CN1117279C - Multifunctional cytomicrophysiological meter for screening medicines - Google Patents
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- CN1117279C CN1117279C CN 00134795 CN00134795A CN1117279C CN 1117279 C CN1117279 C CN 1117279C CN 00134795 CN00134795 CN 00134795 CN 00134795 A CN00134795 A CN 00134795A CN 1117279 C CN1117279 C CN 1117279C
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Abstract
The present invention relates to a multifunctional cytomicrophysiological meter for screening medicines. A multifunctional cell sensor sensitive to various ions of extracellular metabolic products of living cells is designed, various ion sensitive elements are manufactured, and various light sources with different stimulating frequencies are used for stimulating corresponding ion sensitive elements. A digital compensation filter is used for correcting the frequency response characteristic of the sensor so that the sensor has the same signal-to-noise ratio and testing precision to the response signals produced by simulating the light sources. FFT calculation is carried out by a computer, and the response results of the cell sensor to various tested substances under different stimulating frequencies are calculated out. The multifunctional cytomicrophysiological meter can simultaneously measure and analyze the concentration change of various ions, such as H<+>, K<+>, Na<+>, Ca<2+>, Cl<->, etc., and organic compositions in extracellular microenvironment; the multifunctional cytomicrophysiological meter can quantitatively analyze the influence of different medicines and different concentrations on the metabolism and the state of stimulation cells, and can be used for quantitatively screening different medicines, effective components thereof and concentrations thereof.
Description
The present invention relates to a kind of little physiology meter of multi-functional cell that is used for drug screening.
The little physiology meter of cell is to be proposed first by U.S. molecular device company in 1992, its ultimate principle is with living cells and Light Addressable Potentiometric Sensor LAPS (the Light Addresable PotentiometricSensor) formation that combines cell sensor, cell is as the sensor of responsive outside stimulus such as medicine, the composition of medicine can be reflected in born of the same parents outer potential of hydrogen, i.e. H in the cellular metabolism
+The variation of ion concentration or pH value, this variation is come out by the LAPS sensor again.The basic structure of LAPS is EIS (electrolyte/insulation course/silicon), promptly generates an insulation course SiO on semiconductor silicon Si
2, then at SiO
2Deposit Si above again
3N
4Layer is as H
+Sensitive thin film, the pH value variation that is used for measuring solution.Adopt front or the back side of the rayed of certain modulating frequency, just can in external circuit, measure electric current at device.The size of electric current, relevant with thickness (promptly outer bias voltage) of light intensity, depletion layer etc.When light intensity was constant, photocurrent thickened and increases with depletion layer.That is to say the increase with applying bias, the electric current on the external circuit is from reaching maximal value (saturation region) near zero (cut-off region) linear increase (zone of transition).When fixing other parameters, only consider of the influence of the response voltage of ion sensitive membrane and tested gas to depletion layer, the variation of extrinsic current size has just reflected the response of sensitive membrane to ion so, therefore can be applicable to the detection of solution composition and concentration.
Fig. 1 is the structural representation of the little physiology meter of cell of U.S. molecular device company.By producing the alternating signal of certain modulating frequency behind signal source and the driving circuit, drive upper surface or the lower surface irradiation of excitation source at LAPS, measure in the external circuit and be inspired corresponding photocurrent, the size of photocurrent has just reflected the response of sensitive membrane to fluid to be measured.General external circuit adopts three electrodes or two electrode working methods as shown in Figure 1.Contrast electrode is used to the reference potential that provides fixing, and electrode is used for providing certain bias voltage to LAPS, adopts Ohmic contact on working electrode and the LAPS substrate and and to forming a current path between the electrode.The photocurrent response of sensor alternation is converted to voltage signal by continuous current/potentiostat with photocurrent, and the voltage signal of continuous current/potentiostat output carries out the amplification and the pre-service of signal with lock-in amplifier, finally enters computing machine and provides measurement result.
The little physiology meter of cell of U.S. molecular device company invention medicinal application aspect be according to extracellular environment in H
+The rate of change of ion concentration or pH value is measured interested effective ingredient and effective concentration.Can make behind the drug effect H in the extracellular environment by little physiology meter
+The response curve of the rate of change of ion concentration, as shown in Figure 2.Can obtain simultaneously the characteristic concentration of medicine activator of 50% correspondence of little physiology meter peak response, as shown in Figure 3.Its result is consistent with the data that traditional Biochemistry Experiment records.
The subject matter that present instrument exists is can only detect extracellular acidity to change, and can not detect extracellular different kinds of ions and constituent analysis simultaneously, as multiple inorganic ions K
+, Na
+, Ca
2+, Cl
-In real time, detection of dynamic etc.And in many drug screenings are used, usually need high flux, cause the variation of extracellular different kinds of ions and composition after the detection of drugs function cells fast, simultaneously.
The objective of the invention is to design a kind of little physiology meter of the multi-functional cell that is used for drug screening that adopts polyion sensitive element and parallel fast detecting.
In order to achieve the above object, the present invention takes following measures:
The present invention utilizes the fundamental property of LAPS, at insulation course Si
3N
4Other ion sensitive membrane of preparation above the layer, under the situation of certain light source activation, can measure corresponding ion concentration, adopt same wavelength simultaneously and the different a plurality of light sources of modulating frequency excite these ion-sensitive elements simultaneously, on this basis, the employing parallel processing technique has been realized real-time, the detection of dynamic to the multiple inorganic ions of tested extracellular environment.
The present invention includes the peristaltic pump that can make analyzed medicine and cell culture fluid inflow instrument, cell sensor, contrast electrode, to electrode, working electrode, constant potential/electric current instrument, computing machine, light source driving circuit, control circuit.Cell sensor is multi-functional cell sensor, a plurality of lasing light emitters in the multi-functional cell sensor are connected with the light source driving circuit of multiple signals, contrast electrode, to electrode, working electrode connects constant potential/electric current instrument, enter analog band-pass filter after the current signal of multi-functional cell sensor output is converted to voltage signal, filtered signal enters computing machine, finish the correction of sensor frequency characteristic by digital compensation filter, carry out fast Flourier (FFT) computing by computing machine, calculate under each frequency to current magnitude variation between electrode and the working electrode, computing machine rotates through general digital-to-analog conversion control circuit control peristaltic pump.
The useful effect that the present invention has is:
1) designed the multi-functional cell sensor that has living cells born of the same parents extra-metabolite different kinds of ions sensitivity.In same substrate, designed and produced the different kinds of ions sensitive element;
2) adopt the multiple corresponding ion-sensitive element of light source excitation with different stimulating frequencies;
3) having designed the Frequency Response that a kind of digital compensation filter is used to revise sensor makes it excite the response signal of generation to have same signal to noise ratio (S/N ratio) and accuracy of detection to multiple light courcess.By the fast fourier transform of computing machine, parallel computation goes out under each stimulating frequency cell sensor to the response results of multiple measured matter.
The present invention is the H in the outer microenvironment of Measurement and analysis cell born of the same parents simultaneously
+, K
+, Na
+, Ca
2+, Cl
-Etc. the concentration change of different kinds of ions and organic principle, can the quantitative test different pharmaceutical and variable concentrations to the metabolism of irritation cell and the influence of state, thereby can be used for the quantitative screening of different pharmaceutical and effective constituent and concentration.
Below in conjunction with accompanying drawing the present invention is further described.
Description of drawings:
Fig. 1 is the structural representation of the little physiology meter of cell of U.S. molecular device company;
Fig. 2 is H in the outer microenvironment of cell born of the same parents
+The rate of change of ion concentration;
Fig. 3 is the effective concentration response curve of medicine activator;
Fig. 4 is a structure principle chart of the present invention;
Fig. 5 is the structural representation of multi-functional cell sensor of the present invention;
Fig. 6 is the vertical view of multi-functional cell sensor lower cover of the present invention;
Fig. 7 is the light source driving circuit figure of multiple signals;
Fig. 8 is an implementation process synoptic diagram of the present invention;
Fig. 9 is the digital compensation filter signal flow graph;
Figure 10 is an experimental result picture of above-mentioned implementation process;
Figure 11 H of microenvironment that is this instrument after anti-top epilepsy agent dilantin sodium acts on the cardiac muscle cell outside the cell born of the same parents
+, K
+, Ca
2+The testing result of concentration change;
Figure 12 is this instrument phenytoin sodium microenvironment H outside the cell born of the same parents after variable concentrations acts on the cardiac muscle cell
+The testing result of concentration change;
Figure 13 is this instrument H of microenvironment outside the cell born of the same parents after antiaging agent Ligusticum wallichii variable concentrations acts on nephrocyte
+The testing result of concentration change.
As Fig. 4, Fig. 5, shown in Figure 6, it comprises the peristaltic pump that can make analyzed medicine and cell culture fluid flow into instrument, cell sensor, and contrast electrode, to electrode, working electrode, constant potential/electric current instrument, computing machine, light source driving circuit, control circuit.Cell sensor is multi-functional cell sensor 2, a plurality of excitation sources in the multi-functional cell sensor 2 are connected with the light source driving circuit 3 of multiple signals, contrast electrode 4, to electrode 5, working electrode 6 connects constant potential/electric current instrument 7, enter analog band-pass filter 8 after the current signal of multi-functional cell sensor 2 outputs is converted to voltage signal, filtered signal enters computing machine 9, finish the correction of sensor frequency characteristic by digital compensation filter 10, carry out the FFT computing by computing machine 9, and calculate under each frequency to current magnitude variation between electric current and the working electrode, computing machine 9 rotates through general digital-to-analog conversion control circuit 11 control peristaltic pumps 12.
As Fig. 5, shown in Figure 6, multi-functional cell sensor 2 comprises that an end of loam cake has the import 2.2 of analyzed medicine and cell culture fluid, in import 2.2, be equipped with electrode 5, a plurality of excitation sources 2.5 that the arrangement mode that is connected with the light source driving circuit 3 of multiple signals is a square formation are housed in the loam cake, the other end of loam cake has the outlet 2.6 of analyzed medicine and cell culture fluid, in outlet 2.6 contrast electrode 4 is housed; Heating aluminium sheet 2.11 is housed in teflon (Teflon) the material lower cover substrate 2.12, prepare the ion sensitive membrane 2.14 that has with a plurality of excitation source 2.5 same number on the LAPS chip 2.9 on the heating aluminium sheet 2.11, be placed in the dovetail groove 2.8 of ion sensitive membrane, the cover glass and the cell 2.13 of fixed cell are housed in covering the groove 2.1 that has the placement cover glass down, cover down working electrode 6 also is housed.Its annexation: analyze medicine and nutrient solution and enter in micro-groove 2.1 and the miniature flow cavity 2.10 sensitive element 2.14 above reaching by LAPS chip 2.9, the cell 2.13 in the drug effect to 2.1, the outer H of the born of the same parents of generation from 2.2
+, K
+, Ca
2+The variation of plasma concentration is detected by 2.14, and response signal is by producing the photo-signal variation to electrode 5 and working electrode 6.Contrast electrode 4 provides the bias voltage of sensor, 2.11 the working temperature of sensor is provided, 2.5 one group of excitation source is provided, 2.4 be web joint with computer interface, the control signal and the sensor of computing machine are coupled together, and 2.3 is four standard double-screw bolts links together the loam cake of sensor through packing ring 2.7 and lower cover.
As shown in Figure 7, the light source driving circuit of multiple signals [3] comprises each road signal source frequency difference, all adopting model is the special signal generator chip of ICL8038, is that a follower amplifier, model among the LM158P is the power driving circuit that complementary triode that another amplifying circuit among the LM158P and model are S9014, S9015 is formed through model.
The present invention passes through the theoretical modeling to the LAPS sensor of EIS structure, the equivalent circuit model of sensor construction has been proposed, set up this The Mathmatic Models of Instrument Transducers by the System Discrimination technology on this basis, proposed the frequency characteristic that a kind of software digital filter device is used to compensate this sensor according to its mathematical model and made it become the logical characteristic in broadband from narrow bandpass characteristics.Thereby the response signal that light source activation produced that has guaranteed multiple different frequency has identical signal to noise ratio (S/N ratio).In addition, employing FFT (fast fourier transform) technology is carried out spectrum transformation with total time domain response signal of sensor, obtain the response results of the different sensitive membrane of little physiology meter under each light source activation, thereby realized multi-functional detection tested extracellular environment heterogeneity.
As shown in Figure 4, be the structural representation of the little physiology meter of multi-functional cell that is used for drug screening of the present invention invention.The 1st, analyzed medicine and cell culture fluid flow to into multi-functional cell sensor 2 at the computer control lower whorl, and it is that with the difference of common structure the present invention has adopted the different kinds of ions sensitive element.Its number that detects the extracellular environment ion can be 4 (can expand to more), and its arrangement mode is square formation and regional corresponding with each light source irradiation, and will determine the initial position of scanning.The multiple light courcess signal source of the present invention's design takes place and driving circuit 3 driving multiple light courcess are used to excite a plurality of ion-sensitive elements.4,5 is respectively contrast electrode and to electrode, the 6th, working electrode is identical with common structure.This three electrode and LAPS form an electro-chemical test system.7 is EG﹠amp; The constant potential of G company/electric current instrument is used for the current signal of sensor output is converted to voltage signal, and this voltage signal enters analog band-pass filter [8] and carries out Filtering Processing, and is identical with common structure.The signal that comes out from analog band-pass filter 8 enters computing machine 9, finishes the correction of sensor frequency characteristic by digital compensation filter 10, carries out the FFT computing by computing machine 9 at last, and calculates the changes in amplitude under each frequency.Computing machine 9 is finished the detection of the outer microenvironment of cell born of the same parents through general D/A converting circuit 11 control peristaltic pumps 12.
Analog band-pass filter 8 is different with the lock-in amplifier of existing instrument employing, and adopting the standard model is the prime amplifier of SR560.Its bandwidth is selected according to the number of employing excitation source and frequency range.Digital compensation filter 10 is used in the frequency range of used light source, promptly finishes the correction of sensor frequency characteristic in the bandwidth of analog band-pass filter.
The use of carrying out drug screening with this instrument is: at first, cell culture fluid is flowed into this instrument by 1 under the control of peristaltic pump 12, duration is 2 minutes, then tested medicine 1 is flowed into this instrument under the control of peristaltic pump 12, duration is for also being 2 minutes, by computing machine 9 signal that collects is finished the correction of sensor frequency characteristic by digital compensation filter 10, carry out the FFT computing by computing machine 9 at last.Said process calculates the mean value of the changes in amplitude under each frequency at last with circulation 4-5 all after date, the variation of the ion concentration that its reflection is different.According to before and after the drug effect, the variation of the different kinds of ions concentration that this instrument records can be judged action effect, effective constituent, the effective concentration of the medicine of analyzing for specific cell, thereby realizes the screening of medicine.Table 1,2 has provided the sensitivity and the selectivity factor of three kinds of sensitive elements.
The sensitivity of three kinds of sensitive elements of table 1
| H +Sensitive element | K +Sensitive element | Ca 2+Sensitive element | |
| Sensitivity | 70mv/pH | 30mv/pK | 35mv/pCa |
The selectivity factor of three kinds of sensitive membrane of table 2
| Interfering ion | H +Sensitive membrane | K +Sensitive membrane | Ca
2+ |
| H | |||
| + | 1 | 9.5×10 -4 | 7.4×10 -4 |
| K + | 6.8×10 -5 | 1 | 2.8×10 -5 |
| Ca 2+ | 7.2×10 -5 | 1.3×10 -5 | 1 |
What Fig. 7 designed voluntarily for the present invention is main excitation source signal generator and the driving circuit figure that constitutes by ICL8038, this be wherein a road, the circuit diagram on other several roads is identical, just the frequency difference of signal source.The characteristics of this circuit be small-sized, be easy to make multichannel independently signal source circuit offer multiple light courcess.Its major function is with ICL8038 special signal generator chip, produces sine wave signal output, through follow circuit and amplifying circuit, passes through complementary triode power driving circuit driving laser diode at last.The frequency range of signal source be 0.5KHz to 5.5KHz, sample frequency is 20KHz.Carry out spectrum analysis by the method for signal being made fast Fourier transform (FFT), 1000 points of every collection are made a FFT, because frequency resolution is 20Hz, therefore, can select 250 excitation sources with different frequency at 0.5KHz at most in the frequency range of 5.5KHz, be generally and make FFT precision raising as a result, frequency interval should be greater than frequency resolution, so excitation source should be less than 250, as 100.
As shown in Figure 8, it is an implementation process of this scheme, one group of lasing light emitter activated cell sensor produces certain frequency response characteristic, after the digital filter compensation of the response of sensor through computer-internal, obtain wide band response frequency characteristic, pass through computing machine FFT computing again, obtain the spectrogram of the parallel response of various ion concentrations under one group of excitation light source excites.The frequency response of LAPS system is described with transport function, is write as zero limit form:
S=j ω in the formula (ω is angular frequency=2 π f, and f is a frequency, and j is an imaginary part) proofreaies and correct for the frequency response to LAPS, and the present invention designs the frequency response of the logical property filter in a desirable broadband as the LAPS after proofreading and correct in advance.Again according to the LAPS frequency response of reality with proofread and correct the transport function that the back ideal transfer can be obtained the correction link wave filter.Can directly use lag line, multiplier and totalizer to realize, as shown in Figure 9.
Y (n)=b then
0X (n)+b
1X (n-1)+b
2X (n-2)-a
1Y (n-1)-a
2Y (n-2)-a
3Y (n-3)
Wherein: x (n) is the actual response signal of sensor;
Y (n) is the output signal of digital compensation filter;
Coefficient: b
0=0.05579 * 10
-8
b
1＝0.81×10
-8
b
2＝-0.0085×10
-8
Coefficient: a
1=2.6765, a
2=-2.3531, a
3=0.6766.
Adopt that wavelength is identical, amplitude is identical and multiple light source activation sensor that modulating frequency is different.The actual frequency characteristic of sensor has narrow bandpass characteristics, according to the digital compensation filter of sensor mathematical model design obtain after can transport function compensation sensor needed in effective band frequency response be in the logical characteristic in broadband of flat region.
Figure 10 has provided an experimental result of above-mentioned implementation process.Three excitation sources are adopted in this experiment, and stimulating frequency is respectively 3.6KHz, 3.8Khz, 4.0KHz, and cell sensor adopts three kinds of ion-sensitive elements, i.e. H
+, K
+, Ca
2+The response of cell sensor through digital filtering compensation and FFT conversion after to the response characteristic of three excitation sources as shown in figure 10.Can be clear that and to distinguish the response results to measured matter of three kinds of sensitive membrane under three excitation sources on the spectrogram.
The little physiology meter of multi-functional cell is used for the example of drug screening
Figure 11 has provided this instrument H of microenvironment outside the cell born of the same parents after anti-top epilepsy agent dilantin sodium acts on the cardiac muscle cell
+, K
+, Ca
2+The testing result of concentration change.Figure 12 has provided this instrument dilantin sodium H of microenvironment outside the cell born of the same parents after variable concentrations acts on the cardiac muscle cell
+The testing result of concentration change.Figure 13 has provided after antiaging agent Ligusticum wallichii variable concentrations acts on nephrocyte the H of microenvironment outside the cell born of the same parents
+The testing result of concentration change.
Claims (4)
1. the little physiology meter of multi-functional cell that is used for drug screening, it comprises the peristaltic pump that can make analyzed medicine and cell culture fluid flow into instrument, cell sensor, contrast electrode are placed on the exit of nutrient solution, electrode are placed on the inflow point of nutrient solution, working electrode is fixed on the lower surface of sensor chip, constant potential/electric current instrument, computing machine, light source driving circuit, control circuit is characterized in that:
1) cell sensor is multi-functional cell sensor [2], a plurality of lasing light emitters in the multi-functional cell sensor [2] are connected with the light source driving circuit [3] of multiple signals, contrast electrode [4], to electrode [5], working electrode [6] connects constant potential/electric current instrument [7], enter analog band-pass filter [8] after the current signal of multi-functional cell sensor [2] output is converted to voltage signal, filtered signal enters computing machine [9], finish the correction of sensor frequency characteristic by digital compensation filter [10], carry out the fast Flourier computing by computing machine [9], calculate under each frequency to current magnitude variation between electrode [5] and the working electrode [6], computing machine [9] rotates through general digital-to-analog conversion control circuit [11] control peristaltic pump [12];
2) multi-functional cell sensor [2] comprises that an end of loam cake has the import of analyzed medicine and cell culture fluid [2.2], in import [2.2], be equipped with electrode [5], a plurality of excitation sources [2.5] that the arrangement mode that is connected with the light source driving circuit [3] of multiple signals is a square formation are housed in the loam cake, the other end of loam cake has the outlet [2.6] of analyzed medicine and cell culture fluid, in outlet [2.6] contrast electrode [4] is housed; In the lower cover polytetrafluoroethylmaterial material substrate [2.1 2] the heating aluminium sheet is housed, Light Addressable Potentiometric Sensor chip [2.9] on the heating aluminium sheet [2.11] upward prepares the ion sensitive membrane [2.14] that has with a plurality of excitation sources [2.5] same number and is placed in the dovetail groove [2.8] of ion sensitive membrane, the cover glass and the cell [2.13] of fixed cell are housed in covering the groove [2.1] that has the placement cover glass down, cover down working electrode [6] also is housed.
2. the little physiology meter of multi-functional cell that is used for drug screening according to claim 1, it is characterized in that: the light source driving circuit of described multiple signals [3] comprises each road signal source frequency difference, all adopts model is the special signal generator chip of ICL8038, is that the follower amplifier of 1/2LM158P, amplifier that model is 1/2LM158P and model are the power driving circuit that the complementary triode of S9014, S9015 is formed through model.
3. the little physiology meter of multi-functional cell that is used for drug screening according to claim 1, it is characterized in that: described digital compensation filter [10] is 3 rank finite impulse response digital filters, and its operational method is:
y(n)＝b
0x(n)+b
1x(n-1)+b
2x(n-2)-a
1y(n-1)-a
2y(n-2)-a
3y(n-3)
Wherein: x (n) is the actual response signal of sensor;
Y (n) is the output signal of digital compensation filter;
Coefficient: b
0=0.05579 * 10
-8
b
1＝0.81×1
-8
b
2＝-0.0085×10
-8
Coefficient: a
1=2.6765, a
2=-2.3531, a
3=0.6766.
4. the little physiology meter of multi-functional cell that is used for drug screening according to claim 1, it is characterized in that: analog band-pass filter [8] is the prime amplifier of SR560 for the model of standard.
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|---|---|---|---|
| CN 00134795 CN1117279C (en) | 2000-12-04 | 2000-12-04 | Multifunctional cytomicrophysiological meter for screening medicines |
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|---|---|---|---|
| CN 00134795 CN1117279C (en) | 2000-12-04 | 2000-12-04 | Multifunctional cytomicrophysiological meter for screening medicines |
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| EP2631652A1 (en) * | 2005-04-05 | 2013-08-28 | Corning Incorporated | Label free biosensor |
| US8313898B2 (en) * | 2008-03-05 | 2012-11-20 | Corning Incorporated | Dual-target biosensor cell assays |
| CN101705184B (en) * | 2009-11-26 | 2012-01-11 | 浙江大学 | Full-automatic cell physiological parameter analyzer based on multi-parameter detection integrated chip |
| CN104133404B (en) * | 2014-07-23 | 2016-09-07 | 株洲南车时代电气股份有限公司 | A kind of signal processing method and device |
| CN105823815B (en) * | 2016-01-04 | 2018-06-26 | 浙江农林大学 | Anticancer drug docetaxel Composition analyzed device and detection method |
| CN105823817B (en) * | 2016-01-04 | 2018-04-20 | 浙江农林大学 | Cancer therapy drug vinorelbine Composition analyzed device and detection method |
| CN105823808B (en) * | 2016-01-04 | 2018-05-01 | 浙江农林大学 | Cancer therapy drug topotecan Composition analyzed device and detection method |
| CN105866210B (en) * | 2016-03-21 | 2018-04-13 | 杭州市红十字会医院 | A kind of Composition analyzed device and detection method for anti-cancer agent vincristine |
| CN105695329B (en) * | 2016-04-08 | 2018-08-17 | 西南交通大学 | High-flux electric stimulates the experimental provision and method of Cell differentiation inducing activity and medicine controlled releasing |
| CN112098465B (en) * | 2020-08-25 | 2023-09-22 | 天津海星辉科技有限公司 | Microfluidic carbohydrate metabolism analysis detection device and method |
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