US20030215956A1 - Multi-well microfiltration apparatus - Google Patents
Multi-well microfiltration apparatus Download PDFInfo
- Publication number
- US20030215956A1 US20030215956A1 US10/460,819 US46081903A US2003215956A1 US 20030215956 A1 US20030215956 A1 US 20030215956A1 US 46081903 A US46081903 A US 46081903A US 2003215956 A1 US2003215956 A1 US 2003215956A1
- Authority
- US
- United States
- Prior art keywords
- wells
- well
- collection
- plate
- array
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Images
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5025—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures for parallel transport of multiple samples
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
- B01D61/14—Ultrafiltration; Microfiltration
- B01D61/18—Apparatus therefor
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5025—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures for parallel transport of multiple samples
- B01L3/50255—Multi-well filtration
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/0099—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor comprising robots or similar manipulators
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/04—Moving fluids with specific forces or mechanical means
- B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
- B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
- B01L2400/049—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics vacuum
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N2035/00465—Separating and mixing arrangements
- G01N2035/00475—Filters
- G01N2035/00485—Filters combined with sample carriers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
- G01N35/1009—Characterised by arrangements for controlling the aspiration or dispense of liquids
- G01N35/1016—Control of the volume dispensed or introduced
- G01N2035/102—Preventing or detecting loss of fluid by dripping
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
- G01N35/028—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations having reaction cells in the form of microtitration plates
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
- G01N35/1065—Multiple transfer devices
- G01N35/1074—Multiple transfer devices arranged in a two-dimensional array
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/25—Chemistry: analytical and immunological testing including sample preparation
Abstract
The present invention provides multi-well plates and column arrays in which samples (e.g., cell lysates containing nucleic acids of interest, such as RNA) can be analyzed and/or processed. In one embodiment, the microfiltration arrangement is a multilayer structure, including (i) a column plate having an array of minicolumns into which samples can be placed, (ii) a discrete filter element disposed in each minicolumn, (iii) a drip-director plate having a corresponding array of drip directors through which filtrate may egress, and (iv) a receiving-well plate having a corresponding array of receiving wells into which filtrate can flow. The invention provides multi-well microfiltration arrangements that are relatively simple to manufacture and that overcome many of the problems associated with the prior arrangements relating to (i) cross-contamination due to wicking across a common filter sheet or (ii) individual filter elements entrapping sample constituents within substantial dead volumes. Further, the invention provides multi-well microfiltration arrangements that adequately support discrete filter elements disposed in the wells without creating substantial preferential flow. Additionally, the invention provides multi-well microfiltration arrangements that avoid cross-contamination due to aerosol formation, pendent drops and/or splattering. Other disclosed features of the invention provide for the automated covering or heat-sealing of filtrate samples separately collected in an array of wells.
Description
- The present application is a continuation of U.S. patent application Ser. No. 10/199,743, filed Jul. 19, 2002, which in turn is a divisional of U.S. patent application Ser. No. 09/565,202, filed May 4, 2000 (now U.S. Pat. No. 6,506,343 B1), which in turn is a divisional of U.S. patent application Ser. No. 09/182,946, filed Oct. 29, 1998 (now U.S. Pat. No. 6,159,368), all of which are hereby incorporated herein in their entireties by reference.
- The present invention relates to multi-well plates and column arrays in which samples are analyzed or processed.
- In recent years, microtitration wells have assumed an important role in many biological and biochemical applications, such as sample preparation, genome sequencing, and drug discovery programs. A variety of multi-well arrangements, constructed according to standardized formats, are now popular. For example, a tray or plate having ninety-six depressions or cylindrical wells arranged in a 12×8 regular rectangular array is one particularly popular arrangement.
- In some multi-well constructions, a filter sheet or membrane is held against the lower ends, or lips, of open-bottomed wells. Such plates are often manufactured as a multi-layered structure including a unitary sheet of filter material disposed to cover the bottom apertures of all the wells, the filtration sheet being sealed to the outer lip of one or more of the well apertures. The use of a single sheet of filter material in such a manner, however, can lead to cross-contamination between adjacent wells due to the ability of liquid to disperse, e.g., by wicking, across the sheet.
- In an effort to overcome this problem, it has been proposed to provide each well with its own discrete filter element or disc. According to one such design, a pre-cut filter disc is inserted into an upper, open end of each well and pushed down until it rests at the bottom of the well. An O-ring is then press-fit down into each well until it comes to rest against the top of the filter disc. The O-ring frictionally engages the column inner wall, thereby retaining the filter in place. While avoiding the cross-contamination problems of unitary filter sheets, such a construction is obviously cumbersome to manufacture. Also, the portion of the disk that gets pinched between the O-ring and the floor of the well introduces a significant “dead volume,” which can have an adverse impact on sample purification. For example, sample matrix can become entrapped in these areas along a significant portion of the peripheral edge of individual filter discs. When purifying DNA from blood samples, entrapment of small amounts of hemoglobin (heme) on the edges of a cellulose blot membrane will eventually contaminate the final product in the last stages of the purification process. The contaminating heme residue is a strong inhibitor in PCR and sequencing reaction assays of the DNA products.
- Another multi-well arrangement, wherein each well has its own discrete filter element, is formed by positioning a single sheet of filter material between an upper plate, having a plurality of mini-columns formed therein, and a lower plate having a plurality of corresponding “drip directors.” Upon bringing the plates together and forming an ultrasonic bond therebetween, the filter sheet is die-cut into individual filter discs positioned below respective mini-columns. Although this construction is easier to manufacture than the above arrangement, it suffers similar disadvantages. Specifically, a substantial portion of each filter disc's peripheral edge becomes pinched between the column plate and the drip director plate, resulting in a significant dead volume that can adversely impact sample purification.
- There is, thus, a need for a multi-well microfiltration arrangement that is relatively simple to manufacture, and that overcomes the problems associated with the prior arrangements relating to cross-contamination due to wicking across a common filter sheet, or individual filter discs entrapping sample constituents within substantial dead volumes.
- Most of the known multi-well filtration plates, and particularly those providing an individual filter disc for each well, lack adequate space below the filter element to permit an evenly distributed flow of fluid across the filter. In many arrangements, a drip director, at the bottom of each well, provides an expansive, flat surface upon which much of the filter element rests. Preferential flow pathways are thereby created, favoring those areas of the filter element that are not in contact with, or in close proximity to, the drip director surface. Such preferential flow can have an adverse impact on the elution of solutes. For example, preferential flow pathways can impede the leaching of retained sample constituents in non-favored regions of the filter element.
- On the other hand, a lack of adequate support beneath each filter element can be problematic, as well. The filter media used in multi-well trays are typically quite thin and exhibit relatively poor mechanical properties. In certain stressful situations, e.g., high-pressure or vacuum filtration, such membranes may not maintain their integrity. Filter discs that are supported only about their peripheral edges might sag, particularly along their central regions, and may even pull loose from the structure holding their edges. For example, a filter disc might collapse into the cavity of a drip director. This would affect the porosity of the filter, trapping certain sample constituents in the filter that would otherwise elute. Moreover, if a bypass forms along the edges of the filter, due to the filter disc pulling away from the peripheral supporting structure, an undesirable loss of sample may result.
- There is, thus, a need for a multi-well microfiltration arrangement that adequately supports the filter media at each well, without creating substantial preferential flow.
- A few of the known multi-well microfiltration arrangements provide a collection plate, for placement beneath a sample-well plate, having a plurality of closed-bottom collection wells corresponding to the sample wells. Generally, the collection of filtrate takes place upon application of a vacuum to pull the mobile phase through each well. With most of these arrangements, attempts to separately collect the filtrate from each sample well have suffered from unreliable results due to cross-contamination between the wells of the collection plate. A principal cause of such cross-contamination relates to the production of aerosols as the filtrate leaves the drip directors. The aerosols can readily disperse and travel to neighboring collection wells. In addition, aerosols may expose technicians to potentially pathogenic microorganisms, and the like, which may be present in the samples.
- Cross-contamination due to aerosol formation is exacerbated by the typical flow pattern induced by the vacuum arrangements of such systems. Usually, the sample-well plate is mounted above the collection plate, and the collection plate, in turn, sits in a vacuum chamber. Upon evacuation of the chamber, solution within each well is drawn down through the filter element toward a respective collection well. Generally, the vacuum draws along flow pathways extending from within each mini-column, through a respective drip director, and horizontally across the top of the collection plate until reaching one side of the collection plate whereat the flow pathways turn downward toward an exit port. Except for those drip directors located directly adjacent the side of the chamber having the exit port, substances (e.g., entrained aerosols, gases, etc.) pulled along each vacuum flow pathway from each drip director must pass by neighboring collection wells as they travel across the top of the collection plate. Unfortunately, aerosols from filtrate exiting one drip director can become entrained in the flow across the collection plate and make its way over into neighboring wells.
- The potential for cross-contamination is particularly high when the upper sample-well and drip-director plates are removed from the collection plate. Pendent drops of filtrate remaining on the drip directors can inadvertently fall into neighboring wells as the drip directors are moved over the collection plate. With standard multi-well plates, a concerted, manual “touch-off” of all such pendent drops to the inner sides of respective collection wells is difficult, if not impossible, due to the great number of wells. Application of a strong vacuum below the drip directors, in an attempt to pull such pendent drops down and away from the drip directors, can atomize the pendent drops, resulting in the related problem of contamination by aerosol formation, discussed above.
- There is, thus, a need for a multi-well microfiltration arrangement that provides for the separate collection of filtrate from each well, while avoiding cross-contamination due to aerosol formation and/or pendent drops.
- One aspect of the present invention provides a microfiltration apparatus for processing a plurality of fluid samples.
- According to one embodiment, the microfiltration apparatus of the invention includes a first plate having a plurality of columns and a second plate having a plurality of discharge conduits. Each of the columns has a first inner bore defining a lumen within the column and an end region for receiving a filter medium within the column. The column end region defines a second inner bore having a diameter greater than that of the first inner bore and a transition region that joins the second inner bore to the first inner bore. A filter medium for filtering sample is positioned within each column end region, adjacent the transition region. Each discharge conduit has an upstanding upper end region aligned with and received within a corresponding column end region so as to form a substantially fluid-tight interface therebetween. The discharge conduit upper end region has a terminal rim region for supporting a circumferential region of the filter medium such that each filter medium is held between a column transition region and the terminal rim region of a corresponding discharge conduit.
- In one embodiment, the transition region of each column has an annular tapered portion. The circumference of the annular tapered portion decreases in a substantially constant fashion along a direction from the second inner bore to the first inner bore. In a related embodiment, a line running along the tapered portion, longitudinally with respect to the column, forms an acute angle with a plane perpendicular to a longitudinal axis of the column and intersecting the column through a junction of the transition region with the second inner bore. The acute angle, in one embodiment, is within the range of about 30-70 degrees. Preferably, the acute angle is within the range of about 30-60 degrees. In one particular embodiment, the acute angle is about 45 degrees.
- According to one embodiment, the terminal rim region of each discharge conduit contacts no more than about 15%, and preferably less than about 10%, and more preferably less than about 5% of the bottom surface area of a respective filter medium.
- One embodiment provides a plurality of fin-like support buttresses in each of the discharge conduits. In this embodiment, each of the support buttresses has an elongated, narrow, uppermost surface that is substantially coplanar with a plane defined by the terminal rim region of a respective discharge conduit. In a related embodiment, the horizontal cross-sectional area of an upper region of each support buttress decreases in a direction extending towards its uppermost surface in a fashion such that the intersection of the uppermost surface with the plane of the terminal rim region is substantially tangential in nature, forming a line.
- According to another embodiment, the microfiltration apparatus is provided with a gas-permeable matrix comprised at least in part of a porous hydrophilic polymer material. The matrix is attached to the second plate on a face opposite the first plate. Also in this embodiment, the matrix circumscribes a plurality of the discharge conduits.
- A further embodiment provides means for shifting the first and second plates in either of two directions from a reference “home” position along a generally horizontally extending axis, and then returning the plates back to the reference “home” position. The shifting means can include a stepper motor disposed in mechanical communication with the plates such that angular rotation of the stepper motor induces linear motion of the plates.
- In accordance with another embodiment, vacuum means are provided for drawing adherent drops of fluid hanging from the discharge conduits in a direction away from the collection wells and up into the discharge conduits.
- In another of its aspects, the present invention provides a method for forming a plurality of microfiltration wells. In one embodiment, a sheet of filter medium is positioned between a first plate containing a plurality of columns and a second plate having a plurality of discharge conduits. Each of the columns has a first inner bore defining a lumen within the column and an end region defining a second inner bore having a diameter greater than that of the first inner bore and a transition region that joins the second inner bore to the first inner bore. Each of the discharge conduits has an upstanding upper end region facing the first plate and aligned with a corresponding column end region. The plates are pressed together in a manner effective to punch portions of the filter medium from the sheet to afford a filter medium plug situated within the end region of each column in abutment with the column transition region and a terminal rim region of a corresponding discharge conduit upper end region.
- The method of the invention also provides for the compression-fit sealing of each filter element. In one embodiment, compression of each filter element between the column transition region and a terminal rim region of a corresponding discharge conduit upper end region serves to secure and seal the filter element to an inner sidewall of the column.
- In another embodiment, the method further includes the step of securing the first plate to the second plate. The securing step can be effected by forming a bond, such as an ultrasonic weld, between an inner sidewall of each second inner bore and an outer circumferential surface of a respective upper end region.
- A further aspect of the present invention provides a microfiltration apparatus for processing a plurality of fluid samples.
- In one embodiment, the apparatus includes a first plate having a plurality of columns. Each of the columns contains, at one end thereof, a filter element and a fluid discharge conduit beneath the filter element. A second plate is spaced apart from the first plate by a cavity. The second plate has a plurality of receiving or collection wells that are aligned with the columns for receiving sample fluid from the discharge conduits. The second plate is also provided with a plurality of vents adjacent the collection wells. A gas-permeable matrix is positioned in the cavity between the first plate and the second plate so as to fill the space between the confronting surfaces of the two plates. The matrix laterally surrounds the region between at least one discharge conduit and an aligned collection well. The matrix is effective (i) to permit a vacuum drawn from beneath the second plate to extend, via the vents, to a region above the second plate and to the columns, thereby drawing fluid from the columns into the collection wells and (ii) to obstruct movement of aerosols across the top of the second plate, thereby limiting cross-contamination between wells.
- According to one embodiment, the matrix is a continuous sheet having a plurality of openings permitting the passage of filtrate from each discharge conduit to a respective collection well. Each one of the discharge conduits can extend at least partially into a respective one of the openings. Further, the matrix can extend over a plurality of the vents. In one embodiment, the matrix is comprised of a porous hydrophilic polymer material, such as ethyl vinyl acetate (EVA) or the like.
- In one embodiment, the collection wells are arranged in a rectangular array having at least eight wells (e.g., 8, 12, 24, 48, or 384 wells). In one preferred arrangement, the second plate is provided with at least one vent for every four collection wells, and the vents are arranged such that a vent is located between each collection well and at least one adjacent collection well. For example, a vent may be provided between each collection well and at least one diagonally adjacent collection well of the array.
- According to one embodiment, each of the columns has a first inner bore defining a lumen within the column and an end region defining a second inner bore, having a diameter greater than that of the first inner bore, and a transition region that joins the second inner bore to the first inner bore. Each of the discharge conduits has an upstanding upper end region aligned with and received by a corresponding column end region so as to form a substantially fluid-tight interface therebetween. The discharge conduit upper end region has a terminal rim region for supporting a circumferential region of the filter element such that each filter element is held between a column transition region and the terminal rim region of a corresponding discharge conduit.
- In another embodiment, means are provided for shifting the first plate in either of two directions from a reference “home” position along a generally horizontally extending axis, and then returning the plate back to the reference “home” position. The shifting means can include a stepper motor disposed in mechanical communication with the plate such that angular rotation of the stepper motor induces linear movement of the plate.
- In a further embodiment, vacuum means are provided for drawing adherent drops of fluid hanging from the discharge conduits in a direction away from the collection wells and up into the discharge conduits.
- Another aspect of the present invention provides a method for separately collecting filtrate from an array of microfiltration wells in a corresponding array of closed-bottom collection wells held by a collection tray situated below the micro-filtration-well array.
- In one embodiment, the method includes the steps of:
- (A) placing a fluid sample in a plurality of the microfiltration wells;
- (B) drawing a vacuum along pathways extending from each microfiltration well downward through a plane defined by an upper surface of the collection tray at a point at or adjacent a corresponding collection well to a region beneath the collection tray, thereby causing a filtrate to flow from each microfiltration well and to collect in corresponding collection wells; and
- (C) obstructing aerosols formed from the filtrate at any one microfiltration well from moving across the upper surface of the collection tray to a non-corresponding collection well, thereby limiting cross-contamination.
- According to one embodiment, each vacuum pathway passes through a gas-permeable matrix disposed in a cavity between the microfiltration-well array and the collection-well array. The gas-permeable matrix can be comprised of a porous hydrophilic polymer material, such as ethyl vinyl acetate (EVA) or the like. In one preferred arrangement, the gas-permeable matrix circumscribes the region between each microfiltration well and a corresponding collection well.
- In one embodiment, the vacuum pathways pass through the plane of the collection-tray upper surface by way of vents that traverse the collection tray proximate each of said collection wells. Also in this embodiment, the gas-permeable matrix covers the vents.
- In another embodiment, each of the vacuum pathways extends from one microfiltration well into a respective collection well prior to passing through the vents.
- In a further embodiment, wherein a collection tray having open-bottom wells is used, the vacuum pathways pass through the plane of the collection-tray upper surface and then down and out of the open bottoms of the wells.
- The microfiltration wells comprise, according to one embodiment, a first plate having a plurality of columns and a second plate having a plurality of discharge conduits. Each column has a first inner bore defining a lumen within the column and an end region for receiving a filter medium within the column. The end region defines a second inner bore having a diameter greater than that of the first inner bore and a transition region that joins the second inner bore to the first inner bore. A filter medium for filtering sample is positioned within each column end region, adjacent the transition region. Each discharge conduit has an upstanding upper end region aligned with and received within a corresponding column end region so as to form a substantially fluid-tight interface therebetween. The discharge conduit upper end region has a terminal rim region for supporting a circumferential region of the filter medium such that each filter medium is held between a column transition region and the terminal rim region of a corresponding discharge conduit.
- In one embodiment, the method includes the additional steps of:
- (i) touching-off, in a substantially simultaneous fashion, adherent drops of fluid hanging from the bottom of each microfiltration well to an inner sidewall of a respective collection well; and
- (ii) drawing adherent drops of fluid hanging from the discharge conduits in a direction away from the corresponding collection wells and up into the discharge conduits.
- In another of its aspects, the present invention provides an apparatus for avoiding cross-contamination due to pendent drops of fluid hanging from a plurality of discharge conduits disposed in an array above a corresponding array of collection wells.
- According to one embodiment, the apparatus includes:
- (i) a carriage configured to carry one of the arrays and adapted for linear reciprocal motion in either of two directions along a first, generally horizontal, axis from a neutral position whereat the arrays are substantially axially aligned;
- (ii) a stepper motor;
- (iii) a linkage assembly mechanically communicating the stepper motor with the carriage such that each rotational step of the stepper motor induces movement of the carriage a given distance from the neutral position in one of the two directions depending upon the direction of angular rotation of the motor, thereby effecting relative motion between the discharge-conduit array and the collection-well array such that pendent drops of fluid hanging from the discharge conduits are simultaneously touched-off to inner sidewalls of corresponding collection wells; and
- (iv) a compression spring mounted within the linkage assembly in a manner permitting the spring (a) to provide a predetermined amount of resistance to movement of the carriage from the neutral position, and (b) to compensate or absorb some of the linear overshoot due to excess angular rotation of the motor beyond the amount required to move the discharge conduits into firm abutment with the inner sidewalls of the collection wells.
- In one embodiment, a vacuum chamber communicates with the discharge-conduit array from a side thereof opposite the collection-well array. Evacuation of the vacuum chamber is effective to urge pendent drops of fluid hanging from the discharge conduits in a direction away from the collection wells and into the discharge conduits.
- In one preferred embodiment, the carriage is configured to carry the discharge-conduit array, while the collection-well array remains stationary. A vertical positioning assembly can be disposed on the carriage to support the discharge-conduit array for linear movement along a second, generally vertical, axis between a lowered position whereat the discharge conduits extend down into respective collection wells and an elevated position whereat the discharge conduits clear the collection wells.
- Still a further aspect of the present invention provides a method for avoiding cross-contamination due to pendent drops of fluid hanging from a plurality of discharge conduits disposed in an array above a corresponding array of closed-bottom collection wells.
- In one embodiment, the method includes the steps of
- (i) touching-off, in a substantially simultaneous fashion, pendent drops of fluid hanging from the discharge conduits to inner sidewalls of respective collection wells; and
- (ii) drawing pendent drops of fluid hanging from the discharge conduits in a direction away from the corresponding collection-well array and into the discharge conduits.
- The touching-off step can be carried out by shifting the discharge-conduit array along a plane substantially orthogonal to the longitudinal axes of the collection wells, while the collection wells are maintained in a substantially fixed position. In one embodiment, each of the discharge conduits is shifted into contact with one sidewall portion of a respective collection well, and then is shifted into contact with another, laterally opposing sidewall portion of the respective collection well.
- One embodiment provides a stepper motor in mechanical communication with the discharge-conduit array such that angular rotation of the stepper motor induces linear motion of the discharge conduits. In this embodiment, stepping of the stepper motor causes the discharge-conduit array to shift.
- The step of drawing pendent drops of fluid can be effected by establishing a reduced pressure (a vacuum) above the discharge conduits.
- In one embodiment, an upstanding upper end region of each of the discharge conduits is received within a respective column, thereby forming an array of microfiltration wells. Each column has a first inner bore defining a lumen within the column and an end region defining a second inner bore having a diameter greater than that of the first inner bore and a transition region that joins the second inner bore to the first inner bore. A filter element is disposed in each column, between the transition region of the column and the upper end region of a respective discharge conduit.
- In another of its aspects, the present invention provides a removable cover for isolating a plurality of samples separately contained in an array of closed-bottom wells supported in a collection tray.
- According to one embodiment, the cover includes a substantially rigid, rectangular shell portion having a top surface, a bottom surface and a circumferential side-edge region. A plurality of reversibly expandable, tubular sleeves are provided on the top surface of the shell portion. A resiliently compliant undersurface is secured to the bottom surface of the shell portion. A plurality of resiliently deflectable, elongated side arms project below the bottom surface from opposing side-edge regions of the shell portion. In its normal (unstressed) state, each side arm is positioned substantially perpendicular to a plane defined by the bottom surface. An inwardly directed catch is formed at an end of each side arm, distal from the shell portion. The arms, and associated catches, are useful for releasably snap-locking the cover over the wells of a collection tray.
- In one embodiment, the undersurface of the cover includes a plurality of downwardly convex nodules (half-dome features) disposed in an array complementary to the collection-well array. Each nodule is adapted to fit over a corresponding well when the cover is secured over the collection tray.
- A further aspect of the invention provides a method for covering an array of open-top wells held in a collection tray.
- According to one embodiment, the method is carried out in a substantially automated fashion using (i) a support structure adapted for movement along a generally horizontal plane (x/y direction) and (ii) a plurality of elongated, parallel rods depending from the support and adapted for movement along their respective longitudinal axes (y direction). Initially, the rods, while disposed in a retracted position adjacent the support, are positioned over a cover member. Two of the rods are then extended away from the support (y direction) so that their end regions become wedged in respective cavities formed along the top of the cover, while two rods are maintained in the retracted position (i.e., with free end regions). The cover member is then lifted by retracting the wedged rods back toward the support. The support is then moved along the x/y direction so that the cover becomes positioned over the collection tray. The wedged rods are then extended away from the support so that the cover is lowered onto the collection tray, over the well openings. The free ends of two retracted rods are then extended until they abut an upper region of the cover, thereby blocking upward movement of the cover, while the wedged rods are retracted away from the cover so that they are withdrawn (unwedged) from the cavities. As a result, the cover is left resting on top of the collection tray over the well openings.
- From this position, the cover member can be releasably snap-locked to the collection tray. This can be effected, for example, by extending at least one of the rods away from the support and into abutment with an upper region of the cover, thereby pressing the cover into locking engagement with the collection tray. Another of the rods can be extended away from the support and into abutment with another upper region of the cover in order to prevent the cover from flipping up while being locked.
- The method can be carried out, for example, with a cover having (i) an upper, substantially rigid shell portion, (ii) a lower, compliant undersurface secured to the shell portion, and (iii) means for releasably locking the shell portion to the collection tray. The undersurface of the cover can include, for example, a plurality of downwardly convex nodules (half-dome features), disposed in an array complementary to the well array. Further, the shell portion can include a plurality of landing sites along its upper surface configured to receive the lower end regions of the rods.
- Still a further aspect of the invention provides a device for holding a plurality of rectangular, heat-sealable sheets.
- In an exemplary embodiment, the device is comprised of a tray having a substantially rectangular bottom surface, four upwardly divergent sidewalls extending from the bottom surface, and an upper circumferential edge region defining a substantially rectangular open top. A plurality of ribs run along each sidewall, spanning most of the distance between the bottom surface and the upper circumferential edge region. Each of the ribs has a substantially linear surface that (i) faces an opposing sidewall and (ii) is substantially normal to a plane defined by the bottom surface of the tray.
- According to one embodiment, a plurality of heat-sealable sheets, arranged in a vertical stack, is positioned in the tray such that peripheral side-edge regions of the sheets are disposed in contact with the substantially linear surface of each rib.
- Another aspect of the present invention provides a method of sealing a rectangular, heat-sealable sheet over an array of wells held in a collection tray.
- In one embodiment, the method includes the steps of (i) picking up a clear heat-sealable sheet; (ii) placing the sheet over open upper ends of the wells; and (iii) pressing a conformable heated surface against the sheet, from a side opposite the collection tray, with sufficient pressure such that the sheet is heat-sealed to the collection tray over the open upper ends of the wells. Further according to this embodiment, the conformable heated surface is pressed against the sheet using a plurality of spaced-apart elongated rods, disposed substantially normal to an upper surface of the collection plate. The rods can depend from a support structure positioned above the collection plate.
- These and other features and advantages of the present invention will become clear from the following description.
- The structure and manner of operation of the invention, together with the further objects and advantages thereof, may best be understood by reference to the following description taken in conjunction with the accompanying drawings, in which identical reference numerals identify similar elements, and in which:
- FIG. 1 is a perspective view of a multi-well microfiltration apparatus constructed in accordance with an embodiment of the present invention.
- FIG. 2 is an exploded view of the multi-well microfiltration apparatus of FIG. 1.
- FIG. 3 is a partial side-sectional view of the multi-well microfiltration apparatus of FIGS. 1 and 2.
- FIG. 4 shows, in enlarged detail, one microfiltration well from the sectional view of FIG. 3.
- FIG. 5 is a partial side-sectional view showing a microfiltration well constructed in accordance with an embodiment of the present invention.
- FIG. 6 is an exploded view of a microfiltration well showing membrane-support structure in the form of three fin-like support buttresses constructed in accordance with an embodiment of the present invention.
- FIG. 7 is an elevational view from one end of a carriage assembly for effecting relative motion between the drip directors of a drip-director plate and the collection wells of a collection plate, according to an embodiment of the present invention.
- FIG. 8 is a partially exploded, perspective view showing a carriage assembly for effecting relative motion between the drip directors of a drip-director plate and the collection wells of a collection plate, according to an embodiment of the present invention.
- FIGS.9(A)-9(C) are side cross-sectional views showing a touch-off operation whereby a plurality of drip directors is laterally shifted to the right and to the left such that the drip director outlet regions simultaneously abut inner sidewalls of a plurality of corresponding collection wells.
- FIG. 10(A) is a partially schematic top plan view showing a spring-loaded touch-off mechanism in its normal, or neutral, position.
- FIG. 10(B) is a partially schematic top plan view showing the spring-loaded touch-off mechanism of FIG. 10(A) in a first, shifted position.
- FIG. 10(C) is a partially schematic top plan view showing the spring-loaded touch-off mechanism of FIGS.10(A)-10(B) in a second, shifted position.
- FIG. 11 is a perspective view of a cover member, having an array of resiliently flexible half-dome features on its lower face, disposed over a multi-well tray, in accordance with an embodiment of the present invention.
- FIG. 12 is another perspective view of the cover member of FIG. 12, showing a plurality of sites on the cover's upper surface for receiving the lower end regions of elongated, fluid-handling fingers of a fluid-handling robot positioned above the tray, in accordance with an embodiment of the present invention.
- FIG. 13 is a perspective view showing the cover of FIGS. 11 and 12 disposed over the openings of a multi-well tray and releasably snap-locked to the multi-well tray, according to an embodiment of the invention.
- FIGS.14(A) and 14(B) are enlarged, perspective and side-sectional views, respectively, showing a releasable snap-locking assembly for securing a cover of the invention to a multi-well tray, according to an embodiment of the present invention.
- FIG. 15 is a perspective view showing an assembly for releasably securing a cover of the invention to a multi-well tray, according to a further embodiment of the invention.
- FIG. 16 is a perspective view showing an automated high-throughput sample preparation workstation, including, for example, a microfiltration apparatus, cross-contamination control arrangements, collection-well covering and heat-sealing assemblies, and associated components and reagents, in accordance with the teachings of the present invention.
- FIG. 17 is a perspective view of an automated station for applying heat-sealable sheets over the wells of a multi-well tray, in accordance with an embodiment of the present invention.
- FIG. 18 is a perspective view showing a tray or bin for holding a stack of heat-sealable sheets, constructed in accordance with an embodiment of the present invention.
- FIGS.19(A) and 19(B) are enlarged, perspective and side-sectional views, respectively, showing a releasable snap-locking assembly for securing a tray or bin, such as shown in FIG. 18, to a frame assembly situated, for example, at a heat-sealing station such as shown in FIG. 17, in accordance with one embodiment of the present invention.
- FIGS.20 to 23 are perspective views illustrating various features, as well as the operation of, the automated heat-sealing station of FIG. 17, according to an embodiment of the present invention.
- FIG. 24 is a perspective view, with portions broken away, of a heatable platen assembly as used, for example, in the heat-sealing station of FIGS. 17 and 20-23, according to an embodiment of the present invention.
- The following discussion of the preferred embodiments of the present invention is merely exemplary in nature. Accordingly, this discussion is in no way intended to limit the scope of the invention, application of the invention, or the uses of the invention.
- FIGS.1-3 show, in perspective, exploded and partial side-sectional views, respectively, an embodiment of a multi-well microfiltration apparatus constructed in accordance with the present invention. In the assembly stage of manufacture, a filter sheet or membrane, indicated in FIG. 2 by the
reference numeral 8, is located between a column tray, or plate, 10 having an array of open-bottom mini-columns, such as 12, and a drip-director tray, or plate, 14 having an array of drip directors, such as 16, corresponding to the mini-columns. Upon registering and mating mini-columns 12 withdrip directors 16, an array of microfiltration wells are formed, denoted generally in FIG. 3 by thereference numeral 18, each having a discrete filter element or medium (e.g., a plug, disc, or the like), such as 8 a and 8 b, positioned therein. The inner walls of each mated mini-column/drip-director pair bound a flow pathway which extends downward through the well 18. - As shown in FIGS. 2 and 3, each microfiltration well has an interior region, or lumen, that is substantially circular in horizontal cross-section. It should be appreciated, however, that microfiltration wells of any desired geometrical cross-section (egg., oval, square, rectangular, triangular, etc.) could be used. Similarly, the wells may be of any desired shape when viewed along their longitudinal axes, e.g., straight, tapered or other shape. In one embodiment, the walls of each well have a slight outward taper (i.e., the well diameter increases) along the direction extending from the well's upper, loading end toward the filter medium.
- The plates of the microfiltration apparatus may be constructed of any substantially rigid, water-insoluble, fluid-impervious material that is substantially chemically non-reactive with the assay samples. The term “substantially rigid” as used herein is intended to mean that the material will resist deformation or warping under a light mechanical or thermal load, although the material may be somewhat elastic. Suitable materials include acrylics, polycarbonates, polypropylenes and polysulfones. Also, it should be noted that the terms “tray” and “plate” are used synonymously and interchangably herein.
- Optionally, the fluid-contacting surfaces of the drip directors can be comprised of a material and/or provided with a coating that renders such surfaces hydrophobic, reducing the potential for cross-contamination. For example, low surface-energy materials could be used in forming and/or coating the drip directors. Of course, such materials should be compatible with the assay samples.
- The plates may be formed by any conventional means, injection molding being a particularly convenient technique. One embodiment of the invention contemplates the use of injection molded rectangular plastic plates, the length and width of which conform to the commonly used standard of 5.03″×3.37″ (127.8 mm and 85.5 mm). In the embodiment of FIGS.1-3, the wells are formed integrally with such a plate, arranged in a 12×8 regular rectangular array spaced 0.9 cm center-to-center. Alternatively, the wells can be formed as discrete units (not shown) interconnected by plastic webbing to provide an array. In another embodiment, the wells are provided in the form of strips (not shown). For example, a plurality of wells could be disposed in a row with adjacent wells connected to one another by any suitable means, e.g., frangible plastic webs. A plurality of strips could then be arranged side-by-side within a frame designed to hold such strips. For example, twelve 8-well strips could be placed side-by-side in a rectangular frame to form a 96-well array. In a further embodiment, each well is formed as a discrete unit removably positioned within a respective opening formed in a support plate (not shown). For example, a tray could be provided with a 12×8 array of circular openings in which cylindrical wells are received and held, in a fashion similar to test-tubes held in a conventional test-tube rack.
- Although the illustrated embodiments show arrangements configured in accordance with the popular 96-well format, the invention also contemplates any other reasonable number of wells (e.g., 12, 24, 48, 384, etc.) disposed in any suitable configuration.
- With reference once again to FIGS.1-3, an
upper vacuum chamber 20 is situated abovecolumn plate 10.Upper vacuum chamber 20 is adapted for movement between (i) a mounted position, whereat four depending circumferential walls, denoted as 20 a, form a substantially airtight seal with an upper, peripheral surface ofcolumn plate 10 via an interposedresilient gasket 21, and (ii) a retracted position, whereatchamber 20 is spaced apart fromcolumn plate 10. The hollow interior ofchamber 20 is pneumatically connectable to an external vacuum source via ahosecock 23 extending through the top ofchamber 23. A reduced pressure can be established above the sample wells by bringingchamber 20 to its mounted position atopcolumn plate 10 and then evacuatingchamber 20. - In some situations, it may be desirable to establish an increased pressure above the sample wells (e.g., to facilitate the flow of samples through the filter media and out of the wells via the lower discharge conduits). In such cases,
chamber 20 can be pressurized by way of a suitable pressure source (e.g., a pump). - A receiving, or collection,
plate 24 is located belowdrip director plate 14.Collection plate 24 includes an upper planar surface, denoted as 25, and an array of closed-bottom wells, such as 26, depending therefrom. The collection-well array corresponds to the drip-director array, permitting the separate collection of filtrate from each sample well. The collection plate is adapted to fit inside an open reservoir of a lower vacuum chamber, denoted as 29, with the collection wells extending down into the reservoir. - Apertures or vents, such as28, extend through the upper
planar surface 25 ofcollection plate 24. For reasons that will become apparent, at least one aperture should be located adjacent each collection well. Theapertures 28 permit fluid communication between the regions above and below theplate 24. By this construction, a vacuum drawn from beneath the collection plate will extend to the regions above the plate and inside the wells. - Although not shown in the figures, the present invention also provides a plate like
collection plate 24, except having open-bottom wells as opposed to the closed-bottom wells ofplate 24. Otherwise, the plate of open-bottom wells is configured likecollection plate 24. That is, the plate of open-bottom wells provides structure for effectively carrying out filtrations and/or washings, while avoiding cross-contamination. However, instead of separately collecting filtrate in the various wells, the filtrate passes through the wells and out of the open bottoms. It is contemplated that the plate of open-bottom wells will be used in a manner like that described herein forplate 24, except that the situation will not call for the separate collection of filtrate. For example, the plate of open-bottom wells is particularly useful in performing intermediate washings. As used herein, “collection plate” and “receiving plate” are used synonymously and interchangably, with either term referring to a plate, intended for placement beneath a drip-director array, having either open-bottom wells or closed-bottom wells, as appropriate for the task at hand. Where the separate collection of filtrate is to take place, it is understood that the wells are of a closed-bottom type. Optionally, a collection plate having open-bottom wells may be formed without vent features (such as 28), as the vacuum can flow directly down and out through the bottom of each well. - A cross-flow restrictor (also referred to as an aerosol guard), denoted as30, which is generally pervious to gases but substantially impervious to aerosols, is interposed between the upper surface of
collection plate 24 and the lower surface of drip-director plate 14. In the illustrated embodiment,cross-flow restrictor 30 has a plurality of passages, such as 32, arranged in an array complementing the collection-well and drip-director arrays.Passages 32 permit filtrate to pass from eachdrip director 16 to a corresponding collection well 26. In the illustrated arrangement, eachdrip director 16 extends through a respective passage. Except for such passages,cross-flow restrictor 30 substantially fills the area between the confronting faces of the drip-director and collection-well plates (14, 24). - Preferably, means are provided for supporting the assembled mini-column and drip-director plate arrangement, and assisting in the formation of an airtight seal between this arrangement and the
lower vacuum chamber 29. In the illustrated embodiment, a rectangular carriage frame, denoted as 38, is configured to support the mini-column and drip-director plate assembly.Clamps frame 38.Clamps frame 38, with a lowerperipheral edge 40 of the column and drip-director plate assembly pressed against agasket 42 disposed on the upper surface offrame 38 about the frame's central opening. - A spring-loaded centering pin, such as37 and 39, may extend through each
clamp pin 37 has a shank that is urged by aspring 41 to sit within a complementary recess ordepression 43 formed in a sidewall ofcolumn plate 10. In another embodiment (not shown), three spring-loaded centering pins are employed, with two pins located at positions on a long side of the arrangement and one pin located at a position on a short side, together operable to push the tray against a corner. In this way, the components can be readily centered (on axis). - A stepped gasket, indicated generally at44, is disposed adjacent a lower surface of
frame 38 about the frame's central opening.Gasket 44 has (i) an upper, inwardly projecting flap portion, denoted as 44 a, having a lower surface adapted to engage an upwardly projectingridge 48 disposed about the periphery ofcollection plate 24, and (ii) a lower flap portion, denoted as 44 b, that extends diagonally downward and outward for engaging anupper surface 50 surrounding the open reservoir oflower vacuum chamber 29. A central plateau region of steppedgasket 44, denoted as 44 c, is secured to frame 38 by any suitable means. For example,central plateau region 44 c can be attached using an adhesive and/or fasteners. In one embodiment,gasket 44 is interposed betweenframe 38 and a rectangular clamping frame (not shown). In this embodiment, the rectangular clamping frame is disposed adjacent theplateau region 44 c ofgasket 44, on a side ofgasket 44opposite frame 38. The clamping frame is then snugly secured to frame 38 using threaded fasteners that pass through aligned passages (not shown) formed in the clamping frame and gasket, and are received in internally threaded bores extending partially intoframe 38 from the frame's lower surface. Together,upper gasket 42 andlower gasket 44 assist in forming substantially airtight seals between (i) the upper microfiltration well assembly and the carriage frame, and (ii) the carriage frame and the lower vacuum chamber assembly, respectively. - The gaskets (21, 42, and 44) may be formed of any deformable, resilient, substantially inert material capable of forming a seal. Examples of such materials are silicone, rubber, polyurethane elastomer and polyvinyl chloride. The thickness of each gasket is not critical, provided only that it is sufficient to form a seal. Typical gasket thicknesses will range from about 1 mm to about 5 mm.
- Once appropriate airtight seals are formed, evacuation of
lower vacuum chamber 29 establishes a substantially uniform pressure drop over all of thesample wells 18, permitting a plurality of individual samples (e.g., up to ninety-six in the illustrated embodiment) to be processed simultaneously on the membrane of choice. - Those skilled in the art will recognize that the choice of filter medium will depend on the intended use of the well. For example, the filter medium might serve as a size exclusion filter, or it could serve as a solid phase interacting with a species in the liquid phase to immobilize such species upon contact, such as an immunological interaction or any other type of affinity interaction. Examples of suitable filters include, but are not limited to, those of nitrocellulose, regenerated cellulose, nylon, polysulfone, glass fiber, blown microfibers, and paper. Suitable filters are available from a variety of sources, e.g., Schleicher & Schuell, Inc. (Keene, N.H.) and Millipore Corp. (Bedford, Mass.).
- Additional examples of suitable filters include microfiber filters of ultra-pure quartz (SiO2), e.g., as manufactured by Whatman, Inc. (Tewksbury, Mass.) and sold under the trademarks QM-A and QM-B. QM-A filters are about 0.45 mm thick and retain particles of about 0.6 μm. QM-B filters are of the same composition as QM-A, but are two times thicker and therefore provide a longer tortuous path to flow. In one embodiment, a quartz or glass filter element is fired (e.g., at about 400° C.) prior to placement in a microfiltration well in order to reduce particle generation, thereby reducing the potential for clogging of the drip directors.
- In another embodiment the filter medium is a porous element that acts as a frit, serving to contain a column packing material (e.g., reversed-phase or size-exclusion packings).
- Certain aspects of the invention that address the aforementioned problems pertaining to (i) cross-contamination due to wicking across a common filter sheet and (ii) individual filter elements entrapping sample constituents within substantial dead volumes will now be described in greater detail.
- One microfiltration well from the sectional view of FIG. 3 is shown in enlarged detail in FIG. 4.
Mini-column 12 anddrip director 16 are axially aligned and mated, with an upwardly protruding portion ofdrip director 16 snugly received within the lower region of the mini-column lumen to form a substantially fluid-tight well 18. - Means are provided for holding the drip director and mini-column together. In one embodiment, ultrasonic welds or bonds (not shown) formed along an annular region of contact, as designated in FIG. 4 by the
reference numeral 48, holdmini-column 12 anddrip director 16 together. It should be appreciated that such a weld or bond helps to ensure a fluid-tight interface between these elements. In another embodiment, themini-column 12 anddrip director 16 are held together by a tongue-in-groove arrangement (not shown) formed along confronting surfaces ofplates - Means are provided for holding each individual filter element within a respective assembled microfiltration well. In this regard, each filter element is disposed within the mini-column lumen so that a portion of its peripheral edge is held between (i) a constricted-diameter region within the lower portion of the mini-column and (ii) an upper portion of the drip director. The central region of the filter element extends fully across the mini-column lumen.
- In the embodiment of FIG. 4,
mini-column 12 is formed with abore 12 a and acounterbore 12 b, the latter extending upwardly from the mini-column's lower end orlip 12 c. Between thebore 12 a andcounterbore 12 b, lies a transition region. The transition region provides a constricted-diameter region, or shoulder, within the mini-column lumen capable of cooperating with an upper portion of a corresponding drip director to maintain the filter element in place. The junctions of the transition region with the bore and counterbore may be of any suitable shape. For example, such junctions could take the shape of a hard angle or corner, or alternatively, they could take the shape of a smooth curve. Further, the transition region itself, between such junctions, may be of any shape, e.g., flat, curved, stepped, or any combination thereof, provided only that a suitable constricted-diameter region is provided in the mini-column lumen for contacting an upper edge region of the filter element. - In one preferred embodiment, depicted in FIG. 4, the transition region between bore12 a and
counterbore 12 b defines an internal, annular shoulder, denoted as 12 d. In this embodiment, each of the junctions ofshoulder 12 d with bore 12 a andcounterbore 12 b defines a hard angle or corner. Between such junctions, theshoulder 12 d takes the form of an annular wall having a substantially constant taper, with a decreasing circumference along the direction fromcounterbore 12 b to bore 12 a. Longitudinally, the surface ofshoulder 12 d is oblique to the surfaces ofbore 12 a andcounterbore 12 b. Preferably, the surface ofshoulder 12 d forms an acute angle with a plane perpendicular to the mini-column's central axis and extending through the junction ofshoulder 12 d withcounterbore 12 b. In one embodiment, this angle, denoted as a in FIG. 4, falls within the range of about 30-85 degrees; and is preferably within the range of about 60-85 degrees. - Drip-
director 16 is configured to facilitate elution of a mobile phase from the well by funneling it toward a lower opening. In the embodiment of FIG. 4,drip director 16 includes (i) an annular edge or rim 16 a disposed above the plane of the upper surface of drip-director plate 14, (ii) dependingconvergent sidewalls 16 b, and (iii) a downspout oroutlet port 16 c disposed below the plane of the lower surface of drip-director plate 14. The downwardly sloping, inner surface of theconvergent sidewalls 16 b, betweenrim 16 a andoutlet port 16 c, defines a conical and/or horn-shaped cavity at the lower region of the well lumen. - As previously mentioned, an upper portion of
drip director 16 provides supporting structure adapted to abut a lower peripheral edge region of the filter element. In the embodiment of FIG. 4, such structure takes the form of upper,annular rim 16 a. The surface area of the uppermost region ofrim 16 a (i.e., the portion ofrim 16 a that directly confronts, and is available to support, the lower peripheral edge region of the filter element) may vary. In one preferred embodiment, the uppermost region ofrim 16 a defines a narrow circular line. In this embodiment, the contact betweenrim 16 a andfilter element 8 a is tangential in nature. That is, the region of contact betweenrim 16 a andfilter element 8 a defines a very thin, circular line.Rim 16 a contacts no more than about 15%, and preferably less than about 10%, and more preferably less than about 5% of the bottom surface area of thefilter element 8 a. - In the illustrated embodiment, the peripheral edge region of
filter element 8 a is preferably pinched or compressed betweenshoulder 12 d and rim 16 a in a manner effective to secure the filter element in place and to press its circumferential side-edge against the inner surface of the column lumen. This arrangement discourages upward or downward movement of the filter element and prevents leakage around its edges. - FIG. 5 is a partial side-sectional view showing a microfiltration well constructed in accordance with one preferred embodiment of the invention.
Filter element 8 a is compressed between drip-director rim 16 a andmini-column shoulder 12 d such that the membrane is securely held in place. Further, the compression fit causes the outer circumferential side-edge region of the filter element to press against the inner wall of the column lumen in a manner effective to avoid any bypassing of fluid around the edges of the filter element.Shoulder 12 d extends into the mini-column lumen at an angle α of about 45 degrees. Further, the uppermost surface area ofrim 16 a is minimal, approaching that of a circular line, so that only the outermost perimeter of the filter element's lower surface is in contact therewith. - With continued reference to FIG. 5, both the compression and the dead volume have been estimated for a filter element in one such microfiltration well using the computer-aided engineering package “Pro/ENGINEER” (Release 18), by Parametric Technology Corporation (Waltham, Mass.). The membrane compression for a 950 μm thick QM-B (Whatman, Inc., Tewksbury, Mass.) filter element having a diameter of 6.88 mm is estimated to be only about 2.6 μl (
area 52 in FIG. 5), and the dead volume for such a filter element is estimated to be only about 3 μl (area 54 in FIG. 5). - Beneath the
filter element 8 a, the inner surface of theconvergent sidewalls 16 b ofdrip director 16 define a cavity. The cavity is configured to expose the great majority of the filter element's lower surface to open, or free, space. By providing such free space below thefilter element 8 a (i.e., volume between the drip director'sconvergent sidewalls 16 b and the lower surface of the filter element), preferential flow pathways are avoided. - In another embodiment, to prevent sagging or dislodgement of the filter element into the cavity, the invention provides structure for supporting central points or regions of each filter element. For example, a support buttress may be disposed within the cavity of
drip director 16 to provide a resting point, edge or surface for one or more centrally located regions of the filter element's lower surface. Here, the term “central” refers to those portions of the filter element that are located radially inward of the filter element's peripheral edges; and particularly to those portions that are not held or pinched between a constricted-diameter region in a mini-column and an uppermost rim of a drip director. In a preferred embodiment, the uppermost region of such supportive structure is substantially co-planar with the uppermost portion of the drip-director rim. It should be appreciated that such structure prevents downward sagging or dislodgment of the filter element into the cavity. This is particularly advantageous in connection with filter elements lacking in substantial mechanical strength and/or rigidity. - In one preferred embodiment, shown in the exploded view of FIG. 6, such supportive structure takes the form of three fin-like support buttresses, denoted as58 a-58 c, positioned radially and spaced equidistantly within the cavity of drip-
director 16 aboutcentral outlet port 16 c. It should be appreciated that any other reasonable number of support buttresses, e.g., 4 or 6, may be employed instead. Small portions of the lower surface offilter element 8 a rest on top of elongated, narrow, uppermost surfaces or edges of the support buttresses 58 a-58 c. Preferably, the support buttresses 58 a-58 c are configured to support the filter element without introducing substantial dead volume or preferential flow in the system. In this regard, the top of each support buttress, proximate the filter element, may be curved, arched, or angled so that the region of contact between thefilter element 8 a and each buttress is substantially along a line (i.e., tangential in nature). Further, the profile of each support buttress is narrow and streamlined along the direction of fluid flow. - In the illustrated embodiment, the support buttresses58 a-58 c are formed integrally with the
drip director 16. Alternatively, a plurality of discrete support-buttress arrangements (not shown), formed independently of the flow directors, may be removably positioned or permanently affixed within respective drip directors. - Advantageously, the invention also provides a very efficient and cost-effective method for manufacturing the apparatus described herein. According to one embodiment, a sheet of filter material is positioned between a first plate, having a mini-column formed therein into which a sample can be placed, and a second plate having a discharge conduit, or drip director, with an outlet through which sample may egress. The plates are positioned so that the mini-column is axially aligned with the drip director. The plates are then pressed together so that an upwardly protruding portion of the drip director is snugly received within the lower region of the mini-column lumen. During the latter operation, a flow pathway is formed, extending from within the mini-column to the outlet of the drip director. Also during the compression step, a piece of filter media is cut from the sheet and positioned across a section of the flow pathway within the mini-column.
- The method of the invention is particularly advantageous for constructing a multi-well microfiltration apparatus as detailed above. Therefore, the method of the invention will now be described with reference to the illustrated apparatus.
Filter sheet 8 is interposed between the confronting surfaces ofcolumn plate 10 and drip-director plate 14, as shown in FIG. 2. Theplates corresponding drip director 16. Theplates annular rim 16 a of eachdrip director 16 acts as a die to punch out a piece offilter media 8 a (e.g., in the form of a disc) from the filter sheet. Furthermore, compressing thedrip director 16 against themini-column 12 secures the filter element in place within the mini-column lumen. As a result, an outer, peripheral edge portion offilter element 8 a is pinched between an upper,annular rim 16 a ofdrip director 16 and an internal,annular shoulder 12 d ofmini-column 12. Thedrip director 16 andmini-column 12 are then secured together by any suitable means. For example, an ultrasonic weld or a tongue-in-groove arrangement can hold the mini-columns 12 anddrip directors 16 together, as discussed above. - A further aspect of the present invention pertains to a multi-well microfiltration arrangement that provides for the flow of filtrate out of each well, while avoiding cross-contamination due to aerosols or splattering.
- As previously described, the collection-well array corresponds to the drip-director array, with each drip director disposed directly over a receiving or collection well. The collection-well plate, in turn, is adapted to fit within an open reservoir of a lower vacuum chamber, with the collection wells extending down into the reservoir. Upon establishing a suitable vacuum in the lower chamber, filtrate will flow from each microfiltration well and into corresponding collection wells. In accordance with this aspect of the invention, means are provided for discouraging filtrate-associated aerosols and residues present at any one well from traveling to, and potentially contaminating neighboring wells. Such means can include, for example, a cross-flow restrictor, also referred to as an aerosol guard, comprised of a substantially aerosol-impervious material, interposed in the region between the upper surface of collection plate and the lower surface of drip-director plate. While limiting the passage of aerosols and filtrate-associated residues, the cross-flow restrictor is adapted to permit a vacuum to be drawn therethrough.
- With particular reference to the embodiment of FIGS. 2 and 3, a sheet-
like cross-flow restrictor 30 is provided with an array ofpassages 32 complementary to the collection-well and drip-director arrays that permit filtrate to pass from each microfiltration well 18 to a corresponding collection well 26. Except for such passages,cross-flow restrictor 30 substantially fills the area between the confronting faces of the drip-director and collection-well plates (14, 24). In this way, well-to-well movement of aerosols over thecollection plate 24 is substantially blocked. Consequently, the risk of cross-contamination presented by aerosol movement is substantially reduced. Additionally, aerosols formed at any one collection well that inadvertently pass through the cross-flow restrictor (i.e., those that are not effectively blocked or trapped) will be pulled by the vacuum source through anadjacent aperture 28 down to the region belowplate 24 without passing over the openings of neighboring collection wells, as described more fully below. - Embodiments of the present invention contemplate attachment of the cross-flow restrictor to the upper face of the collection-
well plate 24 or to the lower face of the drip-director plate 14. Such attachment may be made by any suitable means, e.g., using fasteners, welds and/or one or more adhesives, such as tapes, gums, cements, pastes, or glues. Instead of attaching the aerosol guard to a plate, the aerosol guard may simply be sandwiched between the confronting surfaces of the plates and maintained in place, for example, by frictional and/or compressive forces. - The aerosol guard may be formed as a single sheet, e.g., about 0.10″ to 0.15″ thick, or, alternatively, it may be formed of two or more sheets, e.g., each about 0.060″ to 0.065″ thick, arranged in layers. In one preferred embodiment, a single-layer aerosol guard made of a porous hydrophilic polymer having compliant characteristics, such as ethyl vinyl acetate (EVA) or the like, is attached to the lower face of the drip-director plate using a pressure sensitive adhesive. Another embodiment contemplates a multi-layered construction, including: (i) a conformant layer comprising a foam pad, about 0.062″ thick and having a pressure sensitive adhesive on both faces, and (ii) a porous, UHMW (ultra-high molecular weight) polymer layer, about 0.062″ thick, that is permeable to air but substantially impermeable to aerosols. In this latter embodiment, the conformant layer is attached to the lower face of the drip-director plate and then the UHMW polymer layer is attached to the conformant layer.
- Other materials (i.e., hydrophobic, non-polymeric, etc.) may be used in forming the compliant aerosol guard of the present invention, provided only that the material(s) effectively limits the passage of aerosols, while permitting the drawing of a vacuum therethrough.
- In another embodiment, the means for avoiding cross-contamination due to the well-to-well movement of aerosols includes vents or
apertures 28 extending through the surface ofcollection plate 24. In one preferred embodiment, at least one such aperture is disposed near each collection well. It should be appreciated that a reduced pressure applied from below the plate will extend through the apertures to the microfiltration wells. - Any number and spatial configuration of apertures may be utilized, provided only that the region between each drip-director outlet and corresponding collection well is disposed in fluid communication (i.e., permissive of a vacuum) with the region below the collection plate along a pathway that does not pass over the openings of neighboring wells. For example, an aperture may be provided centrally within a group of four wells, with the wells being disposed about the corners of a quadrilateral. By providing 24 of such 4-well groupings, each well of a standard 96-well arrangement could be provided with a vent or aperture adjacent thereto. Alternatively, the number of apertures may equal or exceed the number of collection wells, with each well having one or more closely associated apertures proximate thereto. For example, a 96-well collection plate could be provided with at least 96 apertures arranged so that each well has at least one closely-associated aperture. In this regard, the apertures may be laid out, for example, in a 12×8, or 13×9, regular rectangular array.
- As previously noted,
apertures 28 permit fluid communication between the regions above and below the collection-well plate 24. Upon evacuatinglower vacuum chamber 29, a vacuum will be established reaching fromexit port 51 to the region between each microfiltration well and a corresponding collection well. Particularly, the vacuum will pull along flow pathways extending from each microfiltration well 18 into the interface region between the confronting surfaces of drip-director plate 14 and collection-well plate 24. The vacuum flow pathways then will cross downward through the collection plate'ssurface 25, by way ofrespective vents 28, to the open reservoir ofchamber 29. Here, the vacuum flow pathways will extend along the lower chamber until reachingexit port 51. Large, blackened arrows illustrate exemplary vacuum flow pathways in FIG. 3. Advantageously, aerosols and filtrate residues that become entrained in the vacuum flow are largely directed away from each collection well area and out of the system without passing over neighboring collection wells. Also, it should be appreciated that the vacuum pathways are directed in such a manner as to encourage a flow that is largely downward and laminar in nature. Cross-flow, and thus turbulence, is greatly minimized compared to most conventional arrangements. - The illustrated embodiments show a
cross-flow restrictor 30 used in combination with a vented collection-well plate 24, as just described. Notably, thecross-flow restrictor 30 covers theapertures 28, so that a vacuum pathway extending from the region between each microfiltration well 18 and corresponding collection well 26 to the region below the collection-well plate 24, via anearby aperture 28, must pass through thecross-flow restrictor 30. Since thecross-flow restrictor 30 allows a vacuum to be drawn therethrough, but discourages the passage of aerosols, filtrate-associated aerosols are substantially separated (i.e., filtered out by the cross-flow restrictor) from the drawn vacuum and, thus, the potential for well-to-well movement of aerosols over the collection plate'ssurface 25 is even further reduced. - Instead of utilizing a unitary cross-flow restrictor for a plurality of drip directors and collection wells (e.g., a sheet having a plurality of circular perforations extending therethrough), as described above and shown in the accompanying drawings, an alternative embodiment contemplates a plurality of individual collar or skirt-like cross-flow restrictors. In horizontal cross-section, such individual cross-flow restictors can be of any suitable shape, e.g., annular, elliptical, oblong, etc. In one embodiment, each individual cross-flow restrictor co-axially and laterally surrounds the region between one drip director and a corresponding collection well. Such cross-flow restrictors can be formed of a substantially rigid material, e.g., like that of the drip-director plate, or they can be formed of a compliant, porous hydrophilic material, e.g., a polymer such as ethyl vinyl acetate (EVA) or the like. In one embodiment, a plurality of substantially rigid, annular or elliptical cross-flow restrictors are integrally molded with one of the trays, e.g., depending from the lower surface of the drip-director plate and extending down toward the collection-well plate, about respective drip directors. Further, each such rigid cross-flow restrictor is configured to allow a vacuum drawn from beneath a collection plate, situated under the drip-director plate, to extend to the region proximate the encircled drip director. In this regard, each cross-flow restrictor can be configured to encompass, in addition to a corresponding collection well, an adjacent aperture leading to the region below the collection plate. That is, the cross-flow restrictor can extend around both a corresponding collection well and an adjacent aperture. In an alternative embodiment, the cross-flow restrictor extends only around its corresponding collection well. That is, the cross-flow restrictor does not additionally encompass an adjacent aperture. Rather, in this embodiment, a small through-hole formed in the cross-flow restrictor, proximate the aperture, permits fluid communication between the aperture and the region proximate the drip director. It should be appreciated that, like the previously-described sheet-
like cross-flow restrictor 30, the individual cross-flow restrictors shield against filtrate spattering and undesirable lateral movement of aerosols across the upper surface of the collection-well plate that can result in cross-contamination. - As previously mentioned, it is noteworthy that the vacuum flow pathways established between the regions above and below the collection-well plate, in all of the embodiments described herein, are routed in a manner that encourages a largely laminar and downward flow (including any entrained gases and/or aerosols). Compared to most conventional arrangements, horizontal flow over the upper surface of the collection-well plate is greatly minimized. Not only is this the case in the regions proximate the microfiltration and collection wells, but it is also the case for the peripheral-edge regions of the plates. In this regard, and with particular reference to the embodiment of FIG. 3, the contact between the inwardly extending
flap 44 a of steppedgasket 44 and the top ofridge 48 of the collection-well plate 24 is such that airflow therebetween is obstructed or baffled. Thus, upon evacuating thelower vacuum chamber 29, gases located above the steppedgasket 44, in the region denoted byarrow 46, will be drawn into the lower vacuum chamber viavent 28. Gases in the space under the lower surface of steppedgasket 44, denoted generally by thearrow 47, on the other hand, will be drawn into the lower vacuum chamber via agap 49 provided between the collection-well plate and thesurface 50 aboutvacuum chamber 29. By limiting the extent of horizontal airflow across the collection-well plate in this way, turbulence resulting from cross flow along the periphery of the arrangement is minimized. - An additional means for avoiding cross-contamination due to well-to-well movement of aerosols, as well as filtrate splattering, relates to the positioning of each drip director's lower opening relative to the upper rim, or lip, of a corresponding collection well. According to this feature, the
outlet port 16 c of eachdrip director 16 extends downwardly from the drip-director plate 14 so as to enter into a corresponding collection well 26. In this regard, the lower portion of eachdrip director 16 has a diameter that enables it to register with the open top of a corresponding collection well 26 in thecollection plate 24. As shown in the embodiment of FIG. 3, theoutlet port 16c of eachdrip director 16 is situated below the upper rim or lip of a corresponding collection well 26. By placing theoutlet port 16 c at a region that is laterally surrounded by the inner sidewalls of the collection well 26, much of the aerosol generated during filtration will impact upon the collection-well walls, as opposed moving laterally over toward a neighboring collection well. As an additional advantage, such placement of the drip-director outlets helps to reduce filtrate splattering. - In a related aspect, the present invention provides a method for avoiding cross-contamination due to well-to-well movement of aerosols in a multi-well microfiltration system. According to one embodiment, the method includes the steps of:
- (i) providing an array of microfiltration wells (containing fluid samples) over a collection-well tray supporting a corresponding array of collection wells;
- (ii) drawing a vacuum along flow pathways extending (a) from each microfiltration well (b) downward through a plane defined by an upper surface of the collection tray at a point at, or adjacent, a corresponding collection well (c) to a region beneath the collection tray, thereby causing a filtrate to flow from each microfiltration well and into corresponding collection wells; and
- (iii) obstructing aerosols formed from the filtrate at any one microfiltration well from moving across the upper surface of the collection tray to a non-corresponding collection well, thereby limiting cross-contamination.
- It should be appreciated that the apparatus described above is particularly well suited for carrying out this method. For example, a vacuum chamber, such as
lower chamber 29 shown in FIG. 3, may be connected to a low pressure source, such as a vacuum pump (not shown), for establishing a pressure differential acrossfilter elements microfiltration wells 18. The reduced pressure, then, will cause filtrate to emanate fromdrip directors 16.Aerosol guard 30 provides a means to limit filtrate-associated aerosols formed from the filtrate at any one microfiltration well 18 from moving across theupper surface 25 of collection-well plate 24 to a neighboring collection well.Apertures 28, extending through thesurface 25 ofcollection plate 24, permit the vacuum to extend between each microfiltration well and the region below the collection-well plate 24 without having to pass over the openings of neighboring collection wells. - When evacuating the lower chamber, it is advantageous to slowly change (ramp) the pressure to a desired value, combined with the utilization of very low pressures (e.g., less than about 2 psi, and preferably less than about 1 psi), in to further reduce the potential for cross-contamination, as by aerosols. For example, in going from ambient pressure to a value within the range of about 0.75 to about 2 psi, a ramp period of about 2-3 seconds is employed.
- Another aspect of the present invention pertains to a multi-well microfiltration arrangement that provides for the flow of filtrate from each well, while avoiding cross-contamination due to pendent drops which may adhere to the drip directors of the various microfiltration wells. As previously mentioned, such pendent drops can fall into neighboring collection wells when moving the drip-director plate over the collection-well plate.
- According to one embodiment, a microfiltration well is evacuated in the direction of its upper opening, thereby pulling any pendent drops of fluid hanging from its drip director back up into the well. To accomplish the evacuation, a pressure control source, e.g., a vacuum pump, in communication with an upper region of the mini-column is operable to evacuate the mini-column in the direction extending from the drip director to the upper opening.
- Another embodiment provides for “touching off” the tips of the drip directors to remove pendent drops of filtrate that might hang off of the drip directors. In this regard, the drip director outlets of all the microfiltration wells are simultaneously brought into contact with the inner sidewalls of corresponding collection wells.
- Means are provided for effecting relative motion between the drip-director plate and the collection-well plate for simultaneously moving the discharge conduits into and out of contact with inner walls of respective collection wells. In one embodiment, such means are operable to shift the collection-well plate along a plane substantially orthogonal to the longitudinal axes of the microfiltration wells, while the microfiltration wells themselves are maintained in a substantially fixed position. In another embodiment, the means for effecting relative motion are operable to shift the microfiltration wells along a plane substantially orthogonal to the longitudinal axes of the collection wells, while the collection wells are maintained in a substantially fixed position.
- An exemplary arrangement for effecting relative motion is depicted in FIGS. 7 through 10. With initial reference to FIGS. 7 and 8, an L-shaped carriage, as denoted by the
reference numeral 60, is provided with acentral opening 62 configured to receive and support a multi-well microfiltration assembly, indicated generally as 6, from above. Belowcarriage 60, acollection plate 24 having an array ofcollection wells 26 is supported in a lower vacuum chamber (not shown). -
Carriage 60 is mounted on a pair of parallel longitudinal carrier rails for reciprocal linear motion along a first, substantially horizontal, axis. In the illustrated embodiment, one of the carrier rails is a linear bearing rail, denoted as 64, which supports thecarriage 60 via an interposed linear bearingmember 65 attached to the lower surface of thecarriage 60 toward one lateral edge. The other carrier rail is a U-shaped bearing guide, denoted as 66, that receives abearing wheel 68, extending laterally outward from the other edge of thecarriage 60, in an elongated track or slot 66 a. -
Carriage 60 is moved along therails flexible belt 70 having its ends attached at each longitudinal end of aU-shaped bracket 74 forming a part of a spring-loaded motion-control mechanism 72, described more fully below.Belt 70 is passed around a driven 76 roller and anidler roller 78, disposed proximate longitudinally opposing ends of the carrier rail arrangement. To prevent against slippage, the belt may be provided withteeth 70 a adapted for mating engagement with complementary sets ofteeth - Driven
roller 76 is in mechanical communication with a motor, such as 82, through a power train assembly, as indicated generally by thereference numeral 84. Whenmotor 82 is energized,belt 70 will move, causingcarriage 60 to slide along the carrier rails 64, 66, with the direction of movement depending on the rotation of the drive shaft 86 extending frommotor 82.Motor 82 may be of any suitable, known type, e.g., a stepper motor, servo motor, or similar device. - One preferred embodiment of the present invention contemplates the use of a stepper motor to move belt. By way of background, a stepper motor is a specialized type of motor that moves in individual steps. Unlike servo motors, the position of a stepper can be determined without the need for expensive encoders to check its position. Stepper motors are much more cost-effective than servo systems due to their simplified control and drive circuitry. There are no brushes to replace in a stepper motor, reducing the frequency for maintenance. Owing to their ease of use and relatively low cost, steppers are often preferred over servo motors for many modern computerized motion control systems.
- According to this embodiment of the invention, a control system is provided to operate the stepper motor in a desired fashion. For example, a microcontroller, such as a Motorola 68332, may be utilized to control the motor using conventional techniques.
- As previously noted, stepping the
motor 82 causesbelt 70 to move aroundrollers belt 70, in turn, causescarriage 60 to slide alongguide rails drip director array 16 laterally with the respect to thecollection well array 26. If thedrip directors 16 are positioned so that they extend intorespective collection wells 26, sufficient stepping in a given direction will cause thedrip directors 16 to engage the upper, inner surfaces of thecollection wells 26, as shown in the sectional views of FIGS. 9(A)-9(C). In this way, pendent drops of filtrate hanging from thedrip directors 16 are “touched off” to the inner surfaces ofrespective collection wells 26. Similarly, upon reversing the stepping direction, thedrip directors 16 can be moved to engage the upper, inner surfaces on the opposing side of thecollection wells 26 to further ensure effective touching off of pendent drops. - As previously mentioned, alternative embodiments of the invention contemplate the use of a servo motor to move the belt. In one such embodiment, a means for providing positional feedback, such as an encoder (not shown), is provided in order to track the position of the servo motor.
- Carriage additionally supports means for moving and positioning the
microfiltration arrangement 6 along a second, generally vertical, axis. With particular reference to the embodiment of FIG. 7, a vertical-positioning mechanism is disposed on the upper surface of carriage along each lateral side of the microfiltration arrangment. Each vertical-positioning mechanism includes (i) lift springs, such as 92, that provide a continuous, upwardly-directed force tending to raise themicrofiltration arrangement 6 to an elevated position whereat thedrip directors 16 fully clear the upper lips of thecollection wells 26, and (ii) fluid cylinders, such as 94, that are operable to lower themicrofiltration arrangement 6, against the force of the lift springs 92, to a seated position whereat eachdrip director 16 extends into the upper region of a respective collection well 26. At its fully seated (lowered) position, themicrofiltration arrangement 6 forms a seal with the lower vacuum chamber (not shown). - Both the
springs 92 and thefluid cylinders 94 engage, at their upper ends, handles, denoted as 96, that extend upwardly and outwardly from each lateral side of the microfiltration arrangement's supportingframe 38. In one embodiment, the spring/cylinder arrangements are operable to hold the microfiltration arrangement at any one of three positions: (i) an up or travel position, (ii) a touch-off position, and (iii) a down or seal position. - The touch-off operation may be carried out with the
microfiltration arrangement 6 disposed at any position along the second (vertical) axis, provided only that thedrip directors 16 extend at least partially down into thecollection wells 26. In one embodiment, touching off of thedrip directors 16 to the inner sidewalls of thecollection wells 26 is effected with themicrofiltration arrangement 6 slightly raised above its fully seated position so that the lowermost regions of thedrip directors 16, proximate theiroutlets 16 c, will abut the inner surfaces of thecollection wells 26. - The region of each
drip director 16 proximate its outlet may be shaped, e.g., angled or chamfered about its lower circumference, to promote the localization of any pendent drops of filtrate to certain regions of thedrip director 16 and to optimize contact between such regions with the inner sidewall of a corresponding collection well 26 during touch off. Similarly, the upper region of each collection well 26 may also be shaped, e.g., in a manner complementary to (i.e., matching) a shapeddrip director 16, so that adequate contact is made between these elements during touch off for substantially ridding thedrip director 16 of any pendent drops of filtrate. In one preferred embodiment, as can be seen in FIGS. 9A-C, the upper, region of each collection well is formed with an outwardly angled inner sidewall that matches an inwardly angled outer surface along the lower region of a corresponding drip director, thereby providing a substantial abutting surface between these elements during a touch-off operation. - As previously described, the discrete quantity of angular rotation imparted to shaft86 each
time stepper motor 82 is stepped is ultimately translated into a given length of linear movement bybracket 74. For example, stepping themotor 82 once may causebracket 74 to move ¼″ in a particular direction. It should be appreciated that the minimum number of steps required ofstepper motor 82 to effect a touch off may cause thedrip directors 16 to move farther than what is necessary. That is, thedrip directors 16 might be moved into engagement with the inner walls of thecollection wells 26, with continued pressure to move beyond the inner walls. As described next, such linear overshoot can be advantageous, as it can assist in the removal of pendent drops. It should be appreciated that it is desirable to move the drip directors to a suitable position against the collection-well sidewalls (e.g., in firm abutment with the sidewalls) in order to effectively encourage the removal of pendent drops. By providing a suitable amount of linear overshoot into the sideward movement of the drip directors, such positioning can be ensured (i.e., the drip directors will not fall short of the sidewalls), notwithstanding various minor positional inaccuracies inherent in the arrangement. Thus, by providing for a reasonable amount of linear overshoot, the sidewalls themselves determine the final position of the drip directors. It is also desirable to keep the torque relatively low, thereby preventing cogging of the motor. Further, it is desirable to absorb or compensate for some of the linear overshoot to avoid overstressing thedrip directors 16 and/or thecollection wells 26. - In these regards, one embodiment of the invention contemplates the use of a spring-loaded motion-
control mechanism 72 in the mechanical linkage system between themotor 82 and thecarriage 60. The motion-control mechanism 72 ensures accurate positioning of the drip directors in abutment with the sidewalls, while absorbing excess linear motion beyond the amount required to shift thedrip directors 16 into contact with the inner sidewalls of thecollection wells 26. As an additional advantage, the motion-control mechanism 72 provides a damping resistance to sliding movement of thecarriage 60 along therails - In one embodiment, the motion-control mechanism includes a spring disposed such that movement of the carriage in either direction along the first axis will put the spring under compression. With particular reference to the partially schematic top plan views of FIGS.10(A)-(C), the
U-shaped bracket 74 that forms a part of the belt assembly is rigidly connected to ahousing 101 containing large and small bores, respectively indicated generally as 102 and 108.Bore 102 has a large-diameter portion 102 a and a small-diameter portion 102 b, separated by a radial step 102 c. A stepped-diameter shaft, indicated generally as 104, having a large-diameter portion 104 a and a small-diameter portion 104 b, separated by aradial step 104 c, passes throughbore 102 and rigidly attaches, at its large-diameter end, to an extended-arm portion 60 a of the L-shapedcarriage 60. Aguide pin 106, which assists in maintaining the substantially horizontal orientation ofcarriage 60, rigidly attaches to theextended arm portion 60 a ofcarriage 60 at one end and is received insmall bore 108 at its other end. Inside the large-diameter portion 102 a ofbore 102, aspring 110 concentrically mounts the small-diameter portion 104 b ofshaft 104 between a pair of spaced washers, denoted as 112 and 116. The twowashers diameter portion 104 b of steppedshaft 104.Spring 110 urges the twowashers diameter portion 104 b ofshaft 104. A fixed-position washer 114 is seated within a circumferential groove (not shown) formed in the small-diameter portion 104 b ofshaft 104 near its free end. - When
belt 70 movesU-shaped bracket 74 in the direction indicated by the arrow “A,” in FIG. 10B, bore 102 slides alongshaft 104 in a direction toward theextended arm 60 a ofcarriage 60. As a result, anannular lip 120 that extends radially inward at the end ofbore 102 acts against an annular, peripheral region ofwasher 112, causing thewasher 112 to slide along the small-diameter portion 104 b of steppedshaft 104, thereby compressingspring 110. When the compression force overcomes the pre-loaded retaining force,carriage 60 will then shift in the same direction (direction “A”). - When
belt 70 movesU-shaped bracket 74 in the direction indicated by the arrow “B,” in FIG. 10C, bore 102 slides alongshaft 104 in a direction away from theextended arm 60 a ofcarriage 60. As a result, the radial step 102 c ofbore 102 acts against an annular, peripheral region ofwasher 116, causing thewasher 116 to slide along the small-diameter portion 104 b of steppedshaft 104, thereby compressingspring 110. When the compression force overcomes the pre-loaded retaining force,carriage 60 will then shift in the same direction (i.e., direction “B”). - In one embodiment,
spring 110 provides a pre-load force of about 1 pound. Thus, the force provided by thestepper motor 82 will not be effective to move thecarriage 60 until the threshold of about 1 pound is overcome. Advantageously, the arrangement provides (i) a constant-hold mode at the center, or neutral, position, and (ii) a constant-force mode for effecting touch off. Thespring 110 provides compliance in the system, e.g., allowing touch off to start at 1 pound and end at 1.2 pounds. - With reference to the apparatus as described above, one preferred embodiment of the present invention contemplates the following steps:
- (i)
microfiltration arrangement 6 is loaded ontocarriage 60 and clamped in place; - (ii)
carriage 60 is centered over alower vacuum chamber 29; - (iii)
microfiltration arrangement 6 is lowered to its seated position (e.g., by retracting fluid cylinders 94) and sealed over thelower vacuum chamber 29; - (iv) a robot (not shown) lowers
upper vacuum chamber 20 against the top ofmicrofiltration arrangement 6 and, optionally, applies a downward force, e.g., about 5 pounds, to the stacked arrangement; - (v)
lower vacuum chamber 29 is evacuated (e.g., at about 0.5-3 psi) to effect elution/purification; - (vi)
carriage 60 is raised slightly from its fully seated position to a touch-off height whereat only the lowermost regions of thedrip directors 16 extend below the upper lips of thecollection wells 26; - (vii)
motor 82 is stepped in a forward direction to touch off thedrip directors 16 to a sidewall of thecollection wells 26; - (viii)
motor 82 is stepped in a reverse direction to touch off thedrip directors 16 to the opposing inner sidewall of thecollection wells 26; - (ix) forward and reverse stepping of
motor 82 is repeated to perform each of the touch-off steps once more; - (x)
carriage 60 is re-centered overlower vacuum chamber 29; - (xi)
microfiltration arrangement 6 is lowered to its seated position and sealed overlower vacuum chamber 29; - (xii) optionally, the robot can apply a downward force, e.g., about 5 pounds, to the stacked arrangement;
- (xiii)
upper vacuum chamber 20 is evacuated to effect a pull-back of pendent drops (e.g., at about 0.1-0.3 psi); - (xiv)
microfiltration arrangement 6 is raised to its fully elevated position so that thedrip directors 16 fully clear thecollection wells 26; then - (xv)
carriage 60 is moved to next station. - FIG. 16 shows an automated high-throughput
sample preparation workstation 202, including, for example, a microfiltration apparatus, cross-contamination control arrangements, as well as collection-well covering and heat-sealing assemblies (described below), and associated components and reagents, in accordance with the teachings of the present invention. As illustrated, several collection trays can be provided in adjacent vacuum chambers arranged in a side-by-side fashion near one end of the workstation. For example, a closed-bottom collection tray, such astray 24, can sit in each of the two endmost vacuum chambers, while open-bottom collection trays can sit in the two center vacuum chambers.Carriage 60 can then carry amicrofiltration arrangement 6 successively from one vacuum chamber to the next. For instance, an initial collection of filtrate can take place at the vacuum chamber holding closed-bottom collection plate 24 near the front of the workstation. Then successive washings can be carried out at each of the two center vacuum chambers whereat open-bottom collection plates are placed. Next, a final collection of filtrate can take place at the vacuum chamber near the rear of the workstation, whereat another closed-bottom collection tray is located. - With regard to spatial orientation, it should be noted at this point that the various components (e.g., upper chamber, mini-column plate, filter element, drip-director plate, frame, cross-flow restrictor, collection-well plate, and lower chamber) are illustrated and described herein as being stacked in vertical relationship, with the upper vacuum chamber being the topmost component. Further, each microfiltration well is described as having a central axis disposed in a substantially vertical fashion, with a flow pathway extending downwardly through the well. It should be noted, however, that these orientations have been adopted merely for convenience in setting forth the detailed description, and to facilitate an understanding of the invention. In practice, the invention contemplates that the components and wells may be disposed in any orientation.
- In another of its aspects, the present invention provides for the covering and sealing of multi-well trays containing fluid samples.
- In one embodiment, shown in FIGS. 11 through 14, a cover member, indicated generally by the
reference numeral 150, includes an upper shell portion, denoted generally as 154, supporting a sealing layer or undersurface, indicated generally as 156 (FIG. 11), on its lower face.Upper shell portion 154 is comprised of a substantially planar expanse 158 (FIGS. 12 and 13) and a dependingcircumferential sidewall 160 laterally surroundingundersurface 156. Along the length and width dimensions,undersurface 156 is configured with generally the same geometry as the upper surface ofmulti-well plate 24, permitting it to cover the entire array ofwell openings 26 a. - As best seen in FIG. 11, undersurface includes a plurality of individual nodules, such as166, arranged in a rectangular array corresponding to the array of
wells 26 ofcollection tray 24. Each of thenodules 166 preferably has a downwardly convex, e.g., dome-shaped, lower portion, though other shapes may be used. Thenodules 166 are made of a resiliently flexible material held in a predetermined, spaced relationship from each other by a web orsheet 168.Web 168 may be integrally formed withnodules 166, as shown, or it may be formed separately, with the nodules molded or adhesively attached to the web at appropriate locations. -
Cover 150 is preferably comprised of a substantially rigid material that, when pressed down at opposing peripheral edge regions against corresponding regions ofridge 48 along the periphery ofmulti-well plate 24, can maintain an annular region of eachnodule 166 in pressing engagement with anupper lip 26 b of arespective well 26. To evenly distribute the downward force acrossundersurface 156, integral beams, such as 172 and 174, can extend laterally and/or longitudinally across the top surface ofupper shell portion 154, providing increased rigidity. -
Undersurface 156 is formed of a resiliently deformable material that, when compressed overopenings 26 a, is capable of forming a seal. Suitable materials for formingundersurface 156 include, for example, synthetic rubber-like polymers such as silicone, sodium polysulfide, polychloroprene (neoprene), butadiene-styrene copolymers, and the like.Upper shell portion 154 is formed of a substantially rigid material such as nylon, polycarbonate, polypropylene, and the like. - In one preferred embodiment, the cover of the invention is made by an injection co-molding process wherein an upper shell portion is first molded, and then a sealing undersurface is injection molded to the shell portion. A preferred nylon material useful for forming the upper shell is available commercially as ZYTEL® grade 101 (DuPont Co., Wilmington, Del.). To avoid heat-induced damage to the molded nylon shell portion, preferred silicone materials have relatively low injection and curing temperatures (e.g., less than about 180° C.). One particularly preferred silicone material useful for co-molding the undersurface is available commercially as COMPU LSR 2630 clear (Bayer AG, Germany).
- To
secure undersurface 156 toupper shell portion 154, a series of holes (not shown) are formed through the shell'splanar expanse 158. Upon injecting a liquid silicone from the bottom side of theupper shell portion 154, the silicone penetrates the holes and forms nodules, such as 180, having a greater diameter than that of the holes, adjacent the topside of theupper shell portion 154. Upon curing, the silicone contracts slightly, pulling thenodules 180 and theexpansive undersurface 156 toward one another. In this way, a snug attachment is effected at several locations holding theundersurface 156 against the lower face of theupper shell portion 154. -
Cover 150 is secured tomulti-well tray 24 by a releasable attachment means. In the embodiment of FIGS. 11-14, the attachment means includes a plurality of integrally formed, resiliently deflectable arms, such as 184, depending from opposing lateral sides ofupper shell portion 154. At an end distal fromupper shell portion 154, eacharm 184 is provided with a catch or hook 186 adapted to hold on to acircumferential sidewall 24 a formed aboutmulti-well plate 24. As best seen in FIGS. 11 and 14, eachcatch 186 is substantially formed in the shape of a half-arrow, having (i) a downwardly and outwardlyangled cam surface 186 a, and (ii) an upper shoulder or stopportion 186 b. Upon moving thecover 150 toward a seated position over thewell openings 26 a, thecam surface 186 a of eachcatch 186 slides down over thecircumferential sidewall 24 a ofcollection plate 24, thereby deflectingarms 184 laterally outward. Once theshoulder 186 b of eachcatch 186 clears thelower edge 24 b ofcircumferential sidewall 24 a,arms 184 snap inward, locking thecover 154 in a closed position, as shown in FIG. 13. - To release the snap-locked
cover 154 frommulti-well tray 24,arms 184 can be pulled outwardly, away fromcircumferential sidewall 24 a, so that eachshoulder 186 b clearslower edge 24 b. Cover 154 can then be separated from thetray 24 to reveal thewell openings 26 a. - In an alternative embodiment, shown in FIG. 15, the releasable attachment means includes a plurality of nubs or
protrusions 192 having resiliently deformableterminal bulbs 192 a depending at various points along the periphery of the lower surface ofcover 154. In this embodiment,nubs 192 are receivable withincomplementary bores 194 formed along corresponding regions of the upper surface ofmulti-well plate 24. Frictional engagement of eachbulb 192 a with an inner sidewall of arespective bore 194 holds thecover 154 in place over themulti-well plate 24. - In one preferred embodiment, best seen in FIG. 12, structure is provided along the top of
upper shell portion 154 that facilitates automated handling using a robotic fluid-handling apparatus. An exemplary robotic system is available commercially under the tradename TECAN® RSP (Tecan AG; Hombrechtikon, Switzerland). In the illustrated arrangement, the robotic system, denoted generally as 198, includes four elongated aspiration and injection fingers, denoted as 1-4, mounted on arobotic arm 200 at respective points generally defining a line.Arm 200 can translocate fingers in the x/y direction along a generally horizontal plane, throughout which the longitudinal axes of fingers 1-4 are maintained in fixed, spaced relation to each other. The longitudinal axes of fingers 1-4 are evenly spaced from about 9 mm to about 36 mm, and preferably about 18 mm, apart from one another. Each of the fingers 1-4 can be separately translocated in the z direction along a respective, generally vertical axis. Movement ofarm 200 and fingers 1-4 is preferably carried out under the control of a programmed computer (not shown) by known techniques. - The TECAN® RSP can be used, in a known manner, to transfer fluids to and from various chambers, e.g., wells of a
microplate 24,vials 206,troughs 208 and the like, disposed on a working surface, such as theworktable 202 shown in FIG. 16. Other known uses for the TECAN® RSP include, for example, reagent addition, dilution, and mixing. - As previously mentioned, the present invention provides structure along the top of
upper shell portion 154 that facilitates automated handling. Advantageously, such structure expands the capability of therobotic system 198 beyond conventional fluid-handling tasks to include novel tasks such as picking up covers, placing covers over multi-well plates, and securing the covers to the plates, as described below. As shown in the embodiment of FIG. 12, such structure can include longitudinally slotted, resiliently expandable sleeve-like members, such as 211 and 214, each adapted to receive the tip region of one of the fingers 1-4 such that the finger becomes wedged therein. Such structure further includes a plurality of landing seats, e.g., 221-224 and 212-213, defined by rimmed depressions or bores having a diameter wider than that of fingertips (1 a-4 a), providing strategic regions whereat the fingers can abut the upper surface of the cover with a reduced risk of slippage. - Generally, frictional engagement of each
sleeve fingertips 1 a-4 a permits the robot to pick up, carry and/orplace cover 150, as desired. Once suitably placed, the cover can be released by extending one or more free fingers against corresponding landing seats on the upper surface of the cover, while retracting the wedged fingertips. In an exemplary operation,fingers 1, 4 are extended downward in the z direction toward acover 150 disposed, for example, on a surface of aworkstation 202 so thatfingertips 1 a, 4 a enter and become wedged within respectiveexpandable sleeves Fingers 1, 4 are then partially retracted in the z direction, in unison, to liftcover 150 above the working surface. Next, the liftedcover 150 is translocated by movingarm 200 along the x/y direction to another area of the working surface.Fingers 1, 4 are then extended downward, in unison, in the z direction to lowercover 150 onto amulti-well tray 24 containing, for example, a plurality of separately collected fluid samples. Cover 150 is released from therobot 198 by extendingfree fingers landing seats cover 150, and retractingfingers 1, 4 fromsleeves arm 200 to a fully retracted position. - Employing a releasable attachment means, cover150, so placed, can be snap-locked to the
multi-well tray 24 by applying a downward force from above. In an exemplary operation,fingers 1, 4 are extended downward in the z direction toabut landing seats cover 150. The downward motion offinger 1 is continued against landingseat 221 so that thelocking arm 184 thereunder is moved into snapping engagement withcircumferential sidewall 24 a ofmulti-well tray 24. In the meanwhile, finger 4 is held substantially motionlessadjacent landing seat 223 in order to oppose any tendency of the cover to flip up. An appropriate downward force is then applied at landing seats over the remaining arms until all of the arms are snap-locked to the multi-well tray. - While it should be understood that the covers described herein can be employed in a wide variety of situations, they are particularly useful for protecting a plurality of fluid samples separately contained in an array of closed-bottom collection wells against evaporation and/or cross-contamination during long-term storage. For example, fluid filtrate (e.g., containing purified or concentrated nucleic acids, such as RNA or DNA) can be collected using the microfiltration apparatus of FIGS.1 to 3. The collection wells can then be sealed by snap-locking the
cover 150 of FIGS. 11-14 thereto, using a TECAN® RSP fluid-handling robot as just described. The covered multi-well tray can then be placed in a freezer for storage. The covers can be reused multiple times, if desired. - By utilizing a single robotic fluid-handling arm to carry out a variety of tasks at the workstation, valuable working space is conserved. Moreover, equipment and programming expenses are avoided by obviating the need for additional robotic devices, e.g., grippers, for picking up, moving, placing and securing covers.
- The present invention also provides for the sealing of multi-well trays with heat-sealable covers. Generally, the heat-sealing apparatus of the invention includes a pick-and-place assembly adapted to lift an individual, pre-cut, heat-sealable sheet or film from a bin and place the sheet over a plurality of well openings of a multi-well tray. A heatable platen is provided for engaging the sheet, so placed, and heat sealing the sheet to the upper surface of the multi-well plate, thereby forming a seal over each well. Advantageously, the operation is carried out in an automated fashion.
- According to one embodiment, shown in FIGS.16-24, a first, substantially planar work surface, generally denoted as 302, is positioned over a cooler, indicated generally by the
reference numeral 306. A plurality of rectangular cavities, such ascavities 310, are formed through the work surface, each adapted to support a multi-well tray therein, such astray 324, with the lower side of the tray disposed in communication with the temperature-controlled environment of cooler 306. In a preferred embodiment, four such cavities are formed throughwork surface 302. When a multi-well tray is properly positioned in one ofcavities 310, an outer circumferential edge or lip of the tray rests on a region of the surface circumscribing the cavity, with the bottom regions of the wells extending below the surface into the cooler.Cooler 306 is adapted to maintain the samples at a desired, reduced temperature (e.g., about 4° C. for fluid samples containing purified or concentrated nucleic acids, such as RNA). - Means are provided to ensure proper placement (i.e., orientation) of a multi-well tray in a respective cavity. According to one embodiment, one face of a triangular key feature, indicated as322, is rigidly attached to the
work surface 302 proximate a corner of eachcavity 310. Further, one corner of each multi-well tray is angled, as at 324 d, to sit onwork surface 302 closely adjacent the edge ofkey 322 facing thecavity 310, when the tray is properly (fully) seated. It should be appreciated that only theangled corner 324 d oftray 324 can sit onwork surface 302 adjacentkey feature 322. Iftray 324 is placed in the cavity in the wrong orientation, a non-angled corner of tray 324 (i.e., one other than 324 d) will land on the upper face ofkey 322, thereby prohibiting proper (full) seating oftray 324 in manner that will be apparent to an operator. - A second, substantially planar working surface, denoted as332, is positioned alongside
first surface 302, such that the two surfaces are substantially coplanar. A bin or tray, indicated as 336, for holding individual sheets of heat-sealable covers is held in a frame, denoted generally as 338, affixed near one end of second workingsurface 332.Tray 336 is adapted to hold a plurality of heat-sealable sheets, denoted generally as 342, vertically stacked face-to-face, such that the topmost sheet is always presented for retrieval by a suction picker assembly, denoted as 394, at substantially the same, predetermined vertical height. For example,tray 336 can rest on a spring-biased bed (not shown) adapted for vertical motion withinframe 338. -
Tray 336 is preferably formed as an integral unit using a conventional thermoforming process. In one embodiment,tray 336 is formed of a lightweight plastic material, such as PETG, or other suitable thermoplastic resinous material. As best seen in FIG. 18,tray 336 is formed with a bottom 336 a, foursidewalls 336 b, an outwardly extendingcircumferential lip 336 c, and an open top. As is well known in the art of thermoforming, it is generally necessary to provide a draft for the sidewalls of a thermoformed tray. Draft is the slight taper provided in a design of a thermoformed part that permits the part to be removed from the mold, after curing, without disturbing the part's walls. In the thermoformed tray of the present invention, the distance between opposing sidewalls of the tray slightly increases along the direction from the bottom of the tray to the top of the tray. For example, the sidewalls can be provided with a lift-out slope in the range of about 1-10 degrees. In one embodiment, the lift-out slope is about 5 degrees. - As a consequence of the draft, the planar area bounded by the tray's
sidewalls 336 b, parallel to the tray's bottom 336 a, gets progressively larger moving along a direction from the bottom 336 a to the top of the tray. To prevent shifting of the sheets (not shown in FIG. 18) held within the tray, particularly at the wider, upper regions thereof, ribs, such as 337, are provided along eachsidewall 336 b.Ribs 337 are configured to provide a substantially straight surface or edge for continuously contacting a point, and preferably plural points, on each peripheral side-edge of each sheet of a stack, throughout each sheet's range of vertical motion. Thus,ribs 337 serve to guide each sheet as it is moved vertically throughtray 336, and to ensure that each sheet is maintained in a desired orientation within thetray 336. In the illustrated embodiment,ribs 337 are provided as integrally molded, opposing pairs extending along opposing sidewalls of the tray. The ribs running along eachsidewall 336 b are sufficiently spaced apart so as to prevent the sheets held in the tray from becoming skewed. In this embodiment, eachrib 337 provides a vertically extending, elongated line or surface that is substantially normal to a plane defined by the bottom 336 a oftray 336. Due to the upwardly divergent nature of the tray'ssidewalls 336 b, theribs 337 become slightly more pronounced (i.e., they extend further outward from each sidewall's major surface) along the direction from the bottom 336 a oftray 336 to the top oftray 336. - A releasable attachment means is provided to prevent inadvertent removal of
tray 336 fromframe 338. In one embodiment, the attachment means includes resiliently deflectable arms, such as 350, extending upwardly from opposing lateral sides offrame 338. Eacharm 350 is rigidly attached near its lower end, e.g., by way offasteners 352, to a lower region offrame 338proximate work surface 332. As best seen in FIGS. 19(A)-19(B), the upper region of eacharm 350 is provided with a catch or hook 356 adapted to hold on to thecircumferential lip 336 c at the top oftray 336 when the tray is disposed in a fully seated position. Eachcatch 350 is substantially formed in the shape of a half-arrow, having (i) an upwardly and outwardlyangled cam surface 356 a, and (ii) a lower shoulder or stopportion 356 b. Upon movingtray 336 toward a seated position withinframe 338, thecam surface 356 a of eachcatch 356 slides over the outer peripheral edge oflip 336 c, thereby deflecting eacharm 350 laterally outward. Once the lip passes belowshoulder 356 b, the arms snap inward, locking the tray in the frame, as shown in FIG. 17. - To release the snap-locked
tray 336 fromframe 338,arms 350 can be bent outwardly, apart from one another, so that eachshoulder 356 b clears the outer edge oflip 336 c.Tray 336 can then be lifted out offrame 338. - An abutment, denoted as362, is rigidly secured on the upper surface of
frame 338 near each longitudinal end.Abutments 362 provide substantially vertical, confronting surfaces that guidetray 336 as it is being placed inframe 338, and that maintain the tray in a desired position while it is seated. -
Sheets 342 may be made of any substantially chemically inert material that can form a seal with the upper surface of a multi-well tray, or appropriate regions thereof (e.g., an upstanding rim or lip about the opening of each well), when applied with moderate heat (e.g., 90°-170° C.) under moderate pressure (e.g., about 10-35 lbs.). For example,sheets 342 may be formed of a polymeric film, such as a polystyrene, polyester, polypropylene and/or polyethylene film. Suitable polymeric sheets are available commercially, for example, from Polyfiltronics, Inc. (Rockland, Mass.) and Advanced Biotechnologies (Epsom, Surrey England UK). In one embodiment, each sheet is a substantially clear polymeric film, about 0.05 millimeters thick, that permits optical measurement of reactions taking place in the wells oftray 324. For example, the present invention contemplates real time fluorescence-based measurements of nucleic acid amplification products (such as PCR) as described, for example, in PCT Publication WO 95/30139 and U.S. patent application Ser. No. 08/235,411, each of which is expressly incorporated herein by reference. Generally, an excitation beam is directed through a sealing cover sheet into each of a plurality of fluorescent mixtures separately contained in an array of reaction wells, wherein the beam has appropriate energy to excite the fluorescent centers in each mixture. Measurement of the fluorescence intensity indicates, in real time, the progress of each reaction. For purposes of permitting such real time monitoring, each sheet in this embodiment is formed of a heat-sealable material that is transparent, or at least transparent at the excitation and measurement wavelength(s). A preferred heat-sealable sheet, in this regard, is a co-laminate of polypropylene and polyethylene. - Often, heat-sealable films or sheets are obtained as a web in the form of a roll. Not surprisingly, such rolls are often bulky and heavy. Moreover, the equipment required to properly cut them into a desired shape can be costly and space consuming, as well. Advantageously, the heat-sealable sheets provided by the present invention are pre-cut to appropriate dimensions, and stacked inside tray. As contemplated herein, a tray, such as336, holding a stack of
sheets 342 is packaged as a pre-assembled unit, which is readily opened and inserted intoframe 338. - A
linear track 370, supporting acarriage assembly 376, is mounted longitudinally acrosswork surface 332, adjacent to cooler 306. A reversible drive means is adapted to movecarriage 376 back and forth alongtrack 370, as desired. In the illustrated embodiment, the drive means includes anylon rail 382 having upwardly facingteeth 378 formed along its top surface, from one end to the other.Teeth 378 are adapted to mesh with a circular, externally-toothed, motor-driven gear (not shown) disposed for rotation inside the carriage housing. A flexible guide orconduit 386, as can be obtained commercially from KabelSchlepp America, Inc. (Milwaukee, Wis.), is disposed alongsiderail 382 for containing various cables and wires (not shown) of the apparatus. -
Carriage 376 supports a pick-and-place assembly, indicated generally by thereference numeral 388, and a heatable platen assembly, denoted as 412. Pick-and-place assembly 388 includes anelongated picker arm 390 supported above the carriage via arotatable mount 392 extending through an upper surface ofcarriage 376. The rotatable mount can be, for example, a driven shaft coupled to a reversible stepper motor (not shown) held within the carriage housing.Arm 390 is attached to drivenshaft 392 so as to rotate therewith.Arm 390 is adapted for movement along a generally horizontal plane between a “home” postion (FIGS. 16 and 23), a “pick-up” position (FIGS. 17 and 20), and a “dropoff” position (FIGS. 21 and 22). - The other end of
arm 390 supports a suction picker assembly, indicated generally by thereference numeral 394, adapted to pick up a heat-sealable sheet fromstack 342 held intray 336, and to place the sheet over a multi-well tray held in one of the cavities at cooler 306.Suction picker assembly 394 includes four elongated guide rods, denoted as 396 a-396 d, each supported for reciprocal sliding movement within a respective linear bearing 398 a-398 d held in a bore (not shown) extending vertically througharm 390. Rods 396 a-396 d are secured, at their lower ends, to the top of a plenum, denoted as 400. - Plenum400 can be moved up and down to a desired vertical height by way of a linear motion means. The linear motion means can be a stepper motor, such as 402, mounted on arm centrally of rods 396 a-396 d. Rotational motion of
stepper motor 402 causes alead screw 404, passing centrally throughmotor 402, to move up or down along its longitudinal axis, dependent upon the direction of rotation. The lower end oflead screw 404, in turn, is rotatably journaled toplenum 400. Thus, upon steppingmotor 402,plenum 400 will move up or down with linear movement oflead screw 404. - A plurality of suction legs, such as406 a-406 d, depend from a lower side of
plenum 400. In the illustrated embodiment, one such leg is disposed near each corner ofplenum 400. A downwardly facing suction cup, such as 408 a-408 d, is attached at the lower end of each leg 406 a-406 d. The face region of each suction cup 408 a-408 d is disposed in fluid communication withplenum 400 via a channel (not shown) extending longitudinally through a respective leg 406 a-406 d.Plenum 400, in turn, communicates with a remote vacuum source (not shown) via a suitable hose. Upon evacuatingplenum 400, a vacuum is established at the face region of each suction cup 408 a-408 d. - With additional reference to FIG. 24,
platen 412 is a multi-layered assembly, including (from top to bottom) (i) asupport plate 414; (ii) a heat-insulatinglayer 416; (iii) aheater 418; and (iv) a thermally conductive,conformable pad 420; each of which is described more fully below. -
Support plate 414 is formed of a rigid material that, when pressed down from above, is capable of transmitting the downward pressure across thevarious underlayers conformable pad 420 is pressed against the upper surface of a multi-well tray. Suitable materials for formingsupport plate 414 include metals, such as aluminum and the like. A plurality of depressions or indentations, such as 425-428, are provided along the upper surface ofplate 414, providing landing sites, or seats, for the fingers of a fluid-handling robot, such as a four-fingered TECAN® RSP, to abut and press down upon theplaten 412, as described below. - The heat-insulating
layer 416 thermally isolates theupper support plate 414, and associated elements, from heat and hot components thereunder. In one preferred embodiment, the heat-insulating material is a phenolic block. - The
heater 418 is preferably an electrically resistive heating element (not shown) disposed within a heat-conductive metallic plate, such as an aluminum plate or the like. The heating element can be, for example, a silicone rubber heater. A preferred silicone rubber heater (80 Watts, 24 Volts) is available commercially from Minco Products, Inc. (Minneapolis, Minn.). - The thermally conductive,
conformable pad 420 acts as a thermal interface between the heated metallic plate and the area along the upper surface of a multi-well plate. A preferred material for forming the pad is available commercially under the trade name Gap Pad™ from The Bergquist Company; (Edina, Minn.). Gap Pad™ is a highly conformable silicone polymer filled with alumina (See, e.g., U.S. Pat. No. 5,679,457; expressly incorporated herein by reference). The pad, attached to the underside of the heated metallic plate, has a thickness of about 0.10″ to 0.20″, and preferably about 0.160″. The pad provides a heated surface capable of conforming to the contours of the upper surface of the multi-well plate for applying a heat-sealable sheet thereto. -
Platen 412 further includes a frame structure having two substantiallyvertical side panels side panels fasteners 440, so as to form narrow, flat floor regions bridging the confronting faces of theside panels - Each end of
support plate 414 has an overhang region, such as 414 a and 414 b, that projects longitudinally beyond thevarious underlayers overhang region overhang region 414 a faces the upper surface of a crossbar member 438. Although not visible in the figures, it should be noted that the same arrangement exists on the opposing side of the frame structure. - Three elongated, cylindrical rods are disposed substantially normal to an upper, flat surface of each crossbar member, at spaced points generally defining a line. For example, FIG. 24
shows rods platen 412. Similar structure exists near the other end ofplaten 412, as well. The lower end of each rod is rigidly attached to its respective crossbar member, while the upper (free) end is passed through a respective bore (not shown) formed vertically through a respective overhang region, 414 a or 414 b. The two outer rods on each crossbar member, such asrods bearings platen 412 as it moves up and down along a generally vertical direction. The center rod on each crossbar member, such asrod 452, forms a part of a biasing means that acts to urge theplaten 412 upward. In this regard, a compression spring, such asspring 468, is concentrically mounted about the center rod at each end ofplaten 412, with the spring pre-compressed between the upper surface of its respective crossbar member and the lower surface of a confronting overhang region, 414 a or 414 b. In its desire to extend, the spring provides a continuous, upwardly-directed force that, in the absence of an equal or greater opposing force, is sufficient to positionplaten 412 in a fully raised position, whereat thesupport plate 414 is disposed proximate the top edge regions ofside panels - An E-style retaining ring, such as470 and 471, is mounted near the top of each center (spring-bearing) rod, limiting the upward movement of the
support plate 414. In an alternative embodiment (not shown), the upper edge of each side panel can be angled inward, e.g., 90 degrees relative to the major surface of the panel, to form a lip that acts to limit the upward movement of the support plate. - As previously indicated, pick-and-
place assembly 388 is used to pick up individual heat-sealable covers from a holdingtray 336 and place them on amulti-well tray 324. Theheatable platen 412 applies the heat and force necessary for effecting a proper seal. - In an exemplary operation, and with reference to FIGS.16-24, the heat sealing station apparatus begins the sealing process by rotating
picker arm 390 from the home position (FIGS. 16 and 23) to the pick-up position (FIGS. 17 and 20), through an arc of about 90°.Carriage 376 moves alonglinear track 370, as necessary, untilsuction picker assembly 394 is positioned directly above atray 336 holding a stack of polyethylene/polypropylene covers 342. Here,suction picker assembly 394 is driven down, by way ofstepper motor 402 andlead screw 404, until each suction cup 408 a-408 d contacts the uppermost sheet ofstack 342.Plenum 400 is then evacuated by a remote vacuum source (not shown) in order to establish a vacuum, e.g., from about −5 to about −10 psi, at the face region of each suction cup 408 a-408 d.Suction picker assembly 394 is then driven up, thereby lifting a heat-sealable cover 342 a fromstack 342.Picker arm 390 is then rotated another 90°, from the pick-up position to a drop-off position (FIGS. 21 and 22). Here,suction picker assembly 394 is driven down untilsheet 342 a rests on amulti-well tray 324, at which point the vacuum is released.Suction picker assembly 394 is then raised back up, whilesuction picker arm 390 is returned to the home position. Next,carriage 376 is moved forward to positionplaten 412 directly abovemulti-well tray 324. The TECAN® RSP 198 (FIG. 16) is moved along the x/y direction to position its four fingers 1-4 above respective landing sites 425-428 on top ofsupport plate 414. The TECAN® RSP then presses down, along the z direction, with each of fingers 1-4, thereby compressing the bottom surface ofplaten 412, heated to about 105°-120° C., against the heat-sealable sheet 342 a resting onmulti-well tray 324.Heated platen 412 is held against the multi-well tray for a short period (e.g., about 10-20 seconds), at a pressure of about 20 lbs., thereby sealing the heat-sealable sheet 342 a ontotray 324. The fingers 1-4 of theTECAN® RSP 198 are then raised, thereby allowing theheated platen 412 to raise. The above process is repeated for any other multiwell plates held in acavity 310 ofwork surface 302. - As previously mentioned, a computer control unit can be programmed, using known techniques, to automate the above process. To this end, non-contact sensors, for example infrared emitter/detector pairs (not shown), and sensor flags, such as
flag 476, can be strategically positioned to provide position signals for monitoring by the computer control unit. - Those skilled in the art can now appreciate from the foregoing description that the broad teachings of the present invention can be implemented in a variety of forms. Therefore, while this invention has been described in connection with particular embodiments and examples thereof, the true scope of the invention should not be so limited. Various changes and modification may be made without departing from the scope of the invention, as defined by the appended claims.
Claims (16)
1. A method of sealing a heat-sealable sheet over an array of wells held in a collection tray, each of said wells having an open upper end, said method comprising:
picking up a heat-sealable sheet; placing the sheet over said open upper ends; and pressing a conformable heated surface against said sheet, from a side opposite said collection tray, with sufficient pressure such that said sheet is heat-sealed to said collection tray over said open upper ends.
2. The method of claim 1 , wherein said conformable heated surface is pressed against said sheet using a plurality of spaced-apart elongated rods, disposed substantially normal to an upper surface of said collection plate.
3. The method of claim 2 , wherein the rods depend from a support structure positioned above the collection plate.
4. The method of claim 1 , wherein the heat-sealable sheet is optically clear.
5. The method of claim 1 , wherein a surface of the open upper end has raised features.
6. The method of claim 5 , wherein the conformable heated surface, during the step of pressing the conformable heated surface, contacts all points on the surface of the open upper end.
7. The method of claim 4 , further comprising: prior to said placing step, loading a plurality of said wells with respective samples each containing at least one nucleic acid, and, subsequent to said pressing step, subjecting said samples to conditions suitable to amplify said at least one nucleic acid by polymerase chain reaction (PCR).
8. The method of claim 7 , further comprising measuring the generation of nucleic-acid products resulting from said PCR in real-time through said sheet.
9. The method of claim 5 , wherein said tray includes an upper surface, with said wells formed therein and depending therefrom, and wherein said well upper ends define ridges projecting above said tray upper surface.
10. The method of claim 1 , wherein the sealing of heat sealable sheet occurs in a semi-automated or automated fashion.
11. The method of claim 1 , wherein the array of wells is a plate for use in a scientific or laboratory instrument, wherein the plate has a plurality of wells disposed in the plate.
12. The method of claim 1 , wherein the open upper end has a compliant, resilient surface.
13. A system comprising:
at least one heat sealable sheet;
a bin adapted to hold a plurality of heat sealable sheets; and
an array of wells,
wherein the sealing of heat sealable sheets from the bin over the array of wells occurs in a semi-automated or automated fashion.
14. The system of claim 13 , wherein the heat sealable sheet is optically clear.
15. The system of claim 13 , wherein the array of wells is a plate for use in a scientific or laboratory instrument, wherein the plate has a plurality of wells disposed in the plate.
16. A system comprising:
an array of wells;
a heat sealable means for sealing an array of wells; and
a holding means to hold a plurality of heat sealable means, wherein the heat sealable means held in the holding means is adapted to be sealed to the array of wells in semiautomatic or automatic fashion.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/460,819 US20030215956A1 (en) | 1998-10-29 | 2003-06-12 | Multi-well microfiltration apparatus |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/182,946 US6159368A (en) | 1998-10-29 | 1998-10-29 | Multi-well microfiltration apparatus |
US09/565,202 US6506343B1 (en) | 1998-10-29 | 2000-05-04 | Multi-well microfiltration apparatus and method for avoiding cross-contamination |
US10/199,743 US6783732B2 (en) | 1998-10-29 | 2002-07-19 | Apparatus and method for avoiding cross-contamination due to pendent drops of fluid hanging from discharge conduits |
US10/460,819 US20030215956A1 (en) | 1998-10-29 | 2003-06-12 | Multi-well microfiltration apparatus |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/199,743 Continuation US6783732B2 (en) | 1998-10-29 | 2002-07-19 | Apparatus and method for avoiding cross-contamination due to pendent drops of fluid hanging from discharge conduits |
Publications (1)
Publication Number | Publication Date |
---|---|
US20030215956A1 true US20030215956A1 (en) | 2003-11-20 |
Family
ID=22670739
Family Applications (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/182,946 Expired - Lifetime US6159368A (en) | 1998-10-29 | 1998-10-29 | Multi-well microfiltration apparatus |
US09/565,673 Expired - Fee Related US6451261B1 (en) | 1998-10-29 | 2000-05-04 | Multi-well microfiltration apparatus |
US09/565,566 Expired - Lifetime US6338802B1 (en) | 1998-10-29 | 2000-05-04 | Multi-well microfiltration apparatus |
US09/565,202 Expired - Lifetime US6506343B1 (en) | 1998-10-29 | 2000-05-04 | Multi-well microfiltration apparatus and method for avoiding cross-contamination |
US10/199,743 Expired - Lifetime US6783732B2 (en) | 1998-10-29 | 2002-07-19 | Apparatus and method for avoiding cross-contamination due to pendent drops of fluid hanging from discharge conduits |
US10/460,819 Abandoned US20030215956A1 (en) | 1998-10-29 | 2003-06-12 | Multi-well microfiltration apparatus |
Family Applications Before (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/182,946 Expired - Lifetime US6159368A (en) | 1998-10-29 | 1998-10-29 | Multi-well microfiltration apparatus |
US09/565,673 Expired - Fee Related US6451261B1 (en) | 1998-10-29 | 2000-05-04 | Multi-well microfiltration apparatus |
US09/565,566 Expired - Lifetime US6338802B1 (en) | 1998-10-29 | 2000-05-04 | Multi-well microfiltration apparatus |
US09/565,202 Expired - Lifetime US6506343B1 (en) | 1998-10-29 | 2000-05-04 | Multi-well microfiltration apparatus and method for avoiding cross-contamination |
US10/199,743 Expired - Lifetime US6783732B2 (en) | 1998-10-29 | 2002-07-19 | Apparatus and method for avoiding cross-contamination due to pendent drops of fluid hanging from discharge conduits |
Country Status (9)
Country | Link |
---|---|
US (6) | US6159368A (en) |
EP (2) | EP1124637B1 (en) |
JP (3) | JP3725029B2 (en) |
AT (1) | ATE257036T1 (en) |
AU (1) | AU756147B2 (en) |
CA (1) | CA2346860C (en) |
DE (1) | DE69913978T2 (en) |
ES (1) | ES2212652T3 (en) |
WO (1) | WO2000025922A2 (en) |
Cited By (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040086426A1 (en) * | 1999-02-16 | 2004-05-06 | Applera Corporation | Bead dispensing system |
US20050221358A1 (en) * | 2003-09-19 | 2005-10-06 | Carrillo Albert L | Pressure chamber clamp mechanism |
US20050231723A1 (en) * | 2003-09-19 | 2005-10-20 | Blasenheim Barry J | Optical camera alignment |
US20050236346A1 (en) * | 2004-04-27 | 2005-10-27 | Whitney Steven G | Disposable test tube rack |
US20050244932A1 (en) * | 2003-09-19 | 2005-11-03 | Harding Ian A | Inverted orientation for a microplate |
US20050250173A1 (en) * | 2004-05-10 | 2005-11-10 | Davis Charles Q | Detection device, components of a detection device, and methods associated therewith |
US20050269530A1 (en) * | 2003-03-10 | 2005-12-08 | Oldham Mark F | Combination reader |
US20060057715A1 (en) * | 2004-09-10 | 2006-03-16 | Promega Corporation | Methods and kits for isolating sperm cells |
EP1724019A1 (en) * | 2005-05-19 | 2006-11-22 | Millipore Corporation | Receiver plate with multiple cross-sections |
FR2887159A1 (en) * | 2005-06-20 | 2006-12-22 | Ct Hospitalier Regional De Nan | Filtering well for biological analysis has compression surfaces between reservoir and collector to fasten filtering membrane between them |
US20070116444A1 (en) * | 2005-06-16 | 2007-05-24 | Sratagene California | Heat blocks and heating |
US20070134785A1 (en) * | 2002-01-28 | 2007-06-14 | Nanosphere, Inc. | DNA Hybridization Device and Method |
US20070148649A1 (en) * | 2003-10-21 | 2007-06-28 | Fuji Photo Film Co., Ltd. | Cartridge for nucleic acid separation and purification and method for producing the same |
EP1854540A1 (en) * | 2006-05-12 | 2007-11-14 | F. Hoffmann-la Roche AG | Multi-well filtration device |
EP1854542A1 (en) * | 2006-05-12 | 2007-11-14 | F. Hoffmann-La Roche AG | Multi-well filtration device |
US20070272587A1 (en) * | 2006-05-22 | 2007-11-29 | Nguyen Viet X | Vial package |
US20080000892A1 (en) * | 2006-06-26 | 2008-01-03 | Applera Corporation | Heated cover methods and technology |
US20100143878A1 (en) * | 2006-10-06 | 2010-06-10 | Promega Corporation | Methods and kits for isolating cells |
US7858365B2 (en) | 2002-07-30 | 2010-12-28 | Applied Biosystems, Llc | Sample block apparatus and method for maintaining a microcard on a sample block |
US7998435B2 (en) | 2003-09-19 | 2011-08-16 | Life Technologies Corporation | High density plate filler |
US20110201530A1 (en) * | 2003-09-19 | 2011-08-18 | Life Technologies Corporation | Vacuum Assist For a Microplate |
US8277760B2 (en) | 2003-09-19 | 2012-10-02 | Applied Biosystems, Llc | High density plate filler |
US20160243734A1 (en) * | 2015-02-25 | 2016-08-25 | Sony Dadc Austria Ag | Microfluidic or microtiter device and method of manufacture of microfluidic or microtiter device |
US10604292B1 (en) * | 2019-02-20 | 2020-03-31 | Gravitron, LLC | System, method and apparatus for processing cartridges en masse |
US11266179B2 (en) | 2019-02-08 | 2022-03-08 | Gravitron, LLC | Joint smoking device with plunger or auger |
US11918054B2 (en) | 2020-01-16 | 2024-03-05 | Gravitron, LLC | System, method and apparatus for smoking device |
Families Citing this family (246)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7560273B2 (en) | 2002-07-23 | 2009-07-14 | Applied Biosystems, Llc | Slip cover for heated platen assembly |
US6121048A (en) * | 1994-10-18 | 2000-09-19 | Zaffaroni; Alejandro C. | Method of conducting a plurality of reactions |
US6117394A (en) * | 1996-04-10 | 2000-09-12 | Smith; James C. | Membrane filtered pipette tip |
DE19725894A1 (en) * | 1997-06-19 | 1998-12-24 | Biotechnolog Forschung Gmbh | Differential vacuum chamber |
US6486947B2 (en) * | 1998-07-22 | 2002-11-26 | Ljl Biosystems, Inc. | Devices and methods for sample analysis |
FR2776389B1 (en) * | 1998-03-20 | 2000-06-16 | Fondation Jean Dausset Ceph | AUTOMATIC DEVICE FOR PRODUCING SAMPLES FOR THE IMPLEMENTATION OF CHEMICAL OR BIOLOGICAL REACTIONS IN A LIQUID MEDIUM |
AU3865399A (en) * | 1998-04-23 | 1999-11-08 | Otter Coast Automation, Inc. | Method and apparatus for synthesis of libraries of organic compounds |
US6436351B1 (en) * | 1998-07-15 | 2002-08-20 | Deltagen Research Laboratories, L.L.C. | Microtitre chemical reaction system |
US6906292B2 (en) * | 1998-10-29 | 2005-06-14 | Applera Corporation | Sample tray heater module |
US6419827B1 (en) * | 1998-10-29 | 2002-07-16 | Applera Corporation | Purification apparatus and method |
US6896849B2 (en) * | 1998-10-29 | 2005-05-24 | Applera Corporation | Manually-operable multi-well microfiltration apparatus and method |
US6159368A (en) * | 1998-10-29 | 2000-12-12 | The Perkin-Elmer Corporation | Multi-well microfiltration apparatus |
US6689323B2 (en) * | 1998-10-30 | 2004-02-10 | Agilent Technologies | Method and apparatus for liquid transfer |
US6485692B1 (en) * | 1998-12-04 | 2002-11-26 | Symyx Technologies, Inc. | Continuous feed parallel reactor |
US6951762B2 (en) * | 1998-12-23 | 2005-10-04 | Zuk Jr Peter | Apparatus comprising a disposable device and reusable instrument for synthesizing chemical compounds, and for testing chemical compounds for solubility |
US6315957B1 (en) * | 1999-01-15 | 2001-11-13 | Pharmacopeia, Inc. | Article comprising a filter pocket-plate |
GB9906477D0 (en) * | 1999-03-19 | 1999-05-12 | Pyrosequencing Ab | Liquid dispensing apparatus |
CA2367912A1 (en) * | 1999-03-19 | 2000-09-28 | Genencor International, Inc. | Multi-through hole testing plate for high throughput screening |
WO2000066267A1 (en) * | 1999-04-30 | 2000-11-09 | Gentra Systems, Inc. | Preventing cross-contamination in a multi-well plate |
US6635430B1 (en) * | 1999-07-16 | 2003-10-21 | Dupont Pharmaceuticals Company | Filtrate plate device and reversible-well plate device |
US6379626B1 (en) * | 1999-09-03 | 2002-04-30 | Array Biopharma | Reactor plate clamping system |
US6869572B1 (en) * | 1999-09-13 | 2005-03-22 | Millipore Corporation | High density cast-in-place sample preparation card |
DE50001774D1 (en) | 1999-09-29 | 2003-05-22 | Tecan Trading Ag Maennedorf | Thermal cycler and lifting element for microtiter plate |
US6272939B1 (en) | 1999-10-15 | 2001-08-14 | Applera Corporation | System and method for filling a substrate with a liquid sample |
FR2801660B1 (en) * | 1999-11-29 | 2002-01-18 | Chemunex | DEVICE FOR HANDLING A SOLID SUPPORT FOR CONTAMINANTS |
US6692596B2 (en) | 1999-12-23 | 2004-02-17 | 3M Innovative Properties Company | Micro-titer plate and method of making same |
EP1110611A1 (en) * | 1999-12-23 | 2001-06-27 | 3M Innovative Properties Company | Micro-titer plate and method of making same |
US7311880B2 (en) * | 1999-12-23 | 2007-12-25 | 3M Innovative Properties Company | Well-less filtration device |
WO2001051663A2 (en) * | 2000-01-11 | 2001-07-19 | Maxygen, Inc. | Integrated systems and methods for diversity generation and screening |
US7169355B1 (en) * | 2000-02-02 | 2007-01-30 | Applera Corporation | Apparatus and method for ejecting sample well trays |
US6534014B1 (en) * | 2000-05-11 | 2003-03-18 | Irm Llc | Specimen plate lid and method of using |
GB0011443D0 (en) * | 2000-05-13 | 2000-06-28 | Dna Research Instr Limited | Separation device |
WO2001087484A2 (en) * | 2000-05-18 | 2001-11-22 | Millipore Corporation | Multiplewell plate with adhesive bonded filter |
US20020054833A1 (en) * | 2000-05-26 | 2002-05-09 | Daqing Qu | Use of membrane cover in prevention of cross-contamination in multiple biological material isolation processing |
US6358479B1 (en) * | 2000-05-30 | 2002-03-19 | Advanced Chemtech, Inc. | Reaction block assembly for chemical synthesis |
US6994827B2 (en) * | 2000-06-03 | 2006-02-07 | Symyx Technologies, Inc. | Parallel semicontinuous or continuous reactors |
US6455007B1 (en) * | 2000-06-13 | 2002-09-24 | Symyx Technologies, Inc. | Apparatus and method for testing compositions in contact with a porous medium |
US6439036B1 (en) | 2000-06-13 | 2002-08-27 | Symyx Technologics, Inc. | Method for evaluating a test fluid |
US6627159B1 (en) * | 2000-06-28 | 2003-09-30 | 3M Innovative Properties Company | Centrifugal filling of sample processing devices |
US6719949B1 (en) * | 2000-06-29 | 2004-04-13 | Applera Corporation | Apparatus and method for transporting sample well trays |
EP1299182A2 (en) * | 2000-07-07 | 2003-04-09 | Symyx Technologies, Inc. | Methods for analysis of heterogeneous catalysts in a multi-variable screening reactor |
US6563581B1 (en) | 2000-07-14 | 2003-05-13 | Applera Corporation | Scanning system and method for scanning a plurality of samples |
DE10041825A1 (en) * | 2000-08-25 | 2002-03-07 | Invitek Gmbh | Multiwell filtration plate and process for its manufacture |
US6640891B1 (en) * | 2000-09-05 | 2003-11-04 | Kevin R. Oldenburg | Rapid thermal cycling device |
US7070740B1 (en) * | 2000-09-28 | 2006-07-04 | Beckman Coulter, Inc. | Method and apparatus for processing biomolecule arrays |
US6939516B2 (en) * | 2000-09-29 | 2005-09-06 | Becton, Dickinson And Company | Multi-well plate cover and assembly adapted for mechanical manipulation |
US6490782B1 (en) * | 2000-10-16 | 2002-12-10 | Varian, Inc. | Automated in-line filter changing apparatus |
US8097471B2 (en) | 2000-11-10 | 2012-01-17 | 3M Innovative Properties Company | Sample processing devices |
SE0102921D0 (en) * | 2001-08-30 | 2001-08-30 | Astrazeneca Ab | Pharmaceutically useful compounds |
US6896848B1 (en) * | 2000-12-19 | 2005-05-24 | Tekcel, Inc. | Microplate cover assembly |
US20040053402A1 (en) * | 2000-12-20 | 2004-03-18 | Jacobus Stark | Preparation of fluid samples by applying pressure |
US20020093147A1 (en) * | 2001-01-16 | 2002-07-18 | Berna Michael J. | Well plate seal |
US6491873B2 (en) * | 2001-01-23 | 2002-12-10 | Varian, Inc. | Multi-well filtration apparatus |
FR2820058B1 (en) * | 2001-01-29 | 2004-01-30 | Commissariat Energie Atomique | METHOD AND SYSTEM FOR MAKING A CONTINUOUS FLOW REALIZATION OF A BIOLOGICAL, CHEMICAL OR BIOCHEMICAL PROTOCOL |
US6899848B1 (en) * | 2001-02-27 | 2005-05-31 | Hamilton Company | Automated sample treatment system: apparatus and method |
US20050226786A1 (en) * | 2001-03-08 | 2005-10-13 | Hager David C | Multi-well apparatus |
MXPA03008081A (en) * | 2001-03-08 | 2004-11-12 | Exelixis Inc | Multi-well apparatus. |
US7266085B2 (en) * | 2001-03-21 | 2007-09-04 | Stine John A | Access and routing protocol for ad hoc network using synchronous collision resolution and node state dissemination |
US6426215B1 (en) * | 2001-04-06 | 2002-07-30 | Pe Corporation (Ny) | PCR plate cover and maintaining device |
US7135117B2 (en) * | 2001-05-31 | 2006-11-14 | Pall Corporation | Well for processing a fluid |
EP1397212B1 (en) * | 2001-06-14 | 2010-12-08 | Millipore Corporation | Positioning pins for multiwell test apparatus |
DE60215377T2 (en) * | 2001-06-14 | 2007-08-23 | Millipore Corp., Billerica | The multiwell cell growth apparatus |
US6514750B2 (en) | 2001-07-03 | 2003-02-04 | Pe Corporation (Ny) | PCR sample handling device |
EP1281966A3 (en) * | 2001-07-30 | 2003-06-18 | Fuji Photo Film Co., Ltd. | Method and apparatus for conducting a receptor-ligand reaction |
US6632371B2 (en) * | 2001-08-07 | 2003-10-14 | Abbott Laboratories | Method for controlling the proportion of fluid passing through a filter |
DE10139758A1 (en) * | 2001-08-13 | 2003-02-27 | Qiagen Gmbh | Intermediate element, for an automated fluid preparation assembly, comprises a main block with passage openings matching the array of feed channels, leading to a heated plate, without cross contamination or clogging |
US7014744B2 (en) | 2001-08-24 | 2006-03-21 | Applera Corporation | Method of purification and concentration using AC fields with a transfer tip |
US6682703B2 (en) * | 2001-09-05 | 2004-01-27 | Irm, Llc | Parallel reaction devices |
DE10144225C1 (en) * | 2001-09-08 | 2003-02-06 | Eppendorf Ag | Process for drying filters in cavities of micro-titration plate involves using device with nozzles and unit for producing air stream through nozzles |
MXPA04001815A (en) * | 2001-09-20 | 2005-03-07 | Dimensional Pharm Inc | Conductive microtiter plate. |
EP1444500B1 (en) * | 2001-10-15 | 2008-06-11 | Biocept, Inc. | Microwell biochip |
US6942836B2 (en) * | 2001-10-16 | 2005-09-13 | Applera Corporation | System for filling substrate chambers with liquid |
US20030087293A1 (en) * | 2001-10-23 | 2003-05-08 | Decode Genetics Ehf. | Nucleic acid isolation method and apparatus for performing same |
DE10160975A1 (en) * | 2001-12-10 | 2003-06-18 | Univ Schiller Jena | Sample plate for use in dialysis systems |
US7632467B1 (en) * | 2001-12-13 | 2009-12-15 | Kardex Engineering, Inc. | Apparatus for automated storage and retrieval of miniature shelf keeping units |
KR100411946B1 (en) * | 2001-12-18 | 2003-12-18 | 한국해양연구원 | Device for simultaneously collecting filtered water and filter paper |
JP2005513456A (en) * | 2001-12-21 | 2005-05-12 | テカン・トレーディング・アクチェンゲゼルシャフト | Apparatus and method for moving a fluid sample |
EP1323474A1 (en) * | 2001-12-31 | 2003-07-02 | Corning Incorporated | Device and process for simultaneous transfer of liquids |
GB0200157D0 (en) * | 2002-01-04 | 2002-02-20 | Kbiosystems Ltd | Sealing method suitable for use with water-based thermal cyclers |
US7614444B2 (en) | 2002-01-08 | 2009-11-10 | Oldenburg Kevin R | Rapid thermal cycling device |
US7373968B2 (en) * | 2002-01-08 | 2008-05-20 | Kevin R. Oldenburg | Method and apparatus for manipulating an organic liquid sample |
US6783737B2 (en) * | 2002-01-25 | 2004-08-31 | Bristol-Myers Squibb Company | High pressure chemistry reactor |
US6893613B2 (en) * | 2002-01-25 | 2005-05-17 | Bristol-Myers Squibb Company | Parallel chemistry reactor with interchangeable vessel carrying inserts |
US6677151B2 (en) | 2002-01-30 | 2004-01-13 | Applera Corporation | Device and method for thermal cycling |
US20030143124A1 (en) * | 2002-01-31 | 2003-07-31 | Roberts Roger Q. | Unidirectional flow control sealing matt |
US6723236B2 (en) * | 2002-03-19 | 2004-04-20 | Waters Investments Limited | Device for solid phase extraction and method for purifying samples prior to analysis |
US20030190260A1 (en) * | 2002-04-05 | 2003-10-09 | Symyx Technologies, Inc. | Combinatorial chemistry reactor system |
US6982166B2 (en) | 2002-05-16 | 2006-01-03 | Applera Corporation | Lens assembly for biological testing |
US9157860B2 (en) | 2002-05-16 | 2015-10-13 | Applied Biosystems, Llc | Achromatic lens array |
US8007745B2 (en) * | 2002-05-24 | 2011-08-30 | Millipore Corporation | Anti-clogging device and method for in-gel digestion applications |
DE50300434D1 (en) * | 2002-05-31 | 2005-05-19 | Tecan Trading Ag Maennedorf | Apparatus, system and method for aspirating liquids from solid phase extraction plates |
WO2004020983A2 (en) * | 2002-06-06 | 2004-03-11 | Millipore Corporation | Ultrafiltration device for drug binding studies |
EP1371966A1 (en) * | 2002-06-14 | 2003-12-17 | Stiftung Für Diagnostische Forschung | A cuvette for a reader device for assaying substances using the evanescence field method |
US7375807B2 (en) * | 2002-07-15 | 2008-05-20 | Avantium International B.V. | System for the preparation of multiple solid state samples, in particular for spectroscopic and microscopic analysis |
US7122155B2 (en) * | 2002-07-16 | 2006-10-17 | Mcgill University | Electron microscopy cell fraction sample preparation robot |
US7241420B2 (en) | 2002-08-05 | 2007-07-10 | Palo Alto Research Center Incorporated | Capillary-channel probes for liquid pickup, transportation and dispense using stressy metal |
US20040050787A1 (en) * | 2002-09-13 | 2004-03-18 | Elena Chernokalskaya | Apparatus and method for sample preparation and direct spotting eluants onto a MALDI-TOF target |
WO2004034026A2 (en) * | 2002-10-10 | 2004-04-22 | Irm, Llc | Capacity altering device, holder and methods of sample processing |
US7507376B2 (en) * | 2002-12-19 | 2009-03-24 | 3M Innovative Properties Company | Integrated sample processing devices |
US7682565B2 (en) | 2002-12-20 | 2010-03-23 | Biotrove, Inc. | Assay apparatus and method using microfluidic arrays |
US20040129676A1 (en) * | 2003-01-07 | 2004-07-08 | Tan Roy H. | Apparatus for transfer of an array of liquids and methods for manufacturing same |
US20040232075A1 (en) * | 2003-01-31 | 2004-11-25 | Jason Wells | Microfiltration device and method for washing and concentrating solid particles |
US20040179971A1 (en) * | 2003-03-12 | 2004-09-16 | Becton, Dickinson And Company | Method and device for transporting evacuated blood collection tubes |
JP2006526492A (en) * | 2003-05-09 | 2006-11-24 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | Micro processing control components |
CA2467131C (en) * | 2003-05-13 | 2013-12-10 | Becton, Dickinson & Company | Method and apparatus for processing biological and chemical samples |
EP1631668A1 (en) * | 2003-06-06 | 2006-03-08 | Applera Corporation | Purification device for ribonucleic acid in large volumes, and method |
US20040251414A1 (en) * | 2003-06-10 | 2004-12-16 | Stephan Rodewald | Sample matrix for infrared spectroscopy |
US20040258563A1 (en) | 2003-06-23 | 2004-12-23 | Applera Corporation | Caps for sample wells and microcards for biological materials |
US7824623B2 (en) * | 2003-06-24 | 2010-11-02 | Millipore Corporation | Multifunctional vacuum manifold |
EP1491258B1 (en) | 2003-06-24 | 2008-12-03 | Millipore Corporation | Multifunctional vacuum manifold |
DE10329983A1 (en) * | 2003-06-27 | 2005-03-31 | Siemens Ag | Micro-reactor module allows multiple different reactions to be performed simultaneously and to be serviced by a standard automatic micro-titer head, is formed of a multiple recessed base plate which is sealed by a releasable cover plate |
US8277762B2 (en) | 2003-08-01 | 2012-10-02 | Tioga Research, Inc. | Apparatus and methods for evaluating the barrier properties of a membrane |
CN100543126C (en) * | 2003-08-19 | 2009-09-23 | 富士胶片株式会社 | Extraction element |
US7063216B2 (en) * | 2003-09-04 | 2006-06-20 | Millipore Corporation | Underdrain useful in the construction of a filtration device |
US20050103703A1 (en) * | 2003-09-26 | 2005-05-19 | Stephen Young | Method of assembling a filtration plate |
US20070017870A1 (en) | 2003-09-30 | 2007-01-25 | Belov Yuri P | Multicapillary device for sample preparation |
EP1677886A1 (en) * | 2003-09-30 | 2006-07-12 | Chromba, Inc. | Multicapillary column for chromatography and sample preparation |
US8753588B2 (en) * | 2003-10-15 | 2014-06-17 | Emd Millipore Corporation | Support and stand-off ribs for underdrain for multi-well device |
EP1547690B1 (en) * | 2003-12-12 | 2011-07-06 | Becton, Dickinson and Company | Membrane attachment process by hot melting without adhesive |
JP2007526479A (en) * | 2004-03-02 | 2007-09-13 | ダコ デンマーク アクティーゼルスカブ | Reagent delivery system, dispensing device and container for biological staining apparatus |
KR100597870B1 (en) * | 2004-04-01 | 2006-07-06 | 한국과학기술원 | Microfluidic chip for high-throughput screening and high-throughput assay |
US7584577B2 (en) * | 2004-04-06 | 2009-09-08 | Steve E. Esmond | Rain and storm water filtration systems |
US20050236319A1 (en) * | 2004-04-23 | 2005-10-27 | Millipore Corporation | Pendant drop control in a multiwell plate |
US20050236318A1 (en) * | 2004-04-23 | 2005-10-27 | Millipore Corporation | Low holdup volume multiwell plate |
US20050236317A1 (en) * | 2004-04-23 | 2005-10-27 | Millipore Corporation | Pendant drop control in a multiwell plate |
US20050282270A1 (en) * | 2004-06-21 | 2005-12-22 | Applera Corporation | System for thermally cycling biological samples with heated lid and pneumatic actuator |
US7618592B2 (en) * | 2004-06-24 | 2009-11-17 | Millipore Corporation | Detachable engageable microarray plate liner |
JP4762240B2 (en) * | 2004-07-27 | 2011-08-31 | プロテダイン・コーポレーション | Method and apparatus for moving the contents in the wells of a multiwell plate |
US20060024209A1 (en) * | 2004-07-30 | 2006-02-02 | Agnew Brian J | Apparatus, methods, and kits for assaying a plurality of fluid samples for a common analyte |
US20060024204A1 (en) * | 2004-08-02 | 2006-02-02 | Oldenburg Kevin R | Well plate sealing apparatus and method |
US7932090B2 (en) * | 2004-08-05 | 2011-04-26 | 3M Innovative Properties Company | Sample processing device positioning apparatus and methods |
DE102004045054A1 (en) * | 2004-09-15 | 2006-03-30 | Eppendorf Ag | Device for the suction-tight covering of a filter device |
US20080145886A1 (en) * | 2004-10-07 | 2008-06-19 | Istituto Di Ricerche Di Biologia Molecolare P Ange | Assay for Cytochrome P450 Isoforms 3A4 and 3A5 |
US7629140B2 (en) * | 2004-10-07 | 2009-12-08 | Istituto Di Richerche Di Biologia Molecolare P. Angeletti S.P.A. | Assay for cytochrome P450 isoform 2C9 |
JP4653995B2 (en) * | 2004-10-08 | 2011-03-16 | Jsr株式会社 | Bio-separation filter manufacturing method, bio-separation filter, and bio-separation kit using the same |
FR2877859B1 (en) * | 2004-11-17 | 2007-02-16 | Memos Soc Par Actions Simplifi | REACTOR MULTIPUITS |
DE102005001362A1 (en) * | 2005-01-11 | 2006-07-20 | Protagen Ag | Method and device for quantifying proteins |
JP2008534915A (en) * | 2005-01-19 | 2008-08-28 | アイアールエム・リミテッド・ライアビリティ・カンパニー | Multi-well container positioning device, system, computer program product, and method |
TWI253957B (en) * | 2005-02-04 | 2006-05-01 | Taigen Bioscience Corp | Apparatus for processing biochemical sample |
US20060177354A1 (en) * | 2005-02-04 | 2006-08-10 | Taigen Bioscience Corporation | Apparatus for processing biological sample |
GB2424417B (en) * | 2005-03-24 | 2008-11-12 | Amersham Health As | Devices and method for the penetration of a container stopper |
US8021611B2 (en) * | 2005-04-09 | 2011-09-20 | ProteinSimple | Automated micro-volume assay system |
US20080124250A1 (en) * | 2005-04-09 | 2008-05-29 | Cell Biosciences Inc. | Capillary storage and dispensing container for automated micro-volume assay system |
DE102005016755B3 (en) * | 2005-04-11 | 2006-11-30 | Eppendorf Ag | Apparatus, system comprising such apparatus and method for drying cavities in microtiter filter plates and filters disposed therein |
US8414778B2 (en) * | 2005-05-17 | 2013-04-09 | Universal Bio Research Co., Ltd. | Filtration method, filter-incorporated tip, and filtration device |
JP3805352B1 (en) * | 2005-05-25 | 2006-08-02 | 株式会社エンプラス | Fluid handling device and fluid handling unit used therefor |
US20070009394A1 (en) * | 2005-06-16 | 2007-01-11 | Bean Robert J | Device for loading a multi well plate |
CN101351542A (en) * | 2005-07-15 | 2009-01-21 | 阿普尔拉公司 | Fluid processing device and method |
WO2007028157A1 (en) * | 2005-09-02 | 2007-03-08 | Zuk Peter Jr | Systems, apparatus and methods for vacuum filtration |
US20070175897A1 (en) | 2006-01-24 | 2007-08-02 | Labcyte Inc. | Multimember closures whose members change relative position |
US8084005B2 (en) * | 2006-01-26 | 2011-12-27 | Lawrence Livermore National Security, Llc | Multi-well sample plate cover penetration system |
KR20090007692A (en) * | 2006-04-20 | 2009-01-20 | 다이니폰 인사츠 가부시키가이샤 | Filter-carrying micro plate |
WO2007130434A2 (en) * | 2006-05-02 | 2007-11-15 | Applera Corporation | Variable volume dispenser and method |
US8221697B2 (en) | 2007-01-12 | 2012-07-17 | Nichols Michael J | Apparatus for lidding or delidding microplate |
US7767154B2 (en) * | 2007-01-12 | 2010-08-03 | HighRes Biosolutions, Inc. | Microplate kit |
JP4996958B2 (en) * | 2007-03-29 | 2012-08-08 | 富士フイルム株式会社 | Microfluidic device |
WO2008144083A1 (en) * | 2007-05-23 | 2008-11-27 | Nypro Inc. | Methods and apparatus for foam control in a vacuum filtration system |
US20080293157A1 (en) * | 2007-05-24 | 2008-11-27 | Gerald Frederickson | Apparatus and method of performing high-throughput cell-culture studies on biomaterials |
US7651867B2 (en) * | 2007-06-05 | 2010-01-26 | Gideon Eden | Method of making a test device |
US20090004754A1 (en) * | 2007-06-26 | 2009-01-01 | Oldenburg Kevin R | Multi-well reservoir plate and methods of using same |
US20090004064A1 (en) * | 2007-06-27 | 2009-01-01 | Applera Corporation | Multi-material microplate and method |
JP5011012B2 (en) * | 2007-07-18 | 2012-08-29 | 株式会社日立ハイテクノロジーズ | Nucleic acid extraction equipment |
US8231012B2 (en) * | 2007-07-26 | 2012-07-31 | Roush Life Sciences, Llc | Filtrate storage system |
US8235221B2 (en) * | 2007-07-26 | 2012-08-07 | Roush Life Sciences, Llc | Methods for vacuum filtration |
DE102007043614B3 (en) * | 2007-09-13 | 2008-11-20 | Biocrates Life Sciences Gmbh | Retainer for wells of multi-corrugated plate, has support arranged in opening below retaining bar, where retainer rests with lateral outer surfaces of support bars, retaining bar and/or connecting rods against inner side of opening |
WO2009039208A1 (en) * | 2007-09-17 | 2009-03-26 | Twof, Inc. | Supramolecular nanostamping printing device |
WO2009046227A1 (en) | 2007-10-02 | 2009-04-09 | Theranos, Inc. | Modular point-of-care devices and uses thereof |
DE102008008256A1 (en) * | 2007-10-08 | 2009-04-09 | M2P-Labs Gmbh | microreactor |
US20090181359A1 (en) * | 2007-10-25 | 2009-07-16 | Lou Sheng C | Method of performing ultra-sensitive immunoassays |
US8222048B2 (en) * | 2007-11-05 | 2012-07-17 | Abbott Laboratories | Automated analyzer for clinical laboratory |
US20110092686A1 (en) * | 2008-03-28 | 2011-04-21 | Pelican Group Holdings, Inc. | Multicapillary sample preparation devices and methods for processing analytes |
US8076126B2 (en) * | 2008-07-18 | 2011-12-13 | Ortho-Clinical Diagnostics, Inc. | Single column immunological test elements |
US8486335B2 (en) * | 2008-08-29 | 2013-07-16 | Lee H. Angros | In situ heat induced antigen recovery and staining apparatus and method |
FI20085815A (en) | 2008-09-02 | 2010-03-03 | Wallac Oy | Apparatus, system and method for filtering liquid samples |
JP4675406B2 (en) * | 2008-09-29 | 2011-04-20 | 日本分光株式会社 | Sample collection container, sample collection device, and sample collection method in a supercritical fluid system |
EP2350308A4 (en) * | 2008-10-20 | 2012-07-11 | Photonic Biosystems Inc | Multiple filter array assay |
GB0903623D0 (en) * | 2009-03-03 | 2009-04-15 | 4Titude Ltd | Sealing multiwell plates |
US8555520B2 (en) * | 2009-06-25 | 2013-10-15 | Harvard Bioscience, Inc. | Accelerated evaporation process and apparatus utilizing re-circulating loops |
WO2011005801A1 (en) * | 2009-07-08 | 2011-01-13 | Speware Corporation | Luer seal for solid phase extraction columns |
EP2454600B1 (en) * | 2009-07-15 | 2018-11-28 | Agilent Technologies, Inc. | Spin column system and methods |
DE102009043570A1 (en) * | 2009-09-30 | 2011-03-31 | Manz Automation Tübingen GmbH | Module for a laboratory robot and laboratory robot |
WO2011046915A1 (en) * | 2009-10-12 | 2011-04-21 | R.P. Scherer Technologies, Llc | Apparatus for crystallization and method therefor |
JP5933918B2 (en) | 2009-12-10 | 2016-06-15 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Mold-shaped locking system |
JP4924909B2 (en) * | 2010-01-12 | 2012-04-25 | 株式会社日立プラントテクノロジー | Suction air leak prevention mechanism during collection carrier solution filtration and suction air leak prevention method during collection carrier solution filtration |
WO2011094572A2 (en) | 2010-01-28 | 2011-08-04 | Shuichi Takayama | Hanging drop devices, systems and/or methods |
DE102010011485A1 (en) * | 2010-03-16 | 2011-09-22 | Sartorius Stedim Biotech Gmbh | Multi-hole plate with filter medium and its use |
EP2447721B1 (en) | 2010-11-02 | 2017-03-15 | F. Hoffmann-La Roche AG | Instrument and method for automatically heat-sealing a microplate |
US9050548B2 (en) | 2010-12-22 | 2015-06-09 | Agilent Technologies, Inc. | Multi-channel filter assembly and related apparatus and methods |
US9157838B2 (en) | 2010-12-23 | 2015-10-13 | Emd Millipore Corporation | Chromatography apparatus and method |
EP2658653B1 (en) * | 2010-12-30 | 2015-03-04 | Abbott Point Of Care, Inc. | Biologic fluid analysis cartridge with sample handling portion and analysis chamber portion |
CA3097861A1 (en) | 2011-01-21 | 2012-07-26 | Labrador Diagnostics Llc | Systems and methods for sample use maximization |
CN203941178U (en) | 2011-05-20 | 2014-11-12 | 珀金埃尔默保健科学公司 | Laboratory parts and liquid loading and unloading system and complementary flowable materials handling system |
US11559802B2 (en) | 2011-07-20 | 2023-01-24 | Avidien Technologies, Inc. | Pipette tip adapter |
EP3682969B1 (en) * | 2011-07-20 | 2022-03-23 | Avidien Technologies | Pipette tip adapter assembly |
WO2013027747A1 (en) * | 2011-08-22 | 2013-02-28 | 株式会社日立ハイテクノロジーズ | Plug application and removal device and sample processing device |
US8475739B2 (en) | 2011-09-25 | 2013-07-02 | Theranos, Inc. | Systems and methods for fluid handling |
US20140170735A1 (en) | 2011-09-25 | 2014-06-19 | Elizabeth A. Holmes | Systems and methods for multi-analysis |
US9619627B2 (en) | 2011-09-25 | 2017-04-11 | Theranos, Inc. | Systems and methods for collecting and transmitting assay results |
US9664702B2 (en) | 2011-09-25 | 2017-05-30 | Theranos, Inc. | Fluid handling apparatus and configurations |
US8435738B2 (en) | 2011-09-25 | 2013-05-07 | Theranos, Inc. | Systems and methods for multi-analysis |
US9632102B2 (en) | 2011-09-25 | 2017-04-25 | Theranos, Inc. | Systems and methods for multi-purpose analysis |
US8840838B2 (en) | 2011-09-25 | 2014-09-23 | Theranos, Inc. | Centrifuge configurations |
US9268915B2 (en) | 2011-09-25 | 2016-02-23 | Theranos, Inc. | Systems and methods for diagnosis or treatment |
US9810704B2 (en) | 2013-02-18 | 2017-11-07 | Theranos, Inc. | Systems and methods for multi-analysis |
US10012664B2 (en) | 2011-09-25 | 2018-07-03 | Theranos Ip Company, Llc | Systems and methods for fluid and component handling |
US9250229B2 (en) | 2011-09-25 | 2016-02-02 | Theranos, Inc. | Systems and methods for multi-analysis |
WO2013093954A1 (en) * | 2011-12-19 | 2013-06-27 | ヤマハ発動機株式会社 | Object selecting device and object selecting method |
GB2501344A (en) * | 2012-01-13 | 2013-10-23 | Kevin Oldenburg | System and method for harvesting and/or analysing biological samples |
US9073052B2 (en) | 2012-03-30 | 2015-07-07 | Perkinelmer Health Sciences, Inc. | Lab members and liquid handling systems and methods including same |
US10081527B2 (en) * | 2012-05-03 | 2018-09-25 | Vanrx Pharmasystems Inc. | Cover removal system for use in controlled environment enclosures |
US9199237B2 (en) * | 2012-09-04 | 2015-12-01 | Michael Baumgartner | Automated well plate |
JP2014070188A (en) * | 2012-09-28 | 2014-04-21 | Sumitomo Bakelite Co Ltd | Processing apparatus |
JP2014069149A (en) * | 2012-09-28 | 2014-04-21 | Sumitomo Bakelite Co Ltd | Spacer and processing unit |
US9423234B2 (en) | 2012-11-05 | 2016-08-23 | The Regents Of The University Of California | Mechanical phenotyping of single cells: high throughput quantitative detection and sorting |
WO2014145530A1 (en) | 2013-03-15 | 2014-09-18 | Matthew Hale | Aspiration-free well plate apparatus and methods |
KR102091303B1 (en) | 2013-03-19 | 2020-03-19 | 라이프 테크놀로지스 코포레이션 | Thermal cycler cover |
CN105980028B (en) | 2013-12-04 | 2018-10-26 | 普凯尔德诊断技术有限公司 | Filter device with slide-valve and the method using the filter device |
DE102013114732A1 (en) * | 2013-12-20 | 2015-06-25 | Hamilton Bonaduz Ag | Covering device, in particular cover for the cover of reaction vessels |
CN114797474A (en) * | 2014-05-21 | 2022-07-29 | 非链实验室 | System and method for buffer solution exchange |
CN106999347A (en) | 2014-08-08 | 2017-08-01 | 弗雷蒙科学公司 | The intelligent bag used in the physiology and/or physical parameter of bag of the sensing equipped with biological substance |
CA2964422C (en) * | 2014-10-27 | 2018-06-12 | The Governing Council Of The University Of Toronto | Microfluidic device for cell-based assays |
EP3221050B1 (en) | 2014-11-18 | 2021-05-19 | Avidien Technologies, Inc. | Multichannel air displacement pipettor |
US10493449B2 (en) * | 2014-11-19 | 2019-12-03 | Halliburton Energy Services, Inc. | Loading tool for a multi-well chromatography filter plate |
JP6179682B2 (en) * | 2015-01-22 | 2017-08-16 | 株式会社村田製作所 | Void arrangement structure and manufacturing method thereof |
DE102015102350B3 (en) | 2015-02-19 | 2016-05-04 | Sartorius Stedim Biotech Gmbh | Filtration device for liquid samples |
CA3109854C (en) * | 2015-09-01 | 2023-07-25 | Becton, Dickinson And Company | Depth filtration device for separating specimen phases |
IL244922A0 (en) * | 2016-04-05 | 2016-07-31 | Omrix Biopharmaceuticals Ltd | Device and process for sample preparation |
US20190193076A1 (en) * | 2016-07-14 | 2019-06-27 | Hewlett-Packard Development Company, L.P. | Microplate lid |
EP3621716B1 (en) * | 2017-05-10 | 2024-01-17 | EMD Millipore Corporation | Multiwell plate with variable compression seal |
WO2019026026A1 (en) | 2017-08-02 | 2019-02-07 | Pocared Diagnostics Ltd. | Processor filter arrangement that includes method and apparatus to remove waste fluid through a filter |
CN107372195B (en) * | 2017-09-08 | 2023-11-14 | 殷文斐 | Multifunctional chicken raising drinking water system |
DE102017009147A1 (en) * | 2017-09-29 | 2019-04-04 | Sartorius Stedim Biotech Gmbh | Filtration device, method for assembling a modular filtration device and method for characterizing a filter medium and / or medium to be filtered |
US11648564B2 (en) * | 2018-02-02 | 2023-05-16 | Covaris, Llc | Well plate drier and cover |
WO2019210025A1 (en) * | 2018-04-25 | 2019-10-31 | Optofluidics Inc. | Vacuum manifold for filtration microscopy |
US10732083B2 (en) | 2018-05-07 | 2020-08-04 | Fremon Scientific, Inc. | Thawing biological substances |
CN108730519B (en) * | 2018-07-25 | 2023-09-29 | 湖南省天骑医学新技术股份有限公司 | Sealant seat with negative pressure supporting platform and manufacturing method |
EP3837344A4 (en) * | 2018-08-17 | 2022-01-26 | Sierra Biosystems, Inc. | Row-independent oligonucleotide synthesis |
USD905267S1 (en) | 2019-03-27 | 2020-12-15 | Avidien Technologies, Inc. | Pipette tip adapter |
CN111589489B (en) * | 2020-04-13 | 2021-10-22 | 青岛海尔生物医疗股份有限公司 | Test tube storage system and storage method |
CN111905848B (en) * | 2020-09-05 | 2022-04-01 | 海易(大连)实业有限公司 | Use method of electric heating constant-temperature water bath kettle with good stability |
CN112874992B (en) * | 2021-01-07 | 2021-09-21 | 广州市言康生物科技有限公司 | Biological diagnosis kit device |
US20240103025A1 (en) * | 2021-02-03 | 2024-03-28 | Amgen Inc. | Systems and approaches for drug processing |
CN113426173B (en) * | 2021-05-21 | 2023-07-14 | 新疆农业职业技术学院 | Turbid fluid separating device for water-saving irrigation operation |
CN113668669B (en) * | 2021-08-10 | 2023-02-10 | 上海天淼建设工程有限公司 | Sewer construction device and method |
WO2023218373A1 (en) * | 2022-05-11 | 2023-11-16 | Dh Technologies Development Pte. Ltd. | Sample well mixing system and method |
KR102633789B1 (en) * | 2023-03-14 | 2024-02-02 | 황하늘 | Multi-purpose multi-well device with vacuum chamber |
Citations (59)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US297602A (en) * | 1884-04-29 | Thomas hookeb | ||
US3463322A (en) * | 1967-07-28 | 1969-08-26 | Horace W Gerarde | Pressure filtration device |
US3721364A (en) * | 1970-11-17 | 1973-03-20 | Wolfen Filmfab Veb | Plastic magazine for photosensitive sheet materials |
US3775225A (en) * | 1971-07-06 | 1973-11-27 | Gloucester Eng Co Inc | Machine for perforating and heat sealing a web including an elongated element with a multiplicity of drivers |
US3864892A (en) * | 1973-05-29 | 1975-02-11 | Mahaffy & Harder Eng Co | Automatic packaging method and apparatus with heat-sealing elements having resilient heat conducting members |
US3967776A (en) * | 1975-03-27 | 1976-07-06 | Pako Corporation | Continuous multi-layered packaging assembly |
US3988168A (en) * | 1974-06-10 | 1976-10-26 | Polaroid Corporation | Flat battery and manufacture thereof |
US4167875A (en) * | 1976-08-05 | 1979-09-18 | Meakin John C | Filtration method and apparatus |
US4246339A (en) * | 1978-11-01 | 1981-01-20 | Millipore Corporation | Test device |
US4279342A (en) * | 1980-03-24 | 1981-07-21 | Robert Van Pelt | Lunch box employing a built-in radio receiver |
US4304865A (en) * | 1978-08-31 | 1981-12-08 | National Research Development Corporation | Harvesting material from micro-culture plates |
US4422151A (en) * | 1981-06-01 | 1983-12-20 | Gilson Robert E | Liquid handling apparatus |
US4734192A (en) * | 1982-07-01 | 1988-03-29 | Millipore Corporation | Multiwell membrane filtration apparatus |
US4902481A (en) * | 1987-12-11 | 1990-02-20 | Millipore Corporation | Multi-well filtration test apparatus |
US4927604A (en) * | 1988-12-05 | 1990-05-22 | Costar Corporation | Multiwell filter plate vacuum manifold assembly |
US4948442A (en) * | 1985-06-18 | 1990-08-14 | Polyfiltronics, Inc. | Method of making a multiwell test plate |
US4948564A (en) * | 1986-10-28 | 1990-08-14 | Costar Corporation | Multi-well filter strip and composite assemblies |
US4969306A (en) * | 1986-11-19 | 1990-11-13 | Sprinter System Ab | Apparatus for closing a filled, flanged carton tray |
US5002889A (en) * | 1988-10-21 | 1991-03-26 | Genetic Systems Corporation | Reaction well shape for a microwell tray |
US5047215A (en) * | 1985-06-18 | 1991-09-10 | Polyfiltronics, Inc. | Multiwell test plate |
US5108703A (en) * | 1986-03-26 | 1992-04-28 | Beckman Instruments, Inc. | Automated multi-purpose analytical chemistry processing center and laboratory work station |
US5108704A (en) * | 1988-09-16 | 1992-04-28 | W. R. Grace & Co.-Conn. | Microfiltration apparatus with radially spaced nozzles |
US5110556A (en) * | 1986-10-28 | 1992-05-05 | Costar Corporation | Multi-well test plate |
US5114681A (en) * | 1990-03-09 | 1992-05-19 | Biomedical Research And Development Laboratories, Inc. | Superfusion apparatus |
US5116496A (en) * | 1991-03-19 | 1992-05-26 | Minnesota Mining And Manufacturing Company | Membrane-containing wells for microtitration and microfiltration |
US5141719A (en) * | 1990-07-18 | 1992-08-25 | Bio-Rad Laboratories, Inc. | Multi-sample filtration plate assembly |
US5201348A (en) * | 1991-03-07 | 1993-04-13 | Eppendorf-Netheler-Hinz Gmbh | Evacuating apparatus for a microtitration diaphragm plate |
US5208161A (en) * | 1987-08-27 | 1993-05-04 | Polyfiltronics N.A., Inc. | Filter units |
US5227137A (en) * | 1991-04-04 | 1993-07-13 | Nicholson Precision Instruments Inc. | Vacuum clamped multi-sample filtration apparatus |
US5264184A (en) * | 1991-03-19 | 1993-11-23 | Minnesota Mining And Manufacturing Company | Device and a method for separating liquid samples |
US5282543A (en) * | 1990-11-29 | 1994-02-01 | The Perkin Elmer Corporation | Cover for array of reaction tubes |
US5283039A (en) * | 1991-09-18 | 1994-02-01 | Minnesota Mining And Manufacturing Company | Multi-well filtration apparatus |
US5308437A (en) * | 1990-10-31 | 1994-05-03 | Sumitomo Rubber Industries Ltd. | Band member forming apparatus |
US5326533A (en) * | 1992-11-04 | 1994-07-05 | Millipore Corporation | Multiwell test apparatus |
US5342581A (en) * | 1993-04-19 | 1994-08-30 | Sanadi Ashok R | Apparatus for preventing cross-contamination of multi-well test plates |
US5352086A (en) * | 1990-01-27 | 1994-10-04 | Georg Speiss Gmbh | Apparatus for lifting sheets from a stack |
US5368729A (en) * | 1993-07-23 | 1994-11-29 | Whatman, Inc. | Solid phase extraction device |
US5384024A (en) * | 1992-03-13 | 1995-01-24 | Applied Biosystems, Inc. | Capillary electrophoresis |
US5401637A (en) * | 1990-08-29 | 1995-03-28 | Stratecon Diagnostics International | Device for conducting diagnostic assays |
US5409832A (en) * | 1990-08-29 | 1995-04-25 | Stratecon Diagnostics International | Membrane holder for use in an assay device |
US5427265A (en) * | 1993-10-22 | 1995-06-27 | Dart Industries Inc. | Lunchbox with safety lock |
US5459300A (en) * | 1993-03-03 | 1995-10-17 | Kasman; David H. | Microplate heater for providing uniform heating regardless of the geometry of the microplates |
US5475610A (en) * | 1990-11-29 | 1995-12-12 | The Perkin-Elmer Corporation | Thermal cycler for automatic performance of the polymerase chain reaction with close temperature control |
US5582665A (en) * | 1990-07-18 | 1996-12-10 | Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. | Process for sealing at least one well out of a number of wells provided in a plate for receiving chemical and/or biochemical and/or microbiological substances, and installation for carrying out the process |
US5604130A (en) * | 1995-05-31 | 1997-02-18 | Chiron Corporation | Releasable multiwell plate cover |
US5650323A (en) * | 1991-06-26 | 1997-07-22 | Costar Corporation | System for growing and manipulating tissue cultures using 96-well format equipment |
US5665247A (en) * | 1996-09-16 | 1997-09-09 | Whatman Inc. | Process for sealing microplates utilizing a thin polymeric film |
US5679310A (en) * | 1995-07-11 | 1997-10-21 | Polyfiltronics, Inc. | High surface area multiwell test plate |
US5681492A (en) * | 1995-02-17 | 1997-10-28 | Van Praet; Peter | Incubator for micro titer plates |
US5721136A (en) * | 1994-11-09 | 1998-02-24 | Mj Research, Inc. | Sealing device for thermal cycling vessels |
US5736105A (en) * | 1991-02-01 | 1998-04-07 | Astle; Thomas W. | Method and device for simultaneously transferring plural samples |
US5736106A (en) * | 1995-01-26 | 1998-04-07 | Tosoh Corporation | Thermal cycling reaction apparatus and reactor therefor |
US5741463A (en) * | 1993-04-19 | 1998-04-21 | Sanadi; Ashok Ramesh | Apparatus for preventing cross-contamination of multi-well test plates |
US5792425A (en) * | 1995-05-19 | 1998-08-11 | Millipore Coporation | Vacuum filter device |
US5792430A (en) * | 1996-08-12 | 1998-08-11 | Monsanto Company | Solid phase organic synthesis device with pressure-regulated manifold |
US5846493A (en) * | 1995-02-14 | 1998-12-08 | Promega Corporation | System for analyzing a substance from a solution following filtering of the substance from the solution |
US5928907A (en) * | 1994-04-29 | 1999-07-27 | The Perkin-Elmer Corporation., Applied Biosystems Division | System for real time detection of nucleic acid amplification products |
US6159368A (en) * | 1998-10-29 | 2000-12-12 | The Perkin-Elmer Corporation | Multi-well microfiltration apparatus |
US6251343B1 (en) * | 1998-02-24 | 2001-06-26 | Caliper Technologies Corp. | Microfluidic devices and systems incorporating cover layers |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4704255A (en) * | 1983-07-15 | 1987-11-03 | Pandex Laboratories, Inc. | Assay cartridge |
USD297602S (en) * | 1986-10-28 | 1988-09-13 | Metrokane Imports, Inc. | Lunchbox |
DE4022792A1 (en) * | 1990-07-18 | 1992-02-06 | Max Planck Gesellschaft | PLATE WITH AT LEAST ONE RECESS FOR RECEIVING CHEMICAL AND / OR BIOCHEMICAL AND / OR MICROBIOLOGICAL SUBSTANCES AND METHOD FOR PRODUCING THE PLATE |
US5380437A (en) * | 1993-02-02 | 1995-01-10 | Biomedical Research And Development Laboratories, Inc. | Multifunctional filtration apparatus |
GB9311276D0 (en) * | 1993-06-01 | 1993-07-21 | Whatman Scient Limited | Well inserts for use in tissue culture |
US5961926A (en) * | 1993-09-27 | 1999-10-05 | Packard Instrument Co., Inc. | Microplate assembly and method of preparing samples for analysis in a microplate assembly |
DE4412286A1 (en) * | 1994-04-09 | 1995-10-12 | Boehringer Mannheim Gmbh | System for contamination-free processing of reaction processes |
DE19652327C2 (en) * | 1996-12-16 | 2002-04-04 | Europ Lab Molekularbiolog | Method and device for carrying out chemical reaction sequences |
US5961925A (en) | 1997-09-22 | 1999-10-05 | Bristol-Myers Squibb Company | Apparatus for synthesis of multiple organic compounds with pinch valve block |
EP0925828B1 (en) | 1997-12-17 | 2004-09-29 | Europäisches Laboratorium Für Molekularbiologie (Embl) | Device for carrying out sequential chemical reactions |
DE29722473U1 (en) * | 1997-12-19 | 1998-02-19 | Macherey Nagel Gmbh & Co Hg | Separation device for the separation of substances |
-
1998
- 1998-10-29 US US09/182,946 patent/US6159368A/en not_active Expired - Lifetime
-
1999
- 1999-10-28 WO PCT/US1999/025579 patent/WO2000025922A2/en active IP Right Grant
- 1999-10-28 CA CA002346860A patent/CA2346860C/en not_active Expired - Fee Related
- 1999-10-28 EP EP99957491A patent/EP1124637B1/en not_active Expired - Lifetime
- 1999-10-28 DE DE69913978T patent/DE69913978T2/en not_active Expired - Lifetime
- 1999-10-28 EP EP03008785A patent/EP1336433A1/en not_active Withdrawn
- 1999-10-28 AU AU15184/00A patent/AU756147B2/en not_active Ceased
- 1999-10-28 ES ES99957491T patent/ES2212652T3/en not_active Expired - Lifetime
- 1999-10-28 JP JP2000579352A patent/JP3725029B2/en not_active Expired - Fee Related
- 1999-10-28 AT AT99957491T patent/ATE257036T1/en not_active IP Right Cessation
-
2000
- 2000-05-04 US US09/565,673 patent/US6451261B1/en not_active Expired - Fee Related
- 2000-05-04 US US09/565,566 patent/US6338802B1/en not_active Expired - Lifetime
- 2000-05-04 US US09/565,202 patent/US6506343B1/en not_active Expired - Lifetime
-
2002
- 2002-07-19 US US10/199,743 patent/US6783732B2/en not_active Expired - Lifetime
-
2003
- 2003-06-12 US US10/460,819 patent/US20030215956A1/en not_active Abandoned
-
2004
- 2004-08-10 JP JP2004233955A patent/JP2004354393A/en active Pending
-
2007
- 2007-04-09 JP JP2007102163A patent/JP2007263966A/en active Pending
Patent Citations (65)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US297602A (en) * | 1884-04-29 | Thomas hookeb | ||
US3463322A (en) * | 1967-07-28 | 1969-08-26 | Horace W Gerarde | Pressure filtration device |
US3721364A (en) * | 1970-11-17 | 1973-03-20 | Wolfen Filmfab Veb | Plastic magazine for photosensitive sheet materials |
US3775225A (en) * | 1971-07-06 | 1973-11-27 | Gloucester Eng Co Inc | Machine for perforating and heat sealing a web including an elongated element with a multiplicity of drivers |
US3864892A (en) * | 1973-05-29 | 1975-02-11 | Mahaffy & Harder Eng Co | Automatic packaging method and apparatus with heat-sealing elements having resilient heat conducting members |
US3988168A (en) * | 1974-06-10 | 1976-10-26 | Polaroid Corporation | Flat battery and manufacture thereof |
US3967776A (en) * | 1975-03-27 | 1976-07-06 | Pako Corporation | Continuous multi-layered packaging assembly |
US4167875A (en) * | 1976-08-05 | 1979-09-18 | Meakin John C | Filtration method and apparatus |
US4304865A (en) * | 1978-08-31 | 1981-12-08 | National Research Development Corporation | Harvesting material from micro-culture plates |
US4246339A (en) * | 1978-11-01 | 1981-01-20 | Millipore Corporation | Test device |
US4279342A (en) * | 1980-03-24 | 1981-07-21 | Robert Van Pelt | Lunch box employing a built-in radio receiver |
US4422151A (en) * | 1981-06-01 | 1983-12-20 | Gilson Robert E | Liquid handling apparatus |
US4734192A (en) * | 1982-07-01 | 1988-03-29 | Millipore Corporation | Multiwell membrane filtration apparatus |
US4948442A (en) * | 1985-06-18 | 1990-08-14 | Polyfiltronics, Inc. | Method of making a multiwell test plate |
US5047215A (en) * | 1985-06-18 | 1991-09-10 | Polyfiltronics, Inc. | Multiwell test plate |
US5108703A (en) * | 1986-03-26 | 1992-04-28 | Beckman Instruments, Inc. | Automated multi-purpose analytical chemistry processing center and laboratory work station |
US5110556A (en) * | 1986-10-28 | 1992-05-05 | Costar Corporation | Multi-well test plate |
US4948564A (en) * | 1986-10-28 | 1990-08-14 | Costar Corporation | Multi-well filter strip and composite assemblies |
US4969306A (en) * | 1986-11-19 | 1990-11-13 | Sprinter System Ab | Apparatus for closing a filled, flanged carton tray |
US5208161A (en) * | 1987-08-27 | 1993-05-04 | Polyfiltronics N.A., Inc. | Filter units |
US4902481A (en) * | 1987-12-11 | 1990-02-20 | Millipore Corporation | Multi-well filtration test apparatus |
US5108704A (en) * | 1988-09-16 | 1992-04-28 | W. R. Grace & Co.-Conn. | Microfiltration apparatus with radially spaced nozzles |
US5002889A (en) * | 1988-10-21 | 1991-03-26 | Genetic Systems Corporation | Reaction well shape for a microwell tray |
US4927604A (en) * | 1988-12-05 | 1990-05-22 | Costar Corporation | Multiwell filter plate vacuum manifold assembly |
US5352086A (en) * | 1990-01-27 | 1994-10-04 | Georg Speiss Gmbh | Apparatus for lifting sheets from a stack |
US5114681A (en) * | 1990-03-09 | 1992-05-19 | Biomedical Research And Development Laboratories, Inc. | Superfusion apparatus |
US5582665A (en) * | 1990-07-18 | 1996-12-10 | Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. | Process for sealing at least one well out of a number of wells provided in a plate for receiving chemical and/or biochemical and/or microbiological substances, and installation for carrying out the process |
US5141719A (en) * | 1990-07-18 | 1992-08-25 | Bio-Rad Laboratories, Inc. | Multi-sample filtration plate assembly |
US5409832A (en) * | 1990-08-29 | 1995-04-25 | Stratecon Diagnostics International | Membrane holder for use in an assay device |
US5401637A (en) * | 1990-08-29 | 1995-03-28 | Stratecon Diagnostics International | Device for conducting diagnostic assays |
US5308437A (en) * | 1990-10-31 | 1994-05-03 | Sumitomo Rubber Industries Ltd. | Band member forming apparatus |
US5282543A (en) * | 1990-11-29 | 1994-02-01 | The Perkin Elmer Corporation | Cover for array of reaction tubes |
US5710381A (en) * | 1990-11-29 | 1998-01-20 | The Perkin-Elmer Corporation | Two piece holder for PCR sample tubes |
US5602756A (en) * | 1990-11-29 | 1997-02-11 | The Perkin-Elmer Corporation | Thermal cycler for automatic performance of the polymerase chain reaction with close temperature control |
US5475610A (en) * | 1990-11-29 | 1995-12-12 | The Perkin-Elmer Corporation | Thermal cycler for automatic performance of the polymerase chain reaction with close temperature control |
US5736105A (en) * | 1991-02-01 | 1998-04-07 | Astle; Thomas W. | Method and device for simultaneously transferring plural samples |
US5201348A (en) * | 1991-03-07 | 1993-04-13 | Eppendorf-Netheler-Hinz Gmbh | Evacuating apparatus for a microtitration diaphragm plate |
US5620663A (en) * | 1991-03-19 | 1997-04-15 | Minnesota Mining And Manufacturing Company | Support plate accommodating and being integrally connected with a plurality of adjacent sample containers |
US5264184A (en) * | 1991-03-19 | 1993-11-23 | Minnesota Mining And Manufacturing Company | Device and a method for separating liquid samples |
US5116496A (en) * | 1991-03-19 | 1992-05-26 | Minnesota Mining And Manufacturing Company | Membrane-containing wells for microtitration and microfiltration |
US5464541A (en) * | 1991-03-19 | 1995-11-07 | Minnesota Mining And Manufacturing Company | Device and a method for separating liquid samples |
US5227137A (en) * | 1991-04-04 | 1993-07-13 | Nicholson Precision Instruments Inc. | Vacuum clamped multi-sample filtration apparatus |
US5650323A (en) * | 1991-06-26 | 1997-07-22 | Costar Corporation | System for growing and manipulating tissue cultures using 96-well format equipment |
US5283039A (en) * | 1991-09-18 | 1994-02-01 | Minnesota Mining And Manufacturing Company | Multi-well filtration apparatus |
US5384024A (en) * | 1992-03-13 | 1995-01-24 | Applied Biosystems, Inc. | Capillary electrophoresis |
US5326533A (en) * | 1992-11-04 | 1994-07-05 | Millipore Corporation | Multiwell test apparatus |
US5459300A (en) * | 1993-03-03 | 1995-10-17 | Kasman; David H. | Microplate heater for providing uniform heating regardless of the geometry of the microplates |
US5516490A (en) * | 1993-04-19 | 1996-05-14 | Sanadi Biotech Group, Inc. | Apparatus for preventing cross-contamination of multi-well test plates |
US6258325B1 (en) * | 1993-04-19 | 2001-07-10 | Ashok Ramesh Sanadi | Method and apparatus for preventing cross-contamination of multi-well test plates |
US5741463A (en) * | 1993-04-19 | 1998-04-21 | Sanadi; Ashok Ramesh | Apparatus for preventing cross-contamination of multi-well test plates |
US5342581A (en) * | 1993-04-19 | 1994-08-30 | Sanadi Ashok R | Apparatus for preventing cross-contamination of multi-well test plates |
US5368729A (en) * | 1993-07-23 | 1994-11-29 | Whatman, Inc. | Solid phase extraction device |
US5427265A (en) * | 1993-10-22 | 1995-06-27 | Dart Industries Inc. | Lunchbox with safety lock |
US5928907A (en) * | 1994-04-29 | 1999-07-27 | The Perkin-Elmer Corporation., Applied Biosystems Division | System for real time detection of nucleic acid amplification products |
US5721136A (en) * | 1994-11-09 | 1998-02-24 | Mj Research, Inc. | Sealing device for thermal cycling vessels |
US5736106A (en) * | 1995-01-26 | 1998-04-07 | Tosoh Corporation | Thermal cycling reaction apparatus and reactor therefor |
US5846493A (en) * | 1995-02-14 | 1998-12-08 | Promega Corporation | System for analyzing a substance from a solution following filtering of the substance from the solution |
US5681492A (en) * | 1995-02-17 | 1997-10-28 | Van Praet; Peter | Incubator for micro titer plates |
US5792425A (en) * | 1995-05-19 | 1998-08-11 | Millipore Coporation | Vacuum filter device |
US5604130A (en) * | 1995-05-31 | 1997-02-18 | Chiron Corporation | Releasable multiwell plate cover |
US5679310A (en) * | 1995-07-11 | 1997-10-21 | Polyfiltronics, Inc. | High surface area multiwell test plate |
US5792430A (en) * | 1996-08-12 | 1998-08-11 | Monsanto Company | Solid phase organic synthesis device with pressure-regulated manifold |
US5665247A (en) * | 1996-09-16 | 1997-09-09 | Whatman Inc. | Process for sealing microplates utilizing a thin polymeric film |
US6251343B1 (en) * | 1998-02-24 | 2001-06-26 | Caliper Technologies Corp. | Microfluidic devices and systems incorporating cover layers |
US6159368A (en) * | 1998-10-29 | 2000-12-12 | The Perkin-Elmer Corporation | Multi-well microfiltration apparatus |
Cited By (58)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040086426A1 (en) * | 1999-02-16 | 2004-05-06 | Applera Corporation | Bead dispensing system |
US7384606B2 (en) * | 1999-02-16 | 2008-06-10 | Applera Corporation | Bead dispensing system |
US7347975B2 (en) | 1999-02-16 | 2008-03-25 | Applera Corporation | Bead dispensing system |
US20070134785A1 (en) * | 2002-01-28 | 2007-06-14 | Nanosphere, Inc. | DNA Hybridization Device and Method |
US10253361B2 (en) | 2002-07-30 | 2019-04-09 | Applied Biosystems, Llc | Sample block apparatus and method for maintaining a microcard on a sample block |
US8247221B2 (en) | 2002-07-30 | 2012-08-21 | Applied Biosystems, Llc | Sample block apparatus and method for maintaining a microcard on sample block |
US7858365B2 (en) | 2002-07-30 | 2010-12-28 | Applied Biosystems, Llc | Sample block apparatus and method for maintaining a microcard on a sample block |
US20050269530A1 (en) * | 2003-03-10 | 2005-12-08 | Oldham Mark F | Combination reader |
US8638509B2 (en) | 2003-09-19 | 2014-01-28 | Applied Biosystems, Llc | Optical camera alignment |
US8040619B2 (en) | 2003-09-19 | 2011-10-18 | Applied Biosystems, Llc | Optical camera alignment |
US20050221358A1 (en) * | 2003-09-19 | 2005-10-06 | Carrillo Albert L | Pressure chamber clamp mechanism |
US9213042B2 (en) | 2003-09-19 | 2015-12-15 | Applied Biosystems, Llc | Vacuum assist for a microplate |
US20050244932A1 (en) * | 2003-09-19 | 2005-11-03 | Harding Ian A | Inverted orientation for a microplate |
US8906325B2 (en) | 2003-09-19 | 2014-12-09 | Applied Biosystems, Llc | Vacuum assist for a microplate |
US20050231723A1 (en) * | 2003-09-19 | 2005-10-20 | Blasenheim Barry J | Optical camera alignment |
US20100193672A1 (en) * | 2003-09-19 | 2010-08-05 | Life Technologies Corporation | Optical Camera Alignment |
US7460223B2 (en) | 2003-09-19 | 2008-12-02 | Applied Biosystems Inc. | Inverted orientation for a microplate |
US7570443B2 (en) | 2003-09-19 | 2009-08-04 | Applied Biosystems, Llc | Optical camera alignment |
US20070248976A1 (en) * | 2003-09-19 | 2007-10-25 | Applera Corporation | Inverted orientation for a microplate |
US8277760B2 (en) | 2003-09-19 | 2012-10-02 | Applied Biosystems, Llc | High density plate filler |
US20100086977A1 (en) * | 2003-09-19 | 2010-04-08 | Life Technologies Corporation | Pressure Chamber Clamp Mechanism |
US7429479B2 (en) | 2003-09-19 | 2008-09-30 | Applied Biosystems Inc. | Inverted orientation for a microplate |
US20110201530A1 (en) * | 2003-09-19 | 2011-08-18 | Life Technologies Corporation | Vacuum Assist For a Microplate |
US7998435B2 (en) | 2003-09-19 | 2011-08-16 | Life Technologies Corporation | High density plate filler |
US20070148649A1 (en) * | 2003-10-21 | 2007-06-28 | Fuji Photo Film Co., Ltd. | Cartridge for nucleic acid separation and purification and method for producing the same |
US20050236346A1 (en) * | 2004-04-27 | 2005-10-27 | Whitney Steven G | Disposable test tube rack |
US7232038B2 (en) * | 2004-04-27 | 2007-06-19 | Whitney Steven G | Disposable test tube rack |
WO2005114175A3 (en) * | 2004-05-10 | 2006-02-02 | Bioveris Corp | Detection device, components of a detection device, and methods associated therewith |
US20050250173A1 (en) * | 2004-05-10 | 2005-11-10 | Davis Charles Q | Detection device, components of a detection device, and methods associated therewith |
WO2005114175A2 (en) * | 2004-05-10 | 2005-12-01 | Bioveris Corporation | Detection device, components of a detection device, and methods associated therewith |
US20080118909A1 (en) * | 2004-09-10 | 2008-05-22 | Promega Corporation | Methods and kits for isolating sperm cells |
US7320891B2 (en) | 2004-09-10 | 2008-01-22 | Promega Corporation | Methods and kits for isolating sperm cells |
US20060057715A1 (en) * | 2004-09-10 | 2006-03-16 | Promega Corporation | Methods and kits for isolating sperm cells |
US9138742B2 (en) | 2005-05-19 | 2015-09-22 | Emd Millipore Corporation | Receiver plate with multiple cross-sections |
EP1724019A1 (en) * | 2005-05-19 | 2006-11-22 | Millipore Corporation | Receiver plate with multiple cross-sections |
US20060263875A1 (en) * | 2005-05-19 | 2006-11-23 | Scott Christopher A | Receiver plate with multiple cross-sections |
US8968679B2 (en) | 2005-05-19 | 2015-03-03 | Emd Millipore Corporation | Receiver plate with multiple cross-sections |
US20070116444A1 (en) * | 2005-06-16 | 2007-05-24 | Sratagene California | Heat blocks and heating |
FR2887159A1 (en) * | 2005-06-20 | 2006-12-22 | Ct Hospitalier Regional De Nan | Filtering well for biological analysis has compression surfaces between reservoir and collector to fasten filtering membrane between them |
WO2006136514A1 (en) * | 2005-06-20 | 2006-12-28 | Centre Hospitalier Regional De Nancy | Biological analysis filtering well |
EP1854542A1 (en) * | 2006-05-12 | 2007-11-14 | F. Hoffmann-La Roche AG | Multi-well filtration device |
EP1854540A1 (en) * | 2006-05-12 | 2007-11-14 | F. Hoffmann-la Roche AG | Multi-well filtration device |
US20070264163A1 (en) * | 2006-05-12 | 2007-11-15 | F. Hoffmann-La Roche Ag | Multi-well filtration device |
US7867452B2 (en) | 2006-05-12 | 2011-01-11 | F. Hoffmann-La Roche Ag | Multi-well filtration device |
US20070272587A1 (en) * | 2006-05-22 | 2007-11-29 | Nguyen Viet X | Vial package |
US20080000892A1 (en) * | 2006-06-26 | 2008-01-03 | Applera Corporation | Heated cover methods and technology |
US20110164862A1 (en) * | 2006-06-26 | 2011-07-07 | Life Technologies Corporation | Heated cover methods and technology |
US20100143878A1 (en) * | 2006-10-06 | 2010-06-10 | Promega Corporation | Methods and kits for isolating cells |
US20160243734A1 (en) * | 2015-02-25 | 2016-08-25 | Sony Dadc Austria Ag | Microfluidic or microtiter device and method of manufacture of microfluidic or microtiter device |
US11266179B2 (en) | 2019-02-08 | 2022-03-08 | Gravitron, LLC | Joint smoking device with plunger or auger |
US11278053B2 (en) | 2019-02-08 | 2022-03-22 | Gravitron, LLC | Joint smoking device with plunger or auger |
US20200262596A1 (en) * | 2019-02-20 | 2020-08-20 | Gravitron, LLC | System, method and apparatus for processing cartridges en masse |
US20200262597A1 (en) * | 2019-02-20 | 2020-08-20 | Gravitron, LLC | System, method and apparatus for processing cartridges en masse |
US20210147104A1 (en) * | 2019-02-20 | 2021-05-20 | Gravitron, LLC | System, method and apparatus for processing cartridges en masse |
US10604292B1 (en) * | 2019-02-20 | 2020-03-31 | Gravitron, LLC | System, method and apparatus for processing cartridges en masse |
USD962537S1 (en) | 2019-02-20 | 2022-08-30 | Gravitron, LLC | Cartridges filling system |
US11912455B2 (en) * | 2019-02-20 | 2024-02-27 | Gravitron, LLC | System, method and apparatus for processing cartridges en masse |
US11918054B2 (en) | 2020-01-16 | 2024-03-05 | Gravitron, LLC | System, method and apparatus for smoking device |
Also Published As
Publication number | Publication date |
---|---|
US6338802B1 (en) | 2002-01-15 |
DE69913978T2 (en) | 2004-12-23 |
ATE257036T1 (en) | 2004-01-15 |
JP3725029B2 (en) | 2005-12-07 |
EP1336433A1 (en) | 2003-08-20 |
US20020179520A1 (en) | 2002-12-05 |
WO2000025922A3 (en) | 2000-10-19 |
DE69913978D1 (en) | 2004-02-05 |
JP2007263966A (en) | 2007-10-11 |
JP2004354393A (en) | 2004-12-16 |
US6451261B1 (en) | 2002-09-17 |
US6783732B2 (en) | 2004-08-31 |
WO2000025922A2 (en) | 2000-05-11 |
AU1518400A (en) | 2000-05-22 |
EP1124637A2 (en) | 2001-08-22 |
AU756147B2 (en) | 2003-01-02 |
CA2346860A1 (en) | 2000-05-11 |
ES2212652T3 (en) | 2004-07-16 |
CA2346860C (en) | 2005-01-04 |
US6159368A (en) | 2000-12-12 |
EP1124637B1 (en) | 2004-01-02 |
US6506343B1 (en) | 2003-01-14 |
JP2002528265A (en) | 2002-09-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6506343B1 (en) | Multi-well microfiltration apparatus and method for avoiding cross-contamination | |
US7452510B2 (en) | Manually-operable multi-well microfiltration apparatus and method | |
US8007743B2 (en) | Multifunctional vacuum manifold | |
AU2001253586B2 (en) | Purification apparatus and method | |
US4948564A (en) | Multi-well filter strip and composite assemblies | |
US4895706A (en) | Multi-well filter strip and composite assemblies | |
EP1414571B1 (en) | Well for processing and filtering a fluid | |
US6896849B2 (en) | Manually-operable multi-well microfiltration apparatus and method | |
AU2001253586A1 (en) | Purification apparatus and method | |
JP2008116474A (en) | Multifunctional vacuum manifold | |
US20030226796A1 (en) | Modular system for separating components of a liquid sample | |
CA2478306A1 (en) | Multi-well microfiltration apparatus | |
AU2003200550B2 (en) | Multi-well microfiltration apparatus | |
AU2004242438B2 (en) | Apparatus for use with multi-well filtration | |
CA2125159A1 (en) | Assay cartridge |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |