CN103954658A - Dynamic real-time measuring apparatus for cell membrane potential - Google Patents
Dynamic real-time measuring apparatus for cell membrane potential Download PDFInfo
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- CN103954658A CN103954658A CN201410133539.4A CN201410133539A CN103954658A CN 103954658 A CN103954658 A CN 103954658A CN 201410133539 A CN201410133539 A CN 201410133539A CN 103954658 A CN103954658 A CN 103954658A
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- microfluidic chambers
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- hemt
- membrane potential
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Abstract
The invention relates to a dynamic real-time measuring apparatus for cell membrane potential, which comprises a gallium nitride (GaN) high electron mobility transistor (HEMT)device as a biosensor, a micro flow chamber, a micro injection pump and a liquid storage bottle. The micro flow chamber, the micro injection pump and the liquid storage bottle are connected in order to form a sealed circulatory system. The micro flow chamber is used for liquid flowing and cell injecting, and the liquid in the micro flow chamber is transmitted to the liquid storage bottle through the micro injection pump. The HEMT device as the biosensor is coupled with the micro flow chamber, and is used for detecting the real time cell membrane potential of cells in the micro flow chamber under dynamic condition.
Description
Technical field
The present invention relates to a kind of device of dynamic real-time measurement cell membrane potential.
Background technology
Human body fluid flows and can produce shear stress to cell, and then causes the variation of cell potential.Shearing force can affect many aspects of human endothelial cells biological characteristics, relevant to multiple angiocardiopathy.Whether therefore, detect cell membrane potential changes and has important physiology and pathological research meaning.
At present, the method for the cell membrane potential under measurement shearing force mainly comprises fluorescent dye method, microelectrode array method and patch-clamp method.
Fluorescent dye method is to utilize fluorescence intensity can change under shearing force effect, and the identical character of cell membrane potential variation tendency obtaining with patch-clamp, measures a kind of method of cell membrane potential.But this method reaction time and precision have larger gap, and cannot prove that at present fluorescence intensity can replace the electrophysiological phenomena of cell membrane potential characterize cells.
Microelectrode array method adopts integrated circuit silicon technology, can characterize the single myocyte of large volume or the action potential of neurocyte by microelectrode array.But existing, this method measures setup time length, accuracy of measurement and the low shortcoming of sensitivity.
Patch-clamp method is current the most frequently used method, and it is to measure voltage or the difference between current inside and outside single celled film by glass microelectrode, and by certain amplification and conversion, obtains cell membrane potential.But this technology has following congenital deficiency: biological tissue is formed by a large amount of cell close-packed arrays, and that patch-clamp can only be measured is unicellular, can not characterize the response condition of actual many cells film potential to shearing force; When measurement, can destroy cell membrane, change the characteristic of cell, short time inner cell is death, so just limited cell membrane action potential and ion channel and occur in early days the research of phenomenon; While test under fluid environment, due to the existence of shearing force, cell easily comes off from patch-clamp; Patch clamp technique can only record a cell (or a pair of cell) at every turn, and every day, only obtainable data volume was only a few to tens of, took time and effort.
In sum, fluorescent dye method, microelectrode array method and patch-clamp method all cannot solve the measurement problem of live body many cells film potential, accurately characterize the impact of shearing force cell membrane current potential.
Therefore, need a kind of device and method with multiple advantages such as detecting quick, highly sensitive, real-time measurement, result is accurate, bio-compatibility is high, many cells somatometry, carry out the measurement of cell membrane potential.
Summary of the invention
Therefore, complete the present invention for solving the above-mentioned problems in the prior art, the object of the present invention is to provide a kind of device of live body many cells film potential of real-time Measurement accuracy shearing force impact, this device has used gallium nitride (GaN) High Electron Mobility Transistor (HEMT) device technology, and shearing force microfluidic chambers, micro syringe pump and the liquid storage bottle made with certain high resiliency, surface tension macromolecular material little and high transmission rate be connected, can dynamic similation many cells environment and Real-Time Monitoring fluid environment under live body many cells film potential.
Feature of the present invention is to provide dynamic fluid environment by micro syringe pump, to realize the live body many cells film potential under Real-Time Monitoring fluid environment.
The basic structure of apparatus of the present invention is: the HEMT device as biology sensor is connected with microfluidic chambers, micro syringe pump, liquid storage bottle, provide in micro syringe pump under the prerequisite of dynamic fluid environment, by the live body many cells film potential under HEMT device Real-Time Monitoring fluid environment.
The using method of installing in the present invention is: adopt micro syringe pump and cell membrane potential pick-up unit to be connected to form hemodynamics system, this system is erected at holding temperature in 37 DEG C of constant temperature ovens and stablizes, in experiment, use PBS as fluid, and experiment whole process pass into containing 5%CO
2air to keep the potential of hydrogen of fluid environment.
The structure that is applied to the HEMT device of biology sensor in the present invention is: bottom is sapphire material, bottom is upwards followed successively by the GaN cushion of 1.6 μ m left and right, 1.2nm AlN insert layer, AlGaN barrier layer and the 1.5nm GaN cap layer of 8～15nm left and right, barrier layer al composition is between 25%～40%.Cap layer is Si above
3n
4passivation layer, is eclipsed the naked gate region that carves a block length square groove shape in the middle of passivation layer, and naked gate region is electrodeless draws, and size is within the scope of 10 μ m～10mm.
In the present invention, the manufacturing process of HEMT device is:
(1) mesa etch, adopts ICP method etching heterojunction material to form the mesa-isolated of device;
(2) deposit source-drain electrode ohmic metal, adopts the method for electron beam evaporation to obtain ohmic metal layer, and ohmic metal adopts Ti/Al/Ni/Au four-layer structure, and at 830 DEG C, annealing forms alloy, obtains good source-drain electrode Ohmic contact;
(3) adopt PECVD method deposit Si
3n
4material is as passivation layer;
(4) photoetching adopt ICP method etching Si
3n
4, expose naked gate region.
In the present invention, the structure of microfluidic chambers is: above HEMT device, covered the groove shape figure identical with naked grid of manufacturing with macromolecule polymeric material, microfluidic chambers is installed in groove.Microfluidic chambers material selection dimethyl silicone polymer (polydimethylsiloxane, PDMS) material, in addition, also can adopt polymethylmethacrylate (PMMA), the materials such as polyimide (polyimide).Microfluidic chambers reaction chamber size design and device grids figure are consistent.There is sealing-in mouth microfluidic chambers both sides, as the use of liquid flow and cell injection.Microfluidic chambers, for cultured cell, has been cultivated rear connection micro syringe pump, so that accurate flow control to be provided.There is the aperture of two diameters in 0.1mm～0.5mm left and right at microfluidic chambers two ends, can be connected with outside.Microfluidic chambers parts and HEMT device sealing, obtain an airtight passage, and solution can flow in passage, forms the cell membrane potential pick-up unit under fluid dynamics.
In the present invention, the manufacture craft of microfluidic chambers is: first adopt the method for photoetching or the method for reactive ion etching (RIE) to produce the formpiston of microfluidic chambers convex protrusion, then at formpiston top casting PDMS, after solidifying at approximately 50 DEG C of temperature, PDMS is peeled off from formpiston, can make microfluidic chambers parts.The aperture at microfluidic chambers two ends adopts boring method or additive method to obtain.The methods such as microfluidic chambers parts and HEMT chip sealing process using pressure sintering or Method for bonding.
In the present invention, the separation method of active somatic cell is: under aseptic condition, in the fresh human umbilical cord's venous blood to obtain, add 1g/L clostridiopetidase A and 2.5g/L trypsase (1:1) mixed liquor 15mL (V/V), be placed in 37 DEG C of water baths and hatch 8min, digestive juice is collected into centrifuge tube, rinse umbilical vein 2 times with phosphate buffer (PBS), washing fluid is together collected into centrifuge tube, the centrifugal 10min of 1000r/min, get supernatant, add complete culture solution re-suspended cell, make viable count after getting 0.1mL cell suspension 4g/L Trypan Blue.2 × 104/L cell is inoculated in 24 orifice plates, and every hole adds complete culture solution 1mL, is placed in 37 DEG C, 950mL/L O
2, 50mL/L CO
2in incubator, leave standstill and cultivate, and adopt the trypan blue method of exclusion, after the endothelial cell suspension that 0.1mL is mixed and 4g/L trypan blue 0.9mL mix, get 1 and count under the microscope 100 cells.In the time that cell survival rate is greater than 95% in cell suspension, can be used for carrying out primitive cell culture.
In the present invention, the cultural method of active somatic cell is: after with alcohol, HEMT device being sterilized, use fibronectin solution (fibronectin) to process 30min, to strengthen the degree of adhering to of cell.And use PBS to rinse, and inoculating cell, make cell density reach 5000～12000cells/mm
2, and ensure that cell whole process is placed in containing 5%CO
237 DEG C of constant temperature ovens in.
The shearing force that in the present invention, on the naked grid of device, cultured cells is subject to is by the following derivation of equation:
Wherein τ is the shearing force that cell is subject to, and unit is dyne/cm
2; η is that fluid is the viscosity (viscosity) of nutrient solution, and unit is g/ (cms); Q is fluid flow per second, and unit is cm
3/ s; W is the grid width of device, and h is microfluidic chambers inside wall height.By regulating every second flow of pump, the shearing force that gets final product requiredly.
In the present invention, device adopts semiconductor test analytical instrument, as Keithley4200SCS, tests the source-drain current of HEMT device, and can pass through following formula, changes into corresponding cell membrane potential.
Wherein,
for cell membrane potential, (g
m) V
dSby being added drain-source voltage V
dSunder, and gate voltage V
gS-HEMT device mutual conductance corresponding to 70mV～0V place.Because the variation of gate voltage is less, can think
be a constant, by measuring in advance.Measuring method is in advance: on same wafer and adopt the routine three end HEMT devices of identical domain, add identical drain-source voltage V
dS, test its transition curve (V
g-I
d), obtain gate voltage in-device transconductance value corresponding to 70mV～0V place.
Brief description of the drawings
Fig. 1 is structural representation of the present invention.
Fig. 2 is measuring principle figure of the present invention
Embodiment
Below in conjunction with accompanying drawing, the invention will be further described.Embodiments of the present invention include but not limited to subordinate's case.
Embodiment 1
As shown in Figure 1, 2, a kind of device of live body many cells film potential of Measurement accuracy shearing force impact, comprises HEMT device sensor, microfluidic chambers, micro syringe pump and liquid storage bottle.
In the present embodiment, active somatic cell is separated from human umbilical vein, cultivated after breeding, inject microfluidic chambers and cultivate and bonding.Device is placed in to 37 DEG C of constant temperature ovens, liquid is injected to microfluidic chambers by micro syringe pump.In experiment, use PBS as fluid, and experiment whole process pass into containing 5%CO
2air to keep the potential of hydrogen of fluid environment.Utilize HEMT device to measure the viscosity of fluid, and utilize following formula to calculate, obtain the relation of cell membrane potential and time.
The shearing force that in the present invention, on the naked grid of device, cultured cells is subject to is by the following derivation of equation:
Wherein τ is the shearing force that cell is subject to, and unit is dyne/cm
2; η is that fluid is the viscosity (viscosity) of nutrient solution, and unit is g/ (cms); Q is fluid flow per second, and unit is cm
3/ s; W is the grid width of device, and h is microfluidic chambers height.By regulating every second flow of pump, the shearing force that gets final product requiredly.
In the present invention, device adopts semiconductor test analytical instrument, as Keithley4200SCS, tests the source-drain current of HEMT device, and can pass through following formula, changes into corresponding cell membrane potential.
Wherein,
for cell membrane potential,
by being added drain-source voltage V
dSunder, and gate voltage V
gS-HEMT device mutual conductance corresponding to 70mV～0V place.Because the variation of gate voltage is less, can think
be a constant, by measuring in advance.Measuring method is in advance: on same wafer and adopt the routine three end HEMT devices of identical domain, add identical drain-source voltage V
dS, test its transition curve (V
g-I
d), obtain gate voltage in-device transconductance value corresponding to 70mV～0V place.
Although reach the object of explanation by describing exemplary embodiments of the present invention, what it will be understood to those of skill in the art that is, in not departing from as dependent claims, disclosed the scope and spirit of the present invention in the situation that, can carry out various corrections, interpolation and substitute.
Claims (8)
1. the device of a dynamic real-time measurement cell membrane potential, comprise: for the gallium nitride as biology sensor (GaN) High Electron Mobility Transistor (HEMT) device, microfluidic chambers, micro syringe pump and liquid storage bottle, it is characterized in that, described microfluidic chambers, micro syringe pump and liquid storage bottle are connected successively, form the circulation system of a sealing; Described microfluidic chambers is as the use of liquid flow and cell injection, liquid in described microfluidic chambers is transferred to described liquid storage bottle by described micro syringe pump, the described HEMT device as biology sensor and the coupling of described microfluidic chambers, the real-time cell membrane potential for detection of described microfluidic chambers inner cell under dynamic condition.
2. device according to claim 1, wherein said HEMT device is followed successively by Sapphire Substrate layer, GaN cushion, AlN insert layer, AlGaN barrier layer, GaN cap layer and Si by bottom to the accumulation layer on upper strata
3n
4passivation layer; Wherein said GaN buffer layer thickness is 1.6 μ m left and right; Described AlN insert layer thickness is 1.2nm; Described AlGaN barrier layer thickness is 8～15nm left and right; Described GaN cap layer thickness is 1.5nm; The barrier layer al composition of described HEMT device is between 25%～40%; In the middle of the passivation layer of described HEMT device, there is the naked gate region of a block length square groove shape; Electrodeless the drawing of naked gate region of described HEMT device, size is within the scope of 10 μ m～10mm; The material of the coverture of the top of described HEMT device is macromolecule polymeric material, is shaped as the groove shape figure identical with naked grid.
3. device according to claim 2, wherein said microfluidic chambers is arranged in the flute profile space of HEMT device and macromolecule polymeric material formation, and microfluidic chambers reaction chamber size design and device grids figure are consistent.
4. device according to claim 3, the manufactured materials of wherein said microfluidic chambers is selected dimethyl silicone polymer (polydimethylsiloxane, PDMS), in addition, also can adopt polymethylmethacrylate (PMMA), the materials such as polyimide (polyimide).; Microfluidic chambers comprises the sealing-in mouth of its both sides, and microfluidic chambers is connected with micro syringe pump.
5. for a HEMT device for device as claimed in claim 1, its manufacture method comprises step:
1) mesa etch, adopts ICP method etching heterojunction material to form the mesa-isolated of device;
2) deposit source-drain electrode ohmic metal, adopts the method for electron beam evaporation to obtain ohmic metal layer, and ohmic metal adopts Ti/Al/Ni/Au four-layer structure, and at 830 DEG C, annealing forms alloy, obtains good source-drain electrode Ohmic contact;
3) adopt PECVD method deposit Si
3n
4material is as passivation layer;
4) photoetching adopt ICP method etching Si
3n
4, expose naked gate region.
6. for a microfluidic chambers for device as claimed in claim 1, its manufacture method comprises step:
1) adopt the method for photoetching or the method for reactive ion etching (RIE) to produce the formpiston of microfluidic chambers convex protrusion, then at formpiston top casting PDMS, after solidifying at approximately 50 DEG C of temperature, PDMS is peeled off from formpiston, make microfluidic chambers parts;
2) aperture at microfluidic chambers two ends adopts boring method to obtain;
3) microfluidic chambers parts and HEMT chip sealing process using pressure sintering or Method for bonding.
7. the method for measurement device cell membrane potential according to claim 1, described method comprises step:
1) under aseptic condition, the fresh human umbilical cord's venous blood obtaining is added to 1g/L clostridiopetidase A and 2.5g/L trypsase (1:1) mixed liquor 15mL (V/V), be placed in 37 DEG C of water baths and hatch 8min;
2) liquid collection step 1) being obtained enters centrifuge tube, uses phosphate buffer (PBS) to rinse umbilical vein 2 times, and the liquid after rinsing is together collected into centrifuge tube, and the centrifugal 10min of 1000r/min, gets supernatant, adds complete culture solution re-suspended cell;
3) make viable count after getting 0.1mL cell suspension 4g/L Trypan Blue;
4) 2 × 104/L cell is inoculated in 24 orifice plates, every hole adds complete culture solution 1mL, is placed in 37 DEG C, 950mL/L O
2, 50mL/L CO
2in incubator, leave standstill and cultivate, and adopt the trypan blue method of exclusion, after the endothelial cell suspension that 0.1mL is mixed and 4g/L trypan blue 0.9mL mix, get 1 and count under the microscope 100 cells;
5) after HEMT device being sterilized with alcohol, use fibronectin solution (fibronectin) to process 30min, and use PBS to rinse, then inoculating cell, makes cell density reach 5000～12000cells/mm
2, and ensure that cell whole process is placed in containing 5%CO
237 DEG C of constant temperature ovens in;
6) adopt micro syringe pump and cell membrane potential pick-up unit to be connected to form hemodynamics system, this system is erected at holding temperature in 37 DEG C of constant temperature ovens to be stablized, and use PBS as fluid, and experiment whole process passes into containing 5%CO in experiment
2air to keep the potential of hydrogen of fluid environment;
7) shearing force that on the naked grid of device, cultured cells is subject to is by the following derivation of equation:
Wherein τ is the shearing force that cell is subject to, and unit is dyne/cm
2; η is that fluid is the viscosity (viscosity) of nutrient solution, and unit is g/ (cms); Q is fluid flow per second, and unit is cm
3/ s; W is the grid width of device, and h is microfluidic chambers inside wall height;
8) adopt semiconductor test analytical instrument, test the source-drain current of HEMT device, and by following formula, change into corresponding cell membrane potential:
Wherein,
for cell membrane potential,
by being added drain-source voltage V
dSunder, and gate voltage V
gS-HEMT device mutual conductance corresponding to 70mV～0V place.Because the variation of gate voltage is less, can think (g
m) V
dSbe a constant, by measuring in advance.
8. the method for measurement cell membrane potential according to claim 7, is describedly measured as in advance: on same wafer and adopt the routine three end HEMT devices of identical domain, add identical drain-source voltage V
dS, test its transition curve (V
g-I
d), obtain gate voltage in-device transconductance value corresponding to 70mV～0V place.
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Cited By (3)
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| CN105806913A (en) * | 2016-05-17 | 2016-07-27 | 西安电子科技大学 | GaN biosensor with integrated-type solid film reference electrode and producing method |
| CN106018527A (en) * | 2016-05-17 | 2016-10-12 | 西安电子科技大学 | GaN biosensor provided with integrated type solid film Pt reference electrode and manufacturing method |
| CN110389160A (en) * | 2019-06-20 | 2019-10-29 | 天津大学 | Micro- biochemical reactor for cell membrane status monitoring and preparation method thereof and cell membrane state monitoring method |
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|---|---|
| CN103954658B (en) | 2017-02-15 |
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