Patent Publication Number: US-2022214252-A1

Title: Methods, devices, and apparatus for dispensing and aspirating liquids on array plates

Description:
TECHNICAL FIELD 
     The disclosed embodiments relate generally to methods, devices, and apparatus for washing samples (e.g., cells, particles, etc.). More particularly, the disclosed embodiments relate to methods, devices, and apparatus for washing samples on array plates and slides. 
     BACKGROUND 
     An array plate is also called a microtiter plate, microplate, or microwell plate. Array plates are typically used to hold respective liquid droplets separately for biological and/or chemical reaction. For example, a well-type array plate includes a plurality of wells so that each liquid droplet or each sample may be dispensed into a separate well for further processing. Typically, the number of wells is selected from 6, 24, 96, 384, 1536, 3456, and 9600. 
     Samples (e.g., cells) are frequently washed in biological and/or chemical assays or operations. Washing typically involves adding a wash solution to a sample solution, including samples (e.g., cells), on the slide and removing the mixture of the wash solution and the sample solution. By repeating the dilution and partial removal of the sample solution, the concentration of chemicals and/or biological reagents other than the samples are reduced. However, variations in the sample washing increase measurement errors, which are not desirable for accurate assays. 
     In addition, certain cells (e.g., suspension cells, non-adherent cells, and weakly adherent cells) do not strongly adhere to the slide. Thus, during removal of the mixture, cells may be removed along with the mixture, thereby reducing the number of cells that remain on the hydrophilic area of the slide after the washing. Because a reliability of cell-based reactions typically requires a sufficient number of cells, the loss of cells during washing negatively affects cell-based reactions. 
     SUMMARY 
     Accordingly, there is need for methods, devices, and apparatus that provide improved accuracy and reduced time in washing cells. Such methods, devices, and apparatus plates may replace the conventional methods, devices, and apparatus for washing cells. In addition, such methods, devices, and apparatus may better retain cells during washing, and reduce or eliminate the loss of cells during washing, thereby improving the reliability of cell-based reactions. Similarly, such methods, devices, and apparatus may be used in washing other types of samples, such as beads or particles conjugated with target molecules. 
     A number of embodiments that overcome the limitations and disadvantages of existing methods, devices, and apparatus are presented in more detail below. These embodiments provide methods, devices, and apparatus for washing a sample in a solution. 
     As described in more detail below, in accordance with some embodiments, a method includes dispensing a liquid from a first dispenser. The first dispenser has a first piston channel and a first nozzle channel that is non-parallel to the first piston channel and is connected to the first piston channel at a first intersection. The first dispenser includes a first piston configured to slide at least partially within the first piston channel; a first nozzle coupled with the first nozzle channel; a first valve located between a dispensing-liquid reservoir and the first intersection, the first valve configured to allow a liquid in the dispensing-liquid reservoir to flow to the first intersection through the first valve and prevent a liquid in the first intersection from flowing to the dispensing-liquid reservoir through the first valve; and a second valve located between the first intersection and the first nozzle, the second valve configured to allow a liquid in the first intersection to flow to the first nozzle through the second valve and prevent a liquid in the first nozzle to flow to the first intersection through the second valve. Dispensing the liquid from the first dispenser includes pulling the first piston to initiate flow of a liquid in the dispensing-liquid reservoir to the first intersection; and, subsequent to pulling the first piston, pushing the first piston to initiate flow of the liquid in the first intersection to the first nozzle so that the liquid is dispensed from the first nozzle. 
     In some embodiments, the method also includes dispensing a liquid from a second dispenser, the second dispenser having a second piston channel and a second nozzle channel that is non-parallel to the second piston channel and is connected to the second piston channel at a second intersection. The second dispenser includes a second piston configured to slide at least partially within the second piston channel; a second nozzle coupled with the second nozzle channel; a third valve located between the dispensing-liquid reservoir and the second intersection, the third valve configured to allow the liquid in the dispensing-liquid reservoir to flow to the second intersection through the third valve and prevent a liquid in the second intersection from flowing to the dispensing-liquid reservoir through the third valve; and a fourth valve located between the second intersection and the second nozzle, the fourth valve configured to allow a liquid in the second intersection to flow to the second nozzle through the fourth valve and prevent a liquid in the second nozzle to flow to the second intersection through the fourth valve. Dispensing the liquid from the second dispenser includes pulling the second piston to initiate flow of the liquid in the dispensing-liquid reservoir to the second intersection; and, subsequent to pulling the second piston, pushing the second piston to initiate flow of the liquid in the second intersection to the second nozzle so that the liquid is dispensed from the second nozzle. 
     In some embodiments, the method includes concurrently pulling the first piston and the second piston at a same first speed to concurrently initiate the flow of the liquid in the dispensing-liquid reservoir to the first intersection and the second intersection; and, concurrently pushing the first piston and the second piston at a same second speed to concurrently initiate the flow of the liquid in the first intersection to the first nozzle and the flow of the liquid in the second intersection to the second nozzle. 
     In some embodiments, the method further includes aspirating a liquid with a first aspirator having a third piston channel and a third nozzle channel that is non-parallel to the third piston channel and is connected to the third piston channel at a third intersection. The first aspirator includes a third piston configured to slide at least partially within the third piston channel; a third nozzle coupled with the third nozzle channel; a fifth valve located between an aspirated-liquid reservoir and the third intersection, the fifth valve configured to allow a liquid in the third intersection to flow to the aspirated-liquid reservoir through the fifth valve and prevent a liquid in the aspirated-liquid reservoir from flowing to the third intersection through the fifth valve; and a sixth valve located between the third intersection and the third nozzle, the sixth valve configured to allow a liquid in the third nozzle to flow to the third intersection through the sixth valve and prevent a liquid in the third intersection from flowing to the third nozzle through the sixth valve. Aspirating the liquid with the first aspirator includes pulling the third piston to initiate flow of the liquid from the third nozzle to the third intersection; and, subsequent to pulling the third piston, pushing the third piston to initiate flow of the liquid in the third intersection to the aspirated-liquid reservoir. 
     In some embodiments, the method further includes aspirating a liquid with a second aspirator having a fourth piston channel and a fourth nozzle channel that is non-parallel to the fourth piston channel and is connected to the fourth piston channel at a fourth intersection. The second aspirator includes a fourth piston configured to slide at least partially within the fourth piston channel; a fourth nozzle coupled with the fourth nozzle channel; a seventh valve located between the aspirated-liquid reservoir and the fourth intersection, the seventh valve configured to allow a liquid in the aspirated-liquid reservoir to flow to the fourth intersection through the seventh valve and prevent a liquid in the fourth intersection from flowing to the aspirated-liquid reservoir through the seventh valve; and an eighth valve located between the fourth intersection and the fourth nozzle, the eighth valve configured to allow a liquid in the fourth intersection to flow to the fourth nozzle through the eighth valve. Aspirating the liquid with the second aspirator includes pulling the fourth piston to initiate flow of the liquid from the fourth nozzle to the fourth intersection; and, subsequent to pulling the fourth piston, pushing the fourth piston to initiate flow of the liquid in the fourth intersection to the aspirated-liquid reservoir. 
     In some embodiments, the method also includes concurrently pulling the third piston and the fourth piston at a same first speed to concurrently initiate the flow of the liquid in the dispensing-liquid reservoir to the first intersection and the second intersection; and, concurrently pushing the third piston and the fourth piston at a same second speed to concurrently initiate the flow of the liquid in the first intersection to the first nozzle and the flow of the liquid in the second intersection to the second nozzle. 
     In some embodiments, the first piston channel is substantially perpendicular to the first nozzle channel. 
     In accordance with some embodiments, a method includes aspirating a liquid with a first aspirator having a first piston channel and a first nozzle channel that is non-parallel to the first piston channel and is connected to the first piston channel at a first intersection. The first aspirator includes a first piston configured to slide at least partially within the first piston channel; a first nozzle coupled with the first nozzle channel; a first valve located between an aspirated-liquid reservoir and the first intersection, the first valve configured to allow a liquid in the first intersection to flow to the aspirated-liquid reservoir through the first valve and prevent a liquid in the aspirated-liquid reservoir from flowing to the first intersection through the first valve; and a second valve located between the first intersection and the first nozzle, the second valve configured to allow a liquid in the first nozzle to flow to the first intersection through the second valve and prevent a liquid in the first intersection from flowing to the first nozzle through the second valve. Aspirating the liquid with the first aspirator includes pulling the first piston to initiate flow of the liquid from the first nozzle to the first intersection; and, subsequent to pulling the first piston, pushing the first piston to initiate flow of the liquid in the first intersection to the aspirated-liquid reservoir. 
     In some embodiments, the method further includes aspirating a liquid with a second aspirator having a second piston channel and a second nozzle channel that is non-parallel to the second piston channel and is connected to the second piston channel at a second intersection. The second aspirator includes a second piston configured to slide at least partially within the second piston channel; a second nozzle coupled with the second nozzle channel; a third valve located between the aspirated-liquid reservoir and the second intersection, the third valve configured to allow a liquid in the aspirated-liquid reservoir to flow to the second intersection through the third valve and prevent a liquid in the second intersection from flowing to the aspirated-liquid reservoir through the third valve; and a fourth valve located between the second intersection and the second nozzle, the fourth valve configured to allow a liquid in the second intersection to flow to the second nozzle through the fourth valve. Aspirating the liquid with the second aspirator includes pulling the second piston to initiate flow of the liquid from the second nozzle to the second intersection; and, subsequent to pulling the second piston, pushing the second piston to initiate flow of the liquid in the second intersection to the aspirated-liquid reservoir. 
     In some embodiments, the method includes concurrently pulling the first piston and the second piston at a same first speed to concurrently initiate the flow of the liquid in the aspirated-liquid reservoir to the first intersection and the second intersection; and, concurrently pushing the first piston and the second piston at a same second speed to concurrently initiate the flow of the liquid in the first intersection to the first nozzle and the flow of the liquid in the second intersection to the second nozzle. 
     In accordance with some embodiments, a device includes a first dispenser defining a first piston channel and a first nozzle channel that is non-parallel to the first piston channel and is connected to the first piston channel at a first intersection. The first dispenser includes a first piston configured to slide at least partially within the first piston channel; a first nozzle coupled with the first nozzle channel; a first valve located between a dispensing-liquid reservoir and the first intersection, the first valve configured to allow a liquid in the dispensing-liquid reservoir to flow to the first intersection through the first valve and prevent a liquid in the first intersection from flowing to the dispensing-liquid reservoir through the first valve; and a second valve located between the first intersection and the first nozzle, the second valve configured to allow a liquid in the first intersection to flow to the first nozzle through the second valve and prevent a liquid in the first nozzle to flow to the first intersection through the second valve. 
     In some embodiments, the device also includes a second dispenser defining a second piston channel and a second nozzle channel that is non-parallel to the second piston channel and is connected to the second piston channel at a second intersection. The second dispenser includes a second piston configured to slide at least partially within the second piston channel; a second nozzle coupled with the second nozzle channel; a third valve located between the dispensing-liquid reservoir and the second intersection, the third valve configured to allow a liquid in the dispensing-liquid reservoir to flow to the second intersection through the third valve and prevent a liquid in the second intersection from flowing to the dispensing-liquid reservoir through the third valve; and a fourth valve located between the second intersection and the second nozzle, the fourth valve configured to allow a liquid in the second intersection to flow to the second nozzle through the fourth valve and prevent a liquid in the second nozzle to flow to the second intersection through the fourth valve. 
     In some embodiments, the first piston and the second piston are mechanically coupled to each other so that the first piston and the second piston are configured to move at a same speed in a same direction. 
     In some embodiments, the device further includes a first aspirator defining a third piston channel and a third nozzle channel that is non-parallel to the third piston channel and is connected to the third piston channel at a third intersection. The first aspirator includes a third piston configured to slide at least partially within the third piston channel; a third nozzle coupled with the third nozzle channel; a fifth valve located between an aspirated-liquid reservoir and the third intersection, the fifth valve configured to allow a liquid in the third intersection to flow to the aspirated-liquid reservoir through the fifth valve and prevent a liquid in the aspirated-liquid reservoir from flowing to the third intersection through the fifth valve; and a sixth valve located between the third intersection and the third nozzle, the sixth valve configured to allow a liquid in the third nozzle to flow to the third intersection through the sixth valve and prevent a liquid in the third intersection from flowing to the third nozzle through the sixth valve. 
     In some embodiments, the device further includes a second aspirator defining a fourth piston channel and a fourth nozzle channel that is non-parallel to the fourth piston channel and is connected to the fourth piston channel at a fourth intersection. The second aspirator includes a fourth piston configured to slide at least partially within the fourth piston channel; a fourth nozzle coupled with the fourth nozzle channel; a seventh valve located between the aspirated-liquid reservoir and the fourth intersection, the seventh valve configured to allow a liquid in the aspirated-liquid reservoir to flow to the fourth intersection through the seventh valve and prevent a liquid in the fourth intersection from flowing to the aspirated-liquid reservoir through the seventh valve; and an eighth valve located between the fourth intersection and the fourth nozzle, the eighth valve configured to allow a liquid in the fourth intersection to flow to the fourth nozzle through the eighth valve. 
     In some embodiments, the third piston and the fourth piston are mechanically coupled to each other so that the third piston and the fourth piston are configured to move at a same speed in a same direction. 
     In some embodiments, the first piston channel is substantially perpendicular to the first nozzle channel. 
     In accordance with some embodiments, a device includes a first aspirator defining a first piston channel and a first nozzle channel that is non-parallel to the first piston channel and is connected to the first piston channel at a first intersection. The first aspirator including a first piston configured to slide at least partially within the first piston channel; a first nozzle coupled with the first nozzle channel; a first valve located between an aspirated-liquid reservoir and the first intersection, the first valve configured to allow a liquid in the first intersection to flow to the aspirated-liquid reservoir through the first valve and prevent a liquid in the aspirated-liquid reservoir from flowing to the first intersection through the first valve; and a second valve located between the first intersection and the first nozzle, the second valve configured to allow a liquid in the first nozzle to flow to the first intersection through the second valve and prevent a liquid in the first intersection from flowing to the first nozzle through the second valve. 
     In some embodiments, the device further includes a second aspirator defining a second piston channel and a second nozzle channel that is non-parallel to the second piston channel and is connected to the second piston channel at a second intersection. The second aspirator includes a second piston configured to slide at least partially within the second piston channel; a second nozzle coupled with the second nozzle channel; a third valve located between the aspirated-liquid reservoir and the second intersection, the third valve configured to allow a liquid in the aspirated-liquid reservoir to flow to the second intersection through the third valve and prevent a liquid in the second intersection from flowing to the aspirated-liquid reservoir through the third valve; and a fourth valve located between the second intersection and the second nozzle, the fourth valve configured to allow a liquid in the second intersection to flow to the second nozzle through the fourth valve. 
     In some embodiments, the first piston and the second piston are mechanically coupled to each other so that the first piston and the second piston are configured to move at a same speed in a same direction. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       For a better understanding of the aforementioned embodiments as well as additional embodiments, reference should be made to the Description of Embodiments below, in conjunction with the following drawings in which like reference numerals refer to corresponding parts throughout the figures. 
         FIGS. 1A-1F  illustrate a washing operation with a conventional micro-titer plate. 
         FIGS. 2A-2E  illustrate washing operations with an array plate having a hydrophilic region and a hydrophobic area in accordance with some embodiments. 
         FIGS. 3A-3G  illustrate a washing operation in accordance with some embodiments. 
         FIGS. 4A-4C  illustrate a dispenser and its components in accordance with some embodiments. 
         FIG. 4D  illustrates a dispenser coupled with a reservoir in accordance with some embodiments. 
         FIG. 4E  illustrates a set of multiple dispensers in accordance with some embodiments. 
         FIG. 4F  illustrates coupled pistons in accordance with some embodiments. 
         FIGS. 4G and 4H  illustrate a block with piston channels and nozzle channels in accordance with some embodiments. 
         FIGS. 5A-5D  illustrate a dispensing operation in accordance with some embodiments. 
         FIGS. 6A-6E  illustrate an aspiration operation in accordance with some embodiments. 
         FIG. 6F  illustrates a set of multiple aspirators in accordance with some embodiments. 
     
    
    
     Like reference numerals refer to corresponding parts throughout the drawings. 
     DESCRIPTION OF EMBODIMENTS 
     Methods, devices, and apparatus for washing samples are described. Reference will be made to certain embodiments, examples of which are illustrated in the accompanying drawings. While the claims will be described in conjunction with the embodiments, it will be understood that it is not intended to limit the claims to these particular embodiments alone. On the contrary, the embodiments are intended to cover alternatives, modifications and equivalents that are within the spirit and scope of the appended claims. 
     Moreover, in the following description, numerous specific details are set forth to provide a thorough understanding of the embodiments. However, it will be apparent to one of ordinary skill in the art that the embodiments may be practiced without these particular details. In other instances, methods, procedures, components, and networks that are well-known to those of ordinary skill in the art are not described in detail to avoid obscuring aspects of the embodiments. 
     It will also be understood that, although the terms first, second, etc. may be used herein to describe various elements, these elements should not be limited by these terms. These terms are only used to distinguish one element from another. For example, a first piston could be termed a second piston, and, similarly, a second piston could be termed a first piston, without departing from the scope of the embodiments. The first piston and the second piston are both pistons, but they are not the same piston. 
     The terminology used in the description of the embodiments herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the description of the embodiments and the appended claims, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will also be understood that the term “and/or” as used herein refers to and encompasses any and all possible combinations of one or more of the associated listed items. It will be further understood that the terms “comprises” and/or “comprising,” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. 
       FIGS. 1A-1F  illustrate a washing operation with a conventional micro-titer plate. 
       FIG. 1A  illustrates solution  104  containing samples  114  (e.g., cells, particles, etc.) in a well that is defined in micro-titer plate  102 . 
       FIG. 1B  illustrates that dispenser  110  containing wash liquid  106  (e.g., a wash buffer, such as phosphate-buffered saline, Tris-buffered saline, borate-buffered saline, and TE buffer) is used for washing samples  114 . 
     For example, as shown in  FIG. 1C , wash liquid  106  in dispenser  110  is dispensed into solution  104 , thereby forming mixture  108  (e.g., liquid) of solution  104  and wash liquid  106 . As a result, chemical and biological reagents in solution  104  are diluted (e.g., concentrations of chemicals and biological reagents in solution  104  are reduced).  FIG. 1C  also illustrates that at least a portion of samples  114  is lift-off from the bottom of the well and suspended in mixture  108 , due to the liquid flow caused by introduction of wash liquid  106  into solution  104 . 
       FIG. 1D  illustrates that samples  114  settle over time. 
       FIG. 1E  illustrates that aspirator  120  is used to aspirate (e.g., remove) a portion of mixture  108 . 
       FIG. 1F  illustrates that aspirator  120  has aspirated a portion of mixture  108 . The volume of mixture  108  remaining in the well defined in micro-titer plate  102 , after the portion of mixture  108  is aspirated, is determined at least in part by height V of aspirator  120  (e.g., a distance between a nozzle tip of aspirator  120  and a bottom of the well defined in the micro-titer plate  102 ). 
       FIG. 1F  also illustrates that a portion of samples  114  is also aspirated by aspirator  120 . Wells of micro-titer plate  102  have a high aspect ratio (e.g., a ratio between the height of the well and the diameter of the well). Thus, once samples  114  are agitated, it takes a long time for samples  114  to settle down. If a portion of mixture  108  is aspirated before samples  114  have fully settled down, a portion of samples  114  that is aspirated is increased. 
     In addition,  FIG. 1F  illustrates that samples  114  cluster toward corners of the well when the volume of mixture  108  is reduced. In addition, mixture  108  clings toward corners of the well. Both of these can reduce the efficiency of washing. 
       FIGS. 2A-2E  illustrate washing operations with an array plate having a hydrophilic region and a hydrophobic area in accordance with some embodiments. 
       FIG. 2A  is a partial cross-section of an array plate, where hydrophilic region  204  is surrounded by hydrophobic area  206 . In  FIG. 2A , solution  104  containing samples  114  is located over hydrophilic region  204 . Solution  104  is retained over hydrophilic region  204 , as surrounding hydrophobic area  206  prevents spreading of solution  104  beyond hydrophilic region  204 . 
       FIG. 2A  also illustrates dispenser  210  and aspirator  220 . Dispenser  210  includes liquid  106  for washing samples  114  in solution  104  (by dilution of solution  104 ). 
     The array plate illustrated in  FIG. 2A  is configured to hold solution  104  without tall side walls, like conventional micro-titer plates. Thus, in the configuration shown in  FIG. 2A , there are no corners toward which solution  104  and samples  114  cluster. 
     In addition, solution  104  in  FIG. 2A  has a low aspect ratio (e.g., a ratio between the height of solution  104  and the width or diameter of solution  104  on the array plate is less than the height of solution  104  and the diameter of solution  104  in a conventional micro-titer plate, sometimes by a factor of 2, 4, 6, 8, 10, or 20). Thus, when samples  114  are agitated, samples  114  in solution  104  on the array plate can settle faster than samples in solution  104  in a conventional micro-titer plate (shown in  FIG. 1F ). 
     In some embodiments, magnetic particles configured to couple with cells (e.g., coated with materials that can reversibly or irreversibly bind to the cells) are included in solution  104  (e.g., by introducing the magnetic particles into solution  104 ). Once the magnetic particles bind to the cells in solution  104 , a magnetic field is applied to the magnetic particles in solution  104  to accelerate settling of the magnetic particles (and associated cells). 
     In some cases, the distance V between hydrophilic region  204  and aspirator  220  (e.g., a distance between hydrophilic surface  204  and a nozzle tip of aspirator  220 ) is important in improving retention of samples  114 . In some embodiments, aspirator  220  needs to be positioned at least 100 μm from hydrophilic region  204 . In some embodiments, aspirator  220  needs to be positioned at least 200 μm from hydrophilic region  204 . In some embodiments, aspirator  220  needs to be positioned at least 300 μm from hydrophilic region  204 . 
       FIG. 2B  illustrate dispenser  210  and aspirator  220  with improved volume control. A variation in the dispensed volume and/or the aspirated volume contributes to a variation in the dilution factor, which leads to an increased error in assays. Thus, reducing the variation in the volume of the dispensed liquid and/or the volume of the aspirated liquid improves the assay accuracy (e.g., an accuracy of an assay performed using the washing operation). 
     In  FIG. 2B , dispenser  210  includes valve  212  (e.g., a one-way valve, which is also called a check valve, or a check valve) to reduce the variation in the volume of the dispensed liquid, and aspirator  220  includes valve  222  (e.g., a one-way valve or a check valve) to reduce the variation in the volume of the aspirated liquid. For example, a respective valve allows a liquid to flow in one direction but prevents the liquid to flow in the opposite direction (e.g., valve  212  allows the liquid in dispenser  210  to exit from dispenser  210  through valve  212  but prevents a liquid to enter into dispenser  210  through valve  212 , and valve  222  allows mixture  108  to enter into aspirator  220  through valve  222  but prevents mixture  108  in aspirator  220  from exiting from aspirator  220  through valve  222 ). 
       FIG. 2C  is similar to  FIG. 2B , except that dispenser  230  is used in place of dispenser  210  and aspirator  240  is used in place of aspirator  220 . Dispenser  230  includes piston  232  (e.g., a plunger) configured to slide within channel  234  for dispensing wash liquid  106  in channel  234  through valve  212 . Aspirator  240  includes piston  242  (e.g., a plunger) configured to slide within channel  244  for aspirating a liquid (mixture  108 ) into channel  244  through valve  222 . In some embodiments, channel  234  is defined by tube  235 . In some embodiments, channel  244  is defined by tube  245 . 
     In some implementations, the volume of the aspirated liquid is controlled by a movement of piston  242  (e.g., a diameter of channel  244  and a travel distance of piston  242 ). In some embodiments, the diameter of piston  242  is less than the diameter of mixture  108 , which facilitates an accurate control of the volume of the aspirated solution. Similarly, the volume of the aspirated liquid is accurately controlled by a movement of piston  232 . In some implementations, the volume of the aspirated liquid (and/or the remaining liquid) is determined based on a height of an aspirator (e.g., a portion of the liquid located above the tip of aspirator  240  is aspirated and a portion of the liquid located below the tip of aspirator  240  remains, as shown in  FIG. 1F ). 
       FIG. 2D  is similar to  FIG. 2C , except that piston  236  defines channel  238  within piston  236  and piston  236  is coupled with valve  252  (e.g., a one-way valve, a check valve, etc.), and piston  246  defines channel  248  within piston  246  and piston  246  is coupled with valve  262  (e.g., a one-way valve, a check valve, etc.). Channel  238  and valve  252  are configured to deliver a precise volume of wash liquid  106  into channel  234 . Channel  248  and valve  262  are configured to remove mixture  108  in channel  244 . The operations of these components are described further below with respect to  FIGS. 3A-3G . 
       FIG. 2E  is similar to  FIG. 2D , except that filter  250  is coupled with a tip of aspirator  240 . In some implementations, filter  250  reduces or prevents aspiration of cells. In some embodiments, filter  250  has a plurality of pores. In some embodiments, the plurality of pores has a pore size between 0.1 and 20 μm. In some embodiments, the plurality of pores has a pore size between 1 and 10 μm. In some embodiments, the plurality of pores has a pore size between 1 and 5 μm. In some embodiments, the plurality of pores has a pore size between 2 and 8 μm. 
       FIG. 2E  also illustrates that aspirator  240  is coupled with vibrator  254 . In  FIG. 2E , vibrator  254  is positioned adjacent to filter  250 . Vibrator  254  is configured to provide vibration to filter  250 , which reduces clogging of filter  250  by preventing accumulation of cells on filter  250 . In some embodiments, vibrator  254  is a piezo-electric vibrator. 
       FIG. 3A  illustrates that dispenser  230  includes piston  236  in a first position. The channel defined within piston  236  includes wash liquid  106 . 
       FIG. 3B  illustrates that piston  236  moves up to a second position, which allows liquid  106  in the channel defined within piston  236  to flow into channel  234 . During the upward movement of piston  236 , there is a negative pressure within channel  234 , which keeps valve  212  closed. 
     Once channel  234  is filled with a predefined volume of wash liquid  106 , piston  236  moves down to push wash liquid  106  out of channel  234 .  FIG. 3C  illustrates that piston  236  moves down, which causes valve  252  to close. The increased pressure within channel  234  opens valve  212  so that wash liquid  106  in channel  234  is dispensed (e.g., released) into sample solution  104 , thereby forming mixture  108 . 
       FIG. 3D  illustrates that piston  236  has returned to the first position. In  FIG. 3D , piston  246  of aspirator  240  is in a third position. 
       FIG. 3E  illustrates an upward movement of piston  246  to a fourth position. The negative pressure within channel  244  causes valve  222  to open, which allows a portion of mixture  108  to flow into channel  244 . The negative pressure within channel  244  causes valve  262  to close so that mixture  108  does not flow into the channel  248 . 
     Once channel  244  is filled with a predefined volume of mixture  108 , piston  246  moves down to move mixture  108  in channel  244  to channel  248 .  FIG. 3F  illustrates piston  246  moves down, which causes valve  222  to close. The increased pressure within channel  244  opens valve  262  so that mixture  108  in channel  244  flows into channel  248 . 
       FIG. 3G  illustrates that piston  246  has returned to the third position. 
     In some embodiments, dispenser  230  is coupled with a wash liquid source (e.g., a reservoir containing a wash liquid, which is optionally combined with a pump configured to provide the wash liquid). For example, wash liquid  106  is provided to channel  238  by the wash liquid source. In some embodiments, aspirator  240  is coupled with a suction pump. For example, mixture  108  in channel  248  is removed by the suction pump. In some embodiments, aspirator  240  is coupled with a reservoir. For example, mixture  108  in channel  248  is drained to the reservoir while piston  246  moves up. 
     In some embodiments, subsequent to dispensing wash liquid  106  and prior to aspirating a portion of mixture  108 , mixture  108  is shaken and/or agitated (e.g., the array plate on which mixture  108  is located is shaken and/or agitated by placing the array plate on a shaker and activating the shaker). 
     In some embodiments, one or more valves illustrated in  FIGS. 3A-3G  (e.g., valves  212 ,  222 ,  252 , and  262 ) are spring-loaded. A spring-loaded valve is configured to close itself and/or remain closed when a pressure difference applied on the valve is less than a predefined threshold. 
     Although  FIGS. 3A-3G  illustrate that a single dispenser and a single aspirator for a single sample spot, in some embodiments, multiple dispensers and/or multiple aspirators are used for a single sample spot (e.g., using multiple dispensers and multiple aspirators for a particular sample spot can reduce the washing time, especially for a large sample spot). In some embodiments, multiple dispensers are configured for concurrent operations and/or multiple aspirators are configured for concurrent operations. 
     In some embodiments, a single dispenser is used for dispensing a wash liquid into multiple spots. For example, a single dispenser is coupled with a split channel (e.g., 2-channel, 4-channel, 8-channel, 12-channel, 16-channel, 32-channel, 64-channel, 128-channel, 256-channel splitter). In some embodiments, a single aspirator is used for aspirating liquid (e.g., a mixture) from multiple spots. For example, a single aspirator is coupled with a split channel (e.g., 2-channel, 4-channel, 8-channel, 16-channel, 32-channel, 64-channel, 128-channel, 256-channel splitter). 
     In some embodiments, one or more of a dispenser and an aspirator are coupled with a positive displacement pump (e.g., a membrane pump, such as a solenoid micropump). The positive displacement pump reduces the variation in the volume of the dispensed liquid or the volume of the aspirated liquid. In some embodiments, a dispenser is coupled with a positive displacement pump without a valve. In some embodiments, an aspirator is coupled with a positive displacement pump without a valve. 
     Although  FIGS. 2A-2E and 3A-3G  illustrate configurations, in which both a dispenser and an aspirator are concurrently in contact with a liquid (e.g., solution  104  or mixture  108 ), a person having ordinary skill in the art would understand that only one of the dispenser and the aspirator may be in contact with the liquid (e.g., a dispenser comes in contact with solution  104  first for dispensing a wash liquid, while an aspirator remains separated from solution  104 , and the dispenser is subsequently removed from mixture  108  of solution  104  and the wash liquid, and the aspirator comes in contact with mixture  108  for aspirating a portion of mixture  108  while the dispenser remains separated from mixture  108 ). In some embodiments, a dispenser is used at a first time without an aspirator, and an aspirator is used at a second time distinct from the first time (e.g., the second time is subsequent to the first time) without a dispenser. For brevity, these details are omitted. 
     In  FIGS. 1A-1F, 2A-2E, and 3A-3G , top portions of dispensers and aspirators are truncated to simplify the drawings. 
     Although  FIGS. 2A-2E and 3A-3G  illustrate washing operations, analogous operations can be used for introducing reagents to the array plate (or the cells on the array plate). For example, instead of a wash liquid, a reagent liquid (e.g., a liquid containing reagents for reaction with cells) is used in some implementations. Such operations can introduce the reagents without agitating the cells on the array plate, thereby improving the accuracy and reliability of reaction between the reagents and the cells. In addition, the loss of the cells is reduced by using such operations. 
     Although  FIGS. 2A-2E and 3A-3G  illustrate an aspirator located away from a dispenser (e.g., the aspirator and the dispenser are located toward two opposite ends of solution  104 ), in some implementations, the aspirator and the dispenser are located adjacent to each other (e.g., the aspirator and the dispenser are located toward a same end of solution  104 , or toward the center of solution  104 ). 
       FIGS. 4A-4C  illustrate a dispenser and its components in accordance with some embodiments. 
       FIG. 4A  illustrates a first piston channel  412  and a first nozzle channel  414  connected to the first piston channel  412  at a first intersection  416 . The first nozzle channel  414  is non-parallel to the first piston channel  412  (e.g., the first nozzle channel  414  and the first piston channel  412  form an angle that is between 30 and 150 degrees). In some embodiments, the first nozzle channel  414  is substantially perpendicular to the first piston channel  412  (e.g., the first nozzle channel  414  and the first piston channel  412  form an angle that is between 75 and 105 degrees). 
     In some embodiments, at least one of the first nozzle channel  414  and the first piston channel  412  include a stopper to prevent movement of a piston into the first nozzle channel  414 . 
     In some embodiments, the first piston channel  412  is defined in a first barrel (or a pipe or a tube). In some embodiments, the first nozzle channel  414  is defined in a second barrel (or a pipe or a tube). In some embodiments, the first barrel and the second barrel are integrally formed. In some embodiments, the first barrel and the second barrel are separate barrels that are coupled together. 
       FIG. 4B  illustrates that a first piston  422  is located at least partially within the first piston channel  412 . The first piston  422  is configured to slide within the first piston channel  412  (e.g., an outer diameter of the first piston  422  is less than the diameter of the first piston channel, such as an inner diameter of the first barrel defining the first piston channel  412 ). In some embodiments, the first piston  422  is coupled with one or more seals (e.g., o-rings) to prevent leakage through a gap between the first piston  422  and the first piston channel  412 . 
       FIG. 4B  also illustrates that a first nozzle  432  is coupled with the first nozzle channel  414 . In some embodiments, the first nozzle  432  includes one or more seals (e.g., o-rings) to prevent leakage through a gap between the first nozzle  432  and the first nozzle channel  414 . 
       FIG. 4C  illustrates a first dispenser  410  in accordance with some embodiments. The first dispenser  410  includes, in addition to the components shown in  FIG. 4B , a first valve  442  (e.g., a first one-way valve) and a second valve  444  (e.g., a second one-way valve). In some embodiments, the first valve  442  is located above the first intersection  416  in the first nozzle channel  414  and the second valve  444  is located below the first intersection  416  in the first nozzle channel  414 , as shown in  FIG. 4C . In some embodiments, the first valve  442  and the second valve  444  are located adjacent to the first intersection  416 . In some embodiments, the first valve  442  and the second valve  444  are located away from the first intersection  416 . 
       FIG. 4D  illustrates the first dispenser  410  coupled with a reservoir  402  in accordance with some embodiments. In some embodiments, the reservoir  402  is a dispensing-liquid reservoir containing liquid that is to be dispensed through the first dispenser  410 . In some embodiments, the reservoir  402  has an outlet that is coupled toward the first valve  442  of the first dispenser  410 . In some embodiments, the reservoir  402  has one or more inlets. In some embodiments, at least one of the one or more inlets is coupled with a pump or an input line so that the reservoir  402  can receive additional liquid. In some embodiments, at least one of the one or more inlets is exposed to an ambient environment (e.g., air) so that the pressure inside the reservoir  402  corresponds to the atmospheric pressure. 
       FIG. 4E  illustrates a set of multiple dispensers in accordance with some embodiments. The set of multiple dispensers includes the first dispenser  410  and a second dispenser  450 . 
     The second dispenser  450  has a second piston channel  452  and a second nozzle channel  454  that is connected to the second piston channel  452  at a second intersection  456 . In some embodiments, the second nozzle channel  454  is non-parallel to the second piston channel  452 . 
     The second dispenser  450  includes a second piston  462 , a second nozzle  472 , a third valve  482 , and a fourth valve  484 . These components are similar to the first piston  412 , the first nozzle  432 , the first valve  442 , and the second valve  444 , respectively. For brevity, the description of these components is omitted herein. However, a person having ordinary skill in the art would understand their structures and operations based on the description of the corresponding components, namely the first piston  412 , the first nozzle  432 , the first valve  442 , and the second valve  444 , as described herein. 
     In  FIG. 4F , the second dispenser  450  is coupled with a second reservoir  404  that is distinct and separate from the first reservoir  402 . In some embodiments, both the first dispenser  410  and the second dispenser  450  are coupled with the same reservoir  402 . 
       FIG. 4F  illustrates coupled pistons in accordance with some embodiments. In  FIG. 4F , the first piston  422  and the second piston  462  are mechanically coupled to a common holder  490  (which may have the shape of a plate, a rod, a block, etc.) so that a movement of the common holder  490  causes concurrent movement of the first piston  422  and the second piston  462 . 
     In some embodiments, the common holder  490  is coupled to an actuator, which causes a movement of the common holder  490 . In some embodiments, the actuator includes a motor (e.g., a stepper motor, a DC motor, etc.), a linear actuator, etc. 
       FIG. 4G  illustrates a sectional view of a block with piston channels and nozzle channels in accordance with some embodiments. Although  FIGS. 4A-4F  illustrate the first piston channel  412  and the first nozzle channel  414  defined by one or more barrels (e.g., the first piston channel  412  corresponds to a hollow space within a first barrel and the second nozzle channel  414  corresponds to a hollow space within a second barrel), the first piston channel  412  and the first nozzle channel  414  may be defined by using other parts. For example, as shown in  FIG. 4G , piston channels  512  and nozzle channels  514  are defined in a block  500 . In some embodiments, the block  500  is a single integrated block (e.g., a single piece of a particular material, such as metal, ceramics, plastic, or a composite material) with a cavity to define the piston channels  512  and the nozzle channels  514 . In such embodiments, the block  500  may be made by casting (e.g., metal casting), machining, three-dimensional printing, any combination thereof, etc. In some other embodiments, the block  500  is a combination of multiple parts (e.g., one or more plates and/or sub-blocks) that are assembled together to define the piston channel  512  and the nozzle channels  514 . 
     In some embodiments, the block  500  also defines a reservoir  502 . In some embodiments, as shown in  FIG. 4G , the reservoir  502  is coupled to the plurality of nozzle channels  514 . In some embodiments, the block  500  may define multiple reservoirs, including a first reservoir coupled to a first subset of the nozzle channels  514  and a second reservoir coupled to a second subset of the nozzle channels  514  that is different from and mutually exclusive to the first subset of the nozzle channels  514 . 
       FIG. 4G  also shows a plurality of nozzles  532 , a plurality of first valves  542 , and a plurality of second valves  544 , located in respective nozzle channels  514 . In  FIG. 4G , the nozzles  532 , the first valves  542 , and the second valves  544  are not shown for every nozzle channel  514  so as not to obscure other aspects of the block  500 . However, a person having ordinary skill in the art would understand that each nozzle channel  514  may contain a respective nozzle  532 , a respective first valve  542 , and a respective second valve  544 . 
     Also shown in  FIG. 4G  is line A, from which the cross-sectional view of the block  500 , shown in  FIG. 4H , is taken.  FIG. 4H  illustrates the piston channel  512  perpendicularly connected to the nozzle channel  514 . 
       FIGS. 5A-5D  illustrate a dispensing operation in accordance with some embodiments. 
       FIG. 5A  illustrates the dispenser  410  coupled to the reservoir  402  containing a liquid (e.g., a wash solution). 
       FIG. 5B  illustrates that the first piston  422  of the dispenser  410  is pulled, which initiates a flow of the liquid in the reservoir  402  to the first intersection  416  (by providing a pressure differential between the reservoir  402  and the first intersection  416 , which, in turn, opens the first valve  442 ). In some cases, the liquid also flows into the first piston channel  412 , as shown in  FIG. 5B . Pulling the first piston  422  also decreases the pressure within the first intersection  416  (relative to the pressure around an inlet of the first nozzle  432 ) so that the second valve  444  remains closed. 
       FIG. 5C  illustrates that the first piston  422  is pushed, which initiate a flow of the liquid in the first intersection  416  (and optionally, the liquid in the first piston channel  412 ) to the first nozzle  432  (by providing a pressure differential between the first intersection  416  and an inlet of the first nozzle  432 , which, in turn, opens the second valve  444 ) so that the liquid is dispensed from the first nozzle  432 . Pushing the first piston  422  also increases the pressure within the first intersection  416  (relative to the pressure within the reservoir  402 ) so that the first valve  442  remains closed. 
       FIG. 5D  illustrates that, in some cases, after the first piston  422  ceases to move (e.g., the first piston  422  is neither pulled nor pushed), the pressure within the first intersection  416  corresponds to the pressure around the inlet of the first nozzle  432  so that the second valve  444  closes. In some cases, at least one of the first valve  442  and the second valve  444  includes an elastic object (e.g., a spring), which facilitates (or accelerates) closing of the valve. 
       FIGS. 6A-6E  illustrate an aspiration operation in accordance with some embodiments. 
       FIG. 6A  illustrates an aspirator  610  coupled to a reservoir  602  (e.g., an aspirated-liquid reservoir) configured to receive (and optionally store) an aspirated liquid (e.g., a mixture of a sample solution and a wash solution). The aspirator  610  has a first piston channel and a first nozzle channel  614  coupled to the first piston channel. The aspirator  610  includes a first piston  622 , a first nozzle  632 , a first valve  642 , and a second valve  644 . The first piston  622 , the first nozzle  632 , the first valve  642 , and the second valve  644  correspond to the first piston  422 , the first nozzle  432 , the first valve  442 , and the second valve  444  of the first dispenser  410 , except that the directionality of the first valve  442  and the second valve  444  is reversed. 
       FIG. 6B  illustrates that the first piston  622  of the aspirator  610  is pulled, which initiates a flow of the liquid in the first nozzle  632  to the first intersection  616  (by providing a pressure differential between the first nozzle  632  and the first intersection  616 , which, in turn, opens the second valve  644 ). This also facilitates aspirating liquid adjacent to the first nozzle  632  into the first intersection  616 . In some cases, the liquid also flows into the first piston channel  612 , as shown in  FIG. 6B . Pulling the first piston  622  also decreases the pressure within the first intersection  616  (relative to the pressure in the reservoir  602 ) so that the first valve  642  remains closed. 
       FIG. 6C  illustrates that the first piston  622  is pushed, which initiate a flow of the liquid in the first intersection  616  (and optionally, the liquid in the first piston channel  612 ) to the reservoir  602  (by providing a pressure differential between the first intersection  616  and the reservoir  602 , which, in turn, opens the first valve  642 ). Pushing the first piston  622  also increases the pressure within the first intersection  616  (relative to the pressure within the first nozzle  632 ) so that the second valve  642  remains closed. 
       FIGS. 6D and 6E  illustrate that, in some cases, after the first piston  622  ceases to move (e.g., the first piston  622  is neither pulled nor pushed), the pressure within the first intersection  616  corresponds to the pressure in the reservoir  602  so that the first valve  642  closes. In some cases, at least one of the first valve  642  and the second valve  644  includes an elastic object (e.g., a spring), which facilitates (or accelerates) closing of the valve. 
       FIG. 6F  illustrates a set of multiple aspirators in accordance with some embodiments. The set of multiple aspirators includes the first aspirator  610  and a second aspirator  650 . 
     The second aspirator  650  has a second piston channel  652  and a second nozzle channel  654  that is connected to the second piston channel  652  at a second intersection  656 . In some embodiments, the second nozzle channel  654  is non-parallel to the second piston channel  652 . 
     The second aspirator  650  includes a second piston  662 , a second nozzle  672 , a third valve  682 , and a fourth valve  684 . These components are similar to the first piston  612 , the first nozzle  632 , the first valve  642 , and the second valve  644 , respectively. For brevity, the description of these components is omitted herein. However, a person having ordinary skill in the art would understand their structures and operations based on the description of the corresponding components, namely the first piston  612 , the first nozzle  632 , the first valve  642 , and the second valve  644 , as described herein. 
     In some embodiments, the piston channels and the nozzle channels of aspirators are defined using barrels. In some embodiments, the piston channels and the nozzle channels of aspirators are defined in a block (e.g., the block  500 ). 
     Although the dispensers  410  and  460  are illustrated separately from the aspirators  610  and  650 , a person having ordinary skill in the art would understand that the dispensers  410  and  450  may be used in conjunction with the aspirators  610  and  650 , in a manner analogous to those described with respect to  FIGS. 2A-2E and 3A-3G . 
     In some embodiments, a block defines piston channels and nozzle channels for both dispensers and aspirators. This enables a compact washing device. 
     The foregoing description, for purpose of explanation, has been described with reference to specific embodiments. However, the illustrative discussions above are not intended to be exhaustive or to limit the embodiments to the precise forms disclosed. Many modifications and variations are possible in view of the above teachings. The embodiments were chosen and described in order to best explain the principles of the invention and its practical applications, to thereby enable others skilled in the art to best utilize the invention and various embodiments with various modifications as are suited to the particular use contemplated.