CN111073814B - Microneedle electrode array device and control method thereof - Google Patents
Microneedle electrode array device and control method thereof Download PDFInfo
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- CN111073814B CN111073814B CN201911275912.9A CN201911275912A CN111073814B CN 111073814 B CN111073814 B CN 111073814B CN 201911275912 A CN201911275912 A CN 201911275912A CN 111073814 B CN111073814 B CN 111073814B
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M35/00—Means for application of stress for stimulating the growth of microorganisms or the generation of fermentation or metabolic products; Means for electroporation or cell fusion
- C12M35/02—Electrical or electromagnetic means, e.g. for electroporation or for cell fusion
Abstract
The invention relates to the technical field of cell electroporation, in particular to a microneedle electrode array device and a control method thereof, and the microneedle electrode array device comprises a substrate base plate and a microneedle electrode, wherein the microneedle electrode is made of a metal material, the substrate base plate is provided with a through hole penetrating from the front surface to the back surface of the substrate base plate, the microneedle electrode is divided into a first section and a second section along the axial direction of the microneedle electrode, the first section is positioned at the outer side of the front surface of the substrate base plate, the second section is positioned in the through hole, the length of the first section is 0.5-10 mm, the diameter of the bottom of the first section is 10-200 um, and the diameter of the tip of the first section is less than 10 um. The microneedle electrode is made of a metal material, is formed by mechanical micro grinding and cutting, has a size far smaller than that of the traditional microneedle electrode, has higher mechanical strength than that of the microneedle electrode manufactured by the micro nano processing technology, is low in manufacturing cost and simple in process, and realizes cell electroporation with low voltage, low damage and high efficiency through lower cost.
Description
Technical Field
The invention relates to the technical field of cell electroporation, in particular to a microneedle electrode array device and a control method thereof.
Background
The cell electroporation is a technology for implementing drug delivery at the cell level, and the drug to be delivered is injected into a tissue in advance, and then an instantaneous strong electric field is applied around the cell, so that a plurality of nano-scale micropores are formed on the surface of a cell membrane, the permeability of the cell membrane is improved, and at the moment, exogenous macromolecular drugs or DNA, RNA, nucleic acid fragments, protein and the like which cannot enter the cell originally can enter the cell through the micropores to play the functions of cell regulation, gene transfection and the like. Since cell electroporation has the advantages of high biological safety, wide application range, high drug delivery efficiency, etc., it is becoming a technique with a wide application prospect in the biomedical field. The greatest characteristic of cell electroporation is the locality, and only the tissue within the action range of the electric field is electroporated, while the tissue cells at other parts are hardly affected. Due to this feature, practical clinical drug delivery based on electroporation of living cells has great advantages compared to expensive targeted drugs that are injected intravenously or orally. Therefore, the cell electroporation technology is widely used in the next generation of treatment technologies such as the electrochemical therapy technology for delivering chemotherapeutic drugs, the gene therapy technology for delivering gene drugs, and the like. Especially the combination of live cell electroporation and clinical chemotherapy, can reduce the dosage of chemotherapy drugs, control the killing effect on cancer cells only in the tumor area without killing normal cells, and significantly reduce the side effects in the chemotherapy process.
At present, most devices for cell electroporation in the market are plate electrodes, and are often composed of two or more metal conductor structures with the interval of 1-6 mm, so that the plate electrodes clamp tissues or two sides of skin to be electroporated, and the electroporation can be realized by hundreds of volts, which can cause serious electrical damage. Subsequently, there has been an appearance of cell electroporation using needle-shaped electrodes, which are penetrated into the inside of the tissue, instead of plate electrodes, which can reduce the operating voltage and achieve higher electroporation efficiency. However, the conventional needle electrode has a relatively large size, penetrates deeper into a tissue, causes large physical damage in the process of penetrating into the tissue, and the distance between the positive electrode and the negative electrode of the needle electrode is relatively long, so that relatively high voltage is still required to reach the electric field intensity required by cell electroporation, and the electrical damage to the tissue is still large. In recent years, thanks to the progress of micro-nano processing technology, the microneedle electrode prepared based on micro-nano processing has the characteristics of small size, short length, small distance and the like, has small physical damage and electric damage to tissues, and is gradually applied to cell electroporation.
Microneedle electrodes for electroporation of cells have been reported to use materials such as silicon, metal, and polymer. Except for the micro-needle point made of metal materials, the micro-needle structures made of other materials are very fragile, the needle point is easily broken and devices are easily damaged in the process of live cell electroporation, the processing technology of the silicon or polymer-based micro-needle electrode prepared by adopting the micro-nano processing technology is very complex, the cost is greatly increased, and the manufacturing cost is difficult to reduce through process optimization. The existing microneedle electrode based on the metal material is incompatible with the micro-nano processing technology, so that the size and the distance of the microneedle are relatively large, and the improvement degree of tissue injury is insufficient.
Meanwhile, the micro-needle electrodes of the current cell electroporation device are all designed with fixed positive and negative electrodes, namely, the same micro-needle electrode is always used as the positive electrode or the negative electrode in the application process, which can generate serious cathode effect in tissues, namely, water molecules near the negative electrodeThe electrolytic effect is accumulated to cause hydroxyl ions (OH)-) The build-up of local pH can cause damage to and even death of some of the cells, thereby causing additional damage to the electroporated tissue and reducing electroporation efficiency.
Disclosure of Invention
Technical problem to be solved
The invention aims to solve the technical problems that the existing microneedle electrode array device cannot give consideration to firm structure, small size and high density of microneedle electrodes and controllable processing cost.
(II) technical scheme
In order to solve the technical problem, the invention provides a microneedle electrode array device, which comprises a substrate and microneedle electrodes, wherein the microneedle electrodes are made of metal materials, through holes penetrating from the front to the back of the substrate are formed in the substrate, the microneedle electrodes are divided into a first section and a second section along the axial direction of the microneedle electrodes, the first section is located on the outer side of the front of the substrate, the second section is located in the through holes, the length of the first section is 0.5-10 mm, the diameter of the bottom of the first section is 10-200 um, and the diameter of the tip of the first section is smaller than 10 um.
Wherein the center distance between two adjacent microneedle electrodes is less than 1 mm.
The through hole is provided with a conductor which comprises metal rings and a metal layer, the metal rings are arranged at the end edges of the through hole on the front surface and the back surface of the substrate base plate, the metal layer is paved on the inner side wall of the through hole, the two metal rings are connected through the metal layer, and the second section is connected with the metal rings on the back surface of the substrate base plate.
The substrate base plate is provided with three groups of through holes which form array arrangement, each micro-needle electrode is connected with the through hole where the micro-needle electrode is located through a conductor, the substrate base plate is further provided with three leading-out contacts, and the three leading-out contacts are connected with the three groups of conductors in a one-to-one correspondence mode so as to provide electric pulses for the micro-needle electrodes, and the three groups of micro-needle electrodes are sequentially and alternately used as a positive electrode and a negative electrode.
The metal ring, the substrate base plate and the part of the substrate base plate except the leading-out contact are wrapped by the insulating passivation layer, the length of the part wrapping the first section is 0 at minimum, and the length of the part wrapping the first section is 0 at maximum.
The micro-needle electrode comprises a shell, a cavity penetrating through the shell is formed in the shell, a substrate base plate is installed at one end of the cavity, the tip of the micro-needle electrode points to the outside of the shell, a joint is arranged at the other end of the cavity, the leading-out contact is connected with the joint through a lead, and the lead is located in the cavity.
The shell comprises a handle arm and a tail cover, one end of the handle arm is provided with the substrate base plate, the other end of the handle arm is connected with the tail cover through a connecting part, and the joint is arranged on the tail cover.
The shell further comprises at least one extension part, the extension part is arranged between the handle arm and the tail cover, and the adjacent extension parts, the extension part and the handle arm and the extension part and the tail cover are connected through connecting parts.
The connecting part comprises a slot and a plug which are matched with each other, and the slot and/or the plug are/is arranged on the extension part, the handle arm and the tail cover.
The present invention also provides a method for controlling the microneedle electrode array device as described above, comprising: and alternately controlling one group of the three groups of the microneedle electrodes to be a positive electrode, and the other two groups of the microneedle electrodes to be a negative electrode.
(III) advantageous effects
The technical scheme of the invention has the following advantages: according to the microneedle electrode array device provided by the embodiment of the invention, microneedle electrodes are inserted into through holes which are arranged on a substrate in a penetrating manner, the exposed part above the front surface of the substrate is a first section, the part in the through holes is a second section, the diameter of the bottom of the first section close to the front surface of the substrate is 10-200 um, generally 50-200 um, the diameter of the tip far away from the front surface of the substrate is smaller than 50um, and the diameter of the bottom of the first section is always larger than that of the tip, so that the diameter of the tip is generally smaller than 10 um. The microneedle electrode is made of a metal material, is formed by mechanical micro grinding and cutting, has a size far smaller than that of the traditional microneedle electrode, has higher mechanical strength than that of the microneedle electrode manufactured by the micro nano processing technology, is low in manufacturing cost and simple in process, and realizes cell electroporation with low voltage, low damage and high efficiency through lower cost.
In addition to the technical problems addressed by the present invention, the technical features constituting the technical solutions and the advantages brought by the technical features of the technical solutions described above, other technical features of the present invention and the advantages brought by the technical features of the technical solutions will be further explained with reference to the accompanying drawings.
Drawings
Fig. 1 is a schematic structural diagram of a substrate base plate and a microneedle electrode of a microneedle electrode array device according to an embodiment of the present invention;
fig. 2 is a schematic structural view of the back side of a substrate base plate of a microneedle electrode array apparatus according to an embodiment of the present invention;
fig. 3 is a schematic structural view of a first segment of a microneedle electrode array device according to an embodiment of the present invention;
fig. 4 is a schematic structural view of a microneedle electrode array apparatus according to an embodiment of the present invention;
fig. 5 is an exploded schematic view of a housing of a microneedle electrode array apparatus according to an embodiment of the present invention;
fig. 6 is a schematic structural view of a handle arm of a microneedle electrode array device according to an embodiment of the present invention;
fig. 7 is a schematic rear perspective view of a handle arm of a microneedle electrode array device according to an embodiment of the present invention;
fig. 8 is a schematic front perspective view of a handle arm of a microneedle electrode array device according to an embodiment of the present invention;
fig. 9 is a schematic front perspective view of an elongate member of a microneedle electrode array apparatus according to an embodiment of the present invention;
fig. 10 is a schematic rear perspective view of an elongate member of a microneedle electrode array apparatus according to an embodiment of the present invention;
fig. 11 is a schematic front perspective view of a tail cap of a microneedle electrode array apparatus according to an embodiment of the present invention;
fig. 12 is a schematic rear perspective view of a tail cap of a microneedle electrode array apparatus according to an embodiment of the present invention;
fig. 13 is a schematic structural view of a through-hole of a substrate base plate of a microneedle electrode array device according to an embodiment of the present invention.
In the figure: 1: a substrate base plate; 2: a microneedle electrode; 3: an insulating passivation layer; 4: a housing; 6: a joint; 11: a through hole; 12: leading out a contact; 13: a metal ring; 21: a first stage; 41: a cavity; 42: a handle arm; 44: a tail cover; 51: a slot; 52: a plug; 431: an extension member.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
In the description of the present invention, it should be noted that, unless otherwise explicitly specified or limited, the terms "mounted," "connected," and "connected" are to be construed broadly, e.g., as meaning either a fixed connection, a removable connection, or an integral connection; can be mechanically or electrically connected; they may be connected directly or indirectly through intervening media, or they may be interconnected between two elements. The specific meanings of the above terms in the present invention can be understood in specific cases to those skilled in the art.
In addition, in the description of the present invention, unless otherwise specified, "plurality", "plural groups" means two or more, and "several", "several groups" means one or more.
As shown in fig. 1, 2 and 13, the microneedle electrode array device provided in the embodiment of the present invention includes a substrate base plate 1 and a microneedle electrode 2, the microneedle electrode 2 is made of a metal material, a through hole 11 penetrating from a front surface to a back surface of the substrate base plate 1 is formed in the substrate base plate 1, the microneedle electrode 2 is divided into a first section 21 and a second section along an axial direction thereof, the first section 21 is located at an outer side of the front surface of the substrate base plate 1, the second section is located in the through hole 11, a length of the first section 21 is 0.5mm to 10mm, a bottom diameter of the first section 21 is 10um to 200um, and a tip diameter of the first section 21 is smaller than 10 um.
In the microneedle electrode array device of the embodiment of the invention, the microneedle electrode 2 is inserted into the through hole 11 which is arranged on the substrate base plate 1 in a penetrating way, the exposed part above the front surface of the substrate base plate 1 is the first section 21, the part in the through hole 11 is the second section, the diameter of the bottom of the first section 21 close to the front surface of the substrate base plate 1 is 10 um-200 um, generally 50 um-200 um, the diameter of the tip far away from the front surface of the substrate base plate 1 is less than 50um, and the diameter of the bottom of the first section 21 is always greater than the diameter of the tip, so the diameter of the tip is usually less than 10 um. The microneedle electrode 2 is made of a metal material, is formed by mechanical micro-grinding and cutting, has a size far smaller than that of the traditional microneedle electrode, has higher mechanical strength than that of the microneedle electrode manufactured by the micro-nano processing technology, is low in manufacturing cost and simple in process, and realizes low-voltage, low-damage and high-efficiency cell electroporation by lower cost.
In this embodiment, the material of the microneedle electrode 2 may be any conductive metal or other conductive materials, such as stainless steel, gold, silver, platinum-iridium alloy, tungsten, etc., and the surface material of the microneedle electrode 2 is a material with good biocompatibility, such as 304 stainless steel, 316 stainless steel, gold, platinum-iridium alloy, etc. The material of the substrate base plate 1 can be selected from rigid silicon, glass, quartz, ceramic, FR-4 epoxy glass cloth laminated plate, etc., and flexible polyimide, polyethylene terephthalate (PET), Parylene (Parylene), etc.
Wherein, the center distance between two adjacent micro-needle electrodes 2 is less than 1 mm. The distance between the microneedle electrode 2 as the positive electrode and the microneedle electrode 2 as the negative electrode is relatively short, so that compared with the traditional microneedle electrode array device, the microneedle electrode 2 has higher arrangement density, the electric field intensity required by cell electroporation can be achieved without high voltage, and the damage degree to cell tissues during the electroporation is reduced.
The through hole 11 is provided with a conductor, the conductor comprises metal rings 13 and metal layers, the front and the back of the substrate base plate 1 are provided with the metal rings 13 at the end edges of the through hole, the metal layers are paved on the inner side walls of the through hole, the two metal rings 13 are connected through the metal layers, and the second section is connected with the metal rings 13 on the back of the substrate base plate 1. The substrate base plate 1 is provided with a through hole array, the front surface and the back surface of the substrate base plate 1 are respectively provided with a metal ring 13 around the end edge of each through hole 11, and the inner wall of each through hole 11 is paved with a metal layer to electrically conduct the metal rings 13 corresponding to the two surfaces. A micro-needle electrode 2 is arranged in each through hole 11, the tip end of each micro-needle electrode 2 points to the outside of the front surface of the substrate base plate 1, the micro-needle electrode 2 and the metal ring 13 corresponding to the through hole 11 where the micro-needle electrode is located are fixed through welding, coating of conductive adhesive or other electrical connection modes, and a connection point is formed on the metal ring 13 on the back surface of the substrate base plate 1. In this embodiment, the three lead-out contacts 12 are located on the back surface of the substrate base plate 1, and metal lines are further distributed on the substrate base plate 1, so that the metal ring 13 arrays of the three groups of substrate base plates 1 are electrically connected with the three lead-out contacts 12.
The substrate base plate 1 is provided with three groups of through holes 11 which are arranged in an array mode, each micro-needle electrode 2 is connected with the through hole 11 where the micro-needle electrode is located through a conductor, the substrate base plate 1 is further provided with three leading-out contacts 12, the three leading-out contacts 12 are connected with the three groups of conductors in a one-to-one correspondence mode so as to provide electric pulses for the micro-needle electrodes 2, and the three groups of micro-needle electrodes 2 are sequentially and alternately used as positive electrodes and negative electrodes. In this embodiment, the microneedle electrodes 2 form three groups of microneedle electrodes 2 through three groups of through holes 11, each group of microneedle electrodes 2 is connected with an external power supply through corresponding leading-out contacts 12, the leading-out contacts 12 output electric pulses to the microneedle electrodes 2 by controlling the leading-out contacts 12, each microneedle electrode 2 can be grouped and reused, and sequentially and alternately serves as a positive electrode and a negative electrode in different operation time periods, that is, the positions of one group of positive electrodes and two groups of negative electrodesThe alternative transformation of the position is not fixed, thereby avoiding that the same micro-needle electrode 2 is always used as a positive electrode or a negative electrode in the application process, and water molecules are gathered by the electrolytic effect near the negative electrode in the tissue to cause hydroxide ions (OH)-) The accumulation causes the local pH value to rise, and partial cells are injured and even die. The embodiment is suitable for the electroporation of living cells and the electrochemical therapy technology combined with the clinical chemotherapy technology, can reduce the additional damage of the cathode effect on the living cell tissues subjected to electroporation and reduce the electroporation efficiency.
As shown in fig. 1 and 13, in the present embodiment, three groups of through holes 11 are arranged in a regular hexagonal array, each group of through holes 11 includes multiple columns of through holes 11, and the columns of the three groups of through holes 11 are alternately arranged in sequence. The microneedle electrodes 2 form a regular hexagonal array arrangement on the front surface of the substrate base plate 1, in the embodiment, the regular hexagonal array is four microneedle electrodes 2 on each side, 37 microneedle electrodes 2 are totally arranged, the array of the through holes 11 is sequentially divided into three groups a, b and c from left to right according to a longitudinal array in turn, and the three groups are respectively connected with three leading-out contacts 12. In other embodiments, when the array of the microneedle electrodes 2 appears in regular hexagons of other specifications, it is also divided into three groups according to this rule. In other embodiments, the array arrangement of the through holes 11 may also take other forms, such as a rectangular array, a circular array, etc.
As shown in fig. 1, 2 and 3, the microneedle electrode array device according to the embodiment of the invention further includes an insulating passivation layer 3, the insulating passivation layer 3 wraps the metal ring 13, the portion of the substrate base plate 1 excluding the lead-out contact 12, and the length of the portion wrapping the first segment 21 is at least 0 and at most the length of the first segment 21. In this embodiment, the length of the microneedle electrode 2 exposed outside the through hole of the substrate base plate 1 is 0.5mm to 10mm, and the length of the insulating passivation layer 3 is at least 0, that is, the metal surface of the microneedle electrode 2 is completely exposed, and at most, the length of the microneedle electrode 2 is not more than the length of the microneedle electrode 2, that is, the surface of the microneedle electrode 2 is completely covered by the insulating passivation layer 3. The part of the upper part of the micro needle electrode 2, which is not wrapped by the insulation passivation layer 3, can perform electroporation on cells, so that the depth of target tissues for electroporation can be controlled by controlling the length of the insulation passivation layer 3 wrapped on the outer side of the micro needle electrode 2.
In this embodiment, the material of the insulating passivation layer 3 may be selected from Parylene (Parylene), silicon dioxide, silicon nitride, and the like.
As shown in fig. 1, 2 and 4, the microneedle electrode array device according to the embodiment of the present invention further includes a housing 4, a cavity 41 penetrating through the housing 4 is formed inside the housing 4, the substrate base plate 1 is mounted at the housing 4 at one end of the cavity 41, a tip of the microneedle electrode 2 points to the outside of the housing 4, a connector 6 is disposed at the housing 4 at the other end of the cavity 41, the lead-out contact 12 is connected to the connector 6 through a wire, and the wire is located in the cavity 41. The substrate base plate 1 and the joint 6 are fixed in a groove arranged on the shell 4, a cavity 41 communicated with the groove is arranged in the shell 4, three wires are placed in the cavity 41, the joint 6 is respectively connected with three leading-out contacts 12 on the substrate base plate 1, one wire corresponds to one leading-out contact 12, and the microneedle electrodes 2 on the three groups of through holes 11 are independently controlled.
In this embodiment, the connector 6 is a three-pin header connector, and three pin headers are respectively connected to three wires. The material of the housing 4 can be selected from metal materials such as stainless steel, aluminum alloy, iron, copper and the like, and non-metal materials such as Polytetrafluoroethylene (PTFE), acrylonitrile-butadiene-styrene copolymer plastic (ABS), polyvinylidene fluoride (PVDF), resin, nylon and the like, and the housing is processed by numerical control machining or 3D printing and the like.
As shown in fig. 4 and 5, the housing 4 includes a handle arm 42 and a tail cap 44, one end of the handle arm 42 is mounted on the substrate base plate 1, the other end of the handle arm 42 is connected to the tail cap 44 through a connecting portion, and the joint 6 is disposed on the tail cap 44. In this embodiment, the casing 4 is an operation handle, can realize simple and convenient cell electroporation operation, and the main part is the handle arm 42, and the one end setting of handle arm 42 is used for the recess of fixed substrate base plate 1, and the inside of handle arm 42 has the cavity 41 that is used for placing the wire, and recess and cavity 41 are the hollow out construction who is linked together actually. In this embodiment, the tail cap 44 may be directly connected to the handle arm 42 via a connecting portion while maintaining the original length of the handle arm 42. In other embodiments, to change the length of the housing 4, the end of the handle arm 42 may be fitted with the extension 431 and then the tail cap 44.
As shown in fig. 4, 5, 6, 7, 8, and 9, the housing 4 further includes at least one extension part 431, the extension part 431 is disposed between the handle arm 42 and the tail cover 44, and the adjacent extension parts 431, the extension part 431 and the handle arm 42, and the extension part 431 and the tail cover 44 are connected by a connection part. In order to change the final length of the housing 4, different numbers of the extension parts 431 can be continuously installed at the end of the handle arm 42 according to actual needs. The extension part 431 also has a through cavity 41, when the extension part 431 and the handle arm 42 are inserted together, the cavities 41 of the two are communicated with each other and matched at the edge, the tail cover 44 is also provided with a through cavity 41 for installing the joint 6, after the tail cover 44 and the extension part 431 are inserted together, the cavity 41 of the tail cover 44 and the cavity 41 of the extension part 431 are communicated with each other and matched at the edge, and after the lead is connected with the leading-out contact 12, the lead can sequentially pass through the cavity 41 of the handle arm 42, the cavity 41 of the extension part 431 and the cavity 41 of the tail cover 44 to be connected with the joint 6. When the length of the dedicated handle is changed, the length of the wire placed in the interior cavity 41 of the housing 4 correspondingly changes.
As shown in fig. 6, 9, 10, 11 and 12, the connecting portion includes a socket 51 and a plug 52, which are matched with each other, and the socket 51 and/or the plug 52 are disposed on the extension part 431, the handle arm 42 and the tail cover 44. The end face of the handle arm 42 can be provided with a plug slot 51, a plug 52 or both, the end face of the handle arm 42 can be provided with the plug slot 51, the plug 52 or both, the size of the plug 52 or the plug slot 51 on the extension part 431 is matched with the size of the plug 52 or the plug slot 51 on the handle arm 42, the two ends of the extension part 431 are provided with connecting parts which can be plugged with other extension parts 431 or plugged with the tail cover 44, one end of the tail cover 44 is provided with the plug slot 51, the plug 52 or both, and the size of the plug 52 or the plug slot 51 on the tail cover 44 is matched with the size of the plug 52 or the plug slot 51 on the extension part 431.
In this embodiment, each connecting portion includes four slots 51 and four plugs 52, and the end surface of the handle arm 42 is rectangular, so that four sets of slots 51 and plugs 52 that are matched with each other can be divided into two long sides and two short sides, the end surface of the handle arm 42 is provided with four slots 51, one surface of the extension part 431 is provided with four plugs 52, the other surface is provided with four slots 51, and the tail cover 44 is provided with four plugs 52.
Except for the design of the groove side wall in the handle arm 42, the side lines of each plugging surface, each plug 52, the slot 51 and the cavity 41 of the tail cover 44, the side lines and the corners of the rest parts are designed into arc shapes, so that the attractiveness and the hand-held comfort are improved.
An embodiment of the present invention further provides a method for controlling a microneedle electrode array apparatus according to the above embodiment, including: one group of the microneedle electrodes 2 on the three groups of the microneedle electrodes 2 is alternately controlled to be a positive electrode, and the other two groups of the microneedle electrodes 2 are controlled to be a negative electrode.
When the micro-needle electrode array device works, a voltage pulse signal is applied to the connector 6 by an external power supply and is finally conducted to the micro-needle electrodes 2 for cell electroporation. Keeping the state that one group of the micro-needle electrodes 2 on the three groups of through holes 11 is a positive electrode, and the other two groups are negative electrodes, the three groups of the micro-needle electrodes 2 are controlled to be the positive electrode in turn, and the remaining two groups are controlled to be the negative electrodes.
In this embodiment, the group a of microneedle electrodes 2 is used as the positive electrode, the group b and the group c of microneedle electrodes 2 are used as the negative electrode to apply the electric pulse, the group b of microneedle electrodes 2 is used as the positive electrode, the group a and the group c of microneedle electrodes 2 are used as the negative electrode to apply the electric pulse, the group c of microneedle electrodes 2 is used as the positive electrode, the group a and the group b of microneedle electrodes 2 are used as the negative electrode to apply the electric pulse, and the cycle control is performed regularly and repeatedly in sequence. Three groups of electric pulses are sequentially and alternately applied to the three groups of micro-needle electrodes 2, and parameters such as pulse amplitude, width, interval and the like are controlled by an external power supply. The control method of the microneedle electrode array device provided by the embodiment of the invention can group and multiplex the microneedle electrodes 2, and the microneedle electrodes are sequentially used as the positive electrode and the negative electrode in turn in different time periods of cell electroporation operation, so that the damage of the cathode effect on cells can be reduced.
Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (9)
1. A microneedle electrode array device, characterized in that: the micro-needle electrode comprises a substrate base plate and micro-needle electrodes, wherein the micro-needle electrodes are made of metal materials, through holes penetrating from the front surface to the back surface of the substrate base plate are formed in the substrate base plate, the micro-needle electrodes are divided into a first section and a second section along the axial direction of the micro-needle electrodes, the first section is located on the outer side of the front surface of the substrate base plate, the second section is located in the through holes, the length of the first section is 0.5 mm-10 mm, the diameter of the bottom of the first section is 10 um-200 um, the diameter of the tip of the first section is smaller than 10um, electric conductors are arranged at the through holes, the substrate base plate is provided with three groups of through holes arranged in an array mode, the through holes of the three groups are alternately arranged in sequence, each group of the micro-needle electrodes is connected with the through holes at the micro-needle electrodes through electric conductors, the substrate base plate is further provided with three leading-out contacts, and the leading-out contacts are connected with the electric conductors in a one-to-one correspondence manner, so as to provide electric pulse for the micro-needle electrodes, and the three groups of micro-needle electrodes are sequentially and alternately used as a positive electrode and a negative electrode.
2. The microneedle electrode array device according to claim 1, wherein: the center distance between two adjacent microneedle electrodes is less than 1 mm.
3. The microneedle electrode array device according to claim 1, wherein: the conductive body comprises metal rings and metal layers, the metal rings are arranged at the end edges of the through holes on the front surface and the back surface of the substrate base plate, the metal layers are paved on the inner side walls of the through holes, the two metal rings are connected through the metal layers, and the second section is connected with the metal rings on the back surface of the substrate base plate.
4. A microneedle electrode array device according to claim 3, wherein: the insulating passivation layer wraps the metal ring and the part of the substrate base plate except the lead-out contact, and the length of the part wrapping the first segment is 0 minimum and 0 maximum.
5. A microneedle electrode array device according to claim 3, wherein: the micro-needle electrode is characterized by further comprising a shell, a cavity penetrating through the shell is formed in the shell, the substrate base plate is installed at one end of the cavity, the tip of the micro-needle electrode points to the outside of the shell, a joint is arranged at the position of the shell at the other end of the cavity, the leading-out contact is connected with the joint through a lead, and the lead is located in the cavity.
6. The microneedle electrode array device according to claim 5, wherein: the shell comprises a handle arm and a tail cover, one end of the handle arm is provided with the substrate base plate, the other end of the handle arm is connected with the tail cover through a connecting part, and the joint is arranged on the tail cover.
7. The microneedle electrode array device according to claim 6, wherein: the shell further comprises at least one extension part, wherein the extension part is arranged between the handle arm and the tail cover, and the adjacent extension parts, the extension part and the handle arm and the extension part and the tail cover are connected through connecting parts.
8. The microneedle electrode array device according to claim 7, wherein: the connecting part comprises a slot and a plug which are matched with each other, and the slot and/or the plug are/is arranged on the extension part, the handle arm and the tail cover.
9. A method of controlling a microneedle electrode array device according to any one of claims 1 to 8, comprising: the method comprises the following steps: and alternately controlling one group of the three groups of the microneedle electrodes to be a positive electrode, and the other two groups of the microneedle electrodes to be a negative electrode.
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