CN107907485B - Heart chip based on structural color hydrogel and application thereof - Google Patents
Heart chip based on structural color hydrogel and application thereof Download PDFInfo
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- CN107907485B CN107907485B CN201711096076.9A CN201711096076A CN107907485B CN 107907485 B CN107907485 B CN 107907485B CN 201711096076 A CN201711096076 A CN 201711096076A CN 107907485 B CN107907485 B CN 107907485B
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- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
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Abstract
A heart chip based on structural color hydrogel comprises a chip top plate, a chip bottom plate and a structural color hydrogel film on which cardiomyocytes grow, wherein the chip bottom plate is provided with a micro liquid storage pool, one end of the micro liquid storage pool is communicated with a liquid inlet on the chip bottom plate through a flow distribution micro channel, the other end of the micro liquid storage pool is communicated with a liquid outlet on the chip bottom plate, and a hydrogel film mounting micro column is arranged in the micro liquid storage pool and used for placing the structural color hydrogel film; the chip top plate is provided with a liquid inlet hole and a liquid outlet hole, and the positions of the liquid inlet hole and the liquid outlet hole correspond to the liquid inlet and the liquid outlet of the chip bottom plate respectively. The heart chip constructed based on the structural color hydrogel material does not need a complex detection system, has intuition, has no influence on the detected system in the aspects of physiology and pharmacology and the like, and more importantly, the detection method is not influenced by factors such as external environment, chemical reagents and the like, and can show unique inherent advantages of sensitivity, high efficiency and no influence by external conditions in the screening and evaluation of heart drugs.
Description
Technical Field
The invention relates to a heart chip based on structural color hydrogel and application thereof, belonging to the field of organ chips.
Background
The human body is an organism consisting of various complex organs, and the mutual linkage of the organs enables the human body to realize various metabolic behaviors in the body. At present, for the development of human drugs, the action of the drugs on a target object is mainly detected through in vitro cell culture and in vivo animal experiments, so as to judge the drug characteristics; however, the two-dimensional cell structure cultured by the in vitro cell can not truly simulate the human body microenvironment and the complex physiological process among tissues and organs, and meanwhile, the in vivo animal experiment is also limited by the uncertainty of animal models, the complexity of different animal bodies and some humanistic factors; for this reason, constructing cell or organ chips at the cell or organ level to simulate real physiological processes has attracted a wide range of interest.
The heart is one of important organs of a human body, the heart chip is an important implementation mode for simulating the heart function and detection behavior of the human body, however, the constructed heart chip needs a complex detection system, and the detection systems usually need to consume a large amount of time and energy and are lack of intuitiveness; in the research of heart and myocardial cells, the contractility and beating frequency of the myocardial cells are the most important evaluation parameters of the myocardial cells, and are usually important indexes for evaluating the heart function and the activity of the myocardial cells; therefore, the research and development of sensing materials with high sensitivity for detecting the contractility and the beating frequency of the myocardial cells, and the construction of a sensing heart chip and a drug research platform with stable contractility and beating frequency still face serious challenges.
Inspired by the color change caused by the structural change of the micro-photonic crystal of the structural color hydrogel, a novel detection method for culturing the myocardial cells by using the structural color hydrogel and constructing the myocardial cells in an organ chip is constructed. The unique optical sensing technology and the characteristic reflection peak of the photonic crystal structure in the structural color hydrogel are utilized to carry out sensing research on the contractility and the beating frequency of the cardiac muscle cells, and the detection of the cardiac cells is visually realized.
Disclosure of Invention
The technical problem is as follows: the invention aims to provide a heart chip based on structural color hydrogel and application thereof.
The technical scheme is as follows: the invention provides a heart chip based on structural color hydrogel, which comprises a chip top plate, a chip bottom plate and a structural color hydrogel film growing with cardiac muscle cells, wherein the chip bottom plate is provided with a micro liquid storage pool, one end of the micro liquid storage pool is communicated with a liquid inlet on the chip bottom plate through a flow distribution micro channel, the other end of the micro liquid storage pool is communicated with a liquid outlet on the chip bottom plate, and a hydrogel film mounting micro column is arranged in the micro liquid storage pool and used for placing the structural color hydrogel film; the chip top plate is provided with a liquid inlet hole and a liquid outlet hole, and the positions of the liquid inlet hole and the liquid outlet hole correspond to the liquid inlet and the liquid outlet of the chip bottom plate respectively.
Wherein:
the flow distribution micro-channel is of a multi-branch structure, namely one end of the flow distribution micro-channel is communicated with the liquid inlet, the other end of the flow distribution micro-channel is divided into a plurality of branch flow channels which are communicated with the micro liquid storage tank, and the number n of the branch flow channels is 2NWherein N is a number of stages, and N>2。
The structural color hydrogel film is in a multi-tail shape, and the multi-tail part faces the direction of the liquid outlet.
The hydrogel film mounting microcolumn is fixed at the bottom of the micro liquid storage pool, and the sum of the height of the hydrogel film mounting microcolumn and the thickness of the structural color hydrogel film is equal to the height of the micro liquid storage pool.
The structural color hydrogel membrane is made of methacrylate gelatin (Gelma), Bovine Serum Albumin (BSA), quadriarmed-polyethylene glycol (4-arm-PEG) and polyethylene glycol diacrylate (PEGDA).
The structural color hydrogel film is prepared by a template sacrificial method and a deposition method:
1) printing a multi-tail mask plate by using a printer, wherein the multi-tail part is a light-transmitting part, the rest part is a black light-proof part, polymerizing the photonic crystal prepolymer solution by using the mask plate, and removing the unpolymerized part to obtain a multi-tail photonic crystal positive structure template with a positive structure;
2) pouring a biocompatible hydrogel prepolymer into the multi-tailed photonic crystal positive structure template, and removing the photonic crystal positive structure template after polymerization to obtain a multi-tailed inverse opal structure colored hydrogel film;
the structural color and the reflection peak of the prepared structural color hydrogel film are controlled by adjusting the particle size of particles in the photonic crystal prepolymer solution, the structural color covers the visible light range, and the position of the reflection peak is 300 nm-800 nm.
The chip top plate and the chip bottom plate of the heart chip are manufactured by Polydimethylsiloxane (PDMS) photoetching technology or a repeated preparation method of PDMS.
Has the advantages that: compared with the prior art, the invention has the following advantages:
1) the invention discloses a heart chip based on structural color hydrogel, which realizes visual detection of myocardial cell contraction force and beating frequency by combining the heart chip with the structural color hydrogel, and obtains the parameters of myocardial contraction force and beating frequency by detecting the color change of the structural color hydrogel in real time and utilizing characteristic measurement methods such as spectrum and the like;
2) the influence of different drugs on myocardial cells is observed and recorded on line by changing the drugs injected into the heart chip;
3) the invention does not need a complex detection system, has intuition, has no influence on the detected system in the aspects of physiological pharmacology and the like, more importantly, the detection method is not influenced by factors such as external environment, chemical reagents and the like, and has the unique inherent advantages of sensitivity, high efficiency and no influence by external conditions in the screening and evaluation of heart drugs.
Drawings
FIG. 1 is a schematic overall view of a structural color hydrogel-based heart chip of the present invention;
FIG. 2 is a schematic diagram of a chip backplane structure of a heart chip based on structural color hydrogel according to the present invention;
FIG. 3 is a schematic view of the arrangement of hydrogels within a heart chip based on structural color hydrogels of the present invention;
the figure shows that: the chip comprises a chip top plate 1, a chip bottom plate 2, a liquid inlet 3, a liquid outlet 4, a hydrogel film mounting microcolumn 5, a flow distribution microchannel 6, a micro liquid storage pool 7, a structural color hydrogel film 8, a liquid inlet hole 9 and a liquid outlet hole 10.
Detailed Description
Preferred embodiments of the present invention will be described in further detail below with reference to the accompanying drawings so that the advantages and features of the invention may be more readily understood by those skilled in the art:
fig. 1 shows a schematic diagram of a heart chip based on structural color hydrogel, the specific structure of the heart chip comprises a chip top plate 1, a chip bottom plate 2, a liquid inlet hole 9 and a liquid outlet hole 10, the liquid inlet hole 9 and the liquid outlet hole 10 are processed on the chip top plate 1 and are respectively connected with the outside through hoses, wherein the liquid inlet hole 9 is used for injecting culture solution and test solution, the liquid outlet hole 10 is used for recovering the culture solution and the test solution, and after a structural color hydrogel film 8 is installed on a hydrogel film installation microcolumn 5, the top plate 1 and the lower bottom plate 2 are bonded through plasma to form a closed structure.
Fig. 2 is a schematic structural diagram of a chip base plate 2 of a heart chip based on structural color hydrogel, and the specific structure includes a liquid inlet 3, a liquid outlet 4, a hydrogel film mounting microcolumn 5, a flow distribution microchannel 6, and a micro liquid storage tank 7; the hydrogel mounting microcolumn 5 is used for fixing structural color hydrogel between the top plate 1 and the lower plate 2 of the heart chip flow channel structure, and the flow distribution microchannel 6 can realize that culture solution and test solution are uniformly injected into the micro liquid storage tank 7.
FIG. 3 shows a schematic diagram of the arrangement of hydrogel films inside the heart chip based on structural color hydrogel of the present invention; the structural color hydrogel film 8 used in the invention is multi-tail, and the structural color change on each tail hydrogel can be effectively observed.
Example 1: heart chip based on structural color hydrogel for detecting isoproterenol
1) And preparing a structural color hydrogel film 8 with the grown myocardial cells:
① selecting hydrogel material for myocardial culture, methacrylate gelatin (Gelma), and preparing multi-tail structure color hydrogel film 8 by template sacrifice method;
② extracting myocardial cells of SD milk rat, and planting on the surface of the prepared structural color hydrogel for myocardial cell culture;
③ after a certain period of culture, the cardiomyocytes will show contraction and relaxation behaviors on the hydrogel material to obtain a multi-tailed structural color hydrogel membrane 8 with cardiomyocytes growing thereon, and the detection of the contraction and relaxation behaviors of the cardiomyocytes is performed by using an epitaxial device (spectrometer ) according to the color and spectrum changes of the structural color hydrogel membrane 8.
2) Isoadrenaline assay
① placing the prepared multi-tail structure color hydrogel film 8 with cardiomyocytes on the hydrogel film mounting microcolumn 5 of the chip bottom plate 2, and bonding and sealing the chip top plate 1 and the chip bottom plate 2;
② injecting isoadrenalin into the liquid inlet 9, and observing the effect of isoadrenalin on the contraction force of myocardial cells by detecting the color and spectrum change of the structural color hydrogel membrane 8 by using an epitaxial device (a spectrometer or a spectrometer);
(3) the concentration of the injected isoproterenol is adjusted, and the influence of the isoproterenol with different concentrations on the contraction and relaxation behaviors of the myocardial cells is detected, so that the screening and evaluation of the heart drugs are realized.
Example 2: heart chip based on structural color hydrogel for calcium ion detection
1) And preparing a structural color hydrogel film 8 with the grown myocardial cells:
① selecting hydrogel material Bovine Serum Albumin (BSA) for myocardial culture, and preparing the multi-tail structure color hydrogel film 8 by a deposition method;
② extracting myocardial cells of SD milk rat, and planting on the surface of the prepared structural color hydrogel for myocardial cell culture;
③ after a certain period of culture, the cardiomyocytes will show contraction and relaxation behaviors on the hydrogel material to obtain a multi-tail structure color hydrogel membrane 8 with cardiomyocytes growing thereon, and the contractility of the cardiomyocytes is detected by using an epitaxial device (spectrometer ) according to the color and spectrum changes of the structure color hydrogel membrane 8;
2) calcium ion detection
① placing the prepared multi-tail structure color hydrogel film 8 with cardiomyocytes on the hydrogel film mounting microcolumn 5 of the chip bottom plate 2, and bonding and sealing the chip top plate 1 and the chip bottom plate 2;
② injecting calcium ion-containing solution into the liquid inlet 9, and observing the influence of calcium particles on myocardial cell contraction and relaxation by detecting the color and spectrum change of the structural color hydrogel membrane 8 with epitaxial equipment;
③ the concentration of the injected calcium ion-containing solution is adjusted, and the influence of the calcium ion solutions with different concentrations on the contraction and relaxation behaviors of the myocardial cells is detected, so as to realize the screening and evaluation of the heart drugs.
Claims (6)
1. A heart chip based on structural color hydrogel is characterized in that: the heart chip comprises a chip top plate (1), a chip bottom plate (2) and a structural color hydrogel membrane (8) growing with cardiac muscle cells, wherein the chip bottom plate (2) is provided with a micro liquid storage pool (7), one end of the micro liquid storage pool is communicated with a liquid inlet (3) on the chip bottom plate (2) through a flow distribution micro channel (6), the other end of the micro liquid storage pool is communicated with a liquid outlet (4) on the chip bottom plate (2), and a hydrogel membrane mounting micro column (5) is arranged in the micro liquid storage pool (7) and used for placing the structural color hydrogel membrane (8); the chip top plate (1) is provided with a liquid inlet hole (9) and a liquid outlet hole (10) which correspond to the liquid inlet (3) and the liquid outlet (4) of the chip bottom plate (2) respectively, and the structural color hydrogel film has a photonic crystal structure;
the structural color hydrogel (8) film is made of methacrylate gelatin, bovine serum albumin, four-arm-polyethylene glycol and polyethylene glycol diacrylate.
2. The heart chip of claim 1, wherein the structural color hydrogel is selected from the group consisting of: the flow distribution micro-channel (6) is of a multi-branch structure, namely one end of the flow distribution micro-channel (6) is communicated with the liquid inlet (3), the other end of the flow distribution micro-channel is divided into a plurality of branch flow channels to be communicated with the micro liquid storage pool (7), and the number n of the branch flow channels is 2NWherein N is a number of stages, and N>2。
3. The heart chip of claim 1, wherein the structural color hydrogel is selected from the group consisting of: the structural color hydrogel (8) film is in a multi-tail shape, and the multi-tail part faces the direction of the liquid outlet.
4. The heart chip of claim 1, wherein the structural color hydrogel is selected from the group consisting of: the hydrogel film mounting microcolumn (5) is fixed at the bottom of the micro liquid storage pool (7), and the sum of the height of the hydrogel film mounting microcolumn and the thickness of the structural color hydrogel film (8) is equal to the height of the micro liquid storage pool (7).
5. The heart chip of claim 1, wherein the structural color hydrogel is selected from the group consisting of: the structural color hydrogel (8) film is prepared by a template sacrifice method and a deposition method.
6. Use of a heart chip based on a structural color hydrogel as claimed in claim 1, characterized in that: the heart chip is applied to screening and evaluation of heart drugs.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711096076.9A CN107907485B (en) | 2017-11-09 | 2017-11-09 | Heart chip based on structural color hydrogel and application thereof |
| PCT/CN2018/080767 WO2019091037A1 (en) | 2017-11-09 | 2018-03-28 | Heart chip based on structural color hydrogel, and applications thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711096076.9A CN107907485B (en) | 2017-11-09 | 2017-11-09 | Heart chip based on structural color hydrogel and application thereof |
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| CN107907485A CN107907485A (en) | 2018-04-13 |
| CN107907485B true CN107907485B (en) | 2020-03-31 |
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| CN111504941B (en) * | 2020-05-14 | 2021-01-01 | 中国人民解放军陆军军医大学第一附属医院 | Terahertz attenuated total reflection technology platform for unmarked evaluation of response characteristics of responsive hydrogel |
| CN112485247B (en) * | 2020-11-20 | 2022-04-26 | 南京鼓楼医院 | Structure color microfiber of heterostructure, preparation method of microstructure color microfiber and myocardial cell detection method |
| CN114160220B (en) * | 2021-11-26 | 2023-02-03 | 南京国科舰航传感科技有限公司 | Hydrogel and microfluidic based Ca 2+ Ion detection paper chip and preparation method thereof |
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