Patent Abstract:
An apparatus and method for transferring plurality of samples from one sample container to another one is disclosed wherein each sample is randomly accessible and can be “cherry picked”. The disclosed method of actuation allows for using a smaller number of actuators than the number of sample transferring channels or pins and thereby simplifies the design and control of the sample transferring apparatus.

Full Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is a Divisional of U.S. Ser. No. 13/409,620 filed on Mar. 1, 2012, which is a Divisional of U.S. Ser. No. 11/557 filed on Nov. 6, 2006, which received U.S. Pat. No. 8,150,548, issued on Apr. 3, 2012, which claims priority to U.S. Provisional Patent Application No. 60/733,765 filed on Nov. 7, 2005. 
    
    
     BACKGROUND 
     1. Field 
     This invention relates to the field of process automation devices, and, in particular, to automation devices used in processes to be performed on chemical, biochemical, or biological samples and specimens. 
     2. Related Art 
     The use of automation in laboratory environments and pharmaceutical, manufacturing, and packaging or similar industries is well known. In molecular biology laboratories, for example, automation is used to transfer, mix, store, detect and analyze biological samples such as DNA, proteins, cells, tissues or similar samples in a high-throughput manner. In pharmaceutical industries automation is commonly used, for example, for high-throughput screening of compound libraries for discovering a new drug. Such processes usually involve one or more work samples that must go through different operations. Typically, such a system consists of a plurality of devices each of which performs one or more operations on a work sample. In laboratory environments, typically, standard labware or containers are used to hold a plurality of work samples, and a robot or a conveyer is employed to transfer the labware or containers from one device to another. The process, which consists of a set of work samples and operations is usually defined by a process manager, and may need to be re-defined from time to time. Therefore, the majority of such systems include a Computer Processing Unit (CPU) with a software package, which offers a Graphical User Interface (GUI) to the process manager for defining a new process and for running, monitoring, and controlling a process on the said plurality of devices. 
     While there are currently a number of such process automation systems in the market, there are several drawbacks to such systems. The currently available systems typically consist of a plurality of standalone and specialized instruments, such as for example a liquid handling robot, incubators and plate stackers that are integrated using a control computer and software that communicates with all such devices and synchronizes their operation. The drawback of integrating such specialized instruments is usually an increased complexity, higher cost, and lack of enough flexibility and scalability. Another drawback is that such independent instruments do not fully utilize the vertical dimension, which eventually leads to an increased footprint of the system. Also, the current systems typically use a multi-degree of freedom robot or a conveyer belt to transfer the samples. Such transfer mechanisms normally lack the precision required for high-precision operations such as microarraying. Therefore, the work sample has to first be transferred to a precise holder before any operations can be performed upon. Lack of specialized tools such as for example a very high-density pinhead is another shortcoming. 
     Accordingly, it would be advantageous to build a complex process automation system from mostly identical simpler building blocks that could be rearranged and installed in different configurations and could be equipped with a plurality of tools. It would also be advantageous to effectively utilize the vertical space in order to minimize the footprint. Further, it would be advantageous to utilize a high-precision transfer device or conveyer to transfer work samples and at the same time locate the samples for high-precision operations. 
     SUMMARY 
     One object of the invention is to provide a process automation apparatus in which the core of the system is made of mostly similar building blocks, called functional modules. This provides a modular, reconfigurable, and fully scalable approach to automation of processes that are typically found in laboratory environments, pharmaceutical industries, and high-precision manufacturing lines. Such modularity and scalability can be implemented in hardware and software of the apparatus. 
     Another object of the invention is to provide a process automation apparatus that minimizes the overall footprint by effectively using the available vertical space (Z direction). 
     Another object of the invention is to provide a process automation apparatus in which one or more functional modules are arranged along a precise conveyer device such that the conveyer constitutes the X-axis for the functional modules. Therefore, a functional module needs to move the tool in only two directions of Y and Z in order to achieve the full functionality of a 3D X, Y, and Z gantry robot. 
     Another object of the invention is to provide specialized tools and sub-modules for the said process automation apparatus. That includes a very high-density pinhead tool, a re-arrayer pinhead tool and a wash tower sub-module. 
     Another object of the invention is to provide a process automation apparatus in which a computer having user interface elements such as display, keyboard, mouse, and control software is operably connected to the said plurality devices and tools. The control software provides a graphical user interface (GUI) for the user to define new processes or edit the existing ones, and it supports the reconfigurability and scalability features of the hardware. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
       The invention is described by way of example only, with reference to the accompanying drawings, in which: 
         FIG. 1  is a perspective view of an exemplary configuration of the modular and scalable apparatus for automating a process in accordance with an embodiment of the present invention; 
         FIG. 2  is an illustration corresponding to  FIG. 1 , but showing a schematic top view of the exemplary configuration of the modular apparatus in accordance with an embodiment of the present invention; 
         FIG. 3  is a perspective view of an example functional module used in the modular apparatus in accordance with an embodiment of the present invention; 
         FIGS. 4A-4C  correspond to  FIG. 3 , but show the movement of the general purpose tool interface of the present invention in Y and Z directions, in accordance with an embodiment of the present invention; 
         FIGS. 5A and 5B  correspond to  FIGS. 4A and 4B  respectively, but show a schematic top view of the functional module and the movement of the tool interface in Y direction, in accordance with an embodiment of the present invention; 
         FIG. 6  is a perspective view of the tool interface and an exemplary gripping tool attached to the horizontal interface plane in accordance with an embodiment of the present invention; 
         FIG. 7  is a perspective view of the tool interface and an exemplary pinhead tool attached to the horizontal interface plane in accordance with an embodiment of the present invention; 
         FIG. 8  is a schematic top view of a high-capacity labware stacking device comprising a functional module with a rotary base and a plurality of shelves, in accordance with an embodiment of the present invention; 
         FIG. 9  is a schematic top view of another exemplary configuration of the modular and scalable apparatus for automating a process in accordance with an embodiment of the present invention; 
         FIG. 10  is a schematic top view of another exemplary configuration of the modular and scalable apparatus for automating a process in accordance with an embodiment of the present invention; 
         FIG. 11  is a perspective view of a wash tower sub-module of the modular apparatus of an embodiment of the present invention; 
         FIG. 12  is a perspective view corresponding to  FIG. 11 , but shows the assembly of side panels and a wash basin, in accordance with an embodiment of the present invention; 
         FIG. 13  is a perspective view corresponding to  FIG. 11 , but shows another arrangement of the wash stations in which a wash basin is replaced with circular brush station, in accordance with an embodiment of the present invention; 
         FIG. 14  is a perspective view showing the components and assembly of a circular wash station, in accordance with an embodiment of the present invention; 
         FIG. 15  corresponds to  FIG. 14 , but shows cross-sectional views of a circular wash station assembly, in accordance with an embodiment of the present invention; 
         FIG. 16  is a perspective view showing the components and assembly of a circular brush station, in accordance with an embodiment of the present invention; 
         FIG. 17  is a top view of an example replicating pinhead tool of the modular apparatus of an embodiment of the present invention; 
         FIG. 18  corresponds to  FIG. 17 , but shows the first option for constructing the replicating pinhead tool, in accordance with an embodiment of the present invention; 
         FIG. 19A  corresponds to  FIG. 17 , but shows the top view of a 96-pin replicating tool, in accordance with an embodiment of the present invention; 
         FIG. 19B  corresponds to  FIG. 17 , but shows the top view of a 384-pin replicating tool, in accordance with an embodiment of the present invention; 
         FIG. 19C  corresponds to  FIG. 17 , but shows the top view of a 768-pin replicating tool, in accordance with an embodiment of the present invention; 
         FIG. 19D  corresponds to  FIG. 17 , but shows the top view of a 1536-pin replicating tool, in accordance with an embodiment of the present invention; 
         FIG. 20  illustrates a sample plate with 1536 different colonies of Yeast cells made by a 1536-pin replicating tool of  FIG. 19D , in accordance with an embodiment of the present invention; 
         FIG. 21  corresponds to  FIG. 17 , but shows the second option for constructing the replicating pinhead tool, in accordance with an embodiment of the present invention; 
         FIG. 22  is a perspective view of a 96-pin re-arraying pinhead tool of the modular apparatus of an embodiment of the present invention; 
         FIG. 23  corresponds to  FIG. 22 , but shows the side view of a re-arraying tool with 96 separately indexable pins, in accordance with an embodiment of the present invention; 
         FIG. 24  corresponds to  FIG. 22 , but shows the cross-section of one exemplary pin with its guiding and actuation mechanism, in accordance with an embodiment of the present invention; 
         FIG. 25  corresponds to  FIG. 24 , but shows the cross-section of one exemplary pin with its actuation mechanism during the operation, in accordance with an embodiment of the present invention; 
     
    
    
     DETAILED DESCRIPTION 
     In the following description, for purposes of explanation, numerous specific details are set forth in order to provide a thorough understanding of the invention. It will be apparent, however, to one skilled in the art that the invention can be practiced without these specific details. 
     Reference in this specification to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. The appearances of the phrase “in one embodiment” in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments. Moreover, various features are described which may be exhibited by some embodiments and not by others. Similarly, various requirements are described which may be requirements for some embodiments but not other embodiments. 
       FIG. 1  illustrates an exemplary configuration  10  of a modular and scalable apparatus for process automation according to an embodiment of the present invention (hereinafter referred to as an automation system). The automation system  10  for example can be used for replicating or transferring an array of biological samples (e.g., Yeast cells) from one sample container to another one. It is to be understood that the automation systems disclosed herein are not limited to the configuration shown in  FIG. 1 . This will become more evident in subsequent parts of this document where other exemplary configurations of such a system are disclosed. 
       FIG. 2  is an illustration corresponding to  FIG. 1 , but showing a schematic top view of the automation system  10 , in accordance with an embodiment of the present invention. As illustrated in  FIGS. 1 and 2 , one embodiment of the process automation system  10  of the present invention comprises a plurality of functional modules  20 , at least one conveyer  50 , a plurality of tools  42  and  80 , and sub-modules  60  and  70 . The conveyer comprises a tray  52 , which has one or more holders  54  for holding sample containers  98 . The containers  98  are precisely locked in position using actuators  55  and are transferred from one functional module  20  or station to another one by the conveyer  50 . 
     A functional module  20  comprises at least one general-purpose tool interface  26  and a device for moving the tool interface in space. In a preferred embodiment, a functional module  20  comprises a device  22  for moving in Z or vertical direction and a device  24  for moving in Y or horizontal direction towards the sub-modules  60  or  70 . A typical process involves one or more work samples that have to go through a series of operations. Work samples can be any liquid solution or solid components and in one embodiment comprise biological, biochemical or chemical samples such as Yeast, bacteria or other types of cells, DNA, RNA or protein solution samples that are carried in one or more sample containers or labware  98 .  FIG. 20  shows an exemplary sample plate  98  that carries an array of 1536 different colonies of Yeast cells  96 . The cell colonies are grown on a proper growth media  97 . 
     A functional module  20  performs at least one operation on work samples or sample containers. The operation of a functional module  20  is normally determined by the type of tool(s) and sub-module(s) that are operably connected to it. Such a combination of a functional module  20  and a tool(s) and sub-module(s) that are operably connected to it is hereinafter referred to as a machine. For example, in  FIG. 1  (from the right side) and  FIG. 2  (from the left side), each of the first two functional modules  20  is equipped with a gripping tool  42  and a shelf sub-module  60 . The third functional module  20  in  FIG. 1  is equipped with a replicating tool  80  and a wash-tower sub-module  70 . Therefore, there are three machines  11 ,  12 , and  13  and one conveyer  50  in the exemplary automation system embodiment illustrated in  FIG. 1 or 2 . The first two machines  11  and  12  are hereinafter referred to as plate stackers and the third machine is hereinafter referred to as a plate replicator. 
     A plate stacker machine  11  or  12  comprises a functional module  20 , a gripping tool  42 , and a shelf sub-module  60 . The shelf sub-module  60  comprises a plurality of shelves  62 . A shelf is used to store a sample container (hereinafter also called a “plate” or a “micro-titer plate”)  98  in a process. A gripping tool  42  is used by a functional module  20  to grip and transfer a plate from one location to another one, e.g., from a stacker shelf  62  to a conveyer holder  54 , from one stacker shelf  62  to another stacker shelf  62 , or from a conveyer holder  54  to a stacker shelf  62 . A gripping tool  42  is also used to remove the lid of a sample container  98 , to hold a lid or a container in space, or to put back the lid of a sample container  98 . 
     A plate replicator machine  13  comprises a functional module  20 , a replicating tool  80 , and a wash-tower sub-module  70  as illustrated in  FIG. 1  in accordance with an embodiment of the present invention. The machine is used to replicate or transfer an array of work samples such as Yeast cells from one sample container  98  to another one. It is also used to re-format the samples, for example re-formatting four 96-format arrays into one 384-format array of samples. The replicating tool  80  will be described in more detail in subsequent parts of the document. The wash-tower  70  is used to clean and sterilize the replicating tool  80  after a replication and also to pre-condition or pre-wet the tool before a replication. A wash-tower  70  comprises several units (hereinafter also called “modules” or “devices”)  72 ,  74 ,  76 ,  78 , and  79 , wherein a module performs a specific cleaning or pre-conditioning operation. Such units of the wash-tower  70  will be described in more detail in subsequent parts of the document. 
     The abovementioned tools and sub-modules are only two examples of a group of tools and sub-modules that can be connected to a functional module  20  in order to create new machines in accordance with embodiments of the present invention. As should be obvious to one of ordinary skill in the art, an automation system embodiment of the present invention may suitably comprise other tools that are commonly used to automate laboratory processes, including but not limited to different formats of pipettors or liquid handling tools, bar-code readers, CCD (Charge Coupled Device) cameras, colony-picking tools, a magnetic pinhead, and microarraying print-heads. Similarly, by way of example and not limitation, a sub-module as disclosed herein may comprise a stacker shelf, a carousel, a stacker shelf within an incubator, a carousel with incubator, an incubator, a wash tower, a shaker, a centrifuge, a vacuum filteration manifold, a plate reader, a slide scanner, a gel reader, a magnetic stierer, a pierecer, a thermocycler, a plate reader, or a reagent library. 
     It is an advantageous aspect of automation system embodiments of the present invention that adding a new operation or functionality to the system is just a matter of replacing a tool and/or a sub-module. Also, it is to be appreciated that the number of functional modules  20  is not limited to three, and any number of them can be used to automate simpler or more complicated processes. This allows for said modularity, scalability, and reconfigurability of such an automation system. 
     In other words, the building blocks of such an automation system are the functional modules  20  and conveyer(s)  50 . Functional modules are equipped with suitable tools and/or sub-modules to perfoim operations on work samples, and the conveyers are used to transfer the work samples among the functional modules. The functional modules and conveyers are operably connected to at least one controller (hereinafter also referred to as a central processing unit (CPU)) with a human-machine interface (HMI) using one or more communication links. In one embodiment, one or more RS-232, RS-420, RS-485, universal serial bus (USB), or Ethernet links are used in order to exchange signals and commands. The CPU can be a personal computer with 8086 types of processors or any other personal or mini-computer or mainframe. The CPU controls, synchronizes, and integrates the operation of the functional modules, conveyers, and their tools and sub-modules, and the HMI provides a Graphical User Interface (GUI) for a user to define and excecute (or run) a desired laboratory or similar process. 
     A functional module  20  comprises a general-purpose tool interface  26  that provides a unified way for attaching one or more different tools. A functional module further comprises one or more devices such as  22  and  24  that move the tool interface  26  in one or more desired directions in space. In one embodiment, a functional module moves the tool interface  26  in Z and Y directions, as illustrated in  FIG. 4 .  FIG. 3  shows an exemplary embodiment of a functional module  20 , in accordance with an embodiment of the present invention. The device  22  comprises a motor  27  and a linear actuator  21  that are used to move the tool interface  26  in vertical or Z direction. Similarly, the device  24  comprises a motor  23  and a linear actuator  25  that are used to move the tool interface  26  in horizontal direction Y. Such movements are illustrated in  FIGS. 4 and 5 . It is to be appreciated that a functional module may comprise other types or directions of movements for more complicated operations. In one embodiment, a functional module also comprises an enclosure  41  that contains the required electrical, pneumatic and hydraulic components of the module, and a fixed base  94  that defines the location and orientation of the functional module in relation to the other devices in the automation system. 
       FIGS. 6 and 7  show the details of a general-purpose tool interface  26 , in accordance with an embodiment of the present invention. Two exemplary tools, i.e. a gripper  42  and a replicator  80  are shown to demonstrate the function of the general-purpose tool interface  26 . A general-purpose tool interface  26  comprises two interface planes: a vertical plane  28  and a horizontal plane  29 . The two interface planes have similar features, therefore only the interface plane  28  is described here. Having two interface planes instead of one is a unique feature that provides more flexibility in attaching tools to a functional module. Some tools, e.g. a gripper  42  or a replicator  80 , are more suitably attached to the horizontal interface plane  29  as shown in  FIGS. 6 and 7 , and some tools, e.g. a vertical CCD camera, are more suitably attached to a vertical interface plane, in accordance with embodiment of the present invention. More complicated tools may use both interface planes. 
     As illustrated in  FIG. 6 , an interface plane  28  comprises two accurate bushings  31  for precise mechanical registration of a tool with-respect-to the general-purpose tool interface  26 , a screw mechanism  35  and an access hole  34  for attaching or detaching a tool, a plurality of pneumatic or hydraulic ports  32 , and at least one electrical connector  30 , in accordance with an embodiment of the present invention. A tool has an attachment site  46  that is complementary to a tool interface plane  28  or  29 . This means that features on a tool interface plane  28  will suitably pair with corresponding features on a tool&#39;s attachment site  46 . For example, a tool comprises a threaded hole that matches the screw  35  of the general-purpose tool interface plane  26 , or pins that pair with the corresponding bushings  31  of the general-purpose tool interface  26 , and so on. Such an arrangement allows for the electrical and pneumatic or hydraulic connections required for the operation of a tool to be provided after the tool is attached to the interface device  26 . 
     For example, in  FIG. 6 , the gripping tool  42  comprises an attachment site  46 , a pneumatic actuator  45 , two aims  43  with two jaws  44 , and a switch that detects when the gripper is full or empty, in accordance with an embodiment of the present invention. One or more pneumatic lines required for the operation of the actuator  45 , and electrical wires for the detection switch, are automatically connected when the tool  42  is attached to the general-purpose tool interface device  26 . This provides a high level of modularity in which a tool can be easily exchanged in a matter of seconds. The tool exchange can be done manually or can be automated.  FIG. 7  shows how a replicating tool is attached to the tool interface device  26 , in accordance with an embodiment of the present invention. In this case, the replicating tool does not require any electrical, pneumatic, or hydraulic signals for its operation and only requires a mechanical attachment and a precise registration.  FIG. 17  shows the top view of a replicating tool in which the attachment site  46  is illustrated as part of the base plate  141 , in accordance with an embodiment of the present invention. Two mechanical pins  151  will pair with the bushings  31  of the tool interface plane  29  to provide a precise alignment of the tool after attachment. The mechanical attachment is achieved using a screw  35  on the bottom face  29  of the tool interface  26  and a threaded hole  152  on the tool  80 . The access to the bottom screw  35  is obtained through an access hole  34  on top of the tool interface  26  shown in  FIG. 7 . 
     A typical operation cycle of the automation system  10  in  FIG. 1  can be best described by way of example, according to an embodiment of the present invention. For purposes of exemplary illustration, consider that the user wants to replicate twenty sample containers  98  like the one shown in  FIG. 20  (hereinafter referred to as source plates) onto twenty blank sample containers (hereinafter referred to as destination plates). The steps are as follows:
         1. The user loads the shelves  62  of the first stacker machine  11  with twenty source plates and the shelves  62  of the second stacker machine  12  with twenty destination plates starting from the bottom shelf. To load the shelves  62 , the user rotates the shelf sub-module  60  on the base  95  so that the shelves face the user side. This orientation is illustrated in  FIG. 1  for the first stacker  11 . The sub-module  60  can also be removed from the base  95 , loaded outside, and put back on the base  95 . Each shelf  62  holds one source plate  98 . After loading all twenty plates, the user rotates the shelf sub-module  60  on the base  95  such that the shelves  62  face the functional module  20  (as illustrated in the second stacker machine  12 ).   2. The user runs a pre-defined procedure using the HMI of the CPU. A procedure defines the required steps for the system to complete a replication process.   3. Using the functional module  20  and the gripping tool  42 , machine  11  picks up one source plate, and machine  12  picks up one destination plate from their corresponding shelves  62 .   4. The conveyer  50  moves the tray  52  such that the right holder  54  stops in front of the functional module  20  of the first stacker  11 . The distance between the functional modules  20  of the machines  11  and  12  is made equal to the distance between the two holders  54  of the tray  52 . This allows that when the right holder  54  is in front of the functional module  20  of the first stacker  11 , the left holder is in front of the functional module  20  of the second stacker  12 .   5. The first stacker  11  puts the source plate on the right holder  54 , and simultaneously the second stacker  12  puts the destination plate on the left holder  54 . The plates  98  are locked in position using actuators  55 .   6. The first stacker  11  picks up the lid of the source plate, and holds the lid in a safe position above the conveyer.   7. The conveyer moves the tray towards the replicating machine  13  along the X-axis such that the source plate is positioned accurately in front of the replicating machine  13  (see  FIG. 2 ).   8. Referring to  FIG. 20 , the machine  13  picks up samples  96  from the container  98  using a replicating tool  80 . Referring to  FIG. 7 , a replicating tool  80  comprises a plurality of pins  144 , where each pin is used to pick up and replicate one sample  96  from the container  98 . When a pin  144  dips into a cell colony  96 , a large number of cells stick to the tip of the pin. If this pin touches the surface of a new or blank container, part of the cells are transferred (or replicated) onto the new surface. The result generally appears as a small spot on the new surface.   9. The conveyer moves the tray back to the original position such that the source plate is positioned in front of the first stacker  11 .   10. The first stacker  11  puts back the lid of the source plate, and simultaneously, the second stacker  12  picks up the lid of the destination plate.   11. The conveyer moves the tray towards the replicating machine  13  along the X-axis such that the destination plate is positioned accurately in front of the replicating machine  13  (see  FIG. 2 ).   12. The replicating machine  13  replicates the cells that stick to the pins  144  of the replicating tool  80  (see  FIG. 7 ) onto the blank surface of the destination plate.   13. The conveyer moves the tray back to the original position such that the destination plate is positioned in front of the second stacker  12 .   14. The second stacker  12  puts back the lid of the destination plate.   15. The replicating machine  13  starts sterilizing the pins  144  of the replicating tool  80  in the wash-tower sub-module  70 . The sterilization process comprises several steps of washing followed by a drying step at the end in the dryer station  79 . Washing steps comprise moving the replicating tool  80  to different wash stations  72 ,  76 , and  78 .   16. While the tool  80  is being washed, the stacker machines  11  and  12  pick up the first pair of source and destination plates  98  from the holders  54  (Note: the plates are unlocked by de-activating the actuators  55  before they can be picked up from the holders  54 ).   17. The first source and destination plates are put back on the shelves  62  and a new pair is removed from the shelves  62  and transferred to the conveyer holders  54 .   18. After the wash cycle is completed, the replicating process is started from the step 6 above.   19. Such a cycle is repeated until all 20 pairs of source and destination palates are processed.       

     It is to be appreciated that the above procedure is used only to illustrate an operation cycle by way of example, and it will not limit the user from automating any other processes by defining a new set of tasks. The user of the system can define any number of procedures using the provided Graphical User Interface (GUI) and store them for later use. 
       FIG. 11  shows a wash-tower sub-module  70 , according to an embodiment of the present invention. As illustrated in  FIG. 11 , a wash-tower  70  comprises a plurality of devices that are arranged vertically and each device is used to perform an operation on the tool such as pre-conditioning, cleaning, or drying. It is to be appreciated that the wash-tower  70  in  FIG. 11  is presented by way of example and the order, number, and type of devices in the wash-tower is not limited to the one shown in  FIG. 11 . For example,  FIG. 13  shows another configuration of a wash-tower  70  in which the wash basin  76  is replaced with a circular brush station  77 , in accordance with another embodiment of the present invention. A typical wash and sterilization operation involves several steps of cleaning in different solutions followed by a drying step. The number of cleaning steps and the type of solutions used in each step depend on the tool and work samples. For example, for a replicating tool  80  that uses an array of pins  144  (see  FIG. 7 ) for transferring biological samples such as Yeast cells from one sample plate to another one, the following cleaning procedure can be used:
         1. In a first step, the pins are dipped for about thirty seconds or more in the circular wash station  72  which is filled with distilled and de-ionized water. At this step, most contaminants such as Yeast cells tend to separate from the pins and float or subside at the bottom of the wash station. As will be illustrated later, the circular wash station is designed to completely drain, rinse and refill the wash station automatically after one wash or after every few washes. This helps reduce the likelihood of cross-contamination between the washes. Optionally, a wash station may be oval instead of circular.   2. In a second step, the pins are cleaned in an ultrasonic cleaner  78 , which is filled with water or diluted ethanol. The ultrasonic cleaner comprises a metal tank filled with a wash solution and an ultrasonic transducer that induces high-frequency waves inside the solution. The waves generate dynamic forces that separate contaminants from the pins.   3. After cleaning in the ultrasonic cleaner  78 , the pins are dipped in the wash basin  76 , which is filled with diluted ethanol or another disinfectant.   4. In a forth step, the pins are dipped in the second wash basin  76 , which is filled with 90% ethanol or similar solution. This step is generally the last step of sterilization and the first step of drying, as the 90% ethanol evaporates and dries quickly in air.   5. The dryer  79  then dries the pins by blowing warm air from the top.       

     After sterilization, the tool is ready for replicating another set of work samples. A pre-conditioning step might be needed in some cases. For example, it is observed that before replicating some biological samples such as Yeast cells, it would be advantageous to pre-wet the pins in distilled water. A pre-wetting station  74  is used for this purpose. This station comprises a container with a lid, and a lid-lifting mechanism. The lid is removed automatically for pre-wetting the tool, and after pre-wetting, it will be put back on the container to prevent contamination of the pre-wetting solution. 
       FIG. 12  shows an exemplary design of a wash-tower  70  with the main components and their assembly, in accordance with an embodiment of the present invention. The two side parts  105  constitute the main structure. The side covers  106  cover the longitudinal openings of the side parts  105 . Such openings are used to run liquid and gas tubes and electrical wires to the devices at different levels. By removing the side covers  106  one can access the electrical wires or tubes. In one embodiment, one side opening is used for running electrical wires and the other one is used for running tubes. Some devices, such as wash basin  76  and the ultrasonic cleaner  78  are mounted on shelves  107  such that they can slide out horizontally or completely removed (as shown in  FIG. 12  for the wash basin  76 ) for manual draining, cleaning, or refilling after completing a process. 
     As it is shown in  FIG. 12 , a wash basin  76  comprises a top frame  104  and a wash container  102  that can slide on shelves  107  using the side slots  103 . The top frame  104  prevents the liquid to splash out when the basin is filled and manually moved back to the original position shown in  FIG. 11 . 
       FIG. 13  shows another configuration of a wash-tower sub-module  70 , in which the first wash basin  76  in  FIG. 11  is replaced with a circular brush station  77  (see  FIG. 16  for details) for efficient cleaning of sticky samples, in accordance with an embodiment of the present invention. In this configuration, after the first step of cleaning in the circular wash station  72 , the pins are cleaned in a circular brush station  77  filled with diluted ethanol or other sterilization solutions, followed by the ultrasonic cleaner  78 , wash basin  76  with 90% ethanol, and the dryer  79 . 
     An optional embodiment of the automation system, specialized for pre-conditioning, cleaning, or drying, comprises a wash-tower sub-module  70  and a functional module  20 , but no conveyer  50 . An advantage of such an embodiment is that it takes advantage of vertical space and minimizes the footprint of the specialized automation system. 
       FIG. 16  shows the components and assembly of a circular brush station  77 , in accordance with an embodiment of the present invention. The base plate  122  is used to mount the circular brush station  77  on the wash-tower  70  (see  FIG. 13 ). In one embodiment, the base plate  122  is attached to the side parts  105  (see  FIG. 12 ) using screws. As is shown in  FIG. 16 , the circular brush station  77  comprises a rotating mechanism  125 , a container  127 , and a circular brush  128  and  129 . In one embodiment, a top cover  131  may be used to minimize splashing. The rotating mechanism  125  rotates around its central shaft using for example an electrical DC motor and a gear head (not shown in  FIG. 16 ). The gear head reduces the rotation speed to few revolutions per second and amplifies the motor torque. The container  127  contains the wash solution and the circular brush  128  and  129 . The circular brush comprises brushes  129  (only a few brushes are shown in  FIG. 16 ) that are permanently attached to a base  128  such that they become one component. The wash container  127  sits on the rotating mechanism  125  and rotates with the mechanism  125  using two pins  126 . The wash container  127  can be easily removed for manual draining, cleaning, and refilling of the container and the brush. In an embodiment of the present invention, a user lifts and removes the top cover  131 , followed by lifting and removing the circular container  127  with the brush  128  and  129 . Then, if needed, the user drains and cleans the container  127  and the brush  128  and  129 . The brush is placed back into the container, and the container  127  is filled with a proper wash solution. Then, the filled container  127  is put back on the rotating disc  125 , followed by putting back the top cover  131  on the container  127 . The top cover  131  is an optional element that freely sits on the top edge of the container  127  and is positioned between the two side parts  105  of the wash-tower  70  (see  FIG. 12 ). The two side parts  105  prevent the top cover  131  from rotating with the container  127 . The main function of the top cover  131  is to prevent the liquid from splashing out during the operation. 
     During the operation of the device  77 , the rotating mechanism  125 , container  127 , and circular brush  128  and  129  rotate together as shown in  FIG. 16 , in accordance with an embodiment of the present invention. While the brush  129  is rotating, the replicating tool  80  moves back and forth inside the rectangular window of the top cover in the direction shown in  FIG. 16 . The cleaning action happens when the tips of the pins  144  of the tool  80  (see  FIG. 7 ) are in touch with the rotating brush  129 . By moving the tool  80  back and forth, the pins, including the ones that are closer to the center of rotation, are cleaned properly and uniformly. 
       FIG. 14  shows the components and the assembly of a circular wash station  72 , in accordance with an embodiment of the present invention. It comprises a circular or oval container  112 , a top cover  113 , a centerpiece  116 , a drain valve  119 , and a metal ball  115 . The cross-section of the container is shown in  FIG. 15 . The container  112  has one or more side holes or ports  114 . In one embodiment, two side holes  114  (approximately 180° apart) are used. Through each side hole  114 , one tube is inserted into the container  112  tangent to the inside wall. The inserted tube(s) is used to pump a cleaning solution into the container  112 . The liquid enters the container  112  near the top and tangent to the inside wall (see the cross section in  FIG. 15 ). The liquid then follows a spiral path to the bottom of the container  112  towards the centerpiece  116 , creating a whirlpool. The liquid is drained through the side holes  117  and the exit port  118  of the centerpiece  116 , when the valve  119  is open. To improve the draining efficiency, vacuum is used to suck the liquid from the bottom of the valve  119 . The design of the centerpiece  116  and the existence of the metal ball  115  increase the efficiency of the suction. For example, if the centerpiece  116  and the metal ball  115  were not used and the liquid was drained directly through a centre hole, it would mostly drain air rather than liquid because the eye of the whirlpool would be located at that centre of the exit port. Therefore, instead of draining the liquid directly from the centre, the embodiment blocks the centre and uses the side holes  115  to drain the liquid. The metal ball  115  is used to break the symmetry of the whirlpool at the centre and improve the drain efficiency. Optionally, other obstacles, such as a dowel pin attached to the container near the centre, can be used instead of a ball for breaking the symmetry. But, the metal ball has the advantages of simplicity, cost, and performance. When the container  112  is being rinsed, the metal ball  115  slowly rolls inside the container and its own surface will get cleaned as well. 
     A typical operation cycle of a circular wash station  72 , in accordance with an embodiment of the present invention, is as follows:
         1. Fill operation:   To fill the container  112 , the drain valve  119  is closed, and the wash solution is pumped through the ports  114 , preferably with a slow speed in order to avoid creating a whirlpool. Optionally, another input port is used for filling the container.   2. When the wash station is used several times, the wash solution is generally contaminated and needs to be replaced. The container needs to be drained, rinsed, and refilled.   3. Drain operation:   The drain valve  119  is opened, and the contaminated solution is drained through the bottom hole  118  into a waste bottle. For faster draining, vacuum is applied to the waste bottle.   4. Rinse operation:   While the drain valve  119  is open and vacuum is applied to the waste bottle, wash solution is pumped into the container  112  through the input port(s)  114  with high speed. Simultaneously, the input water is drained from the bottom port  118 . The input water creates a whirlpool that cleans the internal surface of the container  112 , and the surfaces of the metal ball  115  and centerpiece  116 .   5. Refill operation:   This operation is identical to the fill operation above.       

       FIG. 17  shows the top view of a replicating pinhead tool  80  (hereinafter also referred to as a “pinhead”), in accordance with an embodiment of the present invention. The tool  80  has an attachment site  46 , which has two pins  151  and a threaded hole  152  for attaching the tool to the general-purpose tool interface  26  (see  FIG. 7 ). A replicating tool  80  comprises a plurality of pins  144  that are arranged in specific formats, for example in a standard rectangular-array format such as a 96-format, 384-format, 768-format, or 1536-format as shown in  FIGS. 19A, 19B, 19C, and 19D  respectively, in accordance with embodiments of the present invention. 
     Replicating tools with solid pins are not new. Other companies, such as V&amp;P Scientific, have been manufacturing replicating pinheads. However, the existing tools comprise one or two solid metal plate(s) with an array of holes that are precisely drilled into the plate(s). The pins freely float inside the holes. The number of pins and their size varies based on the application. The most commonly used formats of such pinheads include: 96=12×8 pins with 9 mm pin-to-pin distance, 384=24×16 with 4.5 mm pin-to-pin distance, and 1536=48×32 pins with 2.25 mm pin-to-pin distance, as shown in  FIGS. 19A, 19B, and 19D  respectively. The drawbacks of such pinheads include high cost of production and problems with manufacturability, especially when high-accuracy and high-density pinheads are needed. For example, drilling a large number of very accurate holes in a metal plate can be expensive. Even if one hole is damaged during the machining, the whole plate will be useless. The pins have to slide freely inside the holes (see  FIG. 18 ), but they should not wobble inside the holes. That means the manufacturing tolerances for the pins and holes must be very tight. To minimize wobbling, we may use a thicker plate. However, that makes drilling the holes even more difficult, and would increase the overall weight. Also, if the pins are very thin, for example 0.7 mm or less, drilling accurate holes of that size can be very costly or nearly impossible. Also, this design is limited in terms of the maximum number of pins that can be fit into the specified standard space (around 108 mm by 72 mm). 
     To overcome such difficulties and minimize the production cost, a new design is disclosed herein.  FIG. 18  shows the design of standard-density (i.e., 96, 384, 768, and 1536 formats) pinheads according to embodiments of the present invention. The new design uses tubes or bushings  147  instead of machined holes. One tube  147  is used for each pin  144 . Such tubes are produced in different sizes of ID (inside diameter), OD (outside diameter) and variety of lengths and with tight tolerances on the ID or OD. Since such tubes are mass-produced, the cost of each tube is very low. A preferred material for the tubes  147  and pins  144  is stainless steel, but other materials are also possible. The length of the tube can be increased to minimize the wobbling without tightening the tolerance between the pin and the tube. Therefore, the tolerance between the pin  144  and the tube  147  can be loosened to help the pin slide more freely. In one embodiment, two plates  142  are used to maintain a uniform distance between the tubes. In  FIG. 18 , the base plate  141  constitutes the base for other components. The base plate  141  is typically made of aluminum or other suitable materials and is machined to precise dimensions. The parts  142  are typically made of polymers such as polycarbonate, polystyrene, polypropylene, or similar types. Other materials, for example Delrine, Teflon, Brass, or Aluminum can also be used. The advantage of using polymers is that they can be easily fabricated in large quantities using injection molding. To assure that the two plates  142  will be precisely aligned and parallel with each other, for example four corner tubes  148  can be used. Since those four corner tubes  148  are tightly fit into the four corner holes of the base plate  141 , and because the base plate  141  is accurately machined, the four corner tubes  148  will be at proper distance and parallel to each other. A preferred method of assembly would be to make the two parts  142  out of polymers and to lightly press-fit the tubes  147  and  148  into the holes of the two plates  142 . In order to simplify the assembly process, the holes can be slightly tapered. As it is shown in  FIG. 18 , each pin  144  has a head  146  that prevents it from falling down and a tip  145  that can be made thinner than or the same size as the middle part of the pin. 
     Using the pin and tube method has another important advantage over the traditional pin and drilled-hole method. As illustrated in  FIG. 21 , tubes can be assembled side-by-side to produce a very high-density pinhead that would have been otherwise nearly impossible or very costly to make with other techniques. In one embodiment, a pusher plate  156  with two setscrews  157  can be used to hold the tubes in place. Other methods can also be used to hold the tubes together. For example one may use epoxy glue to maintain the tubes in place even after removing the fixture. 
     An important feature of an automation system according to embodiments of the present invention is the modularity, scalability, and reconfigurability. This means that the same modules described in the automation system  10  of  FIG. 1 or 2  can be re-arranged in different configurations in order to make new machines or automation systems for new applications.  FIGS. 8 to 10  show other exemplary configurations of the automation system, in accordance with embodiments of the present invention. 
       FIG. 8  shows a high-capacity plate stacker machine (hereinafter also referred to as a “hotel”)  100  comprising a functional module  20  with a rotary base  18  and a plurality of shelf sub-modules  60 , in accordance with an embodiment of the present invention. A gripping tool  42  is used to transfer a labware  98  between the shelves of sub-modules  60  and the tray of conveyer  50 . In order to access a specified shelf  60 , the functional module  20  rotates on the rotary base  18  such that the gripping tool  42  is oriented right in front of the specified shelf  60 . It can be seen that by adding a rotary base  18  to the functional module  20  and by increasing the number of sub-modules  60 , one can create a new stacker machine  100  with a significant increase in capacity as compared with the stacker machine  11  in  FIG. 1 . Another option is to have the functional module fixed and rotate the shelf sub-module assembly, as illustrated in  FIG. 9 , in accordance with an embodiment of the present invention. A hotel  100  may comprise an enclosure  101  that maintains a controlled environment for the plates with physical or chemical conditions such as temperature, pressure, or humidity that are different from those of the outside environment. One may also use a separate enclosure  104  for each individual shelf sub-module  60  in order to maintain a different environmental condition only for specific sub-module(s). 
       FIG. 9  is a diagram showing another exemplary configuration  110  of the automation system according to an embodiment of the present invention. The automation system  110  comprises two hotels  100  that provide a high capacity storage space for sample containers  98 , a plurality of functional modules  20 , a plurality of tools and sub-modules  60 ,  64 ,  65 , and  66 , and two conveyers  50  with a tray that comprise three plate holders  54 . The conveyers  50  are used to move sample plates  98  between the hotels  100  and different functional modules  20 . The applications of such a system are vast. By changing the tools and sub-modules, different functionalities can be added to the system. For example, by using a 96-format or 384-format pipetting head as a tool, the automation system  110  becomes a high-capacity and high-throughput liquid handling system. By using a replicating tool  80  (see  FIG. 1 ) and a wash-tower sub-module  70  (see  FIG. 1 ), the same system in  FIG. 9  becomes a high-capacity cell replicating system. By using two replicating tools  80  and two wash-towers  70  in the same system  110 , the throughput can be doubled as compared with the system  10  in  FIG. 1 . The reason is that when one replicating tool is being washed and sterilized, the second replicating machine can replicate another set of labware. 
       FIG. 10  is a diagram showing another exemplary configuration  120  of the automation system according to an embodiment of the present invention. An automation system like the one in  FIG. 10  can be used to automate very complicated processes, while maintaining a relatively small footprint and a low cost. The cost of the automation system is significantly less than comparable systems, as the core part of the system is made of few relatively simple modules. It not only reduces the development cost and time significantly, but also reduces the production cost due to repetition and reuse of identical or similar components. For example, the machining cost of a component is significantly reduced if a large quantity of that component is produced in one setup. Other advantages are reduced documentation, easier maintenance, and simplified stocking of components. The modularity and scalability of the automation system according to embodiments of the present invention is evident for example from the sequence of configurations presented in  FIGS. 2, 8, 9, and 10 . It is also evident that such a system can be configured with new tools and sub-modules in order to be used for a plurality of applications. It is to be appreciated that the above configurations related to the present invention are by way of example only. Many other variations on such configurations should be obvious to one or ordinary skill in the art and such obvious variations are within the scope of the present invention. 
       FIG. 22  shows the assembly and components of a Re-arraying tool with ninety-six separately indexable pins, in accordance with an embodiment of the present invention. The tool consists of an actuation mechanism  160  with eight pneumatic or electrical actuators  161 . The actuation mechanism  160  moves along the linear bearings (or rails)  162  by means of a motor  168  and a lead screw  165 , in order to access different columns of pins. In this exemplary configuration with ninety-six pins, the pins are arranged in a rectangular format with eight rows and twelve columns. When the actuation mechanism aligns with a specified column of pins, any of those eight pins can be actuated separately or simultaneously by the corresponding actuator(s)  161 .  FIG. 23  shows one column of pins  144  and the actuators  161  from the side view, in accordance with an embodiment of the present invention.  FIG. 22  shows the tool&#39;s attachment site  46  with two locating pins  151 , one electrical connector  164 , and eight pneumatic fittings  163 , in accordance with an embodiment of the present invention. The attachment site is used to connect the tool to the general purpose tool interface  29  (see  FIG. 6 ) of a functional module. When the tool is attached to the tool interface, the electrical connector  164  and pneumatic fittings  163  of the tool will connect to the corresponding connector and fittings of the tool interface  29  of the functional module, which provides the electrical and pneumatic power required for actuating the motor  168  and actuators  161  of the tool. This provides a high degree of modularity and functionality, as the re-arraying tool can be easily detached from a functional module and replaced by another tool, e.g., a replicating pinhead tool  80 , and therefore the same functional module can be used for multiple applications. 
       FIG. 24  illustrates the guiding and actuation mechanisms for each pin  144 , in accordance with an embodiment of the present invention. The pin  144  can float freely and precisely inside a bushing  170 . The bushing  170  also slides up/down in a precise hole  178  on the base plate of the tool. When the actuator  161  is not activated (left figure), the pin and its bushing are moved up by means of a spring  172 . The Cover plate  166  limits the upward movement of the bushing  170 . When the actuator  161  is activated (right figure), it pushes the bushing  170  and the inside pin  144  down against the spring  172 .  FIG. 25  illustrates the operating sequence of a pin. When the actuator  161  is not activated ( FIG. 25 a   ), the bushing  170  and the pin  144  are held up by means of a spring  172 . This represents the normal state of the ninety-six pins. When one pin has to move down to pick up or transfer a sample, the corresponding actuator  161  is activated ( FIG. 25 b   ) and moves the bushing  170  and the pin  144  all the way down. If the pin  144  touches a solid work-surface  176  ( FIG. 25 c   ), it will float up inside the bushing  170  and does not damage the sample or the work-surface. This is a unique and important feature of the re-arrayer device as disclosed herein. Furthermore, and as should be obvious to one of ordinary skill in the art, such floating pins can be used in a re-arrayer that does not comprise a moving actuation mechanism  160 , for example in a re-arrayer that comprises a conventional actuation mechanism. 
     The re-arraying tool in  FIG. 22  can be used for picking randomly distributed samples on a work-surface and transferring them in a standard 96-format rectangular array. In applications related to biology research, the samples are typically biological samples such as bacteria colonies or Yeast cell colonies that are grown on a growth media, e.g., an agar surface. 
     While certain exemplary embodiments have been described and shown in the accompanying drawings, it is to be understood that such embodiments are merely illustrative and not restrictive of the broad invention and that this invention is not limited to the specific constructions and arrangements shown and described, since various other modifications may occur to those ordinarily skilled in the art upon studying this disclosure. In an area of technology such as this, where growth is fast and further advancements are not easily foreseen, the disclosed embodiments may be readily modifiable in arrangement and detail as facilitated by enabling technological advancements without departing from the principals of the present disclosure or the scope of the accompanying claims.

Technology Classification (CPC): 0