CN107238790B

CN107238790B - Digital microfluidic biochip online test structure and method based on coding and decoding

Info

Publication number: CN107238790B
Application number: CN201710388109.0A
Authority: CN
Inventors: 邓立宝; 孙宁; 任涛; 张莉莉; 王华鹏; 周长波
Original assignee: Harbin Institute of Technology Weihai
Current assignee: Harbin Institute of Technology Weihai
Priority date: 2017-05-27
Filing date: 2017-05-27
Publication date: 2020-09-11
Anticipated expiration: 2037-05-27
Also published as: CN107238790A

Abstract

The invention provides a digital microfluidic biochip online test structure and method based on coding and decoding, and solves the technical problems of untimely fault finding, long error repair time, high resource consumption and excessive control pins in online test, which result in overlarge chip scale. The device comprises a decoder, an input end of the decoder is connected with a controller, an output end of the decoder is connected with electrodes, and the decoder is used for converting a voltage signal into an electrode driving sequence according to a decoding rule and acting on each electrode; the input end of the encoder is connected with the electrodes, the output end of the encoder is connected with the controller, and the encoder is used for transmitting the actual voltage signals of the electrodes back to the controller through a data bus after being encoded by a circuit; and the controller is used for comparing the returned voltage signal with the output voltage signal, judging whether the electrode has a fault or not, marking the corresponding electrode as the fault if the electrode has the fault, and adjusting the subsequent liquid drop scheduling. The invention is widely applied to the technical field of digital microfluidic biochip online test.

Description

Digital microfluidic biochip online test structure and method based on coding and decoding

Technical Field

The invention relates to the technical field of digital microfluidic biochip online test, in particular to a structure and a method for digital microfluidic biochip online test based on coding and decoding.

Background

The digital microfluidic biochip mainly comprises a two-dimensional electrode array, wherein the upper polar plate is a large electrode covering all units in the array and is used as a common grounding end; the lower plate is applied with different control voltages as required during use, and can be referred to in reference 1(R.Fair, A.Khlystov, V.Srinivasan, V.Pamula, and K.weaver, "Integrated chemical/biochemical sample collection, pre-concentration, and analysis on chemical microfluidic lab-on-a-chip platform", Proceedings of SPIE, volume 5591, Issue 8, page 113. 124, 2004). Nano-liter sized droplets are confined between two plates during operation based on dielectric wetting technology, and the surface tension of the droplets is changed by simultaneously applying a low level to the electrode on which the droplets are located and a high level to the adjacent electrode, thereby achieving the movement of the droplets from the low level to the high level, as in document 2(r.b. fair, a.khlystov, t.d. Tailor, v.ivanov, r.d. Evans, p.b. Griffin, v.Srinivasan, v.k.Pamula, M.g. Pollack, J.Zhou, Chemical and biological applications of digital-microfluidic devices, IEEE Des.test. 24, 10-24 (2007)). The controller translates the experimental steps into a series of voltage sequences, and the voltage sequences are loaded on each electrode through pins, so that all operations of liquid drop mixing, separation, dilution, injection and the like are realized. With the wide introduction of digital microfluidic biochips in various fields, the functions of the digital microfluidic biochips become more and more complex, a large amount of fluid operation is required to be repeatedly performed on an electrode array in use, the electrodes are continuously contacted with various macromolecular substances which are easily adhered to the electrodes, and the high level is kept for a long time or the high level and the low level are continuously switched, so that the failure rate of the digital microfluidic biochips is increased. Once the failure occurs, the error of droplet movement and fluid operation can be caused, and further the error of test results can be caused, which not only consumes a lot of time and resources such as droplets, but also causes serious consequences in practical application.

Since the digital microfluidic biochip is generally used for health detection, drug development, air quality monitoring and the like, in order to ensure the rapidity, accuracy and reliability of operation results, the digital microfluidic biochip needs to be tested on line in the use process of the biochip.

Document 3 (Aphana, Chuaka, Smart. on-line test path optimization for digital microfluidic biochips based on ant colony algorithm [ J ] Instrument and meters, 2014,35(6):1417-, and controlling the test liquid drop under the condition of not influencing the normal operation of the fluid operation, so that the test liquid drop traverses the current idle electrode unit, and judging whether the corresponding detection area has a fault or not by detecting the state of the test liquid drop. This approach is ineffective against failures in the array area currently in use and the consumption of test droplets is large. Some in-line tests determine whether the operation is normal by testing the droplet status at a preselected test point, where an additional sensor is required to complete the test.

In document 6(t.xu, k.chakrabarty, v.k.pamula, Design and optimization of additive microfluidic biochemical for protein crystallization. in Proceedings IEEE/ACM International Conference on Computer-aid Design, (2008), pp.297-301.), the capacitance sensing circuit is used to read and analyze the test results, which requires an additional step to analyze the pulse sequence to determine whether there is a failure in the microfluidic array under test. The process of reading the test results and analyzing the pulse sequence increases the test time, and the process of analyzing the pulse sequence is particularly prone to introducing errors due to inaccurate sensor scales, and is therefore not practical enough.

As with most on-line tests, fluorescence of the intermediate droplets is detected with a photodetector in document 7(n.jokerst, l.luan, s.palit, m.royal, s.dhar, m.brooke, and t.tyler II, "Progress in chip-scale photosensing", ieee trans.biological Circuits and sys., vol.3, pp.202-211, 2009) to obtain parameters such as volume and substance content. The defects of the method are that errors cannot be found in time and faults cannot be accurately positioned. In the working process of the chip, the result liquid drop of a certain operation is sent to a photoelectric detector for detection and is found to exceed the error allowable range, and then an error is judged to occur, and the result only shows that all units in the operation area are possible to have faults, the accurate time and position of the fault cannot be obtained, and the possibility that the fault occurs in the process that the result liquid drop moves to the detector cannot be eliminated. If the suspected fault area is marked as an obstacle, a large amount of electrode resources are wasted.

Document 8(Yan Luo, krishnidu Chakrabarty, "Hardware/Software Co-Design and optimization for cyber physical Integration in Digital microfluidics", 2014.) proposes that a CCD-based sensor is used to capture images of droplet motion in real time and compare them to expected images, and that errors can be detected in the droplets at a first time and the exact location of the failure confirmed. However, CCD is too costly to be used on such disposable chips, and the light can affect the droplets if there is a light sensitive sample or reagent in the experiment.

In summary, the current on-line testing method can only be realized by means of an additional sensor, but various types of sensors have some problems and disadvantages, and more importantly, the testing method for detecting the state of the liquid drop can only be detected after a fluid operation error caused by a fault occurs, and in order to obtain a correct result, the erroneous operation or even more previous operations need to be performed again, which wastes time and liquid drops. Moreover, in order to avoid the faulty cells in the subsequent operations, the resource allocation and the re-synthesis of the droplet paths are required, which changes the voltage driving sequence applied to the control pins corresponding to the pre-programmed scheme, and in the pin-constrained chip, the correspondence between the control pins and the electrodes is obtained by the pre-programmed voltage driving sequence, so that the in-line testing method cannot be used on the pin-constrained digital microfluidic biochip, but the design of direct addressing of the electrodes would make the chip scale too large. The invention takes the electrode array of the chip as a detection object, and solves the problem of online test from the viewpoint of testability design of the chip structure.

Disclosure of Invention

The invention provides a digital microfluidic biochip online test structure and a method based on coding and decoding, which are timely in fault finding, short in repair time, low in resource consumption and low in pin introduction, aiming at the technical problems of untimely fault finding, long in error repair time and high in resource consumption in the existing digital microfluidic biochip online test and the problem of overlarge chip scale caused by excessive control pins.

The invention provides a digital microfluidic biochip online test method based on coding and decoding, which comprises a decoder, wherein the input end of the decoder is connected with a controller, and the output end of the decoder is connected with electrodes, and is used for converting a voltage signal into a voltage driving sequence of the electrodes according to a decoding rule and acting on each electrode; the input end of the encoder is connected with the electrodes, the output end of the encoder is connected with the controller, and the encoder is used for transmitting the actual voltage signals of the electrodes back to the controller through a data bus after being encoded by a circuit; the controller is used for comparing the returned voltage signal with the output voltage signal, judging whether the electrode has a fault or not, if so, marking the corresponding electrode as the fault, and adjusting the subsequent liquid drop scheduling;

the latch is arranged between the controller and the decoder and used for latching an input voltage signal, releasing a data bus and realizing time-sharing multiplexing of input and output signals;

the decoder is a 2-line to 4-line decoder, and the encoder is a 4-line to 2-line encoder; the number of the decoder and the number of the encoder are the same and are at least 1, and the method comprises the following steps:

(1) application of electrode drive sequence: the controller inputs voltage driving signals in the same period into the latch as a sequence and then outputs the voltage driving signals to the 2-line-4-line decoder, the decoder simultaneously outputs the voltage sequence to corresponding electrodes to enable the chip to work correspondingly, the electrode sequence of the next period is input into the 2-line-4-line decoder bit by bit and then output to the latch, and after the current period is finished, the voltage driving signals are output to the electrodes in parallel;

(2) acquiring actual voltage on the electrode and judging faults: the actual voltage of each electrode in the same period is input into a 4-line-2-line encoder as a sequence, and then is transmitted back to the controller through a data bus, the controller compares the transmitted voltage sequence with the sequence applied in the same period, judges whether a fault occurs and the specific position of the fault, marks the corresponding electrode with the fault, and adjusts the subsequent liquid drop scheduling.

The invention has the advantages that the number of the controllable electrodes is increased in an exponential mode, the use of pins is reduced under the condition of ensuring that the electrodes are mutually independent, the problem that the fault is not found timely in the online test of the digital microfluidic biochip is effectively solved, the fault can be positioned immediately once occurring, the follow-up related operation is adjusted to avoid the fault, the fluid operation error is avoided, the real-time monitoring of the electrode array is realized, the completion time of the biochemical reaction when the fault occurs is reduced, and the test cost is reduced.

Drawings

FIG. 1 is a schematic diagram of the interface structure of a digital microfluidic biochip;

FIG. 2 is a schematic diagram of a 4x4 electrode array grouping;

fig. 3 is a schematic diagram of an input/output structure of a group of electrodes.

Detailed Description

The present invention will be further described with reference to the following examples.

As shown in figure 1, the I/O interface of the digital microfluidic biochip comprises a latch, a 4-line-2-line encoder group and a 2-line-4-line decoder group, the latch, the 2-line-4-line decoder group and an electrode sequence are sequentially connected with the 4-line-2-line encoder group, a controller is connected with the latch and the 4-line-2-line encoder group through a data bus, and time-sharing multiplexing of input and output signals is realized through the latch.

As shown in fig. 3, each output terminal of the 2-line-4-line decoder corresponds to an electrode, and each electrode is simultaneously connected to the input terminal of the 4-line-2-line encoder. I.e., the 4-line-2-line encoder and the 2-line-4-line decoder are the same in number and are one-fourth of the number of electrodes.

The testing process is mainly divided into two stages: (1) application of a voltage drive sequence; (2) and acquiring actual voltage on the electrode and judging the fault.

(1) Application of electrode drive sequence:

because only one bit of each signal is effective in the output signal after decoding, namely, only one electrode can be selected by one 2-4 line decoder at the same time, the controllable electrode number of the 2-4 line decoder is limited, otherwise the normal operation of the fluid operation is influenced. In fluid operation, there is also a constraint that two droplets cannot be in the array unit in direct or diagonal proximity, otherwise the droplets will merge, so that a certain separation distance is required between the droplets.

By combining the two constraint conditions, the invention adopts a 2-line-4-line decoder, namely two pins control four electrodes through the 2-line-4-line decoder. As shown in fig. 2, four electrodes adjacent to each other up, down, left and right are controlled by the same 2-line-4-line decoder, and at most one of the four electrodes is active at the same time, that is, at most one of the four electrodes has a droplet thereon, which just meets the distance limitation of fluid operation to a certain extent and does not affect the synchronous operation of other fluid operations at the same time. The voltage signal input on the data bus is temporarily stored in the latch, so that the data bus can be idle to transmit the test result back to the controller when the electrode voltage is detected.

According to the decoding rule of the 2-line-4-line decoder, the voltage signal actually applied to the input terminal of the 2-line-4-line decoder can be reversely deduced from the voltage driving sequence applied to each electrode. The truth table of the 2-4 line decoder is shown in Table 1, wherein X₁,X₂C represents three input ends of the 2-line-4-line decoder, namely three control pins of the chip, the pin C controls the enabling end of the 2-line-4-line decoder, when C is high, no matter X is₁And X₂2-4 line decoder outputs are all low; when C is low, the output of the 2-line-4-line decoder depends on X₁And X₂The state of (1). E1, E2, E3 and E4 respectively represent four output terminals of a 2-line-4-line decoder, i.e., four electrodes in an electrode array controlled by the same 2-line-4-line decoder.

Table 12 line-4 line decoder truth table

C X₁ X₂	E₁E₂E₃E₄
		000	0001
001	0010
		010	0100
011	1000
		1xx	0000

According to the truth table, the corresponding relation between the voltage signal and the electrode driving sequence is obtained as follows:

as shown in fig. 3, a set of electrode input structures includes four electrodes controlled by the same 2-line-4-line decoder, and three pins for applying voltage signals, and the voltage driving sequence of the electrodes is shown in table 2. Each bit in the voltage driving sequence represents the state of the electrode at a specific time point, and "1" represents effective, i.e. high voltage is applied to the electrode; "0" represents no effect, i.e. a low voltage is applied to the electrodes; "x" indicates that neither 0 nor 1 of the input signal has an effect on the movement of the droplet. Since the application of high voltages for a long time may cause irreversible charge accumulation of the electrodes, "' is all regarded as" 0 "when calculating the voltage signal. After obtaining the voltage driving sequence of each electrode, the corresponding voltage signal on the pin can be obtained through the formulas (1), (2) and (3), and the voltage signal is shown in table 3.

TABLE 2 Voltage drive sequence for electrodes

TABLE 3 Voltage Signal Table corresponding to Pin

(2) Acquiring actual voltage on the electrode and judging faults:

during the working process of the chip, the voltage on each electrode in the electrode array needs to be detected in real time, and the electrodeless fault and the position of the fault electrode are judged according to the signal transmitted back to the controller. The electrode voltage is obtained in the reverse process of voltage signal application, so that a 4-wire-2-wire encoder can be used for encoding the voltage on the electrode array and outputting the encoded voltage to a controller through a pin, and if the encoded voltage signal is the same as the voltage signal applied to the electrode array at the same moment, the electrode works normally; if not, indicating that an electrode has a fault, finding out the non-identical binary bits in the two sequences by comparison, then determining which one or more 4-line-2-line encoder output signals have an abnormality, then marking the corresponding electrode as a fault, and adjusting the subsequent drop scheduling to avoid using the electrode in the subsequent fluid operation. The formula of the code is (1), (2) and (3).

Assuming that the electrodes E1 and E2 are short-circuited due to the remaining liquid in the second clock cycle, as can be seen from table 2, the voltage sequence at this time is E1E2E3E4 is 1000, and the electrode signal on the pin is CX₁X₂011. However, after the short circuit occurs, the low level of E2 becomes high, the voltage signal obtained by the 4-wire-2-wire encoder is E1E2E3E4 equals 1100, and the input end of the 4-wire-2-wire encoder only allows one binary digit to be 1, so that the encoded output will generate an abnormal condition. The controller adjusts the drop schedule immediately after the third clock cycle after discovery and marks E1E2E3E4 as an obstacle in subsequent operations.

However, the above embodiments are only examples of the present invention, and the scope of the present invention should not be limited thereby, and the substitution of equivalent elements or the equivalent changes and modifications made according to the scope of the present invention should be covered by the claims.

Claims

1. The digital microfluidic biochip online testing method based on coding and decoding is characterized by comprising a decoder, wherein the input end of the decoder is connected with a controller, the output end of the decoder is connected with electrodes, and the decoder is used for converting voltage signals into voltage driving sequences of the electrodes according to a decoding rule and acting on each electrode; the input end of the encoder is connected with the electrodes, the output end of the encoder is connected with the controller, and the encoder is used for transmitting the actual voltage signals of the electrodes back to the controller through a data bus after being encoded by a circuit; the controller is used for comparing the returned voltage signal with the output voltage signal, judging whether the electrode has a fault or not, if so, marking the corresponding electrode as the fault, and adjusting the subsequent liquid drop scheduling;

(1) application of electrode drive sequence: the controller inputs voltage driving signals in the same period into the latch as a sequence and then outputs the voltage driving signals to the 2-line-4-line decoder, the decoder simultaneously outputs the voltage sequence to corresponding electrodes to enable the chip to work correspondingly, the chip inputs the electrode sequence of the next period into the 2-line-4-line decoder bit by bit while working correspondingly and then outputs the electrode sequence to the latch, and after the current period is finished, the electrode sequence is output to the electrodes in parallel;