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WO2024110183A1 - A method for operating a microfluidic device, a microfluidic device and a bioreactor system - Google Patents

A method for operating a microfluidic device, a microfluidic device and a bioreactor system Download PDF

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Publication number
WO2024110183A1
WO2024110183A1 PCT/EP2023/080919 EP2023080919W WO2024110183A1 WO 2024110183 A1 WO2024110183 A1 WO 2024110183A1 EP 2023080919 W EP2023080919 W EP 2023080919W WO 2024110183 A1 WO2024110183 A1 WO 2024110183A1
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WO
WIPO (PCT)
Prior art keywords
chamber
sealing member
microfluidic device
connected position
sealed chamber
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2023/080919
Other languages
French (fr)
Inventor
Stefan Giselbrecht
Daniel Jose TEIXEIRA OLIVEIRA CARVALHO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Universiteit Maastricht
Academisch Ziekenhuis Maastricht
Original Assignee
Universiteit Maastricht
Academisch Ziekenhuis Maastricht
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universiteit Maastricht, Academisch Ziekenhuis Maastricht filed Critical Universiteit Maastricht
Publication of WO2024110183A1 publication Critical patent/WO2024110183A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L9/00—Supporting devices; Holding devices
    • B01L9/52—Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips
    • B01L9/527—Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips for microfluidic devices, e.g. used for lab-on-a-chip
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/025—Align devices or objects to ensure defined positions relative to each other
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • B01L2200/027—Fluid interfacing between devices or objects, e.g. connectors, inlet details for microfluidic devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0615—Loss of fluid by dripping
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0689—Sealing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/04—Closures and closing means
    • B01L2300/041—Connecting closures to device or container
    • B01L2300/042—Caps; Plugs
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0803—Disc shape
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces

Definitions

  • the invention relates to a method for operating a microfluidic device comprising a base provided with a chamber configured to receive at least one microfluidic component, and a sealing member provided with fluid passages configured to communicate with the chamber.
  • the invention further relates to a microfluidic device provided with a base provided with a chamber configured to receive at least one microfluidic component, and a sealing member provided with fluid passages configured to communicate with the chamber, wherein the sealing member is connectable to the base from an unconnected position with the base to a connected position with the base providing a leak-free sealed chamber configured for fluid flow by means of the fluid passages of the sealing member and at least one fluid source outside the chamber.
  • the invention also relates to bioreactor system.
  • US2018/0273888 discloses a microfluidic device and a method for operating the microfluidic device.
  • the microfluidic device comprises a base provided with a chamber configured to receive at least one microfluidic component, and a sealing member provided with fluid passages configured to communicate with the chamber.
  • the sealing member is connectable to the base from an unconnected position with the base to a connected position with the base to provide a seal for the chamber, and vice versa.
  • the sealing member of the known microfluidic device includes a threaded stem and a top portion with a larger diameter than the stem. Threaded stem is sized to be inserted into the chamber of the base and to interact with a threaded portion in the chamber to removably couple sealing member to base.
  • Top portion is designed such that it cannot be inserted into the chamber. After contact between the top portion and a top side of the base, the sealing member provides a leak-free sealed chamber.
  • This known microfluidic device can fail due to leakage and one of the main causes is the gradual decrease of the device’s bonding strength throughout culture. For example, it is not unusual that the microfluidic component will permanently or plastically deform throughout the experiment. The problem is aggravated by the lack of countermeasures to stop leakages from occurring.
  • the method for operating a microfluidic device comprising a base provided with a chamber configured to receive at least one microfluidic component, and a sealing member provided with fluid passages configured to communicate with the chamber, the method comprises the following steps: a) connecting the sealing member to the base from an unconnected position with the base to a connected position with the base providing a leak-free sealed chamber configured for fluid flow by means of the fluid passages of the sealing member and at least one fluid source outside the chamber; b) preventing leakage of the sealed chamber by displacing the sealing member in the base from the connected position to at least a second connected position for maintaining the leak-free sealed chamber.
  • the method uses the countermeasure displacement of the sealing member to prevent leakage of the sealed chamber in use of the microfluidic device.
  • preventing leakage also includes reducing or minimizing leakage. Due to processes in the sealed chamber during an experiment the conditions in the sealed chamber will change. For example, in these experiments the at least one microfluidic component provided in the chamber of the microfluidic device is in fluid communication with the fluid passages of the sealing member such that a fluid can be provided between the least one microfluidic component in the chamber and a fluid source outside the chamber or outside the microfluidic device. As a result of changing conditions in the chamber during the experiment the risk for leakages may increase. It is for example not uncommon, that the microfluidic component undergoes permanent deformation (creep) during an experiment.
  • the method as disclosed in this disclosure has the potential to increase the success rates of cultures under flow, in particular long-term cultures under flow.
  • the method of this disclosure adds an extra safety level, in which leakages of possible harmful components can be prevented and contained inside the microfluidic device.
  • At least one microfluidic component may be positioned in the chamber before step a). After providing the leak- free sealed chamber, fluid can flow by means of the fluid passages of the sealing member between the microfluidic component in the chamber and the at least one fluid source outside the chamber.
  • the microfluidic component may include one or more microfluidic channels on a surface thereof and at least one tissue culture chamber configured to house a tissue culture, wherein tissue culture chamber is coupled to at least one of the one or more microfluidic channels.
  • the one or more microfluidic channels and the tissue culture chamber can be positioned in fluid communication with the at least one fluid source outside the chamber through the fluid passages of the sealing member to form a fluid circuit.
  • step a) between step a) and b):
  • - leakage conditions of the sealed chamber are monitored, such as monitoring by visual inspection of the microfluidic device and/or by at least one sensor of the microfluidic device.
  • Monitoring time and/or leakage conditions of the sealed chamber may be parameters to be used for preventing leakage of the sealed chamber.
  • Leakage conditions may be visually monitored from the outside of the microfluidic device. For example visually observed by an operator or by using visual inspection by detector/camera.
  • Monitoring leakage conditions can also include monitoring mechanical pressure, electrical conductance between components, and/or heat transition. Basically all physical parameters can be used for monitoring leakage conditions which could help to do a real time monitoring of the clamping conditions.
  • a sensor can be used to monitor these physical parameters.
  • leakage conditions may be monitored by the microfluidic device itself by at least one sensor in the microfluidic device, in particular in the sealed chamber. Such a sensor may also be communicating or connected with at least one interface, for example the interface comprises an indicator to alarm operators.
  • step b) is performed after:
  • a predetermined period of time for example a predetermined period of time is based on data of previous experiments.
  • the predetermined period of time may be a fixed time interval or based on at least a number of known parameters of the experiment or data from previous experiments, such that for preventing leakage the sealing member is displaced in the base after the predetermined period of time from the connected position to the at least one second connected position for maintaining the leak-free sealed chamber.
  • detection of leakage conditions of the sealed chamber may trigger step b).
  • the sealing member is a threaded cap connectable to a threaded section of the base, wherein the sealing member is configured for cooperation with a rotatable driver for rotating the threaded cap around its center line with a predetermined torque for displacement from the connected position to the at least second connected position.
  • the top part of the threaded cap may be shaped to mate with the rotatable driver, for example the top part of the threaded cap may be shaped with a hexagonal outline that mates with a hex socket or hex bit of the rotatable driver.
  • step b) of the method uses a second predetermined torque to displace the sealing member in the base from the connected position to at least a second connected position for maintaining the leak-free sealed chamber (step b) of the method) allows the experiment to be replicated. It is even possible to use a third predetermined torque if a third connected position is required in use of the microfluidic device and so on.
  • the inventors have found out that the higher the torque of the driver, the stronger the sealing. It has been demonstrated that the sealing strength can be externally tuned during the experiment by simply adjusting the torque by means of a driver, like for example a common screw driver. By using various torques the microfluidic device can be kept leak-free during flow conditions and/or to compensate for gradual decrease of the sealing strength.
  • the microfluidic component before positioning the microfluidic component in the chamber, the microfluidic component is releasably connected to a bottom side of the sealing member, preferably the microfluidic component is releasably connected to the sealing member by using an alignment tool.
  • the microfluidic component may be made from a sticky material, for example PDMS, for providing the releasable connection with the sealing member.
  • the sealing member and the at least one microfluidic component may be provided with circumferential alignment cut-outs cooperating with alignment members of an alignment tool for aligning the sealing member and the at least one microfluidic component with respect for each other.
  • the sealing member and the microfluidic component are aligned and without alignment tool the sealing member with the aligned microfluidic component is connected to the base from an unconnected position with the base to a connected position with the base providing the leak-free sealed chamber, i.e. step a) of the method of this disclosure.
  • the sealing member can be automatically or manually displaced from the connected position to the at least one second connected position, for example after detecting leakage conditions of the sealed chamber or after a predetermined period of time.
  • automatically displaced means displacement without interference of an operator
  • manually displaced requires an operation of the operator, such as for example by hand or by operating the rotatable driver as mentioned above.
  • the operator may use the rotatable driver for manually displacing the sealing member from the connected position to the at least one second connected position.
  • a signal can be provided to an actuator or driver of the microfluidic device for automatically displacing the sealing member from the connected position to the at least one second connected position for maintaining the leak-free sealed chamber.
  • the at least one sensor may also provide an observable instruction to an operator to displace the sealing member, or the sensor may also provide the signal to an actuator or driver of the microfluidic device for automatically displacing the sealing member.
  • the microfluidic device comprises:
  • a base provided with a chamber configured to receive at least one microfluidic component
  • sealing member provided with fluid passages configured to communicate with the chamber, wherein the sealing member is connectable to the base from an unconnected position with the base to a connected position with the base providing a leak-free sealed chamber configured for fluid flow by means of the fluid passages of the sealing member and at least one fluid source outside the chamber,
  • the microfluidic device is configured for preventing leakage of the sealed chamber, in that the sealing member is adapted to displace from the connected position to at least a second connected position for maintaining the leak-free sealed chamber.
  • the conditions in the chamber of the microfluidic device change. These changing conditions may increase the risk for leakages.
  • the sealing member is displaced in the microfluidic device of this disclosure from the connected position to at least a second connected position to maintain the leak-free sealed chamber.
  • the microfluidic device can be re-tightened during experimentation to compensate for any gradual loss of sealing strength (likely caused by material change or failure), hence avoiding the formation of leak spots and eventual leakage throughout the culture time.
  • the microfluidic device as disclosed in this disclosure has the potential to increase the success rates of cultures under flow, in particular the success rates of long-term cultures under flow. Moreover, the microfluidic device adds an extra safety level, in which leakages of possible harmful components can be prevented and contained inside the microfluidic device.
  • the microfluidic device is at least partly made from transparent or translucent material for visually monitoring leakage conditions of the sealed chamber to prevent leakage of the sealed chamber.
  • transparent or translucent material By means of the transparent or translucent material, it is possible to observe visually any changes with respect to the sealed chamber and/or the sealing element and/or the microfluidic component. An operator may visually observe such a change in the leakage conditions and manually displace the sealing member to the at least one second connected position for maintaining the leak-free chamber. It is also possible to use a detector/camera together with for example image analysis software to detect such a change in the leakage conditions.
  • the microfluidic device may comprise at least one sensor configured for monitoring leakage conditions of the sealed chamber to prevent leakage of the sealed chamber. By using such a sensor, the risk of a human mistake can be reduced or even excluded.
  • the sealing member is configured for automatic displacement from the connected position to the at least one second connected position, for example after a predetermined period of time and/or after detecting leakage conditions of the sealed chamber.
  • the sensor or a detector/camera may provide a signal for example by means of a controller to an actuator or driver of the microfluidic device for automatically displacing the sealing member from the connected position to the at least one second connected position for maintaining the leak-free sealed chamber.
  • the sealing member is configured for manual displacement from the connected position to the at least one second connected position, for example after a predetermined period of time and/or after detecting leakage conditions of the sealed chamber.
  • the sensors or the detector/camera may also provide an observable instruction to an operator to displace the sealing member as already discussed.
  • the sealing member is a threaded cap connectable to a threaded section of the base, wherein the threaded cap is configured for cooperation with a rotatable driver for rotating the threaded cap around its center line with a predetermined torque for displacement from the connected position to the at least second connected position.
  • the threaded cap has a top side which is provided with a coupling member adapted to be coupled with the driver. In this manner, the threaded cap can be displaced from the connected position to at least a second connected position for maintaining the leak-free sealed chamber in an easy and user-friendly manner.
  • the invention further relates to a bioreactor system comprising a microfluidic device of this disclosure, at least one microfluidic component which is positioned in a chamber of the microfluidic device and at least one fluid source outside the chamber of the microfluidic device, such that in the bioreactor system fluid can flow by means of the fluid passages of the sealing member between the microfluidic component in the chamber and the at least one fluid source outside the chamber.
  • Figure 1 shows an exploded view of the microfluidic device
  • Figure 2a, b show a top view and cross section of the microfluidic device shown in figure 1 ;
  • Figure 3 shows a perspective view of the microfluidic device shown in figures 1 and 2a, b in a closed position
  • Figure 4 shows a perspective view of another embodiment of a microfluidic device in a closed position
  • Figure 5 shows a flow chart of the method as disclosed herein.
  • Figures 1-3 show a microfluidic device 1 comprising:
  • a base 3 provided with a chamber 5 configured to receive at least one microfluidic component 7, i.e. in the embodiment shown two microfluidic components 7, 7’, - a sealing member 9 provided with fluid passages 11 configured to communicate with the chamber 5, wherein the sealing member 9 is connectable to the base 3 from an unconnected position (figures 1 and 2b) with the base 3 to a connected position (figures 2a and 3) with the base 3 providing a leak-free sealed chamber 5 configured for fluid flow by means of the fluid passages 11 of the sealing member 9 and at least one fluid source (not shown) outside the chamber 5.
  • the base 3 comprises a base ring 3a and a base bottom 3b, wherein the base bottom 3b is attached to the base ring 3a for example by fasteners (not shown). It is also possible to manufacture the base 3 in one-piece (not shown), i.e. a base 3 made in a single undivided piece.
  • the inner wall of the base ring 3a is provided with a threaded section 2.
  • the threaded section 2 extends between the top side 4a and the bottom side 4b of the base ring 3a. It is possible that threaded section only covers a portion of the inner wall of the base ring 3a (not shown).
  • the inner wall of the base ring 3a defines the maximum dimensions of the chamber 5.
  • the inner wall of the base ring 3a, the base bottom 3b and the bottom side 10b of the sealing member 9 define a sealed chamber 5.
  • microfluidic components 7, 7’ are positioned in the chamber 5. After providing the leak-free sealed chamber (figure 2a and 3), fluid can flow by means of the fluid passages 11 of the sealing member 9 between the microfluidic component 7, 7’ in the chamber 5 and the at least one fluid source (not shown) outside the chamber.
  • a bioreactor system (not completely shown in the figures) comprises the microfluidic device 1 , at least one microfluidic component 7, 7’ which is positioned in a chamber 5 of the microfluidic device 1 and at least one fluid source (not shown) outside the chamber of the microfluidic device.
  • the microfluidic components 7, 7’ comprise a number of microfluidic channels 7a, 7’a on a surface thereof and at least one tissue culture chamber 7b, 7’b configured to house a tissue culture, wherein tissue culture chamber 7b, 7’b is coupled to the microfluidic channels 7a, 7’a.
  • the microfluidic channels 7a, 7’a and the tissue culture chamber 7b, 7’b are positioned in fluid communication in use of the microfluidic device 1 with the at least one fluid source (not shown) outside the device 1 through the fluid passages 11 of the sealing member 9 to form a fluid circuit. Different configurations of the microfluidic component 7a, 7’a than shown in the figures are possible.
  • the microfluidic device 1 further comprises a coverslip 14.
  • the coverslip 14 provides a low-friction contact with the base bottom 3b. Such a low-friction contact provided by the coverslip 14 facilitates rotating the sealing member 9 with the microfluidic components 7, 7’ with respect to the base 3, in particular the base bottom 3b.
  • the sealing member 9 is reversibly connected with the base 3, i.e. the chamber 5 can be sealed by reversibly coupling the sealing member 9 to the base 3.
  • the microfluidic device 1 , T (see figure 4: T) is configured for preventing leakage of the sealed chamber 5 in use, in that the sealing member 9; 9’ is adapted to displace from the connected position with the base 3 providing the leak-free sealed chamber 5 to at least a second connected position for maintaining the leak-free sealed chamber.
  • the distance measured in the direction of the center line of the microfluidic device 1 ; T between the first connected position and the second connected position may vary between 0,01 mm and 10 mm, preferably between 0, 1 mm and 5 mm.
  • the microfluidic device 1,1’ is at least partly made from translucent or transparent material for visually monitoring leakage conditions of the sealed chamber 5, wherein upon detection of leakage conditions of the sealed chamber 5, the sealing member 9; 9’ is displaced from the connected position to the at least one second connected position for maintaining the leak-free sealed chamber 5.
  • the microfluidic device 1 comprises at least one sensor 17 configured for monitoring leakage conditions of the sealed chamber 5, wherein upon detection of leakage conditions of the sealed chamber 5 the sealing member 9 is displaced from the connected position to the at least one second connected position for maintaining the leak-free sealed chamber.
  • Different positions for the sensor 17 than the position shown in figure 1 in the microfluidic device 1 are possible. Further, it is possible to provide multiple sensors (not shown) in a microfluidic device of this disclosure.
  • the sealing member 9; 9’ is configured for manual displacement from the connected position to the at least one second connected position, for example after detection of leakage conditions of the sealed chamber or after a predetermined period of time.
  • Manual displacement can be performed by hand or by an operator using a tool such as a rotatable driver to be discussed below.
  • a tool such as a rotatable driver to be discussed below.
  • an observable instruction to an operator may be provided to manually displace the sealing member 9; 9’.
  • the sealing member is in the exemplary embodiment shown a threaded cap 9; 9’ which is connectable to a threaded section 2 of the base 3.
  • the maximum diameter of the threaded cap 9; 9’ is provided by the threads 12 of the threaded cap 9; 9’ which substantially equals the inner diameter of the chamber 5 defined by the inner walls of the base ring 3a.
  • the threaded cap 9; 9’ is configured for cooperation with a rotatable driver (not shown) for rotating the threaded cap 9; 9’ around its center line with a predetermined torque.
  • the threaded cap 9; 9’ has a top side 10a; 10a’ which is provided with a coupling member 13; 13’ adapted to be coupled with for example a tool (driver) used to apply a specific torque to a fastener.
  • the top part of the threaded cap i.e.
  • the coupling member 13; 13’ is shaped to mate with the rotatable driver.
  • the threaded cap 9; 9’ has fluid passages 11 ; 11’ extending through the cap 9; 9’, including the coupling member 13; 13’, to the bottom side 10b of the cap 9; 9’.
  • the threaded cap 9; 9’ can be rotated in an easy, user-friendly and predefined manner.
  • the top part of the threaded cap 9 is shaped with a hexagonal outline that mates with a hex socket. Hence, the hexagonal screw cap 9 can interface with a hex bit socket (not shown).
  • the microfluidic device T shown in figure 4 is identical to the microfluidic device 1 shown in figures 1-3, with the exception that the threaded cap 9’ does not have hexagonal coupling member 13, but a dodecagon coupling member 13’.
  • Any shape adapted to provide a predetermined torque in an user-friendly manner and providing a (fast) coupling with a rotatable driver can be chosen for the coupling member 13; 13’.
  • a coupling member 13; 13’ protruding with respect to the top side 10a; 10a’, it is also possible to provide a recessed coupling member (not shown) in the top side, for example a hexagonal recess (not shown).
  • a predetermined torque for connecting the threaded cap to the base for providing a leak-free sealed chamber has the advantage that the start of the experiment to be performed with the microfluidic device 1 , T is reproducible.
  • using a second predetermined torque to displace the threaded cap 9; 9’ in the base 3 from the (first) connected position to the at least second connected position for maintaining the leak-free sealed chamber allows the experiment to be replicated. It is even possible to use a third predetermined torque for a third connected position and so on.
  • using a predetermined force or torque to establish the connected positions for the leak-free sealed chamber provides reproducible sealing of the microfluidic device 1 ; 1’ allowing experiments to be identically replicated by means of microfluidic device 1 ; 1’.
  • Figure 5 shows the method for operating a microfluidic device 1 ; 1’ as defined in the claims wherein, the method comprises the following steps: a) connecting the sealing member 9; 9’ to the base 3 from an unconnected position with the base to a connected position with the base providing a leak-free sealed chamber 5 configured for fluid flow by means of the fluid passages 11 of the sealing member and at least one fluid source outside the chamber (figure 5: A); b) preventing leakage of the sealed chamber 5 by displacing the sealing member 9; 9’ in the base from the connected position to at least a second connected position for maintaining the leak-free sealed chamber (figure 5: B).
  • At least one microfluidic component 7; 7’ is positioned in the chamber 5 before step a) (figure 5: A).
  • fluid can flow by means of the fluid passages of the sealing member between the microfluidic component in the chamber and the at least one fluid source outside the chamber.
  • - time may be monitored, and/or
  • leakage conditions can be monitored by visual inspection of the microfluidic device 1 ; 1’, or by monitoring mechanical pressure, electrical conductance between components, and/or heat transition. Basically all physical parameters can be used for monitoring leakage conditions which could help to do a real time monitoring of the clamping conditions. At least one sensor 17 of the microfluidic device can be used to monitor at least one of these physical parameters. It is also possible to use external sensors to monitor leakage conditions. Monitoring time and/or leakage conditions of the sealed chamber 5 may be parameters to be used for preventing leakage of the sealed chamber.
  • Step b) (figure 5: B) may be performed after:
  • a predetermined period of time for example a fixed time interval or a predetermined period of time is based on data of previous experiments; and/or - after detecting leakage conditions of the sealed chamber.
  • the sealing member 9; 9’ can be automatically or manually displaced from the connected position to the at least one second connected position, for example after fixed interval or a predetermined period of time and/or after detecting leakage conditions of the sealed chamber.
  • the sealing member 9; 9’ is configured for automatic displacement from the connected position to the at least one second connected position. For example, after detection of changes by the detector/camera (not shown) or the sensor 17, a signal can be provided by means of a controller (not shown) to an actuator or driver (not shown) of the microfluidic device for automatically displacing the sealing member 9; 9’ from the connected position to the at least one second connected position for maintaining the leak-free sealed chamber 5.
  • one of the microfluidic components 7; 7’ is releasably connected to a bottom side of the sealing member 9; 9’.
  • the microfluidic component 7 is releasably connected to the sealing member 9; 9’, in particular the bottom side 10b of the sealing member 9; 9’, by using an alignment tool (not shown).
  • the microfluidic component 7 may be made from a sticky material, for example PDMS, for providing the releasable connection with the bottom side 10b.
  • the sealing member 9; 9’, the microfluidic components 7; 7’ and the coverslip 14 are each provided with at least two circumferential alignment cut-outs 9c, 7c; 7’c, 14c cooperating with alignment members (not shown) of an alignment tool for aligning the sealing member 9; 9’, the microfluidic components 7; 7’ and the coverslip 14 with respect for each other.
  • the two circumferential alignment cut-outs 9c, 7c; 7’c, 14c are diametrically opposed on the sealing member 9; 9’, the microfluidic components 7; 7’ or the coverslip 14.
  • the alignment tool has an alignment tool base and upwards protruding alignment members to be positioned in the cut-outs 9c, 7c; 7’c, 14c without play.
  • the alignment tool base is positioned on the side of the coverslip 14 facing away from the microfluidic component 7’. After using the alignment tool the sealing member 9; 9’, the microfluidic components 7; 7’ and the coverslip 14 are aligned. Without alignment tool the sealing member 9; 9’, the microfluidic components 7; 7’ and the coverslip 14 are connected in one single operation to the base 3 from an unconnected position with the base 3 to a connected position with the base 3 providing the leak- free sealed chamber 5, i.e. step a) (figure 5: A) of the method of this disclosure.
  • the microfluidic device is not transparent or translucent, but made from opaque material which may be important for light sensitive cells or medium compounds used in the experiment.

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Abstract

The invention relates to a method for operating a microfluidic device comprising a base provided with a chamber configured to receive at least one microfluidic component, and a sealing member provided with fluid passages configured to communicate with the chamber. The invention further relates to a microfluidic device provided with a base provided with a chamber configured to receive at least one microfluidic component, and a sealing member provided with fluid passages configured to communicate with the chamber, wherein the sealing member is connectable to the base from an unconnected position with the base to a connected position with the base providing a leak-free sealed chamber configured for fluid flow by means of the fluid passages of the sealing member and at least one fluid source outside the chamber. The invention also relates to bioreactor system.

Description

Title: A method for operating a microfluidic device, a microfluidic device and a bioreactor system
Description:
The invention relates to a method for operating a microfluidic device comprising a base provided with a chamber configured to receive at least one microfluidic component, and a sealing member provided with fluid passages configured to communicate with the chamber.
The invention further relates to a microfluidic device provided with a base provided with a chamber configured to receive at least one microfluidic component, and a sealing member provided with fluid passages configured to communicate with the chamber, wherein the sealing member is connectable to the base from an unconnected position with the base to a connected position with the base providing a leak-free sealed chamber configured for fluid flow by means of the fluid passages of the sealing member and at least one fluid source outside the chamber.
The invention also relates to bioreactor system.
US2018/0273888 discloses a microfluidic device and a method for operating the microfluidic device. The microfluidic device comprises a base provided with a chamber configured to receive at least one microfluidic component, and a sealing member provided with fluid passages configured to communicate with the chamber. The sealing member is connectable to the base from an unconnected position with the base to a connected position with the base to provide a seal for the chamber, and vice versa. The sealing member of the known microfluidic device includes a threaded stem and a top portion with a larger diameter than the stem. Threaded stem is sized to be inserted into the chamber of the base and to interact with a threaded portion in the chamber to removably couple sealing member to base. Top portion is designed such that it cannot be inserted into the chamber. After contact between the top portion and a top side of the base, the sealing member provides a leak-free sealed chamber. This known microfluidic device can fail due to leakage and one of the main causes is the gradual decrease of the device’s bonding strength throughout culture. For example, it is not unusual that the microfluidic component will permanently or plastically deform throughout the experiment. The problem is aggravated by the lack of countermeasures to stop leakages from occurring.
It is an object of the present invention to provide an improved method for operating a microfluidic device.
This object is achieved by the method as defined in claim 1.
The method for operating a microfluidic device comprising a base provided with a chamber configured to receive at least one microfluidic component, and a sealing member provided with fluid passages configured to communicate with the chamber, the method comprises the following steps: a) connecting the sealing member to the base from an unconnected position with the base to a connected position with the base providing a leak-free sealed chamber configured for fluid flow by means of the fluid passages of the sealing member and at least one fluid source outside the chamber; b) preventing leakage of the sealed chamber by displacing the sealing member in the base from the connected position to at least a second connected position for maintaining the leak-free sealed chamber.
The method uses the countermeasure displacement of the sealing member to prevent leakage of the sealed chamber in use of the microfluidic device. In this disclosure preventing leakage also includes reducing or minimizing leakage. Due to processes in the sealed chamber during an experiment the conditions in the sealed chamber will change. For example, in these experiments the at least one microfluidic component provided in the chamber of the microfluidic device is in fluid communication with the fluid passages of the sealing member such that a fluid can be provided between the least one microfluidic component in the chamber and a fluid source outside the chamber or outside the microfluidic device. As a result of changing conditions in the chamber during the experiment the risk for leakages may increase. It is for example not uncommon, that the microfluidic component undergoes permanent deformation (creep) during an experiment. Such a deformation increases the risk for leakages. For preventing leakage, it is according to this disclosure possible to displace the sealing member in the base from the connected position to at least a second connected position to minimize or prevent the leakage before becoming detrimental to the success of the experiment. Hence, due to the displaceable sealing member, the microfluidic device can be re-tightened during experimentation to compensate for any gradual loss of sealing strength (likely caused by material change or failure), hence avoiding the formation of leak spots and eventual leakage throughout the culture time. Therefore, the method as disclosed in this disclosure has the potential to increase the success rates of cultures under flow, in particular long-term cultures under flow. Moreover, the method of this disclosure adds an extra safety level, in which leakages of possible harmful components can be prevented and contained inside the microfluidic device.
For performing experiments in the microfluidic device at least one microfluidic component may be positioned in the chamber before step a). After providing the leak- free sealed chamber, fluid can flow by means of the fluid passages of the sealing member between the microfluidic component in the chamber and the at least one fluid source outside the chamber. The microfluidic component may include one or more microfluidic channels on a surface thereof and at least one tissue culture chamber configured to house a tissue culture, wherein tissue culture chamber is coupled to at least one of the one or more microfluidic channels. The one or more microfluidic channels and the tissue culture chamber can be positioned in fluid communication with the at least one fluid source outside the chamber through the fluid passages of the sealing member to form a fluid circuit.
In certain aspects, between step a) and b):
- time is monitored, and/or
- leakage conditions of the sealed chamber are monitored, such as monitoring by visual inspection of the microfluidic device and/or by at least one sensor of the microfluidic device.
Monitoring time and/or leakage conditions of the sealed chamber may be parameters to be used for preventing leakage of the sealed chamber. Leakage conditions may be visually monitored from the outside of the microfluidic device. For example visually observed by an operator or by using visual inspection by detector/camera. Monitoring leakage conditions can also include monitoring mechanical pressure, electrical conductance between components, and/or heat transition. Basically all physical parameters can be used for monitoring leakage conditions which could help to do a real time monitoring of the clamping conditions. A sensor can be used to monitor these physical parameters. In addition or alternatively, leakage conditions may be monitored by the microfluidic device itself by at least one sensor in the microfluidic device, in particular in the sealed chamber. Such a sensor may also be communicating or connected with at least one interface, for example the interface comprises an indicator to alarm operators.
In certain aspects, step b) is performed after:
- a predetermined period of time, for example a predetermined period of time is based on data of previous experiments; and/or
- after detecting leakage conditions of the sealed chamber.
The predetermined period of time may be a fixed time interval or based on at least a number of known parameters of the experiment or data from previous experiments, such that for preventing leakage the sealing member is displaced in the base after the predetermined period of time from the connected position to the at least one second connected position for maintaining the leak-free sealed chamber. In addition or alternatively, detection of leakage conditions of the sealed chamber may trigger step b).
In certain aspects, the sealing member is a threaded cap connectable to a threaded section of the base, wherein the sealing member is configured for cooperation with a rotatable driver for rotating the threaded cap around its center line with a predetermined torque for displacement from the connected position to the at least second connected position. The top part of the threaded cap may be shaped to mate with the rotatable driver, for example the top part of the threaded cap may be shaped with a hexagonal outline that mates with a hex socket or hex bit of the rotatable driver. Using a predetermined torque for connecting the threaded cap to the base for providing a leak-free sealed chamber (step a) of the method) has the advantage that the start of the experiment is reproducible. In addition, using a second predetermined torque to displace the sealing member in the base from the connected position to at least a second connected position for maintaining the leak-free sealed chamber (step b) of the method) allows the experiment to be replicated. It is even possible to use a third predetermined torque if a third connected position is required in use of the microfluidic device and so on. The inventors have found out that the higher the torque of the driver, the stronger the sealing. It has been demonstrated that the sealing strength can be externally tuned during the experiment by simply adjusting the torque by means of a driver, like for example a common screw driver. By using various torques the microfluidic device can be kept leak-free during flow conditions and/or to compensate for gradual decrease of the sealing strength.
In certain aspects, before positioning the microfluidic component in the chamber, the microfluidic component is releasably connected to a bottom side of the sealing member, preferably the microfluidic component is releasably connected to the sealing member by using an alignment tool. In one aspect, the microfluidic component may be made from a sticky material, for example PDMS, for providing the releasable connection with the sealing member. The sealing member and the at least one microfluidic component may be provided with circumferential alignment cut-outs cooperating with alignment members of an alignment tool for aligning the sealing member and the at least one microfluidic component with respect for each other. After using the alignment tool for alignment, the sealing member and the microfluidic component are aligned and without alignment tool the sealing member with the aligned microfluidic component is connected to the base from an unconnected position with the base to a connected position with the base providing the leak-free sealed chamber, i.e. step a) of the method of this disclosure.
In the method, the sealing member can be automatically or manually displaced from the connected position to the at least one second connected position, for example after detecting leakage conditions of the sealed chamber or after a predetermined period of time. In this disclosure, automatically displaced means displacement without interference of an operator, whereas manually displaced requires an operation of the operator, such as for example by hand or by operating the rotatable driver as mentioned above. After visually observing leakage conditions of the sealed chamber, the operator may use the rotatable driver for manually displacing the sealing member from the connected position to the at least one second connected position. When using a detector or a camera for visually observing leakage conditions of the sealed chamber for example together with image analysis software to detect changes in the leakage conditions, it is possible after detection of changes to provide an observable instruction to an operator to manually displace the sealing member. Alternatively, after detection of changes by the detector/camera, a signal can be provided to an actuator or driver of the microfluidic device for automatically displacing the sealing member from the connected position to the at least one second connected position for maintaining the leak-free sealed chamber. The at least one sensor may also provide an observable instruction to an operator to displace the sealing member, or the sensor may also provide the signal to an actuator or driver of the microfluidic device for automatically displacing the sealing member.
It is a further object of the present invention to provide an improved microfluidic device.
This object is achieved by the independent microfluidic device claim.
The microfluidic device comprises:
- a base provided with a chamber configured to receive at least one microfluidic component,
- a sealing member provided with fluid passages configured to communicate with the chamber, wherein the sealing member is connectable to the base from an unconnected position with the base to a connected position with the base providing a leak-free sealed chamber configured for fluid flow by means of the fluid passages of the sealing member and at least one fluid source outside the chamber,
- the microfluidic device is configured for preventing leakage of the sealed chamber, in that the sealing member is adapted to displace from the connected position to at least a second connected position for maintaining the leak-free sealed chamber.
In use of the microfluidic device, the conditions in the chamber of the microfluidic device change. These changing conditions may increase the risk for leakages. For preventing leakage of the sealed chamber during use of the microfluidic device, the sealing member is displaced in the microfluidic device of this disclosure from the connected position to at least a second connected position to maintain the leak-free sealed chamber. Hence, due to the displaceable sealing member, the microfluidic device can be re-tightened during experimentation to compensate for any gradual loss of sealing strength (likely caused by material change or failure), hence avoiding the formation of leak spots and eventual leakage throughout the culture time. Therefore, the microfluidic device as disclosed in this disclosure has the potential to increase the success rates of cultures under flow, in particular the success rates of long-term cultures under flow. Moreover, the microfluidic device adds an extra safety level, in which leakages of possible harmful components can be prevented and contained inside the microfluidic device.
In certain aspects, the microfluidic device is at least partly made from transparent or translucent material for visually monitoring leakage conditions of the sealed chamber to prevent leakage of the sealed chamber. By means of the transparent or translucent material, it is possible to observe visually any changes with respect to the sealed chamber and/or the sealing element and/or the microfluidic component. An operator may visually observe such a change in the leakage conditions and manually displace the sealing member to the at least one second connected position for maintaining the leak-free chamber. It is also possible to use a detector/camera together with for example image analysis software to detect such a change in the leakage conditions.
The microfluidic device may comprise at least one sensor configured for monitoring leakage conditions of the sealed chamber to prevent leakage of the sealed chamber. By using such a sensor, the risk of a human mistake can be reduced or even excluded.
In certain aspects, the sealing member is configured for automatic displacement from the connected position to the at least one second connected position, for example after a predetermined period of time and/or after detecting leakage conditions of the sealed chamber. The sensor or a detector/camera may provide a signal for example by means of a controller to an actuator or driver of the microfluidic device for automatically displacing the sealing member from the connected position to the at least one second connected position for maintaining the leak-free sealed chamber.
In certain aspects, the sealing member is configured for manual displacement from the connected position to the at least one second connected position, for example after a predetermined period of time and/or after detecting leakage conditions of the sealed chamber. The sensors or the detector/camera may also provide an observable instruction to an operator to displace the sealing member as already discussed.
In certain aspects, the sealing member is a threaded cap connectable to a threaded section of the base, wherein the threaded cap is configured for cooperation with a rotatable driver for rotating the threaded cap around its center line with a predetermined torque for displacement from the connected position to the at least second connected position. The threaded cap has a top side which is provided with a coupling member adapted to be coupled with the driver. In this manner, the threaded cap can be displaced from the connected position to at least a second connected position for maintaining the leak-free sealed chamber in an easy and user-friendly manner.
The invention further relates to a bioreactor system comprising a microfluidic device of this disclosure, at least one microfluidic component which is positioned in a chamber of the microfluidic device and at least one fluid source outside the chamber of the microfluidic device, such that in the bioreactor system fluid can flow by means of the fluid passages of the sealing member between the microfluidic component in the chamber and the at least one fluid source outside the chamber.
The present invention will be explained in more detail below with reference to the appended figures showing an exemplary embodiment of a microfluidic device.
Figure 1 shows an exploded view of the microfluidic device,
Figure 2a, b show a top view and cross section of the microfluidic device shown in figure 1 ;
Figure 3 shows a perspective view of the microfluidic device shown in figures 1 and 2a, b in a closed position;
Figure 4 shows a perspective view of another embodiment of a microfluidic device in a closed position;
Figure 5 shows a flow chart of the method as disclosed herein.
Like parts are indicated by the same reference signs in the various figures. Each feature disclosed with reference to the figure can also be combined with another feature disclosed in this disclosure including the claims, unless it is evident for a person skilled in the art that these features are incompatible.
Figures 1-3 show a microfluidic device 1 comprising:
- a base 3 provided with a chamber 5 configured to receive at least one microfluidic component 7, i.e. in the embodiment shown two microfluidic components 7, 7’, - a sealing member 9 provided with fluid passages 11 configured to communicate with the chamber 5, wherein the sealing member 9 is connectable to the base 3 from an unconnected position (figures 1 and 2b) with the base 3 to a connected position (figures 2a and 3) with the base 3 providing a leak-free sealed chamber 5 configured for fluid flow by means of the fluid passages 11 of the sealing member 9 and at least one fluid source (not shown) outside the chamber 5.
The base 3 comprises a base ring 3a and a base bottom 3b, wherein the base bottom 3b is attached to the base ring 3a for example by fasteners (not shown). It is also possible to manufacture the base 3 in one-piece (not shown), i.e. a base 3 made in a single undivided piece. The inner wall of the base ring 3a is provided with a threaded section 2. The threaded section 2 extends between the top side 4a and the bottom side 4b of the base ring 3a. It is possible that threaded section only covers a portion of the inner wall of the base ring 3a (not shown). The inner wall of the base ring 3a defines the maximum dimensions of the chamber 5. The inner wall of the base ring 3a, the base bottom 3b and the bottom side 10b of the sealing member 9 define a sealed chamber 5.
For performing experiments in the microfluidic device 1 , microfluidic components 7, 7’ are positioned in the chamber 5. After providing the leak-free sealed chamber (figure 2a and 3), fluid can flow by means of the fluid passages 11 of the sealing member 9 between the microfluidic component 7, 7’ in the chamber 5 and the at least one fluid source (not shown) outside the chamber.
A bioreactor system (not completely shown in the figures) comprises the microfluidic device 1 , at least one microfluidic component 7, 7’ which is positioned in a chamber 5 of the microfluidic device 1 and at least one fluid source (not shown) outside the chamber of the microfluidic device.
The microfluidic components 7, 7’ comprise a number of microfluidic channels 7a, 7’a on a surface thereof and at least one tissue culture chamber 7b, 7’b configured to house a tissue culture, wherein tissue culture chamber 7b, 7’b is coupled to the microfluidic channels 7a, 7’a. The microfluidic channels 7a, 7’a and the tissue culture chamber 7b, 7’b are positioned in fluid communication in use of the microfluidic device 1 with the at least one fluid source (not shown) outside the device 1 through the fluid passages 11 of the sealing member 9 to form a fluid circuit. Different configurations of the microfluidic component 7a, 7’a than shown in the figures are possible. The microfluidic device 1 further comprises a coverslip 14. The coverslip 14 provides a low-friction contact with the base bottom 3b. Such a low-friction contact provided by the coverslip 14 facilitates rotating the sealing member 9 with the microfluidic components 7, 7’ with respect to the base 3, in particular the base bottom 3b.
The sealing member 9 is reversibly connected with the base 3, i.e. the chamber 5 can be sealed by reversibly coupling the sealing member 9 to the base 3. The microfluidic device 1 , T (see figure 4: T) is configured for preventing leakage of the sealed chamber 5 in use, in that the sealing member 9; 9’ is adapted to displace from the connected position with the base 3 providing the leak-free sealed chamber 5 to at least a second connected position for maintaining the leak-free sealed chamber. The distance measured in the direction of the center line of the microfluidic device 1 ; T between the first connected position and the second connected position may vary between 0,01 mm and 10 mm, preferably between 0, 1 mm and 5 mm.
The microfluidic device 1,1’ is at least partly made from translucent or transparent material for visually monitoring leakage conditions of the sealed chamber 5, wherein upon detection of leakage conditions of the sealed chamber 5, the sealing member 9; 9’ is displaced from the connected position to the at least one second connected position for maintaining the leak-free sealed chamber 5. In addition, the microfluidic device 1 comprises at least one sensor 17 configured for monitoring leakage conditions of the sealed chamber 5, wherein upon detection of leakage conditions of the sealed chamber 5 the sealing member 9 is displaced from the connected position to the at least one second connected position for maintaining the leak-free sealed chamber. Different positions for the sensor 17 than the position shown in figure 1 in the microfluidic device 1 are possible. Further, it is possible to provide multiple sensors (not shown) in a microfluidic device of this disclosure.
The sealing member 9; 9’ is configured for manual displacement from the connected position to the at least one second connected position, for example after detection of leakage conditions of the sealed chamber or after a predetermined period of time. Manual displacement can be performed by hand or by an operator using a tool such as a rotatable driver to be discussed below. By means of the sensor 17 or by means of a detector/camera (not shown) an observable instruction to an operator may be provided to manually displace the sealing member 9; 9’. The sealing member is in the exemplary embodiment shown a threaded cap 9; 9’ which is connectable to a threaded section 2 of the base 3. The maximum diameter of the threaded cap 9; 9’ is provided by the threads 12 of the threaded cap 9; 9’ which substantially equals the inner diameter of the chamber 5 defined by the inner walls of the base ring 3a. The threaded cap 9; 9’ is configured for cooperation with a rotatable driver (not shown) for rotating the threaded cap 9; 9’ around its center line with a predetermined torque. The threaded cap 9; 9’ has a top side 10a; 10a’ which is provided with a coupling member 13; 13’ adapted to be coupled with for example a tool (driver) used to apply a specific torque to a fastener. In other words, the top part of the threaded cap, i.e. the coupling member 13; 13’, is shaped to mate with the rotatable driver. The threaded cap 9; 9’ has fluid passages 11 ; 11’ extending through the cap 9; 9’, including the coupling member 13; 13’, to the bottom side 10b of the cap 9; 9’. By means of the coupling member 13; 13’, the threaded cap 9; 9’ can be rotated in an easy, user-friendly and predefined manner. In figures 1-3 the top part of the threaded cap 9 is shaped with a hexagonal outline that mates with a hex socket. Hence, the hexagonal screw cap 9 can interface with a hex bit socket (not shown). The microfluidic device T shown in figure 4 is identical to the microfluidic device 1 shown in figures 1-3, with the exception that the threaded cap 9’ does not have hexagonal coupling member 13, but a dodecagon coupling member 13’. Any shape adapted to provide a predetermined torque in an user-friendly manner and providing a (fast) coupling with a rotatable driver can be chosen for the coupling member 13; 13’. Instead of a coupling member 13; 13’ protruding with respect to the top side 10a; 10a’, it is also possible to provide a recessed coupling member (not shown) in the top side, for example a hexagonal recess (not shown). Using a predetermined torque for connecting the threaded cap to the base for providing a leak-free sealed chamber has the advantage that the start of the experiment to be performed with the microfluidic device 1 , T is reproducible. In addition, using a second predetermined torque to displace the threaded cap 9; 9’ in the base 3 from the (first) connected position to the at least second connected position for maintaining the leak-free sealed chamber allows the experiment to be replicated. It is even possible to use a third predetermined torque for a third connected position and so on. In other words, using a predetermined force or torque to establish the connected positions for the leak-free sealed chamber provides reproducible sealing of the microfluidic device 1 ; 1’ allowing experiments to be identically replicated by means of microfluidic device 1 ; 1’.
Figure 5 shows the method for operating a microfluidic device 1 ; 1’ as defined in the claims wherein, the method comprises the following steps: a) connecting the sealing member 9; 9’ to the base 3 from an unconnected position with the base to a connected position with the base providing a leak-free sealed chamber 5 configured for fluid flow by means of the fluid passages 11 of the sealing member and at least one fluid source outside the chamber (figure 5: A); b) preventing leakage of the sealed chamber 5 by displacing the sealing member 9; 9’ in the base from the connected position to at least a second connected position for maintaining the leak-free sealed chamber (figure 5: B).
For the sake of brevity, reference is made to the advantages of the method mentioned above, such that these advantages are not repeated here.
For performing experiments in the microfluidic device 1 ; 1’ at least one microfluidic component 7; 7’ is positioned in the chamber 5 before step a) (figure 5: A). After providing the leak-free sealed chamber, fluid can flow by means of the fluid passages of the sealing member between the microfluidic component in the chamber and the at least one fluid source outside the chamber.
Between step a) (figure 5: A) and b) (figure 5: B):
- time may be monitored, and/or
- leakage conditions of the sealed chamber may be monitored.
For example, leakage conditions can be monitored by visual inspection of the microfluidic device 1 ; 1’, or by monitoring mechanical pressure, electrical conductance between components, and/or heat transition. Basically all physical parameters can be used for monitoring leakage conditions which could help to do a real time monitoring of the clamping conditions. At least one sensor 17 of the microfluidic device can be used to monitor at least one of these physical parameters. It is also possible to use external sensors to monitor leakage conditions. Monitoring time and/or leakage conditions of the sealed chamber 5 may be parameters to be used for preventing leakage of the sealed chamber.
Step b) (figure 5: B) may be performed after:
- a predetermined period of time, for example a fixed time interval or a predetermined period of time is based on data of previous experiments; and/or - after detecting leakage conditions of the sealed chamber.
In the method, the sealing member 9; 9’ can be automatically or manually displaced from the connected position to the at least one second connected position, for example after fixed interval or a predetermined period of time and/or after detecting leakage conditions of the sealed chamber.
The sealing member 9; 9’ is configured for automatic displacement from the connected position to the at least one second connected position. For example, after detection of changes by the detector/camera (not shown) or the sensor 17, a signal can be provided by means of a controller (not shown) to an actuator or driver (not shown) of the microfluidic device for automatically displacing the sealing member 9; 9’ from the connected position to the at least one second connected position for maintaining the leak-free sealed chamber 5.
Before positioning the microfluidic component 7; 7’ in the chamber 5, i.e. before step a (figure 5: A), one of the microfluidic components 7; 7’ is releasably connected to a bottom side of the sealing member 9; 9’. The microfluidic component 7 is releasably connected to the sealing member 9; 9’, in particular the bottom side 10b of the sealing member 9; 9’, by using an alignment tool (not shown). The microfluidic component 7 may be made from a sticky material, for example PDMS, for providing the releasable connection with the bottom side 10b.
The sealing member 9; 9’, the microfluidic components 7; 7’ and the coverslip 14 are each provided with at least two circumferential alignment cut-outs 9c, 7c; 7’c, 14c cooperating with alignment members (not shown) of an alignment tool for aligning the sealing member 9; 9’, the microfluidic components 7; 7’ and the coverslip 14 with respect for each other. The two circumferential alignment cut-outs 9c, 7c; 7’c, 14c are diametrically opposed on the sealing member 9; 9’, the microfluidic components 7; 7’ or the coverslip 14. The alignment tool has an alignment tool base and upwards protruding alignment members to be positioned in the cut-outs 9c, 7c; 7’c, 14c without play. The alignment tool base is positioned on the side of the coverslip 14 facing away from the microfluidic component 7’. After using the alignment tool the sealing member 9; 9’, the microfluidic components 7; 7’ and the coverslip 14 are aligned. Without alignment tool the sealing member 9; 9’, the microfluidic components 7; 7’ and the coverslip 14 are connected in one single operation to the base 3 from an unconnected position with the base 3 to a connected position with the base 3 providing the leak- free sealed chamber 5, i.e. step a) (figure 5: A) of the method of this disclosure.
In alternative embodiment, the microfluidic device is not transparent or translucent, but made from opaque material which may be important for light sensitive cells or medium compounds used in the experiment.

Claims

1. A method for operating a microfluidic device comprising a base provided with a chamber configured to receive at least one microfluidic component, and a sealing member provided with fluid passages configured to communicate with the chamber, the method comprises the following steps: a) connecting the sealing member to the base from an unconnected position with the base to a connected position with the base providing a leak-free sealed chamber configured for fluid flow by means of the fluid passages of the sealing member and at least one fluid source outside the chamber; b) preventing leakage of the sealed chamber by displacing the sealing member in the base from the connected position to at least a second connected position for maintaining the leak-free sealed chamber.
2. The method according to claim 1 , wherein before step a) at least one microfluidic component is positioned in the chamber such that after providing the leak- free sealed chamber fluid can flow by means of the fluid passages of the sealing member between the microfluidic component in the chamber and the at least one fluid source outside the chamber.
3. The method according to claim 1 or 2, wherein between step a) and b):
- time is monitored, and/or
- leakage conditions of the sealed chamber are monitored, such as monitoring by visual inspection of the microfluidic device and/or by at least one sensor of the microfluidic device.
4. The method according to claim 3, wherein step b) is performed after:
- a predetermined period of time, for example a predetermined period of time is based on data of previous experiments; and/or
- after detection of leakage conditions of the sealed chamber.
5. The method according to any of the preceding claims, wherein the sealing member is a threaded cap connectable to a threaded section of the base, wherein the threaded cap is configured for cooperation with a rotatable driver for rotating the threaded cap around its center line with a predetermined torque for displacement from the connected position to the at least second connected position.
6. The method according to claim 2, wherein before positioning the microfluidic component in the chamber, the microfluidic component is releasably connected to a bottom side of the sealing member, preferably the microfluidic component is releasably connected to the sealing member by using an alignment tool.
7. The method according to any of the preceding claims, wherein the sealing member is manually or automatically displaced from the connected position to the at least one second connected position, for example after detecting leakage conditions of the sealed chamber or after a predetermined period of time.
8. A microfluidic device comprising:
- a base provided with a chamber configured to receive at least one microfluidic component,
- a sealing member provided with fluid passages configured to communicate with the chamber, wherein the sealing member is connectable to the base from an unconnected position with the base to a connected position with the base providing a leak-free sealed chamber configured for fluid flow by means of the fluid passages of the sealing member and at least one fluid source outside the chamber,
- the microfluidic device is configured for preventing leakage of the sealed chamber, in that the sealing member is adapted to displace from the connected position to at least a second connected position for maintaining the leak-free sealed chamber.
9. The microfluidic device according to claim 8, wherein the microfluidic device is at least partly made from transparent or translucent material for visually monitoring leakage conditions of the sealed chamber, wherein upon detection of leakage conditions of the sealed chamber the sealing member is displaced from the connected position to the at least one second connected position for maintaining the leak-free sealed chamber.
10. The microfluidic device according to claim 8 or 9, wherein the microfluidic device comprises at least one sensor configured for monitoring leakage conditions of the sealed chamber, wherein upon detection of leakage conditions of the sealed chamber the sealing member is displaced from the connected position to the at least one second connected position for maintaining the leak-free sealed chamber.
11. The microfluidic device according to any of the preceding claims 8-10, wherein the sealing member is configured for automatic displacement from the connected position to the at least one second connected position, for example after a predetermined period of time and/or after detecting leakage conditions of the sealed chamber.
12. The microfluidic device according to any of the preceding claims 8-10, wherein the sealing member is configured for manual displacement from the connected position to the at least one second connected position, for example after a predetermined period of time and/or after detecting leakage conditions of the sealed chamber.
13. The microfluidic device according to any of the preceding claims 8-12, wherein the sealing member is a threaded cap connectable to a threaded section of the base, wherein threaded cap is configured for cooperation with a rotatable driver for rotating the threaded cap around its center line with a predetermined torque for displacement from the connected position to the at least second connected position.
14. The microfluidic device according to claim 13, wherein the threaded cap has a top side which is provided with a coupling member adapted to be coupled with the rotatable driver, for example a tool used to apply a specific torque to a fastener.
15. A bioreactor system comprising a microfluidic device according to any of the preceding claims 8-14, at least one microfluidic component which is positioned in a chamber of the microfluidic device and at least one fluid source outside the chamber of the microfluidic device, such that in the bioreactor system fluid can flow by means of the fluid passages of the sealing member between the microfluidic component in the chamber and the at least one fluid source outside the chamber.
PCT/EP2023/080919 2022-11-21 2023-11-07 A method for operating a microfluidic device, a microfluidic device and a bioreactor system Ceased WO2024110183A1 (en)

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WO2014053678A1 (en) * 2012-10-04 2014-04-10 Universidad De Zaragoza Device and method for encapsulating microfluidic systems
WO2017059436A1 (en) * 2015-10-01 2017-04-06 Cornell University Microfluidic body-on-a-chip device and methods of use thereof
WO2019191685A1 (en) * 2018-03-30 2019-10-03 Arizona Board Of Regents On Behalf Of The University Of Arizona Workstation for automated control of an in vitro system
WO2020037398A1 (en) * 2018-08-23 2020-02-27 Interface Fluidics Ltd. Holder for a microfluidic chip

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014053678A1 (en) * 2012-10-04 2014-04-10 Universidad De Zaragoza Device and method for encapsulating microfluidic systems
WO2017059436A1 (en) * 2015-10-01 2017-04-06 Cornell University Microfluidic body-on-a-chip device and methods of use thereof
US20180273888A1 (en) 2015-10-01 2018-09-27 Cornell University Microfluidic body-on-a-chip device and methods of use thereof
WO2019191685A1 (en) * 2018-03-30 2019-10-03 Arizona Board Of Regents On Behalf Of The University Of Arizona Workstation for automated control of an in vitro system
WO2020037398A1 (en) * 2018-08-23 2020-02-27 Interface Fluidics Ltd. Holder for a microfluidic chip

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