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WO2025068732A1 - Dispositif d'interfaçage d'une biopuce et méthode de culture de cellules faisant appel au dispositif - Google Patents

Dispositif d'interfaçage d'une biopuce et méthode de culture de cellules faisant appel au dispositif Download PDF

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Publication number
WO2025068732A1
WO2025068732A1 PCT/IB2023/000568 IB2023000568W WO2025068732A1 WO 2025068732 A1 WO2025068732 A1 WO 2025068732A1 IB 2023000568 W IB2023000568 W IB 2023000568W WO 2025068732 A1 WO2025068732 A1 WO 2025068732A1
Authority
WO
WIPO (PCT)
Prior art keywords
biochip
segment
channel
ducts
channel support
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.)
Pending
Application number
PCT/IB2023/000568
Other languages
English (en)
Inventor
Rachid Jellali
Eric Leclerc
Cécile LEGALLAIS
Patrick Paullier
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.)
Centre National de la Recherche Scientifique CNRS
Universite de Technologie de Compiegne UTC
Original Assignee
Centre National de la Recherche Scientifique CNRS
Universite de Technologie de Compiegne UTC
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 Centre National de la Recherche Scientifique CNRS, Universite de Technologie de Compiegne UTC filed Critical Centre National de la Recherche Scientifique CNRS
Priority to PCT/IB2023/000568 priority Critical patent/WO2025068732A1/fr
Publication of WO2025068732A1 publication Critical patent/WO2025068732A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/02—Form or structure of the vessel
    • C12M23/16—Microfluidic devices; Capillary tubes
    • 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
    • B01L3/02—Burettes; Pipettes
    • B01L3/0289—Apparatus for withdrawing or distributing predetermined quantities of fluid
    • B01L3/0293—Apparatus for withdrawing or distributing predetermined quantities of fluid for liquids
    • 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
    • B01L3/56—Labware specially adapted for transferring fluids
    • B01L3/563—Joints or fittings ; Separable fluid transfer means to transfer fluids between at least two containers, e.g. connectors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/02—Form or structure of the vessel
    • C12M23/12—Well or multiwell plates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/40—Manifolds; Distribution pieces
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/58—Reaction vessels connected in series or in parallel
    • 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
    • B01L2200/0684—Venting, avoiding backpressure, avoid gas bubbles
    • 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
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0829—Multi-well plates; Microtitration plates
    • 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
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0877—Flow chambers
    • 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 present invention relates to a device for interfacing a biochip.
  • Bioreactors reproduce an environment favorable to the development and organization of cells, close to that of a tissue or an animal or human organ. Thanks to them, one can predict the reaction of an organ to a substance such as a xenobiotic, a cosmetic, a drug or more generally any active principle, and develop relevant in vitro models. These models are increasingly used in pharmaceutical research as they represent a serious alternative to in vivo models, z.e., animal experimentation, against which both economic and ethical pressures are emerging at the international level. Cell culture also represents the basis for the creation of artificial organs capable of replacing failing or absent organs, one of the challenges of tissue engineering.
  • the bioreactors used in dynamic cell culture include at both ends of a culture chamber a fluid inlet and a fluid outlet to allow the passage of a nutritive fluid necessary for the development of cells. Samples are generally taken during the whole cell culture process to monitor its good progress, and during the use of the cells for toxicological studies to determine the metabolic response of the cells to the tested substance, or to observe the kinetics of reaction of the cells. It would be desirable to be able to increase the cell culture surface as much as possible.
  • One solution for this is to use multi-bioreactors, z.e., parallel bioreactors.
  • Various cell culture systems have been proposed for this purpose. However, these known systems are not satisfactory.
  • connection ports reversibly fixed to an upper plate and a lower plate covering the top and the bottom of the wells.
  • the ports fixed to the lower plate allowing a direct connection to the bioreactor while the ports fixed to the upper plate allow a direct access to the wells without removing said plate.
  • the reversible fixation implies some possible leakage at the interface between the plate and the ports.
  • the upper plate, the lower plate and the wells are fixed together using screws. This fixation means implies an increase of manufacturing cost and may lead to the damage of one of the plates when tightening the screws.
  • the use of reversibly fixed ports also increases the manufacturing costs since holes need to be created in the plates in a way that they are complementary to the ports. Last, placing and removing the ports also implies an increase of complexity when using the system by a user.
  • a bubble trap is mandatory in order to avoid the formation of bubbles potentially very harmful to the developing cells when the bioreactors are connected to the perfusion circuit.
  • the presence of bubble traps lengthens the circuits, and increase the internal surface of the pipes. This surface is the seat of adsorption or degradation of the chemical substances in solution.
  • Such adsorption distorts the toxicology tests, because a xenobiotic injected at the beginning of the circuit would see its concentration drop, or even fall to zero before even meeting the cells in culture at the end of the circuit. The risk of false negative is thus not negligible.
  • risk of false negative is thus not negligible.
  • a purpose of this invention is to provide a device for interfacing at least one biochip.
  • a flow for fluidically supplying the biochip may be set via ducts of the device.
  • Each duct is composed of two channels, each channel forming a unitary element leading to a device with a low number of detachable elements.
  • This invention thus relates to a device for interfacing at least one biochip, said device comprising at least one set of ducts, each set of ducts comprising two ducts, each duct comprising a first channel and a second channel, each second channel comprising a biochip segment and a receiving segment, each of the biochip segment and the receiving segment having a section, the section of the biochip segment being smaller than the section of the receiving segment, the biochip segment being configured to be coupled to a biochip, each first channel presenting a first longitudinal axis, the first channels of each set of ducts being linked by a first channel support perpendicularly to said first longitudinal axis of each first channel thereby delimiting an inserting segment and a joining segment for each first channel, the joining segment being configured to allow fluidic communication, the first channel support abutting on the receiving segment of the second channel of each duct so that said inserting segment of each first channel is nested in the receiving segment of one of the second channels.
  • connection ports (the joining segment and biochip segment) which are intrinsically comprised in the device so that they are not reversibly fixed to the device. Therefore, there is no need of an upper plate and a lower plate covering the top and the bottom of the wells to reversibly fix the ports. There is thus no fixation means such as screws in the device.
  • the first channel has a section decreasing along the first longitudinal axis from the joining segment to the inserting segment.
  • the device further comprises a sealing element positioned between the receiving segments of the second channel and the first channel support.
  • the sealing element prevents leaks.
  • the said sealing element has a thickness ranging from 1 mm to 5 mm.
  • the second channel has a second longitudinal axis, the second channels of each of the at least one set of ducts being linked by a second channel support perpendicularly to said second longitudinal axis, the first channel support abutting on the second channel support.
  • the linking between the second channels leads to a device which is easier to use. Indeed, only two elements forms the device: the first channel support comprising the first channels and the second channel support comprising the second channels.
  • the device further comprises a clamping element configured to maintain the first channel support abutted on the second channel support.
  • the clamping element leads to a device which is easy to manipulate since the two supports are maintained together.
  • the clamping element is a lever vice configured to evenly distribute a pressure along the first channel support and the second channel support.
  • the clamping element is thus external to the device. Therefore, no screw is used which avoid damages when manufacturing the device. Moreover, the lever leads to an easy opening of the clamping element so that, for example, to open the device to clean it or to change the first and second channels.
  • the device comprises one set of ducts and forms an elementary module, the elementary module further comprising cooperating means configured to cooperate with cooperating means of at least another elementary module so as to fasten the two elementary modules.
  • the invention also relates to a system for culturing cells comprising at least one biochip interfaced with the device for interfacing at least one biochip hereabove, each biochip comprising an inlet and an outlet, said inlet and outlet of each biochip being coupled to the biochip segments of one set of ducts of the device.
  • the invention also relates to a method for culturing cells using the device for interfacing at least one biochip hereabove, the method comprising the steps of: a. Providing at least one biochip in which at least one cell to be cultured is deposited, each biochip comprising an inlet and an outlet, b. Interfacing said at least one biochip with the device so that said inlet and outlet of each biochip is coupled to the biochip segments of one set of ducts of the device, c. Positioning the device so that the biochip is below the biochip segments, d.
  • Biochip refers to any chip allowing for cell culture.
  • the biochip may be microfluidic or millifluidic.
  • the biochip may be a bioreactor, a reactor, a flow chamber, a perfused chamber, a perfused tissue culture polystyrene (TCPS) cell culture box, a dynamic cell culture system.
  • TCPS tissue culture polystyrene
  • Interfacing refers to allowing the communication between a biochip and a flowing system allowing to flow a liquid through the biochip.
  • “Nested” refers to the inclusion of a segment of a first channel of a duct into a segment of a second channel of the same duct. The section and the length of the nested segment are thus smaller than those of the nesting segment.
  • “Section of a segment” refers to the size of the surface of the segment perpendicular to its longitudinal axis.
  • Figure 1 shows second channels according to an embodiment.
  • Figure 2 shows first channels according to an embodiment.
  • Figure 3 shows a duct according to an embodiment.
  • Figure 4 shows a second channel support with an assembly of 24 second channels.
  • Figure 5 shows a first channel support with an assembly of 24 first channels.
  • Figure 6 is a side view on a system wherein a flow is set up.
  • Figure 7 shows a device comprising 12 set of ducts.
  • Figure 8 is an exploded view of the device.
  • Figure 9 is a top view of a complete system with an assembly of first channels, a sealing element and an assembly of second channels pressed by clamping elements.
  • FIG. 10 is a bottom view of the system of fig. 9.
  • the biochip segments of the second channels are engaged in inlets and outlets of biochips.
  • the invention relates to a device 100.
  • the device 100 is illustratively represented in figures 7 and 8 is architecturally composed as following: the device 100 comprises at least one set of ducts. Each set of ducts comprises two ducts 10. Each duct 10, represented in figure 3, comprises a first channel 20 also represented in figure 2 and a second channel 30 also represented in figure 1.
  • the invention also relates to a system 200 for culturing cells comprising the device 100 interfacing at least one biochip 80.
  • the device 100 allows to fluidically connect the biochip 80 with, for example, a fluid circuit or a sampling pipette.
  • the system 200 is illustratively represented in figures 6 and 10.
  • a device 100 comprising at least two set of ducts 10 (a multireactor) allows to parallelize the bioreactors to simulate, for example, a plurality of organs and the interactions between them.
  • the ducts 10 are preferably arranged in a 2:3 ratio matrix comprising 2 lines and 3 rows (or inversely 2 rows and 3 lines) of ducts 10 and their multiples such as 4 lines and 6 rows, 6 lines and 9 rows, 8 lines and 12 rows, etc.
  • the device 100 may comprise 6, 12, 24, 96 or 384 ducts 10.
  • a device 100 comprising 24 ducts 10 arranged in a 2:3 ratio matrix as represented in figure 7 may have a length ranging from 5 cm to 20 cm and a width ranging between 3 cm to 15 cm.
  • a duct 10 allows a fluid to flow from the entrance of the duct 10 (the first channel 20) to the exit of the duct 10 (the second channel 30).
  • Each channel (20, 30) comprises two segments (22, 24, 32, 34).
  • Each segment (22, 24, 32, 34) has, by definition, a longitudinal axis (25, 35) around which a wall extends.
  • Each segment (22, 24, 32, 34) has two open extremities transversal to the longitudinal axis (25, 35), preferably perpendicular to the longitudinal axis (25, 35).
  • the axes (25, 35) of the four segments (22, 24, 32, 34) of one duct 10 are preferably parallel so that the duct 10 formed by the succession of the four segments (22, 24, 32, 34) extends longitudinally in a straight direction.
  • the first channel 20 represented in figure 2 extends along a first longitudinal axis 25.
  • the first channels 20 of a set of ducts 10 are linked by a first channel support 27 perpendicularly to the first longitudinal axis 25 of each first channel 20.
  • the first channels 20 of the overall set of ducts 10 are linked together by the same first channel support 27 as represented in figure 5. Thanks to the first channel support 27, all the first channels 20 of the device 100 are thus comprised in a first united element.
  • the first channel support 27 delimits two parts of each first channel 20 on either side of the first channel support 27, therefore defining the two segments (22, 24) of this channel.
  • the part on one side of the first channel support 27 is defined as an inserting segment 24 whereas the part on the other side of the support 27 is defined as a joining segment 22 for each first channel 20. Since the first channel 20 extends along the first longitudinal axis 25, the longitudinal axes of joining segment 22 and inserting segment 24 are aligned, the two segments (22, 24) being successive.
  • the inserting segment 24 and the joining segment 22 are preferably in a cylindrical form so that they present a circular section perpendicular to the first longitudinal axis 25 and a cylindrical wall with an inner diameter and an outer diameter.
  • the inner diameter of the first channel 20 is ranging between 1 mm and 7 mm.
  • the joining segment 22 is configured to allow fluidic communication, for example, with the fluid circuit or the sampling pipette.
  • the joining segment 22 is suitable for luer lock connection.
  • the second channel 30 represented in figure 1, also known as a well, comprises two segments: a biochip segment 34 and a receiving segment 32.
  • Each of the biochip segment 34 and the receiving segment 32 extends along a longitudinal axis.
  • the biochip segments 34 of two ducts 10 of a set of ducts 10 allow to interface a biochip 80 with the device 100.
  • Each biochip 80 comprises an inlet and an outlet. Therefore, in the system 200, the inlet and outlet of each biochip 80 is coupled to the biochip segments 34 of one set of ducts 10 of the device 100.
  • the biochip segment 34 and the receiving segment 32 are preferably in a cylindrical form so that they present a circular section perpendicular to their longitudinal axis and a cylindrical wall with an inner diameter and an outer diameter.
  • the section of the biochip segment 34 is smaller than the section of the receiving segment 32.
  • one of the open extremities of the biochip segment 34 is included in the open extremity of the receiving segment 32, z.e., the open extremity of the biochip segment 34 is in the same plan as the open extremity of the receiving segment 32.
  • a part of the biochip segment 34 is received inside the receiving segment 32.
  • the longitudinal axes of the biochip segment 34 and the receiving segment 32 may be parallel.
  • the second channel 30 thus extends along a second longitudinal axis 35 parallel to the longitudinal axes of the biochip segment 34 and the receiving segment 32.
  • the volume of the receiving segment 32 is ranging between 0.5 mL and 8 mL, preferably ranging between 3 mL and 5 mL.
  • the receiving segment 32 may comprise a bottom surface 32’, preferably perpendicular to its longitudinal axis, at the extremity wherein the biochip segment 34 is disposed.
  • the bottom surface 32’ comprises an opening 32” in order to allow a fluidic connection towards the biochip segment 34.
  • the bottom surface 32’ may be flat so that cells may be cultured in the receiving segment 32.
  • the opening 32” may take the form of a channel comprising a wall which is nested/which extends inside the receiving segment 32 to avoid the cultured cells to pass through the opening 32”.
  • the bottom surface 32’ is curved to eliminate meniscus problems and edge effects.
  • the biochip segments 34 of the same set of ducts 10 are preferably positioned so that the distance between them corresponds to the distance between the inlet and the outlet of a biochip 80.
  • the distance between the biochip segments 34 of the same set of ducts 10 ranges from 10 mm to 40 mm, preferably between 20 mm and 30 mm.
  • the joining segment 22 and the biochip segment 34 preferably have an inner diameter of about 2 mm.
  • the second channels 30 of each of the at least one set of ducts 10 may be linked by a second channel support 37 perpendicular to the longitudinal axis of the receiving segment 32 (or the biochip segment 34) as shown in figure 4.
  • the second channel support 37 has a height corresponding to the height (or length) of the receiving segments 32 measured parallelly to its longitudinal axis.
  • the receiving segments 32 are embodied in the second channel support 37 and appear like holes in the support 37 as shown in figure 4. Thanks to the second channel support 37, the overall second channels 30 of the device 100 are comprised in a second united element.
  • the device 100 may thus advantageously be composed of only two elements: the first united element linking the first channels 20 and the second united element linking the second channels 30. Therefore, the installation of the device 100 is facilitated since the user just needs to bring the two united elements together.
  • the open extremity of the receiving segment 32 opposite to the biochip segment 34 is comprised in the second channel support 37.
  • the first channel support 27 abuts on the receiving segment 32 of the second channel 30 of each duct 10 so that said inserting segment 24 of each first channel 20 is nested in (inserted in or received inside) the receiving segment 32 of one of the second channels 30 as represented by transparence in figure 3.
  • the extremity of the receiving segment 32 opposite to the biochip segment 34 abuts against the first channel support 27.
  • the inserting segments 24 of the first channels 20 (which are thus all on the same side of the first channel support 27) are thus inserted inside the receiving segment 32 so that the wall of the receiving segment 32 surrounds the inserting segment 24.
  • the first channel support 27 is abutting towards the second channel support 37. Since the receiving segment 32 receives the inserting segment 24, the volume of fluid (z.e., the capacity) that can be deposited inside the receiving segment 32 is lower than the volume of the receiving segment 32 because of the volume (size) of the inserting segment 24 nested.
  • the section of the inserting segment 24 is smaller than the section of the receiving segment 32 so that the inserting segment 24 can be inserted (nested) inside the receiving segment 32.
  • the first channel 20 may have a section decreasing along the longitudinal axis from the joining segment 22 to the inserting segment 24. This allows to ease the insertion into the receiving segment 32. More specifically, the section of the exterior of the wall (the outer diameter) of the first channel 20 is decreasing whereas the interior or the wall (the inner diameter) of the first channel 20 has a section constant along the axis. This allows to take the advantage of the decreasing section without limiting the flow rate inside the first channel 20.
  • the length of the inserting segment 24 measured along the first longitudinal axis 25 is configured so that the whole length of the inserting segment 24 is nested inside the receiving segment 32 and the receiving segment 32 abuts towards the first channel support 27.
  • the length of the inserting segment 24 is smaller than the length of the receiving segment 32.
  • the length of the inserting segment 24 and the receiving segment 32 is ranging from 5 mm to 30 mm.
  • the first longitudinal axis 25 of the first channel 20 is aligned with the longitudinal axis of the receiving segment 32.
  • the device 100 From the top to the bottom of device 100, the top and the bottom being defined by the position of the device 100 in use as explained later, the device 100 thus presents, parallel to the first longitudinal axis 25, the joining segment 22, the first channel support 27, the receiving segment 32 nesting the inserting segment 24 aligned with the joining segment 22 and the biochip segment 34 as in figure 3.
  • the segments are oriented so that a drop of fluid inserted in the joining segment 22 at the top of the device 100 goes down to the biochip segment 34 at the bottom of the device 100 by gravity.
  • this orientation during the use of the device 100 is advantageous since, even if an air bubble is inserted through the joining segment 22, the Archimedes’ force will push it back to the top of the receiving segment 32. There is thus no need of bubble trap and the risk of false negative when analyzing the culture remains negligible. For the same reason, there is no necessity to purge the pipes during the initial filling.
  • the biochip 80 is first interfaced with the biochip segments 34 of one set of ducts 10 so that the biochip 80 is positioned below the biochip segment 34, z.e., below the bottom of the device 100 as represented in figure 6.
  • the device 100 comprises more than one set of ducts
  • the method comprises the step of setting a flow from the joining segment 22 of the first channel 20 of the duct 10 coupled to the inlet of the biochip 80 to the receiving segment 32 of the duct 10 coupled to the outlet of the biochip 80 successively as represented by the arrows in figure 6.
  • the flow thus passes through the inserting segment 24, the receiving segment 32 and the biochip segment 34 of the duct 10 coupled to the inlet of the biochip 80
  • the flow then enters the biochip 80 via the inlet, goes through the biochip 80 and goes out of the biochip 80 via the outlet.
  • the flow finally passes though the biochip segment 34 of the duct 10 coupled to the outlet of the biochip 80 and can be collected in the receiving segment 32.
  • the flow may comprise a fluid such as culture medium or a saline solution or a gas such as oxygen.
  • interfacing a plurality of biochips 80 allows to simulate the interaction between different organs.
  • the joining segment 22 of a duct 10 connected to the outlet of a biochip 80 may be connected to the joining segment 22 of a duct 10 connected to the inlet of another biochip 80 (z.e., of another set of ducts).
  • the device 100 may further comprise a sealing element 40 positioned between the receiving segments 32 of the second channel 30 and the first channel support 27.
  • the sealing element 40 is disposed all along the surface of the receiving segments 32 abutting against the first channel support 27.
  • the abutment between the receiving segments 32 and the first channel support 27 corresponds to a contact between the receiving segments 32, the first channel support 27 and the sealing element 40 between them.
  • the sealing element 40 may be formed with a flexible and elastically deformable material: an elastomer such as silicone and rubber.
  • the sealing element 40 has a thickness ranging from 0.5 mm to 10 mm, preferably ranging from 1 mm to 5 mm.
  • the sealing element 40 may comprise, in its width, at least one sensor such as pressure sensor, resistive sensor, etc.
  • the sealing element 40 may be disposed over the whole surface of the second channel support 37 as represented in figures 7 and 8.
  • the device 100 may further comprise a clamping element 50 configured to maintain the first channel support 27 abutted on the receiving segments 32.
  • the clamping element 50 is configured to maintain the first channel support 27 abutted on the second channel support 37 as represented in figures 9 and 10.
  • the clamping element 50 is configured to maintain the first channel support 27 abutted on the receiving segments 32 or the second channel support 37 from the outside of the device 100 contrarily to known devices wherein screws are inserted through the different elements.
  • the clamping element 50 is a lever vice configured to evenly distribute a pressure along the first channel support 27 and the receiving segments 32 or the second channel support 37.
  • the clamping element 50 comprises an upper pressing element 51 configured to be uniformly disposed on the first channel support 27.
  • the clamping element 50 also comprises a lower pressing element 53.
  • the lower pressing element 53 is configured in order to individually receive the receiving segments 32.
  • the lower pressing element 53 is configured to be uniformly disposed under the second channel support 37.
  • the lever vice is configured to apply a force on each of the pressing elements (51, 53) so that the first channel support 27 and the receiving segments 32 or the second channel support 37 are pressed against each other. This is particularly advantageous in the embodiment wherein the device 100 comprises a sealing element 40.
  • the pressure may be evenly distributed if, for example, each of the pressing element (51, 53) is disposed all along the circumference of the first channel support 27 and the receiving segments 32 or the second channel support 37.
  • at least one transversal element may be distributed along the surface of the first channel support 27 and/or, in the embodiment wherein the first channel support 27 abutted on the second channel support 37, along the surface of the second channel support 37 as shown in figure 9.
  • the transversal element may have a width ranging from 0.3 mm to 2 cm.
  • the device 100 comprises only one set of ducts 10. Therefore, the device 100 comprises two ducts 10 as described above.
  • the device 100 of this embodiment thus forms an elementary module.
  • the elementary module is advantageous, since only the needed number of elementary modules according to the number of biochips 80 to be connected are used.
  • the elementary module further comprises cooperating means configured to cooperate with cooperating means of at least another elementary module so as to fasten the two elementary modules together.
  • the cooperating means of a first elementary module are characterized by a given gender (male or female) and are thus configured to cooperate with the opposite gender of a second elementary module.
  • the cooperating means are protrusions which are configured to cooperate with cavities, the protrusions and the cavities being disposed on the side of the elementary modules.
  • the cooperating means may also be magnetic clips disposed for example on the first channel support 27 and the second channel support 37.
  • the first channel support 27 and the second channel support 37 form a single first channel support 27 and a single second channel support 37, respectively.
  • the resulting device 100 may thus comprise as many elementary modules as needed.
  • the joining segment 22 and biochip segment 34 are intrinsically comprised in the device 100 of the invention so that they cannot be removed from the device 100. Therefore, there is no need of an upper plate and a lower plate covering the top and the bottom of the wells to reversibly attach the ports.
  • the device 100 may be manufactured by molding so that the joining segment 22 and the biochip segment 34 are made in a single piece with the inserting segment 24 and the receiving segment 32, respectively.
  • the material used is polycarbonate plate, which is inexpensive and perfectly transparent, making it easy to observe the cells during culture.
  • the device 100 comprises 24 ducts 10 arranged in a 2:3 ratio matrix.
  • the device 100 thus comprises 4 rows of 6 ducts 10, the 6 ducts 10 being distributed along the length of the device 100.
  • the device has a total length of 132 mm and a width of 97 mm.
  • the first channel support 27 and the first channels 20 are made in polycarbonate.
  • the first channel support 27 has a thickness of 4 mm.
  • the first channels 20 have a length of 31 mm with a joining segment of 10 mm.
  • the first channels 20 have a section decreasing along the first longitudinal axis 25 from the joining segments 22 to the inserting segments 24.
  • the inner diameter at the extremity of the inserting segment is 3.5 mm.
  • the center of the first channels 20 are separated by 19 mm along the length of the device 100.
  • the first and second rows of ducts 10 as well as the third and fourth rows of ducts 10 are separated by 19 mm.
  • the second and third rows of ducts 10 are separated by 24 mm.
  • the second channel support 37 and the second channels 30 are made in polycarbonate.
  • the second channel support 37 has a height of 18 mm.
  • the height of the second channel support 37 corresponds to the height of the receiving segments 32.
  • the receiving segment 32 comprises a plan bottom surface 32’ perpendicular to its longitudinal axis and an opening 32”.
  • the biochip segments 34 have a section decreasing along the second longitudinal axis 35 from the receiving segments 32.
  • the inner diameter of the extremity of the biochip segments 34 not included in the receiving segment is 3 mm.
  • the inner diameter of the receiving segments 32 is 16 mm.
  • the centers of the receiving segment 32 are at the same position as the center of the first channels 20.
  • the distance between two biochip segments 34 of the same set of ducts 10 is 29 mm.
  • the second channel support 37 is abutted on the first channel support 27.
  • the sealing element 40 is disposed all along the surface of the second channel support 37.
  • the sealing element 40 has a thickness of 2 mm.

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Abstract

L'invention concerne un dispositif d'interfaçage d'une biopuce.
PCT/IB2023/000568 2023-09-26 2023-09-26 Dispositif d'interfaçage d'une biopuce et méthode de culture de cellules faisant appel au dispositif Pending WO2025068732A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IB2023/000568 WO2025068732A1 (fr) 2023-09-26 2023-09-26 Dispositif d'interfaçage d'une biopuce et méthode de culture de cellules faisant appel au dispositif

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2023/000568 WO2025068732A1 (fr) 2023-09-26 2023-09-26 Dispositif d'interfaçage d'une biopuce et méthode de culture de cellules faisant appel au dispositif

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WO2025068732A1 true WO2025068732A1 (fr) 2025-04-03

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130084632A1 (en) * 2010-03-02 2013-04-04 Centre Benjamin Franklin Multi-reactor unit for dynamic cell culture
US20170227525A1 (en) * 2016-02-04 2017-08-10 Massachusetts Institute Of Technology Modular organ microphysiological system with integrated pumping, leveling, and sensing
US20190083974A1 (en) * 2017-09-19 2019-03-21 Advanced Solutions Life Sciences, Llc Well-plate and fluidic manifold assemblies and methods

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130084632A1 (en) * 2010-03-02 2013-04-04 Centre Benjamin Franklin Multi-reactor unit for dynamic cell culture
US20170227525A1 (en) * 2016-02-04 2017-08-10 Massachusetts Institute Of Technology Modular organ microphysiological system with integrated pumping, leveling, and sensing
US20190083974A1 (en) * 2017-09-19 2019-03-21 Advanced Solutions Life Sciences, Llc Well-plate and fluidic manifold assemblies and methods

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