Chip assembly and preparation method thereof

Abstract

The invention relates to the technical field of biology, and provides a chip assembly and a preparation method thereof. The chip assembly comprises a substrate, a circuit layer, a culture piece and a microelectrode array. The microelectrode array is located in the culture tank of the culture piece, the culture tank can be used for containing the to-be-monitored organ, and the to-be-monitored organ can make contact with the substrate and make contact with the microelectrode array when located in the culture tank. The substrate and the microelectrode array are both flexible structural members, so that the substrate and the microelectrode array can deform. Therefore, when the organoid is in the culture tank and the organoid is in contact with the microelectrode array, the microelectrode array deforms to be matched with the appearance of the organoid, so that the organoid is in more sufficient contact with the microelectrode array, the signals, collected by the microelectrode array, of the organoid are more accurate, and the damage of the microelectrode array to the organoid can be reduced. The base is also a flexible structural member, and the microelectrode array arranged on the base can move correspondingly by deforming the base so as to adjust the position of the microelectrode array.

Description

TECHNICAL FIELD

[0001] The application relates to a chip assembly and a preparation method thereof, and belongs to the technical field of biology. BACKGROUND

[0002] A bioelectrode chip is a biosensor, specifically a device integrating a micro-nano electrode structure on a microchip platform, which is specially used for collecting, transmitting and regulating electrical signals in or outside a biological body, and can realize electrical physiological monitoring and stimulation of cells, tissues or organoids. The core is to accurately capture the electrical physiological signals of cells and tissues through a microelectrode array and establish a bidirectional information transmission channel.

[0003] At present, due to the irregular shape of the organoids, the bioelectrode chip is difficult to fully match the organoids, thereby leading to low accuracy of signal collection and easily causing damage to the tissues of the organoids. SUMMARY

[0004] The application provides a chip assembly and a preparation method thereof, so as to solve the problem that a biochip is difficult to match an organoid in the related art.

[0005] In order to achieve the above-mentioned purpose, the application adopts the following technical solutions:

[0006] In a first aspect, the application provides a chip assembly, comprising:

[0007] a substrate;

[0008] a circuit layer disposed on the substrate;

[0009] an insulating layer for encapsulating the circuit layer;

[0010] a culture piece disposed on the substrate, the culture piece having a culture groove and a liquid channel, the liquid channel being in communication with the culture groove, the culture groove penetrating through the culture piece, and the substrate plugging an opening of one end of the culture groove;

[0011] a microelectrode array located in the culture groove, the microelectrode array being electrically connected to the circuit layer;

[0012] wherein the substrate and the microelectrode array are both flexible structural members.

[0013] In some embodiments, the material of the substrate includes at least one of polydimethylsiloxane, polyethylene terephthalate and polyimide.

[0014] In some embodiments, the thickness of the substrate is 200 μm to 1000 μm, and the elastic modulus of the substrate is 400 kPa to 10000 kPa.

[0015] In some embodiments, the microelectrode array comprises a plurality of electrodes, one end of each of the plurality of electrodes is electrically connected to the circuit layer, and the plurality of electrodes are arranged at intervals, and the material of the electrodes comprises poly(3,4-ethylenedioxythiophene)-polystyrene sulfonic acid.

[0016] In some embodiments, among the plurality of electrodes, at least a portion of the electrodes have different lengths.

[0017] In some embodiments, the diameter of the electrodes is 10-100 μm, the length of the electrodes is 10-2000 μm, and the spacing between adjacent electrodes is 10-1000 μm.

[0018] In some embodiments, the number of liquid channels is two, and both of the liquid channels are in communication with the culture groove.

[0019] In some embodiments, the culture piece further has a flow control channel, the flow control channel is arranged around the culture groove, and the flow control channel is in communication with the liquid channel and the culture groove.

[0020] In some embodiments, the culture piece further has a plurality of connecting channels, the two sides of the connecting channels are respectively open to the side wall of the culture groove and the side wall of the flow control channel, the flow control channel is in communication with the culture groove through the connecting channels, and the plurality of connecting channels are arranged at intervals along the circumference of the flow control channel.

[0021] In some embodiments, the material of the culture piece is a silicone gel with thixotropic properties.

[0022] In a second aspect, the present application further provides a chip assembly preparation method, comprising:

[0023] providing a substrate;

[0024] forming a circuit layer on the substrate by a low-temperature plasma jet 3D printing process;

[0025] forming an encapsulation layer by a direct writing printing process, the encapsulation layer encapsulating the circuit layer;

[0026] forming a microelectrode array on one side of the substrate in the thickness direction by a low-temperature plasma jet 3D printing process, the microelectrode array being electrically connected to the circuit layer;

[0027] forming a culture piece by a direct writing 3D printing process, the culture piece being arranged on the substrate, the culture piece having a culture groove and a liquid channel, and the liquid channel being in communication with the culture groove.

[0028] In some embodiments, the substrate and the microelectrode array are both flexible structures.

[0029] In some embodiments, the material of the substrate comprises at least one of polydimethylsiloxane, polyethylene terephthalate, and polyimide.

[0030] In some embodiments, the microelectrode array is formed on one side of the substrate in the thickness direction of the substrate by the low-temperature plasma jet 3D printing process, comprising:

[0031] The poly(3,4-ethylenedioxythiophene)-polystyrene sulfonic acid ink is printed on the substrate by the low-temperature plasma jet 3D printing process to form the microelectrode array.

[0032] In some embodiments, the circuit layer is formed on the substrate by the low-temperature plasma jet 3D printing process, comprising:

[0033] The metal wire is printed on the substrate by the low-temperature plasma jet 3D printing process to form the circuit layer.

[0034] In some embodiments, the metal wire comprises at least one of gold, silver, and copper.

[0035] In some embodiments, the ink used for printing the metal wire is a corresponding nanoparticle ink, a corresponding metal salt solution, or a combination of the two.

[0036] In some embodiments, the process gas of the low-temperature plasma jet 3D printing process comprises at least one of helium, argon, and nitrogen.

[0037] In some embodiments, the flow rate of the process gas of the low-temperature plasma jet 3D printing process is 100 sccm to 3000 sccm.

[0038] In some embodiments, the culture piece is formed by the direct writing 3D printing process, comprising:

[0039] The silica gel with thixotropic properties is printed on the substrate by the direct writing 3D printing process to form the culture piece.

[0040] The chip assembly provided in the application can provide a mounting base for other components of the chip assembly, and can carry an organoid to be monitored. The microelectrode array is located in a culture tank of the culture piece, which can be used to accommodate and culture the organoid to be monitored, and the organoid to be monitored can be in contact with the base and the microelectrode array when located in the culture tank. The microelectrode array can monitor the biological signals of the organoid. The base and the microelectrode array are both flexible structural members, so that the base and the microelectrode array can deform. In this way, when the organoid is placed in the culture tank and the organoid is in contact with the microelectrode array, the microelectrode array deforms to match the shape of the organoid, so that the organoid and the microelectrode array are more fully in contact, the signals of the organoid collected by the microelectrode array are more accurate, and the damage of the microelectrode array to the organoid can be reduced. The base is also a flexible structural member, so that the base can also deform under force. By deforming the base, the microelectrode array arranged on the base can be moved correspondingly to adjust the position of the microelectrode array. In this way, the base can be deformed according to the shape of the organoid, so that the microelectrode array can more fully match and fit the organoid, and the monitoring accuracy of the chip assembly of the application can be improved.

[0041] In the preparation method of the chip assembly provided in the application, since the base is a flexible structural member, the circuit layer and the microelectrode array can be directly formed on the flexible base by the low-temperature plasma jet 3D printing process, and the preparation process is low-temperature processing, which avoids thermal damage to the base. In addition, the in-situ sintering and cross-linking effect of low-temperature plasma can overcome the difficulty of traditional 3D printing, so that the microelectrode array can have a higher aspect ratio. The direct writing 3D printing process can construct a culture piece with a self-supporting structure on a flexible base, so that an irregular three-dimensional structure culture tank can be printed according to the culture requirements of the organoid, and a liquid channel with a higher aspect ratio can also be realized. BRIEF DESCRIPTION OF DRAWINGS

[0042] In order to more clearly illustrate the technical solutions in the embodiments of the application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiments or the prior art description. Obviously, the drawings in the following description are some embodiments of the application, and other drawings can also be obtained by those skilled in the art without any creative effort.

[0043] Figure 1 The schematic diagram of the chip assembly provided in the embodiments of the application;

[0044] Figure 2 The base schematic diagram of the chip assembly provided in the embodiments of the application;

[0045] Figure 3 The schematic diagram of the microelectrode array of the chip assembly provided in the embodiments of the application;

[0046] Figure 4 A schematic view of a culture piece of a chip assembly provided by an embodiment of the present application;

[0047] Figure 5 A schematic view of a flow control channel of a culture piece of a chip assembly provided by an embodiment of the present application;

[0048] Figure 6 A schematic view of a culture piece of a chip assembly provided by an embodiment of the present application; Figure 5 An enlarged display schematic view of area A in the middle;

[0049] Figure 7 A flow schematic view of a chip assembly preparation method provided by an embodiment of the present application.

[0050] Explanation of reference signs:

[0051] 100 - substrate;

[0052] 200 - circuit layer;

[0053] 300 - culture piece; 310 - culture groove; 320 - liquid channel; 330 - flow control channel; 340 - connection channel;

[0054] 400 - microelectrode array; 410 - electrode;

[0055] 500 - packaging layer. DETAILED DESCRIPTION

[0056] In order to make the purpose, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are some of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application. The embodiments described below and the features in the embodiments can be combined with each other without conflict.

[0057] A bioelectrode chip is a kind of biosensor, specifically a device integrating micro-nano electrode structure on a microchip platform, which is specially used for collecting, transmitting and regulating electrical signals in or outside the body, and can realize the electrical physiological monitoring and stimulation of cells, tissues or organoids. The core is to accurately capture the electrical physiological signals of cells and tissues through a microelectrode array and establish a two-way information transmission channel.

[0058] At present, due to the irregular shape of organoids, it is difficult for bioelectrode chips to fully match with organoids, resulting in low accuracy of signal collection and easy damage to the tissues of organoids.

[0059] In the chip assembly proposed in this application, the substrate can provide a mounting base for other components of the chip assembly and can support the organoids to be monitored. The microelectrode array is located within a culture tank of the culture medium. The culture tank can be used to house and culture the organoids to be monitored, and when the organoids are located within the culture tank, they can contact both the substrate and the microelectrode array. The microelectrode array can monitor the biosignals of the organoids. Both the substrate and the microelectrode array are flexible structures, allowing them to deform. Thus, when the organoids are placed in the culture tank and in contact with the microelectrode array, the microelectrode array deforms to match the shape of the organoid, resulting in more complete contact, more accurate signal acquisition, and reduced damage to the organoids. The substrate is also a flexible structure, allowing it to deform under stress. By deforming the substrate, the microelectrode array mounted on it can move accordingly, adjusting its position. Therefore, the substrate can be deformed according to the shape of the organoid, so that the microelectrode array can be more fully matched and attached to the organoid, thereby improving the monitoring accuracy of the chip assembly of this application.

[0060] In the chip component fabrication method proposed in this application, since the substrate is a flexible structure, circuit layers and microelectrode arrays can be formed on the flexible substrate using low-temperature plasma jet 3D printing technology. Furthermore, the low-temperature processing avoids thermal damage to the substrate. In addition, the in-situ sintering and cross-linking effects of low-temperature plasma overcome the difficulties of traditional 3D printing, allowing the microelectrode array to have a high aspect ratio. Direct-write 3D printing technology can construct self-supporting culture media on flexible substrates, enabling the printing of irregular 3D culture tanks according to the culture requirements of organoids, and achieving a high aspect ratio for the liquid channels.

[0061] The contents of this application will now be described in detail with reference to the accompanying drawings, so that those skilled in the art can have a clearer and more detailed understanding of the contents of this application.

[0062] This application proposes a chip assembly belonging to the field of biosensors. (Reference) Figure 1 and Figure 2 As shown, the chip assembly includes a substrate 100, a circuit layer 200, a culture element 300, and a microelectrode array 400. This chip assembly can be used to culture organoids and monitor their biological signals.

[0063] The substrate 100 is the basic component of the chip assembly of this application, and the substrate 100 can provide a mounting base for at least some other components of the chip assembly. The substrate 100 has a sheet structure, which makes the thickness dimension of the substrate 100 relatively small, and the area of ​​the two sides of the substrate 100 in the thickness direction relatively large. At least some other components of the chip assembly can be disposed on the surface of one side of the substrate 100 in the thickness direction.

[0064] The circuit layer 200 is arranged on the substrate 100. Specifically, the circuit layer 200 can be arranged on one side surface of the substrate 100 in the thickness direction. The chip assembly of the present application can be electrically connected to an external circuit through the circuit layer 200, so that the chip assembly can transmit electrical signals to the external circuit. In addition, the circuit layer 200 can also be arranged in the substrate 100, so that at least part of the circuit layer 200 can be embedded in the substrate 100, so that the circuit layer 200 can also be fixed on the substrate 100.

[0065] Reference Figure 4 As shown, the culture piece 300 is arranged on the substrate 100, and specifically arranged on one side surface of the substrate 100 in the thickness direction. The culture piece 300 is a shell structure, and has a culture groove 310 and a liquid channel 320. The culture groove 310 and the liquid channel 320 are cavity structures in the culture piece 300, and the liquid channel 320 is arranged in communication with the culture groove 310. The culture groove 310 can be used to accommodate and culture the organoids to be monitored. The culture groove 310 is a through groove structure through the culture piece 300, so that the culture groove 310 has openings on both sides along its depth direction. One side opening of the culture groove 310 is opposite to the substrate 100, so that the substrate 100 blocks the one side opening of the culture groove 310. The one side surface of the substrate 100 in the thickness direction can serve as the bottom wall of the culture groove 310. When the organoids are located in the culture groove 310, the substrate 100 can carry the organoids.

[0066] The liquid channel 320 can be used to transport nutrient solution required for the culture of the organoids, so that the liquid channel 320 can transport the nutrient solution into the culture groove 310. After the nutrient solution in the culture groove 310 is absorbed by the organoids and becomes waste liquid, the waste liquid can be discharged out of the culture groove 310 through the liquid channel 320. In this way, the nutrient solution in the culture groove 310 can be replaced as needed.

[0067] The microelectrode array 400 is arranged in the culture groove 310 of the culture piece 300, and the microelectrode array 400 is electrically connected to the circuit layer 200. When the organoids are located in the culture groove 310, the organoids can be in contact with the microelectrode array 400 in the culture groove 310. The microelectrode array 400 can collect signals of the organoids and transmit the signals to an external circuit through the circuit layer 200. The circuit layer 200 can also be electrically connected to an external processing device, so that the signals monitored by the microelectrode array 400 can be transmitted to the processing device. The processing device can process the signals to obtain various parameters in the culture process of the organoids, so as to monitor the culture condition of the organoids.

[0068] The microelectrode array 400 is a flexible structure, allowing it to deform under stress. When an organoid is located in the culture tank 310 and in contact with the microelectrode array 400, the microelectrode array 400 can be inserted into the organoid. Under stress, the microelectrode array 400 undergoes micro-deformation to match the shape and dynamic deformation of the organoid, resulting in more thorough contact between the organoid and the microelectrode array 400, and more accurate signal acquisition from the organoid. Furthermore, the flexible structure of the microelectrode array 400 avoids direct, hard contact between the microelectrode array 400 and the organoid, thus mitigating damage and protecting the organoid. Therefore, the chip assembly of this application provides higher accuracy in monitoring organoid signals.

[0069] The substrate 100 is also a flexible structure, allowing it to deform under stress. This deformation enables the microelectrode array 400 mounted on the substrate 100 to move accordingly, adjusting its position. Specifically, deformation of the substrate 100 changes the orientation of the microelectrode array 400. Therefore, the substrate 100 can be deformed according to the shape of the organoid, allowing the microelectrode array 400 to fit more precisely with the organoid, thus improving the monitoring accuracy of the chip assembly in this application.

[0070] In some implementations, reference Figure 1 As shown. The chip assembly of this application may further include a packaging layer 500, which is disposed above the circuit layer 200. The packaging layer 500 can cover the circuit layer 200, thereby encapsulating the circuit layer 200 and preventing short circuits. Specifically, the packaging layer 500 covers part of the circuit layer 200, and the portion of the circuit layer 200 not covered by the packaging layer 500 is used for electrical connection with the microelectrode array 400. The misaligned edge of the packaging layer 500 and the circuit layer 200 is connected to the substrate 100, so that the packaging layer 500 can be fixed to the substrate 100 to fully protect the circuit layer 200.

[0071] In some embodiments, to make the substrate 100 of this application a flexible structural component, the material of the substrate 100 may include at least one of polydimethylsiloxane, polyethylene terephthalate, and polyimide. Specifically, the substrate 100 may be prepared from polydimethylsiloxane, polyethylene terephthalate, or polyimide, and the substrate 100 may also be prepared from a mixture of at least two of polydimethylsiloxane, polyethylene terephthalate, and polyimide.

[0072] Polydimethylsiloxane, polyethylene terephthalate, and polyimide all possess flexible and easily moldable properties, as well as low Young's modulus. This allows for better deformability of the substrate 100, and consequently, deformation of the substrate 100 enables the microelectrode array 400 to be better adapted to organoids.

[0073] In some embodiments, the thickness of the substrate 100 in this application can be set to 200 μm to 1000 μm. When the thickness of the substrate 100 is less than 200 μm, the substrate 100 is too thin, resulting in insufficient mechanical strength and making it prone to fracture under stress and deformation. An excessively thin substrate 100 also reduces the interfacial capacitance, making it unable to support the microelectrode array 400 and affecting the electrostimulation efficiency of the chip assembly for organoids. When the thickness of the substrate 100 is greater than 1000 μm, the substrate 100 is too thick, leading to a decrease in its deformability and preventing sufficient deformation to allow the microelectrode array 400 to fully match the organoid.

[0074] Therefore, by making the thickness of the substrate 100 200 μm to 1000 μm, the substrate 100 can have better deformability while maintaining a certain mechanical strength, thereby enabling the chip assembly of this application to monitor organoid signals with higher accuracy while having a stable structure.

[0075] The elastic modulus of the substrate 100 is 400 kPa to 1000 kPa, which gives the substrate 100 a moderate elastic modulus. Thus, the substrate 100 has good deformability while having a relatively stable structure.

[0076] In some implementations, reference Figure 3 As shown, the microelectrode array 400 of this application may include multiple electrodes 410, one end of each electrode 410 being electrically connected to the circuit layer 200, and the electrodes 410 being spaced apart, thus forming an array to constitute the microelectrode array 400. When the organoid is placed in the culture tank 310 of the culture medium 300, the ends of the electrodes 410 facing away from the circuit layer 200 can contact the organoid. When the electrodes 410 are energized, they can stimulate the organoid and receive the biological signals generated by the organoid. By setting multiple electrodes 410, the stimulation effect of the microelectrode array 400 on the organoid can be better, and the biological signals generated by the organoid received by the microelectrode array 400 can be more precise.

[0077] The material of the electrode 410 includes poly (3, 4-ethylenedioxythiophene)-polystyrene sulfonic acid, i.e. PEDOT: PSS. The material of the electrode 410 can adopt poly (3, 4-ethylenedioxythiophene)-polystyrene sulfonic acid and its composite material, so that the mechanical flexibility of the electrode 410 is good, and the mechanical matching with the organoid tissue is excellent. In addition, poly (3, 4-ethylenedioxythiophene)-polystyrene sulfonic acid has electronic and ionic double-conducting properties, so that the interface capacitance of the electrode 410 is high, and the impedance is low, which can significantly improve the collection sensitivity of the electrode 410 to the neural signal, and is suitable for high-fidelity monitoring of weak electrical signals in the in-vitro brain-like organ.

[0078] In some embodiments, it should be understood that different organoids can have different shapes, and the shape of some organoids is an irregular structure, so that the surface of the organoid is a non-planar structure. Referring to Figure 3 As shown, in the plurality of electrodes 410 of the microelectrode array 400 of the present application, the lengths of at least some of the electrodes 410 are different. Specifically, the lengths of the electrodes 410 can be set according to the shape of the organoid, and the length of the electrode 410 corresponding to the convex structure of the surface of the organoid can be set to be relatively short, and the length of the electrode 410 corresponding to the concave structure of the surface of the organoid can be set to be relatively long. In this way, the plurality of electrodes 410 can match the shape of the organoid, so that the plurality of electrodes 410 can be in full contact with the organoid, to improve the accuracy of the electrodes 410 in receiving the biological signals of the organoid.

[0079] Specifically, when the organoid is a brain organoid, the length of the electrode 410 can be gradually reduced in the direction from the edge of the culture groove 310 to the center of the culture groove 310, so that the microelectrode array 400 can be adapted to the brain organoid.

[0080] In some embodiments, the diameter of the electrode 410 of the present application is 10 μm to 100 μm. When the diameter of the electrode 410 is less than 10 μm, the diameter of the electrode 410 is too small. It should be understood that the impedance of the electrode 410 is inversely proportional to the area of the electrode 410, thereby resulting in too large impedance of the electrode 410, which requires an additional gain amplifier to amplify the signal, which will introduce additional noise, thereby reducing the accuracy of the chip assembly of the present application in monitoring the biological signals of the organoid. In addition, the small diameter of the electrode 410 will also result in insufficient mechanical strength of the electrode 410, which will cause the electrode 410 to be easily broken under external force, thereby causing damage to the chip assembly.

[0081] When the diameter of the electrode 410 is greater than 100 pm, the diameter of the electrode 410 is too large, which results in that the spatial resolution of the microelectrode array 400 is too low to accurately capture the single neuron signal (neuron cell body diameter is about 10 pm to 30 pm), resulting in signal crosstalk or averaging, and reducing the neural coding resolution. In addition, the diameter of the electrode 410 is too large, which results in that the hardness of the electrode 410 is too large, and thus the deformability of the electrode 410 is reduced, so that the electrode 410 is difficult to fully contact the organoid.

[0082] Therefore, by setting the diameter of the electrode 410 to 10 pm to 100 pm, the electrode 410 can have a certain structural strength while maintaining a better deformability, and the accuracy of the electrode 410 in monitoring electrical signals can also be improved.

[0083] The length of the electrode 410 of the present application is set to 10 pm to 2000 pm. When the length of the electrode 410 is less than 10 pm, the length of the electrode 410 is too short, which results in that the deformability of the electrode 410 is reduced, so that the electrode 410 is difficult to fully contact the organoid. When the length of the electrode 410 is greater than 2000 pm, the length of the electrode 410 is too long, which results in that the aspect ratio of the electrode 410 is too high, so that the mechanical strength of the electrode 410 is reduced, and the electrode 410 is easy to break when deformed under external force.

[0084] Therefore, by setting the diameter and length of the electrode 410 to 10 pm to 2000 pm, the electrode 410 can have a certain structural strength while maintaining a better deformability.

[0085] Among the plurality of electrodes 410 of the microelectrode array 400, the spacing between adjacent electrodes 410 is 10 pm to 1000 pm. When the spacing between adjacent electrodes 410 is less than 10 pm, the spacing between adjacent electrodes 410 is too small, which results in that the electrodes 410 in the microelectrode array 400 are too concentrated, so that the area of the microelectrode array 400 in contact with the organoid is small, resulting in reduced accuracy of monitoring biological signals of the organoid.

[0086] When the spacing between adjacent electrodes 410 is greater than 1000 pm, the spacing between adjacent electrodes 410 is too large, which results in that the number of electrodes 410 in the microelectrode array 400 is small, which results in that the spatial resolution of the microelectrode array 400 is too low to accurately capture the single neuron signal.

[0087] Therefore, by setting the spacing between adjacent electrodes 410 to 10 pm to 1000 pm, the accuracy of the microelectrode array 400 in monitoring biological signals of the organoid can be higher.

[0088] In some embodiments, reference is made to Figure 4As shown, the number of liquid channels 320 of the culture device 300 can be set to two, and both of the liquid channels 320 are in communication with the culture tank 310. One of the liquid channels 320 is an inlet channel, which can be connected with an external nutrient solution storage device, and the nutrient solution in the nutrient solution storage device can be delivered into the culture tank 310 through the inlet channel. The other liquid channel 320 is a discharge channel, which can be connected with an external waste liquid storage device, and the used nutrient solution in the culture tank 310 can be delivered into the waste liquid storage device through the discharge channel. By setting two liquid channels 320, the nutrient solution and the waste liquid can be prevented from mixing, so that the culture effect of the organoids in the culture tank 310 is better.

[0089] In some embodiments, with reference to Figure 4 and Figure 5 As shown, the culture device 300 also has a flow control channel 330, which is arranged around the culture tank 310, and the flow control channel 330 is in communication with the liquid channel 320 and the culture tank 310. The flow control channel 330 is a ring-shaped channel structure, and the nutrient solution delivered into the flow control channel 330 through the liquid channel 320 will flow along the flow control channel 330 to be distributed in each region of the flow control channel 330. In this way, the flow rate of the nutrient solution can be reduced, so that the flow rate of the nutrient solution entering the culture tank 310 is relatively low, which can prevent the nutrient solution with too high flow rate from impacting the organoids in the culture tank 310, thereby protecting the organoids.

[0090] In some embodiments, with reference to Figure 5 and Figure 6 As shown, the culture device 300 also has a plurality of connection channels 340, and the two sides of the connection channels 340 are respectively open to the side wall of the culture tank 310 and the side wall of the flow control channel 330, so that the connection channels 340 are in communication with the culture tank 310 and the flow control channel 330, and the flow control channel 330 is in communication with the culture tank 310 through the connection channels 340. The nutrient solution in the flow control channel 330 can be delivered into the culture tank 310 through the connection channels 340, and the waste liquid in the culture tank 310 can also be discharged into the flow control channel 330 through the connection channels 340.

[0091] The plurality of connection channels 340 are arranged along the circumference of the flow control channel 330, so that after the nutrient solution in the flow control channel 330 is delivered into the culture tank 310 through the plurality of connection channels 340, the nutrient solution can be uniformly distributed in each region of the culture tank 310, so that each part of the organoids in the culture tank 310 can be in full contact with the nutrient solution to fully absorb the nutrient solution.

[0092] When the nutrient solution in the culture tank 310 is absorbed by the organoids to form waste liquid, the waste liquid in the culture tank 310 can be discharged into the flow control channel 330 through the plurality of connecting channels 340, so that the waste liquid in each region of the culture tank 310 can be fully discharged into the flow control channel 330 and discharged into the waste liquid storage device through the liquid channel 320.

[0093] The inner diameter of the connecting channel 340 can be 10 μm-1000 μm, so that the nutrient solution in the flow control channel 330 can slowly and uniformly penetrate into the culture tank 310 through the connecting channel 340, so that the organoids in the culture tank 310 can fully absorb the nutrient solution, and the cells of the organoids can maintain metabolic homeostasis. In addition, the absorbed nutrient solution can also penetrate into the flow control channel 330 through the connecting channel 340 after becoming waste liquid.

[0094] In some embodiments, the material of the culture piece 300 of the present application can be a thixotropic silicone, and the culture piece 300 is prepared by direct writing 3D printing. In this way, the culture piece 300 can print the liquid channel 320, the flow control channel 330 and the connecting channel 340 inside the culture piece 300 without support. Specifically, the thixotropic silicone has a reduced viscosity and enhanced flowability under the action of shear force, can fill micron-level flow channels, and can quickly restore to a semi-solid state after the external force is removed, avoiding the collapse of the liquid channel 320, the flow control channel 330 and the connecting channel 340 inside the culture piece 300, so that the structure of the printed piece is stable.

[0095] In addition, the thixotropic silicone does not produce solidification by-products during the preparation of the culture piece 300 by the direct writing 3D printing process, thereby avoiding the generation of toxic substances and improving the safety and reliability of the chip assembly of the present application.

[0096] The present application also provides a chip assembly preparation method, which can prepare the above-mentioned chip assembly, and the preparation method is shown in Figure 1 and Figure 7 The method comprises the following steps:

[0097] S100, providing a substrate.

[0098] S200, forming a circuit layer on the substrate by a low-temperature plasma jet 3D printing process.

[0099] The low-temperature plasma jet 3D printing process is a low-temperature processing process, and a high-frequency power source is used to excite inert gas to generate a low-temperature plasma jet with a temperature of about 40 DEG C. In this way, the substrate 100 is in a low-temperature environment during the preparation of the circuit layer 200, and damage to the substrate 100 due to high temperature during the preparation of the circuit layer 200 can be avoided. The plasma jet also has sterilization function, and can also be sterilized synchronously during the preparation of the circuit layer 200, thereby improving the safety and reliability of the chip assembly.

[0100] S300, forming a microelectrode array on the substrate by a low-temperature plasma jet 3D printing process.

[0101] The microelectrode array is electrically connected to the circuit layer.

[0102] The low-temperature plasma jet 3D printing process is a low-temperature processing process, and in this way, the substrate 100 is in a low-temperature environment during the preparation of the microelectrode array 400, and damage to the substrate 100 due to high temperature during the preparation of the microelectrode array 400 can be avoided.

[0103] In addition, the in-situ sintering and cross-linking effect in the low-temperature plasma jet 3D printing process can overcome the problem of difficulty in traditional printing three-dimensional molding, so that the microelectrode array 400 can have a high aspect ratio to improve the performance of the microelectrode array 400.

[0104] S400, forming a culture piece by a direct writing 3D printing process.

[0105] The culture piece is arranged on the substrate, and the culture piece has a culture groove and a liquid channel, and the liquid channel communicates with the culture groove.

[0106] The direct writing 3D printing process can construct a culture piece 300 with self-supporting characteristics on the flexible substrate 100, can print a liquid channel 320 and a flow control channel 330 with a high aspect ratio according to the culture requirements of the organoid, and can also print a culture piece 300 with an irregular three-dimensional structure. The culture piece 300 is realized by a template-free integrated manufacturing, the preparation efficiency of the culture piece 300 is improved, and the preparation efficiency of the chip assembly of the present application is improved.

[0107] In some embodiments, in order to form the microelectrode array 400, the chip assembly preparation method of the present application can be realized by the following steps:

[0108] S310, printing poly(3,4-ethylenedioxythiophene)-polystyrene sulfonic acid ink on the substrate by a low-temperature plasma jet 3D printing process to form a microelectrode array.

[0109] In some embodiments, in order to form the circuit layer 200, the chip assembly preparation method of the present application can be realized by the following steps:

[0110] S210, printing the metal nanoparticle ink on the substrate by the low-temperature plasma jet 3D printing process to form the circuit layer.

[0111] Specifically, the metal nanoparticles are bombarded by the plasma high-energy particles on the surface of the substrate 100, and the surface of the metal nanoparticles is activated instantaneously, and is directly connected and formed into the circuit layer 200. In this way, the preparation efficiency of the circuit layer 200 is higher.

[0112] In some embodiments, the material of the metal nanoparticles of the present application includes at least one of gold, silver and copper, and accordingly, the material of the circuit layer 200 also includes at least one of gold, silver and copper. Gold, silver and copper materials all have good electrical conductivity, so that the electrical conductivity of the circuit layer 200 is better.

[0113] In some embodiments, the process gas of the low-temperature plasma jet 3D printing process of the present application includes at least one of helium, argon and nitrogen. After argon is ionized, a highly stable plasma jet is formed, which can still maintain uniform discharge at low temperature, so that the printing precision of the circuit layer 200 and the microelectrode array 400 is higher. The cost of using nitrogen as the process gas is lower, which can reduce the cost of the chip assembly preparation method of the present application.

[0114] In some embodiments, the flow rate of the process gas of the low-temperature plasma jet 3D printing process is 100 sccm~3000 sccm. When the flow rate of the process gas is less than 100 sccm, the flow rate of the process gas is too low, which results in insufficient density of high-energy electrons and active oxygen species in the plasma, so that the surface chemical bonds of the material cannot be fully activated, resulting in weak bonding force of the deposited layer. In addition, the low flow rate of the process gas also reduces the heat dissipation capacity, which further causes the local temperature of the substrate 100 to be too high.

[0115] When the flow rate of the process gas is greater than 3000 sccm, the flow rate of the process gas is too high, and the plasma energy density in the unit volume of the process gas is reduced, which results in that the process gas cannot fully activate the metal nanoparticles and the poly(3,4-ethylenedioxythiophene)-polystyrene sulfonic acid ink.

[0116] Therefore, by making the flow rate of the process gas of the low-temperature plasma jet 3D printing process be 100 sccm~3000 sccm, the efficiency of the chip assembly preparation method of the present application can be improved, and the structure of the chip assembly is stable and reliable.

[0117] In some embodiments, in order to form the culture piece 300, the chip assembly preparation method of the present application can include:

[0118] S410, printing the silica gel with thixotropic properties on the substrate by a direct writing 3D printing process to form the culture piece.

[0119] In this way, the culture piece 300 can have self-supporting properties during the printing process, so that the structure of the culture piece 300 is stable.

[0120] In some embodiments, the chip assembly preparation method of the present application further comprises the following steps:

[0121] S500, forming a packaging layer by a direct writing printing process, the packaging layer packaging the circuit layer.

[0122] The packaging layer 500 can package and protect the circuit layer 200.

[0123] Next, three embodiments are provided, all of which are chip assemblies prepared by the chip assembly preparation method of the present application.

[0124] Embodiment one:

[0125] First, polydimethylsiloxane (PDMS) is selected as the substrate 100, the thickness of the substrate 100 is 300 μm, and the elastic modulus is about 500 kPa, so that the substrate 100 can match the soft tissue characteristics of the brain-like organ, and good adhesion and biological compatibility are ensured.

[0126] Second, the surface of the substrate 100 is activated by low-temperature plasma jet, and the gas in the low-temperature plasma jet is oxygen, and the gas flow rate is 500 sccm.

[0127] Third, a pre-stress is applied to the surface of the substrate 100, and an Au nanoparticle ink is formed into a circuit layer 200 by in-situ printing by a plasma jet 3D printing process. The gas used in the plasma jet 3D printing process is argon, and the gas flow rate is 1000 sccm. The power source used in the plasma jet 3D printing process is an alternating current power source, and the printing rate is 50 mm / s. The wire structure in the circuit layer 200 adopts a Greek Cross morphology to enhance the flexible strain adjustment ability, and the wire width is 30 μm. The electrical conductivity of the circuit layer 200 after printing is about 1.0×10 7 S / m, which meets the electrical performance requirements of high-speed transmission of neural signals.

[0128] Fourthly, the microelectrode array 400 is prepared by low-temperature plasma jet 3D printing with pure PEDOT:PSS ink. The microelectrode array 400 is in contact with the electrical connection part of the circuit layer 200 to make the microelectrode array 400 electrically connected with the circuit layer 200. The microelectrode array 400 is arranged in 13*13, and there are 169 channels in total. The diameter of the electrode 410 of the microelectrode array 400 is 20 μm, and the height is gradiently distributed from 60 μm to 100 μm. The spacing between adjacent electrodes 410 is 150 μm, which can adapt to the surface profile of the spherical brain organ and ensure sufficient spatial resolution. The gas used in the low-temperature plasma jet 3D printing process is argon, the gas flow rate is 800 sccm, the power source used is alternating current, and the printing rate is 0.2 mm / s. Through impedance spectrum analysis of the electrode, the interface impedance value of the microelectrode array 400 is about 450 kΩ (1 kHz), which is obviously better than that of the conventional metal electrode structure.

[0129] Fifthly, the polyurethane (PU) ink is formed into the packaging layer 500 by a direct writing printing process. The thickness of the packaging layer 500 is 20 μm. The packaging layer 500 encapsulates the circuit layer 200 and the microelectrode array 400, and makes the contact site of the circuit layer 200 exposed for connecting with the external circuit, so as to connect the chip assembly with the data acquisition system. The nozzle diameter used in the direct writing printing process is 0.5 mm, and the printing rate is 5 mm / s.

[0130] Sixthly, the silicone ink with thixotropic property is used to build the culture piece 300 by direct writing printing. The culture groove 310 is circular, the diameter of the culture groove 310 is 8 mm, and the depth is 2 mm. The culture groove 310 can accommodate human iPSC induced brain organ in the development period of 7-14 days. At the same time, a pair of transmission channels 320 with a diameter of 0.8 mm for conveying nutrient solution and waste liquid respectively are connected to the two sides of the culture groove 310. Each liquid channel 320 is provided with a plurality of micropores with a diameter of 50 μm to form a perfusion bottom plate structure. In this way, slow and uniform penetration of the culture solution and discharge of the waste liquid can be realized, the cell metabolism steady state can be maintained, capillaries can be generated by adding angiogenic factors, and the necrosis of the central region of the brain organ caused by hypoxia or accumulation of metabolites can be effectively avoided. The nozzle diameter used in the direct writing printing process is 0.2 mm, and the printing rate is 20 mm / s.

[0131] Seventhly, the chip assembly is connected to the external programmable peristaltic pump, and the perfusion rate is controlled in the range of 5 μL / min-20 μL / min to realize dynamic culture solution exchange, controllable flow direction and nutrition gradient adjustment, and simulate the microcirculation perfusion environment of the brain organ under physiological conditions.

[0132] After repeated bending tests, the chip assembly as a whole can realize more than 120° bending without breaking or degradation of electrical conductivity, suitable for irregular spherical brain organ attachment and flexible operation, with excellent stretchable and multi-angle adaptive capacity. The chip assembly supports multi-module parallel connection and can be expanded to multiple culture groove layouts, realizing multi-brain organ parallel recording, multi-channel synchronous signal acquisition and perfusion regulation.

[0133] Example Two

[0134] The material of the substrate 100 is PET, and the thickness is 200 μm. Au wires are printed on the surface of the substrate 100 by a low-temperature plasma jet 3D printing process. The printing ink is HAuCl4, and the structure is a Hillbert structure and a needle-shaped three-dimensional PEDOT:PSS electrode. The height of the Au wire is 500 μm. The culture groove 310 is arranged with a column of 16-channel microelectrodes 400, and the distance between adjacent electrodes 410 is 120 μm. The impedance of the electrode 410 is lower than 400 kΩ.

[0135] Four circular culture grooves 310 are formed by controlling the printing path and program. The diameter of the culture groove 310 is 6 mm, and the bottom of the culture groove 310 is provided with two liquid channels 320, and the diameter of the liquid channel 320 is 1 mm. The diameter of the connecting channel 340 is 80 μm to ensure uniform delivery of nutrient solution and the generation of blood vessels.

[0136] The final chip assembly is used to realize the comparison of nerve signals of four cardiac organoids under different conditions, and shows the application prospect of the chip assembly in high-throughput screening of organoids.

[0137] Example Three

[0138] In this example, the substrate 100 is a PI (polyimide) film with a thickness of 100 μm, which makes the substrate 100 have higher thermal stability and mechanical strength.

[0139] The circuit layer 200 uses Cu-based ink, and the structure uses Minikowski curve design to realize scalable interconnection. After printing, plasma is used to strengthen the adhesion and conductivity of the circuit layer 200.

[0140] The density of the microelectrode array 400 is 64 channels (8x8), and each electrode 410 is a conical microneedle made of modified PEDOT:PSS. The diameter of the electrode 410 is 60 μm, and the height is 1200 μm.

[0141] On the basis of the signal acquisition function, the chip assembly of the present application also integrates a multi-modal electrochemical sensor point, which is integrated in the peripheral area of the microelectrode array 400 and the culture piece 300, for real-time monitoring of physiological and chemical parameters in the microenvironment of the organoid, such as pH value, dissolved oxygen (O2), glucose concentration and metabolic products such as lactic acid, thereby enhancing the comprehensive perception ability of the chip assembly to the state of the brain-like tissue.

[0142] The chip assembly is printed with high thixotropy silicone, has dynamic flow regulation capability, and has a micro-pump integrated interface, which is suitable for long-term multi-modal monitoring of organoids.

[0143] Example three shows the scalability of the chip assembly of the present application in the intelligent neural simulation system. The introduction of the multi-modal sensor module significantly expands the functional boundary of the chip assembly, not only improves the response ability to the changes in the microenvironment of the brain-like organoid, but also provides a hardware foundation for realizing integrated observation and regulation of structure-signal-metabolism, and provides precise multi-dimensional data support for future disease modeling, brain-like intelligence research and personalized drug efficacy evaluation.

[0144] It should be noted that the "one embodiment", "embodiment", "exemplary embodiment", "some embodiments" and the like mentioned in the specification mean that the described embodiment can include a specific feature, structure or characteristic, but not necessarily every embodiment includes the specific feature, structure or characteristic. In addition, such phrases do not necessarily refer to the same embodiment. In addition, when describing a specific feature, structure or characteristic in connection with an embodiment, it is within the knowledge of those skilled in the art to realize such feature, structure or characteristic in connection with other embodiments described explicitly or implicitly.

[0145] Generally, the terms should be understood at least partially by the usage in the context. For example, the term "one or more" used in the description can be used to describe any feature, structure or characteristic in the singular or can be used to describe the combination of features, structures or characteristics, depending at least in part on the context in which the term is used. Similarly, terms such as "a", "an" or "the" can also be understood, at least in part, depending at least in part on the context in which the terms are used, to convey a singular usage or to convey a plural usage.

[0146] It should be readily understood that "on", "above" and "over" in the present application should be interpreted in the broadest way, so that "on" not only means "directly on", but also includes the meaning of "on" with intermediate features or layers therebetween, and "above" or "over" not only includes the meaning of "above" or "over", but also can include the meaning of "above" or "over" without intermediate features or layers therebetween (i.e. directly on).

[0147] In addition, spatially relative terms, such as "beneath", "below", "lower", "above", "upper" and the like, can be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. The spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientations depicted in the figures. The devices can be otherwise oriented (rotated 90° or at other orientations) and the spatially relative descriptors used herein interpreted accordingly.

[0148] Finally, it should be noted that the above-described embodiments are merely intended for describing and illustrating, not limiting, the technical solutions of the present application; even though the present application has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions recorded in the foregoing embodiments, or equivalently replace some or all of the technical features thereof; and such modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A chip assembly, characterized by The application relates to a microelectrode array culture device. The application relates to a microelectrode array culture device. The application relates to a microelectrode array culture device. The application relates to a microelectrode array culture device. The application relates to a microelectrode array culture device. The application relates to a microelectrode array culture device.

2. The chip assembly of claim 1, wherein, The application relates to a microelectrode array culture device. The application relates to a microelectrode array culture device.

3. The chip assembly of claim 1, wherein, The application relates to a microelectrode array culture device.

4. The chip assembly of claim 3, wherein The application relates to a microelectrode array culture device. The application relates to a microelectrode array culture device.

5. The chip assembly of any of claims 1-4, wherein, The application relates to a microelectrode array culture device.

6. The chip assembly of claim 5, wherein, The application relates to a microelectrode array culture device.

7. The chip assembly of claim 6, wherein The application relates to a microelectrode array culture device.

8. The chip assembly of any one of claims 1-4, wherein, The application relates to a microelectrode array culture device.

9. A method of making a chip assembly, comprising: The application relates to a microelectrode array culture device. The application relates to a microelectrode array culture device. The application relates to a microelectrode array culture device. The application relates to a microelectrode array culture device. The application relates to a microelectrode array culture device. The application relates to a microelectrode array culture device. The application relates to a microelectrode array culture device. The application relates to a microelectrode array culture device. The application relates to a microelectrode array culture device. The application relates to a microelectrode array culture device. The application relates to a microelectrode array culture device. The application relates to a microelectrode array culture device. The application relates to a microelectrode array culture device. The application relates to a microelectrode array culture device. 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10. The chip component production method according to claim 9, wherein The substrate (100) and the microelectrode array (400) are both flexible structures; The material of the substrate (100) includes at least one of polydimethylsiloxane, polyethylene terephthalate and polyimide.

11. The chip component production method according to claim 10, wherein The microelectrode array (400) is formed on one side of the substrate (100) in the thickness direction by a low-temperature plasma jet 3D printing process, including: Poly(3,4-ethylenedioxythiophene)-polystyrene sulfonic acid ink is printed on the substrate (100) by a low-temperature plasma jet 3D printing process to form the microelectrode array (400).

12. The chip component production method according to claim 9, wherein The circuit layer (200) is formed on the substrate (100) by a low-temperature plasma jet 3D printing process, including: Metal nanoparticle ink is printed on the substrate (100) by a low-temperature plasma jet 3D printing process to form the circuit layer (200); The material of the metal nanoparticle ink includes at least one of gold, silver and copper.

13. The chip component production method according to any one of claims 9 to 12, wherein The process gas of the low-temperature plasma jet 3D printing process includes at least one of helium, argon and nitrogen. The flow rate of the process gas of the low-temperature plasma jet 3D printing process is 100 sccm~3000 sccm.

14. The chip component production method according to any one of claims 9 to 12, wherein The culture piece (300) is formed by a direct writing 3D printing process, including: Silica gel with thixotropy is printed on the substrate (100) by a direct writing 3D printing process to form the culture piece (300).

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