stage and robot driver to maneuver the capillary for loading, unloading, dispensing, and cleaning, a stroboscope and driver pulsed at the frequency of the piezo element to enable viewing of ‘suspended’ droplet characteristics; separate stages for source and designation plates or sample targets (i.e. Si chip); a camera mounted to the robotic arm to view loading to designation plate; and a data station which controls the pressure unit, xyz robot, and piezoelectric driver.
- a piezoelectric element driver which sends a pulsed signal to a piezoelectric element bonded to and surrounding a glass capillary which holds the
- the robotic pintool includes 16 probes housed in a probe block and mounted on an X Y, Z robotic stage.
- the robotic stage was a gantry system which enables the placement of sample trays below the arms of the robot.
- the gantry unit itself is composed of X and Y arms which move 250 and 400 mm, respectively, guided by brushless linear servo motors with positional feedback provided by linear optical encoders.
- a lead screw driven Z axis (50 mm vertical travel) is mounted to the xy axis slide of the gantry unit and is controlled by an in-line rotary servo motor with positional feedback by a motor-mounted rotary optical encoder.
- the work area of the system is equipped with a slide-out tooling plate that holds five microtiter plates (most often, 2 plates of wash solution and 3 plates of sample for a maximum of 1152 different oligonucleotide solutions) and up to ten 20 ⁇ 20 mm wafers.
- the wafers are placed precisely in the plate against two banking pins and held secure by vacuum.
- the entire system is enclosed in plexi-glass housing for safety and mounted onto a steel support frame for thermal and vibrational damping.
- Motion control is accomplished by employing a commercial motion controller which was a 3-axis servo controller and is integrated to a computer; programming code for specific applications is written as needed.
- Samples were dispensed with the serial system onto several surfaces which served as targets in the MALDI TOF analysis including [1] A flat stainless steel sample target as supplied for routine use in a Thermo Bioanalysis Vision 2000; [2] the same design stainless steel target with micromachined nonpits; [3] flat silicon (Si) wafers; [4] polished flat Si wafers; [5] Si wafers with rough (3-6 pLm features) pits; [6](a) 12 ⁇ 12 or ((b) 18 ⁇ 18) mm Si chips with (a) 10 ⁇ 10 (or (b) 16 ⁇ 16) arrays of chemically etched wells, each 800 ⁇ 8001 lm on a side with depths ranging from 99-400 (or(b) 120) micrometer, pitch (a) 1.0 (or(b) 1.125 mm); [7] 15 ⁇ 15 mm Si chips with 28 ⁇ 28 arrays of chemically etched wells, each 450 ⁇ 450 micrometer on a side with depths ranging from 48
- Sample Preparation and Dispensing Serial Oligonucleotides (0.1-50 ng/microliter of different sequence or concentrations were loaded into wells of a 96 well microtiter plate; the first well was reserved for matrix solution. A pitted chip (target 6 a in MALDI targets' section) was placed on the stage and aligned manually. Into the (Windows-based) robot control software were entered the coordinates of the first well, the array size (ie number of spots in x and y) and spacing between elements, and the number of 0.2 nL drops per array element.
- the capillary was filled with ⁇ 10 ⁇ l rinse H 2 O, automatically moved in view of a strobe light-illuminated camera for checking tip integrity and cleanliness while in continuous pulse mode, and emptied.
- the capillary was then filled with matrix solution, again checked at the stroboscope, and then used to spot an array onto flat or pitted surfaces.
- matrix solution typically a 101 ⁇ 10 array of 0.2-20 nL droplets were dispensed.
- the capillary was emptied by application of positive pressure, optionally rinsed with H 2 O, and let to the source oligo plate where ⁇ 5 ⁇ L of 0.05-2.0 ⁇ M synthetic oligo were drawn.
- the capillary was then rastered in a series over each of the matrix spots with 0.2-20 nL aqueous solution added to each.
- olegonucleotides of different sequences or concentrations were loaded into the wells of up to three different 384-well microtiter plates, one set of 16 wells was reserved for matrix solution. The wells of two plates were filled with washing solution. The five microtiter plates were loaded onto the slide-out tooling plate. Ten wafers were placed abutting the banking pins on the tooling plate, and the vacuum turned on. In cases where matrix and oligonucleotide were not pre-mixed, the pintool was used to spot matrix solution first on all desired array elements of the ten wafers.
- a 16 ⁇ 16 array was created, thus the tool must spot each of the ten wafers 16 times, with an offset of 1.125 mm.
- the oligonucleotide solution was spotted in the same pattern to re-dissolve the matrix,
- an array could be made by placing the oligonucleotide solution on the wafer first, followed by the matrix solution, or by pre-mixing the matrix and oligonucleotide solutions.
- FIG. 7 shows a 12 ⁇ 12mm silicon chip with 100 chemically etched wells; mask dimensions and etch time were set such that fustum (i.e., inverted flat top pyramidal) geometry wells with 800 ⁇ 800 ⁇ m (top surface) and 100 ⁇ m depth were obtained.
- the wells can be roughed or pitted.
- the chip edge was aligned against a raised surface on the stage to define the x and y coordinate systems with respect to the capillary. (Alternatives include optical alignment, artificial intelligence pattern recognition routines, and dowel-pin based manual alignment).
- each well was dispensed 20 droplets ( ⁇ 5 nL) of 3-HPA matrix solution without analyte; for the 50% CH 3 CN solution employed, evaporation times for each droplet were on the order of 5-10 seconds.
- each microdispensed matrix droplet as viewed under a 120 ⁇ stereomicroscope generally appeared as an amorphous and ‘milky’ flat disk; such appearances are consistent with those of droplets from which the FIG. 3b spectrum was obtained.
Abstract
Serial and parallel dispensing tools that can deliver defined and controlled volumes of fluid to generate multi-element arrays of sample material on a substrate surface are provided. The substrates surfaces can be flat or geometrically altered to include wells of receiving material. Also provided are tools that allow the parallel development of a sample array. To this end, the tool can be understood as an assembly of vesicle elements, or pins, where each of the pins can include a narrow interior chamber suitable for holding nanoliter volumes of fluid. Each of the pins can fit inside a housing that forms an interior chamber. The interior chamber can be connected to a pressure source that will control the pressure within the interior chamber to regulate the flow of fluid within the interior chamber of the pins. The prepared sample arrays can then be passed to a plate assembly that disposes the sample arrays for analysis by mass spectrometry.
Description
- This application is a continuation of U.S. application Ser. No. 08/787,639 to Little et al., entitled SYSTEMS AND METHODS FOR PREPARING AND ANALYZING LOW VOLUME ANALYTE ARRAY ELEMENTS, filed Jan. 23, 1997. The subject matter of U.S. application Ser. No. 08/787,639 is incorporated herein in its entirety.
- The invention relates to systems and methods for preparing a sample for analysis, and more specifically to systems and methods for dispensing low volumes of fluid material onto a substrate surface for generating an array of samples for diagnostic analysis.
- In recent years, developments in the field of life sciences have proceeded at a breathtaking rate. Universities, hospitals and newly formed companies have made groundbreaking scientific discoveries and advances that promise to reshape the fields of medicine, agriculture, and environmental science. However, the success of these efforts depends, in part, on the development of sophisticated laboratory tools that will automate and expedite the testing and analysis of biological samples. Only upon the development of such tools can the benefits of these recent scientific discoveries be achieved fully.
- At the forefront of these efforts to develop better analytical tools is a push to expedite the analysis of complex biochemical structures. This is particularly true for human genomic DNA, which is comprised of at least about one hundred thousand genes located on twenty four chromosomes. Each gene codes for a specific protein, which fulfills a specific biochemical function within a living cell. Changes in a DNA sequence are known as mutations and can result in proteins with altered or in some cases even lost biochemical activities; this in turn can cause a genetic disease. More than 3,000 genetic diseases are currently known. In addition, growing evidence indicates that certain DNA sequences may predispose an individual to any of a number of genetic diseases, such as diabetes, arteriosclerosis, obesity, certain autoimmune diseases and cancer. Accordingly, the analysis of DNA is a difficult but worthy pursuit that promises to yield information fundamental to the treatment of many life threatening diseases.
- Unfortunately, the analysis of DNA is made particularly cumbersome due to size and the fact that genomic DNA includes both coding and non-coding sequences (e.g., exons and introns). As such, traditional techniques for analyzing chemical structures, such as the manual pipeting of source material to create samples for analysis, are of little value. To address the scale of the necessary analysis, scientist have developed parallel processing protocols for DNA diagnostics.
- For example, scientists have developed robotic devices that eliminate the need for manual pipeting and spotting by providing a robotic arm that carries at its proximal end a pin tool device that includes a matrix of pin elements. The individual pins of the matrix are spaced apart from each other to allow each pin be dipped within a well of a microtiter plate. The robotic arm dips the pins into the wells of the microtiter plate thereby wetting each of the pin elements with sample material. The robotic arm then moves the pin tool device to a position above a target surface and lowers the pin tool to the surface contacting the pins against the target to form a matrix of spots thereon. Accordingly, the pin tool expedites the production of samples by dispensing sample material in parallel.
- Although this pin tool technique works well to expedite the production of sample arrays, it suffers from several drawbacks. First during the spotting operation, the pin tool actually contacts the surface of the substrate. Given that each pin tool requires a fine point in order that a small spot size is printed onto the target, the continuous contact of the pin tool against the target surface will wear and deform the fine and delicate points of the pin tool. This leads to errors which reduce accuracy and productivity.
- An alternative technique developed by scientists employs chemical attachment of sample material to the substrate surface. In one particular process, DNA is synthesized in situ on a substrate surface to produce a set of spatially distinct and diverse chemical products. Such techniques are essentially photolithographic in that they combine solid phase chemistry, photolabile protecting groups and photo activated lithography. Although these systems work well to generate arrays of sample material, they are chemically intensive, time consuming, and expensive.
- It is further troubling that neither of the above techniques provide sufficient control over the volume of sample material that is dispensed onto the surface of the substrate. Consequently, error can arise from the failure of these techniques to provide sample arrays with well controlled and accurately reproduced sample volumes. In an attempt to circumvent this problem, the preparation process will often dispense generous amounts of reagent materials. Although this can ensure sufficient sample volumes, it is wasteful of sample materials, which are often expensive and of limited availability.
- Even after the samples are prepared, scientists still must confront the need for sophisticated diagnostic methods to analyze the prepared samples. To this end, scientists employ several techniques for identifying materials such as DNA. For example, nucleic acid sequences can be identified by hybridization with a probe which is complementary to the sequence to be identified. Typically, the nucleic acid fragment is labeled with a sensitive reporter function that can be radioactive, fluorescent, or chemiluminescent. Although these techniques can work well, they do suffer from certain drawbacks. Radioactive labels can be hazardous and the signals they produce decay over time. Nonisotopic (e.g. fluorescent) labels suffer from a lack of sensitivity and fading of the signal with high intensity lasers are employed during the identification process. In addition, labeling is a laborious and time consuming error prone procedure.
- Consequently, the process of preparing and analyzing arrays of a biochemical sample material is complex and error prone.
- Accordingly, it is an object herein to provide improved systems and methods for preparing arrays of sample material.
- It is a further object to provide systems that allow for the rapid production of sample arrays.
- It is yet another object to provide systems and methods for preparing arrays of sample material that are less expensive to employ and that conserve reagent materials.
- It is a further object to provide systems and methods for preparing arrays of sample material that provide high reproducibility of the arrays generated.
- Other objects of the apparatus and methods provided herein will be apparent from the description also disclosed in the following.
- Serial and parallel dispensing tools that can be employed to generate multi-element arrays of sample material on a substrate surface are provided. The substrates surfaces can be flat or geometrically altered to include wells of receiving material. In one embodiment, a tool that allows the parallel development of a sample array is provided. To this end, the tool can be understood as an assembly of vesicle elements, or pins, wherein each of the pins can include a narrow interior chamber suitable for holding nano liter volumes of fluid. Each of the pins can fit inside a housing that itself has in interior chamber. The interior housing can be connected to a pressure source that will control the pressure within the interior housing chamber to regulate the flow of fluid through the interior chamber of the pins. This allows for the controlled dispensing of defined volumes of fluid from the vesicles. In an alternative embodiment, the invention provides a tool that includes a jet assembly that can include a capillary pin having an interior chamber, and a transducer element mounted to the pin and capable of driving fluid through the interior chamber of the pin to eject fluid from the pin. In this way, the tool can dispense a spot of fluid to a substrate surface by spraying the fluid from the pin. Alternatively, the transducer can cause a drop of fluid to extend from the capillary so that fluid can be passed to the substrate by contacting the drop to the surface of the substrate. Further, the tool can form an array of sample material by dispensing sample material in a series of steps, while moving the pin to different locations above the substrate surface to form the sample array. In a further embodiment, the invention then passes the prepared sample arrays to a plate assembly that disposes the sample arrays for analysis by mass spectrometry. To this end, a mass spectrometer is provided that generates a set of spectra signal which can be understood as indicative of the composition of the sample material under analysis.
- To this end a dispensing apparatus for dispensing defined volumes of fluid, including nano and sub-nano volumes of fluid, in chemical or biological procedures onto the surface of a substrate is provided. The apparatus provided herein can include a housing having a plurality of sides and a bottom portion having formed therein a plurality of apertures, the walls and bottom portion of the housing defining an interior volume; one or more fluid transmitting vesicles, or pins, mounted within the apertures, having a nanovolume sized fluid holding chamber for holding nanovolumes of fluid, the fluid holding chamber being disposed in fluid communication with the interior volume of the housing, and a dispensing element that is in communication with the interior volume of the housing for selectively dispensing nanovolumes of fluid form the nanovolume sized fluid transmitting vesicles when the fluid is loaded with the fluid holding chambers of the vesicles. As described herein, this allows the dispensing element to dispense nanovolumes of the fluid onto the surface of the substrate when the apparatus is disposed over and in registration with the substrate.
- In one embodiment the fluid transmitting vesicle has an open proximal end and a distal tip portion that extends beyond the housing bottom portion when mounted within the apertures. In this way the open proximal end can dispose the fluid holding chamber in fluid communication with the interior volume when mounted with the apertures. Optionally, the plurality of fluid transmitting vesicles are removably and replaceably mounted within the apertures of the housing, or alternatively can include a glue seal for fixedly mounting the vesicles within the housing.
- In one embodiment the fluid holding chamber includes a narrow bore dimensionally adapted for being filled with the fluid through capillary action, and can be sized to fill substantially completely with the fluid through capillary action.
- In one embodiment, the plurality of fluid transmitting vesicles comprise an array of fluid delivering needles, which can be formed of metal, glass, silica, polymeric material, or any other suitable material.
- In one embodiment the housing can include a top portion, and mechanical biasing elements for mechanically biasing the plurality of fluid transmitting vesicles into sealing contact with the housing bottom portion. In one particular embodiment, each fluid transmitting vesicle has a proximal end portion that includes a flange, and further includes a seal element disposed between the flange and an inner surface of the housing bottom portion for forming a seal between the interior volume and an external environment. The biasing elements can be mechanical and can include a plurality of spring elements each of which are coupled at one end to the proximal end of each the plurality of fluid transmitting vesicles, and at another end to an inner surface of the housing top portion. The springs can apply a mechanical biasing force to the vesicle proximal end to form the seal.
- In a further embodiment, the housing further includes a top portion, and securing element for securing the housing top portion to the housing bottom portion. The securing element can comprise a plurality of fastener- receiving apertures formed within one of the top and bottom portions of the housing, and a plurality of fasteners for mounting within the apertures for securing together the housing top and bottom portions.
- In one embodiment the dispensing element can comprise a pressure source fluidly coupled to the interior volume of the housing for disposing the interior volume at a selected pressure condition. Moreover, in an embodiment wherein the fluid transmitting vesicles are filled through capillary action, the dispensing element can include a pressure controller than can vary the pressure source to dispose the interior volume of the housing at varying pressure conditions. This allows the controller varying element to dispose the interior volume at a selected pressure condition sufficient to offset the capillary action to fill the fluid holding chamber of each vesicle to a predetermined height corresponding to a predetermined fluid amount. Additionally, the controller can further include a fluid selection element for selectively discharging a selected nanovolume fluid amount from the chamber of each the vesicle. In one particular embodiment, the apparatus includes a pressure controller that operates under the controller of a computer program operating on a data processing system to provide variable control over the pressure applied to the interior chamber of the housing.
- In one embodiment the fluid transmitting vesicle can have a proximal end that opens onto the interior volume of the housing, and the fluid holding chamber of the vesicles are sized to substantially completely fill with the fluid through capillary action without forming a meniscus at the proximal open end. Optionally, the apparatus can have plural vesicles, wherein a first portion of the plural vesicles include fluid holding chambers of a first size and a second portion including fluid holding chambers of a second size, whereby plural fluid volumes can be dispensed.
- In another embodiment the apparatus can include, a fluid selection element that has a pressure source coupled to the housing and in communication with the interior volume for disposing the interior volume at a selected pressure condition, and an adjustment element that couples to the pressure source for varying the pressure within the interior volume of the housing to apply a positive pressure in the fluid chamber of each the fluid transmitting vesicle to vary the amount of fluid dispensed therefrom. The selection element and adjustment element can be computer programs operating on a data processing system that directs the operation of a pressure controller connected to the interior chamber.
- In a further alternative embodiment, an apparatus for dispensing a fluid in chemical or biological procedures into one or more wells of a multi-well substrate is provided. The apparatus can include a housing having a plurality of sides and a bottom portion having formed therein a plurality of apertures, the walls and bottom portion defining an interior volume, a plurality of fluid transmitting vesicles, mounted within the apertures, having a fluid holding chamber disposed in communication with the interior volume of the housing, and a fluid selection and dispensing means in communication with the interior volume of the housing for variably selecting am amount of the fluid loaded within the fluid holding chambers of the vesicles to be dispensed from a single set of the plurality of fluid transmitting vesicles. Accordingly, the dispensing means dispenses a selected amount of the fluid into the wells of the multi-well substrate when the apparatus is disposed over and in registration with the substrate.
- In yet another embodiment, a fluid dispensing apparatus for dispensing fluid in chemical or biological procedures into one or more wells of a multi-well substrate, that includes a housing having a plurality of sides and top and bottom portions, the bottom portion having formed therein a plurality of apertures, the walls and top and bottom portions of the housing defining an interior volume, a plurality of fluid transmitting vesicles, mounted within the apertures, having a fluid holding chamber sized to hold nanovolumes of the fluid, the fluid holding chamber being disposed in fluid communication with the volume of the housing, and mechanical biasing element for mechanically biasing the plurality of fluid transmitting vesicles into sealing contact with the housing bottom portion is provided.
- FIG. 1 illustrates one system provided herein for preparing arrays of a sample material for analysis;
- FIG. 2 illustrates a pin assembly suitable for use with the system depicted in FIG. 1 for implementing a parallel process of dispensing material to a surface of a substrate;
- FIG. 3 depicts a bottom portion of the assembly shown in FIG. 2;
- FIG. 4 depicts an alternative view of the bottom portion of the pin assembly depicted in FIG. 2;
- FIGS.5A-5D depict one method provided herein for preparing an array of sample material;
- FIGS.6A-6B depict an alternative assembly for dispensing material to the surface of a substrate.
- FIG. 7 depicts one embodiment of a substrate having wells etched therein that are suitable for receiving material for analysis.
- FIG. 8 depicts one example of spectra obtained from a linear time of flight mass spectrometer instrument and representative of the material composition of the sample material on the surface of the substrate depicted in FIG. 7; and
- FIG. 9 depicts molecular weights determined for the sample material having spectra identified in FIG. 8.
- FIG. 1 illustrates one system provided herein for preparing arrays of sample material for analysis by a diagnostic tool. FIG. 1 depicts a system that includes a
data processor 12, amotion controller 14, arobotic arm assembly 1 6, a monitor element 18A, a central processing unit 18B, a microliter plate ofsource material 20, astage housing 22, arobotic arm 24, astage 26, apressure controller 28, aconduit 30, a mountingassembly 32, apin assembly 38, andsubstrate elements 34. In the view shown by FIG. 1, it is also illustrated that therobotic assembly 16 can include amoveable mount element 40 and ahorizontal slide groove 42. Therobotic arm 24 can optionally pivot about apin 36 to increase the travel range of thearm 24 so thatarm 24 can disposes thepin assembly 38 above thesource plate 20. - The
data processor 12 depicted in FIG. 1 can be a conventional digital data processing system such as an IBM PC compatible computer system that is suitable for processing data and for executing program instructions that will provide information for controlling the movement and operation of therobotic assembly 16. It will be apparent to one skilled in the art that thedata processor unit 12 can be any type of system suitable for processing a program of instructions signals that will operate the robotic assembly that is integrated into therobotic housing 16. Optionally thedata processor 12 can be a micro-controlled assembly that is integrated intorobotic housing 16. In further alternative embodiments, the system 10 need not be programmable and can be a singleboard computer having a firmware memory for storing instructions for operating therobotic assembly 16. - In the embodiment depicted in FIG. 1, there is a
controller 14 that electronically couples between thedata processor 12 and therobotic assembly 16. The depictedcontroller 14 is a motion controller that drives the motor elements of therobotic assembly 16 for positioning therobotic arm 24 at a selected location. Additionally, thecontroller 14 can provide instructions to therobotic assembly 16 to direct thepressure controller 28 to control the volume of fluid ejected from the individual pin elements of the depictedpin assembly 38. The design and construction of the depictedmotion controller 14 follows from principles well known in the art of electrical engineering, and any controller element suitable for driving therobotic assembly 16 can be used. - The
robotic assembly 16 depicted in FIG. 1 electronically couples to thecontroller 14. The depictedrobotic assembly 16 is a gantry system that includes an XY table for moving the robotic arm about a XY plane, and further includes a Z axis actuator for moving the robotic arm orthogonally to that XY plane. Therobotic assembly 16 depicted in FIG. 1 includes anarm 24 that mounts to the XY stage which moves the arm within a plane defined by the XY access. In the depicted embodiment, the XY table is mounted to the Z actuator to move the entire table along the Z axis orthogonal to the XY plane. In this way, the robotic assembly provides three degrees of freedom that allows thepin assembly 38 to be disposed to any location above thesubstrates 34 and thesource plate 20 which are shown in FIG. 1 as sitting on thestage 26 mounted to therobotic assembly 16. - The depicted
robotic assembly 16 follows from principles well known in the art of electrical engineering and is just one example of a robotic assembly suitable for moving a pin assembly to locations adjacent a substrate and source plate such as the depictedsubstrate 34. Accordingly, it will be apparent to one of skill in the art that alternative robotic systems can be used. - FIG. 1 depicts an embodiment of a
robotic assembly 16 that includes apressure controller 28 that connects via aconduit 30 to themount 32 that connects to thepin assembly 38. In this embodiment themount 32 has an interior channel for fluidicly coupling theconduit 30 to thepin assembly 38. Accordingly, thepressure controller 28 is fluidicly coupled by theconduit 30 and themount 32 to thepin assembly 38. In this way thecontroller 1 4 can send signals to thepressure controller 28 to control selectively a fluid pressure delivered to thepin assembly 38. - FIG. 2 depicts one embodiment of a
pin assembly 50 suitable for practice with the system depicted in FIG. 1 which includes thepressure controller 28. In the depicted embodiment, thepin assembly 50 includes a housing formed from anupper portion 52 and alower portion 54 that are joined together by the crews 56A and 56B to define aninterior chamber volume 58. FIG. 2 further depicts that to fluidicly seal theinterior chamber volume 58 the housing can include a seal element depicted in FIG. 2 as an O-ring gasket 60 that sites between the upper block and thelower block 54 and surrounds completely the perimeter of theinterior chamber volume 58. FIG. 2 further depicts that thepin assembly 50 includes a plurality of vesicles 62A-62D, each of which include an axial bore extending therethrough to form the depicted holding chambers 64A-64D. Each of the depicted vesicles extends through a respective aperture 68A-68D disposed within thelower block 54 of the housing. - As further shown in the depicted embodiment, each of the vesicles62A-62D has an upper flange portion that sits against a seal element 70A-70D to form a fluid-tight seal between the vesicle and the
lower block 54 to prevent fluid from passing through the apertures 68A-68D. To keep the seal tight, the depictedpin assembly 50 further includes a set of biasing elements 74A-74D depicted in FIG. 2 as springs which, in the depicted embodiments, are in a compressed state to force the flange element of the vesicles 62A-62D against their respective seal elements 70A-70D. As shown in FIG. 2, the biasing elements 74A-74D extend between the vesicles and theupper block 52. Each of the springs 74A-74D can be fixedly mounted to a mounting pad 76A-76D where the spring elements can attach to theupper block 52. Theupper block 52 further includes anaperture 78 depicted in FIG. 2 as a centrally disposed aperture that includes a threaded bore for receiving aswagelok 80 that can be rotatably mounted within theaperture 78. - As further depicted in FIG. 2, the
swagelok 80 attaches by a conduit to avalve 82 than can connect theswagelok 80 to aconduit 84 that can be coupled to a pressure source, or alternatively can couple theswagelok 80 to aconduit 86 that provides for venting of theinterior chamber 58. Acentral bore 88 extends through theswagelok 80 and couples to the tubing element which further connects to thevalve 82 to thereby fluidicly and selectively couple theinterior chamber volume 58 to either a pressure source, or a venting outlet. - The
pin assembly 50 described above and depicted in FIG. 2 disposed above asubstrate element 90 that includes a plurality ofwells 92 that are etched into the upper surface of thesubstrate 90. As illustrated by FIG. 2, the pitch of the vesicles 62A-62D is such that each vesicle is spaced from the adjacent vesicles by a distance that is an integral multiple of the pitch distance betweenwells 92 etched into the upper surface of thesubstrate 90. As will be seen from the following description, this spacing facilitates the parallel dispensing of fluid, such that fluid can be dispensed into a plurality of wells in a single operation. Each of the vesicles can be made from stainless steel, silica, polymeric material or any other material suitable for holding fluid sample. In one example, 16 vesicles are employed in the assembly, which are made of hardened beryllium copper, gold plated over nickel plate. They are 43.2 mm long and the shaft of the vesicle is graduated to 0.46 mm outer diameter with a concave tip. Such a pin was chosen since the pointing accuracy (distance between the center of adjacent tips) can be approximately 501 micrometers. However, it will be apparent that any suitable pin style can be employed for-the device, including but not limited to flat, star-shaped, concave, pointed solid, pointed semi-hollow, angled on one or both sides, or other such geometries. - FIG. 3 shows from a side perspective the
lower block 54 of thepin assembly 50 depicted in FIG. 2. FIG. 3 shows approximate dimensions for one pin assembly suited for use in the methods and with the apparatus provided herein. As shown, thelower block 54 has abottom plate 98 and asurrounding shoulder 100. Thebottom plate 98 is approximately 3 mm in thickness and theshoulder 100 is approximately 5 mm in thickness. - FIG. 4 shows from an overhead perspective the general structure and dimensions for one
lower block 54 suitable for use with the pin assembly for use with thepin assembly 50 shown in FIG. 2. As shown in FIG. 4, thelower block 54 includes a four-by-four matrix ofapertures 68 to provide 16 apertures each suitable for receiving a vesicle. As described above with reference to FIG. 2, the spacing between theaperture 68 is typically an integral multiple of the distance between wells on a substrate surface as well as the wells of a source plate. Accordingly, a pin assembly having thelower block 54 as depicted in FIG. 4 can dispense fluid in up to 16 wells simultaneously. FIG. 4 also shows general dimensions of onelower block 54 such that each side ofblock 54 is generally 22 mm in length and the pitch betweenaperture 68 is approximately 4.5 mm. Such a pitch is suitable for use with a substrate where fluid is to be dispensed at locations approximately 500 μm apart, as exemplified by thesubstrate 90 of FIG. 2. FIG. 4 also shows that thelower block 54 can include an optional O-ring groove 94 adapted for receiving an O-ring seal element, such as theseal element 60 depicted in FIG. 2. It is understood that such agroove element 94 can enhance and improve the fluid seal formed by theseal element 60. - The pinblock can be manufactured of stainless steel as this material can be drilled accurately to about +25 μm, but a variety of probe materials can also be used, such as G10 laminate, PMMA or other suitable material. The pin block can contain any number of apertures and is shown with 16 receptacles which hold the 16 pins in place. To increase the pointing accuracy of each pin, an optional alignment place can be placed below the block so that about 6 mm of the pin tip is left exposed to enable dipping into the wells of a microtiter plate. The layout of the probes in the depicted tool is designed to coordinate with a 384-well microtiter plate, thus the center-to-center spacing of the probes in 4.5 mm. An array of 4×4 probes was chosen since it would produce an array that would fit in less than one square inch, which is the travel range of an xy stage of a MALDI TOF MS employed by the assignee. The pintool assembly is completed with a stainless steel cover on the top side of the device which is then attached onto the Z-arm of the robot.
- With references to FIG. 5, the operation of one embodiment can be explained. In this exemplary embodiment, the
robotic assembly 16 employs apin tool assembly 38 that is configured similarly as thepin tool assembly 50 depicted in FIG. 2. Thepressure controller 28 selectively controls the pressure withinchamber 58. With this embodiment, a control program operates on thedata processor 12 to control therobotic assembly 16 in a way that theassembly 16 prints an array of elements on thesubstrates 34. - In a first step, FIG. 5A, the program can direct the
robotic assembly 16 to move thepin assembly 38 to be disposed above thesource plate 20. Therobotic assembly 16 will then dip the pin assembly into thesource plate 20 which can be a 384 well DNA source plate. As shown in FIG. 4 the pin assembly can include 16 different pins such that thepin assembly 50 will dip 16 pins into different 16 wells of the 384 wellDNA source plate 20. Next thedata processor 12 will direct themotion controller 14 to operate therobotic assembly 16 to move the pin assembly to a position above the surface of thesubstrate 34. Thesubstrate 34 can be any substrate suitable for receiving a sample of material and can be formed of silicon, plastic, metal, or any other such suitable material. Optionally the substrate will have a flat surface, but can alternatively include a pitted surface, a surface etched with wells or any other suitable surface typography. The program operating ondata processor 12 can then direct the robotic assembly, through themotion controller 14, to direct thepressure controller 28 to generate a positive pressure within theinterior chamber volume 58. In this practice, the positive interior pressure will force fluid from the holding chambers of vesicles 62 to eject fluid from the vesicles and into arespective well 92 of thesubstrate 90. - In this practice of the methods and using the apparatus provided herein, the program operating on
data processor 12 can also direct thecontroller 14 to control thepressure controller 28 to control filling the holding chambers with source material from thesource plate 20. Thepressure controller 28 can generate a negative pressure within theinterior chamber volume 58 of the pin assembly. This will cause fluid to be drawn up into the holding chambers of the vesicles 62A-62D. Thepressure controller 28 can regulate the pressure either by open-loop or closed-loop control to avoid having fluid overdrawn through the holding chambers and spilled into theinterior chamber volume 58. Loop control systems for controlling pressure are well known in the art and any suitable controller can be employed. Such spillage could cause cross-contamination, particularly if the source material drawn from thesource plate 20 varies from well to well. -
- where H equals Height, gamma equals surface tension, P equals solution density, G equals gravitational force and R equals needle radius. Thus the volume of fluid held by each vesicle can be controlled by selecting the dimensions of the interior bore. It is understood that at room temperature water will fill a 15 cm length of 100 μm radius capillary. Thus, a short bore nanoliter volume needle will fill to full capacity, but should not overflow because the capillary force is understood to be too small to form a meniscus at the top of the needle orifice. This prevents cross-contamination due to spillage. In one embodiment, the vesicles of the pin assembly can be provided with different sized interior chambers for holding and dispensing different volumes of fluid.
- In an alternative practice, to decrease the volume of liquid that is drawn into the holding chambers of the vesicles, a small positive pressure can be provided within the
interior chamber volume 58 by thepressure controller 28. The downward force created by the positive pressure can be used to counter the upward capillary force. In this way, the volume of fluid that is drawn by capillary force into the holding chambers of the vesicles can be controlled. - FIG. 5B, shows that fluid within the holding chambers of the needle can be dispensed by a small positive pressure introduced through the
central bore 88 extending through aswagelok 80. By regulating the pressure pulse that is introduced into theinterior chamber volume 58, fluid can be ejected either as a spray or by droplet formation at the needle tip. It is understood that the rate of dispensing, droplet versus spray, depends in part upon the pressure applied by thepressure controller 28. In one practice, pressure is applied in the range of between 10 and 1,000 Torr of atmospheric pressure. - To this end the
data processor 12 can run a computer program that controls and regulates the volume of fluid dispensed. The program can direct thecontroller 28 to eject a defined volume of fluid, either by generating a spray or by forming a drop that sits at the end of the vesicle, and can be contacted with the substrate surface for dispensing the fluid thereto. - FIGS. 5C and 5D show the earlier steps shown in FIGS.5A-5B can again be performed, this time at a position on the substrate surface that is offset from the earlier position. In the depicted process, the pin tool is offset by a distance equal to the distance between two
wells 92. However, it will be apparent that other offset printing techniques can be employed. - It will be understood that several advantages of the pin assembly depicted in FIG. 2 are achieved. For example, rinsing between dispensing events is straightforward, requiring only single or multiple pin fillings and emptying events with a rinse solution. Moreover, since all holding chambers fill to full capacity, the accuracy of the volumes dispensed varies only according to needle inner dimensions which can be carefully controlled during pin production. Further the device is cost effective, with the greatest expense attributed to the needles, however because no contact with a surface is required, the needles are exposed to little physical strain or stress, making replacement rare and providing long life.
- Alternatively, deposition of sample material onto substrate surface can include techniques that employ pin tool assemblies that have solid pin elements extending from a block wherein a robotic assembly dips the solid pin elements of the pin assembly into a source of sample material to wet the distal ends of the pins with the sample materials. Subsequently the robotic assembly can move the pin assembly to a location above the substrate and then lower the pin assembly against the surface of the substrate to contact the individual wetted pins against the surface for spotting material of the substrate surface.
- FIGS. 6A and 6B depict another alternative system for dispensing material on or to the surface of the substrate. In particular, FIG. 6A depicts a
jet printing device 110 which includes acapillary element 112, atransducer element 114 and orifice (not shown) 118, afluid conduit 122, and amount 124 connecting to a robotic arm assembly, such as therobotic arm 24 depicted in FIG. 1. As further shown in FIG. 6A thejet assembly 110 is suitable for ejecting from the orifice 118 a series ofdrops 120 of a sample material for dispensing sample material onto thesurface 128. - The
capillary 112 of thejet assembly 110 can be a glass capillary, a plastic capillary, or any other suitable housing that can carry a fluid sample and that will allow the fluid sample to be ejected by the action of a transducer element, such as thetransducer element 114. Thetransducer element 114 depicted in FIG. 6A is a piezo electric transducer element which forms around the parameter of the capillary 112 and can transform an electrical pulse received from the pulse generator within arobotic assembly 16 to cause fluid to eject from theorifice 118 of the capillary 112. One such jet assembly having a piezoelectric transducer element is manufactured by MicroFab Technology, Inc., of Germany. Any jet assembly that is suitable for dispensing defined and controlled the volumes of fluid can be used, including those that use piezoelectric transducers, electric transducers, electrorestrictive transducers, magnetorestrictive transducers, electromechanical transducers, or any other suitable transducer element. In the depicted embodiment, the capillary 112 has afluid conduit 122 for receiving fluid material. In an optional embodiment, fluid can be drawn into the capillary by action of a vacuum pressure that will draw fluid through theorifice 118 when theorifice 118 is submerged in a source of fluid material. Other embodiments of thejet assembly 110 can be employed. - FIG. 6B illustrates a further alternative assembly suitable for use herein, and suitable for being carried on the robotic arm of a robotic assembly, such as the
assembly 1 6 depicted in FIG. 1. FIG. 6B illustrates four jet assemblies connected together, 130A-130D. Similar to the pin assembly in FIG. 2, the jet assembly depicted in FIG. 6B can be employed for the parallel dispensing of fluid material. It will be understood by the skilled artisan in the art of electrical engineering, that each of thejet assemblies 130A-130D can be operated independently of the others, for allowing the selective dispensing of fluid from select ones of the jet assemblies. Moreover, each of thejet assemblies 130A-130D can be independently controlled to select the volume of fluid that is dispensed from each respected one of theassembly 130A-130D. Other modifications and alterations can be made to the assembly depicted in FIG. 6B. - In another aspect, methods for rapidly analyzing sample materials are provided. To this end sample arrays can be formed on a substrate surface according to any of the techniques discussed above. The sample arrays are then analyzed by mass spectrometry to collect spectra data that is representative of the composition of the samples in the array. It is understood that the above methods provide processes that allow for rapidly dispensing definite and controlled volumes of analyte material. In particular these processes allow for dispensing sub to low nanoliter volumes of fluid. These low volume deposition techniques generate sample arrays well suited for analysis by mass spectrometry. For example, the low volumes yield reproducibility of spot characteristics, such as evaporation rates and reduced dependence on atmospheric conditions such as ambient temperature and light.
- Continuing with the example showing in FIG. 1, the arrays can be prepared by loading oligonucleotides (0.1-50 ng/lll) of different sequences or concentrations into the wells of a 96 well
microtiter source plate 20; the first well can be reserved for holding a matrix solution. Asubstrate 34, such as a pitted silicon chip substrate, can be placed on thestage 26 of therobotics assembly 16 and can be aligned manually to orient the matrix of wells about a set of reference axes. The control program executing on thedata processor 12 can receive the coordinates of the first well of thesource plate 20. Therobotic arm 24 can dip thepin assembly 38 intosource plate 20 such that each of the 16 pins is dipped into one of the wells. Each vesicle can fill by capillary action so that the full volume of the holding chamber contains fluid. Optionally, the program executing on thedata processor 12 can direct the pressure controller to fill theinterior chamber 58 of thepin assembly 38 with a positive bias pressure that will counteract, in part, the force of the capillary action to limit or reduce the volume of fluid that is drawn into the holding chamber. - Optionally, the
pin assembly 38 can be dipped into the same 16 wells of thesource plate 20 and spotted on a second target substrate. This cycle can be repeated on as many target substrates as desired. Next therobotic arm 24 can dip thepin assembly 38 in a washing solution, and then dip the pin assembly into 16 different wells of thesource plate 20, and spot onto the substrate target offset a distance from the initial set of 16 spots. Again this can be repeated for as many target substrates as desired. The entire cycle can be repeated to make a 2×2 array from each vesicle to produce an 8×8 array of spots (2×2 elements/vesicle×16 vesicles=64 total elements spotted). However, it will be apparent to one of skill in the art that any process suitable for forming arrays can be used with the methods herein. - In an alternative embodiment, oligonucleotides of different sequences or concentrations can be loaded into the wells of up to three different 384-well microtiter source plates; one set of 16 wells can be reserved for matrix solution. The wells of two plates are filled with washing solution. Five microtiter plates can be loaded onto the stage of the
robotic assembly 16. A plurality of target substrates can be placed abutting an optional set of banking or registration pins disposed on thestage 26 and provided for aligning the target substrates along a set of reference axes. If the matrix and oligonucleotide are not pre-mixed, the pin assembly can be employed to first spot matrix solution on all desired target substrates. In a subsequent step the oligonucleotide solution can be spotted in the same pattern as the matrix material to re-dissolve the matrix. Alternatively, a sample array can be made by placing the oligonucleotide solution on the wafer first, followed by the matrix solution, or by pre-mixing the matrix and oligonucleotide solutions. - After depositing the sample arrays onto the surface of the substrate, the arrays can be analyzed using any of a variety of means (e.g., spectrometric techniques, such as UV/VIS, IR, fluorescence, chemiluminescence, NMR spectrometry or mass spectrometry. For example, subsequent to either dispensing process, sample loaded substrates can be placed onto a MALDI-TOF source plate and held there with a set of beveled screw mounted polycarbonate supports. In one practice, the plate can be transferred on the end of a probe to be held onto a 1 μm resolution, 1″ travel xy stage (Newport) in the source region of a time-of-flight mass spectrometer. It will be apparent to one of skill in the art that any suitable mass spectrometry tool can be employed in the methods and with the apparatus and systems provided herein.
- Preferred mass spectrometer formats include, but are not limited to, ionization (I) techniques including but not limited to matrix assisted laser desorption (MALDI), continuous or pulsed electrospray (ESI) and related methods (e.g. lonspray or Thermospray), or massive cluster impact (MCI); those ion sources can be matched with detection formats including linear or non-linear reflectron time-of-flight (TOF), single or multiple quadruple, single or multiple magnetic sector, Fourier Transform ion cyclotron resonance (FTICR), ion trap, and combinations thereof (e.g., ion-trap/time-of-flight). For ionization, numerous matrix/wavelength combinations (MALDI) or solvent combinations (ESI) can be employed. Subattomole levels of protein have been detected for example, using ESI (Valaskovic, G. A. et al., (1996)Science 273: 1199-1202) or MALDI (Li, L. et al., (1996) J. Am. Chem. Soc 118: 1662-1663) mass spectrometry.
- Thus, that in the processes provided herein a completely non- contact, high-pressure spray or partial-contact, low pressure droplet formation mode can be employed. In the latter, the only contact that will occur is between the droplet and the walls of the well or a hydrophilic flat surface of the
substrate 34. However, in neither practice need there be any contact between the needle tip and the surface. - Definitions
- As used herein the following terms and phrases shall have the meanings set forth below:
- As used herein, the term “nucleic acid” refers to oligonucleotides or polynucleotides such as deoxyribonucleic acid DNA) and ribonucleic acid (RNA) as well as analogs of either RNA or DNA, for example made from nucleotide analog, any of which are in single or double stranded form, Nucleic acid molecules can by synthetic or can be isolated from a particular biological sample using any of a number or procedures which are well-known in the art, the particular isolation procedure chosen being appropriate for the particular biological sample. For example, freeze-thaw and alkaline lysis procedures can be useful for obtaining nucleic acid molecules from solid materials; heat and alkaline lysis procedures can be useful for obtaining nucleic acid molecules for urine; and proteinase K extraction can be used to obtain nucleic acid from blood (Rolff, A. et al. PCR: Clinical Diagnostics and Research, Springer (1994)).
- The terms “protein”, “polypeptide” and “peptide” are used interchangeably herein when referring to a translated nucleic acid (e.g. a gene product).
- “Sample” as used herein, shall refer to a composition containing a material to be detected. In a preferred embodiment, the sample is a “biological sample” (i.e., any material obtained from a living source (e.g. human, animal, plant, bacteria, fungi, protist, virus). The biological sample can be in any form, including solid materials (e.g. tissue, cell pellets and biopsies) and biological fluids (e.g. urine, blood, saliva, amniotic fluid and mouth wash (containing buccal cells)). Preferably solid materials are mixed with a fluid.
- “Substrate” shall mean an insoluble support onto which a sample is deposited. Examples of appropriate substrates include beads (e.g., silica gel, controlled pore glass, magnetic, Sephadex/Sepharose, cellulose), capillaries, flat supports such as glass fiber filters, glass surfaces, metal surfaces (steel, gold, silver, aluminum, copper and silicon), plastic materials including multiwell plates or membranes (e.g., of polyethylene, polypropylene, polyamide, polyvinylidenedifluoride), pins (e.g., arrays of pins suitable for combinatorial synthesis or analysis or beads in pits of flat surfaces such as wafers (e.g., silicon wafers) with or without plates.
- Robot-driven serial and parallel pL-nL dispensing tools were used to generate 10-103 element DNA arrays on <1″ square chips with flat or geometrically altered (e.g. with wells) surfaces for matrix assisted laser desorption ionization mass spectrometry analysis. In the former, a ‘piezoelectric pipette’ (70 μm id capillary) dispenses single or multiple-0.2 nL droplets of matrix, and then analyte, onto the chip; spectra from as low as 0.2 fmol of a 36-mer DNA have been acquired using this procedure. Despite the fast (<5 sec) evaporation, micro-crystals of 3-hydroxypicolinic acid matrix containing the analyte are routinely produced resulting in higher reproducibility than routinely obtained with larger volume preparations; all of 1 00 five fmol sports of a 23-mer in 800 μm wells yielded easily interpreted mass spectra, with 99/100 parent ion signals having signal to noise ration of >5. In a second approach, probes from 384 well microtiter plate are dispensed 1 6 at a time into chip wells or onto flat surfaces using an array of spring loaded pins which transfer-20 nL to the chip by surface contact; MS analysis of array elements deposited with the parallel method are comparable in terms of sensitivity and resolution to those made with the serial method.
- I. Description of the Piezoelectric Serial Dispenser.
- The experimental system built on a system purchased from Microdrop GmbH, Norderstedt Germany and includes a piezoelectric element driver which sends a pulsed signal to a piezoelectric element bonded to and surrounding a glass capillary which holds the solution to be dispensed; a pressure transducer to load (by negative pressure) or empty (by positive pressure) the capillary; a robotic xyz stage and robot driver to maneuver the capillary for loading, unloading, dispensing, and cleaning, a stroboscope and driver pulsed at the frequency of the piezo element to enable viewing of ‘suspended’ droplet characteristics; separate stages for source and designation plates or sample targets (i.e. Si chip); a camera mounted to the robotic arm to view loading to designation plate; and a data station which controls the pressure unit, xyz robot, and piezoelectric driver.
- II. Description of the Parallel Dispenser.
- The robotic pintool includes 16 probes housed in a probe block and mounted on an X Y, Z robotic stage. The robotic stage was a gantry system which enables the placement of sample trays below the arms of the robot. The gantry unit itself is composed of X and Y arms which move 250 and 400 mm, respectively, guided by brushless linear servo motors with positional feedback provided by linear optical encoders. A lead screw driven Z axis (50 mm vertical travel) is mounted to the xy axis slide of the gantry unit and is controlled by an in-line rotary servo motor with positional feedback by a motor-mounted rotary optical encoder. The work area of the system is equipped with a slide-out tooling plate that holds five microtiter plates (most often, 2 plates of wash solution and 3 plates of sample for a maximum of 1152 different oligonucleotide solutions) and up to ten 20×20 mm wafers. The wafers are placed precisely in the plate against two banking pins and held secure by vacuum. The entire system is enclosed in plexi-glass housing for safety and mounted onto a steel support frame for thermal and vibrational damping. Motion control is accomplished by employing a commercial motion controller which was a 3-axis servo controller and is integrated to a computer; programming code for specific applications is written as needed.
- Samples were dispensed with the serial system onto several surfaces which served as targets in the MALDI TOF analysis including [1] A flat stainless steel sample target as supplied for routine use in a Thermo Bioanalysis Vision 2000; [2] the same design stainless steel target with micromachined nonpits; [3] flat silicon (Si) wafers; [4] polished flat Si wafers; [5] Si wafers with rough (3-6 pLm features) pits; [6](a) 12×12 or ((b) 18×18) mm Si chips with (a) 10×10 (or (b) 16×16) arrays of chemically etched wells, each 800×8001 lm on a side with depths ranging from 99-400 (or(b) 120) micrometer, pitch (a) 1.0 (or(b) 1.125 mm); [7] 15×15 mm Si chips with 28×28 arrays of chemically etched wells, each 450×450 micrometer on a side with depths ranging from 48-300 micrometer, pitch 0.5 mm; [8]flat polycarbonate or other plastics; [9] gold and other metals; [10] membranes; [11] plastic surfaces sputtered with gold or other conducting materials. The dispensed volume is controlled from 10−10 to 10−6 L by adjusting the number of droplets dispensed.
- Sample Preparation and Dispensing: Serial Oligonucleotides (0.1-50 ng/microliter of different sequence or concentrations were loaded into wells of a 96 well microtiter plate; the first well was reserved for matrix solution. A pitted chip (target6 a in MALDI targets' section) was placed on the stage and aligned manually. Into the (Windows-based) robot control software were entered the coordinates of the first well, the array size (ie number of spots in x and y) and spacing between elements, and the number of 0.2 nL drops per array element. The capillary was filled with ˜10 μl rinse H2O, automatically moved in view of a strobe light-illuminated camera for checking tip integrity and cleanliness while in continuous pulse mode, and emptied. The capillary was then filled with matrix solution, again checked at the stroboscope, and then used to spot an array onto flat or pitted surfaces. For reproducibilty studies in different MS modes, typically a 101×10 array of 0.2-20 nL droplets were dispensed. The capillary was emptied by application of positive pressure, optionally rinsed with H2O, and let to the source oligo plate where ˜5 μL of 0.05-2.0 μM synthetic oligo were drawn. The capillary was then rastered in a series over each of the matrix spots with 0.2-20 nL aqueous solution added to each.
- Sample Preparation and Dispensing:
- Parallel Programs were written to control array making by offset printing; to make an array of 64 elements on 10 wafers, for example, the tool was dipped into 16 wells of a 384 well DNA source plate, moved to the target (e.g. Si, plastic, metal), and the sample spotted by surface contact. The tool was then dipped into the same 16 wells and spotted on the second target; this cycle was repeated on all ten wafers. Next the tool was dipped in washing solution, then dipped into 16 different wells of the source plate, and spotted onto the target 2.25 mm offset from the initial set of 16 spots; again this as repeated on all 10 wafers; the entire cycle was repeated to make a 2×2 array from each pin to produce an 8×8 array of spots (2×2 elements/
pin X 16 pins=64 total elements spotted). - To make arrays for MS analysis, olegonucleotides of different sequences or concentrations were loaded into the wells of up to three different 384-well microtiter plates, one set of 16 wells was reserved for matrix solution. The wells of two plates were filled with washing solution. The five microtiter plates were loaded onto the slide-out tooling plate. Ten wafers were placed abutting the banking pins on the tooling plate, and the vacuum turned on. In cases where matrix and oligonucleotide were not pre-mixed, the pintool was used to spot matrix solution first on all desired array elements of the ten wafers. For this example, a 16×16 array was created, thus the tool must spot each of the ten
wafers 16 times, with an offset of 1.125 mm. Next, the oligonucleotide solution was spotted in the same pattern to re-dissolve the matrix, Similarly, an array could be made by placing the oligonucleotide solution on the wafer first, followed by the matrix solution, or by pre-mixing the matrix and oligonucleotide solutions. - Mass spectrometry.
- Subsequent to either dispensing scheme, loaded chips were held onto a MALDI-TOF source plate with a set of beveled screw mounted polycarbonated supports. The plate was transferred on the end of a probe to be held onto a 1 μm resolution, 1″ travel xy stage (Newport) in the source region of a time-of-flight mass spectrometer. The instrument, normally operated with 18-26 kV extraction, could be operated in linear or curved field reflectron mode, and in continuous or delayed extraction mode.
- Observations
- I. Serial dispensing with the piezoelectric pipette. While delivery of a saturated 3HPA solution can result in tip clogging as the solvent at the capillary-air interface evaporates, pre-mixing DNA and matrix sufficiently dilutes the matrix such that it remains in solution while stable sprays which could be maintained until the capillary was emptied were obtained; with 1:1 diluted (in H2O) matrix solution, continuous spraying for >>10 minutes was possible. Turning off the piezo element so that the capillary sat inactive for >5 minutes, and reactivating the piezo element also did not result in a clogged capillary.
- Initial experiments using stainless steel sample targets as provided by Finnigan Vision 2000 MALDI-TOF system run in reflectron mode utilized a pre-mixed solution of the matrix and DNA prior to dispensing onto the sample target. In a single microtiter well, 50,uL saturated matrix solution, 25 μL of a 51 μL solution of the 12-mer (ATCG)3, and 25 μL of a 51 μL solution of the 28-mer (ATCG)7 were mixed. A set of 10×10 arrays of 0.6 μL drops was dispensed directly onto a Finnigan Vision 2000 sample target disk; MALDI-TOF mass spectrum was obtained from a single array element which contained 750 attomoles of each of the two oligonucleotides. Interpretable mass spectra has been obtained for DNAs as large as a 53-mer (350 amol loaded, not shown) using this method.
- Mass spectra were also obtained from DNAs microdispensed into the wells of a silicon chip. FIG. 7 shows a 12×12mm silicon chip with 100 chemically etched wells; mask dimensions and etch time were set such that fustum (i.e., inverted flat top pyramidal) geometry wells with 800×800 μm (top surface) and 100 μm depth were obtained. Optionally, the wells can be roughed or pitted. As described above, the chip edge was aligned against a raised surface on the stage to define the x and y coordinate systems with respect to the capillary. (Alternatives include optical alignment, artificial intelligence pattern recognition routines, and dowel-pin based manual alignment). Into each well was dispensed 20 droplets (˜5 nL) of 3-HPA matrix solution without analyte; for the 50% CH3CN solution employed, evaporation times for each droplet were on the order of 5-10 seconds. Upon solvent evaporation, each microdispensed matrix droplet as viewed under a 120× stereomicroscope generally appeared as an amorphous and ‘milky’ flat disk; such appearances are consistent with those of droplets from which the FIG. 3b spectrum was obtained. Upon tip emptying, rinsing, and refilling with a 1.4 μm aqueous solution of a 23-mer DNA (Mr(calc)=6967 Da), the capillary was directed above each of the 100 spots of matrix where 5 nL of the aqueous DNA solution was dispensed directly on top of the matrix droplets. Employing visualization via a CCD camera, it appeared that the aqueous analyte solution mixed with and re-dissolved the matrix (complete evaporation took −10 sec at ambient temperature and humidity). The amorphous matrix surfaces were converted to true micro-crystalline surfaces, with crystalline features on the order of <1 μm.
- Consistent with the improved crystallization afforded by the matrix re-dissolving method, mass spectrum acquisition appeared more reproducible than with pre-mixed matrix plus analyte solutions; each of the 100 five fmol spots of the 23-mer yielded interpreted mass spectra (FIG. 8), with 99/100 parent ion signals having signal to noise rations of >5; such reproducibility was also obtained with the flat silicon and metallic surfaces tried (not shown). The FIG. 8 spectra were obtained on a linear TOF instrument operated at 26 kV. Upon internal calibration of the top left spectrum (well ‘k1’) using the singly and doubly charged molecular ions, and application of this calibration file to all other spectra as an external calibration (FIG. 9), a standard deviation of <9 Da from the average molecular weight was obtained, corresponding to a relative standard deviation of ˜0.1%.
- II. Parallel Dispensing with robotic pintool. Arrays were made with offset printing as described above. The velocity of the X and Y stages are 35 inches/sec, and the velocity of the Z stage is 5.5 inches/sec. It is possible to move the X and Y stages at maximum velocity to decrease the cycle times, however the speed of the Z stage is to be decreased prior to surface contact with the wafer to avoid damaging it. At such axes speeds, the approximate cycle time to spot 16 elements (one tool impression of the same solutions) on all ten wafers is 20 seconds, so to make an array of 256 elements would take ˜5.3 minutes. When placing different oligonucleotide solutions on the array, an additional washing step much be incorporated to clean the pin tip prior to dipping in another solution, thus the cycle time would increase to 25 seconds or 6.7 minutes to make 10 wafers.
- Sample delivery by the tool was examined using radio-labeled solutions and the phosphorimager as described previously; it was determined that each pin delivers approximately 1 nL of liquid. The spot-to-spot reproducibility is high. An array of 256 oligonucleotide elements of varying sequence and concentration was made on flat silicon wafers using the pintool, and the wafer was analyzed by MALDI-TOF MS.
- It will be understood that the above-described examples and illustrated embodiments are provided for describing the invention set forth herein and are not to be taken as limiting in any way, and the scope of the invention is to understood by the claims.
Claims (42)
1. A dispensing apparatus for dispensing nanovolumes of fluid in chemical or biological procedures onto the surface of a substrate, comprising
a housing having a plurality of sides and a bottom portion having formed therein a plurality of apertures, said walls and bottom portion of said housing defining an interior volume,
one or more fluid transmitting vesicles, mounted within said apertures, having a nanovolume sized fluid holding chamber for holding nanovolumes of fluid, said fluid holding chamber being disposed in fluid communication with said interior volume of said housing, and
dispensing means in communication with said interior volume of said housing for selectively dispensing nanovoluments of fluid from said nanovolume sized fluid transmitting vesicles when the fluid is loaded with said fluid holding chambers of said vesicles, whereby said dispensing means dispenses nanovolumes of the fluid onto the surface of the substrate when the apparatus is disposed over and in registration with the substrate.
2. The apparatus of , wherein each said fluid transmitting vesicle has an open proximal end and a distal tip portion that extends beyond said housing bottom portion when mounted within said apertures, said open proximal end disposing said fluid holding chamber in fluid communication with said interior volume when mounted with the apertures.
claim 1
3. The apparatus of , wherein said plurality of fluid transmitting vesicles are removably and replaceably mounted within said apertures of said housing.
claim 1
4. The apparatus of , wherein said plurality of fluid transmitting vesicles include a glue seal for fixedly mounting said vesicles within said housing.
claim 1
5. The apparatus of , wherein said fluid holding chamber includes a narrow bore dimensionally adapted for being filled with the fluid through capillary action.
claim 1
6. The apparatus of , wherein each said fluid holding chamber of said plurality of fluid transmitting vesicles are sized to fill substantially completely with the fluid through capillary action.
claim 1
7. The apparatus of , wherein said plurality of fluid transmitting vesicles comprise an array of fluid delivering needles.
claim 1
8. The apparatus of , wherein said fluid delivering needles are formed of metal.
claim 7
9. The apparatus of , wherein said fluid delivering needles are formed of glass.
claim 7
10. The apparatus of , wherein said fluid delivering needles are formed of silica.
claim 7
11. The apparatus of , wherein said fluid delivering needles are formed of polymeric material.
claim 7
12. The apparatus of , wherein the number of said plurality of fluid transmitting vesicles is less than or equal to the number of wells of a multi-well substrate.
claim 1
13. The apparatus of , wherein said housing further includes a top portion, an further comprising mechanical biasing means of mechanically biasing said plurality of fluid transmitting vesicles into sealing contact with said housing bottom portion.
claim 1
14. The apparatus of , wherein each said fluid transmitting vesicle has a proximal end portion that includes a flange, and further comprising a sealer element disposed between the flange and an inner surface of the housing bottom portion for forming a seal between the interior volume and an external environment.
claim 13
15. The apparatus of , wherein said mechanical biasing means includes a plurality of spring elements each of which are coupled at one end to said proximal end of each said plurality of fluid transmitting vesicles, and at another end to an inner surface of said housing top portion, said spring element applying a mechanical biasing force to said vesicle proximal end to form said seal.
claim 14
16. The apparatus of , wherein said housing further includes a top portion, and further comprising securing means for securing said housing top portion to said housing bottom portion.
claim 1
17. The apparatus of , wherein said securing means comprises a plurality of fastner-receiving apertures formed within one of said top and bottom portions or said housing, and a plurality of fastners for mounting within said apertures for securing together said housing top and bottom portions.
claim 16
18. The apparatus of , wherein said dispensing mens comprises a pressure source fluidly coupled to said interior volume of said housing for disposing said interior volume at a selected pressure condition.
claim 1
19. The apparatus of , wherein said fluid transmitting vesicles are filled through capillary action, and wherein said dispensing means further comprises means for varying said pressure source to dispose said interior volume of said housing at varying pressure conditions, said means for varying disposing said interior volume at a selected pressure condition sufficient to offset said capillary action to fill the fluid holding chamber of each vesicle to a predetermined height corresponding to a predetermined fluid amount.
claim 18
20. The apparatus of 9, wherein said means for varying further comprises fluid selection means for selectively discharging a selected nanovolume fluid amount from said chamber of each said vesicle.
claim 1
21. The apparatus of , wherein said fluid transmitting vesicle has a proximal end that opens onto said interior volume of sid housing, and wherein said fluid holding chamber of said vesicles are sized to substantially completely fill with the fluid through capillary action without forming a meniscus at said proximal open end.
claim 1
22. The apparatus of , wherein said dispensing means comprises fluid selection means for selectively varying the amount of fluid dispensed from said fluid holding chamber of each vesicle.
claim 1
23. The apparatus according to , having plural vesicles, wherein a first portion of said plural vesicles include fluid holding chambers of a first size and a second portion including fluid holding chambers of a second size, whereby plural fluid volumes can be dispensed.
claim 1
24. The apparatus of , wherein said fluid selection means comprises a pressure source coupled to said housing and in communications with said interior volume for disposing said interior volume at a selected pressure condition, and
claim 22
adjustment means coupled to said pressure source for varying said pressure within said interior volume of said housing to apply a positive pressure in said fluid chamber of each said fluid transmitting vesicle to vary the amount of fluid dispensed therefrom.
25. A fluid dispensing apparatus for dispensing a fluid in chemical or biological procedures into one or more wells of a multi-well substrate, comprising
a housing having a plurality of sides and a bottom portion having formed therein a plurality of apertures, said walls and bottom portion defining an interior volume,
a plurality of fluid transmitting vesicles, mounted within said apertures having a fluid holding chamber disposed in communication with said interior volume of said housing,
a fluid selection and dispensing means in communication with said interior volume of said housing for variably selecting an amount of the fluid loaded with said fluid holding chambers of said vesicles to be dispensed from a single set of plurality of fluid transmitting vesicles, and
whereby said dispensing means dispenses a selected amount of the fluid into the wells of the multi-well substrate when the apparatus is disposed over and in registration with the substrate.
26. The fluid dispensing apparatus of , wherein said fluid selection and dispensing means is adapted to select various amounts of fluid to be dispensed from said single set of vesicles.
claim 25
27. The fluid dispensing apparatus of , wherein said fluid selection and dispensing means comprises a pressure source fluidly coupled to said interior volume of said housing for disposing said interior volume at a selected pressure condition.
claim 25
28. The fluid dispensing apparatus of , further compromising means for varying the pressure within the interior volume of the housing to select the amount of fluid to dispense from said fluid transmitting vesicles.
claim 27
29. The fluid dispensing apparatus of , wherein said fluid transmitting vesicles are filled with the fluid through capillary action, and further comprising means for varying said pressure source to dispose said interior volume of said housing at varying pressure conditions, said means for varying disposing said interior volume at a pressure condition sufficient to offset said capillary action to fill the fluid holding chamber of each vesicle to a predetermined height corresponding to a predetermined fluid amount.
claim 27
30. The fluid dispensing apparatus of , wherein said fluid selection means comprises
claim 25
a pressure source coupled to said housing and in communication with said interior volume for disposing said interior volume at a selected pressure condition, and
adjustment means coupled to said pressure source for varying said pressure within said interior volume of said housing to apply a positive pressure in said fluid chamber of each said fluid transmitting vesicle to vary the amount of fluid dispensed therefrom.
31. A fluid dispensing apparatus for dispensing fluid in chemical or biological procedures into one or more wells of a multi-well substrate, said apparatus comprising
a housing having a plurality of sides and top and bottom portions of said bottom portion having formed therein a plurality of apertures, said walls and top and bottom portions of said housing defining an interior volume,
a plurality of fluid transmitting vesicles, mounted within said apertures having a fluid holding chamber sized to hold nanovolumes of the fluid, said fluid holding chamber being disposed in fluid communication with said volume of said housing and
mechanical biasing means for mechanically biasing said plurality of said transmitting vesicles into sealing contact with said housing bottom portion.
32. The fluid dispensing apparatus of , wherein each said fluid transmitting vesicle has a proximal end portion that includes a flange, and further comprising a sealer element disposed between the flange and an inner surface of the housing bottom portion for forming a pressure and fluid seal between the internal and external environment.
claim 31
33. The fluid dispensing apparatus of , wherein said mechanical biasing means includes a plurality of spring elements each of which are coupled at one end to said means includes a plurality of spring elements each of which are coupled at one end to said proximal end of said fluid transmitting vesicle, and at another end to an inner surface of said housing top portion, said spring elements applying a mechanical biasing force to said vesicle proximal end to form said fluid and pressure seal.
claim 31
34. The fluid dispensing apparatus of , further comprising securing means for securing said housing top portion to said housing bottom portion.
claim 31
35. The fluid dispensing apparatus of , wherein said securing means comprises a plurality of fastener-receiving apertures formed within one of said top and bottom portions of said housing, and a plurality of fasteners for mounting within said apertures for securing said housing top and bottom portions together.
claim 34
36. The fluid dispensing apparatus of , further comprising dispensing means in communication with said interior volume of said housing for selectively dispensing the fluid from said fluid transmitting vesicles when the fluid is loaded within said fluid holding chambers of said vesicles, whereby said dispensing means dispenses the fluid into the wells of the multi-well substrate when the apparatus is disposed over an in registration with the substrate.
claim 31
37. The fluid dispensing apparatus of , wherein said dispensing means comprises a pressure source fluidly coupled to said interior volume of said housing for disposing said interior volume at a selected pressure condition.
claim 36
38. The fluid dispensing apparatus of , wherein said plurality of fluid transmitting vesicles are removably and replaceably mounted within said apertures of said housing.
claim 31
39. The fluid dispensing apparatus of , wherein said plurality of fluid transmitting vesicles comprises an array of fluid delivering needles.
claim 31
40. The fluid dispensing apparatus of , wherein said fluid transmitting vesicles are filled with the fluid through capillary action, and wherein said dispensing means further comprises means for varying said pressure source to dispose said interior volume of said housing at varying pressure conditions, said means for varying disposing said interior volumes at a selected pressure condition sufficient to offset said capillary action to fill the fluid holding chamber of each vesicle to a predetermined height corresponding to a predetermined fluid amount.
claim 36
41. The fluid dispensing apparatus of , wherein said dispensing means comprises fluid selection means for selectively varying the amount of fluid dispensed from said fluid holding chamber of each vesicle.
claim 36
42. The fluid dispensing apparatus of , further comprising a pressure source coupled to the housing and in communication with the interior volume for disposing the interior volume at a selected pressure condition, and
claim 31
adjustment means coupled to the pressure source for varying the pressure within the interior volume of the housing to apply a positive pressure to the fluid chamber of each the fluid transmitting vesicle to vary the amount of fluid dispensed therefrom.
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US09/429,683 US6569385B1 (en) | 1997-01-23 | 1999-10-28 | Systems and methods for preparing and analyzing low volume analyte array elements |
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US09/371,150 US20010008615A1 (en) | 1997-01-23 | 1999-08-09 | Systems and methods for preparing and analyzing low volume analyte array elements |
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US08/787,639 Continuation US6024925A (en) | 1996-11-06 | 1997-01-23 | Systems and methods for preparing low volume analyte array elements |
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US09/429,683 Division US6569385B1 (en) | 1997-01-23 | 1999-10-28 | Systems and methods for preparing and analyzing low volume analyte array elements |
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US09/429,683 Expired - Lifetime US6569385B1 (en) | 1997-01-23 | 1999-10-28 | Systems and methods for preparing and analyzing low volume analyte array elements |
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US09/429,683 Expired - Lifetime US6569385B1 (en) | 1997-01-23 | 1999-10-28 | Systems and methods for preparing and analyzing low volume analyte array elements |
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Cited By (44)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6416719B1 (en) * | 2001-01-19 | 2002-07-09 | Gilson, Inc. | Plate locator for precision liquid handler |
WO2002062476A1 (en) * | 2001-02-05 | 2002-08-15 | Autosplice, Inc. | Liquid pin transfer assembly with common pin bias |
US20020182637A1 (en) * | 1999-06-18 | 2002-12-05 | Santarsiero Bernard D. | Method for screening microcrystallizations for crystal formation |
US20030054543A1 (en) * | 1997-06-16 | 2003-03-20 | Lafferty William Michael | Device for moving a selected station of a holding plate to a predetermined location for interaction with a probe |
US20030096426A1 (en) * | 1997-01-23 | 2003-05-22 | Daniel P. Little | Systems and methods for preparing and analyzing low volume analyte array elements |
US6579499B1 (en) * | 2000-05-31 | 2003-06-17 | Autosplice, Inc. | Liquid compound pin replicator with weight bias |
US20030113233A1 (en) * | 2001-10-26 | 2003-06-19 | Elizabeth Nanthakumar | Resin dispensing device |
US6599479B1 (en) * | 1997-12-05 | 2003-07-29 | Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. | Device and procedure for the electrically triggered microdrop release with a dispensing head |
US20030166263A1 (en) * | 2002-12-30 | 2003-09-04 | Haushalter Robert C. | Microfabricated spotting apparatus for producing low cost microarrays |
US20030180748A1 (en) * | 1999-10-13 | 2003-09-25 | Andreas Braun | Methods for generating databases and databases for identifying polymorphic genetic markers |
US20040058452A1 (en) * | 1998-10-30 | 2004-03-25 | Fisher William D. | Method and apparatus for liquid transfer |
US20040132080A1 (en) * | 2002-06-24 | 2004-07-08 | Canon Kabushiki Kaisha | DNA micro-array having standard probe and kit including the array |
US20040177670A1 (en) * | 2001-01-24 | 2004-09-16 | Gilson, Inc. | Probe tip alignment for precision liquid handler |
US20040209255A1 (en) * | 2002-03-11 | 2004-10-21 | Hk Pharmaceuticals, Inc. | Compounds and methods for analyzing the proteome |
US20050009053A1 (en) * | 2003-04-25 | 2005-01-13 | Sebastian Boecker | Fragmentation-based methods and systems for de novo sequencing |
US20050042771A1 (en) * | 2003-01-16 | 2005-02-24 | Hubert Koster | Capture compounds, collections thereof and methods for analyzing the proteome and complex compositions |
US20050089904A1 (en) * | 2003-09-05 | 2005-04-28 | Martin Beaulieu | Allele-specific sequence variation analysis |
US20050112590A1 (en) * | 2002-11-27 | 2005-05-26 | Boom Dirk V.D. | Fragmentation-based methods and systems for sequence variation detection and discovery |
US20050238543A1 (en) * | 2004-04-23 | 2005-10-27 | Giblin Leonard J | Metered dispenser and aspirator device |
US20050272070A1 (en) * | 2004-03-26 | 2005-12-08 | Sequenom, Inc. | Base specific cleavage of methylation-specific amplification products in combination with mass analysis |
US20060073501A1 (en) * | 2004-09-10 | 2006-04-06 | Van Den Boom Dirk J | Methods for long-range sequence analysis of nucleic acids |
US20060223105A1 (en) * | 1995-03-17 | 2006-10-05 | Hubert Koster | Mass spectrometric methods for detecting mutations in a target nucleic acid |
US20060263899A1 (en) * | 2003-02-24 | 2006-11-23 | Agnes George R | Formation of closely packed microspots and irradiation of same |
US7144554B1 (en) * | 2002-08-02 | 2006-12-05 | Hamilton Company | Ultra low volume probe |
US20070026528A1 (en) * | 2002-05-30 | 2007-02-01 | Delucas Lawrence J | Method for screening crystallization conditions in solution crystal growth |
US20080181834A1 (en) * | 1999-06-18 | 2008-07-31 | The Regiments Of The University Of California | Method for screening microcrystallizations for crystal formation |
WO2007087183A3 (en) * | 2006-01-24 | 2008-07-31 | Bio Rad Laboratories | Planar registration of multi-well plate from well side |
US7416710B1 (en) | 2003-12-31 | 2008-08-26 | Takeda San Diego, Inc. | Method and system for performing crystallization trials |
US20090317817A1 (en) * | 2008-03-11 | 2009-12-24 | Sequenom, Inc. | Nucleic acid-based tests for prenatal gender determination |
US7858560B2 (en) | 2001-07-16 | 2010-12-28 | Caprotec Bioanalytics Gmbh | Capture compounds, collections thereof and methods for analyzing the proteome and complex compositions |
US8000837B2 (en) | 2004-10-05 | 2011-08-16 | J&L Group International, Llc | Programmable load forming system, components thereof, and methods of use |
US8450061B2 (en) | 2011-04-29 | 2013-05-28 | Sequenom, Inc. | Quantification of a minority nucleic acid species |
US8476013B2 (en) | 2008-09-16 | 2013-07-02 | Sequenom, Inc. | Processes and compositions for methylation-based acid enrichment of fetal nucleic acid from a maternal sample useful for non-invasive prenatal diagnoses |
US8962247B2 (en) | 2008-09-16 | 2015-02-24 | Sequenom, Inc. | Processes and compositions for methylation-based enrichment of fetal nucleic acid from a maternal sample useful for non invasive prenatal diagnoses |
US8999266B2 (en) | 2000-10-30 | 2015-04-07 | Agena Bioscience, Inc. | Method and apparatus for delivery of submicroliter volumes onto a substrate |
US9068953B2 (en) | 2007-09-17 | 2015-06-30 | Agena Bioscience, Inc. | Integrated robotic sample transfer device |
US9605313B2 (en) | 2012-03-02 | 2017-03-28 | Sequenom, Inc. | Methods and processes for non-invasive assessment of genetic variations |
US9920361B2 (en) | 2012-05-21 | 2018-03-20 | Sequenom, Inc. | Methods and compositions for analyzing nucleic acid |
US9926593B2 (en) | 2009-12-22 | 2018-03-27 | Sequenom, Inc. | Processes and kits for identifying aneuploidy |
CN111278570A (en) * | 2017-10-24 | 2020-06-12 | 惠普发展公司,有限责任合伙企业 | Fluid distributor |
US20200326317A1 (en) * | 2018-01-30 | 2020-10-15 | Hewlett-Packard Development Company, L.P. | Fluidic ejection systems with titration plate form factors |
US11060145B2 (en) | 2013-03-13 | 2021-07-13 | Sequenom, Inc. | Methods and compositions for identifying presence or absence of hypermethylation or hypomethylation locus |
US11332791B2 (en) | 2012-07-13 | 2022-05-17 | Sequenom, Inc. | Processes and compositions for methylation-based enrichment of fetal nucleic acid from a maternal sample useful for non-invasive prenatal diagnoses |
US11365447B2 (en) | 2014-03-13 | 2022-06-21 | Sequenom, Inc. | Methods and processes for non-invasive assessment of genetic variations |
Families Citing this family (266)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6194144B1 (en) | 1993-01-07 | 2001-02-27 | Sequenom, Inc. | DNA sequencing by mass spectrometry |
EP0886681A1 (en) * | 1996-03-04 | 1998-12-30 | Genetrace Systems, Inc. | Methods of screening nucleic acids using mass spectrometry |
US5965363A (en) | 1996-09-19 | 1999-10-12 | Genetrace Systems Inc. | Methods of preparing nucleic acids for mass spectrometric analysis |
DE19782095T1 (en) * | 1996-11-06 | 2000-03-23 | Sequenom Inc | DNA diagnosis based on mass spectrometry |
US6024925A (en) * | 1997-01-23 | 2000-02-15 | Sequenom, Inc. | Systems and methods for preparing low volume analyte array elements |
DK0937096T3 (en) | 1996-11-06 | 2004-06-14 | Sequenom Inc | Method of mass spectrometry analysis |
DE69735445T2 (en) * | 1996-12-10 | 2006-08-10 | Sequenom, Inc., San Diego | NON-VOLATILE, NON-VOLATILE MOLECULES FOR MASS MARKING |
DE19730497C2 (en) * | 1997-07-16 | 2000-02-10 | Heermann Klaus Hinrich | Method for washing, separating and concentrating biomolecules using a magnetic pen |
US6207370B1 (en) | 1997-09-02 | 2001-03-27 | Sequenom, Inc. | Diagnostics based on mass spectrometric detection of translated target polypeptides |
US20110166040A1 (en) * | 1997-09-05 | 2011-07-07 | Ibis Biosciences, Inc. | Compositions for use in identification of strains of e. coli o157:h7 |
US5882930A (en) * | 1997-11-10 | 1999-03-16 | Hyseq, Inc. | Reagent transfer device |
EP1714699B1 (en) * | 1998-01-12 | 2010-08-18 | Massachusetts Institute of Technology | System for analyzing a plurality of samples |
US6893877B2 (en) | 1998-01-12 | 2005-05-17 | Massachusetts Institute Of Technology | Methods for screening substances in a microwell array |
US7875440B2 (en) | 1998-05-01 | 2011-01-25 | Arizona Board Of Regents | Method of determining the nucleotide sequence of oligonucleotides and DNA molecules |
US6780591B2 (en) * | 1998-05-01 | 2004-08-24 | Arizona Board Of Regents | Method of determining the nucleotide sequence of oligonucleotides and DNA molecules |
US6551557B1 (en) * | 1998-07-07 | 2003-04-22 | Cartesian Technologies, Inc. | Tip design and random access array for microfluidic transfer |
DE19940749A1 (en) | 1998-08-28 | 2000-05-18 | Febit Ferrarius Biotech Gmbh | Integrated synthesis and analysis method e.g. for polymers, comprises a carrier body provided with immobilized receptors to provide respective channels before contact with sample and subsequent analysis |
US6461812B2 (en) * | 1998-09-09 | 2002-10-08 | Agilent Technologies, Inc. | Method and multiple reservoir apparatus for fabrication of biomolecular arrays |
JP2003517581A (en) * | 1999-02-16 | 2003-05-27 | ピーイー コーポレイション (エヌワイ) | Bead dispersion system |
CA2367912A1 (en) * | 1999-03-19 | 2000-09-28 | Genencor International, Inc. | Multi-through hole testing plate for high throughput screening |
GB9906477D0 (en) * | 1999-03-19 | 1999-05-12 | Pyrosequencing Ab | Liquid dispensing apparatus |
US20020009394A1 (en) | 1999-04-02 | 2002-01-24 | Hubert Koster | Automated process line |
WO2000062039A1 (en) * | 1999-04-09 | 2000-10-19 | Northeastern University | System and method for high throughput mass spectrometric analysis |
US20020042081A1 (en) * | 2000-10-10 | 2002-04-11 | Eric Henderson | Evaluating binding affinities by force stratification and force panning |
US20030186311A1 (en) * | 1999-05-21 | 2003-10-02 | Bioforce Nanosciences, Inc. | Parallel analysis of molecular interactions |
US20030073250A1 (en) * | 1999-05-21 | 2003-04-17 | Eric Henderson | Method and apparatus for solid state molecular analysis |
US6573369B2 (en) * | 1999-05-21 | 2003-06-03 | Bioforce Nanosciences, Inc. | Method and apparatus for solid state molecular analysis |
US7501245B2 (en) * | 1999-06-28 | 2009-03-10 | Helicos Biosciences Corp. | Methods and apparatuses for analyzing polynucleotide sequences |
US6818395B1 (en) * | 1999-06-28 | 2004-11-16 | California Institute Of Technology | Methods and apparatus for analyzing polynucleotide sequences |
CA2391758C (en) * | 1999-08-13 | 2010-02-16 | Cartesian Technologies, Inc. | Apparatus for liquid sample handling |
WO2001016574A1 (en) | 1999-08-27 | 2001-03-08 | Large Scale Proteomics, Corp. | Devices for use in maldi mass spectrometry |
DE19941871A1 (en) * | 1999-09-02 | 2001-04-19 | Hahn Schickard Ges | Apparatus and method for applying a plurality of microdroplets to a substrate |
JP3723021B2 (en) * | 1999-09-30 | 2005-12-07 | 富士写真フイルム株式会社 | Microarray chip manufacturing equipment |
US6558623B1 (en) * | 2000-07-06 | 2003-05-06 | Robodesign International, Inc. | Microarray dispensing with real-time verification and inspection |
US6979425B1 (en) * | 1999-10-04 | 2005-12-27 | Robodesign International, Inc. | High capacity microarray dispensing |
US20030207297A1 (en) * | 1999-10-13 | 2003-11-06 | Hubert Koster | Methods for generating databases and databases for identifying polymorphic genetic markers |
US7917301B1 (en) | 2000-09-19 | 2011-03-29 | Sequenom, Inc. | Method and device for identifying a biological sample |
KR20020064298A (en) | 1999-10-13 | 2002-08-07 | 시쿼넘, 인코포레이티드 | Methods for generating databases and databases for identifying polymorphic genetic markers |
JP2001186881A (en) * | 1999-10-22 | 2001-07-10 | Ngk Insulators Ltd | Method for producing dna chip |
US6587579B1 (en) * | 2000-01-26 | 2003-07-01 | Agilent Technologies Inc. | Feature quality in array fabrication |
US6399396B1 (en) * | 2000-01-28 | 2002-06-04 | Agilent Technologies, Inc. | Compressed loading apparatus and method for liquid transfer |
US20020151040A1 (en) | 2000-02-18 | 2002-10-17 | Matthew O' Keefe | Apparatus and methods for parallel processing of microvolume liquid reactions |
WO2001061054A2 (en) * | 2000-02-18 | 2001-08-23 | Board Of Trustees Of The Leland Stanford Junior University | Apparatus and methods for parallel processing of micro-volume liquid reactions |
CN1444646A (en) * | 2000-02-23 | 2003-09-24 | 齐翁米克斯股份有限公司 | Chips having elevated sample surfaces |
US6706538B1 (en) | 2000-02-29 | 2004-03-16 | Boston Innovation Inc. | Microvolume liquid dispensing array |
US6620383B1 (en) | 2000-02-29 | 2003-09-16 | Boston Innovation Inc. | Microvolume liquid dispensing device |
US6629626B1 (en) | 2000-03-07 | 2003-10-07 | Dyax, Corporation | Liquid transfer device |
US6897015B2 (en) * | 2000-03-07 | 2005-05-24 | Bioforce Nanosciences, Inc. | Device and method of use for detection and characterization of pathogens and biological materials |
US6447723B1 (en) | 2000-03-13 | 2002-09-10 | Packard Instrument Company, Inc. | Microarray spotting instruments incorporating sensors and methods of using sensors for improving performance of microarray spotting instruments |
US6756232B1 (en) * | 2000-03-20 | 2004-06-29 | Perkinelmer Las, Inc. | Method and apparatus for producing compact microarrays |
US6878554B1 (en) * | 2000-03-20 | 2005-04-12 | Perkinelmer Las, Inc. | Method and apparatus for automatic pin detection in microarray spotting instruments |
CH694009A5 (en) * | 2000-04-04 | 2004-06-15 | Suisse Electronique Microtech | Apparatus and method for sample preparation of biological substances. |
US6759235B2 (en) | 2000-04-06 | 2004-07-06 | Quantum Dot Corporation | Two-dimensional spectral imaging system |
US7521245B1 (en) | 2000-06-05 | 2009-04-21 | Perkinelmer Las, Inc. | Method for washing and drying pins in microarray spotting instruments |
US6660229B2 (en) | 2000-06-13 | 2003-12-09 | The Trustees Of Boston University | Use of nucleotide analogs in the analysis of oligonucleotide mixtures and in highly multiplexed nucleic acid sequencing |
DE60119513T2 (en) * | 2000-06-14 | 2006-11-16 | Board of Regents, The University of Texas System, Austin | DEVICE AND METHOD FOR INJECTING LIQUIDS |
JP2002001092A (en) * | 2000-06-22 | 2002-01-08 | Shimadzu Corp | Apparatus for discharging liquid |
DE10031587A1 (en) * | 2000-06-29 | 2002-01-10 | Basf Ag | Dosing of microscale suspensions for the production of material samples in combinatorial materials research and their testing |
US7025933B2 (en) * | 2000-07-06 | 2006-04-11 | Robodesign International, Inc. | Microarray dispensing with real-time verification and inspection |
US6890760B1 (en) | 2000-07-31 | 2005-05-10 | Agilent Technologies, Inc. | Array fabrication |
US7205400B2 (en) * | 2000-07-31 | 2007-04-17 | Agilent Technologies, Inc. | Array fabrication |
US6599693B1 (en) * | 2000-07-31 | 2003-07-29 | Agilent Technologies Inc. | Array fabrication |
US6613893B1 (en) | 2000-07-31 | 2003-09-02 | Agilent Technologies Inc. | Array fabrication |
US20040018615A1 (en) * | 2000-08-02 | 2004-01-29 | Garyantes Tina K. | Virtual wells for use in high throughput screening assays |
ATE402760T1 (en) * | 2000-08-15 | 2008-08-15 | Bioforce Nanosciences Inc | DEVICE FOR FORMING NANOMOLECULAR NETWORKS |
US6692972B1 (en) * | 2000-08-24 | 2004-02-17 | University Of Chicago | Device for producing microscopic arrays of molecules, a method for producing microscopic arrays of molecules |
US6821413B1 (en) * | 2000-08-31 | 2004-11-23 | Fluidphase Technologies, Inc. | Method and apparatus for continuous separation and reaction using supercritical fluid |
US6455352B1 (en) * | 2000-09-01 | 2002-09-24 | The University Of Chicago | Pin array assembly and method of manufacture |
CA2423552A1 (en) * | 2000-10-13 | 2002-04-18 | Irm Llc | High throughput processing system and method of using |
DE10051396A1 (en) * | 2000-10-17 | 2002-04-18 | Febit Ferrarius Biotech Gmbh | An integrated synthesis and identification of an analyte, comprises particles immobilized at a carrier to be coupled to receptors in a structured pattern to give receptor arrays for biochemical reactions |
WO2002064812A2 (en) * | 2000-10-30 | 2002-08-22 | Robodesign International, Inc. | High capacity microarray dispensing |
CH695544A5 (en) * | 2000-11-17 | 2006-06-30 | Tecan Trading Ag | Apparatus for dispensing or aspirating / dispensing liquid samples. |
US6824024B2 (en) * | 2000-11-17 | 2004-11-30 | Tecan Trading Ag | Device for the take-up and/or release of liquid samples |
WO2002051549A2 (en) * | 2000-12-22 | 2002-07-04 | Amersham Biosciences (Sv) Corp. | High speed liquid deposition apparatus for microarray fabrication |
WO2002082051A2 (en) * | 2001-01-17 | 2002-10-17 | Tubbs Kemmons A | An integrated high throughput system for the analysis of biomolecules |
JP2002228669A (en) * | 2001-01-31 | 2002-08-14 | Shimadzu Corp | Liquid transport device and reaction container |
DE60229173D1 (en) * | 2001-02-06 | 2008-11-13 | Parallel Synthesis Technologie | MICRO-TREATMENT-PRODUCED MUNICIPATING DEVICE FOR THE PRODUCTION OF MICROMATRICES |
DE10107517A1 (en) * | 2001-02-09 | 2002-09-05 | Epigenomics Ag | Device for providing liquids for loading dispensing tools |
FR2821284B1 (en) * | 2001-02-23 | 2004-01-23 | Univ Pasteur | APPARATUS FOR MICRO-NETWORK COLLECTION AND DEPOSITION OF SOLUTIONS |
US7226739B2 (en) | 2001-03-02 | 2007-06-05 | Isis Pharmaceuticals, Inc | Methods for rapid detection and identification of bioagents in epidemiological and forensic investigations |
US20030027135A1 (en) * | 2001-03-02 | 2003-02-06 | Ecker David J. | Method for rapid detection and identification of bioagents |
US7666588B2 (en) | 2001-03-02 | 2010-02-23 | Ibis Biosciences, Inc. | Methods for rapid forensic analysis of mitochondrial DNA and characterization of mitochondrial DNA heteroplasmy |
US20040121335A1 (en) | 2002-12-06 | 2004-06-24 | Ecker David J. | Methods for rapid detection and identification of bioagents associated with host versus graft and graft versus host rejections |
US7718354B2 (en) | 2001-03-02 | 2010-05-18 | Ibis Biosciences, Inc. | Methods for rapid identification of pathogens in humans and animals |
US20030036057A1 (en) * | 2001-03-09 | 2003-02-20 | Andreas Braun | Genes and polymorphisms associated with cardiovascular disease and their use |
WO2002072892A1 (en) * | 2001-03-12 | 2002-09-19 | California Institute Of Technology | Methods and apparatus for analyzing polynucleotide sequences by asynchronous base extension |
DE10112387B4 (en) * | 2001-03-15 | 2004-03-25 | Bruker Daltonik Gmbh | Mass spectrometric genotyping |
DE10117064A1 (en) * | 2001-04-05 | 2003-02-06 | Morphochem Ag | Device for the automatic dispensing of microscopic volumes of fluids |
US6804410B2 (en) * | 2001-04-17 | 2004-10-12 | Large Scale Proteomics Corporation | System for optimizing alignment of laser beam with selected points on samples in MALDI mass spectrometer |
US20020155587A1 (en) | 2001-04-20 | 2002-10-24 | Sequenom, Inc. | System and method for testing a biological sample |
CN1385518A (en) * | 2001-04-23 | 2002-12-18 | 株式会社百尼尔 | Microarrayer for microarrangement for biological test material and microarray pin used in same |
GB2377707B (en) | 2001-04-26 | 2004-10-20 | Thk Co Ltd | Microarraying head and microarrayer |
US20020160427A1 (en) * | 2001-04-27 | 2002-10-31 | Febit Ag | Methods and apparatuses for electronic determination of analytes |
US6943036B2 (en) * | 2001-04-30 | 2005-09-13 | Agilent Technologies, Inc. | Error detection in chemical array fabrication |
JP2005502448A (en) * | 2001-06-20 | 2005-01-27 | サイトノーム インコーポレーテッド | Miniaturized 2-pin liquid sample supply system |
US6808683B2 (en) * | 2001-09-25 | 2004-10-26 | Cytonome, Inc. | Droplet dispensing system |
US7041257B2 (en) * | 2001-09-25 | 2006-05-09 | Cytonome, Inc. | Microfabricated two-pin liquid sample dispensing system |
US7217510B2 (en) | 2001-06-26 | 2007-05-15 | Isis Pharmaceuticals, Inc. | Methods for providing bacterial bioagent characterizing information |
US8073627B2 (en) * | 2001-06-26 | 2011-12-06 | Ibis Biosciences, Inc. | System for indentification of pathogens |
US10272409B2 (en) | 2001-07-11 | 2019-04-30 | Michael E. Hogan | Methods and devices based upon a novel form of nucleic acid duplex on a surface |
EP1417337B1 (en) * | 2001-07-11 | 2009-03-04 | Baylor College of Medicine | Methods and devices based upon a novel form of nucleic acid duplex on a surface |
DE10156329A1 (en) * | 2001-07-17 | 2003-02-06 | Frieder Breitling | Method and arrangement for attaching substances immobilized in transport means as well as monomer particles |
AU2002329606A1 (en) * | 2001-07-17 | 2003-03-03 | Bioforce Nanosciences, Inc. | Combined molecular blinding detection through force microscopy and mass spectrometry |
US20030032198A1 (en) * | 2001-08-13 | 2003-02-13 | Symyx Technologies, Inc. | High throughput dispensing of fluids |
US6857309B2 (en) * | 2001-08-24 | 2005-02-22 | Symyx Technologies, Inc. | High throughput mechanical rapid serial property testing of materials libraries |
US20030044320A1 (en) * | 2001-08-31 | 2003-03-06 | Shun Luo | High throughput screening micro array platform |
US20070054408A1 (en) * | 2001-09-25 | 2007-03-08 | Cytonome, Inc. | Microfabricated two-pin system for biomolecule crystallization |
JP3701594B2 (en) * | 2001-09-25 | 2005-09-28 | 日本碍子株式会社 | Droplet ejection method |
US7153699B2 (en) * | 2001-12-21 | 2006-12-26 | Cytonome, Inc. | Microfabricated two-pin system for biomolecule crystallization |
US7042488B2 (en) | 2001-09-27 | 2006-05-09 | Fujinon Corporation | Electronic endoscope for highlighting blood vessel |
US6936474B2 (en) * | 2001-11-05 | 2005-08-30 | Industrial Technology Research Institute | Method and apparatus for manufacturing biochip |
US6759012B2 (en) * | 2001-11-05 | 2004-07-06 | Genetix Limited | Pin holder for a microarraying apparatus |
US6866762B2 (en) * | 2001-12-20 | 2005-03-15 | Board Of Regents, University Of Texas System | Dielectric gate and methods for fluid injection and control |
US7258839B2 (en) * | 2001-12-21 | 2007-08-21 | Cytonome, Inc. | Temperature controlled microfabricated two-pin liquid sample dispensing system |
US7432342B2 (en) * | 2002-05-03 | 2008-10-07 | Sequenom, Inc. | Kinase anchor protein muteins, peptides thereof and related documents |
US20050239193A1 (en) * | 2002-05-30 | 2005-10-27 | Bioforce Nanosciences, Inc. | Device and method of use for detection and characterization of microorganisms and microparticles |
US7097810B2 (en) * | 2002-06-26 | 2006-08-29 | The Public Health Research Institute Of The City Of New York, Inc. | Delivery of metered amounts of liquid materials |
US20040018635A1 (en) * | 2002-07-26 | 2004-01-29 | Peck Bill J. | Fabricating arrays with drop velocity control |
US7452712B2 (en) | 2002-07-30 | 2008-11-18 | Applied Biosystems Inc. | Sample block apparatus and method of maintaining a microcard on a sample block |
US6997066B2 (en) * | 2002-08-07 | 2006-02-14 | Perkinelmer Las, Inc. | Dispensing apparatus |
US7459128B2 (en) * | 2002-08-13 | 2008-12-02 | Molecular Bioproducts, Inc. | Microfluidic mixing and dispensing |
US8277753B2 (en) * | 2002-08-23 | 2012-10-02 | Life Technologies Corporation | Microfluidic transfer pin |
US20040123650A1 (en) * | 2002-09-17 | 2004-07-01 | Symyx Technologies, Inc. | High throughput rheological testing of materials |
US7112443B2 (en) * | 2002-10-18 | 2006-09-26 | Symyx Technologies, Inc. | High throughput permeability testing of materials libraries |
US6911182B2 (en) * | 2002-10-18 | 2005-06-28 | Indiana University Research And Technology Corporation | Device for placement of effluent |
CA2508726A1 (en) | 2002-12-06 | 2004-07-22 | Isis Pharmaceuticals, Inc. | Methods for rapid identification of pathogens in humans and animals |
US7682565B2 (en) * | 2002-12-20 | 2010-03-23 | Biotrove, Inc. | Assay apparatus and method using microfluidic arrays |
US20060094108A1 (en) * | 2002-12-20 | 2006-05-04 | Karl Yoder | Thermal cycler for microfluidic array assays |
WO2004060044A2 (en) * | 2003-01-02 | 2004-07-22 | Bioforce Nanosciences, Inc. | Method and apparatus for molecular analysis in small sample volumes |
US20040233250A1 (en) * | 2003-03-05 | 2004-11-25 | Haushalter Robert C. | Microcontact printhead device |
US20070141570A1 (en) * | 2003-03-07 | 2007-06-21 | Sequenom, Inc. | Association of polymorphic kinase anchor proteins with cardiac phenotypes and related methods |
US8046171B2 (en) * | 2003-04-18 | 2011-10-25 | Ibis Biosciences, Inc. | Methods and apparatus for genetic evaluation |
US8057993B2 (en) | 2003-04-26 | 2011-11-15 | Ibis Biosciences, Inc. | Methods for identification of coronaviruses |
US7964343B2 (en) * | 2003-05-13 | 2011-06-21 | Ibis Biosciences, Inc. | Method for rapid purification of nucleic acids for subsequent analysis by mass spectrometry by solution capture |
US8158354B2 (en) * | 2003-05-13 | 2012-04-17 | Ibis Biosciences, Inc. | Methods for rapid purification of nucleic acids for subsequent analysis by mass spectrometry by solution capture |
US20050170367A1 (en) * | 2003-06-10 | 2005-08-04 | Quake Stephen R. | Fluorescently labeled nucleoside triphosphates and analogs thereof for sequencing nucleic acids |
ATE387961T1 (en) * | 2003-06-17 | 2008-03-15 | Moussa Hoummady | DEVICE FOR REMOVING AND SEPARATING DROPS OF AT LEAST ONE LIQUID, METHOD OF USING THE DEVICE AND SERVO SYSTEM FOR THE METHOD |
US20040259261A1 (en) * | 2003-06-20 | 2004-12-23 | Phalanx Biotech Group, Inc. | Method for manufacturing a microarray and verifying the same |
US8003317B2 (en) | 2003-07-31 | 2011-08-23 | Sequenom, Inc. | Methods for high level multiplexed polymerase chain reactions and homogeneous mass extension reactions |
US20100129811A1 (en) * | 2003-09-11 | 2010-05-27 | Ibis Biosciences, Inc. | Compositions for use in identification of pseudomonas aeruginosa |
US20060240412A1 (en) * | 2003-09-11 | 2006-10-26 | Hall Thomas A | Compositions for use in identification of adenoviruses |
US8097416B2 (en) | 2003-09-11 | 2012-01-17 | Ibis Biosciences, Inc. | Methods for identification of sepsis-causing bacteria |
US20120122099A1 (en) | 2003-09-11 | 2012-05-17 | Rangarajan Sampath | Compositions for use in identification of bacteria |
US8546082B2 (en) | 2003-09-11 | 2013-10-01 | Ibis Biosciences, Inc. | Methods for identification of sepsis-causing bacteria |
US20100035239A1 (en) * | 2003-09-11 | 2010-02-11 | Isis Pharmaceuticals, Inc. | Compositions for use in identification of bacteria |
US20080138808A1 (en) * | 2003-09-11 | 2008-06-12 | Hall Thomas A | Methods for identification of sepsis-causing bacteria |
US20050226779A1 (en) | 2003-09-19 | 2005-10-13 | Oldham Mark F | Vacuum assist for a microplate |
US20050221358A1 (en) * | 2003-09-19 | 2005-10-06 | Carrillo Albert L | Pressure chamber clamp mechanism |
US20050233472A1 (en) * | 2003-09-19 | 2005-10-20 | Kao H P | Spotting high density plate using a banded format |
US20050226771A1 (en) * | 2003-09-19 | 2005-10-13 | Lehto Dennis A | High speed microplate transfer |
US20070015289A1 (en) * | 2003-09-19 | 2007-01-18 | Kao H P | Dispenser array spotting |
US7019288B2 (en) * | 2003-09-30 | 2006-03-28 | Sequenom, Inc. | Methods of making substrates for mass spectrometry analysis and related devices |
US7169560B2 (en) * | 2003-11-12 | 2007-01-30 | Helicos Biosciences Corporation | Short cycle methods for sequencing polynucleotides |
US20060172408A1 (en) * | 2003-12-01 | 2006-08-03 | Quake Steven R | Device for immobilizing chemical and biochemical species and methods of using same |
US8163895B2 (en) | 2003-12-05 | 2012-04-24 | Ibis Biosciences, Inc. | Compositions for use in identification of orthopoxviruses |
JP4711326B2 (en) * | 2003-12-22 | 2011-06-29 | キヤノン株式会社 | Preparation method of calibration sample and calibration curve |
US7666592B2 (en) | 2004-02-18 | 2010-02-23 | Ibis Biosciences, Inc. | Methods for concurrent identification and quantification of an unknown bioagent |
WO2005080605A2 (en) | 2004-02-19 | 2005-09-01 | Helicos Biosciences Corporation | Methods and kits for analyzing polynucleotide sequences |
US20060046258A1 (en) * | 2004-02-27 | 2006-03-02 | Lapidus Stanley N | Applications of single molecule sequencing |
US8119336B2 (en) * | 2004-03-03 | 2012-02-21 | Ibis Biosciences, Inc. | Compositions for use in identification of alphaviruses |
CA2559171A1 (en) | 2004-03-12 | 2005-09-29 | Biotrove, Inc. | Nanoliter array loading |
US7608394B2 (en) | 2004-03-26 | 2009-10-27 | Sequenom, Inc. | Methods and compositions for phenotype identification based on nucleic acid methylation |
US20050239085A1 (en) * | 2004-04-23 | 2005-10-27 | Buzby Philip R | Methods for nucleic acid sequence determination |
EP1748846B1 (en) * | 2004-04-30 | 2015-04-01 | Bioforce Nanosciences, Inc. | Method and apparatus for depositing material onto a surface |
CA2567839C (en) | 2004-05-24 | 2011-06-28 | Isis Pharmaceuticals, Inc. | Mass spectrometry with selective ion filtration by digital thresholding |
US20050260609A1 (en) * | 2004-05-24 | 2005-11-24 | Lapidus Stanley N | Methods and devices for sequencing nucleic acids |
US20070117104A1 (en) * | 2005-11-22 | 2007-05-24 | Buzby Philip R | Nucleotide analogs |
US20050266411A1 (en) * | 2004-05-25 | 2005-12-01 | Hofstadler Steven A | Methods for rapid forensic analysis of mitochondrial DNA |
US7476734B2 (en) * | 2005-12-06 | 2009-01-13 | Helicos Biosciences Corporation | Nucleotide analogs |
DE602005027700D1 (en) * | 2004-05-25 | 2011-06-09 | Helicos Biosciences Corp | PROCESS FOR NUCLEIC ACID IMMOBILIZATION |
US20070117103A1 (en) * | 2005-11-22 | 2007-05-24 | Buzby Philip R | Nucleotide analogs |
US7811753B2 (en) | 2004-07-14 | 2010-10-12 | Ibis Biosciences, Inc. | Methods for repairing degraded DNA |
US20060018796A1 (en) * | 2004-07-21 | 2006-01-26 | Hans Sitte | Methods and apparatus for preparing multiwell sheets |
US20060024678A1 (en) * | 2004-07-28 | 2006-02-02 | Helicos Biosciences Corporation | Use of single-stranded nucleic acid binding proteins in sequencing |
US20060105453A1 (en) * | 2004-09-09 | 2006-05-18 | Brenan Colin J | Coating process for microfluidic sample arrays |
US8986614B2 (en) * | 2010-02-23 | 2015-03-24 | Rheonix, Inc. | Self-contained biological assay apparatus, methods, and applications |
DE502005003509D1 (en) * | 2004-11-19 | 2008-05-08 | Ebm Papst St Georgen Gmbh & Co | ARRANGEMENT WITH ONE FAN AND ONE PUMP |
US20060118754A1 (en) * | 2004-12-08 | 2006-06-08 | Lapen Daniel C | Stabilizing a polyelectrolyte multilayer |
US7095018B2 (en) * | 2004-12-29 | 2006-08-22 | Wisconsin Alumni Research Foundation | Deposition of samples and sample matrix for enhancing the sensitivity of matrix assisted laser desorption/ionization mass spectrometry |
US7220549B2 (en) * | 2004-12-30 | 2007-05-22 | Helicos Biosciences Corporation | Stabilizing a nucleic acid for nucleic acid sequencing |
US20060172328A1 (en) * | 2005-01-05 | 2006-08-03 | Buzby Philip R | Methods and compositions for correcting misincorporation in a nucleic acid synthesis reaction |
US7560417B2 (en) * | 2005-01-13 | 2009-07-14 | Wisconsin Alumni Research Foundation | Method and apparatus for parallel synthesis of chain molecules such as DNA |
US7482120B2 (en) * | 2005-01-28 | 2009-01-27 | Helicos Biosciences Corporation | Methods and compositions for improving fidelity in a nucleic acid synthesis reaction |
WO2006094049A2 (en) * | 2005-03-01 | 2006-09-08 | Parallel Synthesis Technologies, Inc. | Polymeric fluid transfer and printing devices |
CA2600184A1 (en) * | 2005-03-03 | 2006-09-08 | Isis Pharmaceuticals, Inc. | Compositions for use in identification of adventitious viruses |
US8084207B2 (en) * | 2005-03-03 | 2011-12-27 | Ibis Bioscience, Inc. | Compositions for use in identification of papillomavirus |
EP1871457B1 (en) * | 2005-04-11 | 2012-05-02 | Infotonics Technology Center, Inc. | Blood monitoring systems and methods thereof |
US20060263790A1 (en) * | 2005-05-20 | 2006-11-23 | Timothy Harris | Methods for improving fidelity in a nucleic acid synthesis reaction |
US7597520B2 (en) * | 2005-05-24 | 2009-10-06 | Festo Corporation | Apparatus and method for transferring samples from a source to a target |
US7618590B2 (en) * | 2005-06-29 | 2009-11-17 | Cascade Microtech, Inc. | Fluid dispensing system |
WO2007008824A2 (en) * | 2005-07-11 | 2007-01-18 | Infotonics Technology Center, Inc. | Minimally invasive allergy testing system |
US8026084B2 (en) * | 2005-07-21 | 2011-09-27 | Ibis Biosciences, Inc. | Methods for rapid identification and quantitation of nucleic acid variants |
US7666593B2 (en) | 2005-08-26 | 2010-02-23 | Helicos Biosciences Corporation | Single molecule sequencing of captured nucleic acids |
US7919279B2 (en) * | 2005-09-29 | 2011-04-05 | Children's Hospital & Research Center At Oakland | Methods and compositions for KIR genotyping |
US8150548B2 (en) | 2005-11-07 | 2012-04-03 | Sasan Raghibizadeh | Apparatus for process automation using pin array and actuators |
WO2007061981A2 (en) * | 2005-11-21 | 2007-05-31 | Lumera Corporation | Surface plasmon resonance spectrometer with an actuator-driven angle scanning mechanism |
US20070117102A1 (en) * | 2005-11-22 | 2007-05-24 | Buzby Philip R | Nucleotide analogs |
US20070128610A1 (en) * | 2005-12-02 | 2007-06-07 | Buzby Philip R | Sample preparation method and apparatus for nucleic acid sequencing |
US7463358B2 (en) * | 2005-12-06 | 2008-12-09 | Lumera Corporation | Highly stable surface plasmon resonance plates, microarrays, and methods |
KR100738087B1 (en) * | 2005-12-22 | 2007-07-12 | 삼성전자주식회사 | Quantitative dispensing apparatus for cell using liquid droplet manipulation |
EP2010679A2 (en) | 2006-04-06 | 2009-01-07 | Ibis Biosciences, Inc. | Compositions for the use in identification of fungi |
US8192794B2 (en) * | 2006-04-19 | 2012-06-05 | Northwestern University | Massively parallel lithography with two-dimensional pen arrays |
WO2007126689A1 (en) | 2006-04-19 | 2007-11-08 | Northwestern University | Article for parallel lithography with two-dimensional pen arrays |
WO2007130434A2 (en) * | 2006-05-02 | 2007-11-15 | Applera Corporation | Variable volume dispenser and method |
US20070276211A1 (en) * | 2006-05-26 | 2007-11-29 | Jose Mir | Compact minimally invasive biomedical monitor |
US20100100005A1 (en) * | 2006-07-11 | 2010-04-22 | Infotonics Technology Center, Inc. | Minimally invasive allergy testing system with coated allergens |
JP5420412B2 (en) * | 2006-09-14 | 2014-02-19 | アイビス バイオサイエンシズ インコーポレイティッド | Targeted whole genome amplification method for pathogen identification |
WO2008038812A1 (en) * | 2006-09-28 | 2008-04-03 | Shimadzu Corporation | Method of preparing sample for matrix-assisted laser desorption ionization mass spectrometry and matrix-assisted laser desorption ionization mass spectrometry |
US8053247B2 (en) * | 2006-10-11 | 2011-11-08 | Phynexus, Inc. | Method and device for preparing an analyte for analysis by mass spectrometry |
JP5680304B2 (en) * | 2007-02-23 | 2015-03-04 | アイビス バイオサイエンシズ インコーポレイティッド | Rapid forensic DNA analysis |
WO2008118809A1 (en) * | 2007-03-23 | 2008-10-02 | Ibis Biosciences, Inc. | Compositions for use in identification of mixed populations of bioagents |
US8657550B2 (en) * | 2007-04-12 | 2014-02-25 | Leco Corporation | Crucible shuttle assembly with linearly moving carriage |
US8323565B2 (en) | 2007-04-12 | 2012-12-04 | Leco Corporation | Crucible shuttle assembly and method of operation |
US20090006002A1 (en) * | 2007-04-13 | 2009-01-01 | Sequenom, Inc. | Comparative sequence analysis processes and systems |
WO2009023358A2 (en) * | 2007-05-25 | 2009-02-19 | Ibis Biosciences, Inc. | Compositions for use in identification of strains of hepatitis c virus |
WO2008151023A2 (en) | 2007-06-01 | 2008-12-11 | Ibis Biosciences, Inc. | Methods and compositions for multiple displacement amplification of nucleic acids |
US20110045456A1 (en) * | 2007-06-14 | 2011-02-24 | Ibis Biosciences, Inc. | Compositions for use in identification of adventitious contaminant viruses |
US8328720B2 (en) * | 2007-08-10 | 2012-12-11 | Infotonics Technology Center, Inc. | MEMS interstitial prothrombin time test |
US20090060786A1 (en) * | 2007-08-29 | 2009-03-05 | Gibum Kim | Microfluidic apparatus for wide area microarrays |
US20090104078A1 (en) * | 2007-10-18 | 2009-04-23 | Matrix Technologies Corporation | Apparatus and method for dispensing small volume liquid samples |
US8004669B1 (en) | 2007-12-18 | 2011-08-23 | Plexera Llc | SPR apparatus with a high performance fluid delivery system |
EP2240401A1 (en) * | 2008-01-04 | 2010-10-20 | The Royal Institution for the Advancement of Learning/McGill University | Microfluidic microarray system and method for the multiplexed analysis of biomolecules |
US20110097704A1 (en) * | 2008-01-29 | 2011-04-28 | Ibis Biosciences, Inc. | Compositions for use in identification of picornaviruses |
WO2009151982A1 (en) * | 2008-05-30 | 2009-12-17 | Ibis Biosciences, Inc. | Compositions for use in identification of francisella |
WO2009155103A2 (en) * | 2008-05-30 | 2009-12-23 | Ibis Biosciences, Inc. | Compositions for use in identification of tick-borne pathogens |
WO2009148995A2 (en) * | 2008-06-02 | 2009-12-10 | Ibis Biosciences, Inc. | Compositions for use in identification of adventitious viruses |
US7815798B2 (en) * | 2008-07-10 | 2010-10-19 | Agilent Technologies, Inc. | Discrete drop dispensing device and method of use |
WO2010012002A1 (en) * | 2008-07-25 | 2010-01-28 | Saryna Medical Corporation | Methods and systems for genetic analysis of fetal nucleated red blood cells |
EP2349549B1 (en) | 2008-09-16 | 2012-07-18 | Ibis Biosciences, Inc. | Mixing cartridges, mixing stations, and related kits, and system |
EP2344893B1 (en) | 2008-09-16 | 2014-10-15 | Ibis Biosciences, Inc. | Microplate handling systems and methods |
EP2347254A2 (en) | 2008-09-16 | 2011-07-27 | Ibis Biosciences, Inc. | Sample processing units, systems, and related methods |
WO2010039755A1 (en) * | 2008-10-02 | 2010-04-08 | Ibis Biosciences, Inc. | Compositions for use in identification of members of the bacterial genus mycoplasma |
US20110200985A1 (en) * | 2008-10-02 | 2011-08-18 | Rangarajan Sampath | Compositions for use in identification of herpesviruses |
WO2010039775A1 (en) * | 2008-10-03 | 2010-04-08 | Ibis Biosciences, Inc. | Compositions for use in identification of members of the bacterial class alphaproteobacter |
US20110183344A1 (en) * | 2008-10-03 | 2011-07-28 | Rangarajan Sampath | Compositions for use in identification of clostridium difficile |
WO2010039870A1 (en) * | 2008-10-03 | 2010-04-08 | Ibis Biosciences, Inc. | Compositions for use in identification of neisseria, chlamydia, and/or chlamydophila bacteria |
WO2010039763A2 (en) * | 2008-10-03 | 2010-04-08 | Ibis Biosciences, Inc. | Compositions for use in identification of antibiotic-resistant bacteria |
WO2010039848A2 (en) * | 2008-10-03 | 2010-04-08 | Ibis Biosciences, Inc. | Compositions for use in identification of streptococcus pneumoniae |
US8158936B2 (en) | 2009-02-12 | 2012-04-17 | Ibis Biosciences, Inc. | Ionization probe assemblies |
WO2010104798A1 (en) | 2009-03-08 | 2010-09-16 | Ibis Biosciences, Inc. | Bioagent detection methods |
US9393564B2 (en) | 2009-03-30 | 2016-07-19 | Ibis Biosciences, Inc. | Bioagent detection systems, devices, and methods |
WO2011008971A1 (en) * | 2009-07-17 | 2011-01-20 | Ibis Biosciences, Inc. | Lift and mount apparatus |
WO2011008972A1 (en) | 2009-07-17 | 2011-01-20 | Ibis Biosciences, Inc. | Systems for bioagent identification |
WO2011014811A1 (en) | 2009-07-31 | 2011-02-03 | Ibis Biosciences, Inc. | Capture primers and capture sequence linked solid supports for molecular diagnostic tests |
EP3098325A1 (en) | 2009-08-06 | 2016-11-30 | Ibis Biosciences, Inc. | Non-mass determined base compositions for nucleic acid detection |
US20110065111A1 (en) * | 2009-08-31 | 2011-03-17 | Ibis Biosciences, Inc. | Compositions For Use In Genotyping Of Klebsiella Pneumoniae |
WO2011041695A1 (en) * | 2009-10-02 | 2011-04-07 | Ibis Biosciences, Inc. | Determination of methylation status of polynucleotides |
US9890408B2 (en) * | 2009-10-15 | 2018-02-13 | Ibis Biosciences, Inc. | Multiple displacement amplification |
US8397785B2 (en) * | 2009-11-17 | 2013-03-19 | Asm Assembly Automation Ltd | Transfer apparatus for multiple adhesives |
AU2011221244B2 (en) * | 2010-02-23 | 2014-02-13 | Rheonix, Inc. | Self-contained biological assay apparatus, methods, and applications |
US9102979B2 (en) | 2010-02-23 | 2015-08-11 | Rheonix, Inc. | Self-contained biological assay apparatus, methods, and applications |
US8774488B2 (en) | 2010-03-11 | 2014-07-08 | Cellscape Corporation | Method and device for identification of nucleated red blood cells from a maternal blood sample |
US9758840B2 (en) * | 2010-03-14 | 2017-09-12 | Ibis Biosciences, Inc. | Parasite detection via endosymbiont detection |
US20130053280A1 (en) | 2010-05-10 | 2013-02-28 | Koshin Hamasaki | Nucleic acid analysis device, method for producing same, and nucleic acid analyzer |
ES2683032T3 (en) * | 2010-12-17 | 2018-09-24 | Biomerieux, Inc | Methods of isolation, accumulation, characterization and / or identification of microorganisms using a sample filtration and transfer device, and said device |
US10244981B2 (en) * | 2011-03-30 | 2019-04-02 | SensiVida Medical Technologies, Inc. | Skin test image analysis apparatuses and methods thereof |
US8642951B2 (en) | 2011-05-04 | 2014-02-04 | Agilent Technologies, Inc. | Device, system, and method for reflecting ions |
JP6367183B2 (en) | 2012-04-18 | 2018-08-01 | バイオファイア・ダイアグノスティクス,リミテッド・ライアビリティ・カンパニー | Micro spotting device |
WO2014160278A1 (en) * | 2013-03-14 | 2014-10-02 | Allergan, Inc. | Polymer system for securing implants in syringe needles |
CH708139A2 (en) | 2013-06-06 | 2014-12-15 | Tecan Trading Ag | Pipetting. |
US9399216B2 (en) | 2013-12-30 | 2016-07-26 | General Electric Company | Fluid transport in microfluidic applications with sensors for detecting fluid presence and pressure |
US10076751B2 (en) | 2013-12-30 | 2018-09-18 | General Electric Company | Systems and methods for reagent storage |
US10040048B1 (en) * | 2014-09-25 | 2018-08-07 | Synthego Corporation | Automated modular system and method for production of biopolymers |
PT3277842T (en) | 2015-08-17 | 2019-09-05 | Kura Oncology Inc | Methods of treating cancer patients with farnesyl transferase inhibitors |
US20180336447A1 (en) * | 2017-05-18 | 2018-11-22 | Trutag Technologies, Inc. | Multiple codes in an array pattern with sparse distribution of microparticles |
US11054364B2 (en) | 2018-12-17 | 2021-07-06 | Thermo Finnigan Llc | Apparatus and methods for handling and spectrophotometry of small liquid samples |
Family Cites Families (94)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3568735A (en) * | 1968-06-26 | 1971-03-09 | Cooke Eng Co | Laboratory microtitration dispensing apparatus |
CH543306A (en) * | 1971-10-13 | 1973-10-31 | Hoffmann La Roche | Micropipettor |
US3776700A (en) | 1971-12-08 | 1973-12-04 | Linbro Chem Co Inc | Serial dilution apparatus |
US3999689A (en) * | 1976-01-07 | 1976-12-28 | Ciantro Steven V | Device for simultaneously delivering equal amounts of liquid |
US4218539A (en) * | 1978-03-24 | 1980-08-19 | Weltman Joel K | Enzyme conjugates and method of preparation and use |
US4461328A (en) * | 1982-06-04 | 1984-07-24 | Drummond Scientific Company | Pipette device |
EP0134222A1 (en) | 1982-12-23 | 1985-03-20 | Cooper-Lipotech, Inc. | Lipid-vesicle-surface assay reagent and method |
US4548245A (en) * | 1983-03-04 | 1985-10-22 | Dynatech Laboratories Incorporated | Disposable/reusable dispenser for dispensing contaminatable and noncontaminatable liquids |
DE3329892A1 (en) | 1983-08-18 | 1985-03-07 | Köster, Hubert, Prof. Dr., 2000 Hamburg | METHOD FOR PRODUCING OLIGONUCLEOTIDES |
US4554839A (en) | 1983-10-14 | 1985-11-26 | Cetus Corporation | Multiple trough vessel for automated liquid handling apparatus |
US4849077A (en) | 1984-08-06 | 1989-07-18 | Akademie Der Wissenschaften Der Ddr | Process for solid phase-sequencing of nucleic acid fragments |
US4952518A (en) | 1984-10-01 | 1990-08-28 | Cetus Corporation | Automated assay machine and assay tray |
US5118605A (en) | 1984-10-16 | 1992-06-02 | Chiron Corporation | Polynucleotide determination with selectable cleavage sites |
US5221518A (en) | 1984-12-14 | 1993-06-22 | Mills Randell L | DNA sequencing apparatus |
US5047215A (en) | 1985-06-18 | 1991-09-10 | Polyfiltronics, Inc. | Multiwell test plate |
US4948442A (en) | 1985-06-18 | 1990-08-14 | Polyfiltronics, Inc. | Method of making a multiwell test plate |
US4731335A (en) | 1985-09-13 | 1988-03-15 | Fisher Scientific Company | Method for treating thin samples on a surface employing capillary flow |
US5023187A (en) | 1985-09-13 | 1991-06-11 | Fisher Scientific Company | Method and device for accelerated treatment of thin sample on surface |
US5108703A (en) * | 1986-03-26 | 1992-04-28 | Beckman Instruments, Inc. | Automated multi-purpose analytical chemistry processing center and laboratory work station |
US5000921A (en) * | 1986-10-24 | 1991-03-19 | Hanaway Richard W | Multiple pipette samples |
AU603617B2 (en) | 1986-11-17 | 1990-11-22 | Abbott Laboratories | Apparatus and process for reagent fluid dispensing and printing |
US4877745A (en) | 1986-11-17 | 1989-10-31 | Abbott Laboratories | Apparatus and process for reagent fluid dispensing and printing |
US4779467A (en) * | 1987-01-28 | 1988-10-25 | Rainin Instrument Co., Inc. | Liquid-end assembly for multichannel air-displacement pipette |
CA1285536C (en) * | 1987-03-11 | 1991-07-02 | Akihiro Ohoka | Dispensing machine |
JPS6433070U (en) * | 1987-08-22 | 1989-03-01 | ||
US4902481A (en) | 1987-12-11 | 1990-02-20 | Millipore Corporation | Multi-well filtration test apparatus |
US5670381A (en) | 1988-01-29 | 1997-09-23 | Abbott Laboratories | Devices for performing ion-capture binding assays |
WO1989010786A2 (en) * | 1988-04-22 | 1989-11-16 | Microdrop, Inc. | Process for forming and using microdroplets |
EP0339781A3 (en) | 1988-04-29 | 1991-09-25 | Beckman Instruments, Inc. | Automated capillary injector |
EP0366770B1 (en) * | 1988-05-16 | 1994-02-09 | Vestar, Inc. | Liposomes coupled to hormones |
US5003059A (en) | 1988-06-20 | 1991-03-26 | Genomyx, Inc. | Determining DNA sequences by mass spectrometry |
US4925629A (en) | 1988-07-28 | 1990-05-15 | Bioquant, Inc. | Diagnostic device |
WO1990001564A1 (en) * | 1988-08-09 | 1990-02-22 | Microprobe Corporation | Methods for multiple target analyses through nucleic acid hybridization |
US5077210A (en) * | 1989-01-13 | 1991-12-31 | Eigler Frances S | Immobilization of active agents on substrates with a silane and heterobifunctional crosslinking agent |
CA2015938C (en) | 1989-05-02 | 1999-09-07 | Kevin M. Knigge | Covalent attachment of specific binding members to a solid phase |
US5143854A (en) | 1989-06-07 | 1992-09-01 | Affymax Technologies N.V. | Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof |
US5045694A (en) | 1989-09-27 | 1991-09-03 | The Rockefeller University | Instrument and method for the laser desorption of ions in mass spectrometry |
US5262128A (en) | 1989-10-23 | 1993-11-16 | The United States Of America As Represented By The Department Of Health And Human Services | Array-type multiple cell injector |
US5288644A (en) | 1990-04-04 | 1994-02-22 | The Rockefeller University | Instrument and method for the sequencing of genome |
US5195657A (en) * | 1990-04-30 | 1993-03-23 | Source Scientific Systems | Manifold liquid handling device with backsip function |
DE4024545A1 (en) | 1990-08-02 | 1992-02-06 | Boehringer Mannheim Gmbh | Metered delivery of biochemical analytical soln., esp. reagent |
US5200471A (en) * | 1990-11-05 | 1993-04-06 | Minnesota Mining And Manufacturing Company | Biomolecules covalently immobilized with a high bound specific biological activity and method of preparing same |
WO1992013629A1 (en) | 1991-01-31 | 1992-08-20 | Wayne State University | A method for analyzing an organic sample |
US5210412A (en) | 1991-01-31 | 1993-05-11 | Wayne State University | Method for analyzing an organic sample |
IT1246676B (en) | 1991-02-21 | 1994-11-24 | Seac Srl | IMMUNOLOGICAL ANALYSIS EQUIPMENT. |
US5474796A (en) | 1991-09-04 | 1995-12-12 | Protogene Laboratories, Inc. | Method and apparatus for conducting an array of chemical reactions on a support surface |
US5605662A (en) | 1993-11-01 | 1997-02-25 | Nanogen, Inc. | Active programmable electronic devices for molecular biological analysis and diagnostics |
IL103674A0 (en) | 1991-11-19 | 1993-04-04 | Houston Advanced Res Center | Method and apparatus for molecule detection |
CA2124087C (en) * | 1991-11-22 | 2002-10-01 | James L. Winkler | Combinatorial strategies for polymer synthesis |
US5171989A (en) | 1992-01-24 | 1992-12-15 | Board Of Trustees Of Leland Stanford Jr. University | Method and apparatus for continuous sample ice matrix production for laser desorption in mass spectrometry |
US5312233A (en) | 1992-02-25 | 1994-05-17 | Ivek Corporation | Linear liquid dispensing pump for dispensing liquid in nanoliter volumes |
US5757392A (en) | 1992-09-11 | 1998-05-26 | Brother Kogyo Kabushiki Kaisha | Piezoelectric type liquid droplet ejecting device which compensates for residual pressure fluctuations |
US5795714A (en) | 1992-11-06 | 1998-08-18 | Trustees Of Boston University | Method for replicating an array of nucleic acid probes |
SE9203320D0 (en) * | 1992-11-06 | 1992-11-06 | Pharmacia Lkb Biotech | A METHOD OF PROCESSING NUCLEIC ACID SAMPLES |
US5503980A (en) | 1992-11-06 | 1996-04-02 | Trustees Of Boston University | Positional sequencing by hybridization |
FI925064A (en) | 1992-11-09 | 1994-05-10 | Erkki Juhani Soini | Methods and apparatus for bioaffinicity testing |
US5547835A (en) | 1993-01-07 | 1996-08-20 | Sequenom, Inc. | DNA sequencing by mass spectrometry |
US5605798A (en) | 1993-01-07 | 1997-02-25 | Sequenom, Inc. | DNA diagnostic based on mass spectrometry |
CA2158642A1 (en) | 1993-03-19 | 1994-09-29 | Hubert Koster | Dna sequencing by mass spectrometry via exonuclease degradation |
PT700521E (en) | 1993-05-28 | 2003-10-31 | Baylor College Medicine | METHOD AND MASS SPECTROMETER FOR DESSORING AND IONIZATION OF ANALYZES |
JPH08501882A (en) | 1993-07-09 | 1996-02-27 | マイクロスキャン、インコーポレイテッド | Liquid dispensing device and method |
CA2168671C (en) * | 1993-08-06 | 2007-04-10 | Yechezkel Barenholz | A method for high loading of vesicles with biopolymeric substances |
RU2041263C1 (en) | 1993-08-11 | 1995-08-09 | Геннадий Моисеевич Ершов | Method and apparatus for microdosing and dispensing of aqueous solutions onto carrier |
US5439649A (en) | 1993-09-29 | 1995-08-08 | Biogenex Laboratories | Automated staining apparatus |
US5457041A (en) | 1994-03-25 | 1995-10-10 | Science Applications International Corporation | Needle array and method of introducing biological substances into living cells using the needle array |
AU2360195A (en) | 1994-05-05 | 1995-11-29 | Beckman Instruments, Inc. | Oligonucleotide repeat arrays |
SE9401594D0 (en) * | 1994-05-06 | 1994-05-06 | Pharmacia Lkb Biotech | Method of nucleic acid transfer |
US5807522A (en) * | 1994-06-17 | 1998-09-15 | The Board Of Trustees Of The Leland Stanford Junior University | Methods for fabricating microarrays of biological samples |
SE9402518D0 (en) * | 1994-07-18 | 1994-07-18 | Pharmacia Biotech Ab | Processing system |
US5498545A (en) * | 1994-07-21 | 1996-03-12 | Vestal; Marvin L. | Mass spectrometer system and method for matrix-assisted laser desorption measurements |
US5985356A (en) * | 1994-10-18 | 1999-11-16 | The Regents Of The University Of California | Combinatorial synthesis of novel materials |
US6121048A (en) * | 1994-10-18 | 2000-09-19 | Zaffaroni; Alejandro C. | Method of conducting a plurality of reactions |
US5688642A (en) | 1994-12-01 | 1997-11-18 | The United States Of America As Represented By The Secretary Of The Navy | Selective attachment of nucleic acid molecules to patterned self-assembled surfaces |
US5601982A (en) | 1995-02-07 | 1997-02-11 | Sargent; Jeannine P. | Method and apparatus for determining the sequence of polynucleotides |
US5609907A (en) | 1995-02-09 | 1997-03-11 | The Penn State Research Foundation | Self-assembled metal colloid monolayers |
JP3592780B2 (en) | 1995-02-22 | 2004-11-24 | 富士写真フイルム株式会社 | Liquid injection device |
US5869240A (en) | 1995-05-19 | 1999-02-09 | Perseptive Biosystems, Inc. | Methods and apparatus for sequencing polymers with a statistical certainty using mass spectrometry |
US5830655A (en) | 1995-05-22 | 1998-11-03 | Sri International | Oligonucleotide sizing using cleavable primers |
US5700642A (en) | 1995-05-22 | 1997-12-23 | Sri International | Oligonucleotide sizing using immobilized cleavable primers |
US5589136A (en) | 1995-06-20 | 1996-12-31 | Regents Of The University Of California | Silicon-based sleeve devices for chemical reactions |
US5872010A (en) * | 1995-07-21 | 1999-02-16 | Northeastern University | Microscale fluid handling system |
US5869242A (en) * | 1995-09-18 | 1999-02-09 | Myriad Genetics, Inc. | Mass spectrometry to assess DNA sequence polymorphisms |
US5716825A (en) | 1995-11-01 | 1998-02-10 | Hewlett Packard Company | Integrated nucleic acid analysis system for MALDI-TOF MS |
US5580434A (en) | 1996-02-29 | 1996-12-03 | Hewlett-Packard Company | Interface apparatus for capillary electrophoresis to a matrix-assisted-laser-desorption-ionization mass spectrometer |
DE19617011C2 (en) | 1996-04-27 | 2000-11-02 | Bruker Daltonik Gmbh | Matrix component mixture for matrix-assisted laser desorption and ionization and method for preparing a matrix component mixture |
DE19618032C2 (en) | 1996-05-04 | 2000-04-13 | Bruker Daltonik Gmbh | Prepared Maldi sample carriers that can be stored |
US6083762A (en) | 1996-05-31 | 2000-07-04 | Packard Instruments Company | Microvolume liquid handling system |
DE19628178C1 (en) | 1996-07-12 | 1997-09-18 | Bruker Franzen Analytik Gmbh | Loading matrix-assisted laser desorption-ionisation sample plate for mass spectrometric analysis |
US5743960A (en) | 1996-07-26 | 1998-04-28 | Bio-Dot, Inc. | Precision metered solenoid valve dispenser |
US5864137A (en) | 1996-10-01 | 1999-01-26 | Genetrace Systems, Inc. | Mass spectrometer |
US5885775A (en) | 1996-10-04 | 1999-03-23 | Perseptive Biosystems, Inc. | Methods for determining sequences information in polynucleotides using mass spectrometry |
US6024925A (en) * | 1997-01-23 | 2000-02-15 | Sequenom, Inc. | Systems and methods for preparing low volume analyte array elements |
US5900481A (en) | 1996-11-06 | 1999-05-04 | Sequenom, Inc. | Bead linkers for immobilizing nucleic acids to solid supports |
DE19754978C2 (en) | 1997-12-11 | 2000-07-13 | Bruker Daltonik Gmbh | Sample holder for MALDI mass spectrometry along with the process for producing the plates and applying the samples |
-
1997
- 1997-01-23 US US08/787,639 patent/US6024925A/en not_active Expired - Lifetime
-
1999
- 1999-08-09 US US09/371,150 patent/US20010008615A1/en not_active Abandoned
- 1999-10-28 US US09/429,683 patent/US6569385B1/en not_active Expired - Lifetime
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US20090092977A1 (en) * | 1995-03-17 | 2009-04-09 | Sequenom, Inc. | Mass spectrometric methods for detecting mutations in a target nucleic acid |
US7759065B2 (en) | 1995-03-17 | 2010-07-20 | Sequenom, Inc. | Mass spectrometric methods for detecting mutations in a target nucleic acid |
US20090042203A1 (en) * | 1995-03-17 | 2009-02-12 | Sequenom, Inc. | Mass Spectrometric Methods for Detecting Mutations in a Target Nucleic Acid |
US8821816B2 (en) | 1997-01-23 | 2014-09-02 | Agena Biosciences, Inc. | Matrix-assisted laser desorption ionization mass spectrometry substrates having low volume matrix array elements |
US20030096426A1 (en) * | 1997-01-23 | 2003-05-22 | Daniel P. Little | Systems and methods for preparing and analyzing low volume analyte array elements |
US20030054543A1 (en) * | 1997-06-16 | 2003-03-20 | Lafferty William Michael | Device for moving a selected station of a holding plate to a predetermined location for interaction with a probe |
US6599479B1 (en) * | 1997-12-05 | 2003-07-29 | Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. | Device and procedure for the electrically triggered microdrop release with a dispensing head |
US20040058452A1 (en) * | 1998-10-30 | 2004-03-25 | Fisher William D. | Method and apparatus for liquid transfer |
US20030109063A1 (en) * | 1999-06-18 | 2003-06-12 | Santarsiero Bernard D. | Automated crystallizationexperiment setup apparatus comprising sensor |
US20030119048A1 (en) * | 1999-06-18 | 2003-06-26 | Santarsiero Bernard D. | Dispenser footprint greater than plate footprint |
US20080181834A1 (en) * | 1999-06-18 | 2008-07-31 | The Regiments Of The University Of California | Method for screening microcrystallizations for crystal formation |
US7015041B2 (en) * | 1999-06-18 | 2006-03-21 | The Regents Of The University Of California | Automated method for setting up multiple crystallization experiments in submicroliter volumes |
US20030096293A1 (en) * | 1999-06-18 | 2003-05-22 | Santarsiero Bernard D. | Automated crystallization experiment setup apparatus comprising crystallization device identification code reader |
US20020182637A1 (en) * | 1999-06-18 | 2002-12-05 | Santarsiero Bernard D. | Method for screening microcrystallizations for crystal formation |
US20030180748A1 (en) * | 1999-10-13 | 2003-09-25 | Andreas Braun | Methods for generating databases and databases for identifying polymorphic genetic markers |
US6610253B2 (en) * | 2000-05-31 | 2003-08-26 | Autosplice, Inc. | Liquid pin transfer assembly with common pin bias |
US6579499B1 (en) * | 2000-05-31 | 2003-06-17 | Autosplice, Inc. | Liquid compound pin replicator with weight bias |
US9669376B2 (en) | 2000-10-30 | 2017-06-06 | Agena Bioscience, Inc. | Method and apparatus for delivery of submicroliter volumes onto a substrate |
US8999266B2 (en) | 2000-10-30 | 2015-04-07 | Agena Bioscience, Inc. | Method and apparatus for delivery of submicroliter volumes onto a substrate |
US6416719B1 (en) * | 2001-01-19 | 2002-07-09 | Gilson, Inc. | Plate locator for precision liquid handler |
WO2002057077A1 (en) * | 2001-01-19 | 2002-07-25 | Gilson, Inc. | Plate locator for precision liquid handler |
US20040177670A1 (en) * | 2001-01-24 | 2004-09-16 | Gilson, Inc. | Probe tip alignment for precision liquid handler |
US6901819B2 (en) | 2001-01-24 | 2005-06-07 | Gilson, Inc. | Probe tip alignment for precision liquid handler |
WO2002062476A1 (en) * | 2001-02-05 | 2002-08-15 | Autosplice, Inc. | Liquid pin transfer assembly with common pin bias |
US7858560B2 (en) | 2001-07-16 | 2010-12-28 | Caprotec Bioanalytics Gmbh | Capture compounds, collections thereof and methods for analyzing the proteome and complex compositions |
US20030113233A1 (en) * | 2001-10-26 | 2003-06-19 | Elizabeth Nanthakumar | Resin dispensing device |
US20030124735A1 (en) * | 2001-10-26 | 2003-07-03 | Sequenom, Inc. | Method and apparatus for parallel dispensing of defined volumes of solid particles |
US7159740B2 (en) * | 2001-10-26 | 2007-01-09 | Sequenom, Inc. | Method and apparatus for parallel dispensing of defined volumes of solid particles |
US20040209255A1 (en) * | 2002-03-11 | 2004-10-21 | Hk Pharmaceuticals, Inc. | Compounds and methods for analyzing the proteome |
US20070026528A1 (en) * | 2002-05-30 | 2007-02-01 | Delucas Lawrence J | Method for screening crystallization conditions in solution crystal growth |
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US20090093373A1 (en) * | 2002-06-24 | 2009-04-09 | Canon Kabushiki Kaisha | Dna micro-array having standard probe and kit including the array |
US20040132080A1 (en) * | 2002-06-24 | 2004-07-08 | Canon Kabushiki Kaisha | DNA micro-array having standard probe and kit including the array |
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US7144554B1 (en) * | 2002-08-02 | 2006-12-05 | Hamilton Company | Ultra low volume probe |
US7820378B2 (en) | 2002-11-27 | 2010-10-26 | Sequenom, Inc. | Fragmentation-based methods and systems for sequence variation detection and discovery |
US20050112590A1 (en) * | 2002-11-27 | 2005-05-26 | Boom Dirk V.D. | Fragmentation-based methods and systems for sequence variation detection and discovery |
US20030166263A1 (en) * | 2002-12-30 | 2003-09-04 | Haushalter Robert C. | Microfabricated spotting apparatus for producing low cost microarrays |
US20050042771A1 (en) * | 2003-01-16 | 2005-02-24 | Hubert Koster | Capture compounds, collections thereof and methods for analyzing the proteome and complex compositions |
US20100298168A1 (en) * | 2003-01-16 | 2010-11-25 | Koester Hubert | Capture compounds, collections thereof and methods for analyzing the proteome and complex compositions |
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US20100248264A1 (en) * | 2003-01-16 | 2010-09-30 | Koster Hubert | Capture compounds, collections thereof and methods for analyzing the proteome and complex compositions |
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US20060263899A1 (en) * | 2003-02-24 | 2006-11-23 | Agnes George R | Formation of closely packed microspots and irradiation of same |
US20050009053A1 (en) * | 2003-04-25 | 2005-01-13 | Sebastian Boecker | Fragmentation-based methods and systems for de novo sequencing |
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US9394565B2 (en) | 2003-09-05 | 2016-07-19 | Agena Bioscience, Inc. | Allele-specific sequence variation analysis |
US7435379B1 (en) | 2003-12-31 | 2008-10-14 | Takeda San Diego, Inc. | System for performing crystallization trials |
US7416710B1 (en) | 2003-12-31 | 2008-08-26 | Takeda San Diego, Inc. | Method and system for performing crystallization trials |
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US7416709B1 (en) | 2003-12-31 | 2008-08-26 | Takeda San Diego, Inc. | Method for performing crystallization trials |
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US7452419B1 (en) | 2003-12-31 | 2008-11-18 | Takeda San Diego, Inc. | Method for performing crystallization trials |
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US7455814B2 (en) * | 2004-04-23 | 2008-11-25 | Giblin Leonard J | Metered dispenser and aspirator device |
US20060073501A1 (en) * | 2004-09-10 | 2006-04-06 | Van Den Boom Dirk J | Methods for long-range sequence analysis of nucleic acids |
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