CN119391527A - Microfluidic devices and nerve cell action potential detection system - Google Patents
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Abstract
本发明涉及一种微流控器件，包括由下至上依次排列的基板、微流道层、多孔微电极阵列和细胞培养层，微流道层固定在基板上，多孔微电极阵列的至少部分固定于微流道层和细胞培养层之间，细胞培养层与微流道层固定；细胞培养层上设有第一通孔和第二通孔，微流道层靠近细胞培养层的一面上设有第一盲孔、第二盲孔和微流通道，微流通道的两端分别与第一盲孔和第二盲孔连通，第一通孔与第一盲孔对齐，多孔微电极阵列的位于微流道层和细胞培养层之间的部分上设有多个第三通孔，第一通孔和第一盲孔通过各第三通孔中的至少部分相互连通，第二通孔与第二盲孔对齐并相互连通。
The present invention relates to a microfluidic device, comprising a substrate, a microfluidic layer, a porous microelectrode array and a cell culture layer arranged in sequence from bottom to top, wherein the microfluidic layer is fixed on the substrate, at least part of the porous microelectrode array is fixed between the microfluidic layer and the cell culture layer, and the cell culture layer is fixed to the microfluidic layer; a first through hole and a second through hole are arranged on the cell culture layer, a first blind hole, a second blind hole and a microfluidic channel are arranged on a side of the microfluidic layer close to the cell culture layer, two ends of the microfluidic channel are respectively connected to the first blind hole and the second blind hole, the first through hole is aligned with the first blind hole, a portion of the porous microelectrode array located between the microfluidic layer and the cell culture layer is provided with a plurality of third through holes, the first through hole and the first blind hole are connected to each other through at least part of each of the third through holes, and the second through hole is aligned with the second blind hole and connected to each other.
Description
Technical Field
The invention relates to the fields of neuroscience and biomedical engineering, in particular to a microfluidic device and a nerve cell action potential detection system.
Background
In vitro detection of neuronal action potentials is of great importance in neuroscience research. Action potential is a basic unit for transmitting information by nerve cells, and the working principle of a nerve circuit can be deeply revealed and the pathological process of the nervous system diseases can be clarified by researching the generation, transmission and regulation mechanisms of the action potential. In addition, the in vitro detection technology has wide application potential in the fields of drug screening, development of new therapies, early diagnosis of neurodegenerative diseases and the like. Therefore, the development of the high-efficiency and accurate in-vitro neuron action potential detection technology is not only important to the basic research of neuroscience, but also plays a key role in diagnosis and treatment of the neurological diseases.
Action potentials are induced by the depolarization and repolarization processes of the neuronal membrane. When the nerve cells receive external stimuli, the membrane potential rises rapidly from the resting potential (typically-60 to-70 mV), and beyond the threshold potential, the trigger voltage gates the opening of the sodium ion channel, resulting in rapid influx of sodium ions, causing the membrane potential to rapidly reach positive values (+30 to +50 mV), a stage known as depolarization. Subsequently, the sodium channel is closed, the potassium channel is opened, the potassium ion flows out, and the membrane potential returns to the rest level, a process called repolarization. Currently, technologies for detecting neuronal action potentials in vitro are mainly divided into the following two categories:
1. patch Clamp technology (Patch-Clamp technology)
Patch clamp technology is a gold standard method for detecting neuronal action potentials. The technology can directly record the potential difference at two sides of the cell membrane and accurately measure the action potential of a single neuron. The patch clamp technology has the main advantages of high detection precision, capability of detecting very fine electrophysiological changes, extremely high time and voltage resolution (which can reach millivolt magnitude), capability of accurately controlling cell membrane voltage and capability of researching neuron reactions under different voltage conditions. However, the technology has obvious limitations that only single cells can be detected at a time, the group analysis of the nerve circuit is difficult to realize, the requirement of large-scale experiments cannot be met, the technical requirements are high, the operation is complicated, the experiment cost is high, and long-time recording is difficult to carry out.
2. Microelectrode array technology (Microelectrode Array, MEA)
Microelectrode array technology records action potential discharges of neuronal populations by planar electrodes. Its main advantages include that the technology can detect the electric activity of a large number of neurons at the same time, and is helpful for the research of nerve loops. However, the technology has some defects, because the contact surface between the electrode and the neuron is not tight enough, the electrode is generally in a plane structure, the nerve tissue is often in a curved surface structure, the acquired signal is weaker, the signal to noise ratio is lower, and in the long-time detection process, the displacement between the electrode and the nerve tissue can occur, so that the detection accuracy is affected.
Disclosure of Invention
The invention aims to provide a microfluidic device and a nerve cell action potential detection system, which can not only meet the requirement of simultaneous detection of a large number of neurons, but also maintain good acquisition signal to noise ratio so as to solve the limitations of the prior art and provide an advanced test platform for the research of complex nerve networks and nerve diseases.
According to the purpose, the micro-fluidic device comprises a substrate, a micro-channel layer, a porous micro-electrode array and a cell culture layer which are sequentially arranged from bottom to top, wherein the micro-channel layer is fixed on the substrate, at least part of the porous micro-electrode array is fixed between the micro-channel layer and the cell culture layer, the cell culture layer is fixed with the micro-channel layer, a first through hole and a second through hole are formed in the cell culture layer, a first blind hole, a second blind hole and a micro-channel are formed in one surface of the micro-channel layer, which is close to the cell culture layer, two ends of the micro-channel are respectively communicated with the first blind hole and the second blind hole, the first through hole is aligned with the first blind hole, a plurality of third through holes are formed in a part of the porous micro-electrode array, which is positioned between the micro-channel layer and the cell culture layer, the first through holes are communicated with each other through at least part of the third through holes, and the second through holes are aligned with the second blind holes and communicated with each other.
Further, a culture groove is formed in one surface, far away from the micro-channel layer, of the cell culture layer, and the first through hole is located in the culture groove.
Further, the microchannel layer and the cell culture layer are both made of polydimethylsiloxane material.
Further, the porous microelectrode array comprises a substrate, a first packaging layer, a conducting wire layer, a bonding pad layer and a second packaging layer which are sequentially arranged from bottom to top, wherein the conducting wire layer is used for forming a plurality of electrode sites for acquiring nerve signals, and the bonding pad layer is used for transmitting the signals to a signal acquisition device.
Further, the porous microelectrode array is divided into a first part and a second part, each third through hole is positioned on the first part, and the bonding pad layer is positioned on the second part.
Further, the first encapsulation layer and the second encapsulation layer are both made of SU-8 material.
Further, the sizes of the third through holes are all the same or are partially the same or different.
Further, each third through hole is uniformly disposed around each electrode site.
Further, the substrate, the microchannel layer, the porous microelectrode array and the cell culture layer are all sequentially fixed together by heating and curing a polydimethylsiloxane precursor solution.
The invention further provides a nerve cell action potential detection system which comprises a signal acquisition device, a pressure controller and the microfluidic device, wherein the signal acquisition device is connected with the porous microelectrode array of the microfluidic device and used for acquiring nerve cell action potential signals, and the pressure controller is connected with the second through hole of the microfluidic device and used for providing negative pressure for the second through hole so as to enable nerve tissues in nerve cell culture solution to be tightly adsorbed on the porous microelectrode array.
The micro-fluidic device and the nerve cell action potential detection system are characterized in that the porous microelectrode array is provided with a plurality of third through holes, so that nerve tissues can be tightly adsorbed on the porous microelectrode array under the action of negative pressure, the collected signals are stronger, the signal to noise ratio is higher, a large number of nerve cells can be simultaneously detected, the detection flux is high, and the first packaging layer and the second packaging layer of the porous microelectrode array are made of SU-8 materials, so that a small amount of deformation can be generated, the cell adhesion is better, and the signal to noise ratio of the collected signals is further improved.
Drawings
Fig. 1 is a schematic structural diagram of a microfluidic device according to an embodiment of the present invention;
Fig. 2 is an exploded view of a microfluidic device according to an embodiment of the present invention;
fig. 3 is a cross-sectional view of a porous microelectrode array of a microfluidic device according to an embodiment of the present invention.
Detailed Description
Preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings.
As shown in fig. 1 and 2, the embodiment of the invention provides a microfluidic device, which comprises a substrate 100, a micro-channel layer 200, a porous microelectrode array 300 and a cell culture layer 400 which are sequentially arranged from bottom to top, wherein the micro-channel layer 200 is fixed on the substrate 100, at least part of the porous microelectrode array 300 is positioned between the micro-channel layer 200 and the cell culture layer 400 and is respectively fixed with the micro-channel layer 200 and the cell culture layer 400, the cell culture layer 400 is fixed with the micro-channel layer 200, a first through hole 410 and a second through hole 420 are arranged on the cell culture layer 400, a first blind hole 210, a second blind hole 220 and a microfluidic channel 230 are arranged on one surface of the micro-channel layer 200, which is close to the cell culture layer 400, two ends of the microfluidic channel 230 are respectively communicated with the first blind hole 210 and the second blind hole 220, the first through hole 410 is aligned with the first blind hole 210, a part of the porous microelectrode array 300 positioned between the micro-channel layer 200 and the cell culture layer 400 covers the first blind hole 410 and is provided with a plurality of third through holes, the first through holes 410 and the first blind holes 420 are mutually communicated with at least part of the second blind holes 220 through the third through holes 420. In use, the neural cell culture fluid can be injected into the first through hole 410 and a certain negative pressure is applied at the second through hole 420, under the action of the negative pressure, the neural cell culture fluid sequentially passes through the first through hole 410, the third through hole on the porous microelectrode array 300, the first blind hole 210, the microfluidic channel 230, the second blind hole 220 and the second through hole 420 and flows out of the second through hole 420, under the action of the negative pressure, the neural tissue is tightly adsorbed on the porous microelectrode array 300, and then the porous microelectrode array 300 can simultaneously detect the electrical activity of a large number of neurons. Because the porous microelectrode array 300 is provided with the plurality of third through holes, negative pressure can be applied to the second through holes 420, so that nerve tissue is tightly adsorbed on the porous microelectrode array 300 under the action of the negative pressure, and compared with the prior scheme that the nerve tissue is directly placed on the microelectrode array, the contact between the nerve tissue and the porous microelectrode array 300 is tighter, so that the acquired signal is stronger and the signal-to-noise ratio is higher.
In some embodiments, a culture groove 430 is formed on a surface of the cell culture layer 400 away from the micro flow channel layer 200, the first through hole 410 is located in the culture groove 430, the culture groove 430 is used for containing a neural cell culture solution, when in use, the neural cell culture solution can be injected into the culture groove 430, then negative pressure is applied to the second through hole 420, under the action of the negative pressure, the neural cell culture solution in the culture groove 430 is sucked into the first through hole 410, and flows out from the second through hole 420 after sequentially passing through the third through hole, the first blind hole 210, the micro flow channel 230 and the second blind hole 220, and meanwhile, the neural tissue is tightly adsorbed on the porous microelectrode array 300 under the action of pressure.
In some embodiments, the culture tank 430 is a rectangular tank with a depth of 2 mm, a length and a width of the rectangular tank can be set according to needs, diameters of the first through hole 410 and the first blind hole 210 are 4 mm, diameters of the second through hole 420 and the second blind hole 220 are 3 mm, a depth and a width of the microfluidic channel 230 are 1mm, and a length of the microfluidic channel 230 can be set according to needs.
In some embodiments, both the microchannel layer 200 and the cell culture layer 400 are made of Polydimethylsiloxane (PDMS) material. Specifically, the high-precision molds of the micro flow channel layer 200 and the cell culture layer 400 can be prepared by using a 3D printing or Computer Numerical Control (CNC) processing mode, then the PDMS precursor solution (prepared by mixing a PDMS base monomer and a curing agent according to a ratio of 10:1) is poured onto the prepared molds, and placed in a vacuum environment to remove bubbles, and then placed in an 80 ℃ oven for 3 hours, PDMS is cured, and then the micro flow channel layer 200 and the cell culture layer 400 can be obtained by demolding and punching.
In some embodiments, the substrate 100 may be made of a glass material.
As shown in fig. 3, in some embodiments, the porous microelectrode array 300 includes a substrate 310, a first encapsulation layer 320, a conducting wire layer 330, a bonding pad layer 340 and a second encapsulation layer 350 sequentially disposed from bottom to top, the conducting wire layer 330 may include chromium, gold, and chromium sequentially disposed from bottom to top, the bonding pad layer 340 may include chromium, nickel, and gold sequentially disposed from bottom to top, the conducting wire layer 330 is used to form a plurality of electrode sites for acquiring nerve signals, the bonding pad layer 340 is connected with a customized signal acquisition device for conducting electrical signals, the porous microelectrode array 300 may be divided into two parts, i.e., a first part in a dashed frame and a second part outside the dashed frame in fig. 3, the first part is a part sandwiched between the cell culture layer 400 and the micro-channel layer 200, the first part is provided with a plurality of third through holes 360, the bonding pad layer 340 is located on the second part, and the second part is located outside the cell culture layer 400 and the micro-channel layer 200 for facilitating connection of the bonding pad layer 340 with the signal acquisition device and conducting electrical signals.
In some implementations, the dimensions of each third through-hole 360 may be all the same, e.g., about the same as the dimensions of the electrode site, or the dimensions of each third through-hole 360 may be partially the same, or the dimensions of each third through-hole 360 may be different. The third through holes 360 may be uniformly disposed around the electrode sites so that the nerve tissue may be better adhered to the electrode sites.
In some implementations, the first encapsulation layer 320 and the second encapsulation layer 350 are both made of SU-8 material, SU-8 is a negative photoresist based on epoxy, which is softer, while the bottom of the first portion of the porous microelectrode array 300 is free of substrate, and the electrode sites of the lead layer 330 are covered only by the first encapsulation layer 320 and the second encapsulation layer 350, so that the first portion will have flexibility, be bendable, and the electrodes can be formed in a curved configuration, so that the contact surface with nerve tissue is larger, further improving the signal to noise ratio of the acquired signal.
The assembling method of the microfluidic device of the embodiment of the invention comprises the following steps:
Firstly, the pre-prepared substrate 100, the micro flow channel layer 200, the porous microelectrode array 300 and the cell culture layer 400 are obtained, then PDMS precursor solution is coated on the contact surfaces among the four components, for example, the PDMS precursor solution is coated on the upper surface of the substrate 100, the lower surface and the upper surface of the micro flow channel layer 200, the upper surface and the lower surface of the porous microelectrode array 300 and the lower surface of the cell culture layer 400, and when the PDMS precursor solution is coated, the first through hole 410, the second through hole 420, the first blind hole 210, the second blind hole 220, the micro flow channel 230 and the third through hole 360 are avoided, then the components are aligned and stacked together in sequence, and the stacked components are heated to solidify the PDMS precursor solution, so that the assembly among the components is realized.
The embodiment of the invention also provides a nerve cell action potential detection system, which comprises a signal acquisition device, a pressure controller and the micro-fluidic device, wherein the signal acquisition device is connected with the porous microelectrode array 300 of the micro-fluidic device and is used for acquiring nerve cell action potential signals, and the pressure controller is connected with the second through hole 420 through an air pipe and is used for providing stable negative pressure for the second through hole 420, so that nerve tissues in nerve cell culture solution are tightly adsorbed on the porous microelectrode array 300, and the nerve cell action potential detection system and the nerve cell action potential detection method can be tightly attached.
The working process of the nerve cell action potential detection system is as follows:
The nerve cell culture solution is injected into the culture tank 430, then a certain pressure (namely negative pressure) for extracting the culture solution outwards is applied to the second through hole 420 through the pressure controller, so that the culture solution flows from the culture tank 430 to the second through hole 420, in the flowing process, nerve tissues are tightly attached to the porous microelectrode array under the action of the negative pressure, each electrode of the porous microelectrode array transmits nerve cell potential signals to the signal acquisition device, and the signal acquisition device acquires the nerve cell potential signals.
According to the microfluidic device and the nerve cell action potential detection system, the porous microelectrode array 300 is provided with the plurality of third through holes, so that nerve tissues can be tightly adsorbed on the porous microelectrode array 300 under the action of negative pressure, the collected signals are stronger, the signal to noise ratio is higher, a large number of nerve cells can be detected simultaneously, the detection flux is high, the first packaging layer 320 and the second packaging layer 350 of the porous microelectrode array 300 are made of SU-8 materials, and therefore small amount of deformation can be generated, the cell adhesion is better, and the signal to noise ratio of the collected signals is further improved.
The foregoing description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention, and various modifications can be made to the above-described embodiment of the present invention. All simple, equivalent changes and modifications made in accordance with the claims and the specification of this application fall within the scope of the patent claims. The present invention is not described in detail in the conventional art.
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