Handling module, perfusion system and operation platform

Abstract

An operation platform for replicating an environment of a human or animal tissue such as a human blood labyrinth barrier, comprises at least one handling module (2) and a perfusion system (3). The handling module (2) comprises a device seat (21) configured to receive a microfluidic device having at least one channel and a membrane to be exposed to a fluid provided through the at least one channel, wherein the at least one channel has an inlet and an outlet; a medium reservoir formation (22) configured to provide at least one medium fluid; microfluidics (23) configured to be connected to the inlet of the at least one channel of the microfluidic device and to the outlet of the at least one channel of the microfluidic device when the microfluidic device is received in the device seat (21 ) of the handling module (2); and a medium forwarding member (24) configured to forward the at least one medium fluid from the medium reservoir formation (22) through the microfluidics (23) into the inlet of the at least one channel of the microfluidic device and out of the outlet of the at least one channel of the microfluidic device when the microfluidic device is received in the device seat (21) of the handling module (2). The perfusion system comprises at least one module seat (31 ) configured to receive the handling module (2) having a sampling unit (32, 37) configured to collect the at least one medium fluid forwarded by the medium forwarding member (24) through the microfluidic device when the handling module (2) is received in the at least one module seat (31) and the microfluidic device is received in the device seat (21 ) of the handling module (2); and a control unit connected to the sampling unit (32, 37) and configured to control the sampling unit (32, 37) to collect the at least one medium fluid forwarded by the medium forwarding member (24) through the microfluidic device when the handling module (2) is received in the at least one module seat (31 ) and the microfluidic device is received in the device seat (21) of the handling module (2).

Description

New International Patent Application Universitat BaselAttorney ref.: P6799PC00DESCRI PTIONTitleHANDLING MODULE, PERFUSION SYSTEM AND OPERATION PLATFORMTechnical Field

[0001] The present invention relates to a handling module for operating a microfluidic device and, more particularly, to a perfusion system including a such a handling module and an operation platform including such a perfusion system together with the microfluidic device. Such modules, systems and platforms can be used for analyzing tissue under specifically defined conditions. For example, human or animal tissue such as, e.g., blood labyrinth barrier (BLB) tissue of a human ear can be analyzed when being exposed to certain conditions such as exposition to specific substances like drugs or similar can be analyzed. Beyond others, analysis of tissue in this way can be an efficient alternative to animal testing.Background Art

[0002] In medical research and development of therapies or drugs, it is increasingly important to model in vitro conditions as they exist in vivo for understanding physiological processes and for understanding behavior and mechanisms under specific conditions such as when pharmaceutically active ingredients are applied. For such modelling, often specific microfluidic chips are used. Said chips typically comprise a membrane for culturing cells and microfluidics to provide media and adjust pressure or other properties at the membrane.

[0003] For example, an application where microfluidic chips can essentially improve research and development relates to hearing impairment being a global health problem with a high socioeconomic impact and being associated with a high unmet medical need. Auditory hair cell damage in the inner ear due to aging, acoustic trauma, or exposure to antibiotics or chemotherapy underlies most cases of sensorineural hearing loss. Hearingloss is one of the ten leading causes of disability globally. Drug therapies that can protect or restore hearing are generally not available today.

[0004] Specifically, inner ear auditory hair cells and the blood labyrinth barrier (BLB) of the human ear are critical for normal hearing but hardly accessible for analysis. The BLB comprises endothelial cells, ECs, pericytes, PCs, and perivascular macrophages like melanocytes, PVM / Ms, which are essential for maintaining BLB integrity. The BLB between the systemic circulation and stria vascularis is crucial for maintaining cochlear and vestibular homeostasis, facilitating nutrient and metabolite transport into the cochlea, and protecting the cochlea against inflammation and disease. BLB defects are associated with inner ear diseases that lead to hearing loss, including vascular malformations, Meniere’s disease, and Alport syndrome.

[0005] As mentioned, delivering therapeutics to the cochlea and vestibular system of the inner ear is complicated by its inaccessible location. It is particularly difficult to avoid adverse effects due to off-target binding, such as ototoxicity from antibiotics and chemotherapy. Systemic delivery of therapeutics to cochlea involves numerous challenges. Therefore, in view of the complexity and inaccessibility of the inner ear there has been a device for modelling a blood labyrinth barrier of a human ear developed and described in WO 2022 / 189400 A1 .

[0006] However, even though microfluidic chips and similar devices allow sophisticated modelling, they typically are quite labor intensive and time consuming. Also, the handling of such devices typically involves a number of manual operations which may lower accuracy and reliability.

[0007] Therefore, there is a need for a system or specific components allowing a semi or fully automized, efficient and / or sophisticated operation of microfluidic devices.Disclosure of the Invention

[0008] According to the invention this need is settled by a handling module as it is defined by the features of independent claim 1 , by a perfusion system as it is defined by the features of independent claim 15, and by an operation platform as it is defined by the features of independent claim 22. Preferred embodiments are subject of the dependent claims.

[0009] In a first aspect, the invention is a handling module comprising a device seat, a medium reservoir formation, microfluidics and a medium forwarding member. The device seat is configured to receive a microfluidic device having at least one channel and a membrane to be exposed to a fluid provided through the at least one channel, wherein the at least one channel has an inlet and an outlet. The medium reservoir formation is configured to provide at least one medium fluid.

[0010] The microfluidics are configured to be connected to the inlet of the at least one channel of the microfluidic device and to the outlet of the at least one channel of the microfluidic device when the microfluidic device is received in the device seat of the handling module. The medium forwarding member is configured to forward the at least one medium fluid from the medium reservoir formation through the microfluidics into the inlet of the at least one channel of the microfluidic device and out of the outlet of the at least one channel of the microfluidic device when the microfluidic device is received in the device seat of the handling module.

[0011] The term “module” as used herein can relate to a physical entity combining all the structures it comprises in one unit. In particular, such unit can be a handling unit allowing to be used and handled as one.

[0012] The microfluidic device can be a microfluidic chip. It can comprise a plurality of plates or layers being specifically designed and mounted together. For example, the microfluidic device can be embodied as described in WO 2022 / 189400 A1 .

[0013] The device seat can be configured to receive the microfluidic device by having a recess mating the shape of the microfluidic device and / or a support structure capable of holding the microfluidic device. Advantageously, the device seat is equipped with a recess having a through hole and a border or step on which the microfluidic device is to be positioned. Also, the device seat can comprise a fastening member for temporarily fixing the microfluidic device in the device seat. In particular, by means of the device seat the microfluidic device can be precisely located and oriented. Thereby, the inlet and outlet of the channel can efficiently be accessed. Also, the device seat can be configured or designed to assure the microfluidic device being located at a bottom or support which may be configured to transfer heat to the microfluidic device. For example, the bottom may be arranged to be heated itself.

[0014] The medium reservoir formation can be or comprise a container which houses the at least one medium, or a seat to receive a container housing the at least one medium. It can further have an adapter or port for accessing an opening of the medium container and for connecting the container to the microfluidics.

[0015] The microfluidics can comprise a body equipped with a channel system designed to suit a particular or aimed flow of the medium to and from the microfluidic device. For example, the body can be a plate like member made of a rigid material. It can have one or more tubes, e.g. held in open channels or grooves, or the body can internally include the channel system.

[0016] The medium forwarding member can be embodied in various ways to achieve the intended flow of medium. For example, it can include a port or adapter to be coupled to a pump or a pressure provision member such as a pressurized tank. Or advantageously it is equipped with the pump or pressure provision member itself, or some components thereof. It can further have a valve or similar member to adjust a flow of the medium. Also, it can comprise a mixing formation in order to mix plural media.

[0017] For operating and configuring the medium forwarding device, it can include a processing unit. Such processing unit can be pre-programmed or, advantageously, programmable. When being programmable, the processing unit can efficiently be variably adapted to various modelling or experiments. For example, the processing unit of the medium forwarding device can have a printed circuit board (PCB) equipped with a processor, wherein the PCB may be programmed or configured by means of an external computing device such as a control unit of a perfusion system and / or an external computing device.

[0018] By combining the device seat, the medium reservoir formation, the microfluidics and the medium forwarding member into the handling module, components specifically adapted to a particular microfluidic device or a particular simulation or experiment can be unified on one single entity. This allows for an efficient handling of these components and, thus, a (semi-)automatic modelling operation. For example, the handling module may be placed in a sterile cabinet for sterile connection and disconnection of fluidic tubings, bottles and microfluidic chip. This is, the handling module may allow to focus operations in a sterile environment being limited to those operations requiring sterility. All other operations can conveniently be performed in a regular or non-sterile environment.Moreover, while modelling a specific situation in the microfluidic device, the installation can be kept and, at the same time, the handled like removed or the like. This may allow to prevent that other components not required during the complete modelling but temporarily only to be centralized. This may increase efficiency particularly when plural modellings or experiments are performed in parallel. Thus, the handling module according to the invention allows a (semi-)automized, sophisticated and efficient operation of the microfluidic device or, particularly, a plurality thereof in parallel.

[0019] Preferably, the handling module comprises an effluent receptacle connected to the microfluidics to collect the at least one medium fluid forwarded out of the outlet of the at least one channel of the microfluidic device through the microfluidics. The effluent receptacle may comprise a container to collect the medium forwarded out of the microfluidic device, or a container seat for receiving such container. By means of such effluent receptacle, a controlled and efficient collection of used medium can be achieved.

[0020] Preferably, the handling module comprises a heating member in contact with the microfluidics and configured to heat the at least one medium fluid forwarded to the microfluidic device. The heating member can particularly be configured to directly heating the microfluidics. The term “in contact with” in connection with the microfluidics can relate to the heating member being coupled and particularly thermally coupled to the microfluidics, or the heating member being or forming the microfluidics itself. By heating the microfluidic device, the heating member can specifically be configured to heat or preheat the at least one fluid in the microfluidics before being forwarded into the inlet of the at least one channel of the microfluidic device. The heating member can comprise a heating plate or heating pad coupled to the microfluidics, wherein the heating plate or pad can be integral with the microfluidics. Particularly, the heating plate can be equipped with the channel system and thus forming the microfluidics. The heating member allows to provide the at least one medium at a target temperature into the microfluidic device. Thereby, the need for an incubator may be eliminated.

[0021] The heating member preferably comprises a temperature sensor. Such sensor allows to control and / or supervise heat transferred to the at least one medium. Specifically, the temperature sensor allows for implementing a feedback loop relating to heating of the at least one medium.

[0022] Preferably, the handling module comprises a device heating element configured to heat the microfluidic device when the microfluidic device is received in the device seat of the handling module. Such device heating element can be embodied as heating pad positioned below the microfluidic device, e.g., in or on the bottom of the device seat, to heat cells in the microfluidic device, and one heating pad below the fluidic meanders to pre-heat the liquid before entering the microfluidic chip. In addition to the heating pad, there is a temperature sensor (per heating pad) which allows for a feedback loop.

[0023] The device heating element preferably comprises a temperature sensor. Such sensor allows to control and / or supervise heat transferred to the microfluidic device and, specifically, to cells cultivated therein. Specifically, the temperature sensor allows for implementing a feedback loop relating to heating of the microfluidic device or cells cultivated in the microfluidic device.

[0024] Preferably, the medium reservoir formation comprises at least one container seat configured to receive a container housing a medium fluid. Thereby, the at least one container seat of the medium reservoir formation preferably comprises a plurality of container seats each configured to receive one container housing one of the at least one medium fluid such that the at least one medium fluid is a plurality of medium fluids. Such an arrangement allows for making specific media required for a particular modelling or experiment available to the microfluidic device. Thereby, a high efficiency and configurability can be achieved.

[0025] Thereby, the plurality of medium fluids preferably comprises a gaseous medium and at least one liquid medium. The gaseous medium can be carbon dioxide or a similar gas provided together with a liquid or separated therefrom. For modelling specific situations or conditions, a combination of gas and liquids is necessary. Thus, such arrangement allows to model a broad variety of situations.

[0026] Thereby, the at least one liquid medium preferably comprises a cell liquid having cells to be seeded on the membrane of the microfluidic device. Including such cell liquid may allow to efficiently model specific tissues.

[0027] The at least one liquid medium preferably comprises a growth liquid configured to grow cells seeded on the membrane of the microfluidic device. Including such medium allows for efficiently maintaining and growing the cells seeded on the membrane.

[0028] The at least one liquid medium preferably comprises a test liquid having a substance to be tested on the membrane. Such test liquid may include an active pharmaceutical ingredient (API) or drug substance, or biological or other pathogens.

[0029] Preferably, the gaseous medium is a control gas. Such control gas can be required in various experiments. For example, the gaseous medium can be 5% CO2 to buffer the cell culture medium to the correct pH, or other control gas such as low O2 concentration or a gas composition to recreate hypoxic testing conditions, if it is desired for the respective modelling or experiment. Thus, it allows for achieving an efficient implementation of various modellings or experiments.

[0030] Thereby, the handling module preferably comprises a mixing structure having an air flow controller and a carbon dioxide flow controller, wherein the mixing structure is configured to mix the control gas by adjusting the air flow controller and the carbon dioxide controller.

[0031] The handling module preferable comprises a switching structure configured to selectively provide any of the plurality of medium fluids or any combination thereof. Particularly, when plural media are involved which have to be provided in a flexible or changing manner such switching structure may be beneficial.

[0032] Preferably, the medium forwarding member comprises a peristaltic mechanism. Such mechanism allows to provide the medium fluids at comparably low flow rates and at comparably high precision.

[0033] Preferably, the microfluidics are configured to be connected to a plurality of inlets and to a plurality of outlets such that the microfluidic device microfluidic device can have a plurality of channels each connected to one of the plurality of inlets and one of the plurality of outlets. Such configuration allows for implementing or modelling comparably complex situations or conditions.

[0034] In another aspect, the invention is a perfusion system comprising at least one module seat configured to receive a handling module as described above, a sampling unit and a control unit. The sampling unit is configured to collect the at least one medium fluid forwarded by the medium forwarding member through the microfluidic device when the handling module is received in the at least one module seat and the microfluidic device is received in the device seat of the handling module. The control unit is connectedto the sampling unit and configured to control the sampling unit to collect the at least one medium fluid forwarded by the medium forwarding member through the microfluidic device when the handling module is received in the at least one module seat and the microfluidic device is received in the device seat of the handling module. Thereby, the sampling unit is advantageously configured to automatically the at least one medium fluid. This may be achieved by the control unit being appropriately configured or programmed such that the control unit may control automatic sampling by the sampling unit.

[0035] The control unit can comprise a computer. The term “computer” in this connection relates to any electronic data processing device and associated interface components or the like. It may include individual devices such as laptop computers, desktop computers, server computers, tablets, smartphones, systems embedded in other devices (embedded systems), integrated controllers or similar devices. It also covers combined devices or computer networks such as distributed systems with components in different locations. Computers are typically composed of various building blocks or components such as processors (CPU), permanent data storage devices with a recording medium such as a hard disk, flash memory or similar, random access memory (RAM), read-only memory (ROM), communication adapters such as USB adapters, LAN adapters, WLAN adapters, Bluetooth adapters, or similar, user interfaces such as keyboards, mice, touch-sensitive screens (touchscreens), monitors, microphones, speakers, and other components. Computers can be assembled in very different designs from the above components and / or other components.

[0036] By having the sampling unit controlled by the control unit, the perfusion system can be programmed or arranged to automatically take samples of the at least one medium fluid at pre-definable points in time. For example, it may be appropriate to predefine a number of between 1 and 100 points in time. The mentioned points in time may be predefined in a software executed by the control unit. The automatic and preferably customized or predefined operation of the system and specifically of the sampling unit via the control unit allows to ensure standardized or comparable results to be provided or generated.

[0037] The perfusion system and its preferred embodiments described below allow to efficiently achieve the effects and benefits described in connection with the handling module and its preferred embodiments described above.

[0038] Moreover, particularly when a plurality of module seats is provided, a plurality of modellings can be efficiently performed in parallel. Thereby, the same sampling unit and other central components can be used for all modellings or experiments. This allows for a particularly efficient procedure in parallel.

[0039] Preferably, the perfusion system comprises at least one heating inducer configured to be coupled to the heating member of the handling module and / or to the device heating element of the handling module when the handling module is received in the at least one module seat, wherein the control unit is connected to the at least one heating inducer and configured to control the at least one heating inducer to adapt the heating member to heat the at least one fluid in the microfluidics before being forwarded into the inlet of the at least one channel of the microfluidic device and / or to heat the microfluidic device. The heating inducer can have a power source and a structure to electrically provide heat by means of the heating member and / or the device heating element. For example, such heat can be resistively or inductively generated. Such heating inducer and control unit allow for accurately controlling heating of the microfluidics as desired for a specific modelling or experiment implemented.

[0040] Preferably, the perfusion system comprises a sample storage configured to receive the at least one medium fluid collected by the sampling unit. Such sample storage allows for gathering various samples at plural stages of one or more modellings or experiments. Like this, a sophisticated analysis of the results can be provided over time.

[0041] Thereby, the sample storage preferably comprises a multiwell plate seat. The term “multiwell plate” as used herein particularly relates to plates or microplates having a plurality of wells arranged in a predefined order. Such microplates are often embodied in a standardized manner with 96, particularly 384 or 1536 wells organized in a specific order. By allowing to involve a multiwell plate for gathering the samples collected, an efficient handling and analysis of the samples can be achieved.

[0042] Further, the sample storage advantageously has at least one cleaning recess. Such cleaning recess can be filled with a sterilizing or other cleaning agent. In order to prevent cross contamination between plural samples, the sampling unit can be cleaned and / or sterilized or disinfected between transferring two samples from the handling module to the sample storage. Like this, contamination between or mixing of samples can be prevented.

[0043] Also, the sample storage advantageously has a cover structure such as a lid or a silicone or other foil. Such cover structure allows to avoid evaporation of medium fluid received in the sample storage over time such as during a sampling period.

[0044] Preferably, the perfusion system comprises a transepithelial electrical resistance (TEER) sensor arranged to sense in the microfluidic device when the handling module is received in the at least one module seat and the microfluidic device is received in the device seat of the handling module. Such sensor may allow for quantifying a barrier function or similar properties of the tissue or cells grown on the membrane of the microfluidic device.

[0045] Preferably, the sampling unit comprises a sampling syringe. Such sampling syringe allows to achieve a comparably high dosing accuracy by comparably simple means.

[0046] Preferably, the perfusion system comprises an optical check unit configured to optically verify quality of the at least one medium fluid forwarded from the medium reservoir formation through the microfluidics into the inlet of the at least one channel of the microfluidic device. By means of such optical checking a high quality of the medium can be ensured which allows to prevent deterioration of the modelling or experiment.

[0047] Advantageously, the perfusion system comprises an initializing unit configured to provide a cell medium to the membrane of the microfluidic device when the handling module is received in the at least one module seat and the microfluidic device is received in the device seat of the handling module. Such initializing unit allows for initializing the microfluidic device to a specific modelling or experiment. For example, cells can be seeded on the membrane - preferably on both sides thereof - when initializing the microfluidic device. Thereby, the initializing unit can be used for plural microfluidic devices in parallel. Also during an ongoing modelling it may be desired to implement initialization, e.g., to model changing conditions or the like.

[0048] In a further other aspect, the invention is an operation platform for replicating an environment of a human or animal tissue such as a human blood labyrinth barrier, comprising at least one handling module as described above and a perfusion system as described above.

[0049] The operation platform and its preferred embodiments described below allow to efficiently achieve the effects and benefits described in connection with the handling module and its preferred embodiments described above as well as with the perfusion system and its preferred embodiments described above.

[0050] Preferably, the operation platform comprises a microfluidic device having at least one channel and a membrane to be exposed to a fluid provided through the at least one channel, wherein the at least one channel has an inlet and an outlet and wherein the microfluidic device is configured to be received in the device seat.

[0051] Thereby, at least one channel of the microfluidic device preferably comprises a plurality of channels, wherein each channel has a separate inlet and a separate outlet.

[0052] Preferably, the module seat of the perfusion system of the operation platform is configured to repeatedly receive and remove the at least one handling module while the microfluidic device is received in the device seat of the at least one handling module. A front part with medium holders may be detachable, so the modules can be taken out individually.Brief Description of the Drawings

[0053] The handling module, perfusion system and operation platform according to the invention are described in more detail hereinbelow by way of an exemplary embodiments and with reference to the attached drawings, in which:Fig. 1 shows a perspective view of an embodiment of a handling module according to the invention; andFig. 2 shows a perspective view of an embodiment of an operation system according to the invention comprising an embodiment of a perfusion system according to the invention which includes a plurality of the handling modules of Fig. 1 .Description of Embodiments

[0054] In the following description certain terms are used for reasons of convenience and are not intended to limit the invention. The terms “right”, “left”, “up”, “down”, “under" and “above" refer to directions in the figures. The terminology comprises the explicitly mentioned terms as well as their derivations and terms with a similar meaning. Also, spatially relative terms, such as "beneath", "below", "lower", "above", "upper", "proximal","distal", and the like, may be used to describe one element's or feature's relationship to another element or feature as illustrated in the figures. These spatially relative terms are intended to encompass different positions and orientations of the devices in use or operation in addition to the position and orientation shown in the figures. For example, if a device in the figures is turned over, elements described as "below" or "beneath" other elements or features would then be "above" or "over" the other elements or features. Thus, the exemplary term "below" can encompass both positions and orientations of above and below. The devices may be otherwise oriented (rotated 90 degrees or at other orientations), and the spatially relative descriptors used herein interpreted accordingly. Likewise, descriptions of movement along and around various axes include various special device positions and orientations.

[0055] To avoid repetition in the figures and the descriptions of the various aspects and illustrative embodiments, it should be understood that many features are common to many aspects and embodiments. Omission of an aspect from a description or figure does not imply that the aspect is missing from embodiments that incorporate that aspect. Instead, the aspect may have been omitted for clarity and to avoid prolix description. In this context, the following applies to the rest of this description: If, in order to clarify the drawings, a figure contains reference signs which are not explained in the directly associated part of the description, then it is referred to previous or following description sections. Further, for reason of lucidity, if in a drawing not all features of a part are provided with reference signs it is referred to other drawings showing the same part. Like numbers in two or more figures represent the same or similar elements.

[0056] Fig. 1 shows a perspective view of an embodiment of a handling module 2 according to the invention. The handling module 2 comprises a base plate 25, a medium reservoir formation 22 and a peristaltic pump 24 as medium forwarding device. The base plate 25 is equipped with a microfluidics 23 forming a device seat 21 . It has an essentially rectangular shape and is provided with two grips 251 at its longitudinal ends.

[0057] The microfluidics 23 includes a body equipped with six inflow channels 231 each extending from the peristaltic pump 24 to the device seat 21 where it ends in an inlet port 232, and six outflow channels 234 each extending from the device seat 21 where it starts at an outlet port 233. The inflow channels 231 and the outflow channels 232 are embodied by grooves extending along a top surface of the body, and tubes held in these grooves (not visible in Fig. 1 ). The device seat 21 is configured to receive a microfluidic chip asmicrofluidic device having six channels and a membrane to be exposed to a fluid provided through the channels, wherein each of the channels has an inlet connected to one of the inlet ports 232 when the microfluidic chip is received in the device seat 21 , and an outlet connected to one of the outlet ports 233 when the microfluidic chip is received in the device seat 21 .

[0058] The device seat 21 has an opening 211 allowing optical access to the microfluidic chip from a bottom side of the handling module 2. Towards an upper end of the opening 211 a circumferential step-like edge 212 is formed. The edge 212 is dimensioned to precisely hold the microfluidic chip in a predefined location and orientation. Further, the device seat 21 is provide with an interface 213 of a transepithelial electrical resistance (TEER) sensor.

[0059] The medium reservoir formation 22 comprises eight container seats 221 each configured to receive one container. Two container seats 221 are larger in size and arranged to receive containers housing a medium fluid such that the medium reservoir formation 22 is configured to provide two medium fluids. In particular, the medium fluids include a cell liquid having cells to be seeded on the membrane of the microfluidic chip, a growth liquid configured to grow the cells seeded on the membrane of the microfluidic chip and a test liquid having a substance to be tested on the membrane of the microfluidic chip. Further, the other six container seats 221 are each arranged to receive a waste container associated to one of the six channels of the microfluidic chip.

[0060] The container seats 221 provided with medium containers are connected to the peristaltic pump 24 by means of respective tubes (not visible in Fig. 1 ) via six sampling ports 26 as switching structures. The peristaltic pump 24 has six dispense tubes 241 each coupled to or extending along one of the inflow channels 231. In particular, the inflow channels 231 and the outflow channels 234 comprise open channels or grooves equipped with tubes held therein. The microfluidics 23 further comprises a heating member 234 thermally coupled to the inflow channels 231 to heat liquid passing the inflow channels 231 , if required.

[0061] The peristaltic pump 24 is configured to forward the medium fluids from the medium reservoir formation 22 through the six inflow channels 231 of the microfluidics 23 into the inlets of the six channels of the microfluidic chip via the inlet ports 232, out of the outlets of the six channels of the microfluidic chip into the outflow channels 234 of themicrofluidics 23 via the outlet ports 233, through the outflow channels 234 of the microfluidics 23 and from there into the waste container. In particular, the peristaltic pump 24 includes a printed circuit board (PCB) equipped with a programmable and controllable processor. Downstream the outflow channels 234 six sampling ports 26 are arranged. In particular, each of the sampling ports 26 is connected to one of the outflow channels 234 such that medium fluid exiting the outflow channels passes one of the sampling ports 26.

[0062] In Fig. 2 a perspective view of an embodiment of an operation platform 1 according to the invention is shown. The operation platform 1 comprises an embodiment of a perfusion system 3 according to the invention having three handling modules 2 each embodied as shown in Fig. 1.

[0063] The perfusion system 3 comprises a sample storage 36 and three module seats 31 each receiving one of the handling modules 2. It further has a frame 33 with a rail 332 to which a sledge 331 is mounted such that it can be horizontally moved along the rail 332. For driving the sledge 331 along the rail 332, the perfusion system 3 is equipped with a first motor 38. The frame 33 extends over the module seats 31 .

[0064] As can be seen in Fig. 2, the handling modules 2 have gas ports 222 to provide gaseous medium such as carbon dioxide (CO2) into the microfluidics 23 of the handling modules 2.

[0065] The sledge 331 carries a syringe pump as sampling unit having a sampling syringe 32 and a second motor 37. The second motor 37 is configured to vertically move the sampling syringe 32. Thereby, the second motor 37 allows for downwardly moving the sampling syringe 32 when being located above one of the sampling ports 26 of the handling module 2. Like this, a septum in the sampling port 26 can be pierced by a needle of the sampling syringe 32 and the sampling syringe 32 can precisely withdraw fluid passing the sampling port 26. After withdrawal, the second motor 37 can upwardly move the sample syringe 32 and the first motor 38 can transfer the sample syringe 32 to the sample storage 36.

[0066] The sample storage 36 comprises a microplate seat 362 configured to receive a multiwell microplate. When the sample syringe 32 is transferred to one of the wells of the multiwell microplate, it dispenses the sample into the respective well. The sample storage 36 further has a series of cleaning wells 361 as cleaning recesses provided with cleaningand disinfecting liquids. After the sample syringe 32 has dispensed the sample into one of the wells of the multiwell microplate received in the microplate seat 362, it is transferred to the cleaning wells in order to clean its needle for preventing cross contamination between multiple samples gathered one after the other.

[0067] The perfusion system 3 further has an instrument box 35 housing a control unit, other electronics and pneumatic controls such as proportional flow controllers for CO2 provision, CO2 sensors or electrical connectors. The control unit is connected to the syringe pump and configured to control the second motor 37 as well as the sampling syringe 32 for collecting samples from the three handling modules 2. Further, the control unit is connected to the PCB of the peristaltic pumps 24 of the handling modules 2 to adapt and configure medium provision through the microfluidic devices in each of the handling modules 2.

[0068] The perfusion system 3 comprises a heating component (not visible in Fig. 2) configured to be coupled to the heating members 234 of the microfluidics 23 of the handling modules 2. The control unit is connected to the heating component and configured to control the heating members 234 to heat the fluids in the microfluidics 23 before being forwarded into the microfluidic devices received in the device seats 21 of the handling modules 2.

[0069] The perfusion system 3 further comprises TEER sensor components coupled to the interfaces 213 of the handling modules 2 such that together they form the TEER sensor. Thereby, the TEER sensor is arranged to quantify a barrier function of the membranes in the microfluidic devices arranged in the handling modules 2.

[0070] This description and the accompanying drawings that illustrate aspects and embodiments of the present invention should not be taken as limiting-the claims defining the protected invention. In other words, while the invention has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive. Various mechanical, compositional, structural, electrical, and operational changes may be made without departing from the spirit and scope of this description and the claims. In some instances, well-known circuits, structures and techniques have not been shown in detail in order not to obscure the invention. Thus, it will be understood that changes and modifications may be made by those of ordinary skill within the scope and spirit of thefollowing claims. In particular, the present invention covers further embodiments with any combination of features from different embodiments described above and below.

[0071] The disclosure also covers all further features shown in the Figs, individually although they may not have been described in the afore or following description. Also, single alternatives of the embodiments described in the figures and the description and single alternatives of features thereof can be disclaimed from the subject matter of the invention or from disclosed subject matter. The disclosure comprises subject matter consisting of the features defined in the claims or the exemplary embodiments as well as subject matter comprising said features. Also, the present disclosure covers intermediate generalizations of features or groups of features of the embodiments described and shown in the figures. Le., specific features or groups of features as disclosed in the figures and the associated sections of the description may be combined with the more general embodiments of the invention disclosed in connection with the description of the invention. In particular, such specific features or groups of features may be provided in the more general embodiments of the invention in isolation from further specific features shown in the figures. For example, a syringe pump with sampling syringe and associated motor as shown in the Figs, may be embodied as sampling unit of the generic perfusion system of the invention without requiring any further specific features as shown in the Figs, such as the associated sledge or the like. It is understood that those skilled in the art are able to incorporate specific features from the description of the figures into the embodiments of the description of the invention.

[0072] Furthermore, in the claims the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality. A single unit or step may fulfil the functions of several features recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. The terms “essentially”, “about”, “approximately” and the like in connection with an attribute or a value particularly also define exactly the attribute or exactly the value, respectively. The term “about” in the context of a given numerate value or range refers to a value or range that is, e.g., within 20%, within 10%, within 5%, or within 2% of the given value or range. Components described as coupled or connected may be electrically or mechanically directly coupled, or they may be indirectly coupled via one or more intermediatecomponents. Any reference signs in the claims should not be construed as limiting the scope.

Claims

New International Patent ApplicationUniversitat BaselAttorney ref.: P6799PC00CLAI MS1. An operation platform for replicating an environment of a human or animal tissue such as a human blood labyrinth barrier, comprising: at least one handling module (2) and a perfusion system (3); wherein the handling module (2) comprises a device seat (21 ) configured to receive a microfluidic device having at least one channel and a membrane to be exposed to a fluid provided through the at least one channel, wherein the at least one channel has an inlet and an outlet; a medium reservoir formation (22) configured to provide at least one medium fluid; microfluidics (23) configured to be connected to the inlet of the at least one channel of the microfluidic device and to the outlet of the at least one channel of the microfluidic device when the microfluidic device is received in the device seat (21 ) of the handling module (2); and a medium forwarding member (24) configured to forward the at least one medium fluid from the medium reservoir formation (22) through the microfluidics (23) into the inlet of the at least one channel of the microfluidic device and out of the outlet of the at least one channel of the microfluidic device when the microfluidic device is received in the device seat (21 ) of the handling module (2), and wherein the perfusion system comprises at least one module seat (31 ) configured to receive the handling module (2); a sampling unit (32, 37) configured to collect the at least one medium fluid forwarded by the medium forwarding member (24) through the microfluidic device when the handling module (2) is received in the at least one module seat (31 ) and the microfluidic device is received in the device seat (21 ) of the handling module (2); anda control unit connected to the sampling unit (32, 37) and configured to control the sampling unit (32, 37) to collect the at least one medium fluid forwarded by the medium forwarding member (24) through the microfluidic device when the handling module (2) is received in the at least one module seat (31 ) and the microfluidic device is received in the device seat (21 ) of the handling module (2).

2. The operation platform of claim 1 , wherein the handling module (2) comprises an effluent receptacle connected to the microfluidics (23) to collect the at least one medium fluid forwarded out of the outlet of the at least one channel of the microfluidic device through the microfluidics (23).

3. The operation platform of claim 1 or 2, wherein the handling module (2) comprises a heating member (234) in contact with the microfluidics (23) and configured to heat the at least one medium fluid forwarded to the microfluidic device.

4. The operation platform of any one of the preceding claims, wherein the handling module (2) comprises a device heating element configured to heat the microfluidic device when the microfluidic device is received in the device seat (21 ) of the handling module (2).

5. The operation platform of claim 3 or 4, wherein in the handling module (2) the heating member and / or the device heating element comprise(s) a temperature sensor.

6. The operation platform of any one of the preceding claims, wherein in the handling module (2) the medium reservoir formation (22) comprises at least one container seat (221 ) configured to receive a container housing a medium fluid.

7. The operation platform of claim 6, wherein in handling module (2) the at least one container seat (221 ) of the medium reservoir formation (22) comprises a plurality of container seats (221 ) each configured to receive one container housing one of the at least one medium fluid such that the at least one medium fluid is a plurality of medium fluids.

8. The operation platform of claim 7, wherein in handling module (2) the plurality of medium fluids comprises a gaseous medium and at least one liquid medium.

9. The operation platform of claim 8, wherein in the handling module (2) the at least one liquid medium comprises a cell liquid having cells to be seeded on the membrane of the microfluidic device.

10. The operation platform of claim 8 or 9, wherein in the handling module (2) the at least one liquid medium comprises a growth liquid configured to grow cells seeded on the membrane of the microfluidic device.

11. The operation platform of any one of claims 8 to 10, wherein in the handling module (2) the at least one liquid medium comprises a test liquid having a substance to be tested on the membrane of the microfluidic device.

12. The operation platform of any one of claims 8 to 11 , wherein in the handling module (2) the gaseous medium is a control gas.

13. The operation platform of claim 12, wherein the handling module (2) comprises a mixing structure having an air flow controller and a carbon dioxide flow controller, wherein the mixing structure is configured to mix the control gas by adjusting the air flow controller and the carbon dioxide controller.

14. The operation platform of any one of claims 8 to 13, wherein the handling module (2) comprises a switching structure configured to selectively provide any of the plurality of medium fluids or any combination thereof.

15. The operation platform of any one of the preceding claims, wherein in the handling module (2) the medium forwarding member (24) comprises a peristaltic mechanism.

16. The operation platform of any one of the preceding claims, wherein in the handling module (2) the microfluidics (23) are configured to be connected to a plurality of inlets and to a plurality of outlets such that the microfluidic devicemicrofluidic device can have a plurality of channels each connected to one of the plurality of inlets and one of the plurality of outlets.

17. The operation platform of any one of the preceding claims, wherein the perfusion system (3) comprises a heating inducer configured to be coupled to the heating member (234) of the handling module (2) and / or the device heating element of the handling module (2) when the handling module (2) is received in the at least one module seat (31 ), wherein the control unit is connected to the heating inducer and configured to control the heating inducer to adapt the heating member (234) to heat the at least one fluid in the microfluidics (23) before being forwarded into the inlet of the at least one channel of the microfluidic device and / or the device heating element to heat the microfluidic device.

18. The operation platform of any one of the preceding claims, wherein the perfusion system (3) comprises a sample storage (36) configured to receive the at least one medium fluid collected by the sampling unit (32, 37).

19. The operation platform of claim 18, wherein in the perfusion system (3) the sample storage (36) comprises a multiwell plate seat (362).

20. The operation platform of any one of the preceding claims, wherein the perfusion system (3) comprises a transepithelial electrical resistance sensor arranged to sense in the microfluidic device when the handling module (2) is received in the at least one module seat (31 ) and the microfluidic device is received in the device seat (21 ) of the handling module (2).21 . The operation platform of any one of the preceding claims, wherein in the perfusion system (3) the sampling unit (32, 37) comprises a sampling syringe (32).

22. The operation platform of any one of the preceding claims, wherein the perfusion system (3) comprises an optical check unit configured to optically verify quality of the at least one medium fluid forwarded from the medium reservoir formation (22) through the microfluidics (23) of the handling module (2) into the inlet of the at least one channel of the microfluidic device.

23. The operation platform of any one of the preceding claims, comprising a microfluidic device having at least one channel and a membrane to be exposed to a fluid provided through the at least one channel, wherein the at least one channel has an inlet and an outlet and wherein the microfluidic device is configured to be received in the device seat (21 ).

24. The operation platform of claim 23, wherein at least one channel of the microfluidic device comprises a plurality of channels, wherein each channel has a separate inlet and a separate outlet.

25. The operation platform of claim 23 or 24, wherein the module seat (31 ) of the perfusion system (3) is configured to repeatedly receive and remove the at least one handling module (2) while the microfluidic device is received in the device seat (21 ) of the at least one handling module (2).

26. A handling module (2) comprising a device seat (21 ) configured to receive a microfluidic device having at least one channel and a membrane to be exposed to a fluid provided through the at least one channel, wherein the at least one channel has an inlet and an outlet; a medium reservoir formation (22) configured to provide at least one medium fluid; microfluidics (23) configured to be connected to the inlet of the at least one channel of the microfluidic device and to the outlet of the at least one channel of the microfluidic device when the microfluidic device is received in the device seat (21 ) of the handling module (2); and a medium forwarding member (24) configured to forward the at least one medium fluid from the medium reservoir formation (22) through the microfluidics (23) into the inlet of the at least one channel of the microfluidic device and out of the outlet of the at least one channel of the microfluidic device when the microfluidic device is received in the device seat (21 ) of the handling module (2).

27. The handling module (2) of claim 26, comprising an effluent receptacle connected to the microfluidics (23) to collect the at least one medium fluid forwarded out of the outlet of the at least one channel of the microfluidic device through the microfluidics (23).

28. The handling module (2) of claim 26 or 27, comprising a heating member (234) in contact with the microfluidics (23) and configured to heat the at least one medium fluid forwarded to the microfluidic device.

29. The handling module (2) of any one of claims 26 to 28, comprising a device heating element configured to heat the microfluidic device when the microfluidic device is received in the device seat (21) of the handling module (2).

30. The handling module (2) of claim 28 or 29, wherein the heating member and / or the device heating element comprise(s) a temperature sensor.

31. The handling module (2) of any one of claims 26 to 30, wherein the medium reservoir formation (22) comprises at least one container seat (221) configured to receive a container housing a medium fluid.

32. The handling module (2) of claim 31 , wherein the at least one container seat (221 ) of the medium reservoir formation (22) comprises a plurality of container seats (221) each configured to receive one container housing one of the at least one medium fluid such that the at least one medium fluid is a plurality of medium fluids.

33. The handling module (2) of claim 32, wherein the plurality of medium fluids comprises a gaseous medium and at least one liquid medium.

34. The handling module (2) of claim 33, wherein the at least one liquid medium comprises a cell liquid having cells to be seeded on the membrane of the microfluidic device.

35. The handling module (2) of claim 33 or 34, wherein the at least one liquid medium comprises a growth liquid configured to grow cells seeded on the membrane of the microfluidic device.

36. The handling module (2) of any one of claims 33 to 35, wherein the at least one liquid medium comprises a test liquid having a substance to be tested on the membrane of the microfluidic device.

37. The handling module (2) of any one of claims 33 to 36, wherein the gaseous medium is a control gas.

38. The handling module (2) of claim 37, comprising a mixing structure having an air flow controller and a carbon dioxide flow controller, wherein the mixing structure is configured to mix the control gas by adjusting the air flow controller and the carbon dioxide controller.

39. The handling module (2) of any one of claims 33 to 38, comprising a switching structure configured to selectively provide any of the plurality of medium fluids or any combination thereof.

40. The handling module (2) of any one of claims 26 to 39, wherein the medium forwarding member (24) comprises a peristaltic mechanism.

41. The handling module (2) of any one of claims 26 to 40, wherein the microfluidics (23) are configured to be connected to a plurality of inlets and to a plurality of outlets such that the microfluidic device microfluidic device can have a plurality of channels each connected to one of the plurality of inlets and one of the plurality of outlets.

42. A perfusion system (3) comprising: at least one module seat (31 ) configured to receive a handling module (2) according to any one of the preceding claims; a sampling unit (32, 37) configured to collect the at least one medium fluid forwarded by the medium forwarding member (24) through the microfluidic device when the handling module (2) is received in the at least one module seat (31 ) and the microfluidic device is received in the device seat (21 ) of the handling module (2); and a control unit connected to the sampling unit (32, 37) and configured to control the sampling unit (32, 37) to collect the at least one medium fluid forwarded by the medium forwarding member (24) through the microfluidic device when the handling module (2) is received in the at least one module seat (31 ) and the microfluidic device is received in the device seat (21 ) of the handling module (2).

43. The perfusion system (3) of claim 42, comprising a heating inducer configured to be coupled to the heating member (234) of the handling module (2) and / or the device heating element of the handling module (2) when the handling module (2) is received in the at least one module seat (31 ), wherein the control unit is connected to the heating inducer and configured to control the heating inducer to adapt the heating member (234) to heat the at least one fluid in the microfluidics (23) before being forwarded into the inlet of the at least one channel of the microfluidic device and / or the device heating element to heat the microfluidic device.

44. The perfusion system (3) of claim 42 or 43, comprising a sample storage (36) configured to receive the at least one medium fluid collected by the sampling unit (32, 37).

45. The perfusion system (3) of claim 44, wherein the sample storage (36) comprises a multiwell plate seat (362).

46. The perfusion system (3) of any one of claims 42 to 45, comprising a transepithelial electrical resistance sensor arranged to sense in the microfluidic device when the handling module (2) is received in the at least one module seat (31 ) and the microfluidic device is received in the device seat (21 ) of the handling module (2).

47. The perfusion system (3) of any one of claims 42 to 46, wherein the sampling unit (32, 37) comprises a sampling syringe (32).

48. The perfusion system (3) of any one of claims 42 to 47, comprising an optical check unit configured to optically verify quality of the at least one medium fluid forwarded from the medium reservoir formation (22) through the microfluidics (23) of the handling module (2) into the inlet of the at least one channel of the microfluidic device.

Images