阅读说明：本技术 平面模块化微流体系统 (Planar modular microfluidic system ) 是由 卓艺群 王骏业 克里斯托弗·托斯塔多 于 2018-10-23 设计创作，主要内容包括：提供了平面模块化微流体模块、系统和制造这样的模块的方法。模块包括基层和被配置成附接到基层并位于基层上的流体层,从而将基层和所述流体层配置成形成单个基础模块；被配置成围绕其横向侧覆盖基础模块的护套,以便对基础模块提供坚固性并形成被护套覆盖的模块。护套包括被配置成在相邻模块之间实现横向连接的物理连接器,所述物理连接器定位在护套覆盖的模块的至少一个横向侧上；以及位于所述物理连接器内并被配置成在相邻模块之间实现流体流动连接的流体连接端口。所述物理连接器可以是磁性连接器。(Planar modular microfluidic modules, systems, and methods of making such modules are provided. The module comprises a base layer and a fluidics layer configured to be attached to and located on the base layer, thereby configuring the base layer and the fluidics layer to form a single base module; a sheath configured to cover the base module about its lateral sides to provide rigidity to the base module and form a sheath covered module. The sheath comprises physical connectors configured to effect lateral connections between adjacent modules, the physical connectors being positioned on at least one lateral side of the modules covered by the sheath; and a fluid connection port located within the physical connector and configured to enable fluid flow connection between adjacent modules. The physical connector may be a magnetic connector.)

1. A planar modular microfluidic module, comprising:

a base layer;

a fluidics layer configured to be attached to and located on the base layer;

a physical connector configured to enable a lateral connection between adjacent modules, the physical connector positioned on at least one side of the planar modular microfluidic module; and

a fluid connection port configured to enable fluid flow connections between adjacent modules, wherein the fluid connection port is located within the physical connector.

2. The planar modular microfluidic module of claim 1, further comprising a conductive node configured to provide an integrated circuit for electrical connection or data transfer between adjacent modules.

3. The planar modular microfluidic module of claim 1, wherein said base layer comprises an electrical circuit or an electronic component.

4. The planar modular microfluidic module of claim 1, wherein said fluidic layer comprises fluidic channels for fluid flow between adjacent modules.

5. The planar modular microfluidic module of claim 4, wherein the planar modular microfluidic module comprises more than one fluidic connection port arranged diagonally within at least one physical connector to enable an imaging system to image the fluidic channel.

6. The planar modular microfluidic module of claim 1, further comprising a top layer configured to bond with the fluidic layer to conform the planar modular microfluidic module to a standard size.

7. The planar modular microfluidic module of claim 1, further comprising a plug on one side of the planar modular microfluidic module, the plug configured to prevent flow therethrough.

8. The planar modular microfluidic module of claim 1, wherein the planar modular microfluidic module comprises more than one physical connector located on at least one side of the planar modular microfluidic module and arranged in a diagonal orientation with respect to the fluidic layer.

9. The planar modular microfluidic module of claim 1, wherein said physical connector is a magnetic connector.

10. The planar modular microfluidic module of claim 1, wherein said fluidic layer is made of Polydimethylsiloxane (PDMS), Polymethylmethacrylate (PMMA), polyethylene terephthalate (PET), polystyrene, polycarbonate, transparent 3D printing resin, glass, or any combination thereof.

11. The planar modular microfluidic module of claim 1, wherein said base layer is made of Polydimethylsiloxane (PDMS), Polymethylmethacrylate (PMMA), polyethylene terephthalate (PET), polystyrene, polycarbonate, transparent 3D printing resin, glass, or any combination thereof plus neodymium or any other strong magnetic material.

12. The planar modular microfluidic module of claim 1, wherein said planar modular microfluidic module is configured to be imaged by a fluorescence microscope, a confocal microscope, or a High Content Screening (HCS) imaging system.

13. The planar modular microfluidic module of claim 1, wherein said planar modular microfluidic module is configured to connect with any type of fluidic connector.

14. The planar modular microfluidic module of claim 13, wherein said fluidic connector is selected from the group consisting of: a four-way connector configured to enable fluid flow through four outlets, a three-way connector configured to enable fluid flow through three outlets, a two-way "L" connector configured to enable fluid flow through two outlets positioned perpendicular to each other, and a two-way straight connector configured to enable fluid flow through two outlets positioned along a line.

15. A planar modular microfluidic module, comprising:

a base layer; and

a fluidics layer configured to be attached to and located on the base layer;

the base layer and the fluidic layer are configured to create a single base module;

a sheath configured to cover the single base module around lateral sides of the single base module to provide robustness to the single base module and create a sheath covered module, wherein the sheath comprises:

a physical connector configured to enable a lateral connection between adjacent modules, the physical connector positioned on at least one lateral side of a module covered by the sheath; and

a fluid connection port configured to enable fluid flow connections between adjacent modules, wherein the fluid connection port is located within the physical connector.

16. The planar modular microfluidic module of claim 15, wherein said physical connector is a magnetic connector.

17. The planar modular microfluidic module of claim 15, wherein the sheath comprises a spacer positioned between the sheath and the physical connector, the spacer configured to maintain a leak-proof connection between adjacent modules.

18. The planar modular microfluidic module of claim 15, wherein said sheath comprises a needle adapter configured to effect fluidic connection between adjacent modules.

19. The planar modular microfluidic module of claim 15, wherein said sheath comprises a single sheathing member configured to accommodate said module plus solidified liquid PDMS positioned between said single base module and said sheath.

20. The planar modular microfluidic module of claim 15, wherein said sheath comprises a plurality of sheath pieces interconnected around said single base module.

21. The planar modular microfluidic module of claim 20, wherein said plurality of sheathing members are interconnected by an internal magnetic connector located within each of said plurality of sheathing members.

22. The planar modular microfluidic module of claim 15, wherein said sheath further comprises circuitry configured to provide electrical connections between adjacent modules.

23. The planar modular microfluidic module of claim 15, wherein said module is capable of performing biological or engineering functions.

24. The planar modular microfluidic module of claim 15, wherein a plurality of modules are interconnected, and wherein the order and type of the plurality of modules are interchangeable.

25. The planar modular microfluidic module of claim 15, wherein said module is configured to be imaged by a fluorescence microscope, a confocal microscope, or a High Content Screening (HCS) imaging system.

26. The planar modular microfluidic module of claim 15, wherein said sheath-covered module comprises at least two physical connectors located on at least one side of said sheath-covered module and arranged diagonally with respect to a side of said planar modular microfluidic module.

27. The planar modular microfluidic module of claim 26, wherein the sheath covered module comprises at least two fluidic connection ports arranged diagonally within the at least two physical connectors to enable an imaging system to image fluidic channels connected by the at least two fluidic connection ports.

28. At least one microfluidic connector within a planar modular microfluidic module, comprising:

at least one physical connector configured to enable lateral connection between adjacent planar microfluidic modules, the physical connector positioned on at least one side of the planar modular microfluidic modules; and

at least one fluidic connection port configured to enable fluidic flow connections between adjacent planar microfluidic modules, wherein the at least one fluidic connection port is located within the at least one physical connector.

29. The microfluidic connector of claim 28, further comprising at least one conductive node for conducting electrical charge or data.

30. A method for fabricating a planar modular microfluidic module, the method comprising:

providing a microfluidic base module comprising a base layer and a fluidic layer;

providing a sheath comprising a magnetic connector, a fluid connection port, and an electrical circuit; and

fitting the sheath around the microfluidic base module to provide modularity, protection, and robustness to the microfluidic base module, thereby creating a sheath covered module.

Technical Field

The present disclosure relates generally to planar modular microfluidic modules and systems that enable multi-organ system interactions.

Background

Cell-based microfluidic models, also known as "organ-on-chips," are being developed for various cell-based in vitro testing applications due to their ability to mimic physiological tissue architecture or environment and the ability to flow fluids to facilitate the delivery of reagents and drugs to cells. Current microfluidic cell models are used to perform various types of cell-based assays, including acute toxicity reactions (IC of drugs)₅₀) Therapeutic efficacy or potency (EC of drug)₅₀) Chronic drug response, combined effects of drugs or cytokines, and pharmacodynamics and pharmacokinetics (PD/PK). In addition to microfluidic cell or tissue models, other microfluidic functional units must be included in the microfluidic system, such as pumps, valves, bubble traps, and gradient generators, to maintain perfusion culture of cells/tissues, and to deliver reagents (e.g., drugs and buffers) for performing assays.

To date, microfluidic systems for performing cell-based assays have been designed and operated mostly as fully integrated systems that are difficult to develop and operate. Since the design of integrated systems is often laboratory or company specific, it is difficult to standardize cell-based microfluidic assays between different laboratories, which limits the practical use of end users such as pharmaceutical companies, biologists or clinical diagnostic laboratories. In addition, since the integrated system already contains all microfluidic cell or tissue types and all microfluidic functional units required for each specific test application, each test application requires a pre-designed integrated microfluidic system, with no modification of any components once assembly is complete. Furthermore, the microfluidic system should be compatible with existing imaging systems, such as High Content Screening (HCS) systems, fluorescence microscopes, confocal microscopes, etc., which are designed to accept microscope slides and microplates in order to automate image acquisition and analysis.

Accordingly, there is a need for systems and methods for achieving modularity and versatility in assembling microfluidic systems.

Disclosure of Invention

The present disclosure provides a system comprising a plurality of planar modular microfluidic modules, each module comprising a base layer; a fluidic layer configured to attach to and over the base layer; physical connectors configured to effect lateral connections between adjacent modules, wherein the physical connectors are positioned on at least one side of the modules; and a fluid connection port configured to enable fluid flow connections between adjacent modules, wherein the fluid connections are located within the physical connector.

In some embodiments, the planar modular microfluidic module may further comprise a conductive node configured to provide an integrated circuit for electrical connection or data transfer between adjacent modules.

In some embodiments, the base layer may include circuitry or electronic components.

In some embodiments, the fluidic layer may include fluidic channels for fluid flow between adjacent modules.

In some embodiments, the planar modular microfluidic module may further comprise a top layer configured to bond with the fluidic layer such that the size of the module conforms to a standard size.

In some embodiments, the planar modular microfluidic module may further comprise a plug on one side of the module, the plug configured to prevent flow through.

In some embodiments, the module may include more than one physical connector located on at least one side of the module and arranged in a diagonal manner to enable an imaging system to image each fluid connection port of the more than one physical connector.

In some embodiments, the module may include more than one fluid connection port arranged diagonally within at least one physical connector to enable an imaging system to image the fluid channel. In some embodiments, the physical connector may be a magnetic connector. In some embodiments, the fluidic layer may be made of Polydimethylsiloxane (PDMS), Polymethylmethacrylate (PMMA), polyethylene terephthalate (PET), polystyrene, polycarbonate, transparent 3D printing resin, glass, or any combination thereof. In some embodiments, the base layer may be made of Polydimethylsiloxane (PDMS), Polymethylmethacrylate (PMMA), polyethylene terephthalate (PET), polystyrene, polycarbonate, transparent 3D printing resin, glass, or any combination thereof plus neodymium or any other strong magnetic material.

In some embodiments, the module may be configured to be imaged by a fluorescence microscope, a confocal microscope, or a High Content Screening (HCS) imaging system. In some embodiments, the module may be configured to connect with any type of fluid connector.

In some embodiments, the fluid connector may be selected from: a four-way connector configured to enable fluid flow through four outlets, a three-way connector configured to enable fluid flow through three outlets, a two-way "L" connector configured to enable fluid flow through two outlets positioned perpendicular to each other, and a two-way straight connector configured to enable fluid flow through two outlets positioned along a line.

According to some embodiments, the present disclosure provides a system comprising a plurality of planar modular microfluidic modules, each module comprising a base layer and a fluidic layer, wherein the fluidic layer may be configured to be attached to and on the base layer such that the base layer and the fluidic layer may be configured to create a single base module. The modules may further include a jacket configured to cover the single base module around lateral sides of the single base module to provide robustness to the single base module and create a jacket cover, wherein the jacket may include physical connectors configured to enable lateral connection between adjacent modules, the physical connectors being positioned on at least one lateral side of the jacket covered modules; and a fluid connection port configured to enable a fluid flow connection between adjacent modules, wherein the fluid connection may be located within the physical connector of the sheath.

In some embodiments, the physical connector may be a magnetic connector.

In some embodiments, the sheath may include a bulkhead positioned between the sheath and the physical connector, which may be configured to maintain a leak-proof connection between adjacent modules. In some embodiments, the sheath may include a needle adapter configured to enable fluid connection between adjacent modules.

In some embodiments, the jacket may comprise a single jacket piece configured to contain the module plus solidified liquid PDMS positioned between the base module and the jacket. In some embodiments, the jacket may include a plurality of jacket members interconnected around the base module. In some embodiments, the plurality of sheathing members are interconnected by an internal magnetic connector located within each of the plurality of sheathing members.

In some embodiments, the enclosure may further include circuitry configured to provide electrical connections between adjacent modules. In some embodiments, the module may be capable of performing biological or engineering functions. In some embodiments, multiple modules may be interconnected, and the order and type of the multiple modules may be interchangeable. In some embodiments, the module may be configured to be imaged by a fluorescence microscope, a confocal microscope, or a High Content Screening (HCS) imaging system.

In some embodiments, the boot-covered module may include at least two physical connectors located on at least one side of the boot-covered module and arranged in a diagonal orientation. In some embodiments, the sheath covered module may include at least two fluid connection ports arranged diagonally within the at least two physical connectors to enable an imaging system to image a fluid channel created by the fluid connection ports.

According to some embodiments, the present disclosure provides at least one microfluidic connector within a planar modular microfluidic module, comprising at least one physical connector configured to enable lateral connection between adjacent planar microfluidic modules, the physical connector positioned on at least one side of the planar modular microfluidic module; and at least one fluidic connection port configured to enable fluidic flow connections between adjacent planar microfluidic modules, wherein the at least one fluidic connection port is located within the at least one physical connector.

In some embodiments, the microfluidic connector further comprises at least one conductive node for conducting electrical charge or data.

The present disclosure provides methods for fabricating planar modular microfluidic modules, which may include providing a microfluidic base module comprising a base layer and a fluidic layer; providing a sheath, wherein the sheath can include a magnetic connector, a fluid connection port, and an electrical circuit; and fitting the sheath around the microfluidic base module to provide modularity, protection and robustness to the microfluidic base module, thereby creating a sheath covered module.

Drawings

Some non-limiting exemplary embodiments or features of the disclosed subject matter are illustrated in the following figures.

In these drawings:

fig. 1A-1C are schematic diagrams of a perspective view, a side view, and a top view, respectively, of a single modular microfluidic module, according to embodiments of the present disclosure;

fig. 1D-1E are schematic diagrams of different layers and fluidic channels of a single microfluidic cartridge according to embodiments of the present disclosure;

fig. 1F-1H are schematic diagrams of a magnetic connector and its attachment to a microfluidic cartridge according to embodiments of the present disclosure;

fig. 2A-2D are schematic diagrams of front/back, side, bottom, and top views of different types of individual modular microfluidic modules according to embodiments of the present disclosure;

fig. 3A-3D are schematic diagrams of perspective, front, top and side views of different connectors according to embodiments of the present disclosure;

fig. 4A-4B are schematic diagrams of two modular microfluidic systems incorporating different microfluidic connector units according to embodiments of the present disclosure;

fig. 5A-5B are schematic diagrams of a plurality of modular microfluidic functional modules connected together to modify flow from one unit to the next to create unidirectional perfusion flow in an automated, wireless manner, according to embodiments of the present disclosure;

figure 6 schematically illustrates different modular multifunctional microfluidic modules and their possible implementation as part of different modular microfluidic systems according to embodiments of the present disclosure;

figures 7A-7C are schematic diagrams of a sheath snapped together when connected to a single modular microfluidic module, a sheath snapped together with a magnetized microfluidic module, and a microfluidic module located inside a single sheath, respectively, according to embodiments of the present disclosure;

fig. 8A-8C schematically illustrate the connection between a modular microfluidic module and a sheath according to embodiments of the present disclosure;

fig. 9A-9G are schematic views of a sheath composed of a different number of pieces, according to embodiments of the present disclosure;

fig. 10A to 10C are schematic diagrams of exploded views of a lung-on-a-chip (lung-on-a-chip) device of the prior art, an actual lung-chip device, and a planar modular microfluidic system equivalent to the lung-chip device, respectively, according to embodiments of the present disclosure; and

fig. 11 is a schematic flow diagram illustrating a method for fabricating a microfluidic cartridge according to an embodiment of the present disclosure.

Referring now in detail to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the embodiments of the present disclosure. In this regard, the description taken with the drawings make it apparent to those skilled in the art how the embodiments of the disclosure may be practiced.

Identical or duplicate or equivalent or similar structures, elements or parts appearing in one or more of the drawings are generally labeled with the same reference numeral, optionally with an additional letter to distinguish between similar entities or variations of entities, and may not be repeatedly labeled and/or described. References to the aforementioned elements are implicit, and no further reference to the drawings or description is necessary when they occur.

The dimensions of the components and features shown in the figures are chosen for convenience or clarity of presentation and are not necessarily shown to scale or true perspective. Some elements or structures are not shown or only partially shown for convenience or clarity and/or are shown at different viewing angles or from different points of view.

Detailed Description

To overcome the limitations of currently common integrated microfluidic systems, the present disclosure provides modular microfluidic modules and systems. These novel planar modular microfluidic systems allow for simple and flexible configuration of microfluidic systems by assembly of various standardized microfluidic modules that perform specific functional operations that may be adapted for cell-based assays, such as 2D/3D cell culture, fluid transport (e.g., via flow connectors), pumping (e.g., via hydrostatic, peristaltic or vacuum driven pumps), flow control (e.g., via valves), concentration generators, combinatorial mixers and bubble traps. Each microfluidic module of the present disclosure may include at least one universal fluid connector capable of forming a reversible seal with any other type of module, thereby allowing connections to be established between any number of different modules in virtually any orientation while minimizing the risk of contamination of the different modules.

One embodiment of a planar modular microfluidic module may include a base microfluidic module having physical connectors to enable lateral connections between adjacent modules, and fluidic connection ports to enable fluidic connections between adjacent modules. Another embodiment of a planar modular microfluidic module may include a base microfluidic module housed within a sheath that provides rigidity to the base module, wherein the sheath includes physical connectors that enable lateral connections between adjacent modules, and fluid connection ports that enable fluid connections between modules covered by adjacent sheaths. Both types of microfluidic modules may provide connectivity by and when typically connected to the same type of module. When a plurality of modules are connected to each other, a modular microfluidic system can be created which can simulate the function of a single organ of the human body or of several organs of the human body, as well as the effect of the function of one "organ" on the other "organs".

An important requirement for the successful implementation of a modular organ-chip system is that it must be suitable for high resolution imaging to observe and interrogate the phenotype and function of cells growing or present in the device. Ideally, microfluidic systems should be compatible with existing imaging systems, such as High Content Screening (HCS) systems, fluorescence microscopes, confocal microscopes, and the like, that are configured for microscope slides and microplates in order to automate image acquisition and analysis. This requires that one side of the microfluidic system (e.g. the side to be imaged in the HCS system) should be between 130 μm and 170 μm thick in order to fall within the working distance of the high power objective. Nor should the overall height of the microfluidic system exceed the height of a standard microplate (i.e., about 15 mm). However, in case the microfluidic system is imaged with other microscopes, the module height of the system should be between about 3mm to 10 mm. This width constraint due to imaging constraints also means that each modular microfluidic module (either a base module with physical connectors and fluidic connection ports, or a sheath covered module that also includes physical connectors and fluidic connection ports for communication between adjacent modules) includes lateral connections, rather than upwardly oriented connections. Thus, the modular microfluidic module is actually a planar modular microfluidic module.

In relation to the present disclosure, the modularity of the planar microfluidic cartridge refers to allowing a simple and flexible configuration of the microfluidic system for performing different cell-based assays on a given type of tissue chip. For example, a tumor chip can be implemented in several different configurations: (a) dose response can be measured to obtain the EC for cancer drugs₅₀The microfluidic system requires a tumor chip and a concentration gradient generator; (b) a microfluidic system that can determine the optimal combination of three standard of care anti-cancer drugs for a given patient's tumor requires a tumor chip and a combination mixer; (c) microfluidic systems that can determine the side effects of anticancer drugs on other tissues, such as liver or bone marrow, require tumor chips, liver or bone marrow chips, peristaltic pumps, and connectors.

Each planar modular microfluidic module can be designed, manufactured, optimized, and operated independently of the other modules, which reduces the time to develop an overall microfluidic system for performing a particular cell-based assay as compared to an integrated microfluidic system. The modular microfluidic modules are also less expensive to manufacture, since each module is manufactured separately and multiple modules are connected to each other only when a complete microfluidic system is required for cell-based assays. That is, the modularity of microfluidic modules refers to the ability to select from a variety of different modules, and the ability to assemble any type and number of modules, in order to assemble a complete microfluidic system suitable for a wide range of clinical and research applications.

With respect to the present disclosure, the words "module" and "brick" may be interchangeable and may refer to the same base unit, when different types of modules or bricks are connected to each other, the entire cell-based assay microfluidic system is assembled. This is due to the fact that each module can be considered as one of the various bricks that "build" the entire microfluidic system.

Reference is now made to fig. 1A-1C, which are schematic illustrations of perspective, side and top views, respectively, of a single modular microfluidic module 100, according to embodiments of the present disclosure. According to some embodiments, any modular microfluidic cell or module, such as microfluidic module 100, may be composed of a fluidic layer 104 and a base or cap layer 106. In some embodiments, the modular microfluidic module may further comprise a top layer 102 and may include one or more means for stopping fluid flow. For example, the module 100 may include a penetrable septum or plug or stopper to prevent fluid flow through the end of the module 100 where the plug is located. For example, the plugs 108, 110 may be located on opposite sides of the microfluidic module so as to prevent fluid from flowing from one end of the microfluidic module to the other, typically the opposite end of the module. In other embodiments, the plugs may be located on other sides of the microfluidic cartridge when fluid flow is to be prevented. In other embodiments, the plug may be positioned on either side of the microfluidic cartridge. In other embodiments, when fluid flow should not be stopped, the plug will not be used as part of the microfluidic cartridge.

According to some embodiments, the top layer 102 may be configured to enable access ports (e.g., cell seeding) or may be used for sizing purposes. That is, to manufacture a standardized microfluidic cartridge that can fit into an HCS imaging system, the size of the top layer 102 and/or the size of the base layer 106 can be adjusted to match the size of any microfluidic cartridge to a certain standardized size. For example, the standardized height may be between 3mm and 10 mm. Thus, depending on the complexity of the module, for example, if the module includes multiple fluidic layers, the thickness of the top layer 102 and/or the base layer 106 may have to be adjusted to conform to the standardized height required for all planar modular microfluidic modules.

In some embodiments, the fluidic layer 104 may include fluidic channels (illustrated as fluidic channels 120), and the base or cap layer 106 may be configured to seal the fluidic layer from one side of the assembled module, e.g., from the bottom side. In some embodiments, the base layer 106 may include circuitry or any electronic component.

In some embodiments, plugs, such as plug 108 and plug 110, may include means to achieve a connection between adjacent modules. For example, the plug may comprise a magnetic element, such as a magnet, such that adjacent modules each having a plug containing a magnetic element may be magnetically connected to each other. In other embodiments, the base microfluidic module 100, including the fluidic layer 104 and the base layer 106, may include at least one physical connector, such as a magnetic connector, located on at least one lateral side of the base module 100, so as to enable lateral connections between adjacent modules. In some embodiments, each or more than one side of the module 100 may include at least one connector to enable additional modules to be connected to almost any side of the module 100. This enables modularity with respect to the order and type of modules creating a modular microfluidic system. The order and type of modules may be interchangeable when creating a modular microfluidic system.

In some embodiments, the top layer 102 and the fluidic layer 104 may be made of the same material, for example, Polydimethylsiloxane (PDMS), Polymethylmethacrylate (PMMA), polyethylene terephthalate (PET), polystyrene, polycarbonate, transparent 3D printing resin, glass, or any combination thereof. In some embodiments, the base layer 106 may be made of the same material from which the top layer 102 is made, plus neodymium or any other strong magnet, as well as conductive wires and loops (resistors, capacitors, microcontrollers, sensors, etc.). In some embodiments, the plugs, such as plug 108 and plug 110, may be made of the same material as top layer 102, plus neodymium or any other strong magnet.

According to some embodiments, the length of the microfluidic cartridge may be between 10mm and 80mm, while a preferred length may be between 40mm and 60 mm. According to some embodiments, the width of the microfluidic cartridge may be between 10mm and 50mm, while the preferred length may be between 20mm and 40 mm. According to some embodiments, the microfluidic cartridge may be between 2mm and 18mm in height, while a preferred length may be between 9mm and 12 mm.

Reference is now made to fig. 1D-1E, which are schematic illustrations of different layers and fluidic channels of a single microfluidic cartridge, according to embodiments of the present disclosure. According to some embodiments, individual microfluidic modules may be created by casting Polydimethylsiloxane (PDMS) on a pre-existing mold in a weight ratio of elastomer and curing agent of, for example, 10: 1. The PDMS may then be cured at 70 ℃ for 4 hours. For peristaltic pump type modules, an on-chip pump module may be fabricated by a common irreversible bond between the pneumatic substrate 120, fluidic substrate 122, and glass substrate 124 to form a complete fluidic channel 130. The pneumatic layer 120 and the fluid layer 122 may each be composed of a Polydimethylsiloxane (PDMS) layer, prepared by thoroughly mixing a polymeric substrate and a curing agent (e.g., Sylgard 184, Dow Corning) in a 10:1 weight ratio. The PDMS prepolymer mixture may then be degassed in a desiccator until all air bubbles are removed. After degassing, the PDMS prepolymer mixture may be poured into pneumatic and fluidic molds and may be placed into a dryer for another round of degassing. Subsequently, the PDMS prepolymer may be thermally cured in an oven at 70 ℃ for 4 hours. The pneumatic layer 120, which may be located at the top of the module, may be plasma bonded to the fluidic layer 122, and the fluidic layer 122 may be located below the pneumatic layer 120. In some embodiments, holes may be punched through the pneumatic layer 120 and the fluidic layer 122, respectively, to allow connection for external vacuum access and create inlets and outlets for fluidic access to the fluidic channels (fig. 1E). The plasma bonding layer may then be connected to a vacuum source through an external conduit to ensure that the actuated valve 132 is in an open state when plasma bonded to the glass substrate 124 or thin PDMS film (not shown), forming a fluidic channel (fig. 1D).

In some embodiments, with respect to microfluidic cell culture modules, gradient generator modules, and connector modules, PDMS modules can be fabricated in a similar manner and carefully removed from their respective molds and can be plasma treated with oxygen using a plasma generator with a thin PDMS film, which can then be bonded to a glass substrate or thin PDMS film.

Reference is now made to fig. 1F-1H, which are schematic illustrations of magnetic connectors and their attachment to microfluidic modules according to embodiments of the present disclosure. According to some embodiments, the magnetic connector 140 for connecting adjacent modules may be composed of a nickel plated neodymium ring magnet (N426.35mm OD X3.175 mm ID X1.5875 mm thick, K & J Magnetics, USA), which may be embedded between the two layers of PDMS 142 and 144 (FIG. 1E). The PDMS prepolymer mixture 142 may be degassed to remove bubbles, and a teaspoon of red PDMS prepolymer may be poured into a square container shaped into a magnetic PDMS block. Subsequently, the PDMS prepolymer mixture may be thermally cured in an oven at 70 ℃ for at least 4 hours. Then, a ring magnet may be placed on the cured PDMS layer 142 and may be covered by a transparent PDMS prepolymer layer 144, and the prepolymer layer 144 may be allowed to cure at room temperature for at least two days. The overall thickness of the magnetic connector 146 may be about 5 mm.

Such magnetic connectors can be bonded to the inlet and outlet of a peristaltic pump module (fig. 1H) and then through two layers of perforations 148 on each side of the module to ensure a consistent passage of the inlet and outlet (fig. 1I). Instead of being bonded to a glass slide, such as a glass substrate 124 (fig. 1D), the pneumatic layer 120 and fluidic layer 122 may be bonded to a thin PDMS layer 150 (fig. 1H) to allow holes to be punched therethrough to create inlets and outlets. Finally, a thin PDMS layer, such as layer 120, may be bonded on top of the pneumatic layer to seal any holes in the pneumatic layer 120, thereby forming a complete fluid channel. Throughout the assembly of the magnetic connector with the planar modular microfluidic peristaltic pump module, the vacuum source should remain active to ensure that the valve pads are not permanently bonded to the thin PDMS.

Reference is now made to fig. 2A-2D, which are schematic illustrations of front/back, side, bottom, and top views of different types of individual modular microfluidic modules according to embodiments of the present disclosure. In some embodiments, each microfluidic module, such as module 200, may include a physical connector, such as magnetic connector 202, configured to connect between one module and another, a fluidic connection port 204 configured to enable fluidic connection between two adjacent connected modules, and a conductive node 206 for an integrated circuit configured to provide power or energy to the module as needed for normal operation. As shown in the example of fig. 2A, the module 200 includes one magnetic connector 202 on the back or front side of the module 200. In some embodiments, the magnetic connector 202 may include a single fluid connection port 204. In some embodiments, magnetic port 202 need not include a fluid connection port. In some embodiments, the magnetic ports may be located on the rear, front, or lateral sides of the module. For example, fig. 2A shows one lateral side of the module 200, which includes more than one magnetic port, such as magnetic port 208, magnetic port 209, and magnetic port 210. Each magnetic port may have a different number of fluid connection ports. For example, magnetic port 208 may not comprise a fluid connection port, magnetic port 209 may comprise a fluid connection port, and magnetic port 210 may not comprise a fluid connection port.

In some embodiments, the bottom side of the module 200 may include a layout of conductive nodes and integrated circuits, while the top side of the module 200 may include fluid channels. As shown, the module 200 includes one fluid passage between the rear and front sides of the module 200, and another fluid passage between two opposing lateral sides of the module 200.

As shown in fig. 2B, another module, such as module 220, may include a magnetic port 222 on the back or front side of module 200, and magnetic port 222 may include more than one fluid connection port. For example, the back or front side of the module 200 may include two fluid connection ports, e.g., fluid connection ports 224, 225 within a single magnetic port 222, configured to enable fluid passage between the front and back sides of the module 200 along two different fluid paths. In some embodiments, each fluidic connection port 224, 225 may enable a different type of fluid to pass through each of these ports, thereby providing the possibility of creating more complex microfluidic systems to perform different cell-based assays. In some embodiments, multiple ports within a single magnetic connector may be oriented horizontally (as shown in fig. 2B) or may be oriented vertically to accommodate multiple fluid layers. The module 200 may also include a conduction node 226 on its back or front side for conducting charge or data (as shown in fig. 2C). Module 200 may include more than one magnetic connector on its lateral sides, for example, magnetic port 228, magnetic port 229, and magnetic port 230. Magnetic port 228, magnetic port 229, and magnetic port 230 may each include a different number of fluid connection ports. For example, magnetic port 228 may not comprise a fluid connection port, magnetic port 229 may comprise two fluid connection ports, and magnetic port 230 may not comprise a fluid connection port. Similarly, for module 200, the bottom side of module 220 may include a layout of conductive nodes and integrated circuits, while the top side of module 220 may include fluid channels. As described above, the module 220 includes two fluid channels between the front and rear sides of the module 200, and may also include two fluid channels between two opposing lateral sides of the module 220. The use of more than one fluid channel enables the provision of two or more different fluids operating in the same system through a single physical connector, for example a magnetic connector. This enables the design of more complex microfluidic systems using a reduced number of microfluidic modules.

In the example shown in fig. 2C, a microfluidic module, such as module 240, may include more than one magnetic port on the front or back side of module 240. In some embodiments, multiple magnetic connectors (each of which may have no, single, or more than one fluid port inside) may be oriented diagonally (as shown in fig. 2C), vertically, or horizontally, depending on the number of fluidic layers desired.

In the example shown in fig. 2D, multiple magnetic connectors may be implemented on each side of the module, with a different number of fluid ports within each magnetic connector. Depending on the number and complexity of fluidic layers required, the magnetic connectors may be oriented diagonally (as shown in fig. 2D), vertically, or horizontally. According to fig. 2D, there are three magnetic ports on the back or front side of the module 260. Each of the three magnetic ports contains a different number of fluid ports. According to fig. 2D, the lateral sides of module 260 may also include a plurality of magnetic ports, each containing a different number of fluid ports, which may be oriented horizontally (as shown in fig. 2D) or may be oriented vertically to accommodate multiple fluid layers. Thus, the fluid channels are illustrated on the top side of the module 260. The horizontal and diagonal orientation of the ports may enable an observer to maximize the visibility of the fluid channels using existing imaging equipment. Thus, the orientation of the fluid ports is preferably such that they do not overlap from a vertical perspective, although it is contemplated that in some alternative embodiments, vertical overlap of the ports may be useful in some circumstances. According to some embodiments, additional sensors and electronics may be placed on either side of the module as needed or desired. For example, as shown in fig. 2A through 2D, electronic components along with circuitry may be placed on the bottom side of each module 200, 220, 240, and 260.

Reference is now made to fig. 3A-3D, which are schematic illustrations of perspective, front, top, and side views, respectively, of various connectors according to embodiments of the present disclosure. According to some embodiments, the planar modular microfluidic system may include various types of connectors that may enable simple fluidic connections between adjacent planar microfluidic modules. Such connectors may also indicate the direction of fluid flow between modules assembled as part of a modular microfluidic system. That is, when combined with other microfluidic functional modules, connector modules or bricks can be used to fabricate fluidic circuits.

For example, fig. 3A schematically illustrates a four-way connector 300. Such a four-way connector may enable fluid to pass through each of the four sides of the connector, and thus, such a four-way connector may be implemented, for example, at an "intersection" in a microfluidic system that requires fluid flow in four different directions. That is, the four-way connector 300 may be configured to enable fluid to flow through the four outlets via the fluid channels 314. The connector 300 may include a magnetic port on each side thereof. For example, the magnetic port 302 may be positioned on the positive side of the connector 300. Magnetic port 302 may include at least one fluid port, such as fluid port 304, but any other number of fluid ports may be implemented within magnetic port 302. Connector 300 may include additional magnetic ports, such as magnetic port 306, magnetic port 310, magnetic port 312, wherein each of these magnetic ports may include at least one fluid port. For example, one side of the connector 300 may include a magnetic port 306, and the magnetic port 306 may include a fluid port 308.

In the example shown in FIG. 3B, a three-way "T" connector 320 is provided. The tee or "T" connector 320 may be positioned in a "T" interconnect of a microfluidic system. The three-way connector 320 can be configured to enable fluid flow through the three outlets. The three-way or "T" connector 320 may include magnetic ports (e.g., 322, 326, 330, 332) on each of its four sides, however, unlike the connector 300, one of the magnetic ports of the connector 320 includes an occluder 334 in addition to the magnetic port 332. The stopper 334 may be used to block fluid flow there through, creating a three-way connector 320. The addition of an obturator 334 to magnetic port 332 prevents fluid from flowing through the fluid port of magnetic port 332 because obturator 334 does not comprise a fluid port.

In some embodiments, a plug or stopper, such as plug 334, may not contain a fluid port, but may contain a magnetic element to provide a magnetic connection between adjacent modules, which may be necessary for purposes other than fluid connection. The magnetic element of the plug may be in the shape of a disk (e.g., a ring) with a hole, similar to the shape of the magnetic port containing the fluid port, or it may be in the shape of a disk, square, rectangle, etc. without a hole. In case of implementing a disc shape, the diameter of the circular magnetic element may be about 5 mm.

In the example shown in FIG. 3C, a two-way "L" shaped connector 340 is provided. The two-way connector 340 may be configured to enable fluid flow through two perpendicular outlets. Two-way "L" shaped connector 340 is manufactured by adding an occluder on two adjacent sides of connector 340 to block the flow of fluid in the two adjacent sides. For example, the connector 340 may include four sides that each include a magnetic port (e.g., 342, 350), and each magnetic port may include at least one fluid port (e.g., 344, 358). However, both sides of the connector 340 may include stoppers or plugs; the magnetic port 350 may be accompanied by an obturator or plug 352 and the magnetic port 354 may be accompanied by an obturator 356. The occluder 352 and the occluder 356 may ensure that no fluid passes there through.

Fig. 3D shows a two-way straight connector 360 that may include two plugs or stoppers located on two opposite sides of the connector 360 to enable fluid flow along a straight line. The two-way connector 360 may be configured to enable fluid flow through two outlets positioned along the same line. Thus, the connector 360 may include four magnetic ports (e.g., 362, 374), each located on a different side of the connector 360. In addition, two opposing sides of connector 360 may include magnetic ports, such as magnetic port 370 and magnetic port 362, which may have a plug 372 or stopper 364 attached, respectively. Stopper 364 may prevent fluid from flowing therethrough and plug 372 may prevent fluid from flowing therethrough, however, fluid port 376 of magnetic port 374 and fluid port 366 of magnetic port 362 may allow fluid to pass therethrough.

According to some embodiments, the various connectors may consist of the same basic connector module, which may be combined with a plug/stopper device that may be used to create four different types of connectors depending on the number and location of the plugs/stoppers. In some embodiments, the magnetic interconnect or port of each of the four types of connectors may include more than one fluid port.

Reference is now made to fig. 4A-4B, which are schematic illustrations of two modular microfluidic systems incorporating different microfluidic connector units and microfluidic modules, according to exemplary embodiments of the present disclosure. As shown in fig. 4A and 4B, the modular microfluidic system 400 and the modular microfluidic system 440 may include similar microfluidic functional units to achieve circular flow. For example, the system 400 and system 440 may include a 3D tissue culture unit 402 (which may contain hepatocytes), a peristaltic pump unit 404, a peristaltic pump unit 406, a 2D tissue culture unit 408 (which may contain tumor cells); a media storage unit 410, which may contain cell culture media to be circulated; and a media storage unit 412 that may contain cell culture media to be circulated. In some embodiments, a peristaltic pump unit, such as peristaltic pump unit 406, is considered an "engineering" brick because its function is the driving force to pump a medium through a fluidic circuit. The media storage unit and the two-way connector unit are also considered as engineering bricks for controlling the flow. The 2D tissue culture unit is considered a "biological" brick and contains one of the tissue types (e.g., tumor cells) used within the circuit. These tumor cells may represent a living tumor growing in the human body, maintained by the perfusion flow of nutrients in the fluid circuit.

According to some embodiments, the modular microfluidic system makes it possible to modify the flow from one module to the next by changing the ability of the connector types along the system 400 and the system 440, and thus to achieve modularity of the functionality of each system, in particular modularity in the fluid flow direction, indicating which units participate in the circuit.

For example, the system 400 includes two-way "L" shaped connectors 420 at the four corners of the system 400. In addition, system 400 includes a two-way "L" connector 430 between peristaltic pump unit 404 and peristaltic pump unit 406, and a two-way "L" connector 430 between media storage unit 410 and media storage unit 412. In fact, the use of two-way "L" connectors 430 in the above-described locations prevents fluid from passing along the main square configuration of system 400, but only allows fluid to flow along "loop 1," which is created by the two-way "L" connectors 430, peristaltic pump unit 406, 2D tissue culture unit 408, media storage unit 410, media storage unit 432, and the two "L" connectors 420. In such a case, some of the microfluidic cells of the system 400 are in a ready state, as fluid is prevented from passing therethrough. For example, the fluid does not reach the peristaltic unit 404, the 3D tissue culture unit 402, or the media storage unit 412. This example of fluid flow through "loop 1" contains circulating cell culture medium, while tumor cells in 2D cell culture unit 408 grow alone, virtually away from any other tissue type (e.g., grow alone with hepatocytes in 3D tissue culture 402). When a cancer drug is introduced into ring 1, any response exhibited by the tumor cells is physiologically insignificant, since the drug is usually first metabolized by the liver in humans before it can react with the tumor cells.

In contrast, the system 440 includes a two-way straight connector 422 between the peristaltic pump 404 and the peristaltic pump 406, and another two-way straight connector 422 between the media storage unit 410 and the media storage unit 412. Thus, the fluid flow can follow the main square configuration of the system 440, i.e., the fluid flow can pass through the "ring 2". The "loop 2" is created by two-way "L" connectors 430, peristaltic pump unit 404, peristaltic pump unit 406, 2D tissue culture unit 408, media storage unit 410, media storage unit 412, and two straight two-way connectors 422 positioned at the four corners. Such operation of the system 440 disables fluid flow through the media storage unit 432 alone. This example of fluid flow through "ring 2" contains a circulating medium between two different tissue types: tumor cells in the 2D tissue culture unit 408 and hepatocytes contained in the 3D tissue culture unit 402. The "loop 2" is simply implemented by switching the two-way "L" shaped connectors 420 into two-way straight connectors 422 in the middle of the loop flow. In system 440, the hepatocytes (located in 3D tissue culture unit 402) may process any compounds or drugs that are pumped through the circuit and may release different compounds/metabolites that may flow sequentially to the tumor cells (located in 2D tissue culture unit 408) in the fluidic circuit. At this point, the response of tumor cells to metabolized drug over time is more physiologically relevant and more closely mimics the in vivo response to drug in humans.

It should be noted that the microfluidic functional unit and the microfluidic connector unit are both connected by lateral connections, thus creating a planar modular microfluidic system that can be easily and conveniently imaged using the HCS system. These examples of system 400 and system 440 illustrate the various possibilities for assembling multiple types of planar modular microfluidic systems using different microfluidic functional units and microfluidic connector units, according to exemplary embodiments of the present disclosure.

Reference is now made to fig. 5A-5B, which are schematic illustrations of a plurality of modular microfluidic functional modules connected together to modify flow from one cell to the next to create unidirectional perfusion flow in an automated, wireless manner, according to embodiments of the present disclosure. Fig. 5A-5B illustrate an example of a microfluidic system 500 including a plurality of modular tiles connected together to modify flow from one module to another adjacent module.

In some embodiments, the system 500 may include six unique modules that are connected to achieve unidirectional vacuum-driven perfusion flow. System 500 may include two bio-type tiles, such as a 3D tissue culture unit 504 that may contain hepatocytes and a 2D tissue culture unit 506 that may contain tumor cells, and four engineered tiles, such as a media storage unit 502, a valve unit 508, a battery unit 510, and a vacuum unit 512. Vacuum unit 512 may include a chamber with low pressure, media storage unit 502 may include liquid cell culture medium at (or slightly above) atmospheric pressure, valve unit 508 may act as a gate to control flow, and battery unit 510 may provide power to the microvalves and circuitry in valve unit 508. The flow within this fluid circuit of the system 500 may be driven by the pressure differential between the vacuum unit 512 and the media storage unit 502, as the fluid flow naturally moves from a high (higher) pressure region to a low (lower) pressure region.

The different bricks or modules may be connected to each other in a straight line and the flow moves from the media storage unit 502 to the vacuum unit 512. An advantage of using the valve unit 508 and vacuum driven flow is that no external wiring or piping is required. The valve unit 508 may include an on-board microcontroller and microvalves that may be controlled wirelessly by commands sent via the main controller. Fig. 5B shows an exemplary flow diagram of the connected microfluidic tile of fig. 5A. The imaging area is shown within the dashed box. That is, the area of system 500 being imaged includes biotype tiles, e.g., 3D tissue culture unit 504 and 2D tissue culture unit 506. Due to the fact that the system 500 is a planar modular microfluidic system and the connections between the modules are lateral connections (rather than oriented upwards), imaging by HCS systems can be achieved.

Reference is now made to fig. 6, which schematically illustrates different modular multifunctional microfluidic modules and their possible implementation as part of different modular microfluidic systems, according to embodiments of the present disclosure. As shown in fig. 6, a planar modular microfluidic system according to the present disclosure may include various microfluidic functional modules. For example, there may be several biotype modules, e.g., tissue culture modules, such as 3D tissue culture module 602, 2D tissue culture module 604, and multiplex 2D/3D tissue culture module 606. Another type of module may be an engineering type, such as a gradient generator module 608, a media storage module 610, a vacuum unit 612, a valve unit 614, a battery unit 616, and a peristaltic pump unit 618. As described herein above with respect to fig. 3A-3D, the modular microfluidic system may also include four types of connector units, e.g., a four-way connector unit 620, a three-way connector unit 622, a two-way "L" connector unit 624, and a two-way straight connector 626. In addition, a plug or stopper 628 may be implemented as needed to control fluid flow or lack thereof.

Each of these microfluidic modules, connectors and plugs may be implemented as part of a planar modular microfluidic system, while applying lateral connections between the individual modules. For example, modules 602(3D tissue culture), 604(2D tissue culture), 610 (media storage), 612 (vacuum), 614 (valves), and 616 (battery pack) may be part of a planar modular microfluidic system 650 for drug bioactivation studies, similar to system 500 shown in fig. 5A-5B. Another example may implement modules 610 (media storage), 608 (gradient generator), 606 (multiplex 2D/3D tissue culture), 614 (valves), 612 (vacuum), and 616 (battery pack) to assemble a planar modular microfluidic system 600 for multiplex drug screening. Yet another example may combine modules 602(3D tissue culture), 604(2D tissue culture), 610 (media storage), 618 (peristaltic pump) and several connectors such as 624 and 626, and plugs 628 to assemble a system 640, which may be similar to system 400 and system 440, as shown in fig. 4A-4B.

Reference is now made to fig. 7A-7C, which are schematic illustrations of a sheath snapped together when connected to a single modular microfluidic module, a sheath snapped together with a magnetized microfluidic module, and a microfluidic module located inside a single sheath, respectively, in accordance with embodiments of the present disclosure. According to some embodiments, when a planar modular microfluidic system contains a large number of interconnected modules, the magnetic connection between modules or bricks through the magnetic ports is not stable enough and requires additional robustness. Thus, each microfluidic cartridge may comprise additional elements that may cover at least four sides of the microfluidic cartridge and may enhance the strength of the system to maintain the connection between all the cartridges of the system. The additional reinforcing element may be a sheath-like element. The sheath can enhance sterility, ensure that all modules are connected to the same plane, enable easy reversible connection with subsequent modules, and can enhance the protection and robustness of modules typically made of PDMS.

In accordance with the present disclosure, the sheath is connected to the microfluidic cartridge by three configurations. The connection arrangement between the sheath and the microfluidic cartridge shown in fig. 7A includes a plurality of individual pieces 704 of sheath that can be physically connected to each other around a brick or cartridge 702 (the bricks are made of Polydimethylsiloxane (PDMS)) to support the brick and form a housing around the brick. In some embodiments, the sheathing members may be interconnected by a snap fit. Once the sheathing members 704 are connected together, the assembled sheathing 714 may hold the tiles 702 tightly in place. In some embodiments, the outer magnets 706 and the spacer 708 may be located within a sheath to accommodate a magnetic connection similar to a magnetic connection that is part of any module that does not contain a sheath. The modules and jacket form a reinforcement module 710.

The configuration of the connection between the sheath and the microfluidic module shown in fig. 7B includes a PDMS brick 702 located in a mold 704, and liquid PDMS containing iron particles may be poured around the brick to form a boundary. The PDMS is located in the mold 704 prior to connecting the mold 704 to the sheathing member 724. The PDMS may be cured (i.e., set) and then the individual boots 724 may be magnetically snapped together with the magnetized tiles. The sheath members may contain internal magnets allowing them to snap together with other sheath members which also contain internal magnets. Once the sheathing member 724 is attached around the PDMS tile 702, an assembled reinforcement module 730 is created.

According to some embodiments, the sheathing members may be modular and thus may be interconnected in different ways in order to accommodate microfluidic bricks of various sizes. The sheathing member may also be easily connected and disconnected to the microfluidic cartridge.

The connection configuration between the sheath and the microfluidic cartridge shown in fig. 7C includes a single, complete sheath 740, and the bricks 754 can be placed within the sheath 740. The sheath 740 may have the outer magnets 742 and the spacer 744 attached thereto to form the complete sheath 750. Subsequently, enough uncured liquid PDMS 752 was poured over the brick 754 so that the total volume of the brick with uncured PDMS matched the volume within the complete sheath 750. The liquid PDMS 752 may be cured, i.e., set, and the brick 754 may be securely fixed in place at substantially the center of the sheath 750. Thus, the sheath 750 may be connected and attached to the tile 754 using physical, magnetic, and/or chemical means. Once the brick 754 is secured within the jacket 750 after the liquid PDMS 752 is added, the assembled reinforced module 760 is created.

According to some embodiments, a single piece sheath structure may be stronger than a sheath composed of multiple small pieces. A single piece of sheath can be attached to the tile (in the case of a PDMS microfluidic tile) by adding more PDMS and creating a permanent bond of the device to the sheath to achieve a more robust connection.

According to some embodiments, the sheath, whether comprising a single integral piece or comprising multiple pieces that need to be snapped together to form a housing around the microfluidic module, may be made of Polymethylmethacrylate (PMMA), polystyrene, polycarbonate, 3D printed resin (proprietary), thermoplastics such as Acrylonitrile Butadiene Styrene (ABS) or polylactic acid (PLA), and/or glass or any of them. The sheath may include circuitry contained therein that may include conductive wiring and common electrical components (e.g., resistors, capacitors, microcontrollers, sensors, etc.). The circuitry may be used to transfer power and information throughout the system and from one microfluidic cartridge to another.

According to some embodiments, the outer magnet may be made of neodymium or any other ferromagnetic material. The size and shape of the outer magnet may be of any kind.

According to some embodiments, a bulkhead attachable to a sheath can be used to maintain a leak-proof connection between adjacent modules and can help maintain sterility within a fluid circuit consisting of multiple interconnected modules. The size and shape of the baffle may be flat or cylindrical with varying thicknesses. According to some embodiments, the separator may be made of chlorobutyl rubber, Ethylene Tetrafluoroethylene (ETFE), natural rubber, Polytetrafluoroethylene (PTFE)/butadiene, silicone, or any combination thereof.

According to some embodiments, the use of a unique in-plane PDMS device with magnetic coupling and a sheath system allows existing PDMS devices and designs to be retrofitted such that no changes to the underlying design are required. This is part of the implementation of a modular system that allows for easy selection of the appropriate microfluidic module for the required inspection, while enabling changes to any module to alter the required system operation.

According to some embodiments, the sheath may be made of a strong and robust material that may be more resistant to bending, deformation, and crushing than the material most commonly used to create microfluidic devices (i.e., PDMS). Thus, the microfluidic cartridge and the sheath together result in a more robust and robust cartridge.

In some embodiments, the sheath may be designed to be of uniform size. Most current microfluidic modules vary in size and shape, often due to minor inconsistencies in human processes or due to quality control issues. The sheath is therefore designed to have a size greater than the standard size of the device itself, and the increase in width, height, length necessary to bring the module to the standard size can be added.

Furthermore, sheaths made of hard materials may be more suitable for integration with circuitry and other electronic components, such as wirelessly controlled solenoid actuated microvalves. Furthermore, a hard jacket material may be more suitable for integration with magnets used to create a connection between modules so that the magnets will no longer move or wear as easily as when integrated in a soft material.

Reference is now made to fig. 8A-8C, which schematically illustrate the connection between a modular microfluidic module and a sheath, according to embodiments of the present disclosure. Fig. 8A shows in more detail the components of the reinforcement module that will be created assembled according to the second configuration shown in fig. 7B. According to a second sheath assembly configuration, the sheath may be made up of a plurality of pieces 804, each piece including an internal magnet 806 to enable the sheath pieces to be snapped and thereby interconnected. In other embodiments, other means for connecting the sheathing members together may be implemented. The sheathing member will cover and contain the tiles 802. Generally, each shield 804 may include at least one outer magnet 808. The outer magnet 808 is a magnetic connector that allows the different modules to be connected to each other. In some embodiments, the outer magnet 808 may have a spacer 810 attached thereto between the outer magnet 808 and the shield. As described above, the spacer plates can be used to maintain a leak-proof connection between adjacent modules and can help maintain sterility within a fluid circuit made up of a plurality of interconnected modules. In some embodiments, the connections between adjacent microfluidic modules, each housed within a sheath, may be made through a needle adapter, such as needle adapter 812. As shown in fig. 8B, the needle adapter 812 may include a needle inserted through a flexible element. One side of the needle may be configured to be inserted onto a first microfluidic cartridge, while the opposite side of the needle 812 may be configured to be inserted onto a second adjacent microfluidic cartridge, as shown in fig. 8C. In some embodiments, the needle adapter 812 may be composed of ferritic stainless steel, which may provide attraction to and alignment with external magnetic connectors of different microfluidic modules.

Reference is now made to fig. 9A-9G, which are schematic illustrations of a sheath composed of a different number of pieces, according to an embodiment of the present disclosure. According to some embodiments, there may be different sheath configurations configured to accommodate the microfluidic cartridge and provide robust robustness and protection to the microfluidic cartridge. The sheath may be designed to fit around the tile and, depending on the size and shape of the tile, the sheath may be configured in several ways. Fig. 9A-9G illustrate some configurations that may be used to create a sheath, including a one-piece sheath, two configurations of a two-piece sheath, two configurations of a four-piece sheath, a six-piece sheath, and an eight-piece sheath. The sheath can be designed to maintain a planar connection of the tiles and also rely on magnetism, physics, or a combination of both to connect the sheath pieces and to connect two different sheaths to each other.

The one-piece sheath of fig. 9A conforms to the configuration described in detail above with respect to fig. 7C. The two-piece sheath may have two configurations; one includes connections between the two pieces that are oriented along a transverse axis of the microfluidic cartridge (fig. 9B), and the other includes connections between the two pieces that are oriented along a longitudinal axis of the microfluidic cartridge (fig. 9C).

The four-piece sheath may also include two configurations, one including connections between every three pieces that are positioned along a lateral axis of the microfluidic cartridge (fig. 9D), and the other including connections between every three pieces that are positioned along a longitudinal axis of the microfluidic cartridge (fig. 9E).

The six-piece sheath may include connections oriented along the longitudinal and transverse axes of the microfluidic cartridge (fig. 9F), similar to the eight-piece sheath (fig. 9G).

Reference is now made to fig. 10A-10C, which are schematic illustrations of exploded views of a prior art lung chip device, an actual lung chip device, and a planar modular microfluidic system equivalent to the lung chip device, respectively, according to embodiments of the present disclosure. Fig. 10A-10B show a prior art lung chip device, while fig. 10C shows a planar modular microfluidic system that performs the same operations but has the advantage of being planarized by including lateral connections between modules rather than upwardly oriented connections, and modular by including modular microfluidic cells that enable changing directions or even replacing modules with different ones.

FIG. 10A shows an exploded view of a lung chip set made by Takayama laboratories (Lab-on-a-chip 11(4): 609-19. 2011.2). The Takayama laboratory apparatus consists of several layers; a cell culture chamber layer and an actuator chamber layer, wherein an air vacuum chamber may be used to simulate the pressure associated with cells lining the alveoli of a human lung in a disease situation. The actual Takayama laboratory apparatus used and shown in fig. 10B is composed of PDMS and does not conform to any standard dimensions. However, a corresponding and equivalent modular microfluidic system can be created to perform exactly the same function as the lung chip device of the Takayama laboratory, as shown in fig. 10C. The planar modular microfluidic system includes a tissue culture chamber 1002, a semi-permeable membrane 1004, and an actuation chamber 1006, performing the same functions as the prior art lung chip. Cells may be introduced into tissue culture chamber 1002 and allowed to adhere to membrane 1004. Tissue culture chamber 1002 may then be filled with a liquid suitable for cell growth. The actuation chamber 1006 may be coupled to a vacuum that may deform the membrane 1004 and thereby deform the lung epithelium attached to the membrane 1004. It should be noted that although the orientation of chambers 1002 and 1006 are upwardly oriented, the connection ports are all located on the side surfaces of the module, unlike the prior art which includes upwardly oriented connections. Thus, the planar modular microfluidic modules of the present disclosure and examples can achieve lateral connections between such exemplary modules and other planar modular microfluidic modules. The planar modular microfluidic system includes lateral (rather than upwardly oriented) connections between different modules. Planar modular microfluidic systems conform to defined standard dimensions and integrate magnetic connectors for connecting between modular microfluidic modules. That is, the planar modular microfluidic system provided in the present disclosure makes it possible to convert an upwardly oriented microfluidic system into a planar modular microfluidic system, which enables modularity and imaging under HCS systems (e.g., a Perkin Elmer Operetta imaging system). Other prior art microfluidic systems can also be converted to planar modular microfluidic systems while providing the same functionality and having the advantages of modularity, ease of assembly, standard size compliance, lateral connectivity, etc.

Reference is now made to fig. 11, which is a schematic flow diagram illustrating a method for fabricating a microfluidic cartridge according to an embodiment of the present invention. According to some embodiments, a method 1100 for fabricating a planar modular microfluidic module may include an operation 1102, operation 1102 including providing a base microfluidic module comprising a base layer and a fluidic layer. In some embodiments, the microfluidic cartridge may further comprise a top layer and a plug. As shown in fig. 1A, each planar modular microfluidic module or brick includes a base layer upon which a fluidic layer including fluidic channels is positioned. In some embodiments, the fluid layer may be on top of the top layer. In some embodiments, the top, fluidic, and base layers may be made of PDMS, but other materials may be used. Each planar modular microfluidic module may further comprise at least one plug or stopper, typically positioned on opposite sides of the planar modular microfluidic module.

According to some embodiments, the method 1100 may further include an operation 1104, the operation 1104 may include providing a sheath including the magnetic connector, the fluid connection port, and the electrical circuit. As described in detail above with respect to fig. 8A, a sheath configured to receive a planar modular microfluidic cartridge may include external magnets that act as magnetic connectors (e.g., magnetic connector 808 in fig. 8A) between adjacent planar modular microfluidic cartridges. Further, the sheath may include a fluid connection port (e.g., fluid port 814 in fig. 8A), which may be located within the magnetic connector. Additionally, circuitry can be included within the enclosure to enable power to be transferred from, for example, a battery module (e.g., module 510 in fig. 5A-5B) to any planar modular microfluidic module that requires energy for proper operation.

According to some embodiments, the method 1100 may further include an operation 1106 including fitting a sheath around the base microfluidic cartridge to provide modularity, protection, and robustness to the microfluidic cartridge to create a sheath covered cartridge. As described in detail above with respect to fig. 7A-7C, the sheath may provide additional protection and robustness to the less strong materials that make up the planar modular microfluidic module. Furthermore, the sheath provides modularity in that it resizes the planar modular microfluidic modules to standard dimensions, which enables modules to be used interchangeably, replaces one module with another, and is able to connect any module to any other module in a simple and quick manner. Unless the context clearly indicates otherwise, a combined term such as "property of thing" refers to the property of thing. In the case of an electrical or electronic device, it is assumed that a suitable power supply is used for its operation.

The flowchart and block diagrams illustrate the architecture, functionality, or operation of possible implementations of systems and methods according to various embodiments of the subject matter disclosed herein. It should also be noted that in some alternative implementations, the operations shown or described may occur in different orders or combinations or as a simultaneous operation rather than an ordered operation, to achieve the same or equivalent results.

The corresponding structures, materials, acts, and equivalents of all means or step plus function elements in the claims below are intended to include any structure, material, or act for performing the function in combination with other claimed elements as specifically claimed. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises," "comprising," and/or "having," and other variations of these terms, as used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.

Unless otherwise indicated, the terminology used herein should not be understood as limiting, and is for the purpose of describing particular embodiments only, and is not intended to limit the disclosed subject matter. While certain embodiments of the disclosed subject matter have been shown and described, it should be clear that the disclosure is not limited to the embodiments described herein. Numerous modifications, changes, variations, substitutions and equivalents are not excluded.