WO2003015912A2

WO2003015912A2 - Multiplexed cartesian-based split-platter microarrayer and method of production of microarrays

Info

Publication number: WO2003015912A2
Application number: PCT/US2002/026453
Authority: WO
Inventors: Brian A. Haab
Original assignee: Van Andel Research Institute
Priority date: 2001-08-21
Filing date: 2002-08-20
Publication date: 2003-02-27
Also published as: WO2003015912A3; AU2002326701A1

Abstract

A microarrayer comprises a platter formed from multiple rectangular segments mounted for linear movement about an axis and comprises preferably multiple robotic arms, each with a print head for distribution of microarrays on slides. The cooperative motion of each segment of the platter combined with the independently controlled motion of the arms forms a more efficient method of creating microarrays upon multiple, often many, slides. In addition, the use of multiple robotic arms and print head deposits the microarrays on the slides much faster than with prior art microarrays.

Description

MULTIPLEXED CARTESIAN-BASED SPLIT-PLATTER MICROARRAYER AND METHOD OF PRODUCTION OF MICROARRAYS

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Serial No. 60/314,029, filed August 21, 2001.

BACKGROUND OF THE INVENTION Field of the Invention

The invention relates to microarrays. In one of its aspects, the invention relates to an apparatus for depositing closely-aligned microarrays of material onto an array of slides for laboratory use. In another of its aspects, the invention relates to a microarrayer apparatus for efficiently and quickly depositing the microarrays onto slides located on a platter comprising multiple rectangular segments. In another of its aspects, the invention relates to a process for efficently depositing closely-aligned microarrays of material onto an array of slides for laboratory use. Description of the Related Art

Microarrayers are used in laboratories for depositing microarrays made up of multiple samples (even tens of thousands) of material, such as DNA and other biomolecules) onto a glass slide for analysis. Microarrays are very useful in genetic research and have been used to provide highly parallel concentration information on thousands of nucleic acid fragments in a miniaturized, low-volume format. The ability to quantify multiple DNA or RNA fragments simultaneously has many applications, such as basic biological research, molecular classification of disease subtypes, identification of therapeutic markers and targets, and profiling of response to toxins and pharmaceuticals. In one mode of use, mRNA from a population of cells is fluorescently labeled, mixed with a differentially labeled reference pool of mRNA, and hybridized to a microarray. Detection of the binding to the array by fluorescence scanning reveals the transcriptional profile of the cells. The mRNA expression of nearly every gene in yeast can be measured using cDNA arrays to examine transcriptional changes during diauxic shifts and to identify cell cycle regulated genes. Expression profiles of cultured human cells can be measured to gain insight into the response of fibroblasts to serum stimulation, the response of various cell lines to drugs, the effect of HTV infection on CD4+ T cells, and the effects of genetic changes. mRNA taken from human tissue has been examined to identify subtypes of diffuse large B-cell lymphoma, to establish a molecular classification of two types of acute leukemia, to identify multiple sclerosis associated genes, and to classify breast cancer samples based on gene expression patterns. DNA microarrays have had other applications in addition to mRNA expression analysis, including the examination of genomic copy number changes and the subcellular location of RNA transcripts.

The microarrayers typically employed to create these microarrays often include a large, square-shaped moveable platter that is configured to align many glass slides, often in excess of one hundred slides, so that a deposit mechanism can deposit material onto the slides. The deposit mechanism typically comprises a robotic arm with a specially- configured depending member having a "print head" having several print head pins thereon, each print head pin configured to deposit a single microscopic sample of material onto a slide. The robotic arm is then traversed over each of the slides positioned on the platter.

A robotic microarrayer for spotting solutions of biomolecules onto glass slides was developed by Brown and Shalon in 1994 and is disclosed in part in U.S. Patent. No. 5,807,522, issued September 15, 1998, incorporated by reference in its entirety. Referring now to FIGS. 1-9, a prior art microarrayer 10 is shown comprising a square platter 12 mounted for linear y-axis movement with respect to a table 14 upon a linear slide 16 and powered by a first motor 18. The table 14 further includes an arch structure 20 comprising a pair of legs 22 interconnected at upper portions thereof by a cross member 24. The cross member 24 defines rails on which a robotic arm 26 is mounted for linear x-axis movement via a linear slide 28 and powered by a second motor 30.

The robotic arm 26 preferably comprises a body 32 defining rails on which a print head 34 is mounted for linear z-axis movement via a linear slide 36 and powered by a third motor 38. The first, second and third motors 18, 30 and 38, respectively, are known members for imparting linear movement to the slides 16, 28 and 36, respectively. The print head 34 is a well-known member typically comprising a matrix of closely-spaced print head pins 40 biased by a spring (not shown) to perform the microarray deposition function.

Other typical components employed with prior art linear microarrayers 10 include a washing station 42, a drying station 44 that is fluidly interconnected to a vacuum source 46, and a microtiter sample plate 48.

By way of background and as shown in detail in FIGS. 2-3, the platter 12 comprises a square member 50 having a pattern 52 of raised alignment knobs 54 defining a plurality of slide-receiving areas 57. Several slides 58 are placed within these areas 57. The knobs 54 serve to retain the slides 58 in place during deposition of microarrays thereon. FIGS. 2-3 show that the square member 52 can include a tray 60 typically located at a corner portion thereof adapted to receive the sample plate 48 therein. The location of the sample plate 48 on the platter 12 provides a common reference location for a controller 56 for the linear microarrayer 10. FIG. 4 shows an example of the sample plate 48 typically employed with the prior art platter 12 of FIGS. 1-3. The sample plate 48 typically comprises a rectangular member 62 having a closely-aligned matrix of wells 64 therein configured to receive a predetermined volume of material for deposition by the microarrayer 10. FIG. 5 shows an example of a prior art rack 68 of print head pins 40 disposed within protective sheaths 66. These print head pins 66 are loaded into the print head 34 typically in a matrix-like fashion for creating microarrays having a geometric pattern corresponding to the print head matrix.

In use, after a predetermined number of print head pins 40 have been installed on the print head 34 and this information fed to the controller 56, the platter 12 is typically positioned in a "home" position where the microtiter sample plate 48 located on a corner of the platter 12 is positioned adjacent the side-by-side washing and drying stations 42 and 44, respectively. The print head 34 is typically positioned along the x- and y-axes in vertical alignment above the washing station 42 and is then lowered and raised in oscillating fashion along the z-axis to insert the print head pins into and withdraw them from the washing station 42. This movement, and subsequently described x-, y- and z-axis movements are accomplished by the controller 56 sending signals to the first, second and third motors 18, 30 and 38 to actuate the first, second and third slides 16, 28 and 36, respectively.

Then, as shown in FIG. 7, the print head 34 is traversed along the x-axis into alignment with the drying station 44 and is traversed in oscillating fashion along the z- axis to insert the print head 34 into, and withdraw it from, the drying station 44. The controller 56 typically sends a signal to the vacuum source 46 as the print head pins 40 descend into the drying station 44 to withdraw by suction any remaining material and washing fluid from the pins 40. As is commonly known, the positioning of the print head 34 within the washing station 42 and subsequently within the drying station 44 is often repeated for multiple cycles to ensure an effective cleaning of the print head pins 40.

FIG. 8 shows the next typical location of the print head 34 with respect to the table 14 wherein the print head 34 has traversed along the x-axis into alignment with the sample plate 48 and has traversed in. oscillating fashion along the z-axis to insert the print head 34 into, and withdraw it from, the wells 64 of the sample plate 48. This descent of the print head pins 40 into the wells 64 (obviously containing a volume of material desired to be deposited on the slides 58 of the linear microarrayer 10) accumulates a small volume of the material to be deposited within each of the print head pins 40. FIG. 9 shows the prior art linear microarrayer 10 wherein the print head 34 is traversed along the x- and y-axes in a serpentine path 70 over each of the slides 58 on the platter 12. As is well known, the print head 34 also traverses in oscillating fashion along the z-axis to contact the print head pins 40 with, and raise them from, each of the slides 58 in succession to deposit a sub-microarray on each slide along the serpentine path 70.

As described above, the linear microarrayer 10 is a well-known device for making DNA and other microarrays, which are now widely used for biological studies. As shown in the Brown '522 Patent as well as in FIGS. 1-9, known microarrayer technology uses a single print head located above a single platter and manipulated linearly along the x-, y- and z-axes to take samples from the sample plate 48 and to deposit the samples onto slides 58. Since many thousands of DNA samples are typically "spotted" onto each of the slides 58, fabrication of the microarrays can take a substantial amount of time. For example, if an array of 20,000 "spots" is to be created on each of one hundred slides positioned on the square platter 12 with twenty-five print head pins 40 provided on the print head 34, then the arm 26 mounting the print head 34 must thereby make eight hundred passes over each of the one hundred slides. This process can take many hours, even days, to complete a useable set of microarrayed slides, costing a laboratory valuable research time and machine down time.

This main limitation of prior art microarrayers is throughput in the array generation, or speed of production. The time required to produce microarrays is determined by the speed of the repetitive transfer of DNA solutions from microtiter plates 48 to the surfaces of the slides 58. Standard print heads 34 capable of depositing microarrays are typically only able to deposit about 16-48 spots per pass of the print head 34. A single print head 34 cannot transfer more than 48 spots at a time due to the size limitation of the commonly used.l x 3 inch microscope slide and the physical limitations of packing additional print head pins 40 into the print head 34. With the fastest robotics available, it takes about nine hours to deposit 20,000 spots on 100 slides. When spotting more slides, the time increases accordingly making it difficult for core facilities and companies making microarrays to meet current demand for microarrays, often requiring after-hours shifts to complete microarray generation.

SUMMARY OF THE INVENTION

The microarrayer of the present invention comprises a platter formed from multiple rectangular segments mounted for linear movement about an axis and preferably comprises multiple robotic arms, each with a print head for distribution of microarrays on slides. The cooperative motion of each segment of the platter combined with the independently-controlled motion of the arms forms a more efficient method of creating microarrays upon multiple, often many, slides. In addition, the use of multiple robotic arms and print heads deposits the microarrays on the slides much faster. The microarrayer spots samples (such as DNA or, protein,) from microtiter sample plates onto microscope slides using the robotic arms. The microtiter sample plates can either be placed onto the sub-platters or adjacent thereto next to washing and drying stations. As in the prior art, the print head comprises print head pins for picking up fluid and depositing in a microarray pattern. A z-axis motor drops and lifts the print head as needed to accomplish the washing, drying, sample collection and microarray deposition functions.

Outside the microtiter plates, relative to the platter, lay a wash station for washing the print head pins and a dry station for drying them. The print heads simultaneously pick up samples from the microtiter plates, and each, through independent motion, drop down to spot the microscope slides that are linearly and radially placed on the platter. The print head pins are then washed and dried, and new samples (from the same or replacement sample microtiter plates) are picked up. The spotting is repeated until all samples have been spotted (microarrayed). Through the simultaneous use of multiple print heads and a subdivided platter having independently- controlled sub-platters, the speed of microarray production is increased. hi one aspect, the invention relates to an apparatus for printing microarrays of at least one substance on at least one slide comprising: a base; a first platter and a second platter mounted to the base for movement along a first axis, the first platter and the second platter being independently-controllable with respect to each other; at least one arm mounted to the base above the first and second platters for movement with respect to a second axis normal to the first axis; and a print head mounted to the at least one arm for reciprocating movement along a third axis normal to both the first and second axes. The print head can have at least one substance-dispensing device thereon. The at least one substance can thereby be printed onto the at least one slide in the form of a microarray by the independent incremental movement of the platter along the first axis, the movement of the at least one arm along the second axis, and by the reciprocating movement of the print head along the third axis. In various embodiments of the invention, a controller can be operably interconnected to the first and second platters, to the at least one arm and to the print head for controlling the movement of the planers, the at least one arm and the print head. At leas^4" one of the first and second platters can be rectangular. The at least one. slide can comprise several slides arranged on the first and second platters in a predetermined configuration. The at least one arm can comprise at least two arms mounted to the base above the first and second platters for independently-controllable movement with respect to the second axis over both of the first and second platters. One of the first and second platters can comprise an elongated rectangular member aligned in generally parallel configuration with the other of the first and second platters. The controller can control the movement of the first and second platters, the at least one arm and the print head associated with the at least one arm independently of one another.

In another aspect, the invention relates to a method of printing microarrays of at least one substance on at least two slides comprising the steps of: loading a print head with the at least one substance; positioning the print head over one of the at least two slides on a first platter; depositing the at least one substance on the print head onto the one of the at least two slides on the first platter; repositioning the print head over another of the at least two slides on a second platter, the second platter being physically separate from the first platter; and depositing the at least one substance on the print head onto the another of the at least two slides on the second platter.

In various other embodiments of the invention, the method can also include the steps of: indexing one of the first and second platters in a linear direction independent of the other of the first and second platters; and/or depositing the at least one substance on the print head onto one of the at least two slides on one of the first and second platters occurs generally contemporaneously with the step of linearly indexing the other of the first and second platters. The at least two slides can comprise several slides. These steps can be repeated until the at least two slides have a predetermined number of deposits thereon.

BRIEF DESCRIPTION OF THE DRAWINGS OF THE INVENTION

In the drawings: FIG. 1 is a perspective view of a prior art linear microarrayer comprising a platter mounted for linear y-axis movement with respect to a table, a robotic arm mounted for x axis movement with respect to ths table located above the table on a bracket, and. a depending print head mounted to the bracket for z-axis movement.

FIG. 2 is an enlarged perspective view of the prior art platter of FIG. 1 wherein the platter has a pattern of raised alignment knobs for aligning a matrix of slides along x- and y-axes of the platter.

FIG. 3 is an enlarged, fragmentary perspective view of the prior art platter, specifically with reference to the area marked HI of FIG. 2.

FIG. 4 is a perspective view of an example of a prior art sample tray typically employed with the prior art platter of FIGS. 1-3. FIG. 5 is a perspective view of an example of a prior art rack of print head pins typically employed with the prior art print head of FIG. 1.

FIG. 6 is a perspective view of the prior art linear microarrayer of FIG. 1 wherein the print head has been traversed along the x-axis to be aligned with a washing station and traversed in oscillating fashion along the z-axis to insert the print head into and withdraw it from the washing station.

FIG. 7 is a perspective view of the prior art linear microarrayer of FIG. 1 wherein the print head has been traversed along the x-axis to be aligned with a drying station and traversed in oscillating fashion along the z-axis to insert the print head into and withdraw it from the drying station. FIG. 8 is a perspective view of the prior art linear microarrayer of FIG. 1 wherein the print head has been traversed along the x-axis to be aligned with a sample plate and traversed in oscillating fashion along the z-axis to insert the print head into and withdraw it from the sample plate.

FIG. 9 is a perspective view of the prior art linear microarrayer of FIG. 1 wherein the print head has been traversed along the x- and y-axes to be aligned in a serpentine-like path fashion with each of the slides on the platter in succession and traversed in oscillating fashion along the z-axis to contact the print head with and withdraw it from each of the slides in succession to deposit a sub-microarray on each slide. FIG. 10 is Li perspective view of an embodiment of a microarrayer according to the invention comprising a platter split into two sub-platters, wherein each sub-platter has an associated robotic arm with a corresponding print head.

FIG. 11 is a schematic view from a top plan perspective of the microarrayer of FIG. 10 showing a first and a second sub-platter in a generally medial position with respect to a y-axis and a first and a second robotic arm associated with the first and second sub-platters, respectively.

FIG. 12 is a schematic view in the same orientation as FIG. 11 showing the first sub-platter positioned in a generally rearward position with respect to the y-axis and the second sub-platter independently positioned in a generally medial position with respect to the y-axis.

FIG. 13 is a schematic view in the same orientation as FIG. 11 showing the first sub-platter positioned in a generally forward position with respect to the y-axis and the second sub-platter independently positioned in a generally medial position with respect to the y-axis.

FIG. 14 is a schematic view in the same orientation as FIG. 11 showing the first sub-platter positioned in a generally rearward position with respect to the y-axis and the second sub-platter independently positioned in a generally forward position with respect to the y-axis. FIG. 15 is a schematic view from a top plan perspective of the microarrayer of

FIG. 10 showing P sub-platters in a generally medial position with respect to a y-axis and A robotic arms associated with the P sub-platters, respectively, and H print heads associated with each of the A robotic arms, illustrating that the inventive concepts related to the microarrayer described herein can be applied to any number of multiple sub-platters, arms and print heads.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Referring now to the drawings and to Fig. 10, in particular, it will be understood that the following description of a microarrayer 110 shown in the drawings according to the invention employs reference numerals increased by 100 for elements of the prior art microarrayers described in the prior art section above. In addition, the reference numerals also employ a hyphenated convention for element'; with multiple components (e.g., a microarrayer platter according to the invention is split into P sub-platters 112-1, 112-2, 112-3, ..., 112-P, A robotic arms 126-1, 126-2, 126-3, ..., 126-A, and lϊ print heads 134-1, 134-2, 134-3, ..., 134-H) each independently controllable by a controller 156. Although the embodiment of FIGS. 10-14 shows the microarrayer having two sub- platters 112-1, 112-2, two arms 126-1, 126-2, and two print heads 134-1, 134-2, i.e., P = A = H = 2, it will also be understood that additional or fewer as well as unequal numbers of each of the sub-platters 112, arms 126 and print heads 134 can be employed without departing from the scope of this invention as long as at least one of P, A or H is greater than one as shown in the general schematic of FIG. 15.

Variables employed herein to describe the structure, assembly and operation of the split-platter microarrayer 110 are as follows (as used herein, the "zero location" term means a calibrated Cartesian-based position corresponding to a (0,0,0) coordinate location):

It has been found that certain constraints placed on the above variables provides greater efficiencies during the deposition of microarrays on the S slides. Preferably, the number of sub-platters 112 is equal to the number of arms 126:

P = A allowing each arm 1..A to independently deposit specimens on ?• corresponding sub- platter 1..P.

The axial location of each of the platters Y(1..P) as well as the lateral location of each of the robotic arms X(1..A) would be tracked by the controller 156 for this system. The controller 156 also tracks the z-location Z(1..H) of each print head. The controller 156 would also calibrate the axial and lateral distances between each of the arms 1..A and the sub-platters 1..P. The number of slides S located on each of the sub-platters 1..P can be tracked by the controller 156. It has been determined that the most efficient printing patterns can be obtained if each sub-platter 1..P is provided with an equal number of slides, or:

subplatter slides = — . A

Referring to FIGS. 10-14, the microarrayer 110 preferably comprises a platter

112 sub-divided into at least two sub-platters 112-1, 112-2 mounted adjacent to one another for linear movement about a y-axis with respect to a table 114 upon a linear slide 116-1 and 116-2 and powered by a motor (not shown in the perspective view of FIG. 10 but configured, selected and mounted in similar fashion as the prior art . microarrayer 10 shown by example in FIG. 1). Examples of suitable motors can include indexable linear slides, motors, servomotors, and the like. The motor is preferably operably interconnected to the linear slides to perform precise, indexable movement of each of the sub-platters 112-1, 112-2, ... , of the microarrayer 110.

The table 114 further includes A arch structures 120-1, 120-2 comprising a pair of legs 122-1, 122-2 interconnected at upper portions thereof by at least one cross member 124-1, 124-2. Each cross member 124 defines rails on which a corresponding one of the A robotic arms 126 are mounted for linear x-axis movement via a linear slide 128-1, 128-2 and each is powered by a second motor 130-1, 130-2. Each robotic arm 126-1, 126-2 preferably comprises a body 132-1, 132-2 defining rails on which a print head 134-1, 134-2 is mounted for linear z-axis movement via a linear slide 136-1, 136-2 and powered by a third motor 138-1, 138-2. The first motor 118-1, 118-2 and each of the second and third motors 130-1, 130-2 and 138-1, 138-2 respectively corresponding to each of the robotic arms 126-1, 126-2, are known members for imparting linear movement to the slides 178-1, 128-2 and 136-1, 136-2, respectively.

The print head 134-1, 134-2 is a well-known member typically comprising the matrix of closely-spaced pin-like print head pins 140-1, 140-2 biased by a spring (not shown) to perform the microarray deposition function as described with respect to the print head 34 and the print head pins 40 in the Background section of this specification.

Other typical components typically employed with prior art microarrayers 10 are also included with respect to the inventive microarrayer 110 of this invention — but preferably the microarrayer 110 includes one of these typical components corresponding to each of the robotic arms 126-1, 126-2. Thus, in the example of the microarrayer 110 shown in FIG. 10, a washing station 142-1, 142-2, a drying station 144-1, 144-2 fluidly interconnected to a vacuum source 146 and a sample plate 148 are shown on the table 114 for each of the robotic arms 126-1, 126-2. As noted above, additional or fewer robotic arms 126 (and thus additional or fewer components 142-148) can be employed without departing from the scope of this invention. Also, a single washing station 142 and a single drying station 144 can be employed for space- saving and/or cost-saving purposes (e.g., the single washing and drying stations can be located on a sub-platter 112 so that the stations 142, 144 can be selectively aligned with one or more arms 126). Further, the drying station(s) 144 can be interconnected to a common vacuum source 146.

In use, after a predetermined number of print head pins 140-1, 140-2 have been installed on each of the H print heads 134-1, 134-2 and this information fed to the controller 156, each of the platters 112-1, 112-2 is positioned in a "home" position where the sample plate 148 located on or adjacent to each sub-platter 112-1, 112-2 is positioned adjacent to the corresponding side-by-side washing and drying stations 142-1, 142-2 and 144-1 and 144-2, respectively.

Each print head 134-1, 134-2 is positioned along the x-axis in vertical alignment above the corresponding washing station 142-1, 142-2 and can be lowered and raised in oscillating fashion along the z-axis to insert the corresponding print head 134-1, 134-2 into and withdraw it from the corresponding washing station 142-1, 142-

This x- and z-axis movement, and subsequently described x- and z-axis movements are accomplished by the controller 156 sending signals to each of the second and third motors 130 and 138 to actuate the second and third slides 128 and 136, respectively, for each of the A arms. Each of the sub-platters 112-1, 112-2 can be positioned in along the y-axis by actuating the corresponding first motor 118. Then, as shown in FIG. 12, each of the print heads 134-1, 134-2 is traversed along the x-axis into alignment with the corresponding drying station 144-1, 144-2 and traversed in oscillating fashion along the z-axis to insert the print head 134-1, 134-2 into and withdraw it from the corresponding drying station 144-1, 144-2. As the print head pins 140-1, 140-2 of the particular print head 134-1, 134-2 descends into the corresponding drying station 144-1, 144-2, the controller 156 typically sends a signal to the vacuum source 146 to apply suction for removal of any remaining material and washing station fluid from the pins 140-1, 144-2.

As was described in the Background section, the positioning of the print head 134-1, 134-2 within the washing station 142-1, 142-2 and subsequently within the drying station 144-1, 144-2 can be repeated for multiple cycles to ensure an effective cleaning of the print head pins 140-1, 144-2. The print heads 134-1, 134-2 are then moved with respect to the table 114 after the print heads 134-1, 134-2 have traversed along the x-axis into alignment with the corresponding sample plate 148-1, 148-2 and traversed in oscillating fashion along the z-axis to insert each of the print heads 134-1, 134-2 into (and subsequently to be withdrawn from) the wells of the corresponding sample plate 148-1, 148-2. This descent of the print head pins 140-1, 140-2 into the wells that contain a volume of material desired to be deposited on slides 158 (positioned on each of the sub-platters 112-1, 112-2) accumulates a small volume of the material to be deposited within each of the print head pins 140-1, 140-2.

The microarrayer 110 is then at the stage wherein each print head 134-1, 134-2 traverses along the x-axis in an orderly path (such as a serpentine path) and is positioned over slides 158 that are arrayed linearly on each of the sub-platters 112-1, 112-2. Each print head 134-1, 134-2 also traverses in oscillating fashion along the z- axis to contact the print head pins 140- 1, 140-2 of each of the print heads 134-1, 134-2 with (and subsequently to be raised from) each of the slides 158 positioned along the particular robotic arm's path. During this contact, the print head pins 140-1, 140-2 deposit a sub-microarray on each slide 158. Once the path has been completed, the controller 156 issues a signal to the first motor 118-1, 118-2 (potentially independently of one another) to linearly move the corresponding sub-platter 112-1, 112-2, to a next successive linear y-axis position. Then each of the print heads 134-1, 134-2 traverses again in the opposite direction along the x-axis to deposit microarrays on slides 158 that are arrayed along successive locations on each sub-platter 112-1, 112-2.

It will be understood that each print head 134 would likely finish one entire sub-platter 112 before moving on to the next sub-platter 112. Of course, depending upon the value of the SameSub variable in the controller, other sub-platters may not need to be spotted if other print head(s) 134 contain the same substance - as indicated by the value of the SameSub variable or array. Samples would not be typically needed to be reloaded on the print head(s) 134 until each of the sub-platters 112 were completely spotted.

Although the drawings show multiple print heads 134 acting in unison, i.e., having the same general position with respect to each sub-platter 112, each of the print heads 134-1, 134-2 can be independently controlled by the controller 156. For example, if one of the print heads 134-1, 134-2 had a different number of print head pins 140-1, 140-2 than another print head 134-1, 134-2 (thus requiring a different number of passes to place the same number of spots on the slides), the controller 156 need merely adjust the x-axis positioning of the skewed print head(s) 134 and control each sub-platter 112 to refrain from a y-axis repositioning step until each of the print heads 134 has completed its prescribed spotting along its corresponding path 170.

Through the use of multiple print heads 134 on multiple robotic arms 126, the speed of making microarrays is increased in proportion to the increase in the number of print heads 134 that are accommodated by the sub-divided platter format of the inventive microarrayer 110. The proportional increase in the speed of microarray deposition is believed even to exceed a direct fractional- relationship. For example, at first glance, it appears that adding a second robotic arm 126-2 with a second print head 134-2 (in addition to the first robotic arm 126-1 with its associated print head 134-1) should permit spotting of the same number of slides with the same number of spots in exactly one-half of the time. However, it is expected that the increase in speed will be even greater. The split-platter and the potential for simultaneous operation of multiple arms and print heads contribute to this basis for the unexpected benefits of the performance of the multiple sub-platter, multiple arm microarrayer 110 described herein as compared to the prior art microarrayer 10.

FIGS. 11-14 also illustrate, by way of example, the flexibility of the microarrayer 110 described herein. FIG. 11 is a schematic view from a top plan perspective of the microarrayer of FIG. 10 showing a first and a second sub-platter 112-1 and 112-2 in a generally medial position with respect to a y-axis and a first and a second robotic arm 126-1 and 126-2 associated with the first and second sub- platters, respectively. FIG. 12 shows the first sub-platter 112-1 positioned in a generally rearward position with respect to the y-axis and the second sub-platter 112-2 independently positioned in a generally medial position with respect to the y-axis. FIG. 13 shows the first sub-platter 112-1 positioned in a generally forward position with respect to the y-axis and the second sub-platter 112-2 independently positioned in a generally medial position with respect to the y-axis. FIG. 14 shows the first sub- platter 112-1 positioned in a generally rearward position with respect to the y-axis and the second sub-platter 112-2 independently positioned in a generally forward position with respect to the y-axis. This independent control of the multiple sub-platters (to the extent a subdivided platter 112 is employed) allows for greater control over the microarrayer process. For example, if a first microtiter plate 148-1 had a different number of samples than a second microtiter plate 148-2, the arms 126-1 and 126-2 can move at different rates, i.e., the deposition of the samples is not slowed to the lowest common denominator as well as allowing deposition of additional samples simultaneously through the use of multiple arms 126 (and, thus, multiple print heads 134). This invention also contemplates the further sub-d ision of the platter 112 and the provision of additional arms 126 and print heads 134. FIG. 15 shows this example taken to its broadest sense in which P sub-platters (positioned in a generally medial position with respect to a y-axis) and A robotic arms associated with the P sub- platters, respectively, and H print heads associated with each of the A robotic arms are employed.

Of course, as with all of the FIGS. 11-15, each of the sub-platters 112, the arms 124 and the print heads 134 are interconnected by appropriate connections to the controller 156. When a split platter 112 is employed in accordance with the invention described herein, (as opposed to simply having two print heads 134 on one or two arms 126), it becomes possible for two or more arms 126 and two or more print heads 134 to continuously traverse over the platter sub-segments. With only a single platter, when one print head 134-1 is printing at the edge of the platter, any other print heads may be unavoidably positioned outside the perimeter of the platter due to the y-axis spacing of the arms. The split platter 112 described herein eliminates that problem, so that the individual platters 112-1, 112-2, ..., 112-P are adjusted to the different y-axis locations of the print heads 134-1, 134-2, ..., 134-H.

The controller 156 can take any suitable form, such as a programmable logic controller (PLC), a computer, a microprocessor, or any other known way by which the components of the inventive microarrayer described herein can be independently controlled.

While the invention has been described in connection with certain specific embodiments thereof, it is to be understood that this is by way of illustration and not of limitation. Reasonable variation and modification are possible within the scope of the forgoing description of the invention without departing from the spirit of the invention.

Claims

CLAIMSThe embodiments for which an exclusive property or privilege is claimed are defined as follows:

1. An apparatus for printing microarrays of at least one substance on at least one slide comprising: a base; a first platter and a second platter mounted to the base for movement along a first axis, the first platter and the second platter being independently-controllable with respect to each other; at least one arm mounted to the base above the first and second platters for movement with respect to a second axis normal to the first axis; and a print head mounted to the at least one arm for reciprocating movement along a third axis normal to both the first and second axes, the print head having at least one substance-dispensing device thereon; whereby the at least one substance can be printed onto the at least one slide in the form of a microarray by the independent incremental movement of the platter along the first axis, the movement of the at least one arm along the second axis, and by the reciprocating movement of the print head along the third axis.

2. The apparatus of claim 1 and further comprising a controller operably interconnected to the first and second platters, to the at least one arm and to the print head for controlling the movement of the platters, the at least one arm and the print head.

3. The apparatus of claim 2 wherein at least one of the first and second platters is rectangular.

4. The apparatus of claim 3 wherein the at least one slide comprises several slides arranged on the first and second platters in a predetermined configuration.

5. The apparatus of claim 4 wherein the at least one arm comprises at least two arms mounted to the base above the first and second platters for independently-controllable movement with respect to the second axis over both of the first and second platters.

6. The apparatus of claim 5 wherein one of the first and second platters comprises an elongated rectangular member aligned in generally parallel configuration with the other of the first and second platters.

7. The apparatus of claim 2 wherein the controller controls the movement of the first and second platters, the at least one<arm and the print head associated with the at least one arm independently of one another.

8. The apparatus of claim 1 wherein at least one of the first and second platters is rectangular.

9. The apparatus of claim 1 wherein the at least one slide comprises several slides arranged on each of the first and second platters in a predetermined configuration.

10. The apparatus of claim 1 wherein the at least one arm comprises at least two arms mounted to the base above both of the first and second platters for independently-controllable movement with respect to the second axis.

11. The apparatus of claim 1 wherein one of the first and second platters comprises an elongated rectangular member aligned in generally parallel configuration with the other of the first and second platters.

12. The apparatus of claim 1 and further comprising a controller wnich controls the movement of the first and second platters, the at least one arm and the print head associated with the at least one arm independently of one another.

13. A method of printing microarrays of at least one substance on at least two slides comprising the steps of: loading a print head with the at least one substance; positioning the print head over one of the at least two slides on a first platter; depositing the at least one substance on the print head onto the one of the at least two slides on the first platter; repositioning the print head over another of the at least two slides on a second platter, the second platter being physically separate from the first platter; and depositing the at least one substance on the print head onto the another of the at least two slides on the second platter.

14. The method of claim 13 and further comprising the step of indexing one of the first and second platters in a linear direction independent of the other of the first and second platters.

15. The method of claim 14 wherein the step of depositing the at least one substance on the print head onto one of the at least two slides on one of the first and second platters occurs generally contemporaneously with the step of linearly indexing the other of the first and second platters.

16. The method of claim 15 wherein the at least two slides comprise several slides.

17. The method of claim 16 wherein these steps are repeated until the at least two slides have a predetermined number of deposits thereon.

18. The method of claim 13 wherein the at least two sli ^y= -comprise several slides.

95 19. The method of claim 13 wherein these steps are repeated until the at least two slides have a predetermined number of deposits thereon.