CN110029058A - A kind of online non-destructive testing cardiac muscular tissue chip of multiple-sensor integration - Google Patents
A kind of online non-destructive testing cardiac muscular tissue chip of multiple-sensor integration Download PDFInfo
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- CN110029058A CN110029058A CN201910322804.6A CN201910322804A CN110029058A CN 110029058 A CN110029058 A CN 110029058A CN 201910322804 A CN201910322804 A CN 201910322804A CN 110029058 A CN110029058 A CN 110029058A
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Abstract
The present invention relates to a kind of online non-destructive testing cardiac muscular tissue chips of multiple-sensor integration comprising: chip base, culture cavity, the first, second culture chamber, integrated sensor and modular member；First culture chamber is the input terminal of cardiac muscular tissue's chip, and bottom is provided with the first inlet, the first liquid outlet and gas exchanges mouth；Output end of second culture chamber as cardiac muscular tissue's chip, bottom are provided with the second inlet for being connected with the first liquid outlet and the second liquid outlet for being connected with external medium recovery end, constitute closed-loop system；Integrated sensor includes microtrabeculae sensor and electrochemical sensor, and microtrabeculae sensor and electrochemical sensor pass through the contact conductor being arranged in chip base respectively and be connected with external on-line detecting system, carry out online full information acquisition to cardiac muscular tissue.The present invention can be widely applied to the on-line checking field of external cardiac muscular tissue.
Description
Technical field
The present invention relates to a kind of external cardiac muscular tissue's chips, more particularly to a kind of online lossless inspection of multiple-sensor integration
Thought-read muscular tissue chip.
Background technique
With the development of organ chip and cardiac muscle tissue engineering, there is diversified myocardium chip.Heart it is basic
Function is beating conveying blood, is mainly clinically generally heart rate, myocardial movement intensity and the heart to the evaluation criterion of cardiac function
The biomarker of vascular diseases.Therefore, it is myocardium core that myocardium chip, which can be realized the premise of accurate, high-throughput drug screening,
Piece can feed back complete evaluation information.However due to the operating mode of moment sensor is single, evaluation method is complicated etc.,
Signal feedback in myocardium chip is difficult to lossless, multi-functional and on-line real-time measuremen.
In addition, myocardium chip only undertakes the function of cardiac muscular tissue's carrier in the course of the research.Most myocardium chip at present
Only devise the ontology of myocardium chip --- namely the carrier part of cardiac muscular tissue, and only minority relates to the structure of whole system
Part provides effect of online, the real-time detection cardiac muscular tissue under different pharmaceutical effect.Drug screening complete for one,
For the pathological research of medicine, the only carrier part of cardiac muscular tissue can not completely support the research work of myocardium chip, and
Existing signal acquiring system also cannot achieve the full signal acquisition of myocardium chip.
Summary of the invention
In view of the above-mentioned problems, the object of the present invention is to provide a kind of online non-destructive testing cardiac muscular tissues of multiple-sensor integration
Chip, can be online lossless to external cardiac muscular tissue progress convergent force, extracellular mass current potential and biomarker release journey
Cardiac muscular tissue's functional evaluation of degree.
To achieve the above object, the present invention takes following technical scheme: a kind of online non-destructive testing of multiple-sensor integration
Cardiac muscular tissue's chip comprising: chip base, is arranged in the culture culture cavity that the chip base side is arranged in
Intracorporal first, second culture chamber of chamber, the integrated sensor being arranged in two culture chambers and for supporting cardiac muscular tissue
The modular member of chip operation；Input terminal of first culture chamber as cardiac muscular tissue's chip, bottom is provided with
Be respectively used to the first inlet being connected with external medium supply side, the first liquid outlet being connected with second culture chamber and
The gas exchanges mouth being connected with external oxygen input/output terminal；Output of second culture chamber as cardiac muscular tissue's chip
End, bottom are provided with the second inlet for being connected with first liquid outlet and are used for and external medium recovery end
The second connected liquid outlet constitutes closed-loop system；The integrated sensor passes through the electrode layer being arranged in the chip base
It is connected with external detection system, such as microelectrode array extracellular electrode records system, oscillograph, electrochemical workstation, to cardiac muscle
Tissue carries out full information acquisition.
Further, the first inlet, the first liquid outlet and gas exchanges mouth of first culture chamber bottom and institute
The second inlet and the second liquid outlet structure for stating the second culture chamber bottom are all the same, including orthogonal first, second liang
Microchannel, the first microchannel setting is in the culture cavity bottom, one end and first culture chamber or the second training
It supports chamber to be connected, the other end is connected with second microchannel, and syringe needle is plugged in second microchannel, and the syringe needle passes through
Rubber tube is connected with external medium supply side, recovery end or oxygen input/output terminal.
Further, the integrated sensor includes that the microtrabeculae sensor being arranged in first culture chamber and setting exist
Electrochemical sensor in second culture chamber, the microtrabeculae sensor is to myocardium group in first culture chamber of culture
It knits and carries out convergent force, extracellular mass electrical potential information and be acquired, the electrochemical sensor is to the life in second culture chamber
Object marker releasing degree information is acquired, and is acquired data by the electrode layer and is sent to external detection system.
Further, the microtrabeculae sensor includes being capable of providing lossless, on-line checking cardiac muscular tissue convergent force sensing
Group's potentiometric sensor outside device and cardiac bistiocyte, and group's electricity outside force snesor and cardiac bistiocyte shrinks in the cardiac muscular tissue
Level sensor becomes one.
Further, the cardiac muscular tissue shrinks force snesor and includes the piezoelectric membrane with array electrode and be placed on institute
The PDMS film that PDMS micro-pillar array is had on piezoelectric membrane is stated, and piezoelectric membrane and PDMS film carry out plasma using PDMS
Body handles post package.
Further, the PDMS micro-pillar array is n*n array, and the size of each microtrabeculae is 10~2000 microns of diameter, high
30~6000 microns, 30~6000 microns are divided between the center of circle；PDMS film with a thickness of 5~500 microns；On the piezoelectric membrane
The array electrode of setting is corresponding with the PDMS micro-pillar array, is acquired for the pressure to each microtrabeculae, and is sent to outer
Portion's detection system.
Further, group's potentiometric sensor includes conductive layer and trace layer, the conductive layer outside the cardiac bistiocyte
For the PDMS microtrabeculae for shrinking force snesor in the cardiac muscular tissue using the method for metal deposit or droplet ejection high molecular material
The layer of conductive material of surface covering, the conductive layer are directly contacted with external cardiac muscular tissue；The trace layer is using metal
Material or macromolecule conducting material composition contact conductor, the contact conductor respectively with the conductive layer and outside on-line checking
System is connected.
Further, the conductive layer with a thickness of 1 angstrom~1 micron.
Further, the electrochemical sensor is cardiac muscular tissue's biomarker sensor, cardiac muscular tissue's biology
Marker sensor includes working electrode, reference electrode and auxiliary electrode, and fixed in sequence in each electrode surface
MUA, EDC, NHS, SPV and biotinylation biomarker monoclonal antibody, each electrode pass through contact conductor and outside electrification
Work station is learned to be connected.
Further, the modular member includes temperature measuring device, pH measuring device, culture liquid circulating device and training
Nutrient solution gas defoaming device；The temperature measuring device is by temperature sensitive device, to entrance the first culture chamber of cardiac muscular tissue's chip
Culture solution carries out temperature measurement；The pH measuring device exports the second culture chamber of cardiac muscular tissue's chip by online pH measuring instrument
Culture solution measure；The culture liquid circulating device is provided by micro peristaltic pump for the culture solution in cardiac muscular tissue's chip
Circulation power；The defoaming device is set to cardiac muscular tissue's chip input terminal, using the gas permeability principle of PDMS, to film one end
Vacuum is carried out, realizes the de-bubble of film other end solution.
The invention adopts the above technical scheme, which has the following advantages: 1, the present invention is arranged the in chip base
One, the second culture chamber, and microtrabeculae sensor is set in the first culture chamber, electrochemical sensor, energy are set in the second culture chamber
Enough while online is acquired the convergent force, extracellular mass current potential and biomarker releasing degree of cardiac muscular tissue, real
Lossless, the multi-functional and real-time full signal acquisition to cardiac muscular tissue is showed.2, microtrabeculae sensor includes cardiac muscular tissue in the present invention
Shrink the outer group's potentiometric sensor of force snesor and cardiac bistiocyte, cardiac muscular tissue shrink force snesor use piezoelectric membrane and
PDMS film on piezoelectric membrane with PDMS microtrabeculae is constituted, on the one hand PDMS microtrabeculae is used to fix hydrogel cardiac muscular tissue
On the other hand position cooperates the convergent force of the cardiac muscular tissue to culture on microtrabeculae to detect, the third aspect with piezoelectric membrane
As the carrying of group's potentiometric sensor outside cardiac bistiocyte, two kinds of sensor integration one, so that size sensor is smaller.3,
Cardiac muscular tissue of the present invention, which shrinks, is provided with array electrode corresponding with PDMS micro-pillar array on the piezoelectric membrane in force snesor,
The pressure acquisition to microtrabeculae single on PDMS film is realized, so that testing result is more accurate.4, the present invention is due to cardiac muscular tissue
Extracellular mass potentiometric sensor is deposited on PDMS micro-post surface, so that three-dimensional structure, energy is presented in the sensor in structure
Enough current potentials to cardiac muscular tissue carry out three-dimensional acquisition.Therefore, the present invention can be widely applied to cardiac bistiocyte's on-line checking
Field.
Detailed description of the invention
Fig. 1 is the perspective view of external cardiac muscular tissue chip of the invention；
Fig. 2 is the top view of external cardiac muscular tissue chip of the invention；
Fig. 3 is the main view of external cardiac muscular tissue chip of the invention；
Fig. 4 is the exploded view of external cardiac muscular tissue chip of the invention；
Fig. 5 is the exploded view that force snesor shrinks in cardiac muscular tissue of the present invention.
Specific embodiment
The present invention is described in detail below with reference to the accompanying drawings and embodiments.
As shown in Figure 1, a kind of online non-destructive testing cardiac muscular tissue chip of multiple-sensor integration provided by the invention, packet
It includes: chip base 1, the culture cavity 2 that 1 side of chip base is set, the first, second culture being arranged in culture cavity 2
Chamber 3,4, the integrated sensor that is arranged in two culture chambers and the modular member (figure for supporting cardiac muscular tissue's chip operation
In be not shown).Wherein, input terminal of first culture chamber 3 as cardiac muscular tissue's chip, bottom, which is provided with, to be respectively used to and outside
The first connected inlet 5 of culture solution supply side, the first liquid outlet 6 being connected with the second culture chamber 4 and with external oxygen input
The connected gas exchanges mouth 7 of output end；Output end of second culture chamber 4 as cardiac muscular tissue's chip, bottom, which is provided with, to be used for
The second inlet 8 being connected with the first liquid outlet 6 and the second liquid outlet 9 for being connected with external medium recovery end, structure
At closed-loop system.Integrated sensor includes the microtrabeculae sensor 10 being arranged in the first culture chamber 3 and is arranged in the second culture chamber 4
Interior electrochemical sensor 11, and microtrabeculae sensor 10 and electrochemical sensor 11 are respectively by being arranged in chip base 1
Electrode layer 12 and external detection system, such as microelectrode array extracellular electrode record system, oscillograph, electrochemical workstation phase
Even, to hydrogel by way of cardiac muscular tissue of the culture in the first culture chamber 3 on microtrabeculae sensor 10 carry out convergent force, carefully
Biomarker releasing degree information in extracellular group's current potential and the second culture chamber 4 carries out online acquisition.
As a preferred embodiment, chip base 1 is made of silastic material, such as PDMS (poly dimethyl silicon
Oxygen alkane) material.
As a preferred embodiment, the first inlet 5, the first liquid outlet 6 and the gas of 3 bottom of the first culture chamber are handed over
The second inlet 8 and 9 structure of the second liquid outlet for changing 4 bottom of mouth 7 and the second culture chamber are all the same, include orthogonal
Two microchannels 13,14, the setting of the first microchannel 13 is in culture 2 bottom of cavity, one end and first or second culture chamber phase
Even, the other end is connected with the second microchannel 14, and syringe needle is plugged in the second microchannel 14, and syringe needle passes through rubber tube and external training
Nutrient solution supply side, recovery end or oxygen input/output terminal are connected.
As a preferred embodiment, microtrabeculae sensor 10 includes being capable of providing lossless, on-line checking cardiac muscular tissue
Group's potentiometric sensor outside force snesor and cardiac bistiocyte is shunk, and force snesor and cardiac bistiocyte are shunk by cardiac muscular tissue
Outer group's potentiometric sensor becomes one, and records system, oscillography by contact conductor and the extracellular external electrode of microelectrode array respectively
Device is connected.
As a preferred embodiment, as shown in Figure 4, Figure 5, it includes piezoelectric membrane 15 that force snesor shrinks in cardiac muscular tissue
And it is placed on the PDMS film that PDMS micro-pillar array is had on piezoelectric membrane 15, and piezoelectric membrane 15 and PDMS film use
PDMS carries out corona treatment post package.Wherein, the PDMS micro-pillar array on PDMS film is that n*n array (is adopted in the present invention
For 3*3 array), the size of each microtrabeculae is 10~2000 microns of diameter, 30~6000 microns high, it is divided into 30 between the center of circle~
6000 microns；PDMS film with a thickness of 5~500 microns.It is provided with array electrode on piezoelectric membrane 15, the array electrode is just
Each micro-pillar array on pole 151 and PDMS film corresponds, and online acquisition, array electricity are carried out for the pressure to each microtrabeculae
The positive and negative electrode 151,152 of pole is sent to external charge amplifier, low-pass filtering by the contact conductor on electrode layer 12 respectively
Device, oscillograph.
As a preferred embodiment, group's potentiometric sensor includes conductive layer and trace layer outside cardiac bistiocyte,
In, conductive layer is the PDMS for shrinking force snesor in cardiac muscular tissue using the method for metal deposit or droplet ejection high molecular material
Conductive material of a layer thickness of micro-post surface covering at 1 angstrom~1 micron, the conductive layer are directly contacted with external cardiac muscular tissue；
Trace layer is the contact conductor formed using metal material or macromolecule conducting material, and the contact conductor is respectively with conductive layer and outside
Portion's detection system is connected.In the present invention, since conductive layer is deposited on PDMS micro-post surface, thus group's electricity outside cardiac bistiocyte
Level sensor is three-dimensional microelectrode array, can the online current potential to cardiac muscular tissue carry out three-dimensional acquisition.
As a preferred embodiment, electrochemical sensor 11 uses cardiac muscular tissue's biomarker sensor, packet
Include working electrode, reference electrode and auxiliary electrode, and MUA (the 11- mercapto-undecanoic fixed in sequence in each electrode surface
Acid), EDC (1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride), NHS (n-hydroxysuccinimide), SPV (chain
Mould Avidin) and biotinylation biomarker monoclonal antibody, lead and external electrochemistry of each electrode by electrode layer
Work station is connected.In the present invention, using golden material production, reference electrode is made of ag material for working electrode and auxiliary electrode,
But not limited to this, making material, such as platinum, carbon nanotube of each electrode etc. can be selected according to actual needs.
As a preferred embodiment, modular member includes temperature measuring device, pH measuring device, culture solution circulation
The functional components such as device and culture solution gas defoaming device.Wherein, the input of cardiac muscular tissue's chip is arranged in temperature measuring device
End carries out temperature measurement to the culture solution for entering the first culture chamber；PH measuring device is by online pH measuring instrument to cardiac muscular tissue
The culture solution of chip output carries out ph measurement；Culture liquid circulating device includes culture solution holding vessel and micro peristaltic pump, culture
The outlet of liquid is connected with the arrival end of micro peristaltic pump, the first culture chamber in the outlet end of micro peristaltic pump and cardiac muscular tissue's chip
3 the first inlet 5 is connected, and the second liquid outlet 9 of the second culture chamber 4 is connected with the entrance of culture solution holding vessel, micro wriggling
Pump is for provide circulation power into the culture solution of cardiac muscular tissue's chip；The input of cardiac muscular tissue's chip is arranged in defoaming device
End carries out vacuum to PDMS film one end, realizes the de-bubble of film other end solution using the gas permeability principle of PDMS film.
As a preferred embodiment, in modular member, it can access and take out in a modular manner according to demand
Each functional component.
In the use of the present invention, firstly, using silicone tube by the first of the first culture chamber 3 of external cardiac muscular tissue's chip into
Liquid mouth 5 is connected with culture solution supply side, and gas exchanges mouth is connected with oxygen inlet end, the first liquid outlet 6 of the first culture chamber 3
It is connected with the second inlet 8 of the second culture chamber 4, the second liquid outlet 6 is connected with external medium recovery end；Then, training is opened
Micro peristaltic pump in nutrient solution circulator makes external medium from the input terminal of cardiac muscular tissue's chip to output end recycle stream
It is dynamic, and in this process, the temperature of On-line sampling system cardiac muscular tissue chip input terminal culture solution, output end culture solution pH with
And convergent force, extracellular mass current potential and the biomarker releasing degree information of cardiac muscular tissue.
The various embodiments described above are merely to illustrate the present invention, wherein the structure of each component, connection type and manufacture craft etc. are all
It can be varied, all equivalents and improvement carried out based on the technical solution of the present invention should not exclude
Except protection scope of the present invention.
Claims (10)
1. a kind of online non-destructive testing cardiac muscular tissue chip of multiple-sensor integration, it is characterised in that: comprising: chip base,
The culture cavity of the chip base side is set, setting exists in intracorporal first, second culture chamber of the culture chamber, setting
Integrated sensor in two culture chambers and the modular member for supporting cardiac muscular tissue's chip operation；
Input terminal of first culture chamber as cardiac muscular tissue's chip, bottom, which is provided with, to be respectively used to cultivate with external
The first connected inlet of liquid supply side, the first liquid outlet being connected with second culture chamber and with external oxygen input and output
The connected gas exchanges mouth in end；
Output end of second culture chamber as cardiac muscular tissue's chip, bottom are provided with for going out liquid with described first
The second connected inlet of mouth and the second liquid outlet for being connected with external medium recovery end, constitute closed-loop system；
The integrated sensor passes through the electrode layer being arranged in the chip base and is connected with external on-line detecting system, to the heart
Muscular tissue carries out full information acquisition.
2. a kind of online non-destructive testing cardiac muscular tissue chip of multiple-sensor integration as described in claim 1, it is characterised in that:
The first inlet, the first liquid outlet and the gas exchanges mouth of first culture chamber bottom and second culture chamber bottom
Second inlet and the second liquid outlet structure are all the same, including orthogonal first, second liang of microchannel, and described first is micro-
Circulation road is arranged in the culture cavity bottom, and one end is connected with first culture chamber or the second culture chamber, the other end and institute
It states the second microchannel to be connected, syringe needle is plugged in second microchannel, the syringe needle passes through rubber tube and external medium
Supply side, recovery end or oxygen input/output terminal are connected.
3. a kind of online non-destructive testing cardiac muscular tissue chip of multiple-sensor integration as described in claim 1, it is characterised in that:
The integrated sensor includes the microtrabeculae sensor being arranged in first culture chamber and is arranged in second culture chamber
Electrochemical sensor, the microtrabeculae sensor carries out convergent force, thin to cardiac muscular tissue of the culture in first culture chamber
Extracellular group's electrical potential information carries out online acquisition, and the electrochemical sensor discharges the biomarker in second culture chamber
Degree information carries out online acquisition, acquires data by the electrode layer and is sent to external on-line detecting system.
4. a kind of online non-destructive testing cardiac muscular tissue chip of multiple-sensor integration as claimed in claim 3, it is characterised in that:
The microtrabeculae sensor includes being capable of providing lossless, on-line checking cardiac muscular tissue to shrink outside force snesor and cardiac bistiocyte
Group's potentiometric sensor, and the cardiac muscular tissue shrinks group's potentiometric sensor outside force snesor and cardiac bistiocyte and is integrated into one
Body.
5. a kind of online non-destructive testing cardiac muscular tissue chip of multiple-sensor integration as claimed in claim 4, it is characterised in that:
It includes that the piezoelectric membrane with array electrode and being placed on the piezoelectric membrane has that force snesor shrinks in the cardiac muscular tissue
The PDMS film of PDMS micro-pillar array, and piezoelectric membrane and PDMS film carry out corona treatment post package using PDMS.
6. a kind of online non-destructive testing cardiac muscular tissue chip of multiple-sensor integration as claimed in claim 5, it is characterised in that:
The PDMS micro-pillar array is n*n array, and the size of each microtrabeculae is 10~2000 microns of diameter, 30~6000 microns high, the center of circle
Between be divided into 30~6000 microns；PDMS film with a thickness of 5~500 microns；The array electrode that is arranged on the piezoelectric membrane with
The PDMS micro-pillar array is corresponding, is acquired for the pressure to each microtrabeculae, and be sent to external detection system.
7. a kind of online non-destructive testing cardiac muscular tissue chip of multiple-sensor integration as claimed in claim 4, it is characterised in that:
Group's potentiometric sensor includes conductive layer and trace layer outside the cardiac bistiocyte, and the conductive layer is using metal deposit or micro-
The method of drop injection high molecular material shrinks one layer of conduction of the PDMS micro-post surface covering of force snesor in the cardiac muscular tissue
Material, the conductive layer are directly contacted with external cardiac muscular tissue；The trace layer is using metal material or conductive polymer material
Expect that the contact conductor of composition, the contact conductor are connected with the conductive layer and external on-line detecting system respectively.
8. a kind of online non-destructive testing cardiac muscular tissue chip of multiple-sensor integration as claimed in claim 7, it is characterised in that:
The conductive layer with a thickness of 1 angstrom~1 micron.
9. a kind of online non-destructive testing cardiac muscular tissue chip of multiple-sensor integration as claimed in claim 3, it is characterised in that:
The electrochemical sensor is cardiac muscular tissue's biomarker sensor, and cardiac muscular tissue's biomarker sensor includes work
Make electrode, reference electrode and auxiliary electrode, and MUA, EDC, NHS, SPV for being fixed in sequence in each electrode surface and life
Object element biomarker monoclonal antibody, each electrode are connected by contact conductor with external electrochemical workstation.
10. a kind of online non-destructive testing cardiac muscular tissue chip of multiple-sensor integration as described in claim 1, feature exist
In: the modular member includes temperature measuring device, pH measuring device, culture liquid circulating device and culture solution gas de-bubble dress
It sets；
The temperature measuring device carries out temperature by temperature sensitive device, to the culture solution for entering the first culture chamber of cardiac muscular tissue's chip
Measurement；
The pH measuring device is surveyed by the culture solution that online pH measuring instrument exports the second culture chamber of cardiac muscular tissue's chip
Amount；
The culture liquid circulating device provides circulation power by micro peristaltic pump for the culture solution in cardiac muscular tissue's chip；
The defoaming device is set to cardiac muscular tissue's chip input terminal, using the gas permeability principle of PDMS, carries out to film one end
Vacuum realizes the de-bubble of film other end solution.
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| CN201910322804.6A CN110029058B (en) | 2019-04-22 | 2019-04-22 | Multi-sensor integrated on-line nondestructive testing myocardial tissue chip |
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| CN110029058B CN110029058B (en) | 2021-01-22 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113046242A (en) * | 2021-03-23 | 2021-06-29 | 齐鲁工业大学 | Chip and method for similar in vivo heart organ |
| CN113717851A (en) * | 2021-07-14 | 2021-11-30 | 西安交通大学 | Tissue chip and preparation method thereof |
| CN113832030A (en) * | 2021-08-20 | 2021-12-24 | 深圳大学 | Integrated electrochemical micro-column platform and application thereof |
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Cited By (3)
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| CN113046242A (en) * | 2021-03-23 | 2021-06-29 | 齐鲁工业大学 | Chip and method for similar in vivo heart organ |
| CN113717851A (en) * | 2021-07-14 | 2021-11-30 | 西安交通大学 | Tissue chip and preparation method thereof |
| CN113832030A (en) * | 2021-08-20 | 2021-12-24 | 深圳大学 | Integrated electrochemical micro-column platform and application thereof |
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| Publication number | Publication date |
|---|---|
| CN110029058B (en) | 2021-01-22 |
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