WO2024013323A1

WO2024013323A1 - Systems and methods for cleaning microfluidic chips

Info

Publication number: WO2024013323A1
Application number: PCT/EP2023/069529
Authority: WO
Inventors: Trillian Ashley GREGG; Tanneke Geertruida YPMA; Myles MCGARRIGLE; Remie LETHER; Mattijs Tjepkema; Pekka Juhani TYNKKYNEN
Original assignee: Lumicks Ca Holding B.V.
Priority date: 2022-07-15
Filing date: 2023-07-13
Publication date: 2024-01-18

Abstract

A system is disclosed for automatically cleaning one or more microfluidic chips. Each microfluidic chip comprises a fluid inlet for receiving fluid, a fluid outlet for discharging fluid from the microfluidic chip, and a holding space for holding a sample. The holding space is fluidly connected to the fluid inlet and the fluid outlet. The system comprises a tube system for transporting cleaning agents from respective one or more containers to the fluid inlets of the respective one or more microfluidic chips so that the cleaning agents from the one or more containers pass through the holding spaces and are discharged via the fluid outlets of the respective one or more microfluidic chips. The system also comprises one or more actuators for controlling a volumetric flow rate of cleaning agent out of each container to the fluid inlets of the respective one or more microfluidic chips. The system further comprises a control system that is configured to perform steps of: - storing a cleaning program, the cleaning program indicating, for each cleaning agent and for each of a plurality of times, a value of volumetric flow rate of the cleaning agent in question through the holding spaces of the respective one or more microfluidic chips, and - controlling the actuators of the tube system such that cleaning agents flow through the one or more holding spaces in accordance with the stored cleaning program.

Description

SYSTEMS AND METHODS FOR CLEANING MICROFLUIDIC CHIPS

FIELD OF THE INVENTION

This disclosure relates to a system and method for automatically cleaning one or more microfluidic chips, in particular to such system and method wherein actuators of a tube system are controlled in accordance with a cleaning program. This disclosure further relates to a control system, computer program and computer-readable storage medium for performing such methods and/or for use in such systems.

BACKGROUND

Microfluidic chips are used for research and development in a variety of fields, and are sometimes embodied as lab-on-a-chip devices. Often, microfluidic chips are cleaned manually, which is very cumbersome. Hence, there is a need in the art for improved methods for cleaning microfluidic chips.

SUMMARY

To that end, a system is disclosed for automatically cleaning one or more microfluidic chips. Each microfluidic chip comprises a fluid inlet for receiving fluid, a fluid outlet for discharging fluid from the microfluidic chip, and a holding space for holding a sample. The holding space is fluidly connected to the fluid inlet and the fluid outlet. The system comprises a tube system for transporting cleaning agents from respective one or more containers to the fluid inlets of the respective one or more microfluidic chips so that the cleaning agents from the one or more containers pass through the holding spaces and are discharged via the fluid outlets of the respective one or more microfluidic chips. The system also comprises one or more actuators for controlling a volumetric flow rate of cleaning agent out of each container to the fluid inlets of the respective one or more microfluidic chips. The system further comprises a control system that is configured to perform steps of:

- storing a cleaning program, the cleaning program indicating, for each cleaning agent and for each of a plurality of times, a value of volumetric flow rate of the cleaning agent in question through the holding spaces of the respective one or more microfluidic chips, and

- controlling the actuators of the tube system such that cleaning agents flow through the one or more holding spaces in accordance with the stored cleaning program.

The system provides for very easy cleaning since it can clean several chips, in parallel or subsequently, without requiring any manual labour or other user input during the cleaning itself. A user may for example input a cleaning program into the system, for example by simply selecting one of several pre-stored programs, and the system will ensure that the chips are cleaned in accordance with that program. The system for example enables to clean microfluidic chips overnight and use the chips for experimental executions during office hours.

Typical samples that may be present in the holding space of a microfluidic chip during experiments and thus prior to cleaning may include water, bleach, cell culture media, PBS, air and biological materials such as tissues, cells, sub cellular materials, proteins, nucleic acids, etc. The one or more microfluidic chips are for example chips as described in WO 2018/083193 As referred to herein, a cleaning agent may be any substance, usually a liquid, that can remove undesired matter from the holding space, such as residue substances/materials that have remained in the holding space after previous experiments. Water may for example also be a cleaning agent referred to herein. Non-limiting examples of cleaning agents are distilled H2O, HCL, NaOH, Tween 20 (Polysorbate 20), Ionic Liquid (e.g. 1-Ethyl-3-methylimidazolium dicyanamide, > 98.5% purity) and Bleach (e.g. Sodium Hypochlorite, 5% (w/v) in water).

The tube system for example comprises tubes made out of PTFE and manifolds made out of polyether ether ketone (PEEK). Typically, some tubes out of the tube system merge with each other whereas other tubes branch out into several tubes.

A cleaning agent flowing through the one or more holding spaces in accordance with a cleaning program may be understood as that, at any given time, the volumetric flow rate of the cleaning agent through the one or more holding spaces has a value that is defined by the cleaning program for that cleaning agent and for that time.

Preferably, the cleaning program does not indicate two or more nonzero volumetric flow rates for two respective cleaning agents at any time, so that mixing of the cleaning agents is prevented. Preferably, the cleaning program indicates for any given time at most one nonzero volumetric flow rate for one of the cleaning agents.

As referred to herein, the plurality of times for which the cleaning program indicates respective values of volumetric flow rate may be understood to be times relative to some reference time, for example relative to a start time of the cleaning program. The cleaning program may indicate a value of volumetric flow rate in the sense that it indicates the value of a binary parameter, corresponding e.g. “on” or “off’, wherein the on-value indicates that the value of volumetric flow rate is higher than zero, and the off-value indicates that the volumetric flow rate is zero.

In an embodiment, the system also comprises the one or more containers referred to above. Preferably, each container of the one or more containers comprises a cleaning agent. In any case, the system preferably comprises one or more container holders for holding one or more such containers. If this is the case, then preferably each container holder is associated with a specific cleaning agent, for example in the sense that a first container holder should always hold a container having a first cleaning agent and a second container holder should always hold a container having a second cleaning agent, et cetera. The system may be provided with, optionally computer-readable, marks that indicate for each container holder which type of cleaning agent should be in the container that is positioned in the holder in question. This prevents unintended mixture of chemicals and/or prevents that the cleaning program is not executed properly, e.g. in the sense that wrong cleaning agents are used.

In an embodiment, the system comprises one or more heater elements that are configured to heat the one or more microfluidic chips during cleaning, for example in order to dry the microfluidic chips and/or the holding spaces of the chips. The cleaning program may also indicate when the heater elements should be turned on. Optionally, the cleaning program may indicate how much heat the heater elements should generate at a plurality of times.

In an embodiment, the actuators comprise one or more pumps and/or one or more valves. Preferably, the system comprises at least one valve for each container, the at least one valve being configured to control the volumetric flow rate out of its associated container.

Preferably, the system comprises at least one valve for each microfluidic chip that is to be cleaned, the at least one valve being configured to control the volumetric flow rate through the chip in question. More preferably, the system comprises at least two valves for each chip, one valve at the fluid inlet of the chip and one valve at the fluid outlet of the chip.

Preferably, the system, in particular the tube system, comprises at least one valve for each waste container (if present, see below), the at least one valve being configured to control the volumetric flow rate into its associated waste container. In an embodiment the system comprises several waste containers. Having several waste containers has as an advantage that the risk of mixing chemicals is avoided.

Each valve referred to herein can for example be controlled to adopt either of two states, an open state in which a predetermined volumetric flow rate can flow through the valve, and a closed state in which no cleaning agent can flow through the valve. Preferably, however, each valve can adopt a plurality of states, wherein a different volumetric flow rate can pass through the valve for each state. The latter enables to more gradually control the volumetric flow rate that can pass through the valve.

Preferably, the system comprises a pump that is configured to cause a fluid flow from the one or more containers through the one or more microfluidic chips, and optionally to the one or more waste containers (if present, see below).

The pump may be configured to cause a relatively low pressure at some position in tube system in order to cause cleaning agents to flow to that position, which is for example a position at fluid outlets of the one or more microfluidic chips and/or at the one or more waste containers (if present). The pump may then be said to suck cleaning agents from the one or more containers through the tube system and through the one or more microfluidic chips. Additionally or alternatively, the pump may be configured to cause a relatively high pressure at some position in the tube system in order to cause cleaning agent to flow away from that position, which is for example a position at the one or more containers holding the cleaning agents herewith “pushing” cleaning agents out of the one or more containers.

The control system referred to herein may be configured to control each valve and control each pump in the system, for example by sending appropriate control signal to them.

In an embodiment, the tube system is configured to transport a first cleaning agent form a first container and a second cleaning agent from a second container to the fluid inlets of the respective one or more microfluidic chips.

In an embodiment, the tube system is also configured to transport fluid from the fluid outlets of the respective one or more microfluidic chips to a plurality of waste containers. The plurality of waste containers comprises a first waste container and a second waste container. Further, in such embodiment, the system comprises second one or more actuators for controlling into which waste container out of the plurality of waste containers fluid from the fluid outlets is transported. The control system is configured to perform a step of controlling the second one or more actuators such that the first cleaning agent is transported to the first waste container and the second cleaning agent is transported to the second waste container. This embodiment enables to collect different cleaning agents in different waste containers. This prevents that the cleaning agents react with each other in an uncontrolled and/or undesired manner. Several cleaning agents may be collected in a single waste container. In a preferred embodiment, the system comprises two waste containers, one for disposing water and bleach, another for disposal of water, Tween 20, NaOH, Ionic Liquid

The cleaning program may indicate for each cleaning agent into which waste container it should be collected after use. As such, the cleaning agents may be transported to different waste containers in accordance with the cleaning program.

The tube system may comprise connectors, such as PTFE, for fluidly connecting tubes of the tubes system to the one or more containers and to the respective fluid inlets of the one or more microfluidic chips and for fluidly connecting tubes of the tube system to the respective fluid outlets of the one or more microfluidic chips and to the one or more waste containers.

The system preferably comprises waste container holders for holding the waste containers. The system preferably comprises a first container holder and a second container holder for holding the first resp. second container.

In an embodiment, the system comprises a first valve and a second valve and a pressure sensor for measuring a pressure in the tube system between the first valve and the second valve and a pump for pumping fluid through the tube system. In such embodiment, the controller may be configured to perform steps of:

- controlling the pump to pump fluid into or out of the tube system during a first time period herewith achieving, at the end of the first time period, a first pressure value in the tube system between the first and second valve, and

- controlling the first valve to be closed during the first time period and the second valve to be open during the first time period, and

- receiving from the pressure sensor a signal indicative of the first pressure value.

As will be explained below, this embodiment allows to detect leaks and/or blockages in the system, which may reduce the effectiveness of the cleaning. The first and second valve referred to herein may for example (non-limiting examples) sit on either side of a chip, on either side of a container, or on either side of a waste container.

As referred to herein, achieving a pressure value may be understood as achieving a pressure that has that pressure value.

Preferably, the tests described herein are performed one by one for each chip, thus not for several chips in parallel.

In an embodiment, the controller is configured to perform steps of comparing the first pressure value with a first threshold value, and determining, based on this comparison, that there is a leak in the tube system between the first valve and the pump.

This embodiment allows for a very straightforward manner of leak detection. If for example, the pump is controlled to create a vacuum between the first valve and the second valve, and thus between the first valve and the pump, then this may fail due to a fluid, such as air, entering the tube system through a leak somewhere between the pump and the first valve. This may for example occur when a lid of a container, such as a waste container, has not been tightened properly. In such case, the first pressure value will be higher than expected, e.g. higher than the first threshold value. Then, the controller can determine that there is a leak between the first valve and the pump.

The controller may be configured to, based on determining that a leak is present in the tube system, refrain from starting the cleaning process.

The control system may determine, based on the comparison between the first pressure value and the first threshold value, that there is no leak, or at least not a large leak, in the tube system between the first and second valve. The control system may then initiate the cleaning process in accordance with the cleaning program.

In an embodiment, controller is configured to perform steps of:

- controlling the pump to refrain from pumping fluid into or out of the tube system for a second time period following the first time period, and- controlling the second valve to close at the end of the first time period and/or at the start of the second time period and controlling the first and second valve to remain closed during the second time period, and

- receiving from the pressure sensor a second signal indicative of a second pressure value measured at the end of the second time period, and

- determining, based on the first pressure value and second pressure value, whether there is a leak in the tube system between the first and second valve.

This embodiment is advantageous in that the system can detect relatively small leaks as well. In principle, the pressure between the first and second valve should remain constant throughout the second time period because the first and second valve are closed. However, if there is a small leak between the first and second valve, then the pressure may change rather slowly. Therefore, such change, induced by a small leak, may only be detectable after some time, e.g. at the end of the second time period.

As referred to herein, a fluid may be a gas or a liquid. Further, as referred to herein, “at the beginning/end of a time period” may be understood as within a few second, e.g. 2 seconds, from the beginning/end of the time period”.

In an embodiment, the controller is configured to perform a step of determining, based on a difference between the first and second pressure value being larger or smaller than a second threshold value, determining that there is a leak or, respectively, that there is no leak in the tube system between the first and second valve.

In an embodiment, the controller is further configured to perform steps of:

- controlling the first or second valve to open at the end of the second time period and/or at the start of a third time period following the second time period,

- receiving from the pressure sensor a signal indicative of a third pressure value measured at the end of the third time period, and

- determining, based on the third pressure value whether there is a blockage in the tube system between the first and second valve. This embodiment enables to detect blockages in the system. Such blockage may namely prevent cleaning agents from flowing through the microfluidic chip and thus prevent that the chip is properly cleaned.

Preferably, the controller is configured to determine whether there is a blockage in the tube system by comparing the third pressure value with a third threshold value.

Preferably, another valve is controlled to open as well when the first or second valve is open, in order to allow air to freely flow into the system. As a result, the pressure between the first and second valve should become atmospheric. If this is not the case, then it may be concluded that there is a blockage somewhere between the first and second valve.

The control system may refrain from starting a cleaning procedure if a blockage is detected. Also, the control system may be configured to, based on no blockage being detected, initiate the cleaning process.

It should be appreciated that the above-described blockage detection can be performed without performing the leak detection procedure, in principle.

To illustrate, one aspect of this disclosure relates to a system for automatically cleaning one or more microfluidic chips, wherein each microfluidic chip comprises a fluid inlet for receiving fluid, a fluid outlet for discharging fluid from the microfluidic chip, and a holding space for holding a sample, the holding space being fluidly connected to the fluid inlet and the fluid outlet, the system comprising a tube system fortransporting cleaning agents from respective one or more containers to the fluid inlets of the respective one or more microfluidic chips so that the cleaning agents from the one or more containers pass through the holding spaces and are discharged via the fluid outlets of the respective one or more microfluidic chips, wherein the system comprises one or more actuators for controlling a volumetric flow rate of cleaning agent out of each container to the fluid inlets of the respective one or more microfluidic chips, and the system comprising a control system that is configured to perform steps of:

- controlling the actuators of the tube system such that cleaning agents flow through the one or more holding spaces in accordance with the stored cleaning program, wherein the system comprises a first valve and a second valve and a pressure sensor for measuring a pressure in the tube system, between the first valve and the second valve and a pump for pumping fluid through the tube system, wherein the controller is configured to perform steps of:

- controlling the first valve to be closed during the first time period and the second valve to be open during the first time period, or vice versa, and

- controlling the first and/or second valve to be open during a further time period after the first time period, - receiving from the pressure sensor a signal indicative of a further pressure value measured at the end of the further time period, and

- determining, based on the further pressure value whether there is a blockage in the tube system between the first and second valve.

In this aspect, the control system may thus perform a clog test, without having to perform a leak test as well. Thus, in this aspect, it is not required that the pump is controlled to refrain from pumping fluid out of the tube system and keep the valves closed for some time in order to test whether there is a leak between the two valves. In this aspect, the first and second valve may be valves that sit on either side of a container, for example, in order to test whether the container is clogged. Alternatively, the first and second valve may sit at opposite sides of one of the microfluidic chips in order to test whether the chip is clogged.

It should be appreciated that there may be a leak and/or a clog in a chip of which both the fluid inlet and the fluid outlet are connected to the tube system. In such case, determining that there is a leak or clog between two valves that sit on either side of the chip may be understood as determining that there is a leak or clog in the tube system. A chip having both its fluid inlet and fluid outlet connected to the tube system may be understood as part of the tube system.

In an embodiment, the system is configured to automatically clean a plurality of microfluidic chips. To this end, the tube system may be comprise a plurality of connectors, wherein each connecter is fluidly connectable to the fluid inlet of fluid outlet of a microfluidic chip.

In an embodiment, the system comprises a plurality of chip detectors, wherein each chip detector is configured to detect whether a chip is connected to the tube system at a respective position. The control system may be configured to determine the appropriate amounts of cleaning agents that are to be used when the cleaning program is executed.

In an embodiment, the system comprises the one or more containers, wherein the system comprises at least one sensor that is configured to detect an amount of cleaning agent that is present in one of the one or more containers. Additionally or alternatively, the system comprises the one or more waste containers, wherein the system comprises at least one sensor that is configured to detect an amount of waste that is present in a waste container of the one or more waste containers.

An example of such sensor is a capacitive sensor that can be positioned outside of the (waste) container in question.

Preferably, the system comprises a sensor for each container and/or for each waste container so that the amount of cleaning agent in each container and/or the amount of waste in each waste container can be detected, e.g. measured.

In an embodiment, the system comprises the one or more containers. Herein, each container of the one or more containers may comprise a sensor that is configured to measure an amount of cleaning agent that is present in the container in question. Additionally or alternatively, each waste container may comprise a sensor that is configured to measure an amount of waste that is present in the waste container in question.

In one example, such sensor for measuring an amount of cleaning agent and/or waste may be embodied as a float-type sensor. Additionally or alternatively, such sensor may be embodied as a sensor that can detect whether it is in contact with cleaning agent and that is positioned at a fixed height within the container. If the cleaning agent level drops below the height of the sensor, then the sensor changes its output, based on which the control system can determine the amount of cleaning agent left in the container. In an example, the latter type of sensor is positioned at the bottom of a waste container, so that it can be confirmed that the waste container in question is completely empty.

The sensor for measuring an amount of cleaning agent and/or waste may be embodied as a system comprising a pressure sensor and a pump. For example, the time that it takes to cause the pressure in a waste container to be lower than a certain threshold pressure depends on how full the waste container in question is. Hence, based on the time that it takes to, while pumping fluid, e.g. air, out of the waste container, reach the threshold pressure, is a measure for the amount of waste in the waste container.

The sensor for measuring an amount of cleaning agent and/or waste may comprise an optical level sensor, e.g. based on a camera or on a simple optical beam and a photodiode.

In an embodiment, the system comprises the one or more microfluidic chips, wherein, for each microfluidic chip, the fluid inlet, and preferably also the fluid outlet, is fluidly connected to the tube.

One aspect of this disclosure relates to a computer-implemented method for automatically cleaning one or more microfluidic chips, the computer-implemented method comprising:

- storing a cleaning program, the cleaning program indicating, for each cleaning agent out of one or more cleaning agents that are present in one or more respective containers, and for each of a plurality of times, a value of volumetric flow rate of the cleaning agent in question through one or more holding spaces of respective one or more microfluidic chips, wherein each microfluidic chip comprises a fluid inlet for receiving fluid, a fluid outlet for discharging fluid from the microfluidic chip, and a holding space for holding a sample, the holding space being fluidly connected to the fluid inlet and the fluid outlet, and

- controlling one or more actuators of a tube system - the one or more actuators being configured for controlling a volumetric flow rate of cleaning agent out of each container to the fluid inlets of the respective one or more microfluidic chips - such that cleaning agents flow through the one or more holding spaces in accordance with the stored cleaning program, wherein the tube system is configured to transport cleaning agents from the respective one or more containers to the fluid inlets of the respective one or more microfluidic chips so that the cleaning agents from the one or more containers pass through the holding space and are discharged via the fluid outlets of the respective one or more microfluidic chips.

The computer-implemented method may comprises any of the steps described herein that may be performed by any of the control systems referred to herein.

One aspect of this disclosure relates to a control system comprising a processor that is configured to perform any of the methods described herein.

One aspect of this disclosure relates to a computer comprising a computer readable storage medium having computer readable program code embodied therewith, and a processor, preferably a microprocessor, coupled to the computer readable storage medium, wherein responsive to executing the computer readable program code, the processor is configured to perform any of the methods described herein. One aspect of this disclosure relates to a computer program comprising instructions to cause any of the systems described herein to perform any of the methods described herein.

One aspect of this disclosure relates to a computer program comprising instructions to cause any of the control systems referred to herein to perform any of the computer-implemented methods referred to herein.

One aspect of this disclosure relates to a computer program or suite of computer programs comprising at least one software code portion or a computer program product storing at least one software code portion, the software code portion, when run on a computer system, being configured for executing any of the methods described herein.

One aspect of this disclosure relates to a non-transitory computer-readable storage medium having stored thereon any of the computer programs referred to herein.

One aspect of this disclosure relates to a non-transitory computer-readable storage medium storing at least one software code portion, the software code portion, when executed or processed by a computer, is configured to perform any of the methods described herein.

As will be appreciated by one skilled in the art, aspects of the present invention may be embodied as a system, a method or a computer program product. Accordingly, aspects of the present invention may take the form of an entirely hardware embodiment, an entirely software embodiment (including firmware, resident software, micro-code, etc.) or an embodiment combining software and hardware aspects that may all generally be referred to herein as a "circuit," "module" or "system." Functions described in this disclosure may be implemented as an algorithm executed by a processor/microprocessor of a computer. Furthermore, aspects of the present invention may take the form of a computer program product embodied in one or more computer readable medium(s) having computer readable program code embodied, e.g., stored, thereon.

Any combination of one or more computer readable medium(s) may be utilized. The computer readable medium may be a computer readable signal medium or a computer readable storage medium. A computer readable storage medium may be, for example, but not limited to, an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system, apparatus, or device, or any suitable combination of the foregoing. More specific examples of a computer readable storage medium may include, but are not limited to, the following: an electrical connection having one or more wires, a portable computer diskette, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or Flash memory), an optical fiber, a portable compact disc read-only memory (CD-ROM), an optical storage device, a magnetic storage device, or any suitable combination of the foregoing. In the context of the present invention, a computer readable storage medium may be any tangible medium that can contain, or store, a program for use by or in connection with an instruction execution system, apparatus, or device.

A computer readable signal medium may include a propagated data signal with computer readable program code embodied therein, for example, in baseband or as part of a carrier wave. Such a propagated signal may take any of a variety of forms, including, but not limited to, electro-magnetic, optical, or any suitable combination thereof. A computer readable signal medium may be any computer readable medium that is not a computer readable storage medium and that can communicate, propagate, or transport a program for use by or in connection with an instruction execution system, apparatus, or device.

Program code embodied on a computer readable medium may be transmitted using any appropriate medium, including but not limited to wireless, wireline, optical fiber, cable, RF, etc., or any suitable combination of the foregoing. Computer program code for carrying out operations for aspects of the present invention may be written in any combination of one or more programming languages, including an object oriented programming language such as Java(TM), Smalltalk, C++ or the like and conventional procedural programming languages, such as the "C" programming language or similar programming languages. The program code may execute entirely on the user's computer, partly on the user's computer, as a stand-alone software package, partly on the user's computer and partly on a remote computer, or entirely on the remote computer or server. In the latter scenario, the remote computer may be connected to the user's computer through any type of network, including a local area network (LAN) or a wide area network (WAN), or the connection may be made to an external computer (for example, through the Internet using an Internet Service Provider).

Aspects of the present invention are described below with reference to flowchart illustrations and/or block diagrams of methods, apparatus (systems), and computer program products according to embodiments of the present invention. It will be understood that each block of the flowchart illustrations and/or block diagrams, and combinations of blocks in the flowchart illustrations and/or block diagrams, can be implemented by computer program instructions. These computer program instructions may be provided to a processor, in particular a microprocessor or a central processing unit (CPU), of a general purpose computer, special purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer, other programmable data processing apparatus, or other devices create means for implementing the functions/acts specified in the flowchart and/or block diagram block or blocks.

These computer program instructions may also be stored in a computer readable medium that can direct a computer, other programmable data processing apparatus, or other devices to function in a particular manner, such that the instructions stored in the computer readable medium produce an article of manufacture including instructions which implement the function/act specified in the flowchart and/or block diagram block or blocks.

The computer program instructions may also be loaded onto a computer, other programmable data processing apparatus, or other devices to cause a series of operational steps to be performed on the computer, other programmable apparatus or other devices to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide processes for implementing the functions/acts specified in the flowchart and/or block diagram block or blocks.

The flowchart and block diagrams in the figures illustrate the architecture, functionality, and operation of possible implementations of systems, methods and computer program products according to various embodiments of the present invention. In this regard, each block in the flowchart or block diagrams may represent a module, segment, or portion of code, which comprises one or more executable instructions for implementing the specified logical functions). It should also be noted that, in some alternative implementations, the functions noted in the blocks may occur out of the order noted in the figures. For example, two blocks shown in succession may, in fact, be executed substantially concurrently, or the blocks may sometimes be executed in the reverse order, depending upon the functionality involved. It will also be noted that each block of the block diagrams and/or flowchart illustrations, and combinations of blocks in the block diagrams and/or flowchart illustrations, can be implemented by special purpose hardware-based systems that perform the specified functions or acts, or combinations of special purpose hardware and computer instructions.

Moreover, a computer program for carrying out the methods described herein, as well as a non- transitory computer readable storage-medium storing the computer program are provided. A computer program may, for example, be downloaded (updated) to the existing control systems (e.g. to the existing or be stored upon manufacturing of these systems.

Elements and aspects discussed for or in relation with a particular embodiment may be suitably combined with elements and aspects of other embodiments, unless explicitly stated otherwise. Embodiments of the present invention will be further illustrated with reference to the attached drawings, which schematically will show embodiments according to the invention. It will be understood that the present invention is not in any way restricted to these specific embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

Aspects of the invention will be explained in greater detail by reference to exemplary embodiments shown in the drawings, in which:

FIG. 1 schematically illustrates a system for automatically cleaning one or more microfluidic chips according to an embodiment;

FIG. 2 shows in more detail a connector of the system according to an embodiment;

FIGs. 3A-3D show aspects of the system in more detail;

FIG. 4A shows an embodiment of the system;

FIG. 4B shows an embodiment of a container holder;

FIG. 5 is a flow chart illustrating a method according to an embodiment;

FIG. 6 shows different configurations of the system, in particular different states of respective valves;

FIGs. 7, 8 and 9 illustrate several user interfaces that a control system according to an embodiment can present;

FIGs. 10 and 11 illustrate two configurations of an embodiment in which a back and forth fluid flow can be achieved;

FIG. 12 illustrates a data processing system according to an embodiment.

DETAILED DESCRIPTION OF THE DRAWINGS

In the figures, identical reference numbers indicate identical or similar elements.

Figure 1 schematically illustrates a system 2 for automatically cleaning one or more microfluidic chips 8. In figure 1 , four individual chips are shown 8a, 8b, 8c, 8d. The depicted system is thus configured to automatically clean several chips. In the depicted example, the system is configured for cleaning five microfluidic chips, however, the skilled person will understand that the system can be adapted to clean any number of chips in one batch. Even further, in the depicted embodiment, although the system can automatically clean five chips, only four chips 8a-8d are present. There is one free spot 10 where a chip can be placed, but isn’t. Hence, valves 20e and 24e are assumed to be closed so that cleaning agents do not leak out of valve 20e and/or so that no air enters the system via valve 20e and/or 24e.

The system 2 comprises a tube system 3a, 3b, one or more actuators, such as valves 18 and 20 and pump 16, and a control system 100, which may also be referred to as computer or data processing system. In the depicted example, the system 2 also comprises a second tube system 3b, however this is not strictly required.

Each microfluidic chip 8 comprises a fluid inlet for receiving fluid, a fluid outlet for discharging fluid from the microfluidic chip, and a holding space 12 for holding a sample. The holding space is fluidly connected to the fluid inlet and the fluid outlet.

The tube system depicted in figure 1 may be understood to comprise two subsystems, namely subsystem 3a and subsystem 3b. Tube subsystem 3a is configured to transport cleaning agents from respective one or more containers 4a, 4b, 4c to the fluid inlets of the respective one or more microfluidic chips 8 so that the cleaning agents 6a, 6b, 6c from the one or more containers 4 pass through the holding spaces 12a, 12b, 12c, 12d and are discharged via the fluid outlets of the respective one or more microfluidic chips 8.

Tube subsystem 3b is suitable for transporting fluid from the fluid outlets of the respective one or more microfluidic chips 8 to a plurality of waste containers 14a and 14b. It is readily understood that one or more pumps can be used to move fluid, such as cleaning agents, through the tube system 3a and through the tube system 3b. Such one or more pumps may be present anywhere in system 2.

The actuators 18 and 20 are suitable for controlling a volumetric flow rate of cleaning agent out of each container to the fluid inlets of the respective one or more microfluidic chips 8. To illustrate, if at some point in time only cleaning agent 6a is to be provided to the fluid inlets of chips 8a, 8b, 8c, 8d, then valve 18a should be open, valves 18b, 18c should be closed, and valves 20a-20d should be open. Then, a fluid path would be established between container 4a and the fluid inlets of chips 8a-8c. In the depicted embodiment, a pump 16 is connected to the outlets of waste containers 14a and 14b. Hence, in this embodiment, assuming that the pump 16 is configured to vacuum fluid out of the tube system 3b, in order to move cleaning agent 6a to the fluid inlets of chips 8a-8d, all valves 24a-24d should be open. In addition, the pair of valves 26a, 28a or the pair of valves 26b, 28b should be open.

It may also be that a cleaning program indicates that at some point in time only cleaning agent 6b should be provided to the fluid inlet of chip 8c only. In that case valve 18b should be open, valves 18a and 18c should be closed, valves 20a, 20b, 20d should be closed and valve 20c should be open. Then, a fluid path would be established between container 4b to fluid inlet of chip 8c.

The valves 24, 26, 28 can be used for controlling into which waste container 14a or 14b fluid from the fluid outlets is transported.

The system also comprises pressure sensors 22 that are configured to measure a pressure, in the tube system. In the depicted embodiment, the pressure sensors are positioned between valves 20 and valves 24 (and thus also between valves 20 and valves 26). Further, valve 25 can control whether air can flow into the system or not. When valve 25 is open, then any point in the tube system fluidly connected to valve 25 should be at atmospheric pressure. Valve 25 can be used for checking whether there is a blockage in the tube system as described above.

Further depicted is a control system 100 that is configured to control each actuator of the system, for example by sending appropriate control signals to these actuators. Such control signal may be sent over a wire and/or wireless. The control system may be a distributed system in the sense that some components are separated. The control system can store a cleaning program that indicates, for each cleaning agent and for each of a plurality of times, a value of volumetric flow rate of the cleaning agent in question through the holding spaces of the respective one or more microfluidic chips.

The control system may control the actuators of the tube system such that cleaning agents flow through the one or more holding spaces in accordance with the stored cleaning program.

The cleaning program optionally also indicates to which waste container each cleaning agent should be transported. In that case, the control system 100 can control the valves such that the cleaning agents are transported to the appropriate waste container, in accordance with the cleaning program.

Although not depicted, the containers 4 and/or the waste containers 14 may be part of the system. Each container 4 and each waste container may comprise a sensor that is configured to detect an amount of cleaning agent that is present in the container in question. As referred to herein, a container comprising a sensor does not necessarily mean that the sensor is positioned inside that container. The sensor may also be positioned on an outer surface of the container, for example.

The following table indicates a cleaning program according to an embodiment.

The scrubbing referred to herein will be explained in more detail with reference to figures 10 and 11.

Figure 2A shows in more detail how a microfluidic chip 8 may be connected to the tube subsystem 3a and/or tube subsystem 3b.

Figure 2B shows a connector element 30 for connecting the tube system to the chip. The connector element comprises a threaded inner surface 32 so that the connector element can be screwed onto the chip, as illustrated in figure 3A-3C and as illustrated in figure 3D. The connector element 30 also comprises an O-ring 34 in order to ensure a fluid tight connection, and, of course, an opening 36 via which fluid, e.g. cleaning agents can pass from the chip to tube 5 of the tube system.

Figure 3A shows that a chip as referred to herein may comprise a chip valve 38, which is configured to control whether fluid can flow through the holding space of the chip. Of course, in case the chip is to be cleaned, then such chip valve should be open.

Figures 3B and 3C illustrate how, in an embodiment, a connector element 30 is used to connect the tube subsystem 3b to a fluid outlet 40 of the chip, namely by sliding the connector element 30 over the fluid outlet 40 and rotating the connector 30 to tighten the connection. Figure 3D illustrates that the tube system can be connected to a fluid inlet 42 of the chip 8 in a similar manner.

Figure 4A shows an embodiment of the system. Figure 4a shows that the system comprises a number of positions each of which is configured to receive a chip that is to be cleaned. One of these positions is indicated by reference number 10a. In this embodiment, the system also comprises a plurality of container holders, two of which are indicated by reference number 49a and 49b.

Figure 5 is a flow chart illustrating a method as may be performed by the control system 100 according to an embodiment. The method starts at 50 and comprises performing a leak test and a clog test subsequently for each chip. Step 52 indicates that the first leak test clog test combination is performed for chip 8a. After this first test has been successfully completed for chip 8a, it is performed again for chip 8b (as indicated in step 73), chip 8c, et cetera.

In step 54 all valves in the system are closed (for illustration purposes, reference is made to the valves depicted in figure 1). In step 56, the pressure as measured by pressure sensor 22a is received by the control system 100. It should be appreciated that in this step, the pump 16 is inactive.

In step 58, the control system controls the pump during 30 seconds, which may be referred to as the “first time period” herein, to pump fluid out of the tube system to achieve some pressure value in the tube system between valve 20a and valve 26a. Note that this pressure value can be measured by pressure sensor 22a which may then send a signal indicative of this pressure value to the control system 100. The control system 100 stores this measured value. It should be appreciated that in order to achieve this pressure value, the control system controls valve 20a to be closed, and valves 26a and 28a to be open while the pump is active. This is also depicted in figure 6A where an “O” above a valve indicates that the valve is open and a “C” above a valve indicates that the valve is closed.

Step 60 comprises comparing the pressure value as measured at the end of the 30 seconds (step 58) with a first threshold value, in this example 600 mbar. If the measured pressure is higher than 600 mbar, then apparently a relatively large leak is present somewhere between the pump 16 and valve 20a. Typically, such relatively large leak is caused by one of the waste bottles not being tightened properly. The flow chart then leads to step 62 in which the leak is detected, which leads to the end 76 of the procedure.

However, if the measured pressure is lower than 600 mbar, then the control system 100 performs step 64, which involves controlling the valves 20a and 26a to close and then controlling the valves 20a and 26a to remain closed for 30 seconds, which may be referred to herein as “the second time period”. This configuration is shown in figure 6B. Optionally, the pressure, as measured by pressure sensor 20a, is measured at the beginning of this 30 seconds time period, however, this is not strictly necessary since it was measured also at the end of the 30 seconds time period of step 58. In any case, at the end of the 30 seconds of step 64, the pressure is again measured.

Then, in step 66, the control system 100 compares the two pressure values before (or at the beginning of) step 64 and at the end of step 64. If the pressure has changed, e.g. increased, more than 50 mbar, then the control system may determine (step 62) that there is a leak between valve 20a and 26a. Preferably, the control system 100 then outputs an indication which chip caused the failure. A user may then check whether that chip has been connected correctly to the tube systems.

If the pressure change is smaller than 50 mbar, then the control system may perform step 68, which may be regarded as the first step of the clog test.

In step 68, the control system 100 opens valve 20a and 25 in order to cause the pressure at pressure sensor 22a to become atmospheric. Figure 6C illustrates a configuration in which the pressure at pressure sensor 22a should become atmospheric. After a time period of two seconds, which may be referred to herein as the “third time period”, pressure sensor 22a again measures the pressure. This allows the control system in step 70 to verify that indeed atmospheric pressure is achieved. If the measured pressure value at the end of the two-second period is still lower than 900 mbar, then a blockage is detected (step 74), which leads to the end of the procedure 76, preferably with the system indicating which chip caused the blockage. If the measured pressure is higher than 900 mbar, then the test for chip 8a is completed.

In step 72, the control system checks whether all chips have been tested. If so, then the procedure ends. If not, then the steps are performed again, only now for the next chip, until all chips have been tested.

Figures 7, 8 and 9 illustrate several user interfaces that the control system 100 can present to a user.

User interface 80 for example indicates for each container how much cleaning agent is left. The button “Cleaning” may be pressed to start a cleaning program.

User interface 82 may be presented instructing a user to install chips, e.g. to connect the chips to the tube systems of the system. User interface 84 may be presented so that a user can select which chips are to be cleaned. In the example, three chips at respective positions “1 ”, “2” and “4” are going to be cleaned.

User interface 86 may be presented to a user prior to performing a leak and clog test described herein. The user may press “Start” to initiate the testing procedure.

User interface 88 may be presented in order to inform the user of the status of the test procedure.

User interface 89 shows that the tests for chips at respective positions “1 ”, “2” and “4” were successful. A user may press “Start” to initiate the cleaning program.

Continuing with figure 8, user interface 90 may be presented to inform a user about the respective amounts of cleaning agents in the containers and about the respective amounts of waste material in the waste containers.

User interface 91 may be presented to inform a user that a leak and/or blockage has been detected when testing a specific chip.

User interface 92 may be presented to verify that a user indeed wishes to abort the cleaning program.

User interface 93 may be presented to inform a user that the cleaning program was automatically aborted.

User interface 94 may be presented to verify that a user wants to rinse the chips after an automatic abortion of the cleaning program.

User interface 95 may be presented to verify that a user wants to rinse the chips after a power shortage.

User interface 96 may be presented to a user in response to the control system determining in step 66 (see figure 5) that the pressure is higher than the first threshold value referred to herein.

User interface 97 may be presented to a user in response to the control system determining in step 74 (see figure 5) that there is a blockage in the system.

User interface 98 may be presented to a user in response to the control system determining in step 60 (see figure 5) that the pressure is higher than the first threshold value referred to herein.

Figures 10 and 1 1 illustrate an embodiment of the cleaning system that is configured to cause a back and forth fluid flow through the microchips. In this embodiment, the tube system comprises a first forward flow valve 29a and a second forward flow valve 29b and a first back flow valve 27a and a second back flow valve 27b.

In these figures, it is assumed that the pump 16 is configured to suck fluid out of the tube system and thus create a vacuum. In the configuration of figure 10, valves 27a and 27b are closed, whereas valves 29a and 29b are open. As a result, as indicted by the arrows, fluid from one or more of the containers 4 flows in the “forward direction” through the chips.

In figure 11 , however, valves 27a and 27b are open, whereas valves 29a and 29b are closed. As a result, as indicated by the arrows, fluid from one or more of the containers 4 flows in the “backwards directions”.

Hence, by alternately switching between the configuration of figure 10 and figure 11 , a back and forth fluid flow can be achieved. This allows to use the same cleaning agent multiple times and thus enables efficient usage of cleaning agent. Optionally, the cleaning system also comprises a bubble valve 31 . This valve, when open, lets in air into the system in such amounts that bubbles are present in the fluid that flows through the microchips. Preferably, the bubble valve 31 is only open when the fluid flows in the backwards direction. Of course, if bubbles would be desired in the forward flow as well, then an additional bubble valve could be implemented in the system, for example between valve 29a and valve 20a.

The bubbles in the fluid flowing though the microchips may be understood to scrub the inside of the microfluidic chips. The bubbles passing through the chip force the surface bound molecules/detritus entrained in the fluid to detach from the surface.

Fig. 12 depicts a block diagram illustrating a data processing system according to an embodiment.

As shown in Fig. 12, the data processing system 100 may include at least one processor 102 coupled to memory elements 104 through a system bus 106. As such, the data processing system may store program code within memory elements 104. Further, the processor 102 may execute the program code accessed from the memory elements 104 via a system bus 106. In one aspect, the data processing system may be implemented as a computer that is suitable for storing and/or executing program code. It should be appreciated, however, that the data processing system 100 may be implemented in the form of any system including a processor and a memory that is capable of performing the functions described within this specification.

The memory elements 104 may include one or more physical memory devices such as, for example, local memory 108 and one or more bulk storage devices 1 10. The local memory may refer to random access memory or other non-persistent memory device(s) generally used during actual execution of the program code. A bulk storage device may be implemented as a hard drive or other persistent data storage device. The processing system 100 may also include one or more cache memories (not shown) that provide temporary storage of at least some program code in order to reduce the number of times program code must be retrieved from the bulk storage device 110 during execution.

Input/output (I/O) devices depicted as an input device 112 and an output device 114 optionally can be coupled to the data processing system. Examples of input devices may include, but are not limited to, a keyboard, a pointing device such as a mouse, a touch-sensitive display, or the like. Examples of output devices may include, but are not limited to, a monitor or a display, speakers, or the like. Input and/or output devices may be coupled to the data processing system either directly orthrough intervening I/O controllers.

In an embodiment, the input and the output devices may be implemented as a combined input/output device (illustrated in Fig. 12 with a dashed line surrounding the input device 112 and the output device 114). An example of such a combined device is a touch sensitive display, also sometimes referred to as a “touch screen display” or simply “touch screen”. In such an embodiment, input to the device may be provided by a movement of a physical object, such as e.g. a stylus or a finger of a user, on or near the touch screen display.

A network adapter 116 may also be coupled to the data processing system to enable it to become coupled to other systems, computer systems, remote network devices, and/or remote storage devices through intervening private or public networks. The network adapter may comprise a data receiver for receiving data that is transmitted by said systems, devices and/or networks to the data processing system 100, and a data transmitter for transmitting data from the data processing system 100 to said systems, devices and/or networks. Modems, cable modems, and Ethernet cards are examples of different types of network adapter that may be used with the data processing system 100.

As pictured in Fig. 12, the memory elements 104 may store an application 118. In various embodiments, the application 118 may be stored in the local memory 108, the one or more bulk storage devices 110, or apart from the local memory and the bulk storage devices. It should be appreciated that the data processing system 100 may further execute an operating system (not shown in Fig. 12) that can facilitate execution of the application 118. The application 118, being implemented in the form of executable program code, can be executed by the data processing system 100, e.g., by the processor 102. Responsive to executing the application, the data processing system 100 may be configured to perform one or more operations or method steps described herein.

In one aspect of the present invention, the data processing system 100 may represent a control system as described herein.

Various embodiments of the invention may be implemented as a program product for use with a computer system, where the program(s) of the program product define functions of the embodiments (including the methods described herein). In one embodiment, the program(s) can be contained on a variety of non-transitory computer-readable storage media, where, as used herein, the expression “non- transitory computer readable storage media” comprises all computer-readable media, with the sole exception being a transitory, propagating signal. In another embodiment, the program(s) can be contained on a variety of transitory computer-readable storage media. Illustrative computer-readable storage media include, but are not limited to: (i) non-writable storage media (e.g., read-only memory devices within a computer such as CD-ROM disks readable by a CD-ROM drive, ROM chips or any type of solid-state non-volatile semiconductor memory) on which information is permanently stored; and (ii) writable storage media (e.g., flash memory, floppy disks within a diskette drive or hard-disk drive or any type of solid-state random-access semiconductor memory) on which alterable information is stored. The computer program may be run on the processor 102 described herein.

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.

The corresponding structures, materials, acts, and equivalents of all means or step plus function elements in the claims below are intended to include any structure, material, or act for performing the function in combination with other claimed elements as specifically claimed. The description of embodiments of the present invention has been presented for purposes of illustration, but is not intended to be exhaustive or limited to the implementations in the form disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the present invention. The embodiments were chosen and described in order to best explain the principles and some practical applications of the present invention, and to enable others of ordinary skill in the art to understand the present invention for various embodiments with various modifications as are suited to the particular use contemplated.

Claims

1 . A system for automatically cleaning one or more microfluidic chips, wherein each microfluidic chip comprises a fluid inlet for receiving fluid, a fluid outlet for discharging fluid from the microfluidic chip, and a holding space for holding a sample, the holding space being fluidly connected to the fluid inlet and the fluid outlet, the system comprising: a tube system fortransporting cleaning agents from respective one or more containers to the fluid inlets of the respective one or more microfluidic chips so that the cleaning agents from the one or more containers pass through the holding spaces and are discharged via the fluid outlets of the respective one or more microfluidic chips, wherein the system comprises one or more actuators for controlling a volumetric flow rate of cleaning agent out of each container to the fluid inlets of the respective one or more microfluidic chips, and the system comprising a control system that is configured to perform steps of:

2. The system according to claim 1 , wherein the actuators comprise one or more pumps and/or one or more valves.

3. The system according to claim 1 or 2, wherein the tube system is configured to transport a first cleaning agent form a first container and a second cleaning agent from a second container to the fluid inlets of the respective one or more microfluidic chips, wherein the tube system is also configured to transport fluid from the fluid outlets of the respective one or more microfluidic chips to a plurality of waste containers, the plurality of waste containers comprising a first waste container and a second waste container, wherein the system comprises second one or more actuators for controlling into which waste container out of the plurality of waste containers fluid from the fluid outlets is transported, and wherein the control system is configured to perform a step of

- controlling the second one or more actuators such that the first cleaning agent is transported to the first waste container and the second cleaning agent is transported to the second waste container.

4. The system according to any of claims 1-3, wherein the system comprises a first valve and a second valve and a pressure sensor for measuring a pressure in the tube system between the first valve and the second valve and a pump for pumping fluid through the tube system, wherein the controller is configured to perform steps of:

5. The system according to claim 4, wherein the controller is configured to perform steps of:

- comparing the first pressure value with a first threshold value, and

- determining, based on this comparison, that there is a leak in the tube system between the first valve and the pump.

6. The system according to claim 4 or 5, wherein the controller is configured to perform steps of:

- controlling the pump to refrain from pumping fluid into or out of the tube system for a second time period following the first time period, and

- controlling the second valve to close at the end of the first time period and/or at the start of the second time period and controlling the first and second valve to remain closed during the second time period, and

7. The system according to claim 6, wherein the controller is configured to perform a step of:

- determining, based on a difference between the first and second pressure value being larger or smaller than a second threshold value, determining that there is a leak or, respectively, that there is no leak in the tube system between the first and second valve.

8. The system according to any of the preceding claims 6-7, wherein the controller is further configured to perform steps of:

- determining, based on the third pressure value whether there is a blockage in the tube system between the first and second valve.

9. The system according to any of the preceding claims, wherein the system is configured to automatically clean a plurality of microfluidic chips.

10. The system according to any of the preceding claims, wherein the system comprises the one or more containers, wherein the system comprises at least one sensor that is configured to detect an amount of cleaning agent that is present in one of the one or more containers, and/or wherein the system comprises the one or more waste containers, wherein the system comprises at least one sensor that is configured to detect an amount of waste that is present in a waste container of the one or more waste containers.

11 . The system according to any of the preceding claims, further comprising the one or more microfluidic chips, wherein, for each microfluidic chip, the fluid inlet, and preferably also the fluid outlet, is fluidly connected to the tube system.

12. A computer-implemented method for automatically cleaning one or more microfluidic chips, the computer-implemented method comprising

13. A control system comprising a processor that is configured to perform the method according to claim 12.

14. A computer program comprising instructions to cause the system according to any of the preceding claims 1-11 to perform the method according to claim 12.

15. A non-transitory computer-readable storage medium having stored there on the computer program of claim 14.