Micro-diaphragm pumping system for precise laboratory dispensing

Abstract

Aspects of a microfluidic diaphragm pumping system are disclosed including a flexible membrane and a substrate. The substrate including a plurality of fluid access ports and defining, at least in part, a domed cavity that surrounds the flexible membrane. The flexible membrane extending across the domed cavity like a diaphragm and having an adjustable stroke path from a first position to an adjustable second position that varies depending on user preferences and / or calibration. The adjustable stroke path defining an adjustable volume within the domed cavity, and the adjustable volume being based on where the second position is set to. The substrate also including the plurality of fluid access ports in fluid communication with the flexible membrane such that, when the flexible membrane is actuated, fluid passes between a first fluid access port and a second fluid access port of the plurality of fluid access ports.

Description

MICRO-DIAPHRAGM PUMPING SYSTEM FOR PRECISE LABORATORYDISPENSINGCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 622,231 filed January 18, 2024. The contents of the foregoing application are incorporated by reference as if fully set forth herein in its entirety.FIELD

[0002] This disclosure relates to micro-diaphragms and, in particular, diaphragm pumps and diaphragm pumping systems for making the process of dispensing selected liquids or fluid samples, in any combination of specified discrete volumes, quick, efficient, and repeatable.BACKGROUND

[0003] Challenges exist in designing fluid handling devices that may be deployed across a wide variety of tasks in a mixture of laboratory settings. In this regard, there is a long sought need for a fluid handling device that can effectively deliver fluid quickly and efficiently, while maintaining a compact form for increased density in a laboratory setting. A further challenge is to produce a fluid handling device capable of repeatable (in terms of precision and / or accuracy) substance dispensing at low volumes. A further challenge is to produce a fluid handling device that does not need rigorous, laborious, and / or constant calibration. A further challenge is to produce a fluid handling device that has flexibility around the liquid classes it can handle. A further challenge is to produce a fluid handling device that yields low-dead volume (e.g., wasted liquid). A further challenge is to produce a fluid handling device with gentle yet effective valves and pumps that allows for cells and beads, etc. Various arrangements exist that attempt to meet these often competing criteria but none have been able to resolve the challenges present in the art.SUMMARY

[0004] According to its major aspects and briefly recited, disclosed herein is examples of a microfluidic diaphragm pumping system having a flexible membrane; and a substrate. The substrate comprising a plurality of fluid access ports and defining, at least in part, a domed cavity. The domed cavity surrounding the flexible membrane, and the flexible membrane extending across the domed cavity and having an adjustable stroke path from a first position to an adjustable second position. The adjustable stroke path defining an adjustable volume within the domed cavity. The plurality of fluid access ports in fluid communication with the flexible membrane, and the flexible membrane being adapted to deflect from the first position along a first side of the domed cavity to the adjustable second position away from the first side of the domed cavity so as to allow fluid to pass between a first fluid access port and a second fluid access port upon membrane actuation.

[0005] In some aspects, a method of actuating a microfluidic diaphragm pumping system is disclosed herein. The method including providing a flexible membrane. The method also including providing a substrate comprising a plurality of fluid access ports and defining, at least in part, a domed cavity, the domed cavity surrounding the flexible membrane, the flexible membrane extending across the domed cavity and having an adjustable stroke path from a first position to an adjustable second position, the adjustable stroke path defining an adjustable volume within the domed cavity, the plurality of fluid access ports in fluid communication with the flexible membrane. The method also including supplying a pressure to the flexible membrane such that the flexible membrane presses against the first side of the domed cavity in a first position. The method also including reducing the pressure to the flexible membrane such that the flexible membrane deflects from the first position along a first side of the domed cavity to the adjustable second position away from the first side of the domed cavity so as to allow fluid to pass between a first fluid access port and a second fluid access port.

[0006] These and other advantages will be apparent to those skilled in the art.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Many aspects of the present disclosure will be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, with emphasis instead being placed upon clearly illustrating the principles of the disclosure. Moreover, in the drawings, like reference numerals designate corresponding parts throughout the several views. It should be recognized that these implementations and embodiments are merely illustrative of the principles of the present disclosure. Therefore, in the drawings:

[0008] FIG. 1 is a schematic representation of an example fluid handling device;

[0009] FIG. 2A is a perspective view of an illustration of an example fluid handling device having a manifold collector, an ingredient manifold, a metering assembly, and control modules;

[0010] FIG. 2B is a bottom perspective view of an illustration of the fluid handling device of FIG. 2A, showing a shared control module;

[0011] FIG. 2C is a top view of an illustration of another example fluid handling device;

[0012] FIG. 3A is a top view of an illustration of an example ingredient manifold;

[0013] FIG. 3B is a top view of an illustration of another example ingredient manifold;

[0014] FIG. 3C is a side view of an illustration of the ingredient manifold of FIG. 3 A;

[0015] FIG. 4A is a top view of an illustration of an example control module;

[0016] FIG. 4B is a top view of an illustration of an example manifold collector and shared control module;

[0017] FIG. 4C is a top view of an illustration of another example control module;

[0018] FIG. 5 is a perspective view of an illustration of an example of layers forming oneexample of a metering chamber;

[0019] FIG. 6 is an enlarged top view of an illustration of an example metering chamber showing channels and valves;

[0020] FIG. 7 is a top view of an illustration of an example of several metering chambers and valve clusters;

[0021] FIG. 8A is a perspective view of an illustration of an example valve cluster;

[0022] FIG. 8B is an enlarged top view of an illustration of an example valve cluster placed between metering chambers;

[0023] FIG. 9A is a schematic representation of a side view of an example individual valve in a closed configuration;

[0024] FIG. 9B is a schematic representation of a side view of an example individual valve in an open configuration;

[0025] FIG. 10A depicts one example of a process of filling a metering chamber;

[0026] FIG. 10B depicts one example of a process of beginning to dispense from a metering chamber;

[0027] FIG. 10C depicts one example of a process of metering and dispensing a small volume output;

[0028] FIG. 10D depicts one example of a process of metering and dispensing a medium volume output;

[0029] FIG. 10E depicts one example of a process of metering and dispensing a large volume output;

[0030] FIG. 10F depicts one example of a process of washing a metering chamber;

[0031] FIG. 11 is a one example of a software interface employed to control a fluid handling device;

[0032] FIG. 12 is a cross-sectional view of an illustration of an example valve cluster comprising a fixed valve and a “top hat” diaphragm assembly;

[0033] FIG. 13 is a perspective view of a partial illustration of an example diaphragm pumping system comprising a flexible membrane and a substrate defining a domed cavity, according to the present disclosure;

[0034] FIG. 14 is a cross-sectional view of an illustration of an example diaphragm pumping system comprising a flexible membrane and a substrate defining a domed cavity, according to the present disclosure;

[0035] FIG. 15 is a cross-sectional view of an illustration of an example diaphragm pumping system comprising a flexible membrane and a screw-type structure for limiting the adjustable stroke path, according to the present disclosure;

[0036] FIG. 16 is a magnified, cross-sectional view of an illustration of an example screwtype structure for limiting the adjustable stroke path, according to the present disclosure;

[0037] FIG. 17 is an exploded, top perspective view of an illustration of the example fluidic chip including a valve cluster having a valve cluster having a flexible membrane, according to the present disclosure; and

[0038] FIG. 18 is an exploded, top perspective view of an illustration of the example fluidic chip including a valve cluster having a valve cluster having a flexible membrane, according to the present disclosure.DETAILED DESCRIPTION

[0039] The presently disclosed subject matter now will be described more fully hereinafter with reference to the accompanying drawings, in which some, but not all embodiments of the presently disclosed subject matter are shown. Like numbers refer to like elements throughout. The presently disclosed subject matter may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Indeed, many modifications and other embodiments of the presently disclosed subject matter set forth herein will come to mind to one skilled in the art to which the presently disclosed subject matter pertains having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims.

[0040] Throughout this specification and the claims, the terms “comprise,” “comprises,” and “comprising” are used in a non-exclusive sense, except where the context requires otherwise. Likewise, the term “includes” and its grammatical variants are intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that can be substituted or added to the listed items.I. Example Use Case Scenarios

[0041] A metering assembly may generally include a fluidic chip and a plurality of metering chambers disposed within the fluidic chip. Each metering chamber defines a chamber volume. A plurality of valves communicate with each metering chamber. Each of the valves provide an outlet from the metering chamber and each of the valves is selectable to provide a discrete output volume that can be dispensed from the metering chamber.

[0042] A metering assembly may also generally include a metering chamber defining achamber volume. A plurality of valves communicates with each metering chamber. The valves are grouped into a plurality of subsets of valves. Each subset of valves defines a discrete output volume that can be dispensed from the metering chambers. Each subset of valves is commonly controlled.

[0043] A metering assembly may also generally include a plurality of pressure ports disposed within the fluidic chip and a plurality of valves disposed within the fluid chip. Each valve communicates with a pressure port and a metering chamber. Application of pressure through the pressure port actuates the valve.

[0044] A plurality of valves may also communicate with each metering chamber. The valves are grouped into a plurality of clusters of valves having a common substrate and a plurality of valve membranes according to the present disclosure formed thereon such that each valve in a cluster shares the common substrate. Each cluster of valves has at least one first valve in communication with a first metering chamber and having at least one second valve in communication with a second metering chamber.

[0045] A method of dispensing a fluid from a fluid chip may generally include: a) selectively filling a plurality of fixed volume metering chambers in the fluid chip with a selected fluid; and b) outputting the fluid from the fixed volume metering chambers to corresponding output locations. The method also includes repeating a) and b) until a desired volume is obtained at each output location when the desired volume is larger than the fixed volume of the metering chamber(s). Conversely, the method may also generally include filling a plurality of fixed volume metering chambers in the fluid chip with a selected fluid; and b) selectively outputting the fluid from the fixed volume metering chambers to corresponding output locations. The method also includes repeating a) and b) until a desired volume is obtained at each output location when the desired volume is larger than the fixed volume.

[0046] The method may also generally include providing a fluid chip having a plurality of metering chambers, each having a fixed fill volume and each providing a plurality of selectablediscrete output volumes; b) selecting a fluid from a plurality of different fluids; c) determining a well fill volume of the selected fluid to be dispensed into each well; d) filling, to the fixed fill volume, at least a subset of the plurality of metering chambers with the selected fluid; e) selecting a first discrete output volume of the metering chamber; f) outputting to the well the fluid from each metering chamber in response to the selected first discrete output volume; g) accumulating a total output volume of fluid dispensed from each metering chamber; h) determining whether the discrete output volume from each metering chamber equals the accumulated total output volume; i) refilling the subset of the plurality of metering chambers with the selected fluid when the accumulated total output volume from each metering chamber is less than the well fill volume; j) selecting a second discrete output volume of the metering chambers; and k) outputting to the well the fluid from each metering chamber in response to the selected second discrete output volume. The method also includes 1) repeating g) through k) until the accumulated volume equals the well fill volume. The method also includes repeating b) through 1) for another one of the selected fluid from a plurality of different fluids.

[0047] For purposes of the present disclosure, diaphragm pumps and / or valves may be formed as multi-level structures, for example, formed as multi-level valves or diaphragms with flat top portion distinct from base portions. Diaphragm pumps and / or valves may also be formed as single thickness or tapered structures (e.g., lacking multi-levels or distinct top and base portions) such as for example, a flexible membrane. Diaphragm pumps and / or valves may also be formed into groups as elastomeric clusters. Moreover, diaphragm pumps and / or valves may be actuated by pneumatic or hydraulic methods. Using such pneumatic or hydraulic actuation, to actuate diaphragm pumps and / or valves, the microfluidic dispensing system may include pressure ports or fluid access ports whereby pressure within the ports causes membranes of the diaphragm pumps and / or valves to actuate such that a diaphragm pump and / or valve may open or close. Other suitable structures and actuation arrangements may be employed, as described in detail herein.

[0048] A fluidic chip may have one or more diaphragm pumps or pumping systems having a flexible membrane, and a substrate. The substrate comprising a plurality of fluid access ports anddefining, at least in part, a domed cavity. The domed cavity surrounding the flexible membrane, and the flexible membrane extending across the domed cavity and having an adjustable stroke path from a first position to an adjustable second position. The adjustable stroke path defining an adjustable volume within the domed cavity. The plurality of fluid access ports are in fluid communication with the flexible membrane, and the flexible membrane is adapted to deflect from the first position along a first side of the domed cavity to the adjustable second position away from the first side of the domed cavity so as to allow fluid to pass between a first fluid access port and a second fluid access port upon membrane actuation.

[0049] A method of actuating a diaphragm pumping system according to the present disclosure may generally include providing a flexible membrane and a substrate comprising a plurality of fluid access ports and defining, at least in part, a domed cavity, the domed cavity surrounding the flexible membrane and the flexible membrane extending across the domed cavity and having an adjustable stroke path from a first position to an adjustable second position. The adjustable stroke path defines an adjustable volume within the domed cavity, the plurality of fluid access ports in fluid communication with the flexible membrane. The method also including supplying a pressure to the flexible membrane such that the flexible membrane presses against the first side of the domed cavity in a first position. The method also includes reducing the pressure to the flexible membrane such that the flexible membrane deflects from the first position along a first side of the domed cavity to the adjustable second position away from the first side of the domed cavity so as to allow fluid to pass between a first fluid access port and a second fluid access port.II. Assemblies and Methods

[0050] Aspects of the present disclosure are directed to a fluid handling device that includes arrangement(s) and / or technique(s) for making the process of dispensing selected fluid samples in any combination of specified discrete volumes quick and efficient. The fluid handling device can include a number of components and includes a metering assembly.

[0051] The metering assembly includes a fluidic chip having metering chambers. In one aspect, selectable outlet valves communicate with each metering chamber to provide a discrete dispensed volume. The valves may be commonly controlled and may be formed as multi-level valves. The valves may be grouped into common substrate valve clusters.

[0052] In one aspect, a process of dispensing a fluid into any number of output wells as desired is provided. The fluidic chip contains several metering chambers that each define a fixed fill volume, yet provide the ability to selectively dispense a number of discrete output volumes. It should be understood that the fluidic chip can be designed to include any desired number of metering chambers, corresponding to any desired number of output wells, as the present disclosure is not limited in this respect. It should also be understood that each metering chamber can be designed to define any suitable fixed volume. Each metering chamber can also be designed to define any number of suitable discrete output volumes. In a similar manner, any discrete output volume can be defined within the scope of the fixed volume of each metering chamber, as the present disclosure is not limited in this respect.

[0053] Any suitable ingredient can be dispensed from the metering chamber. In one aspect, the particular ingredient selected to be dispensed can be one of any number of ingredients that are supplied from a source outside of the fluidic chip. It should be appreciated that there is no limitation to the variety of ingredients that may be supplied to the metering chambers within the fluidic chip.

[0054] In one aspect, a desired volume of the selected ingredient to be dispensed into each well is predetermined and / or adjustable according to the present disclosure. Then, the selected metering chambers that correspond to the selected wells to be dispensed into are filled with the selected ingredient. Afterwards, a predetermined and / or adjustable ingredient output volume is dispensed into each metering chamber and it is determined whether or not the actual output volume from each metering chamber is equivalent to the desired, predetermined, and / or adjustable dispensed volume of the selected ingredient to be dispensed in each corresponding well.

[0055] In one aspect, the methods and process according the present disclosure can be made to be automated to run quickly and efficiently and in a highly repeatable manner.

[0056] Aspects of the present disclosure also relate to metering chambers that are provided in an efficiently designed structure and equipped with valves at pre-specified locations along the metering chamber such that the device has the ability to dispense out discrete output volumes depending on which valves of the metering chamber are activated. Once the metering chamber is filled, the volume fraction of the fluid sample within the metering chamber that will be dispensed is controlled by controlling which valves are opened or closed, or actuated. As a result, a variety of output volumes may be dispensed from a single metering chamber through respective outlets. It should be appreciated that the present disclosure is not limited to the amount of discrete output volumes. Thus, in one aspect, each metering chamber can provide at least two discrete output volumes. In another aspect, each metering chamber can provide at least ten discrete output volumes. Indeed, the present disclosure is not limited to having discrete sub-volume outputs at all as it is possible for only one output volume to be provided as well.

[0057] In one aspect, each metering chamber can dispense, up to 10 pL. It should also be understood that there is no limitation placed on the overall capacity of the chamber, as the present disclosure can be designed to support output volumes between approximately as small as 1 nL and as large as 10 L. In one aspect, a small volume output that can dispensed from a metering chamber is between approximately 50 nL and approximately 500 nL. In another aspect, a medium volume output that can be dispensed from a metering chamber is between approximately 500 nL and approximately 1 pL. In yet another aspect, a large volume output that can be dispensed from a metering chamber is between approximately 1 pL and approximately 10 pL. It should also be appreciated that the present disclosure can incorporate one or more outlets so that all or a portion of the fixed camber volume can be dispensed.

[0058] As discussed above, each metering chamber may include several outlet valves, each corresponding to a specified discrete output volume from the metering chamber. In one aspect, thevalves for each desired output volume from the metering chamber are commonly controlled together for all of the metering chambers within the fluidic chip. In this manner, when a particular output volume is to be dispensed from all of the metering chambers on a single fluid handling device, all of the valves that correspond to the desired output volume may be controlled or actuated together, further simplifying the complexity of control without compromising overall dispense efficiency.

[0059] Thus, in one aspect, each valve corresponding to one particular metering chamber for one particular discrete output volume may be controlled separately individually. In another aspect, a first fraction of valves corresponding to a subgroup of metering chambers can be controlled together according to the corresponding discrete output volume of each valve fraction of valves corresponding to the same subgroup of metering chambers can be controlled together separately from the first fraction of valves. Likewise, different sets of valves corresponding to other subgroups of metering chambers can be controlled together as desired. Indeed, it should be appreciated that there is no limitation to be placed on the number of valves corresponding to any number of metering chambers within the fluid handling device. To be sure, the present disclosure may be designed for any type of valve control, common or separate, however it is suitably desired within the scope of the existing system.

[0060] Another aspect relates to pump regions that are structured with diaphragm pumps of varying sizes and with valves at particular locations such that a broader microfluidic dispensing system has the ability to dispense discrete output volumes depending on how the diaphragm pumps and valves are actuated. When the pump space of a diaphragm pump is filled, the volume of ingredient within that pumps space will be dispensed. In another aspect, multiple diaphragm pumps are located in a pump region, each of the diaphragm pumps having different diaphragm pump space fill sizes. In another aspect, a variety of discrete output volumes may be dispensed from a pump region given the discrete volume pump space sizes of each diaphragm pump.

[0061] In one aspect, a diaphragm pump that is filled may subsequently dispense up to about10 pL. It should also be understood that there is no limitation placed on the overall capacity of the pump space for each diaphragm pump, as the pump can be designed to support output volumes between approximately as small as 1 nL and as large as 10 pL. In another aspect, a small volume output that can be dispensed from a diaphragm pump is between approximately 50 nL and approximately 500 nL. In another aspect, a medium volume output that can be dispensed from a diaphragm pump is between approximately 500 nL and approximately 1 pL. In yet another aspect, a large volume output that can be dispensed from a diaphragm pump is between approximately 1 pL and approximately 10 pL.

[0062] A further aspect relates to the construction of diaphragm pumps and / or valves. In particular, in one aspect, diaphragm pumps and / or valves may include physical features that improve performance, particularly with regard to mechanical flexibility and structural integrity. In another aspect, a multi-level construction is employed for diaphragm pumps and / or valves. Multilevel diaphragm pumps and / or valves may be made of a firm but compliant material or structure with an added base structure around the diaphragm pump and / or valve providing for extra surface area, which may give rise to a more effective air-tight seal. A lip that extends upwardly may also be included in a multi-level diaphragm pump and / or valve to provide for an extra compression surface.

[0063] In one aspect, diaphragm pumps and / or valves are controlled through a pressure inlet or port that either serves to push air against a flexible membrane, closing the diaphragm pump and / or valve, or serves to refrain from applying pressure to a flexible membrane, resulting in the opening of a diaphragm pump and / or valve. In another aspect, a vacuum is applied to further facilitate opening of a diaphragm pump and / or valve, allowing for improved flow through a diaphragm pump and / or valve. In another aspect, a diaphragm pump and / or valve are configured such a way that application of pressure through an inlet to a flexible membrane serve to open a diaphragm pump and / or valve and that not applying pressure, or applying a vacuum, through an inlet could serve to close a diaphragm pump and / or valve.

[0064] In one aspect, diaphragm pumps and / or valves may be formed out of a wide variety of suitable materials. Thus, in one aspect, diaphragm pumps and / or valves may be made of an elastomeric material such as silicone, rubber, polyurethane, polydimethylsiloxane, or any suitable polymeric equivalent or suitable combinations thereof.

[0065] In one aspect, clusters of diaphragm pumps and / or valves may be formed of any suitable material and in any suitable arrangement or combinations of materials / arrangements, such as those described above with respect to the diaphragm pumps and / or valves. In addition, the clusters of diaphragm pumps and / or valves may be molded together in a single elastomeric piece. In one aspect, discrete output volumes may be controlled as desired from one or more particular diaphragm pumps in a cluster. In such a case, clusters of diaphragm pumps and / or valves may include diaphragm pumps that open or close appropriately depending on what discrete output volume is desired.

[0066] It should be appreciated that a number of alternative embodiments exist for clustering of diaphragm pumps and / or valves. In one aspect, a cluster of diaphragm pumps and / or valves may be used to control a particular pump region associated with an outlet (e.g., nozzle) for dispensing. In another aspect, a cluster of diaphragm pumps and / or valves may be in fluid communication with only a portion of a pump region associated with an outlet for dispensing. In another aspect, a cluster of diaphragm pumps and / or valves may be in communication with a number of pump regions, each of the pump regions being associated with an outlet for dispensing. It should be appreciated that any appropriate manner in which clusters of diaphragm pumps and / or valves suitable for controlling pump regions may be designed.

[0067] A further aspect relates to the construction of the diaphragm pumps, in particular. In several aspects, the diaphragm pumps include physical features that maximize their performance, particularly with regard to mechanical flexibility, structural integrity, efficiency, and efficacy. In one aspect, a diaphragm pump includes structural features that allow for repeatable discrete dispensing of liquids or fluids via pneumatic control. In one aspect, a diaphragm pumping systemis employed. The diaphragm pumping system, in one aspect, includes a diaphragm-membrane type structure that is made of a firm but compliant material or structure, such as silicone or perfluoroelastomer (PFE), and that leverages diaphragm-based dispensing.

[0068] In one aspect, a diaphragm pumping system includes a flexible membrane and a substrate. The substrate includes a plurality of fluid access ports and defines, at least in part, a domed cavity. In one aspect, the domed cavity is a slightly curved cavity that occupies volume. The domed cavity surrounds the flexible membrane and the flexible membrane extends across the domed cavity. Like a diaphragm, the flexible membrane extending across the domed cavity has an adjustable stroke path from a first position along a first side of the domed cavity to an adjustable second position. The adjustable second position can vary depending on user preferences and / or calibration and, therefore, the stroke path is adjustable depending on where the second position is set to. Moreover, the adjustable stroke path defines an adjustable volume within the domed cavity, and the adjustable volume may be based on where the second position is set to. The substrate also includes the plurality of fluid access ports in fluid communication with the flexible membrane such that, when the flexible membrane deflects from the first position along the first side of the domed cavity to the adjustable second position away from the first side of the domed cavity (also known as membrane actuation), fluid passes between a first fluid access port and a second fluid access port of the plurality of fluid access ports. Moreover, the flexible membrane may be progressively thicker such that the thickest portion is the middle of the membrane / diaphragm, or uniformly thick.

[0069] In one aspect, the adjustable second position is a fixed position and, therefore, the stroke path is a fixed stroke path from the first position to the fixed second position. The fixed stroke path defining a fixed volume within the domed cavity. In another aspect, the fixed volume of the fixed stroke path is equal to or less than the volume of the domed cavity over all. In another aspect, the first position of the flexible membrane during a stroke path is along the first side of the domed cavity such that no gap is between the flexible membrane and the first side of the domed cavity. In another aspect, the second position of the flexible membrane during a stroke path is along a second side of the domed cavity antipodal to the first side of the domed cavity. In anotheraspect, when in the second fixed position, the flexible membrane has no gap between itself and the second side of the domed cavity. As such, in one aspect, the flexible membrane / diaphragm is supported by the floor or the ceiling of the domed cavity, which enables more repeatable dispense volumes across a wide range of operating conditions.

[0070] In one aspect, the diaphragm pumping system also includes a component of subsystem for adjusting the adjustable volume of the adjustable stroke path within the domed cavity. In another aspect, the component or subsystem for adjusting the adjustable volume of the adjustable stroke path is a component or subsystem for adjusting the adjustable second position of the adjustable stroke path within the domed cavity. In another aspect, the component or subsystem for adjusting the adjustable second position of the adjustable stroke path is a screw extending into the domed cavity, and the screw is configured to limited the adjustable stroke path within the domed cavity based on a length the screw extends into the domed cavity opposite the first side of the domed cavity. In still another aspect, the component or subsystem for adjusting the adjustable volume of the adjustable stroke path within the domed cavity is instead a heating element, and the heating element is configured to warm the flexible membrane and expand the adjustable stroke path within the domed cavity. In still another aspect, the component or subsystem for adjusting the adjustable volume of the adjustable second position is a screw like mechanism configured to flatten the ceiling of the domed cavity (e.g., to deform a thin layer(s) defining the domed cavity within the microfluidic chip).

[0071] In one aspect, and turning to valves, valves may also be controlled by a pressure inlet that either serves to push air against the valve membrane (closing the valve) or serves to refrain from applying pressure to the valve membrane (opening the valve). In some cases, a vacuum is applied to allow for enhanced fluid ingredient flow. It should also be appreciated that in another aspect, the valve can be designed in such a way that application of pressure through an inlet to the valve membrane could serve to open the valve and that not applying pressure (or applying a vacuum) through an inlet could serve to close the valve. It should be understood that the valves may be formed out of a wide variety of suitable materials. Thus, in one aspect, the valves may bemade of an elastomeric material such as silicone, rubber, polyurethane, polydimethylsiloxane, or any suitable polymeric equivalent or suitable combinations thereof. In another aspect, the valves may be made of a suitable rigid material, such as a metal or a ceramic, that can be actuated through any appropriate arrangement, whether electrical or mechanical in nature. If a rigid material is used, a hinge or gateway that can be opened or closed may be employed.

[0072] In another aspect, clusters of valves may be molded together in a single elastomeric piece. In another aspect, partial control of discrete output volumes to be dispensed from metering chambers that are located adjacent to one another may be provided. In this case, clusters of valves that partially control neighboring metering chambers allow for overall space conservation and ease of manufacture.

[0073] It should be appreciated that a number of alternative aspects exist for clustering of valves. In one aspect, a cluster of valves may be used to control every valved region of an individual metering chamber. In another aspect, a cluster of valves may be in communication with only a portion of the valved regions for at least one metering chamber. In another aspect, a cluster of valves may be in partial communication with at least two separate metering chambers. In another aspect, a cluster of valves may be in partial communication with at least three separate metering chambers. In another aspect, a cluster of valves could be in partial communication with at least four separate metering chambers. Indeed, in yet another aspect, a cluster of valves may be in partial communication with only one metering chamber, as the present disclosure is not limited in this respect. In a similar manner, a cluster of valves may be in full communication with all of the metering chambers within the fluidic chip. It should be appreciated that there is no limitation to be placed on the manner in which clusters of valves partially (or fully) controlling regions in metering chambers are designed.

[0074] It should be appreciated that various arrangements and combinations of valves and diaphragm pumps as discussed above may be constructed in a dispensing device for precise control of fluid flow direction and volume to occur as desired. In this respect, valves on either side ofa diaphragm pump may control when fluid is to be dispensed and the diaphragm pump may serve to meter and push out a suitable amount of fluid through the fluid channels and out of the device when valves and other parts of the device are appropriately actuated. In this regard, when incorporated into different aspects of the overall microfluidic dispensing device, depending on how diaphragm pumps are constructed, dispense volumes may range widely from approximately 10 nanoliters to approximately 100 microliters. In one aspect, dispense volumes may be approximately 100 nanoliters. In another aspect, dispense volumes may be approximately 3 microliters.

[0075] In one aspect, the diaphragm pumps and / or valves are actuated through electrical switching means. In another aspect, diaphragm pumps and / or valves are actuated through mechanical switching. In another aspect, diaphragm pumps and / or valves are actuated pneumatically and / or hydraulically. In another aspect, diaphragm pumps and / or valves are actuated through use of piezoelectric materials.

[0076] In one aspect, any number of diaphragm pumps and valves may be employed in any suitable configuration. In some aspects, any number of diaphragm pumps of suitable size may be included along a fluid channel in a pump region with valves at the ends of the fluid channel. For example, instead of two diaphragm pumps included along a fluid channel within a pump region with valves at the ends of the fluid channel, one diaphragm pump may be incorporated. Or alternatively, three or more diaphragm pumps may be incorporated along a fluid channel within a pump region with valves at the ends of the fluid channel.

[0077] Moreover, in another aspect, valves may be incorporated in between diaphragm pumps along a fluid channel within a pump region, as desired. For example, for the two diaphragm pump arrangement, a valve may be incorporated along the fluid channel between the diaphragm pumps. Furthermore, in another aspect, any suitable number of fluid channels may extend from diaphragm pumps; for example, a fluid channel within a pump region may extend from one diaphragm pump into two or more valves rather than a single valve.

[0078] In one aspect, the valves may also be used in facilitating transport of fluid back and forth through fluid access port holes. For example, the number of fluid access ports that contact the structure from a fluid layer, for example, may vary. In one aspect, one port hole may serve as both an inlet and outlet for a diaphragm pump. In another aspect, a plurality of ports, serving as inlets and / or outlets may be employed.

[0079] In one aspect, diaphragm pumps may also serve as metering chambers themselves, where fluid that is to be dispensed from a microfluidic assembly at a precise amount may be temporarily stored within a pump space. In this regard, valves and diaphragm pumps may be used in whatever suitable fashion to control efficient and accurate dispensing of a multiple of ingredients as desired.

[0080] It should be appreciated that the above aspects may be employed in any suitable combination, as the present inventions are not limited in this respect. Also, any or all of the above aspects may be employed in a microfluidic dispensing system for use with dispensing fluid to wells of a microplate; however, the present inventions are not limited in this respect, as aspects may be used with any microfluidic dispensing systems. Various aspects and embodiments of the inventions will now be described in more detail with respect to the accompanying drawing figures. The inventions are not, however, limited to the aspects and embodiments shown.III. With Reference to the Figures

[0081] United States Patent 8016260, 8205856, and 8550298 are assigned to the Applicant of the present application, and are incorporated herein in their entirety by reference.

[0082] Turning now to the figures, FIG. 1 is a schematic representation of an example fluid handling device 10. The fluid handling device 10 includes a collection of reservoirs, channels, and valves that are adapted for quick and efficient dispensing of selected ingredients into selected wells in predetermined output volumes. As shown in the schematic of FIG. 1, a number of different ingredients 12 are provided in corresponding source reservoirs 20a, 20b, 20c, 20d, 20e, and 20fand are connected to ingredient valves 22a, 22b, 22c, 22d, 22e, and 22f through which ingredients may be selectively supplied for further handling. Ingredients may Be selected one at a time and subsequently allowed to flow into an ingredient channel 24. Channel 24 is directed into a main fill channel 26. In one aspect, individual ingredient channels and fill channels that correspond to each source reservoir may be provided. It should be apparent that any number of source reservoirs and corresponding ingredient valves may be employed, as the present disclosure is not limited in this respect.

[0083] Continuing with FIG. 1 , the main fill channel 26 is connected to metering chambers 30a, 30b, 30c, 30d, and 30e, where flow is individually controlled via fill valves 28a, 28b, 28c, 28d, and 28e to completely fill each selected metering chamber with the desired ingredient.

[0084] It should be understood that in other examples, there may be any amount of metering chambers and corresponding fill valves for each metering chamber and that the number presented herein should not limit the present disclosure in any way. In one aspect, there is at least one metering chamber. In another aspect, there are at least two metering chambers. In another aspect, there are at least three metering chambers. In another aspect, there are at least four metering chambers. In another aspect, there are at least five metering chambers. In another aspect, there are at least twelve metering chambers. In another aspect, there are at least ninety-six metering chambers. In one aspect, the number of metering chambers corresponds to the number of wells employed in a microplate into which the fluid from the fluid handling device is dispensed.

[0085] Each metering chamber is also equipped with a plurality of small volume output valves 32a, 32b, 32c, 32d, and 32e, a plurality of medium volume output valves 34a, 34b, 34c, 34d, and 34e, and a plurality of large volume output valves, 36a, 36b, 36c, 36d, and 36e. These valves are employed to set the desired output volume that is to be dispensed from the respective metering chamber through dispense nozzles 38a, 38b, 38c, 38d, and 38e and into corresponding output wells 40a, 40b, 40c, 40d, and 40e. The particular volume dispensed will depend on which output valve is actuated for that ingredient within the metering chamber. It should be appreciated that in otherexamples, there may be any number of output valves that each metering chamber is equipped with, allowing for any number of desired output volumes to be dispensed from the respective metering chamber.

[0086] It should be appreciated that there is no limitation placed on the number of ingredients that may be selected and subsequently dispensed. Thus, in one example, there is at least one ingredient from which to select and dispense. In another example, there may be two to six ingredients. In yet another example, there are at least twenty-five ingredients from which to select and dispense. In another example, there are at least ninety-six ingredients from which to select and dispense. It should also be understood that the ingredients to be selected from and dispensed can take on any suitable form, phase, or mixture thereof. For example, ingredients can be in liquid, gaseous, or solid phase. Furthermore, ingredients can also be a combination of one of the aforementioned phases, such as in an emulsion, immiscible mixture, or in a dissolved state.

[0087] It should also be appreciated that the manner in which the ingredients are selected and outputted to the wells can also be performed in a number of different ways. In one example, at least one individual fill channel through which ingredients are deposited into metering chambers is provided. In another example, at least two individual fill channels through which ingredients are deposited into metering chambers is provided. In another example, at least three individual fill channels through which ingredients are deposited into metering chambers is provided. In another example, at least four individual fill channels through which ingredients are deposited into metering chambers is provided. In another example, at least five individual fill channels through which ingredients are deposited into metering chambers is provided. In another example, at least twelve individual fill channels through which ingredients are deposited into metering chambers is provided. In another example, at least ninety-six individual fill channels through which ingredients are deposited into metering chambers is provided. In general, it should be appreciated that the number of ingredients, reservoirs, channels, and valves can be scaled to whatever number is desired.

[0088] In addition, the number of metering chambers does not have to coincide with the be accomplished, for example, by incorporating mobility into the system where metering chamber nozzles are able to dispense out and move over to selected wells for subsequently dispensing. In the same way, the system could have metering chambers dispense out into selected output wells and then have other output wells move under selected output nozzles for subsequent dispensing. In one example, it is possible for one metering chamber to dispense into at least two output wells. In another example, it is possible for one metering chamber to dispense into at least three output wells. In another example, it is possible for one metering chamber to dispense into at least ninety- six output wells.

[0089] FIGS. 2 A and 2B are exploded perspective of an illustration of an example fluid handling device 10. The device includes five main components, a manifold collector 100, a shared control module 150, an ingredient manifold 200, a fluidic chip 300 having conduits to allow fluid flow there through, and several control modules, six of which are shown, namely 400a, 400b, 400c, 400d, 400e, and 400f. A bottom perspective view of the same components without the fluidic chip 300 or the ingredient manifold 200 is shown in FIG. 2B. The manifold collector 100 includes slots where the other four components may be attached. One such slot 103 is shown for attachment of the fluidic chip 300.

[0090] Fluid flow may be controlled using any suitable arrangement. In one example, fluid is controlled with solenoid actuated valves, as will be explained in greater detail below. In one example, different groups of valves on the fluidic chip 300 share control from single solenoid control sources. These shared solenoid control sources are arranged together on a shared control module 150 that is attached to the underside of the manifold collector 100. In one example, the shared control module 150 includes shared valve solenoids 160 that allow for control of shared purge and volume output sizes. The ingredient manifold 200 includes connections for where ingredient reservoirs 210, a purge air tube 212, a wash water tube 214, and a separate overflow and waste container 216 (or tube) may be plugged in for ingredient and purge material supply into the fluidic chip 300 and providing waste out from the fluidic chip 300. The fluidic chip 300includes a metering assembly where fluid flow of ingredients and purge materials, metering of ingredients, and eventual dispensing occurs. Control modules 400a, 400b, 400c, 400d, 400e, and 400f, attached to opposite sides of the manifold collector 100, include solenoids that enable control of the different valves within the fluidic chip 300. Included within each control module 400 shown in FIGS. 2A and 2B are sixteen individual fill solenoids 402 that control ingredient filling into respective metering chambers within the fluidic chip 300. This arrangement of control modules gives rise to ninety-six separately controlled fill valves for each metering chamber. It should be appreciated that additional control modules may be used and / or more or less solenoid valves on each control module may also be employed.

[0091] The shared control module 150 is disposed adjacent to the manifold collector 100 and includes shared valve solenoids 160 which serve to commonly control each selectable discrete output volume dispense as well as the purge wash. In one example, the small output volumes are controlled by a single solenoid valve. The medium output volumes are controlled by a different single solenoid valve, and the large output volumes are controlled by a yet another single solenoid valve. The purge wash is controlled by a single solenoid valve. It should be appreciated that each of the discrete output volume dispenses as well as the purge do not have to be commonly controlled. In fact, the present disclosure may be designed in such a manner that each valve on the entire fluidic chip 300 may be controlled individually by separate valves. The shared control module 150 also incorporates an overflow pressure supply port 170 which functions to control pressure to overflow valves 650, shown in FIG. 8B, for enhanced fill rate control. In this manner, such pressure control serves to minimize excessive ingredient waste as overflow valve pressure may be controlled separately than for. the other valves. A shared manifold connection 180 allows the shared control module 150 to communicate with the manifold collector 100. The manifold collector 100 also includes shared valve connections 190 which serve as conduits between the valves on the shared control module 150 to communicate with the shared valves on the fluidic chip 300.

[0092] FIG. 2C is a top view illustration of another example fluid handling device 10. Thedevice includes three main components, an ingredient manifold 200, a fluidic chip 300, and a control module 400. In this example, there is no shared control module. The ingredient manifold 200 includes connections for where ingredient reservoirs 210, an air and water supply tube 213, a waste container 225, and an overflow container 215 may be plugged in for ingredient and purge material supply into the fluidic chip 300 and providing waste out from the fluidic chip 300. The fluidic chip 300 includes a metering assembly where fluid flow of ingredients and purge materials, metering of ingredients, and eventual dispensing occurs. A control module 400 includes solenoid valves that enable control of the different valves within the fluidic chip 300. Included within a control module 400 are individual fill solenoids 402 that control ingredient filling into the fluidic chip 300.

[0093] It should be appreciated that the fluid handling device should not be limited to the present example. For example, in one example, the ingredient supply, the fluidic metering and dispensing, and the control supply aspects could all be combined together on one general manifold. In another example, the ingredient supply and the fluidic metering could be combined together on one common substrate and the control supply could be attached thereon. In this way, the processes of ingredient and purge material supply, metering, and dispensing would occur on one multipurpose substrate while the components that control how the processes are performed would be disposed at another region of the overall device. In a separate example, the ingredient supply and the control supply could be combined together on one substrate and the fluidic metering could be attached thereon. In this regard, ingredient and purge material supply and aspects that allow for control would be provided at one common region and fluidic metering and dispensing would occur at a separate section of the device. In a different example, the fluidic metering and the control supply could be combined together on one separate substrate and the ingredient supply could be attached thereon. In this manner, aspects that allow for control as well as fluidic metering and dispensing would occur together on that substrate while ingredient and purge materials would be supplied from a different region of the overall device. In another example, structural aspects of the ingredient supply, control means, and metering and dispensing may be intermingled together.Indeed, it should be appreciated that there are several design examples that may be incorporated into the device and are all meant to be understood as part of the present disclosure.

[0094] In one example, a manifold collector 100 is also made up of thermoplastic layers, shown in FIG. 2B. A collector thick layer 104 is sandwiched between a collector thin top layer 102 and a collector thin bottom layer 106. In one example, the layers are held to ether by screws. In another example, the layers are held together by a suitable adhesive material. In a different example, the layers are heat sealed together. It should be understood that the manifold collector 100 is not limited to being a layered device, but could be a single monolithic piece. Indeed, in another example, the manifold collector 100 could also be made up of any suitable number of layers. In addition, the layer material is not meant to be limited to thermoplastic, but could be a number of suitable materials, for example, a metal or ceramic.

[0095] In one example, the shared control module 150 is also made up of thermoplastic layers, shown in FIG. 2B. A shared manifold thin layer 152 is disposed adjacent to a shared manifold thick layer 154. In one example, the layers are held together by screws. In another example, the layers are held together by a suitable adhesive material. In a different example, the layers are heat sealed together. It should be understood that the manifold collector 100 is not limited to being a layered device, but could be a single monolithic piece. Indeed, in another example, the manifold collector 100 could also be made up of any suitable number of layers. In addition, the layer material is not meant to be limited to thermoplastic, but could be a number of suitable materials, for example, a metal or ceramic.

[0096] As best shown in FIG. 3A, the ingredient manifold 200 functions to bring fluid to the fluidic chip 300 and carry waste out from the fluidic chip 300. In one example, the ingredient manifold 200 is also made up of a number of layers, that are best depicted in FIG. 3C, which is a cross section taken along line 3C-3C of FIG. 3 A. An ingredient manifold thick layer 250 may be a thermoplastic piece with milled channels attached to an ingredient manifold thin layer 260 which can be a thinner thermoplastic element that seals off appropriate channels, acting as a suitablecomplement to the ingredient manifold thick layer 250. In one example, the ingredient manifold thick layer 250 and the ingredient manifold thin layer 260 are held together by screws. In another example, the ingredient manifold thick layer 250 and ingredient manifold thin layer 260 are held together by a suitable adhesive material. In a different example, the layers are heat sealed. It should.be understood that the ingredient manifold 200 is not limited to being a layered device, but could be a single monolithic piece. Indeed, in another example, the ingredient manifold 200 could also be made up of any suitable number of layers. In addition, the layer material is not meant to be limited to thermoplastic, but could be a number of suitable materials, for example, a metal or ceramic.

[0097] Ingredient solenoid valves 280 are also assembled on to the ingredient manifold 200, as shown in FIG. 3A, contributing in controlling ingredient flow into the fluidic chip 300 and waste flow outward from the fluidic chip 300. The ingredient solenoid valves 280 may be either in an open or closed state. An instant tube fitting 290 may also be in place, connecting tubing and external fluid reservoirs to channels in the ingredient manifold 200. In one example, the instant tube fitting 290 can be adapted to be screwed into the ingredient manifold 200. In another example, an adhesive may be used to properly place and hold the instant tube fitting 290 in the ingredient manifold 200. In a different example, the instant tube fitting 290 may be properly placed in the ingredient manifold 200 and heat sealed. Within the ingredient manifold 200 are ingredient fill channels 220 that are connected with ingredient reservoirs 210 so that when an appropriate ingredient solenoid valve 280 is actuated to be open, a selected ingredient from a respective ingredient reservoir 210 may flow into an ingredient fill channel 220 and subsequently into a main fill channel 222, where flow may continue on to metering chambers 510 within the fluidic chip 300 (See FIG. 7). In this case, there are twenty-five different ingredient reservoirs 210 that may each be selected to fill metering chambers in the fluidic chip 300. It should be appreciated that any number of ingredients may be incorporated into the ingredient manifold 200.

[0098] In one example, overflow outlet 224 is provided on ingredient manifold 200. Excess ingredient that flows through and past the metering chambers exits the overflow outlet 224 andflows into a separate overflow and waste container 216, shown in FIG. 3 A. In another example, when the fluidic chip 300 is washed, waste may flow through the same main fill channel 222 line backwards from the fluidic chip 300 into a waste channel 226, through a waste valve 227, and eventually into the separate overflow and waste container 216.

[0099] In one example, purge channel 228 is provided on ingredient manifold 200. Purge channel 228 supplies pressurized air and / or water or other suitable fluid to push ingredients through the different channels associated with the device. A three-way solenoid valve 230 may be located on the ingredient manifold 200, switching purge ingredients between air and water which are supplied from a purge air tube 212 and a wash water tube 214.

[0100] Another example of the ingredient manifold 200 is shown in FIG. 3B. Similar to the previous example, the ingredient manifold 200 is made up of a number of thermoplastic layers with milled channels that are appropriately sealed off. In one example, the layers are held together by screws. In another example, the layers are held together by a suitable adhesive material. In a different example, the layers are heat sealed. It should be understood that the ingredient manifold 200 is not limited to being a layered device, but could be a single monolithic piece. Indeed, in another example, the ingredient manifold 200 could also be made up of any suitable number of layers. In addition, the layer material is not meant to be limited to thermoplastic, but could be a number of suitable materials, for example, a metal or ceramic.

[0101] Similar to the previous example, ingredient solenoid valves 280 are also assembled on to the ingredient manifold 200, contributing to control ingredient flow into the fluidic chip 300 and waste flow outward from the fluidic chip 300. Incorporated on the ingredient manifold 200, the ingredient solenoid valves 280 may be either in an open or closed state in communication with ingredient fill channels 220 which are connected, with corresponding ingredient reservoirs 210 in the manifold 200. In one example, when an appropriate ingredient solenoid valve 280 is opened, a selected ingredient from a respective ingredient reservoir 210 may flow into an ingredient fill channel 220 and subsequently into a main fill channel 222, where flow may continue on tometering chambers 510 within the fluidic chip 300 (See FIG. 7). In this case, there are three different ingredient reservoirs 210 that may each be selected to fill metering chambers in the fluidic chip 300. It should be appreciated that any number of ingredients may be incorporated into the ingredient manifold 200.

[0102] In this example, the ingredient manifold also includes an overflow outlet 224. Excess ingredients that flow through and past the metering chambers exits the overflow outlet 224 and flows into a separate overflow container 215. As with the previous example, when the fluidic chip 300 is washed, waste may flow through the main fill channel 222 line backwards from the fluidic chip 300 into a waste channel 226, through a waste valve 227, and eventually into a waste container225. The main difference between this example and the previous example is that the overflow and waste materials are distributed to separate overflow containers 215 and separate waste container 225 in this example, shown in FIG. 3B, whereas the overflow and waste materials are flowed to a separate overflow and waste container 216, shown in FIG. 3 A.

[0103] Also in this example, purge channel 228 supplies pressurized air and / or water (or other suitable fluid) to push ingredients through the different channels associated with the device. Another solenoid valve that provides for three way switching may be used to switch purge ingredients between air and water.

[0104] It should be appreciated that the present disclosure should not be limited in this respect to the present examples. For example, in another example, waste back from the fluidic chip 300 does not flow back through the main fill channel 222, but through a connected to the main fill channel 222. In another example, the overflow outlet 224 may be connected with the waste channel226. It should be understood that the channels that supply ingredients and purge materials as well as channels that bring overflow and waste materials out may be designed to communicate with the fluidic chip 300 in any suitable manner.

[0105] As mentioned, several control modules 400, shown in FIGS. 2A and 2B, serve toactuate the different valves in the device 10, typically through pressure management. In one example of a control module 400, a control module thick layer 410 is coupled to a control module thin layer 420. A control module thick layer 410 may be a thermoplastic piece attached to a control module thin layer 420 which can be a thinner thermoplastic that functions as a suitable complement to the control module thin layer 420. In one example, the control module thick layer 410 and the control module thin layer 420 are held together by screws. In another example, the control module thick layer 410 and the control module thin layer 420 are held together by a suitable adhesive material. In a different example, the control module thick layer 410 and the control module thin layer 420 are heat sealed together. It should be understood that a control module 400 is not limited to being a layered device, but could be a single monolithic piece. Indeed, in another example, a control module 400 could also be made up of any suitable number of layers. In addition, the layer material is not meant to be limited to thermoplastic, but could be a number of suitable materials, for example, a metal or ceramic.

[0106] One control module 400 is shown in FIG. 4A. The control module 400 may incorporate outlets 421 to connect control channels 422 that are routed to the manifold collector 100 and then to the fluidic chip 300. Each of the control channels 422 eventually communicate with valves, shown in FIG. 8B, such as at least one fill valve 640.

[0107] As mentioned, in the example of FIGS. 2A and 2B, the device includes a manifold collector 100 and a shared control module 150. FIG. 4B shows examples of the manifold collector 100 and the shared control module 150. The manifold collector 100 includes a pressure supply inlet 110 that allows for pressure distribution to the neighboring control modules 400. Ingredient channels 120 serve as conduits for ingredients to be supplied from the ingredient manifold 200 to the fluidic chip 300. Collector control channels 130 also run through the manifold collector 100 serving as conduits for control lines from the control modules 400 to reach the fluidic chip 300.

[0108] As mentioned above, air pressure is controlled by the opening and closing of control solenoid valves 470, shown in FIG. 4A, on a control module 400 which then gets routed to thefluidic chip 300. In one example of a control module 400, a first valve input port 440 supplies control pressure. Control pressure may be in the range of 20-30 PSI, and in one example, is approximately 25 PSI. In another example of a control module 400, a second valve input port 442 may be open to atmospheric pressure conditions. In another example, the second valve input port 442 may be in communication with a vacuum source. Valve outlet ports 444 may connect the corresponding control channel 422 to either the first valve input port 440 or the second valve input port 442.

[0109] In one example, a control pressure supply port 460 connects externally generated and regulated pressure from the manifold collector 100 to the module. It should be understood that the control modules 400 may be designed in other ways; for example, it is possible to design the control modules 400 to incorporate at least two pressure supply ports. In other examples, each valve may correspond to a respective pressure supply port. Indeed, the present example is not to be limited in this manner.

[0110] In one example, screw holes 450 are provided to aid in mounting valves to the control modules 400. In another example, an adhesive is provided to aid in mounting valves to the control modules 400.[OHl] In another example of the present disclosure, a single control module 400, shown in FIG. 4C, functions to actuate all of the control valves in the device 10, including the shared control valves. In this example, the control module 400 is manufactured similarly to the modules described above and is similarly not limited to the specific examples described. The control module 400 may incorporate outlets 421 to connect control channels 422 that are routed directly to the fluidic chip 300. In order to minimize excessive ingredient waste, overflow valve pressure may be controlled differently than for the other valves. In one example, a module overflow pressure supply port 462 controls pressure to overflow valves 650, shown in FIG. 8B, for enhanced fill rate control. In this respect, all valves except the overflow receive the same control pressure. A control pressure supply port 460 connects externally generated and regulated pressure directly to the module. The maindifference between this example and that shown in FIGS. 4A and 4B is that this example incorporates solenoid valves that are shared on the fluidic chip (i.e., purge and different size outlet volumes), the overflow pressure supply port, and the control pressure supply port directly on the module. In the example depicted in FIGS. 4A and 4B, these mentioned features are located on other parts of the overall device, namely the manifold collector 100 and the shared control module 150. It should be understood that the control module 400 may be designed in other ways; for example, it is possible to design the control module 400 to incorporate at least two pressure supply ports. In other examples, each valve may correspond to a respective pressure supply port. Indeed, the present example is not to be limited in this manner.

[0112] It is also possible in other examples for control channels 422 to communicate with other sets of valves shown in FIG. 8B, for example a particular size volume output valve, purge valve 660, or overflow valve 650. It should be appreciated that in some examples, control modules 400 may be designed in such a way that each of the control channels 422 could separately control a separately individual valve on the fluidic chip 300. In other examples, control modules 400 may be designed in such a way that each of the control channels 422 could control all of the valves on the fluidic chip 300 commonly together. In one example, control channels 422 are designed to control each of the fill valves 640 on the fluidic chip 300 separately individually. In another example, control channels 422 are designed to control all of the valves on the fluidic chip 300 corresponding to one particular discrete output volume commonly. Indeed, it should be understood that the examples presented herein are not limiting, but that the control channels 422 may be designed in any combination of desired valve control on the fluidic chip 300 as desired.

[0113] Although in the examples described, the valves are actuated through the application of pressure, the present disclosure is not limited in this regard. Thus, in another example, the valves are actuated through electrical switching means. In another example, valves are actuated through mechanical switching.

[0114] As mentioned above, one or more metering assemblies are incorporated into a fluidicchip 300, as shown in the exploded view in FIG. 5. The fluidic chip 300 measures and dispenses designated ingredients to designated output wells. In one example, the fluidic chip 300 is made up of two main layers: a control thick layer 310, and a fluid layer 350. The control thick layer 310 may be constructed of a control thin top layer 312, a control thick middle layer 314, and a control thin bottom layer 316. In one example, the control thin top layer 312 may have control holes 313 that interface with the control modules 400. Portions of the control thin top layer 312 appropriately seal off fluid control channels 330 that may be located in the top side of the control thick middle layer 314. In this manner, the fluid control channels 330 are sealed so that pressure can be properly distributed in a suitable way. The fluid control channels 330 may be suitably etched in the control thick middle layer 314. Other suitable techniques for manufacturing channels in the control thick middle layer 314 may be employed, as the present disclosure is not limited in this respect. For example, the channels may be milled or molded in the layer. The control thin bottom layer 316 may also include control access holes 318 for the fluid control channels 330 and valves to be in communication. It should be understood that the fluidic chip 300 and the other layered modules are not limited to being a layered device, but could be a single monolithic piece and may be formed through suitable techniques such as molding or stereolithography techniques. Indeed, in another example, the fluidic chip 300 could also be made up of any suitable number of layers.

[0115] In one example of the fluidic chip 300, the layers in the control thick layer 310 are held together by screws which are placed through screw holes 302 that run through all of the layers. In another example, the layers in the control thick layer 310 are held together by a suitable adhesive material. In one example of the fluidic chip 300, the layers in the fluid layer 350 are held together by screws that run through screw holes 302. In another example, the layers in the fluid layer 350 are held together by a suitable adhesive material. In a different example, the layers are heat sealed together.

[0116] The fluid control channels 330, shown in FIG. 5, distribute pressure to particular valves in the fluidic chip 300 in a controlled manner according to a desired outcome, receiving pressure signals from the control channels 422 in the control modules 400 that are shown in FIG.4. The fluid control channels 330 may be located in both upper and lower regions of the control thick layer 310 so that separate fluid control channels 330 do not interfere with one another. A spacer and valve layer 320 can also be incorporated in the fluidic chip 300 where valves and spacers are located and aligned in between the control thick layer 310 and the fluid layer 350. In this manner, a spacer and valve layer 320 ensures that the control and fluid layers are a suitable distance apart for optimal mechanical function for the fluidic chip 300.

[0117] In one aspect, the fluid layer 350 may be made up of a fluid thin layer 352 and a fluid thick layer 360. The fluid thin layer 352 may have access through fluid access holes 354 located between liquid channels and valves to allow fluid access to the valves. In one aspect, the fluid thin layer 352 is approximately 250 pm thick. In one aspect, for every valve, one control access hole 318 corresponding to the control thick layer 310 and two fluid access holes 354 corresponding to the fluid layer 350 is provided. In this example, the metering and dispensing occurs in the fluid thick layer 360. Similarly, that to that described above for the control layer, suitable techniques for manufacturing channels in the fluid layer 350 may be employed, as the present disclosure is not limited in this respect. For example, the channels may be milled or molded in the layer.

[0118] FIG. 6 is a perspective view of an illustration of an example metering chamber 510, a number of which are located in the fluid thick layer 360 with separate portions corresponding to a large channel portion 512, a medium channel portion 514, a small channel portion 516, a fill channel 520, an overflow channel 530, and a purge channel 540. One example of a metering chamber 510, shown in FIG. 6, incorporates several features that allow quick and efficient ingredient separation and dispensing to occur therein. Here, ingredients 500 are flowed through from a source and through a dispensing chamber (rather than being aspirated in from a source through the same nozzle or region as the eventual exit outlet). The large channel portion 512 follows a tortuous path, allowing for more volume to be dispensed from a chamber given the overall space that it occupies. The tortuous chamber structure in the metering chamber 510 may also help to prevent bubble formation amidst the ingredients 500 within the chamber. In addition, portions of the metering chamber 510 may be shaped in any suitable manner to provide for accurateand desired dispense output. For example, in the example shown in FIG. 6, the top down perspective illustrates the large channel portion 512 to be thicker than the medium channel portion 514 and the small channel portion 516. End regions of the large channel portion are shown to be tapered in order to provide a smooth transition between neighboring channel thicknesses.

[0119] As described above, the metering chamber 510 may be divided into three channel portions: a large channel portion 512, a medium channel portion 514, and a small channel portion 516. For each channel portion, a corresponding large volume transfer region 513, medium volume transfer region 515, and small volume transfer region 517 may also be incorporated. As mentioned above, it should be appreciated that the metering chamber 510 may be divided into any suitable number of channel portions. In one aspect, the volume of the large channel portion 512 added together with the medium channel portion 514 and small channel portion 516 may range between approximately 1 pL and approximately 10 pL, the volume of the medium channel portion 514 added together with the small channel portion 516 may range between approximately 500 nL and approximately 1 pL, and the volume of the small channel portion 516 alone may range between approximately 50 nL and approximately 500 nL. It should be understood that a metering chamber 510 is not to be limited in the number of discrete volume outputs or the actual volumes that are outputted. It should be appreciated that it may also be suitable, but not limiting, for the channel thicknesses at each volume transfer region to be relatively uniform in order to provide for accurate dispensing.

[0120] In one aspect, each metering chamber 510 also includes a fill channel 520 along with an associated fill transfer region 521 that provides the desired fill ingredient 500 access to that particular metering chamber 510. In this case, the fill ingredient originates from the ingredient manifold 200, is transferred from the main fill channel 222, shown in FIG. 3, to a common fill channel 362, shown in FIG. 7, and finally enters the fill channel 520. A fill valve 640, shown in FIG. 8B, corresponding to fill transfer region 521 may be actuated so that the desired ingredient 500 is able to flow through into the selected metering chamber 510, which includes the large channel portion 512, medium channel portion 514, and small channel portion 516. In one aspect,a single fill line is routed to each metering chamber 510 through a corresponding fill channel 520, and the fill valve 640 for each metering chamber 510 is controlled separately. In this respect, each metering chamber 510 may be selectively filled with any ingredient from the ingredient manifold 200.

[0121] When the metering chamber 510 is completely filled, ingredient overflow will occur, which will flow into an overflow channel 530 through an overflow transfer region 532. In order to prevent excessive overflow, a restriction valve region 550 may be actuated so that the fill velocity into the metering chamber 510 is reduced. In one aspect, a restriction tube is provided within the restriction valve region 550 which may be appropriately constricted, through pressure application or any suitable means, in order to reduce flow velocity. In this manner, reduced flow velocity may be controlled as desired. In another aspect, a capillary structure is provided within the restriction valve region 550 without outside pressure application or other stimulus, reducing flow velocity without outside control.

[0122] When a dispense or wash of the metering chamber 510 is desired, purge contents 30 may be flowed through a purge channel 540 through a purge transfer region 542, by actuating purge valve 660, shown in FIG. 8B, and into the metering chamber. If desired, fill channel 520 may also receive purge contents. When a dispense is required, the fill transfer region 521 is actuated so that no material is permitted to or from the fill channel 520, and air is used to push out the appropriate volume of contents from the metering chamber 510. In this case, the volume of the ingredient 500 to be dispensed is controlled by which transfer region is actuated to open while keeping the other valves closed. In this example, a single metering chamber 510 can be used to measure out a variety of discrete output volumes. For example, if a large volume amount is to be dispensed, then the medium volume transfer region 51 and the small volume transfer region 517 are actuated to prevent flow through while the large volume transfer region 513 is actuated to allow flow through. If a medium volume amount is to be dispensed, then the large volume transfer region 513 and the small volume transfer region 517 are actuated to prevent flow through while the medium volume transfer region 515 is actuated to allow flow through. If a small volume amountis to be dispensed, then the medium volume transfer region 515 and the large volume transfer region 513 are actuated to prevent flow through while the small volume transfer region 517 is actuated to allow flow through. Once ingredients 500 are to be dispensed out of the metering chamber 510 purge transfer region 542 actuates and pressurized purge material pushes the selected ingredients 500 through the appropriate transfer region and out an outlet nozzle 560. In this respect, air is used as the motive force to push the ingredients out through the outlet nozzle 560. For clarity, it should be mentioned that air may be used either as a force to dispense or to purge, depending what the desired function may be. When a wash is required, the purge content is typically a combination of air and water and the contents of fill channel 520 are washed through. In this aspect, it is possible to selectively choose what volumes to eject out of each metering chamber 510 and then selectively repeat this process however many times as desired.

[0123] The process involved in filling, metering, and dispensing will be described in more detail later. More specific structural features of the fluidic chip 300 and how neighboring metering chambers and corresponding valves relate to one another will now be illustrated. In one aspect, valve cluster 600a, 600b, 600c, etc. may be placed in suitable locations corresponding respectively to neighboring metering chambers 510a, 510b, 510c, etc. , as shown in FIG. 7. It can be seen in this example that the fluid layer 350 includes a common fill channel 362 that fills several fill channels 520a, 520b, 520c, etc. and a common purge channel 364 that acts as a purge materials source for several purge channels 540a, 540b, 540c, etc. It should also be appreciated that the present example should not be limited in this manner. For example, in one aspect, at least one common fill channel fills the several fill channels. In another aspect, at least two common fill channels fill separate groups of the several fill channels. In another aspect, at least three common fill channels fill separate groups of the several fill channels. Indeed, it should be appreciated that any number of common fill channels could be used to fill any number of groups of fill channels.

[0124] In one aspect, the valves employed to control fluid flow may be clustered together on a single substrate. These valve clusters 600 may be suitably located so as to control a number of metering chambers 510 while taking up a minimal amount of space. One example of a valve cluster600 shown in FIGS. 8A and 8B is placed on a fluid layer 350 and allows for partial valve control of three separate metering chambers 510a, 510d, and 510e. In this example, the valve cluster 600 has a large volume valve 610 and a fill valve 640 operable to control a large volume transfer region 513 and a fill transfer region 521 for neighboring metering chamber 510a. For metering chamber 510d, the position of the valve cluster 600 allows for control of a medium volume transfer region 515 through a medium volume valve 620. For metering chamber 510e, the position of the valve cluster 600 allows for control of a small volume transfer region 517 through a small volume valve 630, an overflow transfer region 532 through an overflow valve 650, and a purge transfer region 542 through a purge valve 660. In this example, a bridge connection 670 is provided between overflow channels 530a and 530b to allow for overflow fluid to pass over while permitting fluid flow to occur simultaneously between one another in neighboring metering chambers 510. In one aspect, no restriction of flow through the bridge connection 670 is provided. In another aspect, a valve is provided at the bridge connection 670 for flow to be controlled. It should be appreciated that the manner in which valves are clustered for a valve cluster 600 is not limited to this example. In addition, there is no limitation to be placed on the number valves that are located on a valve cluster 600. In one aspect, each valve cluster holds only one valve. In another aspect, all valves are located on a single valve cluster. Indeed, it should be understood that valves may be clustered in any suitable manner so as to save space and manufacturing costs.

[0125] The valves can be controlled in a variety of suitable ways. In one aspect, shown in FIGS. 9 A and 9B, is actuated through a single fluid control channel 330 inlet by the application of pressure. In FIG. 9A, the valve 700 is shown in a closed stated as pressure is applied through the fluid control channel 330 that runs through a control thick middle layer 314 and has access through a port access hole in a control thin bottom layer 316. In FIG. 9B, the valve 700 is shown in an open state as ingredient is permitted to pass in the fluid layer 350 from one fluid access hole 354a to another fluid access hole 354b. In this case, the pressure applied from the fluid control channel 330 is not sufficient to prevent ingredient access from one inlet to another in the fluid layer 350. In another aspect, a vacuum is applied through the fluid control channel 330, allowing for greaterflow of ingredient from one inlet to another.

[0126] In one aspect, the valve 700 is disposed between the control thick layer 310 and the fluid layer 350, serving as a conduit for communication to occur between the two layers.

[0127] The valve is constructed as a multi-level molded silicone valve 700 and includes a base 702, a valve membrane 704, and a valve lip 706. The base 702 provides a surface for compression against a fluid thin layer 352, making an airtight seal supported by spacers 322. In one aspect, spacers 322 are slightly shorter than the valve lip 706. Spacers 322 are located in the spacer and valve layer 320, shown in FIG. 5, between the control thin bottom layer 316 and the fluid thin layer 352. In one aspect, the base 702 is thicker than the valve membrane 704. The added thickness may aid in preventing the valve membrane 704 from stretching and skewing. In one aspect, the base 702 may be approximately 300 pm thick.

[0128] In a closed state, valve membrane 704 prevents a fluid ingredient 500 from passing through from one fluid access hole 354a to another fluid access hole 354b when sufficient pressure to close the membrane is applied through the fluid control channel 330, shown in FIG. 9A. By the same manner, in an open state, valve membrane 704 allows for a fluid ingredient 500 to pass through from one fluid access hole 354a to another fluid access hole 354b when the pressure to close the membrane is not great enough, as shown in FIG. 9B. In one aspect, the valve membrane 704 may be approximately 100 pm thick.

[0129] Valve lip 706 may provide added stability once pressure is applied to the system. The valve lip extends upward from the valve membrane and in one aspect is about 200 pm tall above the base 702. The relatively large height as compared to the valve membrane thickness may also compensate for variances in tolerance between the layers of the fluid chip. In this manner, when the device is assembled and the layers are brought together, any fluctuation in layer thickness (or even lip height itself) is accommodated due to the amount of the lip can deflect due to its relatively tall height.

[0130] In operation, one example of the process of filling, supplying purge materials, metering and dispensing discrete output volumes, and washing as it occurs in the fluidic chip 300 is shown in FIGS. 10A-10F for the small, medium, and large dispenses and will now be described.

[0131] In describing the process illustrated in FIGS. 10A-10F, reference will be made from FIG. 7 to metering chamber 510e which is in communication with valves corresponding to valve cluster 600a, 600b, and 600e. In this case, FIGS. 10A-10F depict an exploded view of metering chamber 510e as shown in FIG. 7. An ingredient manifold 200 supplies an ingredient to a fill channel 520 in the metering chamber 510e. As shown in FIG. 10A, fill valve 640 of valve cluster 600e is opened, and the contents from the fill channel 520 are delivered to the metering chamber 510e. In the process of filling, the large volume valve 610 of valve cluster 600e, the medium volume valve 620 of valve cluster 600b, the small volume valve 630 of valve cluster 600a, and the purge valve 660 of valve cluster 600a are closed. The overflow valve 650 of valve cluster 600a is left open for extraneous ingredients to spill into the overflow channel 530. Once the metering chamber 510e is completely filled, the fill valve 640 is closed and the purge valve 660 is then opened for purge material, which is air in this case, to run through the purge channel 540 and push extra overflow into the overflow channel 530 as shown in FIG. 10B. At this point, the fill valve 640, the large volume valve 610, the medium volume valve 620, and the small volume valve 630 are all closed. Now, the metering chamber 510e is full of the desired ingredient and the metering chamber is ready to dispense the desired output volume. In this case, the purge valve 660 remains open so that air pressure is able to push the contents out from the metering chamber 510e in the desired volume, depending on which volume output valve is opened. If a small output volume is desired, then the appropriate small volume valve 630 is opened with the medium volume valve 620 and the large volume valve 610 both closed as shown in FIG. 10C. If a medium output volume is desired, then the appropriate medium volume valve 620 is opened with the small volume valve 630 and the large volume valve 610 both closed as shown in FIG. 10D. If a large output volume is desired, then the appropriate large volume valve 610 is opened with the small volume valve 630 and the medium volume valve 620 both closed as shown in FIG. 10E. Throughout these dispenses,the purge valve 660 and the overflow valve 650 remain open, and the fill valve 640 remains closed. Finally, once the desired ingredient has been dispensed and is ready to be washed completely from the metering chamber 510e, the purge valve 660 and the overflow valve 650 remain open, and the fill valve 640 also opens, as shown in FIG. 10F. In addition, the large volume valve 610, the medium volume valve 620, and the small volume valve 630 are all closed. As a result, purge material, which may be cycled between air and water, is subsequently flowed through the entire metering chamber and also through both the fill and overflow channels for a complete wash. The contents from the fill channel 520 and the overflow channel 530 are then directed through appropriate channels from the metering assembly and eventually to the ingredient manifold where overflow and waste materials are disposed of. The process may be repeated for another selected ingredient and for another or the same dispense volume, as desired.

[0132] A software control system may be integrated into the fluid handling device allowing for ease of use. A main console or user interface 800, graphically depicted in FIG. 11, may be provided for efficient and intuitive control. Ingredient control 810 from the ingredient manifold 200 provides for valve and pressure management so as to selectively introduce the proper ingredient into the fluidic chip 300 at the desired moment. Waste valve control 820 allows for a waste valve at the end of the ingredient manifold 400 to direct wash materials into a waste container. Purge wash control 830 functions to allow for air or water to be selected for use as purge material whenever desired. As explained above, in one aspect, either air or water can be used as the purge material. Stop control 840 serves to discontinue the current sequence whenever desired. Individual fill valve control 850 allows a user to manipulate which ingredients are chosen to load which particular metering chambers. Wash cycle control 870 functions to set the wash cycle in motion so that metering chambers can be filled with subsequent ingredients. A dispense sequence control 880 enables the system to run a dispense sequence for a single well. A multi-dispense control 890 allows for a full dispense of all the ingredients according to a dispense grid 892, with washing in between ingredient dispenses. The values in the dispense grid 892 can be changed so that different volumes can be dispensed into different wells. Functions also exist in the softwarefor pre-made grids to be loaded in or saved as necessary. Means for running the software using a simulation control 860 feature allows for program use without the actual fluid handling device attached to the system. The software may be implemented in a stand-alone computer or on a multipurpose general computer, as desired.

[0133] Referring now to FIG. 12, FIG. 12 is a cross-sectional view of an illustration of an example valve cluster having a fixed valve and a “top hat” diaphragm assembly. The valve cluster 1200 comprises a “top hat” configuration for the diaphragm or valve membrane 704. In particular, the “top hat” diaphragm or valve membrane 704 has a stepped shape with two distinct thicknesses inside a cylindrical cavity. The “top hat” diaphragm or valve membrane 704 can be characterized, in one aspect, as having a stable position and a stretched position. Moreover, the valve cluster 1200 also comprises a control layer 310 and a fluid layer 350, and the “top hat” diaphragm or valve membrane 704 is situated therebetween

[0134] Referring now to FIG. 13, FIG. 13 is a magnified, perspective view of an illustration of an example microfluidic valve, or microfluidic diaphragm pumping system, comprising a flexible membrane and a substrate according to the present disclosure is shown. In particular, in one aspect, of the diaphragm pumping system 1300 includes a substrate 1302 and a flexible membrane 1304. The flexible membrane 1304 (best seen in FIGS. 14-15) is configured as a diaphragm structure that is thickest at the middle or that has uniform thickness (in contrast to the “top hat” configuration of FIG. 12) and that is situated within a domed cavity 1306.

[0135] Moreover, in one aspect, the substrate 1302 comprises several layers of plastic that are stacked together with the flexible membrane, as described in detail herein. In another aspect, the layers are engaged together to form the substrate 1302 including sealed air and liquid channels (e.g., fluid channels), as described in detail herein. In another aspect, the substrate 1302 provides multi-level flats seals around any diaphragm pumps and / or valves. In another aspect, the substrate 1302 defines air and liquid channel(s) going to / from the domed cavity 1306.

[0136] As such, in one aspect, the structure according to the present disclosure affords the diaphragm pumping system 1300 with a bi-stable configuration that, in one aspect, reduces the amount of time and force required to cycle the diaphragm when pumping more viscous liquids. In another aspect, the structure according to the present disclosure is better supported by the floor and ceiling of the domed cavity 1306, which enables more repeatable dispense volumes across a wide range of operating conditions. Moreover, in another aspect, unlike the “top hat” configuration, the most flexible part of the flexible membrane 1304 (e.g. the outer edge) is fully supported by the substrate 1302 in the expanded / filled state. As such, in one aspect, valve timing, pressure levels, and / or liquid properties do not act on what were previously (e.g., under the “top hat” configured) unsupported edges in a way that would change the displaced volume. Instead, the domed cavity 1306 ceiling and floor of the present disclosure act like a hard-stop for the full shape of the diaphragm. This has the effect of reducing variability due to operating factors as compared to the “top hat” configurations.

[0137] In one aspect, the substrate 1302 includes a plurality of fluid access ports and defines, at least in part, a domed cavity 1306. The domed cavity 1306 surrounds the flexible membrane 1304 and the flexible membrane 1304 extends across the domed cavity 1306. Like a diaphragm, the flexible membrane 1304 extending across the domed cavity 1306 has an adjustable stroke path from a first position along a first side 1308 of the domed cavity 1306 to an adjustable second position. The adjustable second position can vary depending on user preferences and / or calibration and, therefore, the stroke path is adjustable depending on where the second position is set to (for example, in one aspect, see FIG. 14). Moreover, the adjustable stroke path defines an adjustable volume within the domed cavity 1306, and the adjustable volume may be based on where the second position is set to. The substrate 1302 also includes the plurality of fluid access ports in fluid communication with the domed cavity 1306 such that, when the flexible membrane 1304 is actuated, fluid passes between a first fluid access port and a second fluid access port of the plurality of fluid access ports.

[0138] In another aspect, the adjustable second position is a fixed position and, therefore, thestroke path is a fixed stroke path from the first position to the fixed second position. In this example, the fixed stroke path defines a fixed volume within the domed cavity 1306. In another aspect, the fixed volume of the fixed stroke path is equal to or less than the volume of the domed cavity 1306 overall. In another aspect, the first position of the flexible membrane 1304 during a stroke path is along the first side 1308 of the domed cavity 1306 such that no gap is between the flexible membrane 1304 and the first side 1308 of the domed cavity 1306. In another aspect, the second position of the flexible membrane 1304 during a stroke path is along a second side 1310 of the domed cavity 1306 antipodal to the first side 1308 of the domed cavity 1306. In another aspect, when in the second fixed position, the flexible membrane 1304 has no gap between itself and the second side 1310 of the domed cavity 1306.

[0139] Referring now to FIG. 14, FIG. 14 is a cross-sectional view of an illustration of an example microfluidic diaphragm pumping system comprising a flexible membrane and a substrate according to the present disclosure. The microfluidic diaphragm pumping system also includes a component or subsystem 1401 for adjusting the adjustable volume of the adjustable stroke path within the domed cavity 1306, in particular, a component or subsystem 1401 for adjusting the adjustable second position of the adjustable stroke path within the domed cavity 1306. More specifically, in one aspect, the component or subsystem 1401 for adjusting the adjustable second position of the adjustable stroke path includes a screw-type structure 1402 extending into the domed cavity 1306, and the screw-type structure 1402 is configured to limited the adjustable stroke path within the domed cavity 1306 based on a length the screw-type structure 1402 extends / is screwed into the domed cavity 1306 opposite the first side 1308 of the domed cavity 1306. In another aspect, the component or subsystem 1401 for adjusting the adjustable volume of the adjustable stroke path within the domed cavity 1306 is instead a heating element (not shown), and the heating element is configured to warm the flexible membrane 1304 and expand the adjustable stroke path within the domed cavity 1306.

[0140] More specifically, in one aspect, in one particular implementation, the center of the flexible membrane 1304 within the domed cavity 1306 can be flattened out to decrease the internalvolume of the domed cavity 1306. In another aspect, for an 8-channel dispenser implementation for example, the component or subsystem 1401 for flattening the center of the flexible membrane is screw- type structure 1402 that flattens the center part of the second side 1310 of the domed cavity 1306. In another aspect, for a single-channel dispenser implementation for example, this is achieved by permanently deforming a thinner section of the flexible membrane 1304 with heat and / or pressure. As such, in one aspect, with this inventive feature and concept, the need to disassemble and reassemble a fluidic device to make structural adjustments is decreased. In another aspect, this inventive feature and concept also removes the inherent variability that arises from the assembly / manufacturing process, and allows for tighter tolerance for the volumetric accuracy of the device.

[0141] Referring now to FIG. 15, FIG. 15 is a cross-sectional view of an illustration of an example microfluidic diaphragm pumping system comprising a flexible membrane and a screwtype structure 1402 for limiting the adjustable stroke path according to the present disclosure. In particular, several elastomer parts (e.g., silicone or PFE) are compressed between two hard plastic parts such that open channels on each plastic part are sealed by the elastomer, and such that microfluidic diaphragm pumping system 1500 is situated between the control layer 310 and fluid layer 350. The fluid layer 350 sees input from a user's reagents, for example, and the control layer 310 receives air controlled air pressure inputs from a primary microfluidic system (not shown). In combination with the outer plastic parts, each elastomeric part or each flexible membrane 1304 creates individually controlled valves or individually controlled diaphragms within the domed cavity 1306.

[0142] Referring now to FIG. 16, FIG. 16 is a magnified, cross-sectional view of an illustration of an example screw-type structure for limiting the adjustable stroke path according to the present disclosure is shown. The control layer 310 includes a screw head pocket 1602. The screw head pocket 1602 leads to the threaded section 1604 through which the screw- type structure 1402 extends. The screw-type structure 1402 also extend into through the silicone air-sealer cavity 1606 whereby a seal is formed. The screw-type structure 1402, in one aspect, includes a combinedadjuster rod and air supply pathway 1608, which extends through the pressure / vacuum air supply channel 1610. Moreover, the control layer 310 also includes a domed cavity ceiling 1612 and edge seal structures 1614 for the domed cavity 1306.

[0143] Referring now to FIG. 17, FIG. 17 is an exploded, top perspective view of an illustration of the example fluidic chip including a valve cluster having a valve cluster having a flexible membrane, according to the present disclosure.

[0144] In one aspect, the fluidic chip 1700 includes a substrate including a control layer 310 and a fluid layer 350, and a plurality of diaphragm / valve clusters 1720 each having a flexible membrane. In particular, in one aspect, the substrate specifically includes the control layer and 310 and the fluid layer 350. In another aspect, the control layer 310 includes ports configured to receive one or more pressurized air inputs. In another aspect, as illustrated in FIGS. 4, the fluidic chip 1700 may be assembled by: (i) providing a control layer 310 configured to receive one or more pressurized air inputs, (ii) providing a fluid layer 350, (iii) providing one or more diaphragm / valve clusters 1720 each having a flexible membrane; (iv) stacking the control layer 310 and the fluid layer 350, with the one or more diaphragm / valve clusters 1720 therebetween; and (v) using bolts, screws, and / pegs to assemble the fluidic chip 1700.

[0145] Referring now to FIG. 18, FIG. 18 is an exploded, top perspective view of an illustration of the example fluidic chip including a valve cluster having a valve cluster having a flexible membrane, according to the present disclosure.

[0146] In one aspect, the chip 1800 includes a substrate 1302 including a control layer 310 and a fluid layer 350, and a diaphragm / valve cluster 1820 having a flexible membrane. In another aspect, the substrate 1302 specifically includes a control layer 310 and a fluid layer 350. As illustrated in FIG. 9, the substrate 1302 includes ports configured to receive one or more pressurized air inputs. In another aspect, as illustrated in FIG. 9, the chip 1800 may be assembled by: (i) providing a control layer 310 configured to receive one or more pressurized air inputs, (ii)providing a fluid layer 350; (iii) providing two adjacent valve clusters 1820a, 1820b; (iv) stacking the control layer 310 and the fluid layer 350, with the valve cluster 1820a and the valve cluster 1820b therebetween, such that a closed fluid channel is defined between the control layer 310 and fluid layer 350, and such that the valve cluster 1820a and the valve cluster 1820b are interposed along the closed fluid channel on the fluid layer of the substrate 1302; and (v) snapping or friction fitting the control layer 310 to the fluid layer 350 (or vice versa) to assemble the chip 1800. In another aspect, not illustrated, the control layer 310 and the fluid layer 350 may be engaged via an adhesive, an ultrasonic method, laser bonding, or mechanical bolts or screws or pegs.IV. Embodiments

[0147] Certain implementations of systems and methods consistent with the present disclosure are provided as follows:

[0148] 1. A microfluidic diaphragm pumping system comprising:

[0149] a flexible membrane; and

[0150] a substrate comprising a plurality of fluid access ports and defining, at least in part, a domed cavity, the domed cavity surrounding the flexible membrane, the flexible membrane extending across the domed cavity and having an adjustable stroke path from a first position to an adjustable second position, the adjustable stroke path defining an adjustable volume within the domed cavity, the plurality of fluid access ports in fluid communication with the flexible membrane, the flexible membrane being adapted to deflect from the first position along a first side of the domed cavity to the adjustable second position away from the first side of the domed cavity so as to allow fluid to pass between a first fluid access port and a second fluid access port upon membrane actuation.

[0151] 2. The microfluidic diaphragm pumping system of implementation 1, wherein the adjustable second position is a fixed position, wherein the adjustable stroke path is a fixed strokepath from the first position to the fixed second position, and wherein the fixed stroke path defines a fixed volume within the domed cavity.

[0152] 3. The microfluidic diaphragm pumping system of any of implementations 1-2, wherein the domed cavity defines a volume and wherein the fixed volume of the fixed stroke path is equal to or less than the volume of the domed cavity.

[0153] 4. The microfluidic diaphragm pumping system of implementation 3, wherein the first position is along the first side of the domed cavity such that no gap is between the flexible membrane and the first side of the domed cavity.

[0154] 5. The microfluidic diaphragm pumping system of implementation 3, wherein the second position is along a second side of the domed cavity such that no gap is between the flexible membrane and the second side of the domed cavity, and wherein the second side of the domed cavity is antipodal to the first side of the domed cavity.

[0155] 6. The microfluidic diaphragm pumping system of implementation 3, wherein the first position is along the first side of the domed cavity such that no gap is left between the flexible membrane and the first side of the domed cavity, wherein the second position is along a second side of the domed cavity such that no gap is left between the flexible membrane and the second side of the domed cavity, and wherein the second side of the domed cavity is antipodal to the first side of the domed cavity.

[0156] 7. The microfluidic diaphragm pumping system of any of the preceding implementations, further comprising a component or subsystem for adjusting the adjustable volume of the adjustable stroke path within the domed cavity.

[0157] 8. The microfluidic diaphragm pumping system of implementation 7, wherein the component or subsystem for adjusting the adjustable volume of the adjustable stroke path is a component or subsystem for adjusting the adjustable second position of the adjustable stroke pathwithin the domed cavity.

[0158] 9. The microfluidic diaphragm pumping system of implementation 8, wherein the component or subsystem for adjusting the adjustable second position of the adjustable stroke path is a screw extending into the domed cavity, and wherein the screw is configured to limited the adjustable stroke path within the domed cavity based on a length the screw extends into the domed cavity opposite the first side of the domed cavity.

[0159] 10. The microfluidic diaphragm pumping system of implementation 7, wherein the component or subsystem for adjusting the adjustable volume of the adjustable stroke path within the domed cavity is a heating element, and wherein the heating element is configured to warm the flexible membrane and expand the adjustable stroke path within the domed cavity.

[0160] 11. A method of actuating a microfluidic diaphragm pumping system, the method comprising:

[0161] providing a flexible membrane;

[0162] providing a substrate comprising a plurality of fluid access ports and defining, at least in part, a domed cavity, the domed cavity surrounding the flexible membrane, the flexible membrane extending across the domed cavity and having an adjustable stroke path from a first position to an adjustable second position, the adjustable stroke path defining an adjustable volume within the domed cavity, the plurality of fluid access ports in fluid communication with the flexible membrane;

[0163] supplying a pressure to the flexible membrane such that the flexible membrane presses against the first side of the domed cavity in a first position; and

[0164] reducing the pressure to the flexible membrane such that the flexible membrane deflects from the first position along a first side of the domed cavity to the adjustable second position away from the first side of the domed cavity so as to allow fluid to pass between a firstfluid access port and a second fluid access port.

[0165] 12. The method of implementation 11, wherein the flexible membrane deflects such that the flexible membrane presses against a second side of the domed cavity in the adjustable second position, and wherein the second side of the domed cavity is antipodal to the first side of the domed cavity

[0166] 13. The method of implementation 11, further comprising:

[0167] providing a component or subsystem for adjusting the adjustable volume of the adjustable stroke path within the domed cavity; and

[0168] adjusting the adjustable volume of the adjustable stroke path within the domed cavity.

[0169] 14. The method of implementation 13, wherein the adjustable volume of the adjustable stroke path is adjusted before the pressure to the flexible membrane is reduced.

[0170] 15. The method of any of the preceding implementations, further comprising:

[0171] providing a component or subsystem for adjusting the adjustable second position of the adjustable stroke path within the domed cavity; and

[0172] adjusting the adjustable second position of the adjustable stroke path within the domed cavity.

[0173] 16. The method of implementation 15, wherein the adjustable second position of the adjustable stroke path is adjusted before the pressure to the flexible membrane is reduced.

[0174] 17. The method of implementation 15, wherein the component or subsystem for adjusting the adjustable second position of the adjustable stroke path is a screw, and wherein the method further comprises turning the screw such that a length of the screw extends into the domed cavity, opposite the first side of the domed cavity, such that the screw limits the adjustable strokepath within the domed cavity.

[0175] 18. The microfluidic diaphragm pumping system of implementation 13, wherein the component or subsystem for adjusting the adjustable volume of the adjustable stroke path within the domed cavity is a heating element, and wherein the method further comprises warming the flexible membrane via the heating element such that the flexible membrane expands the adjustable stroke path within the domed cavity.

[0176] 19. The microfluidic diaphragm pumping system of implementation 7, wherein the component or subsystem for adjusting the adjustable volume of the adjustable stroke path is a component or subsystem for deforming a domed ceiling of the domed cavity, thereby adjusting the adjustable second position of the adjustable stroke path within the domed cavity.

[0177] 20. The microfluidic diaphragm pumping system of implementation 10, wherein the component or subsystem for deforming the domed ceiling of the domed cavity is a screw configured to press against the domed ceiling, and wherein a deformed ceiling limits the adjustable stroke path within the domed cavity based on a length the screw presses into the domed ceiling.

[0178] 21. The method of implementation 13, wherein the component or subsystem for adjusting the adjustable volume of the adjustable stroke path is a component or subsystem for deforming a domed ceiling of the domed cavity.

[0179] 22. The method of implementation 21 , wherein the component or subsystem for deforming the domed ceiling of the domed cavity is a screw configured to press against the domed ceiling, and wherein the method further comprises turning the screw such that the domed ceiling is deformed and such that a deformed domed ceiling limits the adjustable stroke path within the domed cavity.

[0180] It should be emphasized that the above-described aspects of the present disclosure are merely possible examples of implementations set forth for a clear understanding of the principlesof the disclosure. Many variations and modifications may be made to the above-described aspect(s) without departing substantially from the spirit and principles of the disclosure. All such modifications and variations are intended to be included herein within the scope of this disclosure and protected by the following claims.

Claims

CLAIMSTherefore, the following is claimed:

1. A microfluidic diaphragm pumping system comprising: a flexible membrane; and a substrate comprising a plurality of fluid access ports and defining, at least in part, a domed cavity, the domed cavity surrounding the flexible membrane, the flexible membrane extending across the domed cavity and having an adjustable stroke path from a first position to an adjustable second position, the adjustable stroke path defining an adjustable volume within the domed cavity, the plurality of fluid access ports in fluid communication with the flexible membrane, the flexible membrane being adapted to deflect from the first position along a first side of the domed cavity to the adjustable second position away from the first side of the domed cavity so as to allow fluid to pass between a first fluid access port and a second fluid access port upon membrane actuation.

2. The microfluidic diaphragm pumping system of claim 1, wherein the adjustable second position is a fixed position, wherein the adjustable stroke path is a fixed stroke path from the first position to a fixed second position, and wherein the fixed stroke path defines a fixed volume within the domed cavity.

3. The microfluidic diaphragm pumping system of claim 2, wherein the domed cavity defines a volume and wherein the fixed volume of the fixed stroke path is equal to or less than the volume of the domed cavity.

4. The microfluidic diaphragm pumping system of claim 3, wherein the first position is along the first side of the domed cavity such that no gap is between the flexible membrane and the first side of the domed cavity.

5. The microfluidic diaphragm pumping system of claim 3, wherein the adjustable second position is along a second side of the domed cavity such that no gap is between the flexible membrane and the second side of the domed cavity, and wherein the second sideof the domed cavity is antipodal to the first side of the domed cavity.

6. The microfluidic diaphragm pumping system of claim 3, wherein the first position is along the first side of the domed cavity such that no gap is left between the flexible membrane and the first side of the domed cavity, wherein the adjustable second position is along a second side of the domed cavity such that no gap is left between the flexible membrane and the second side of the domed cavity, and wherein the second side of the domed cavity is antipodal to the first side of the domed cavity.

7. The microfluidic diaphragm pumping system of claim 1, further comprising a component or subsystem for adjusting the adjustable volume of the adjustable stroke path within the domed cavity.

8. The microfluidic diaphragm pumping system of claim 7, wherein the component or subsystem for adjusting the adjustable volume of the adjustable stroke path is a component or subsystem for adjusting the adjustable second position of the adjustable stroke path within the domed cavity.

9. The microfluidic diaphragm pumping system of claim 8, wherein the component or subsystem for adjusting the adjustable second position of the adjustable stroke path is a screw extending into the domed cavity, and wherein the screw is configured to limited the adjustable stroke path within the domed cavity based on a length the screw extends into the domed cavity opposite the first side of the domed cavity.

10. The microfluidic diaphragm pumping system of claim 7, wherein the component or subsystem for adjusting the adjustable volume of the adjustable stroke path is a component or subsystem for deforming a domed ceiling of the domed cavity, thereby adjusting the adjustable second position of the adjustable stroke path within the domed cavity.

11. The microfluidic diaphragm pumping system of claim 10, wherein the component or subsystem for deforming the domed ceiling of the domed cavity is a screw configured to press against the domed ceiling, and wherein a deformed ceiling limits the adjustable stroke path within the domed cavity based on a length the screw presses into the domed ceiling.

12. A method of actuating a microfluidic diaphragm pumping system, the method comprising: providing a flexible membrane; providing a substrate comprising a plurality of fluid access ports and defining, at least in part, a domed cavity, the domed cavity surrounding the flexible membrane, the flexible membrane extending across the domed cavity and having an adjustable stroke path from a first position to an adjustable second position, the adjustable stroke path defining an adjustable volume within the domed cavity, the plurality of fluid access ports in fluid communication with the flexible membrane; supplying a pressure to the flexible membrane such that the flexible membrane presses against a first side of the domed cavity in a first position; and reducing the pressure to the flexible membrane such that the flexible membrane deflects from the first position along a first side of the domed cavity to the adjustable second position away from the first side of the domed cavity so as to allow fluid to pass between a first fluid access port and a second fluid access port.

13. The method of claim 12, wherein the flexible membrane deflects such that the flexible membrane presses against a second side of the domed cavity in the adjustable second position, and wherein the second side of the domed cavity is antipodal to the first side of the domed cavity.

14. The method of claim 12, further comprising: providing a component or subsystem for adjusting the adjustable volume of the adjustable stroke path within the domed cavity; and adjusting the adjustable volume of the adjustable stroke path within the domed cavity.

15. The method of claim 14, wherein the adjustable volume of the adjustable stroke path is adjusted before the pressure to the flexible membrane is reduced.

16. The method of claim 12, further comprising: providing a component or subsystem for adjusting the adjustable second positionof the adjustable stroke path within the domed cavity; and adjusting the adjustable second position of the adjustable stroke path within the domed cavity.

17. The method of claim 16, wherein the adjustable second position of the adjustable stroke path is adjusted before the pressure to the flexible membrane is reduced.

18. The method of claim 16, wherein the component or subsystem for adjusting the adjustable second position of the adjustable stroke path is a screw, and wherein the method further comprises turning the screw such that a length of the screw extends into the domed cavity, opposite the first side of the domed cavity, such that the screw limits the adjustable stroke path within the domed cavity.

19. The method of claim 14, wherein the component or subsystem for adjusting the adjustable volume of the adjustable stroke path is a component or subsystem for deforming a domed ceiling of the domed cavity.

20. The method of claim 19, wherein the component or subsystem for deforming the domed ceiling of the domed cavity is a screw configured to press against the domed ceiling, and wherein the method further comprises turning the screw such that the domed ceiling is deformed and such that a deformed domed ceiling limits the adjustable stroke path within the domed cavity.

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