An imaging method based on the combination of OECT and EIT

Abstract

The present invention develops an imaging method based on the combination of OECT and EIT, which belongs to the technical field of sensors. The technical key points are: substrate, OECT array electrode assembly, electrolyte; the substrate is made of non-conductive material and has a rectangular shape; the OECT array electrode assembly includes eight OECTs, and 2 OECTs are arranged on each side of the substrate; each of the OECTs includes: a source electrode, a gate electrode, a drain electrode and a channel; the channel is used to connect the source electrode and the drain electrode, and is prepared using the organic material PEDOT:PSS; wherein an electrolyte is also arranged above the substrate. Using the imaging method based on the combination of OECT and EIT of the present application, cells or tissues can be easily monitored.

Description

Technical Field

[0001] The present invention relates to the technical field of sensor electronic components, and in particular to an imaging method based on the combination of OECT and EIT. Background Art

[0002] Traditional detection methods for cells and tissues are optical imaging methods and in vitro toxicology methods. However, the demand for reliable technologies for high-throughput screening is increasing, and electrical detection, a low-cost and more universal method, has attracted widespread attention.

[0003] Electrical Impedance Tomography (EIT) is a new detection technology that can perform functional imaging. It has the advantages of no radiation, non-invasiveness, and real-time monitoring. It is very suitable for medical imaging and biological research, as shown in the following literature:

[0004] Reference 1: Xu Dehong, Deng Qi, Yao Jiafeng. Development of cell detection sensor based on electrical impedance imaging technology[J]. Sensors and Microsystems. 2023, 42(11).

[0005] Reference 2: Zhang Yijia. Development of electrical impedance imaging system for cell detection[D]. Nanjing University of Aeronautics and Astronautics, 2021.

[0006] Impedance imaging is challenging in microscale cell imaging. This is mainly because the detection signal is affected by noise caused by factors such as the double electric layer at the microscale. Its spatial resolution is limited, making it difficult to accurately distinguish and capture tiny cells. The measured and calculated resistivity differences are not significant enough, resulting in poor imaging quality and more artifacts after conductivity image reconstruction.

[0007] Organic Electrochemical Transistors (OECTs) are bioelectronic devices that convert biological signals of the detected object into clear and readable electrical signals. They have been widely used in the field of biosensing due to their advantages such as high sensitivity and low detection limit.

[0008] Therefore, how to integrate OECT and EIT sensors to improve the detection accuracy of EIT at cell size has become a research hotspot. Summary of the invention

[0009] The purpose of the present invention is to provide a microscale cell detection sensor to solve the deficiencies of the prior art.

[0010] Another object of the present invention is to provide a measuring method.

[0011] Another object of the present invention is to provide a solution method.

[0012] Another object of the present invention is to provide an imaging method based on the combination of OECT and EIT.

[0013] A microscale cell detection sensor, comprising: a substrate (100), an OECT array electrode assembly (200), and an electrolyte (300);

[0014] The base is made of non-conductive material and has a rectangular shape;

[0015] The OECT array electrode assembly (200) comprises eight OECTs, with two OECTs arranged on each side of the substrate; each of the OECTs comprises: a source electrode, a gate electrode, a drain electrode and a channel; the channel is a channel for connecting the source electrode and the drain electrode, and is made of an organic material PEDOT:PSS;

[0016] Wherein, an electrolyte is also arranged above the substrate.

[0017] Furthermore, the electrolyte is a 1 mol / L NaCl solution.

[0018] A measurement method, eight OECT arrays are sequentially numbered as: No. 1 to No. 8 OECT; the gates of No. 1 to No. 8 OECT are stimulated in sequence, and the source-drain output currents of No. 1 to No. 8 OECT and the input currents of the eight gates are measured simultaneously during the stimulation.

[0019] Furthermore, for any gate excitation of the i-th OECT, the method for measuring the source-drain output current of the 1st to 8th OECTs and the input current of the i-th gate is as follows:

[0020] Excitation conditions: Use the given frequency f and gate excitation voltage V Gi The AC signal excites the gate of the i-th OECT, and the drains of the 1st to 8th OECTs are connected to a fixed voltage V D , the sources of OECTs No. 1 to 8 are all grounded;

[0021] Measurement conditions: Measure the source-drain output current I of OECT No. 1 to No. 8 in sequence Di1 ~I Di8 At the same time, measure the input current I of the gate of the i-th OECT Gi (I Gi It represents the gate current of the sensor input through the gate of the i-th OECT when the gate of the i-th OECT is stimulated).

[0022] A solution method for solving a gate shunt current matrix comprises the following steps:

[0023] Step 1: Input: measurement data and structural parameters;

[0024] The measurement data includes: gate excitation voltage vector V G , source-drain measurement current vector I D , Gate measurement current vector I G , drain excitation voltage V D , cut-off voltage V T , excitation frequency f;

[0025] V G =(V G1 , V G2 , ..., V G8 ), which is 8 data;

[0026] I D =(I D11 , I D12 ,…I Dij ……I D88 ), which is 64 data;

[0027] I G =(I G1 , I G2 ,…I Gi ……I G8 ), which is 8 data;

[0028] Among them, V Gi represents the gate excitation voltage of the i-th OECT, where i is a natural number from 1 to 8;

[0029] Among them, I Dij It represents the source-drain output current of OECT No. j when the gate of OECT No. i is stimulated, and both i and j are natural numbers from 1 to 8;

[0030] Among them, I Gi represents the gate current of the sensor input through the gate of the i-th OECT when the gate of the i-th OECT is stimulated, i is a natural number from 1 to 8;

[0031] The structural parameters include: W, d, L; W and d are the channel width and depth, and L is the channel length;

[0032] Step 2: Calculate the proportional equivalent capacitance μ×C * 11 ~μ×C * 88 :

[0033]

[0034] Where, μ×C * ijrepresents the proportional equivalent capacitance between the channel and the electrolyte of the jth OECT when the gate of the i-th OECT is stimulated, and i and j are both natural numbers ranging from 1 to 8;

[0035] Step 3: Calculate the proportional equivalent impedance

[0036]

[0037] in, It represents the proportional equivalent impedance between the channel of the jth OECT and the electrolyte when the gate of the i-th OECT is stimulated, and i and j are both natural numbers ranging from 1 to 8;

[0038] Step 4: Calculate the gate shunt current matrix:

[0039]

[0040] Among them, any element I Gij The calculation is done using the following formula:

[0041]

[0042] I Gij It represents the current between the gate of the i-th OECT and the channel of the j-th OECT when the gate of the i-th OECT is stimulated, and i and j are both natural numbers from 1 to 8.

[0043] An imaging method, characterized in that it comprises the following steps:

[0044] First, the sensitivity matrix S of the field at the excitation frequency f is calculated using the finite element simulation method;

[0045] Second, calculate the gate shunt current matrix I' when the sensitive field is empty G-空 ;I' G-空 The acquisition method is: first, the basic data is obtained by using the aforementioned measurement method when no cells are added to the microscale cell detection sensor; then, the gate shunt current matrix is ​​solved by using the aforementioned gate shunt current matrix solution method in the empty sensitive field;

[0046] Third, calculate the gate shunt current matrix I' when the cells or tissues to be tested are placed in the electrolyte G-细胞 ;I' G-细胞 The acquisition method is: first, add the cells or tissues to be tested and place them in the electrolyte, and use the aforementioned measurement method to obtain basic data; then, use the aforementioned method to solve the gate shunt current matrix when the cells or tissues to be tested are placed in the electrolyte to solve the gate shunt current matrix;

[0047] Fourth, calculate the gate shunt current difference matrix ΔI'G :ΔI' G =I' G-细胞 -I' G-空 ;

[0048] Fifth, according to ΔI' G , draw the image.

[0049] The beneficial effects of this application are:

[0050] First, the sensor proposed in this application adds an OECT array to the traditional EIT sensor. The OECT gate voltage directly regulates ion injection. For a small change in the gate voltage caused by an external signal, the channel current will produce a large magnitude change, which can make up for the shortcomings of the traditional EIT method electrode measurement at the microscale. In addition, consider monitoring cells or tissues. If the physiological structure, morphology, function, etc. of cells and tissues undergo great changes during the monitoring process, or exchange ions and organic matter with the outside world, OECT can capture this change due to its good biocompatibility, and then visualize and analyze this change through imaging technology.

[0051] Second, the present application proposes an imaging method for an OECT array, which comprises the following steps:

[0052] 2.1, Calculate the gate shunt current matrix I' when the sensitive field is empty G-空 ;I' G-空 The acquisition method is: first, the excitation-measurement method is used to obtain basic data when no cells are added to the microscale cell detection sensor; then, the gate shunt current matrix is ​​solved by the gate shunt current matrix solution method in the empty sensitive field;

[0053] 2.2, Calculate the gate shunt current matrix I' when the cells or tissues to be tested are placed in the electrolyte G-细胞 ;I' G-细胞 The acquisition method is as follows: first, add the cells or tissues to be tested and place them in the electrolyte, and use the excitation-measurement method to obtain basic data; then, use the gate shunt current matrix solution method to solve the gate shunt current matrix when the cells or tissues to be tested are placed in the electrolyte;

[0054] 2.4, Calculate the gate shunt current difference matrix ΔI' G :ΔI' G =I' G-细胞 -I' G-空 ;

[0055] 2.4, according to ΔI' G , draw the image. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] The present invention will be further described in detail below in conjunction with the embodiments in the accompanying drawings, but this does not constitute any limitation to the present invention.

[0057] Figure 1 It is a schematic diagram of the three-dimensional structure of the microscale cell detection sensor of the present application.

[0058] Figure 2 It is a structural principle diagram of the OECT part of the sensor of this application.

[0059] Figure 3 It is a schematic diagram of the equivalent circuit analysis of the channel part.

[0060] Figure 4 It is a top view of the OECT array electrode assembly of the present application.

[0061] Figure 1-Figure 4 The reference numerals in the figures are described as follows:

[0062] Substrate 100 , OECT array electrode assembly 200 , electrolyte 300 . DETAILED DESCRIPTION

[0063] The purpose, advantages and features of the present invention will be explained by the non-limiting description of the following preferred embodiments. These embodiments are only typical examples of the application of the technical solution of the present invention, and any technical solution formed by equivalent replacement or equivalent transformation falls within the scope of protection claimed by the present invention.

[0064] <Example 1: A microscale cell detection sensor>

[0065] like Figure 1 As shown, a microscale cell detection sensor comprises: a substrate 100, an OECT array electrode assembly 200, and an electrolyte 300;

[0066] The substrate is made of non-conductive material and has a rectangular shape. The OECT array electrode assembly 200 includes eight OECTs, with two OECTs disposed on each side of the substrate. An electrolyte is also disposed above the substrate.

[0067] Each of the OECTs comprises: a source electrode, a gate electrode, a drain electrode and a channel; the channel is made of PEDOT:PSS organic material;

[0068] The source and drain are used together as electrodes to apply voltage to measure the current;

[0069] The gate serves as a corresponding excitation electrode in the EIT field;

[0070] The channel portion serves as a measurement electrode in the EIT field;

[0071] The electrolyte is used as a sensitive field in the EIT theory;

[0072] The electrical properties of the channel material are regulated by the gate voltage and are also affected by the cells in the electrolyte, which in turn affects the output current between the source and drain. The current between the source and drain is the output of the overall measurement system.

[0073] <Example 2: An imaging method>

[0074] <2.1, Theoretical basis>

[0075] like Figure 2 and Figure 3 As shown, the equivalent circuit analysis of the OECT channel is performed:

[0076] I D =W×d×e×μ×p(x)×[dV(x) / d(x)]

[0077] p(x)=SO3 - -M + (x)

[0078] M + (x)=(C * / e)×[V G -V(x)]

[0079] Among them, I D represents the source-drain output current of the OECT, or drain current; W and d are the width and depth of the channel; e is the charge carried by each ion; μ is the carrier mobility; p(x) is the carrier concentration; [dV(x) / dx] is the potential differential term; M + (x) is the concentration of cations entering the channel; C * is the equivalent capacitance between the gate and the channel; V(x) is the accumulated potential over the length dx.

[0080] The integration gives the governing equation of OECT:

[0081] I D =(W×d / L)×μ×C * ×[V T -V G +V D / 2]×V D

[0082] Where L is the channel length.

[0083] Among them, V T The definition is as follows:

[0084] V T =e×SO3 - / C*

[0085] Among them, V G is a given gate drive, V D is a given drain excitation, V T and I D are the cut-off voltage and source-drain current, respectively, obtained by measurement.

[0086] Based on this, the equivalent capacitance μ×C * for:

[0087]

[0088] Correspondingly, the equivalent impedance for:

[0089]

[0090] <2.2, Imaging method based on gate shunt current matrix>

[0091] First, the empty sensitive field is stimulated and the gate shunt current matrix I' is calculated when the sensitive field is empty. G-空 ;

[0092] Second, use tweezers or a dropper to place the cells or tissues to be tested in the electrolyte (place the cells to be tested in the field by appropriate methods, usually close to the center), stimulate the sensitive field again, and calculate the gate shunt current matrix I' at this time G-细胞 ;

[0093] Third, calculate the gate shunt current difference matrix ΔI' G ;

[0094] ΔI' G =I' G-细胞 -I' G-空 .

[0095] Fourth, according to ΔI' G , draw the image.

[0096] For I' G-空 , I' G-细胞 The method of obtaining is similar, the only difference is that: when obtaining I' G-空 When the microscale cell detection sensor is not added with cells, I' G-细胞 When the cells were added, the microscale cell detection sensor was used.

[0097] <2.3, Stimulus-Measurement Method>

[0098] When the microscale cell detection sensor of Example 1 is working, the eight OECTs are numbered sequentially as: OECT No. 1 to OECT No. 8, and the gates of OECT No. 1 to OECT No. 8 are stimulated in turn. During the stimulation, the source-drain output current of OECT No. 1 to OECT No. 8 and the input current of the 8 gates are measured simultaneously.

[0099] For the gate excitation of any i-th OECT, the method for measuring the source-drain output current of OECTs 1 to 8 and the input current of the i-th gate is as follows:

[0100] (1) Excitation conditions: Use the given frequency f and peak voltage V Gi The gate of the i-th OECT is excited by an AC signal (hereinafter referred to as the gate excitation voltage), and the drains of the 1st to 8th OECTs are connected to a fixed voltage V D , the sources of OECTs No. 1 to 8 are all grounded;

[0101] (2) Measurement conditions: Under the gate excitation of the i-th OECT, the source-drain output currents of the 1st to 8th OECTs are measured in sequence to obtain 8 source-drain current outputs I Di1 ~I Di8 (After measurement, a total of 8×8, 64 source-drain output currents were obtained);

[0102] At the same time, the input current I of the gate of the i-th OECT is measured under the gate excitation of the i-th OECT. Gi .

[0103] <2.4, Solution of gate shunt current matrix>

[0104] μ×C of OECT No. 1-8 under gate excitation of OECT No. 1 * , respectively recorded as proportional equivalent capacitance μ×C * 11 to μ×C * 18 , the OECT gates 1-8 are stimulated in turn, and the following results are obtained:

[0105]

[0106] For any parameter μC * ij , which represents the equivalent capacitance between the channel and the electrolyte of the jth OECT when the gate of the i-th OECT is stimulated, i and j are both natural numbers from 1 to 8, which is calculated using the following formula:

[0107]

[0108] From the impedance formula we can get:

[0109]

[0110] For any parameter It represents the equivalent impedance between the channel and the electrolyte of the jth OECT when the gate of the i-th OECT is stimulated, i and j are both natural numbers from 1 to 8, which are calculated using the following formula:

[0111]

[0112] According to the current shunt characteristics, we can know that:

[0113] I Gi =I Gi1 +I Gi2 +|I Gi7 +I Gi8

[0114] Among them, I Gij (i, j = 1, ..., 8) represents the current between the gate of the i-th OECT and the channel of the j-th OECT when the gate of the i-th OECT is stimulated. At the same time, since all drain voltages V D Equal, all sources are grounded, and it can be seen that the average potential of each channel is the same, so I Gij The expression is as follows:

[0115]

[0116] Based on the above formula, the gate shunt current matrix I' can be obtained G :

[0117]

[0118] The pseudo code of the above process is as follows:

[0119] Input: Gate excitation voltage vector V G , source-drain measurement current vector I D , Gate measurement current vector I G , drain excitation voltage V D , cut-off voltage V T , excitation frequency f;

[0120]

[0121]

[0122] <2.5, Method for solving the conductivity column vector of the gate shunt current matrix>

[0123] The conductivity of the sensitive domain Ω formed by the electrolyte is σ, and the 8 OECTs are at the boundary of the sensitive domain. In the figure, OECTs 1 to 8 are denoted as O1 to O8, and the excitation-measurement pair of any OECT is (O i , O j ); wherein, i, j = 1 to 8.

[0124] To obtain the sensitivity matrix and use the correlation algorithm to solve for the conductivity column vector:

[0125] 1. First, the channel of each OECT is used as the relative ground end of the sensitive domain. The equivalent circuit analysis of the OECT part is performed: the material PEDOT:PSS of the jth OECT channel is evenly distributed in a geometric rectangle of W×d×L, and the potentials on both sides of the channel are the source potential V Sj (ground is 0), drain potential V Dj It is easy to know that the equivalent ground potential is (V Sj +V Dj ) / 2, and denote it as V SDj At this time, there is a relative excitation voltage V Gij '=V Gi -V SDj ;

[0126] 2. If Figure 4 As shown, let U represent a relative excitation voltage U GAB Add to OECT pair (O A , O B ) when the voltage distribution in the sensitive area is GAC Represents OECT pair (O A , O C ) is the gate shunt current measured on the GAC Add to OECT pair (O A , O C ) when the voltage distribution in the sensitive area is GAB Represents OECT pair (O A , O B ) and define the mutual impedance as:

[0127] Z=V GAC / I GAB =U GAB / I GAC .

[0128] Consider the Laplace equation satisfied by voltage U:

[0129]

[0130] Select the virtual displacement function V and consider the weak form of the above equation:

[0131]

[0132] Using Green's first formula, we get:

[0133]

[0134] Similarly:

[0135]

[0136] We can get:

[0137] U GAB I GAB =V GAC I GAC .

[0138] Divide U on both sides GAB V GAC ,have

[0139]

[0140] Excitation voltage U GAB Add to OECT pair (O A , O B ), consider that the conductivity of the region changes from σ disturbance to σ+Δσ, the voltage distribution of the region changes from U to U+ΔU, the mutual impedance changes from Z to Z+ΔZ, and the voltage V remains unchanged, so:

[0141]

[0142] Since ΔZ and Δσ have opposite signs, we have:

[0143]

[0144] Expand the term ▽U(σ+Δσ) at σ, and we have

[0145]

[0146] Where Z is the measured impedance, Z (k) The conductivity distribution is σ (k) is the transmission impedance, and k represents the number of iterations. (k) The expression is

[0147]

[0148] Divide the sensitive area into n units, assuming that each unit Ω i The conductivity inside is constant, and the OECT is A , O B ) is 64, then the change of the i-th transmission impedance is

[0149]

[0150] In the formula, S ij It represents the sensitivity coefficient of the conductivity of the i-th OECT pair to the j-th unit, Z i and Z i (k) They represent the jth unit of the ith OECT pair at the kth iteration (the unit conductivity is Δσ (k) ) measurement impedance and transmission impedance; S ij Obtained through computer simulation.

[0151] The transmission impedance change vector of the kth iteration is The conductivity change vector is Then there is

[0152]

[0153] Where, the gate shunt current difference column vector ΔI G The gate current difference matrix ΔI' G Zhang Cheng, a total of 64, Relative excitation voltage column vector V G 'By V Gij 'Composition, a total of 64, V G '=(V G11 ',V G12 ',.....V G21 ',V G22 '......V G88 ') T , S (k) is a 64×n matrix, Δσ (k) is a column vector of conductivity changes in n rows, where n is the number of finite element division units, which is defined by the user.

[0154] The conductivity change column vector is solved according to the sensitivity matrix and the gate shunt current difference column vector.

[0155] The above embodiments are preferred implementation modes of the present invention and are only used to facilitate the description of the present invention. They are not intended to limit the present invention in any form. Any person with ordinary knowledge in the relevant technical field, if they do not depart from the scope of the technical features of the present invention, can make equivalent embodiments by partial changes or modifications to the technical contents disclosed in the present invention, and they still fall within the scope of the technical features of the present invention without departing from the technical features of the present invention.

Claims

1. An imaging method based on the combination of OECT and EIT, characterized in that: It includes the following steps: First, calculate the gate shunt current matrix I' when the sensitive field is empty G-空 ;I' G-空 The method to obtain is: First, basic data were obtained when no cells were added to the microscale cell detection sensor; The microscale cell detection sensor comprises: a substrate (100), an OECT array electrode assembly (200), and an electrolyte (300); wherein the substrate is made of a non-conductive material and is rectangular in shape; wherein the OECT array electrode assembly (200) comprises eight OECTs, and two OECTs are arranged on each side of the substrate; each of the OECTs comprises: a source electrode, a gate electrode, a drain electrode, and a channel; the channel is a channel for connecting the source electrode and the drain electrode, and is prepared using an organic material PEDOT:PSS; wherein an electrolyte is also arranged above the substrate; the source electrode and the drain electrode are used together as electrodes to apply voltage to measure the current; the gate electrode serves as a corresponding excitation electrode in the EIT field; the channel portion serves as a measuring electrode in the EIT field; and the electrolyte serves as a sensitive field in the EIT theory; The OECT is an organic electrochemical transistor; The EIT represents electrical impedance tomography; Then, the gate shunt current matrix is ​​solved for the empty sensitive field; Second, calculate the gate shunt current matrix I′ when the cells or tissues to be tested are placed in the electrolyte G-细胞 ; I′ G-细胞 The method to obtain is: First, add the cells or tissues to be tested and place them in the electrolyte to obtain basic data; Then, the gate shunt current matrix is ​​solved when the cells or tissues to be tested are placed in the electrolyte; Third, calculate the gate shunt current difference matrix ΔI' G :ΔI' G =I' G-细胞 -I' G-空 ; Fourth, according to ΔI' G , draw the image; Among them, the measurement method for obtaining basic data is: The eight OECTs are sequentially numbered as: OECT No. 1 to OECT No. 8; the gates of OECT No. 1 to OECT No. 8 are stimulated in turn, and the source-drain output currents of OECT No. 1 to OECT No. 8 and the input currents of the eight gates are measured simultaneously during the stimulation; For the gate excitation of any OECT No. i, the measurement method for the source-drain output current of OECT No. 1 to No. 8 and the input current of the gate No. i is as follows: Excitation conditions: using a given frequency f and gate excitation voltage V Gi The AC signal excites the gate of the i-th OECT, and the drains of the 1st to 8th OECTs are connected to a fixed voltage V D , the sources of OECTs No. 1 to No. 8 are all grounded; measurement conditions: the source-drain output current I of OECTs No. 1 to No. 8 is measured in sequence Di1 ~I Di8 At the same time, measure the input current I of the gate of the i-th OECT Gi ; The method for solving the gate shunt current matrix includes the following steps: Step 1: Input: measurement data and structural parameters; The measurement data includes: gate excitation voltage vector V G , source-drain measurement current vector I D , Gate measurement current vector I G , drain excitation voltage V D , cut-off voltage V T , excitation frequency f; V G =(V G1 ,V G2 ,……,V G8 ); I D =(I D11 ,I D12 ,…I Dij ……I D88 ); I G =(I G1 ,I G2 ,…I Gi ……I G8 ); Among them, V Gi represents the gate excitation voltage of the i-th OECT, where i is a natural number from 1 to 8; Among them, I Dij It represents the source-drain output current of OECT No. j when the gate of OECT No. i is stimulated, and both i and j are natural numbers from 1 to 8; Among them, I Gi represents the gate current of the sensor input through the gate of the i-th OECT when the gate of the i-th OECT is stimulated, i is a natural number from 1 to 8; The structural parameters include: W, d, L; W and d are the channel width and depth, and L is the channel length; Step 2: Calculate the proportional equivalent impedance It represents the proportional equivalent impedance between the channel of the jth OECT and the electrolyte when the gate of the i-th OECT is stimulated, and i and j are both natural numbers ranging from 1 to 8; Step 3: Calculate the gate shunt current matrix: Among them, any element I Gij The calculation is done using the following formula: I Gij It represents the current between the gate of the i-th OECT and the channel of the j-th OECT when the gate of the i-th OECT is stimulated, and i and j are both natural numbers from 1 to 8.

2. The imaging method based on the combination of OECT and EIT according to claim 1, characterized in that: The electrolyte is a 1 mol / L NaCl solution.

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