A heart chip integrated with piezoresistive sensors

Abstract

The application discloses a heart chip integrated with a piezoresistive sensor, which comprises a chip body, wherein structural units are arranged in an array on the chip body, and a micro sensor is installed on each structural unit; each structural unit comprises a culture pool, and a myocardial cell culture solution is added into the culture pool; each micro sensor comprises two micro beams, and the micro beams are assembled in the culture pool; the myocardial cells beat to drive the micro beams to deform, so that the micro sensor generates a change in electric resistance; and the change in electric resistance is measured by using an external monitoring device to realize real-time monitoring of the beating of the myocardial cells; the structural unit comprises the culture pool for myocardial cell culture and a groove for installing the micro sensor; the micro beam is a three-layer core package structure, wherein an elastic fiber is selected as a substrate for an inner layer, a flexible piezoresistive material is selected as a conductive coating for a middle layer, and an elastic insulating material is selected for encapsulation for an outermost layer; electrodes are installed at two ends of the conductive coating; and the application can realize in-situ real-time monitoring of the contraction and beating of myocardial cells.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of heart-on-chip, and particularly relates to a heart-on-chip integrated with a piezoresistive sensor. BACKGROUND

[0002] The heart is one of the most important organs of the human body. In order to study the physiological and pathological mechanisms of the heart, a corresponding heart model needs to be constructed. The traditional way is to use animal experiments or to culture cells in vitro in a culture dish, but the effects of these models are not ideal. There are species differences between animals and humans, and experimental results cannot be completely used for the human body; and cells in a culture dish often grow on the bottom and form a two-dimensional thin layer, which has a large difference in function from the three-dimensional structure of the heart in the body. Heart-on-chip, as a new technology that has emerged in recent years, can overcome the above difficulties.

[0003] Heart-on-chip is a kind of microfluidic cell culture device. The cultured myocardial cells can realize basic functions such as beating and contraction, and have advantages such as high throughput and low cost, and have a broad application prospect in the field of drug development. One of the main functions of the heart is contractility, and the size and frequency of the contractility are important indicators of heart function. For myocardial cells on the heart-on-chip, the measurement of contractility has become the focus of researchers. If the beating and contraction of myocardial cells on the heart-on-chip can be measured, the functional state of myocardial cells can be quantified.

[0004] The current method for measuring the contractility of myocardial cells is to take the heart-on-chip out of the incubator, use a microscope to take pictures of the beating of myocardial cells, and then calculate the contractility, beating frequency and other information of myocardial cells after post-processing. For example, Agarwal et al. cultured myocardial cells on a thin film and observed the contraction of the thin film by a microscope to observe the beating and contraction of the cells (Lab Chip, 2013, 13, 3599-3608); Oyunbaatar et al. cultured cells on a microcolumn array and calculated the contractility of myocardial cells by observing the bending deformation of the microcolumn (Colloid Surf. B, 2019, 174, 103-109). The disadvantage of this method is that the heart-on-chip needs to be taken out of the incubator, and the observation environment has a certain impact on the physiological state of the cells, and real-time monitoring in situ cannot be performed. Therefore, how to design a heart-on-chip to realize real-time monitoring of the beating and contraction of myocardial cells in situ is an important challenge faced by the current heart-on-chip. SUMMARY

[0005] In order to overcome the above-mentioned shortcomings of the prior art, the purpose of the present application is to provide a heart-on-chip integrated with a piezoresistive sensor, which can realize real-time monitoring of the beating and contraction of myocardial cells in situ.

[0006] In order to achieve the above-mentioned purpose, the technical scheme adopted by the present application is:

[0007] The heart chip with integrated piezoresistive sensor comprises a chip body 2, a plurality of structural units are arranged on the chip body 2, and a micro sensor 1 is arranged on each structural unit; each structural unit comprises a culture pool, and a myocardial cell culture solution is added in the culture pool; each micro sensor 1 comprises two micro beams, and the micro beams are assembled in the culture pool; the myocardial cells beat to drive the micro beams to deform, so that the micro sensor 1 generates a change in resistance, and the change in resistance is measured by using an external monitoring device to realize real-time monitoring of the beating of the myocardial cells.

[0008] The structural unit of the chip body 2 comprises a culture pool 2-1 for myocardial cell culture and a groove 2-2 for mounting the micro sensor 1, wherein the length l1, the width w1 and the height h1 of the culture pool 2-1, and the width w2 and the height h2 of the groove 2-2 are micrometers, and the length l3, the width w3 and the height h3 of the whole structural unit are millimeters.

[0009] The chip body 2 is prepared by a mold method, mechanical processing or 3D printing.

[0010] The two micro beams of the micro sensor 1 are a three-layer core package structure: the inner layer selects an elastic fiber as a substrate 1-1, the middle layer selects a flexible piezoresistive material as a conductive coating 1-2, and the outermost layer selects an elastic insulating material 1-4 for encapsulation as a protective layer; electrodes 1-5 are arranged at two ends of the conductive coating 1-2 for connection with a monitoring device; the diameter d1 of the micro sensor 1 is micrometers, and the length l4 is centimeters.

[0011] The elastic fiber comprises spandex, the flexible piezoresistive material comprises a carbon nanotube, the elastic insulating material comprises PDMS, and the monitoring device comprises an oscilloscope.

[0012] In use, the myocardial cells 3 are inoculated into the culture pool 2-1 of the heart chip, the myocardial cell culture solution is added, the myocardial cells 3 automatically gather and wrap the micro sensor 1, the micro sensor 1 is in a natural straight state when the myocardial cells 3 are not contracted, at this time, the micro sensor 1 has no change in indication; when the myocardial cells 3 beat and contract, the micro sensor 1 is bent and deformed, the micro sensor 1 has a piezoresistive effect, the bending and deformation causes a change in resistance of the micro sensor 1, the change in resistance is detected by the external device, and the frequency and amplitude of the beating of the myocardial cells are obtained.

[0013] The heart chip with integrated piezoresistive sensor comprises a chip body 2, a plurality of structural units are arranged on the chip body 2, and a micro sensor 1 is arranged on each structural unit; each structural unit comprises a culture pool, and a myocardial cell culture solution is added in the culture pool; each micro sensor 1 comprises two micro beams, and the micro beams are assembled in the culture pool; the myocardial cells beat to drive the micro beams to deform, so that the micro sensor 1 generates a change in resistance, and the change in resistance is measured by using an external monitoring device to realize real-time monitoring of the beating of the myocardial cells.

[0014] One of the challenges in measuring the contractile force of myocardial cells is their small size, thus requiring the microsensor 1 to have high sensitivity. To address this, the present invention pre-stretches the conductive coating 1-2 to create microcracks 1-3 on its surface, thereby improving the sensor's sensitivity. When the microsensor 1 is subjected to the contractile force of the cells, the microcracks 1-3 on its surface expand, causing a sharp increase in the resistance of the conductive coating 1-2. A small external force causes a large change in resistance, thus resulting in extremely high sensitivity.

[0015] The cardiac chip of this invention can monitor the contraction and beating of myocardial cells in situ in real time. The cardiac chip provides a new technical platform for the construction of in vitro cardiac models and has great potential in the exploration of cardiac physiology and pathology as well as drug screening. Attached Figure Description

[0016] Figure 1 This is a schematic diagram of the cardiac chip structure unit of the present invention.

[0017] Figure 2 This is a schematic diagram of the chip body of the present invention.

[0018] Figure 3-1 This is a schematic diagram of the fabrication of the microsensor 1 of the present invention; Figure 3-2 This is a schematic diagram of the microsensor 1 after the electrodes are installed and packaged according to the present invention.

[0019] Figure 4-1 This is a schematic diagram of the cardiac chip of the present invention when the myocardial cells are not contracted; Figure 4-2 This is a schematic diagram of myocardial cell contraction within the cardiac chip of the present invention. Detailed Implementation

[0020] The present invention will now be described in detail with reference to the accompanying drawings and embodiments.

[0021] A cardiac chip integrating a piezoresistive sensor includes a chip body 2, on which structural units are arranged in an array, such as... Figure 1 As shown, each structural unit is equipped with a microsensor 1; each structural unit includes a culture tank containing cardiomyocyte culture medium for culturing cardiomyocytes; each microsensor 1 includes two microbeams assembled in the culture tank, and the microbeams are made of flexible piezoresistive material; the beating of cardiomyocytes causes the microbeams to deform, thereby causing a change in resistance in the microsensor 1 composed of the two microbeams, and the change in resistance is measured by an external monitoring device (such as an oscilloscope) to achieve real-time monitoring of the beating of cardiomyocytes.

[0022] The structural unit of the chip body 2 comprises a culture pool 2-1 for myocardial cell culture and a groove 2-2 for mounting the micro sensor 1, wherein the length l1, the width w1 and the height h1 of the culture pool 2-1 and the width w2 and the height h2 of the groove 2-2 are microns, and the length l3, the width w3 and the height h3 of the whole structural unit are millimeters, as shown in Figure 2 .

[0023] The chip body 2 is prepared by a mold method, mechanical processing, 3D printing or the like.

[0024] The two micro beams of the micro sensor 1 are three-layer core package structures, each micro beam selects elastic fiber (such as spandex) as a substrate 1-1, selects a flexible piezoresistive material (such as a carbon nanotube) as a conductive coating 1-2, pre-stretches the conductive coating 1-2, generates micro cracks 1-3 on the surface of the conductive coating 1-2, and improves the sensitivity of the sensor; a flexible insulating material (such as PDMS) 1-4 is selected to encapsulate the conductive coating 1-2, so as to prevent the conductive coating 1-2 from falling off and the interference of the external environment on the micro sensor 1; electrodes 1-5 are installed at both ends of the conductive coating 1-2, which are used to connect monitoring equipment (such as an oscilloscope); the diameter d1 of the micro sensor 1 is microns, and the length l4 is centimeters, as shown in Figure 3-1 , Figure 3-2 .

[0025] In use, the myocardial cells 3 are inoculated into the culture pool 2-1 of the heart chip, myocardial cell culture solution is added, the myocardial cells 3 automatically aggregate and wrap the micro sensor 1, when the myocardial cells 3 are not contracted, the micro sensor 1 is in a natural straight state, at this time, the micro sensor 1 has no indication change, as shown in Figure 4-1 ; when the myocardial cells 3 beat and contract, the micro sensor 1 produces bending deformation, the micro sensor 1 has a piezoresistive effect, the bending deformation can cause the resistance of the micro sensor 1 to change, the change amount of the resistance is detected by the external device, and the frequency and amplitude of the myocardial cell beating are obtained, as shown in Figure 4-2 .

[0026] The heart chip integrated with the piezoresistive sensor has the following advantages: the micro sensor 1 uses a piezoresistive material to prepare the conductive coating 1-2, the micro sensor 1 is stretched and deformed by the myocardial cells, thereby generating resistance changes, and the beating of the myocardial cells can be monitored in real time by using an external device. The micro sensor 1 generates micro cracks 1-3 on the surface of the conductive coating 1-2 in a pre-stretching manner, thereby improving the sensitivity of the micro sensor 1. The heart chip prepared by the application provides a new platform for in vitro model construction, and has great potential in the exploration of heart physiology and pathology and drug screening.

Claims

1. A cardiac chip comprising an integrated piezoresistive sensor, comprising a chip body (2), characterized in that: The chip body (2) is arranged with structural units, and each structural unit is mounted with a micro sensor (1); each structural unit comprises a culture pool, and a myocardial cell culture solution is added in the culture pool; each micro sensor (1) comprises two micro beams, and the micro beams are assembled in the culture pool; the myocardial cell beats to drive the micro beams to deform, so that the micro sensor (1) generates a resistance change, and the resistance change is measured by an external monitoring device to realize real-time monitoring of the myocardial cell beating; The structural unit of the chip body (2) comprises a culture pool (2-1) for myocardial cell culture and a groove (2-2) for mounting the micro sensor (1), wherein the length l1, the width w1 and the height h1 of the culture pool (2-1) are microns, and the width w2 and the height h2 of the groove (2-2) are microns, and the length l3, the width w3 and the height h3 of the whole structural unit are millimeters; The two micro beams of the micro sensor (1) are a three-layer core package structure: the inner layer selects elastic fiber as a substrate (1-1), the middle layer selects flexible piezoresistive material as a conductive coating (1-2), and the outermost layer selects elastic insulating material (1-4) for packaging as a protective layer; electrodes (1-5) are mounted at both ends of the conductive coating (1-2) for connecting the monitoring device; the diameter d1 of the micro sensor (1) is microns, and the length l4 is centimeters; the conductive coating (1-2) is pre-stretched, micro cracks (1-3) are generated on the surface of the conductive coating (1-2), so as to improve the sensitivity of the micro sensor (1); In use, the myocardial cells (3) are inoculated into the culture pool (2-1) of the heart chip, the myocardial cell culture solution is added, the myocardial cells (3) automatically aggregate and wrap the micro sensor (1), the myocardial cells (3) are in a natural straight state when the myocardial cells (3) are not contracted, at this time, the micro sensor (1) has no indication change; when the myocardial cells (3) beat and contract, the micro sensor (1) produces bending deformation, the micro sensor (1) has a piezoresistive effect, the bending deformation causes the resistance change of the micro sensor (1), the change amount of the resistance is detected by the external device, and the frequency and amplitude of the myocardial cell beating are obtained; The chip body (2) is prepared by a mold method, mechanical processing or 3D printing; The elastic fiber comprises spandex, the flexible piezoresistive material comprises carbon nanotubes, the elastic insulating material comprises PDMS, and the monitoring device comprises an oscilloscope.

Images