Micropump for organ chip, manufacturing and using method of micropump and liquid conveying system

Abstract

The invention provides a micropump for an organ chip. The micropump comprises a gas storage shell, an elastic film and a liquid channel shell which are sequentially arranged from top to bottom, a gas cavity is defined in the gas storage shell, a gas source connector communicated with the gas cavity is formed in the top of the gas storage shell, and the gas source connector is connected with a gas source through an electromagnetic valve. A liquid cavity and two liquid channels communicated with the liquid cavity are defined in the liquid channel shell; one-way valves are arranged at outlets, away from the liquid cavity, of the two liquid channels. The invention further provides a corresponding manufacturing and using method and a liquid conveying system. The micropump for the organ chip is independent of the chip, is plug-and-play, is adaptive to organ chips with different structures, and is assembled with the organ chip to form an integrated chip, so that the requirement of liquid flow conveying of the organ chip is met, the size of the chip is reduced, and the flexibility is improved.

Description

Technical Field

[0001] The present invention belongs to the field of organ-on-a-chip, and particularly relates to a micropump for an organ-on-a-chip, a manufacturing and using method thereof, and a liquid delivery system. Background Art

[0002] An organ-on-a-chip is a microfluidic device that simulates the functions of human tissues and organs, and contains culture chambers and microchannels for cells, tissues or organs. The fluid delivery system is a key part of the organ-on-a-chip system, which needs to control the liquid flow to provide nutrients for cells, tissues or organs and take away metabolites, conduct drug transport, realize the material exchange and interaction between different culture units, and provide an appropriate shear stress microenvironment for cells, tissues or organs. Applications such as drug screening require high-throughput operation of the organ-on-a-chip, and an efficient and accurate multi-channel liquid flow delivery system is needed.

[0003] Currently, there are the following several ways of liquid flow delivery for organ-on-a-chip:

[0004] 1) Liquid flow delivery is achieved through peripheral devices (such as peristaltic pumps, diaphragm pumps, syringe pumps, pressure pumps) [1,2] , as the power source for the microchannel.

[0005] The inlets and outlets of the organ-on-a-chip are connected to the peripheral pump with hoses, realizing unidirectional circulation drive of the liquid flow, which can better mimic the flow mode in human blood vessels and is applicable to multi-organ-on-a-chip systems containing multiple tissue and organ culture units. However, the number of independently controlled channels is the same as the number of pumps. In high-throughput applications, a large number of peripheral pumps are required, which occupy a large space and their purchase costs are also high. At the same time, the long and numerous liquid flow tubes between the organ-on-a-chip and the pump not only waste the culture medium, but also dilute the cytokines secreted by cells, tissues or organs, which is not conducive to the detection of secretions and the study of biological interactions.

[0006] 2) Liquid flow delivery is achieved through a rocking shaker, as the power source for the microchannel.

[0007] Such as Figure 1 shown for the organ-on-a-chip and rocking shaker of MIMETAS company. During the rocking process of the rocking shaker, there is a liquid level difference at the inlet and outlet. Under the drive of gravity, the liquid flow reciprocates in the pipeline. This liquid flow mode is easy to achieve high throughput, but the upstream and downstream relationship of the liquid flow is lost, which is different from the situation of blood flow in the body.

[0008] 3) Integrating a micropump in the organ-on-a-chip. Integrating the micropump directly into the organ-on-a-chip increases the complexity and flexibility of chip manufacturing. The method is to add a layer of PDMS elastic membrane in the chip. Above and below the elastic membrane are the pneumatic channel and the liquid flow channel respectively. Using air pressure to drive three elastic PDMS membranes to close sequentially, so as to achieve unidirectional liquid flow, and the liquid flow can circulate unidirectionally in the chip. For example, TissUse company[3,4] and the Griffith research group [5-7] adopted this method in their multi-organ chip system.

[0009] However, although this method does not require a peripheral pump, it requires peripheral valves, especially solenoid valves. At the same time, it also requires three pneumatic units and corresponding three solenoid valves. Therefore, the structure is relatively more complex.

[0010] As Figure 2 shown, each pneumatic unit 1, 2, 3 is a micropump structure, including three independent elastic membranes driven and controlled by air channels. Three closely connected air channel interfaces respectively correspond to the elastic membranes below them. Therefore, three solenoid valves are required to open and close the air channels; and a liquid flow channel is provided below the elastic membrane.

[0011] Thus, the closed (pressurized) and open (depressurized) states of the three pneumatic units 1, 2, 3 are as follows:

[0012] Stage 1: The first pneumatic unit 1 is closed and the second pneumatic unit 2 and the third pneumatic unit 3 are open. The elastic membrane of the first pneumatic unit 1 is pressed down to start the liquid flow;

[0013] Stage 2: The first pneumatic unit 1 and the second pneumatic unit 2 are closed, and the third pneumatic unit 3 is open. The elastic membrane of the second pneumatic unit 2 is pressed down. Since the first pneumatic unit 1 is closed, the liquid flow is directed to the third pneumatic unit 3;

[0014] Stage 3: The second pneumatic unit 2 and the third pneumatic unit 3 are closed and the first pneumatic unit 1 is open. The elastic membrane of the third pneumatic unit 3 is pressed down. Since the second pneumatic unit 2 is closed, the liquid flow still flows directionally. At the same time, the elastic membrane of the first pneumatic unit 1 rebounds to suck in new liquid;

[0015] Stage 4: The third pneumatic unit 3 is closed and the first pneumatic unit 1 and the second pneumatic unit 2 are open. The elastic membrane of the second pneumatic unit 2 rebounds to suck in liquid, and so on to achieve directional liquid flow drive.

[0016] In addition, when all the elastic membranes remain in the pressurized closed state, the liquid flow naturally stops.

[0017] Therefore, if only one pneumatic unit such as the first pneumatic unit 1 is used, the repeated opening and closing of the 1 membrane will only cause the effect of hammering the liquid and cannot achieve directional liquid flow. Therefore, the elastic membranes of the three pneumatic units 1, 2, 3 need to cooperate to achieve the function. The main function of the elastic membrane of the first pneumatic unit 1 is to restrict the liquid flow direction to prevent backflow. The elastic membrane of the second pneumatic unit 2 is responsible for most of the liquid drive (realized in stage 2), and the elastic membrane of the third pneumatic unit 3 is responsible for the remaining liquid drive (realized in stage 3).

[0018] The solenoid valve is a two-way three-way solenoid valve. One end is connected to the gas channel interface with an elastic membrane, and the other end corresponds to two states. Therefore, it is respectively connected to the positive pressure gas source (used for pressurization to press down the elastic membrane and close the channel) and the atmospheric pressure (used for pressure relief to make the elastic membrane rebound and open the channel).

[0019] The references are as follows:

[0020] 1. Novak, R.; Ingram, M.; Marquez, S.; Das, D.; Delahanty, A.; Herland, A.; Maoz, B. M.; Jeanty, S. S. F.; Somayaji, M. R.; Burt, M.; et al. Robotic fluidic coupling and interrogation of multiple vascularized organ chips. Nat Biomed Eng 2020, 4(4), 407 - 420. DOI: 10.1038 / s41551 - 019 - 0497 - x.

[0021] 2. Ronaldson - Bouchard, K.; Teles, D.; Yeager, K.; Tavakol, D. N.; Zhao, Y.; Chramiec, A.; Tagore, S.; Summers, M.; Stylianos, S.; Tamargo, M.; et al. A multi - organ chip with matured tissue niches linked by vascular flow. Nat Biomed Eng 2022, 6(4), 351 - 371. DOI: 10.1038 / s41551 - 022 - 00882 - 6.

[0022] 3. Schimek, K.; Busek, M.; Brincker, S.; Groth, B.; Hoffmann, S.; Lauster, R.; Lindner, G.; Lorenz, A.; Menzel, U.; Sonntag, F.; et al. Integrating biological vasculature into a multi - organ - chip microsystem. Lab on a chip 2013, 13(18), 3588 - 3598. DOI: 10.1039 / c3lc50217a.

[0023] 4. Maschmeyer, I.; Lorenz, A. K.; Schimek, K.; Hasenberg, T.; Ramme, A. P.; Hubner, J.; Lindner, M.; Drewell, C.; Bauer, S.; Thomas, A.; et al. A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents. Lab on a chip 2015, 15(12), 2688-2699. DOI: 10.1039 / c5lc00392j.

[0024] 5. Trapecar, M.; Communal, C.; Velazquez, J.; Maass, C. A.; Huang, Y. J.; Schneider, K.; Wright, C. W.; Butty, V.; Eng, G.; Yilmaz, O.; et al. Gut-Liver Physiomimetics Reveal Paradoxical Modulation of IBD-Related Inflammation by Short-Chain Fatty Acids. Cell Syst 2020, 10(3), 223-239e229. DOI: 10.1016 / j.cels.2020.02.008.

[0025] 6. Edington, C. D.; Chen, W. L. K.; Geishecker, E.; Kassis, T.; Soenksen, L. R.; Bhushan, B. M.; Freake, D.; Kirschner, J.; Maass, C.; Tsamandouras, N.; et al. Interconnected Microphysiological Systems for Quantitative Biology and Pharmacology Studies. Scientific reports 2018, 8(1), 4530. DOI: 10.1038 / s41598-018-22749-0.

[0026] 7.Chen,W.L.K.;Edington,C.;Suter,E.;Yu,J.;Velazquez,J.J.;Velazquez,J.G.;Shockley,M.;Large,E.M.;Venkataramanan,R.;Hughes,D.J.;et al.Integrated gut / liver microphysiological systems elucidates inflammatory inter-tissue crosstalk.Biotechnol Bioeng 2017,114(11),2648-2659.DOI:10.1002 / bit.26370. Summary of the Invention

[0027] The object of the present invention is to provide a micropump for an organ-on-a-chip, its manufacturing and use methods, and a liquid delivery system, so as to meet the requirements of liquid flow delivery in the organ-on-a-chip, reduce the chip size, and improve flexibility.

[0028] To achieve the above object, the present invention provides a micropump for an organ-on-a-chip, which is characterized by comprising a gas storage housing, an elastic membrane, and a liquid channel housing arranged in sequence from top to bottom;

[0029] A gas chamber is defined within the gas storage housing, and a gas source interface communicating with the gas chamber is provided at the top of the gas storage housing. The gas source interface is connected to the gas source through a solenoid valve;

[0030] A liquid chamber and two liquid channels communicating with the liquid chamber are defined within the liquid channel housing; check valves are provided at the outlets of the two liquid channels away from the liquid chamber.

[0031] A check valve for liquid discharge is provided at the outlet of one of the two liquid channels to serve as the outlet of the micropump, and a check valve for liquid intake is provided at the outlet of the other to serve as the inlet of the micropump.

[0032] The openings of the gas chamber and the liquid chamber face each other, and the elastic membrane covers the openings of the gas chamber and the liquid chamber.

[0033] The gas source includes a positive gas pressure source and a negative gas pressure source. The solenoid valve is a three-way solenoid valve, and the gas source interface is connected to the positive gas pressure source and the negative gas pressure source simultaneously through a gas pipeline and the solenoid valve;

[0034] Alternatively, the gas source includes one of a positive gas pressure source and a negative gas pressure source and an atmospheric gas source. The solenoid valve is a three-way solenoid valve, and the gas source interface is connected to the two gas sources simultaneously through a gas pipeline and the solenoid valve.

[0035] The solenoid valve is connected to a computer through a driver.

[0036] The material of the elastic membrane is PDMS, and the materials of the gas storage housing and the liquid channel housing are PDMS or thermoplastic materials, and the thermoplastic materials are PMMA or PC.

[0037] On the other hand, the present invention provides a method for manufacturing a micropump for an organ chip, which is characterized by including:

[0038] Step S1: Manufacture the gas storage housing and the liquid channel housing respectively; when the housing material is PDMS, first process the mold through numerical control machine tool technology or three-dimensional printing technology, and then perform PDMS casting and curing based on the mold; when the housing material is thermoplastic material, directly process and manufacture the gas storage housing and the liquid channel housing through injection molding process or numerical control machine tool technology;

[0039] Wherein, a gas chamber is defined in the gas storage housing, and a gas source interface communicating with the gas chamber is provided at the top of the gas storage housing; a liquid chamber and two liquid channels communicating with the liquid chamber are defined in the liquid channel housing;

[0040] Step S2: Bond the gas storage housing, the elastic membrane and the liquid channel housing together from top to bottom. When the materials of the gas storage housing and the liquid channel housing are PDMS, directly bond them after plasma treatment; when the materials of the gas storage housing and the liquid channel housing are thermoplastic materials, perform surface silanization treatment after plasma treatment, and then bond them; wherein the openings of the gas chamber and the liquid chamber face each other, and the elastic membrane covers the openings of the gas chamber and the liquid chamber, so as to realize the mutual sealing of the gas chamber and the liquid chamber through the elastic membrane;

[0041] Step S3: Connect two one-way valves for liquid inlet and outlet respectively to the outlets of the two liquid channels of the liquid channel housing according to the liquid flow direction, and connect the gas source interface to the gas source through a solenoid valve to obtain a micropump for an organ chip; when the materials of the gas storage housing and the liquid channel housing are PDMS, directly insert the one-way valve into the housing to achieve airtight connection; when the materials of the gas storage housing and the liquid channel housing are plastic materials, insert the one-way valve with an O-ring into the housing to achieve airtight connection.

[0042] On the other hand, the present invention provides a method for using a micropump for an organ chip, which is characterized by including:

[0043] Step S1': Provide the micropump for an organ chip described above, and connect the two one-way valves for liquid inlet and outlet of the micropump to the liquid flow output port and the liquid flow input port of the organ chip respectively to obtain an organ chip with a liquid flow delivery system;

[0044] Step S2': Use a solenoid valve to control the on / off of the gas source, drive the elastic membrane to reciprocally deform, and push the liquid to flow directionally through the reciprocal deformation of the elastic membrane.

[0045] On the other hand, the present invention provides an organ chip with a liquid flow delivery system, characterized in that it includes a micropump for an organ chip as described above and an organ chip connected to the micropump; the two one-way valves for liquid inlet and outlet of the micropump are respectively connected to the liquid flow output port and the liquid flow input port of the organ chip.

[0046] The organ chip is an array integrated by multiple organ chip units, and each organ chip unit is only connected to one micropump; all the micropumps share a common gas source and a multi-channel solenoid valve. The multi-channel solenoid valve includes multiple solenoid valve channels and each solenoid valve channel corresponds to one micropump; the two one-way valves for liquid inlet and outlet of the micropump are respectively connected to the liquid flow output port and the liquid flow input port of the organ chip unit; or, the organ chip only has one organ chip unit and the number of the micropumps is 1.

[0047] The pneumatic unit of the micropump for an organ chip of the present invention is based on a one-way valve to simultaneously achieve the functions of orientation and driving, ensure the unidirectional flow of the liquid, change the pneumatic unit from 3 to 1, thereby reducing the number of solenoid valves required for a single micropump and the number of gas source tracheas, making the chip structure more compact, and the micropump is more suitable for large-scale liquid flow delivery of organ chips. In addition, the micropump is connected to the organ chip through a one-way valve and is detachable relative to the organ chip. It is inserted into the organ chip flow channel through simple plugging and unplugging, which reduces the complexity of organ chip manufacturing, reduces the chip cost, and can be adapted to different organ chips by fine-tuning the structure and size of the micropump. Description of the Drawings

[0048] Figure 1 is a structural diagram of an organ chip of MIMETAS Company in the prior art and a rocking shaker.

[0049] Figure 2 is a position distribution diagram of the pneumatic unit of an organ chip of TissUse Company.

[0050] Figure 3 is a front view of a micropump for an organ chip according to the first embodiment of the present invention.

[0051] Figure 4 is a three-dimensional structural diagram of a micropump for an organ chip according to the first embodiment of the present invention.

[0052] Figure 5 is an exploded view of a micropump for an organ chip according to the first embodiment of the present invention.

[0053] Figure 6 It is a schematic block diagram of the gas circuit module of the micropump for the organ-on-a-chip according to the first embodiment of the present invention.

[0054] Figure 7 It is a three-dimensional structure diagram of a group of organ chip units and a micropump of an organ-on-a-chip with a liquid flow delivery system according to the fourth embodiment of the present invention, in which the first arrangement example is given.

[0055] Figure 8 It is Figure 7 an exploded view of.

[0056] Figure 9 It is a three-dimensional structure diagram of a group of organ chip units and a micropump of an organ-on-a-chip with a liquid flow delivery system according to the fourth embodiment of the present invention, in which the second arrangement example is given.

[0057] Figure 10 It is the overall structure diagram of the organ-on-a-chip with a liquid flow delivery system according to the fourth embodiment of the present invention. Detailed implementation manners

[0058] The present invention will be further described below in conjunction with specific embodiments. It should be understood that the following embodiments are only used to illustrate the present invention and not to limit the scope of the present invention.

[0059] The present invention provides a micropump for an organ-on-a-chip to meet the liquid flow delivery requirements during the large-scale application of the organ-on-a-chip, and on this basis, a high-throughput liquid delivery system for the organ-on-a-chip based on the micropump is constructed.

[0060] The working principle of the micropump for the organ-on-a-chip of the present invention is similar to that of the micropump in the background art. It drives the deformation of the elastic membrane through the air duct and then drives the liquid flow, so that the liquid flow circulates in the organ-on-a-chip. However, the differences are as follows: 1) The pneumatic unit of the micropump is realized based on a one-way valve to simultaneously achieve the functions of orientation and driving, ensure the unidirectional flow of the liquid flow, change the pneumatic unit from 3 to 1, thereby reducing the number of solenoid valves required for a single micropump; 2) The micropump is connected to the organ-on-a-chip through a one-way valve and is detachable relative to the organ-on-a-chip. It is connected to the flow channel of the organ-on-a-chip through simple plugging and unplugging, which reduces the complexity of manufacturing the organ-on-a-chip, reduces the chip cost, and can be adapted to different organ-on-a-chips by fine-tuning the structure and size of the micropump; 3) By optimizing the three pneumatic units (corresponding to three air pipes) used in a single micropump to a single pneumatic unit, in a large-scale system, an organ-on-a-chip only needs one air pipe to be connected to the common gas source to achieve driving. For a system of 100 organ-on-a-chips, compared with the three-pneumatic structure, our structure reduces the use of 200 air pipes and greatly reduces the volume; for the same common gas source, since the gas flux of the gas source has an upper limit and its driving ability is limited, if the limit of the gas source is reached, the number of chips connected by our structure is three times that of the traditional three-pneumatic unit structure chips; therefore, the micropump of the present invention is more suitable for large-scale liquid flow transportation of organ-on-a-chips.

[0061] First Embodiment: Micropump for Organ-on-a-Chip

[0062] As Figures 3 - 6 shown, the micropump for the organ-on-a-chip of the present invention includes a gas storage housing 10, an elastic membrane 20, and a liquid channel housing 30 that are sequentially arranged from top to bottom.

[0063] The gas storage housing 10 is located in the upper layer. A gas chamber 11 is defined inside the gas storage housing 10. A gas source interface 12 communicating with the gas chamber 11 is provided at the top of the gas storage housing 10. The gas source interface 12 is connected to the gas source through a solenoid valve 13 to drive the reciprocating deformation of the elastic membrane 20 by controlling the on-off of the gas source through the solenoid valve 13.

[0064] In this embodiment, the gas source includes a positive gas pressure source and a negative gas pressure source. The solenoid valve 13 adopts a three-way solenoid valve, and the gas source interface 12 is connected to the positive gas pressure source and the negative gas pressure source simultaneously through a gas pipeline and a solenoid valve, so that the gas chamber 11 is alternately communicated with the positive gas pressure source and the negative gas pressure source through the three-way solenoid valve. For example, at the current moment, the gas chamber 11 is communicated with the positive gas pressure source, and at the next moment, the state of the solenoid valve changes, and the gas chamber 11 is communicated with the negative gas pressure source. The positive gas pressure source and the negative gas pressure source are two different gas sources. The positive gas pressure source can adopt an air compressor, a high-pressure gas storage tank, etc., and the negative gas pressure source can adopt a vacuum pump.

[0065] In other embodiments, the gas source may only include one of a positive air pressure source and a negative air pressure source and an atmospheric gas source, and it is not necessary to include both a positive air pressure source and a negative air pressure source. Correspondingly, the solenoid valve 13 is a three-way solenoid valve, and the gas source interface 12 is connected to both the atmospheric pressure source and the positive air pressure source (or negative air pressure source) through a gas pipeline and a solenoid valve, so that the gas chamber 11 is alternately communicated with the atmospheric pressure source and the positive air pressure source (or negative air pressure source) through the three-way solenoid valve.

[0066] In this embodiment, the air pressure range of the gas source is adjusted according to the size of the air chamber, the thickness of the elastic membrane 20, and the liquid viscosity. The typical value is between -80 kPa and 90 kPa to avoid membrane rupture or insufficient deformation. Preferably, the air pressure of the gas source is such that the elastic membrane can deform to fill the entire chamber (that is, when the elastic membrane deforms downward, it fits against the bottom of the liquid chamber 31 and squeezes out all the liquid in the liquid chamber 31). The larger the air chamber, the thicker the elastic membrane 20, and the larger the viscosity coefficient of the liquid, the greater the air pressure required for the gas source.

[0067] The solenoid valve can be connected to a computer 62 through a driver 61, so as to realize various customized driving modes for the on-off control of the gas source. Specifically, by programming on the computer, the on-off state, frequency, etc. of the solenoid valve can be directly set on the computer to achieve various customized driving modes. In other embodiments, the driver is replaced by a microcontroller (such as Arduino or LabVIEW), and the on-off control of the air pressure of the micropump is realized through programming.

[0068] The elastic membrane 20 is located in the middle layer. The elastic membrane 20 is disposed between the gas storage housing 10 and the liquid channel housing 30 to hermetically isolate the gas chamber defined by the gas storage housing 10 from the liquid chamber 31 defined by the liquid channel housing 30. The elastic membrane 20 is made of PDMS or a similar elastic material, has a uniform thickness, and generates reciprocating deformation by the air pressure in the gas chamber.

[0069] The liquid channel housing 30 is located in the lower layer. A liquid chamber 31 and two liquid channels 32 communicating with the liquid chamber 31 are defined in the liquid channel housing 30.

[0070] One-way valves 40 are provided at the outlets of the two liquid channels 32 far from the liquid chamber 31. The liquid chamber 31 and the two liquid channels 32 are all filled with liquid. One of the outlets of the two liquid channels 32 is provided with a one-way valve 40 for liquid discharge as the outlet of the micropump, and the other outlet is provided with a one-way valve 40 for liquid inlet as the inlet of the micropump. When one of the one-way valves 40 is opened, the other one-way valve 40 is closed to prevent backflow.

[0071] Therefore, when the gas chamber 11 is connected to a positive air pressure source so that the elastic membrane 20 is pressed downward and deformed, the liquid in the liquid chamber 31 is squeezed. Also, since there are one-way valves at both ends of the liquid channel 32, the liquid will be squeezed out from the outlet of the micropump (i.e., the outlet of one of the liquid channels 32). When the gas chamber 11 is connected to a negative air pressure source so that the elastic membrane 20 rebounds, the volume in the liquid chamber 31 becomes larger, and the liquid will be sucked from the inlet of the micropump to fill the liquid chamber 31. Thus, the reciprocating deformation of the elastic membrane 20 is used to drive the directional flow of the liquid.

[0072] In this embodiment, the shapes of both the gas chamber 11 and the liquid chamber 31 are hemispherical, and the openings of the gas chamber 11 and the liquid chamber 31 face each other. The elastic membrane 20 covers the openings of the gas chamber 11 and the liquid chamber 31, thereby realizing the mutual sealing of the gas chamber 11 and the liquid chamber 31 through the elastic membrane 20. In other embodiments, the shapes of the gas chamber 11 and the liquid chamber 31 do not have to be two semi - circles, and can also be any other desired structures (such as wavy, slit - shaped, etc.). As long as the openings of the gas chamber 11 and the liquid chamber 31 face each other and the elastic membrane 20 covers the openings of the gas chamber 11 and the liquid chamber 31. Different shapes of the gas chamber 11 and the liquid chamber 31 may have different effects on the liquid flow rate.

[0073] The materials of the gas storage housing 10 and the liquid channel housing 30 include but are not limited to PDMS (polydimethylsiloxane). In other embodiments, other materials that are easy to process into chambers and channels and can be bonded to the elastic membrane can also be used. Thermoplastic materials can also be used, and the thermoplastic materials are PMMA (polymethyl methacrylate) or PC (polycarbonate).

[0074] Second Embodiment: Manufacturing Method of a Micropump for an Organ - on - a - Chip

[0075] Taking the use of PDMS as an example, the manufacturing method of the micropump will be introduced below.

[0076] According to the second embodiment of the present invention, the manufacturing method of a micropump for an organ - on - a - chip specifically includes the following steps:

[0077] Step S1: Manufacture the gas storage housing 10 and the liquid channel housing 30 respectively;

[0078] When the materials of the gas storage housing 10 and the liquid channel housing 30 (i.e., the housing materials) are PDMS, first process the molds of the gas storage housing 10 and the liquid channel housing 30 through numerical control machine tool technology or three - dimensional printing technology, and then perform PDMS casting and curing based on the molds; when the materials of the gas storage housing 10 and the liquid channel housing 30 are thermoplastic materials, directly process and manufacture the gas storage housing and the liquid channel housing through injection molding process or numerical control machine tool technology;

[0079] Perform PDMS casting and curing based on the mold, specifically including: mixing the PDMS prepolymer and the curing agent in proportion, casting them into the molds of the gas storage housing 10 and the liquid channel housing 30, removing the bubbles, and then heating and curing (for example, curing for 1 hour at 80 °C).

[0080] As described above, a gas chamber 11 is defined within the gas storage housing 10, and a gas source interface 12 communicating with the gas chamber 11 is provided at the top of the gas storage housing 10. The gas source interface 12 is used to connect to a gas source to drive the deformation of the elastic membrane 20. A liquid chamber 31 and two liquid channels 32 communicating with the liquid chamber 31 are defined within the liquid channel housing 30.

[0081] Step S2: Bonding and assembling; that is, bonding the gas storage housing 10, the elastic membrane 20, and the liquid channel housing 30 together from top to bottom, where the openings of the gas chamber 11 and the liquid chamber 31 face each other and the elastic membrane 20 covers the openings of the gas chamber 11 and the liquid chamber 31, so as to realize the mutual sealing of the gas chamber 11 and the liquid chamber 31 through the elastic membrane 20.

[0082] The specific steps of step S3 include: when the materials of the gas storage housing 10 and the liquid channel housing 30 (i.e., the housing materials) are PDMS, directly bond them after plasma treatment; when the materials of the gas storage housing 10 and the liquid channel housing 30 are thermoplastic materials, perform surface silanization treatment on them after plasma treatment, and then bond them.

[0083] Step S3: Interface integration; connect two one-way valves 40 for liquid inlet and outlet respectively to the outlets of the two liquid channels 32 of the liquid channel housing 30 according to the liquid flow direction, and connect the gas source interface 12 to the gas source through an electromagnetic valve to obtain a micropump for an organ chip.

[0084] Among them, when the materials of the gas storage housing 10 and the liquid channel housing 30 are PDMS, the one-way valve 40 is directly inserted into the housing to achieve airtight connection; when the materials of the gas storage housing 10 and the liquid channel housing 30 are plastic materials, the one-way valve 40 is inserted into the housing with an O-ring to achieve airtight connection.

[0085] The third embodiment: The usage method of the micropump for an organ chip

[0086] According to the third embodiment of the present invention, the usage method of the micropump for an organ chip specifically includes:

[0087] Step S1': System connection; that is, connect the two one-way valves 40 for liquid inlet and outlet of the micropump to the liquid flow output port and the liquid flow input port of the organ chip respectively, to obtain as Figure 6 and Figure 7The organ-on-a-chip with a liquid flow delivery system as shown;

[0088] Among them, the specific structure of the micropump is exactly the same as that of the micropump in the first embodiment of the present invention.

[0089] Step S2': Use the solenoid valve 13 to control the on-off of the gas source to drive the elastic membrane 20 to reciprocally deform, and push the liquid to flow directionally through the reciprocal deformation of the elastic membrane 20.

[0090] Specifically, when the air chamber pressure increases, the elastic membrane 20 is pressed and concave, the volume of the lower liquid channel decreases, and the liquid flows out from the outflow check valve and enters the organ-on-a-chip; when the air chamber pressure decreases, the elastic membrane 20 rebounds and convexes, the volume of the lower liquid flow channel increases, and the liquid flows into the micropump from the organ-on-a-chip through the inflow check valve, and the alternating cycle realizes the directional flow of the liquid.

[0091] In this embodiment, the gas source includes a positive air pressure source and a negative air pressure source. The solenoid valve 13 adopts a three-way solenoid valve, and the gas source interface 12 is connected to the positive air pressure source and the negative air pressure source simultaneously through a gas pipeline and the solenoid valve, so that the gas chamber 11 is alternately connected to the positive air pressure source and the negative air pressure source through the three-way solenoid valve. For example, at the current moment, the gas chamber 11 is connected to the positive air pressure source, and at the next moment, the state of the solenoid valve changes, and the gas chamber 11 is connected to the negative air pressure source. The positive air pressure source and the negative air pressure source are two different gas sources. The positive air pressure source can adopt an air compressor, a high-pressure gas storage tank, etc., and the negative air pressure source can adopt a vacuum pump.

[0092] In other embodiments, the gas source can only include one of the positive air pressure source and the negative air pressure source and the atmospheric gas source, and it is not necessary to include both the positive air pressure source and the negative air pressure source. Correspondingly, the solenoid valve 13 adopts a three-way solenoid valve, and the gas source interface 12 is connected to the atmospheric pressure source and the positive air pressure source (or negative air pressure source) simultaneously through a gas pipeline and the solenoid valve, so that the gas chamber 11 is alternately connected to the atmospheric pressure source, the positive air pressure source (or negative air pressure source) through the three-way solenoid valve.

[0093] In this embodiment, the air pressure range of the gas source is adjusted according to the size of the air chamber, the thickness of the elastic membrane 20 and the liquid viscosity. The typical value is between -80 kPa and 90 kPa to avoid membrane rupture or insufficient deformation. Preferably, the air pressure of the gas source satisfies that the elastic membrane can deform to fill the entire chamber (that is, when the elastic membrane is pressed and deformed, it fits with the bottom of the liquid chamber 31 and squeezes out all the liquid in the liquid chamber 31). The larger the air chamber, the thicker the elastic membrane 20, and the larger the viscosity coefficient of the liquid, the greater the air pressure required for the gas source.

[0094] The solenoid valve can be connected to a computer through a driver, enabling various personalized driving modes for controlling the on / off of the air source. Specifically, by programming on the computer, the switching state, frequency, etc. of the solenoid valve can be directly set on the computer to achieve various personalized driving modes.

[0095] Thus, through the different sizes of the gas chamber 11 and the liquid chamber 31, in combination with different air pressures and elastic membrane driving frequencies, the pulsating liquid flow has different average flow rates (0.1 - 100 μL / min) and pulsation amplitudes (for example: a large-volume chamber with high-pressure and low-frequency driving and a small-volume chamber with low-pressure and high-frequency driving can obtain the same average flow rate, but the liquid flow of the latter is smoother than that of the former).

[0096] Fourth Embodiment: An organ-on-a-chip with a liquid flow delivery system

[0097] As Figures 6 - 10 shown, according to the fourth embodiment of the present invention, the organ-on-a-chip with a liquid flow delivery system includes a micropump for the organ-on-a-chip and the organ-on-a-chip connected to the micropump. The micropump and the flow channels in the organ-on-a-chip form the liquid flow delivery system of the organ-on-a-chip.

[0098] Among them, the structure of the micropump for the organ-on-a-chip is exactly the same as the structure of the micropump for the organ-on-a-chip in the first embodiment of the present invention, and it includes a gas storage housing, an elastic membrane, and a liquid channel housing arranged in sequence from top to bottom.

[0099] In this embodiment, as Figure 10 shown, the organ-on-a-chip is an array integrated by multiple organ-on-a-chip units 100 to form a high-throughput organ-on-a-chip to meet the high-throughput requirements; each organ-on-a-chip unit 100 is only connected to one micropump 200, so as to realize the independent driving of the organ-on-a-chip unit 100 by the micropump 200.

[0100] All the micropumps share a common air source 300 and a multi-channel solenoid valve. The multi-channel solenoid valve includes multiple solenoid valve channels and each solenoid valve channel corresponds to one micropump to achieve independent solenoid valve control. Thus, through the common air source and independent solenoid valve control, time-sharing or pressure-sharing driving is realized. The common air source is connected to the air source interfaces of each micropump 200 through the multi-channel solenoid valve. Each solenoid valve channel uses a three-way solenoid valve to achieve precise regulation. The common air source 300 can be a positive air pressure source and a negative air pressure source, or one of the positive air pressure source and the negative air pressure source and the atmospheric air source.

[0101] In other embodiments, the organ-on-a-chip only has one organ-chip unit 100, and the number of micropumps 200 is one. Then, the micropump uses an independent gas source and a conventional three-way solenoid valve to achieve precise regulation. The gas source can be a positive gas source and a negative gas source, or one of the positive gas source and the negative gas source and the atmospheric gas source. The two one-way valves of the micropump for liquid inlet and outlet are respectively connected to the liquid flow output port and the liquid flow input port of the organ chip.

[0102] Please refer to Figures 7 - 9 , for a group of organ-chip units 100 and micropumps 200, the two one-way valves 40 of the micropump for liquid inlet and outlet are respectively connected to the liquid flow output port and the liquid flow input port of the organ-chip unit 100.

[0103] The organ-chip unit 100 can be designed with various structures according to requirements, as long as there are a liquid flow output port and a liquid flow input port. The positions of the liquid flow output port and the liquid flow input port of the organ-chip unit 100 correspond to the position of the micropump 200, which can realize the direct connection between the one-way valve 40 of the micropump 200 and the organ-chip unit 100, minimizing the dead volume of peripheral equipment. In addition, if the design requirement is that the positions of the liquid flow output port and the liquid flow input port of the organ-chip unit 100 do not correspond to the position of the micropump 200, the liquid flow output port and the liquid flow input port can also be connected to the one-way valve 40 of the micropump through a silicone hose or the like.

[0104] The pneumatic unit of the micropump for the organ-on-a-chip of the present invention is based on a one-way valve to simultaneously achieve the functions of orientation and driving, ensure the unidirectional flow of liquid, change the pneumatic unit from 3 to 1, thereby reducing the number of solenoid valves required for a single micropump and the number of gas source tracheas, making the chip structure more compact, and the micropump is more suitable for large-scale liquid flow delivery of organ-on-a-chip. In addition, the micropump is connected to the organ chip through a one-way valve and is detachable relative to the organ chip. It is connected to the organ chip flow channel through simple plugging, which reduces the complexity of organ chip manufacturing, reduces the chip cost, and can be adjusted by fine-tuning the structure and size of the micropump to adapt to different organ chips.

[0105] The micropump of the present invention is independent of the chip, plug-and-play, adapts to organ chips with different structures, and is assembled with the organ chip into an integrated chip, meeting the requirements of liquid flow delivery of the organ-on-a-chip, reducing the chip size, and improving flexibility.

[0106] The above are only the preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various changes can be made to the above embodiments of the present invention. All simple, equivalent changes and modifications made according to the claims and the content of the specification of the present invention application fall within the scope of the claims of the present invention patent. The content not described in detail in the present invention is all conventional technical content.

Claims

1. A micropump for an organ chip, characterized in that: It includes an air storage housing, an elastic membrane and a liquid channel housing which are arranged in sequence from top to bottom; A gas chamber is defined in the gas storage shell, and a gas source interface communicating with the gas chamber is provided on the top of the gas storage shell, and the gas source interface is connected to the gas source through a solenoid valve; A liquid chamber and two liquid channels communicating with the liquid chamber are defined in the liquid channel housing; one-way valves are arranged at the outlets of the two liquid channels away from the liquid chamber.

2. The micropump for an organ chip according to claim 1, characterized in that: The outlet of one of the two liquid channels is provided with a one-way valve for liquid discharge to serve as the outlet of the micro pump, and the outlet of the other one is provided with a one-way valve for liquid intake to serve as the inlet of the micro pump.

3. The micropump for an organ chip according to claim 1, characterized in that: The openings of the gas chamber and the liquid chamber face each other, and the elastic membrane covers the openings of the gas chamber and the liquid chamber.

4. The micropump for an organ chip according to claim 1, characterized in that: The gas source includes a positive gas pressure source and a negative gas pressure source, the solenoid valve adopts a three-way solenoid valve, and the gas source interface is connected to the positive gas pressure source and the negative gas pressure source at the same time through a gas pipeline and a solenoid valve; Alternatively, the gas source includes one of a positive pressure source and a negative pressure source and an atmospheric gas source, the solenoid valve is a three-way solenoid valve, and the gas source interface is connected to two gas sources simultaneously through a gas pipeline and a solenoid valve.

5. The micropump for an organ chip according to claim 1, characterized in that: The solenoid valve is connected to the computer via a driver.

6. The micropump for an organ chip according to claim 1, characterized in that: The elastic film is made of PDMS, the gas storage housing and the liquid channel housing are made of PDMS or a thermoplastic material, and the thermoplastic material is PMMA or PC.

7. A method for making a micropump for an organ chip, characterized in that: include: Step S1: respectively manufacturing an air storage housing and a liquid channel housing; when the material of the air storage housing and the liquid channel housing is PDMS, firstly machining a mold by CNC machine tool technology or 3D printing technology, and then performing PDMS pouring and curing based on the mold; when the material of the air storage housing and the liquid channel housing is a thermoplastic material, directly machining and manufacturing the air storage housing and the liquid channel housing by injection molding process or CNC machine tool technology; Among them, a gas chamber is defined in the gas storage shell, and a gas source interface connected to the gas chamber is provided on the top of the gas storage shell; a liquid chamber and two liquid channels connected to the liquid chamber are defined in the liquid channel shell; Step S2: bonding the gas storage housing, the elastic membrane and the liquid channel housing together from top to bottom. When the material of the gas storage housing and the liquid channel housing is PDMS, the gas storage housing, the elastic membrane and the liquid channel housing are directly bonded after plasma treatment. When the gas storage housing and the liquid channel housing are made of thermoplastic materials, the gas storage housing, the elastic membrane and the liquid channel housing are subjected to plasma treatment, surface silanization treatment and then bonding; wherein the openings of the gas chamber and the liquid chamber are directly opposite to each other and the elastic membrane covers the openings of the gas chamber and the liquid chamber, thereby realizing that the gas chamber and the liquid chamber are sealed to each other through the elastic membrane; Step S3: Two one-way valves, respectively used for liquid inlet and liquid outlet, are connected to the outlets of the two liquid channels of the liquid channel housing according to the liquid flow direction, and the air source interface is connected to the air source through an electromagnetic valve to obtain a micropump for an organ chip; when the material of the gas storage housing and the liquid channel housing is PDMS, the one-way valve is directly inserted into the housing to achieve an airtight connection; when the material of the gas storage housing and the liquid channel housing is a plastic material, the one-way valve is added with an O-ring and then inserted into the housing to achieve an airtight connection.

8. A method for using a micropump for an organ chip, characterized in that: include: Step S1': providing a micropump for an organ chip according to any one of claims 1 to 6, and connecting two one-way valves for liquid inlet and liquid outlet of the micropump to the liquid flow outlet and liquid flow inlet of the organ chip, respectively, to obtain an organ chip with a liquid flow delivery system; Step S2': using the electromagnetic valve to control the on-off of the gas source to drive the elastic membrane to reciprocate, and the reciprocating deformation of the elastic membrane is used to promote the directional flow of the liquid.

9. An organ chip with a fluid delivery system, characterized in that: It comprises a micropump for an organ chip according to any one of claims 1 to 6 and an organ chip connected to the micropump; two one-way valves for liquid inlet and liquid outlet of the micropump are respectively connected to the liquid flow outlet and liquid flow inlet of the organ chip.

10. The organ chip with a fluid delivery system according to claim 9, characterized in that: The organ chip is an array integrated with multiple organ chip units, each organ chip unit is connected to only one micropump; all micropumps share a common air source and a multi-channel solenoid valve, the multi-channel solenoid valve includes multiple solenoid valve channels and each solenoid valve channel corresponds to a micropump; two one-way valves for liquid inlet and liquid outlet of the micropump are respectively connected to the liquid flow outlet and liquid flow inlet of the organ chip unit; Alternatively, the organ chip has only one organ chip unit, and the number of the micropump is 1.

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