WO2024011830A1 - 一种裂纹传感器及制备方法与其在收缩力测量中的应用 - Google Patents

一种裂纹传感器及制备方法与其在收缩力测量中的应用 Download PDF

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WO2024011830A1
WO2024011830A1 PCT/CN2022/137584 CN2022137584W WO2024011830A1 WO 2024011830 A1 WO2024011830 A1 WO 2024011830A1 CN 2022137584 W CN2022137584 W CN 2022137584W WO 2024011830 A1 WO2024011830 A1 WO 2024011830A1
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layer
crack
crack sensor
pdms
cnt
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PCT/CN2022/137584
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English (en)
French (fr)
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王力
徐兴元
陈俊
苏伟光
李安庆
陈照强
许崇海
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齐鲁工业大学
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01L—MEASURING FORCE, STRESS, TORQUE, WORK, MECHANICAL POWER, MECHANICAL EFFICIENCY, OR FLUID PRESSURE
    • G01L1/00—Measuring force or stress, in general
    • G01L1/20—Measuring force or stress, in general by measuring variations in ohmic resistance of solid materials or of electrically-conductive fluids; by making use of electrokinetic cells, i.e. liquid-containing cells wherein an electrical potential is produced or varied upon the application of stress
    • G01L1/22—Measuring force or stress, in general by measuring variations in ohmic resistance of solid materials or of electrically-conductive fluids; by making use of electrokinetic cells, i.e. liquid-containing cells wherein an electrical potential is produced or varied upon the application of stress using resistance strain gauges
    • G01L1/225—Measuring circuits therefor
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01L—MEASURING FORCE, STRESS, TORQUE, WORK, MECHANICAL POWER, MECHANICAL EFFICIENCY, OR FLUID PRESSURE
    • G01L1/00—Measuring force or stress, in general
    • G01L1/20—Measuring force or stress, in general by measuring variations in ohmic resistance of solid materials or of electrically-conductive fluids; by making use of electrokinetic cells, i.e. liquid-containing cells wherein an electrical potential is produced or varied upon the application of stress
    • G01L1/22—Measuring force or stress, in general by measuring variations in ohmic resistance of solid materials or of electrically-conductive fluids; by making use of electrokinetic cells, i.e. liquid-containing cells wherein an electrical potential is produced or varied upon the application of stress using resistance strain gauges
    • G01L1/2287—Measuring force or stress, in general by measuring variations in ohmic resistance of solid materials or of electrically-conductive fluids; by making use of electrokinetic cells, i.e. liquid-containing cells wherein an electrical potential is produced or varied upon the application of stress using resistance strain gauges constructional details of the strain gauges
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5061—Muscle cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/10—Screening for compounds of potential therapeutic value involving cells

Definitions

  • the invention belongs to the technical field of electronic core industry and relates to the manufacturing of sensitive components and sensors. Specifically, it relates to a crack sensor and a preparation method and its application in shrinkage force measurement.
  • a metal crack sensor encapsulated in a rubber cantilever can detect the contraction movement generated by cardiomyocytes (CM).
  • CM cardiomyocytes
  • the crack in the metal crack sensor experienced reversible fracture at the connection of the metal layer.
  • the opening and reconnection process causes the crack sensor's resistance to change rapidly.
  • the shrinkage movement of this CM causes bending cracks in the Ag layer. When the shrinkage is restored, the cracks repeatedly change, causing the cracks to expand, thus reducing the stability of the crack sensor.
  • the purpose of the present invention is to provide a crack sensor and a preparation method and its application in shrinkage force measurement.
  • the crack sensor provided by the present invention effectively resists crack expansion and significantly improves the performance of the crack sensor. Stability and high sensitivity.
  • a crack sensor includes a flexible film.
  • One side of the flexible film is provided with a number of linear protrusions.
  • the other side of the flexible film is provided with a linear structure.
  • the linear structure includes a silver layer, a chromium layer and CNT-PDMS layer, the material of the CNT-PDMS layer is polydimethylsiloxane (PDMS) doped with carbon nanotubes (CNT), the silver layer is provided with a crack structure, and the crack structure can follow the silver Deformation of the layer produces varying cracks.
  • PDMS polydimethylsiloxane
  • CNT carbon nanotubes
  • the present invention arranges the linear structure on the flexible film, so that the contraction force of the cardiomyocytes can be transmitted to the linear structure through the flexible film, thereby deforming the silver layer in the linear structure, thereby causing the crack to change, and realizing the resistance of the crack sensor through the change of the crack. Rapid changes.
  • a CNT-PDMS layer is set up in the linear structure, which can effectively resist crack expansion through CNT bridging in PDMS, significantly improving the stability of the crack sensor.
  • the purpose of arranging several linear protrusions in the present invention is to culture cells.
  • a chromium layer is provided between the CNT-PDMS layer and the silver layer.
  • a method for preparing the above-mentioned crack sensor includes coating the surface of the substrate with a photoresist layer, etching a number of microchannels on the surface of the photoresist layer, and coating a layer of polydimethyl silicon on the surface of the photoresist layer.
  • Oxane, after solidification, a polydimethylsiloxane layer with several linear protrusions on one side and a smooth other side is obtained; the smooth side of the polydimethylsiloxane layer is covered with a template with linear through holes, and on the side of the template
  • a crack sensing device in a third aspect, includes the above-mentioned crack sensor, a bracket and a cell culture component.
  • the crack sensor is located between the bracket and the cell culture component.
  • the bracket is provided with a groove or a through hole, and the crack sensor covers the groove or through hole. Part or all of the linear structure of the crack sensor is located in the groove or through hole.
  • the fourth aspect is an application of the above-mentioned crack sensor or crack sensing device in shrinkage force measurement.
  • the fifth aspect is an application of the above-mentioned crack sensor or crack sensing device in the preparation of cardiac drugs.
  • the crack sensor provided by the present invention combines the Ag layer and the CNT-PDMS layer.
  • the shrinkage movement of the CM causes bending cracks in the Ag layer, and the Ag islands are bridged by CNTs doped in PDMS.
  • This structure effectively resists crack expansion and significantly improves the stability of the crack sensor (stability period >2,000,000 cycles).
  • the disconnection/reconnection of Ag cracks causes the conductive network to change rapidly, resulting in high sensitivity with a gauge factor up to 108,241.7.
  • Figure 1 shows a highly sensitive and highly stable crack sensor for CM shrinkage force detection prepared according to an embodiment of the present invention
  • a(i) schematic diagram shows a crack sensor integrated onto a micro-channel PDMS film for CM shrinkage force measurement.
  • Working principle of the crack sensor the shrinkage of the CM causes bending cracks in the Ag layer, and the Ag islands are bridged by CNTs doped in PDMS
  • b Four compositions of shrinkage detection in each device array Part, (ii) SEM image of PDMS surface with microchannels for anisotropic growth of CM (scale bar: 10 ⁇ m), (iii) CM cultured on PDMS surface with microchannels (scale bar: 70 ⁇ m);
  • c Fabrication sequence (i) 2.5cm ⁇ 2.5cm glass slides by O2 plasma etching on the surface, (ii) fabricated on the photoresist surface by soft lithography with a width of 3 ⁇ m and a depth of 2 ⁇ m of microchannels,
  • Figure 2 is a characterization diagram of the crack sensor prepared in the embodiment of the present invention
  • a The noise and signal-to-noise ratio of the Ag/CNT-PDMS crack sensor with different CNT weight ratios under 0.01% strain
  • d Stability of the crack sensor during 2,000,000 stretch-release cycles at 0.5% strain inset: enlarged response curve showing the stretch-release cycle; e Hysteresis curve for 2,000,000 stretch release cycles at 0.5% strain, inset: GF and squared correlation coefficient (R2) as the stretch release cycle increases;
  • Figure 3 is a graph showing the results of measuring the shrinkage of CM by the crack sensor according to the embodiment of the present invention
  • a The crack sensor of the CM and the commercial silicon strain sensor were measured for 14 days
  • b The beating rate of the CM at different stages of maturity, from the signals of the crack sensor and the silicon strain sensor Statistically obtained
  • c Comparison of waveforms of CM shrinkage recorded from crack sensors and commercial silicon strain sensors on different dates
  • d, e The rise and fall times of CMs beat waveforms at different maturity stages, statistics from crack sensors and commercial silicon strain sensors
  • g pneumatic calibration settings h calibration relationship between ⁇ R/R0 and crack sensor pressure before and after CMs culture
  • FIG. 4 is a diagram showing the shrinkage changes of CMs treated with drugs by the crack sensor according to the embodiment of the present invention
  • a Changes in ⁇ R/R0 of CMs cultured on the crack sensor at different concentrations from 0.01 nM to 1 ⁇ M
  • b c verapamil Contractile stress and beating rate of CMs after treatment
  • f Changes in CMs cultured on the crack sensor after treating CMs with isoproterenol at different concentrations from 0.1 nM to 1 ⁇ M
  • g h Contractile stress and beating of CMs after isoproterenol treatment rate
  • i Isoproterenol dose-response curve of CM
  • the present invention proposes a crack sensor and a preparation method and its application in shrinkage force measurement.
  • a typical implementation of the present invention provides a crack sensor, which includes a flexible film.
  • One side of the flexible film is provided with a number of linear protrusions.
  • the other side of the flexible film is provided with a linear structure.
  • the linear structure is arranged from bottom to top. It includes a silver layer, a chromium layer and a CNT-PDMS layer in sequence.
  • the CNT-PDMS layer is made of polydimethylsiloxane doped with carbon nanotubes.
  • the silver layer is provided with a crack structure. The crack structure is able to Cracks change with the deformation of the silver layer.
  • the flexible film is a polydimethylsiloxane film.
  • the thickness of the polydimethylsiloxane film is 5 to 20 ⁇ m.
  • the thickness of the silver layer is 90-110 nm.
  • the thickness of the chromium layer ranges from 2 to 10 nm.
  • the thickness of the CNT-PDMS layer is 5-20 ⁇ m.
  • the added amount of carbon nanotubes in the CNT-PDMS layer is 0.01 to 5 wt%.
  • the added amount of carbon nanotubes is 2 to 4 wt% (especially 2.5 to 3.5 wt%), the sensing effect is better.
  • the diameter of CNT is 8 ⁇ 15nm and the length is 3 ⁇ 12 ⁇ m.
  • the CNT-PDMS layer connects the electrodes.
  • the linear structure may be linear, curved, etc.
  • the linear structure is U-shaped.
  • the U-shaped linear structure makes it easier to connect circuits.
  • Another embodiment of the present invention provides a method for preparing the above-mentioned crack sensor.
  • the surface of the substrate is coated with a photoresist layer, a number of microchannels are etched on the surface of the photoresist layer, and the surface of the photoresist layer is coated with A layer of polydimethylsiloxane.
  • a layer of polydimethylsiloxane After solidification, a polydimethylsiloxane layer with several linear protrusions on one side and a smooth other side is obtained; the smooth side of the polydimethylsiloxane layer is covered with linear channels.
  • For a template with holes prepare a silver layer, a chromium layer and a CNT-PDMS layer in sequence on the side of the template, remove the template, and pre-stretch it.
  • the substrate is glass, and before coating the photoresist layer, the substrate is first treated with O 2 plasma.
  • a vacuum evaporation method is used to prepare the silver layer and the chromium layer.
  • a screen printing method is used to prepare a CNT-PDMS layer on the surface of the chromium layer.
  • pre-stretching is performed at a strain of 1.5 to 2.5%.
  • the third embodiment of the present invention provides a crack sensing device, including the above-mentioned crack sensor, a bracket and a cell culture component.
  • the crack sensor is located between the bracket and the cell culture component.
  • the bracket is provided with grooves or through holes.
  • the crack sensor Covering the groove or through hole, part or all of the linear structure of the crack sensor is located in the groove or through hole.
  • the cell culture component of the present invention can be a glass tube, and one end of the glass tube can be bonded to the crack sensor. At this time, the crack sensor and the glass tube form a cavity for cultivating cells.
  • a glass substrate is included, and the stent is bonded to the glass substrate.
  • the glass substrate is treated with O2 plasma.
  • the scaffold is treated with O2 plasma.
  • the fourth embodiment of the present invention provides an application of the above-mentioned crack sensor or crack sensing device in shrinkage force measurement.
  • Abnormal myocardial contraction can lead to heart failure, atrial fibrillation and other cardiovascular diseases. Therefore, the application described in the present invention can be used for the diagnosis and treatment of diseases, and can also be used for the purpose of non-disease diagnosis and treatment such as scientific research. It can also be used For use in the preparation of medical devices for monitoring the heart.
  • the present invention also uses the above-mentioned crack sensor or crack sensing device for the analysis of drug efficacy.
  • Research shows that cardiac drugs can regulate the excitation-contraction coupling process to affect the contraction behavior of CM, thereby quantifying the effectiveness of drug effects, which can both Screening effective drugs can also evaluate the dosage of drugs, which can be used in the process of preparing cardiac drugs. Therefore, the fifth embodiment of the present invention provides an application of the above-mentioned crack sensor or crack sensing device in the preparation of cardiac drugs.
  • the manufacturing process of the shrinkage force measurement device with integrated crack sensor is shown in Figure 1c.
  • the device mainly consists of three parts: a crack sensor integrated on the PDMS film, a PDMS support part, and a glass tube part for culturing cells.
  • a crack sensor integrated on the PDMS film 2.5cm ⁇ 2.5cm glass was cleaned with absolute ethanol and treated with O plasma (Zhengzhou Chengyue Science Instruments Co., Ltd. CY-P2L-B) at a power of 100 for 120s W.
  • a mask template with a microchannel pattern was coated on the glass slide, exposed by photolithography for 3 s, and then developed for 10 s.
  • a microchannel with a width of 3 ⁇ m and a depth of 2 ⁇ m is formed on the surface of the photoresist.
  • 0.5g of PDMS solution (the ratio of curing agent to PDMS polymer (Sylgard 184, Dow Corning) is 1:10) was spin-coated on the surface of the microchannel at a speed of 8,500r/min for 1min, and cured for 2h to obtain a 10 ⁇ m thick film. film.
  • the back side of the PDMS film is treated with O2 plasma (120s), and then a 10 ⁇ m thick "U-shaped" through hole structure mask is covered on the back side of the PDMS film, and a 100 nm thick mask is applied through a vacuum evaporation machine (Angstrom engineering). And a 5nm thick Ag/Cr film is deposited on the back of the PDMS film.
  • This U-shaped structure allows the electrode to be at one end of the entire measurement device, which is conducive to the connection of external circuits.
  • CNTs (diameter: 8-15 nm, length: 3-12 ⁇ m, Tanfeng technology) and PDMS (Sylgard 184, Dow Corning) were mixed by a magnetic stirrer (Sedulis 85-2A) at a weight ratio of 3:97 (12 h).
  • a magnetic stirrer (Sedulis 85-2A) at a weight ratio of 3:97 (12 h).
  • 10 ⁇ m thick CNT-PDMS strips were screen printed on the surface of the Ag layer.
  • the mask of the "U-shaped" via structure is removed and the CNT-PDMS strips are connected using Ag electrodes.
  • the film was pre-stretched at 2% strain.
  • a PDMS scaffold with dimensions of 2.5cm ⁇ 2.5cm ⁇ 2mm was prepared using the casting method.
  • the 5mm ⁇ 0.5mm ⁇ 0.5mm air hole at the bottom is designed to calibrate the pressure (P) with ⁇ R/R 0 .
  • the square glass (2.5cm ⁇ 2.5cm) and PDMS support parts were sealed by O plasma treatment. Finally, the PDMS film integrated with the crack sensor is bonded to the PDMS film support part and the glass tube part through PDMS.
  • the Ag/CNT-PDMS crack sensor was integrated onto a thin microchannel PDMS film used to culture CM ( Figure 1a and b).
  • the shrinkage and relaxation of CMs can lead to the deflection of the PDMS film (Fig. 1a(i)).
  • the cracks in the sensor open and close accordingly, causing a change in resistance (Fig. 1a(ii)).
  • microchannels width, 3 m; depth, 2 m
  • SNR Signal-to-noise ratio
  • the noise of the Ag/CNT-PDMS crack sensor dropped from 0.425 ⁇ to 0.015 ⁇ (about 23 times), and the SNR at 0.01% strain increased from 2.5 to 73.4 ( about 28 times), as shown in Figure 2a.
  • the working range of Ag-PDMS without CNTs (0 wt.%) is between 0.01% and 4%.
  • the working range of the Ag/CNT-PDMS crack sensor doped with different CNT weight ratios is significantly improved.
  • the maximum operating range of the Ag/CNT 0.03 -PDMS crack sensor (doped with 3 wt.% CNT) reaches 44%, as shown in Figure 2b.
  • the Ag-PDMS crack sensor In the small strain range (strain ⁇ 1%, which is the maximum range of CMs beating), the Ag-PDMS crack sensor has a gauge coefficient of 36.01; in comparison, the hybrid Ag/CNT 0.02 -PDMS crack sensor and Ag/CNT 0.03
  • the strain coefficient of -PDMS crack sensor can reach 166,099.0 and 108,241.7 under the same strain, as shown in Figure 2b
  • the strain coefficient of the mixed Ag/CNT 0.02 -PDMS crack sensor and Ag/CNT 0.03 -PDMS crack sensor can reach 166,099.0 and 108,241.7 under the same strain.
  • 166,099.0 and 108,241.7 which are 4612 times and 3005 times that of Ag-PDMS respectively, proving that the sensitivity has been significantly improved.
  • CM shrinkage >14 days, that is, >1,500,000 beat cycles
  • 2,000,000 cyclic tensile release tests were performed at a rate of 50 ⁇ m/s and a strain of 0.5%.
  • Monitoring the ⁇ R/R 0 of the Ag-PDMS crack sensor without CNTs showed that the device was unstable after 20,000 cycles, which may be due to the continued propagation of the Ag crack along the vertical tensile direction until fatigue.
  • the ⁇ R/ R of the Ag/CNT 0.03 -PDMS crack sensor shows high stability due to the bridging effect between CNTs and Ag islands, as shown in Figure 2d.
  • FIG. 3a shows the ⁇ R/R 0 of the shrinkage-induced crack sensor of the CM and a commercial silicon strain gauge during 14 days of culture.
  • the contractile behavior of the CM was detected on day 2, and as the CM grew, the contractility reached a maximum on day 8 and then decreased to day 14.
  • the same pattern was observed in beat rate and beat waveform, as shown in Figure 3b and Figure 3c.
  • Comparison of pulsation waveforms over multiple days shows that the pulsation waveform measured by the crack sensor has shorter rise time (Day 10: 134.91ms vs.
  • the shrinkage detection device integrated with the crack sensor was calibrated before and after the experiment.
  • CM is 0.95 ⁇ 0.040kPa (day 14).
  • Figure 4a shows the ⁇ R/ R0 changes after CM treatment with verapamil from 0.01 nM to 1 ⁇ M.
  • the relative contractility and beating rate of CMs began to decrease, and cardiac arrest was measured at concentrations of 10 ⁇ M or higher.
  • the corresponding shrinkage stress and runout rate are shown in Figure 4b and Figure 4c.
  • the EC 50 values of contractility and beating rate calculated from the drug dose-response curve were 8.029 ⁇ 10 -7 M and 9.210 ⁇ 10 -7 M, as shown in Figure 4d and Figure 4e.
  • Figure 4f shows the ⁇ R/ R0 changes caused by the contractility of CM after isoproterenol treatment.
  • concentration of isoproterenol increases from 0.1 nM to 1 ⁇ M, contractility and beating speed slowly increase.
  • concentration of isoproterenol reaches 100 nM, CM begins to exhibit symptoms of tachycardia due to saturation of contractility.
  • the corresponding shrinkage stress and run-out rate are shown in Figure 4g and Figure 4h.
  • the EC 50 values of contractility and beating rate calculated based on the drug dose-response curve were 9.262 ⁇ 10 -8 M and 7.144 ⁇ 10 -8 M, as shown in Figure 4i and Figure 4j.

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Abstract

一种裂纹传感器，包括柔性膜，柔性膜的一面设置若干线性凸起，柔性膜的另一面设置线性结构，线性结构由下至上依次包括银层、铬层以及CNT‑PDMS层，CNT‑PDMS层的材质为掺杂碳纳米管的聚二甲基硅氧烷，银层设置裂纹结构，裂纹结构是能够随银层的形变产生变化的裂纹。裂纹传感器有效地抵抗了裂纹扩展，显着提高了裂纹传感器的稳定性，同时还具有较高的灵敏度。还提供了一种裂纹传感器制备方法。

Description

一种裂纹传感器及制备方法与其在收缩力测量中的应用
本发明要求于2022年7月15日提交中国专利局、申请号为202210833004.2、发明名称为“一种裂纹传感器及制备方法与其在收缩力测量中的应用”的中国专利申请的优先权，其全部内容通过引用结合在本发明中。
技术领域
本发明属于电子核心产业技术领域，涉及敏感元件及传感器制造，具体涉及一种裂纹传感器及制备方法与其在收缩力测量中的应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解，而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
据发明人研究了解，将金属裂纹传感器封装在橡胶悬臂中，能够检测心肌细胞(CM)产生的收缩运动，在检测过程中，金属裂纹传感器中的裂纹在金属层的连接处经历了可逆的断开和重新连接过程，导致裂纹传感器的电阻快速变化。然而，据发明人研究发现，这种CM的收缩运动导致Ag层出现弯曲裂纹，在收缩恢复时，使得裂纹反复变化，导致裂纹扩展，从而降低裂纹传感器的稳定性。
发明内容
为了解决现有技术的不足，本发明的目的是提供一种裂纹传感器及制备方法与其在收缩力测量中的应用，本发明提供的裂纹传感器有效地抵抗了裂纹扩 展，显着提高了裂纹传感器的稳定性，同时还具有较高的灵敏度。
为了实现上述目的，本发明的技术方案为：
一方面，一种裂纹传感器，包括柔性膜，所述柔性膜的一面设置若干线性凸起，所述柔性膜的另一面设置线性结构，所述线性结构由下至上依次包括银层、铬层以及CNT-PDMS层，所述CNT-PDMS层的材质为掺杂碳纳米管(CNT)的聚二甲基硅氧烷(PDMS)，所述银层设置裂纹结构，所述裂纹结构是能够随银层的形变产生变化的裂纹。
本发明将线性结构设置在柔性膜上，使得心肌细胞的收缩力能够通过柔性膜传递至线性结构，从而使得线性结构中银层发生形变，进而使得裂纹产生变化，通过裂纹的变化实现裂纹传感器的电阻快速变化。同时，线性结构中设置CNT-PDMS层，通过PDMS中的CNT桥接，能够有效地抵抗裂纹扩展，显着提高了裂纹传感器的稳定性。本发明设置若干线性凸起的目的在于培养细胞。为了提高CNT-PDMS层与银层的粘结性，在CNT-PDMS层与银层之间设置铬层。
另一方面，一种上述裂纹传感器的制备方法，将基底表面涂覆光刻胶层，在光刻胶层表面刻蚀若干微通道，在光刻胶层表面涂覆一层聚二甲基硅氧烷，凝固后获得一面有若干线性凸起、另一面光滑的聚二甲基硅氧烷层；在聚二甲基硅氧烷层的光滑面覆盖带有线形通孔的模板，在模板侧依次制备银层、铬层以及CNT-PDMS层，将模板去除即得。
第三方面，一种裂纹传感装置，包括上述裂纹传感器、支架和细胞培养部件，裂纹传感器位于支架和细胞培养部件之间，支架设置凹槽或通孔，裂纹传感器覆盖凹槽或通孔，裂纹传感器的部分线性结构或全部线性结构位于凹槽或通孔内。
第四方面，一种上述裂纹传感器或裂纹传感装置在收缩力测量中的应用。
第五方面，一种上述裂纹传感器或裂纹传感装置在制备心脏药物中的应用。
本发明的有益效果为：
本发明提供的裂纹传感器，将Ag层和CNT-PDMS层结合，CM的收缩运动导致Ag层出现弯曲裂纹，并且Ag岛由掺杂在PDMS中的CNT桥接。这种结构有效地抵抗了裂纹扩展，显着提高了裂纹传感器的稳定性(稳定周期>2,000,000次循环)。与CNT-PDMS的稳定导电网络相比，Ag裂纹的断开/重新连接使导电网络快速变化，从而导致高灵敏度，量规因子可达108,241.7。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。
图1为本发明实施例的制备的用于CM收缩力检测的高灵敏度和高稳定性裂纹传感器；a(i)示意图显示了集成到微沟道PDMS薄膜上用于CM收缩力测量的裂纹传感器，(ii)裂纹传感器的工作原理，CM的收缩性导致Ag层出现弯曲裂纹，并且Ag岛由掺杂在PDMS中的CNT桥接；b(i)每个设备阵列中收缩性检测的四个组成部分，(ii)带有微沟道的PDMS表面的SEM图像，用于CM的各向异性生长(比例尺：10μm)，(iii)在带有微沟道的PDMS表面上培养的CM(比例尺：70μm)；c制造顺序，(i)2.5cm×2.5cm玻璃载玻片，通过O 2等离子蚀刻在表面上进行，(ii)通过软光刻在光刻胶表面制作宽度为3μm、深度为2μm的微沟道，(iii)将PDMS(10μm厚)旋涂在带有微沟道的光刻胶模具上，(iv)通过真空蒸发在PDMS背面沉积100nm厚度的Ag层和5nm厚度的Cr层，(v)通过丝网印刷将厚度为10μm的CNT-PDMS层沉积在Ag层的表面上，(vi)3μm厚的Ag电极用于连接导线，并通过预处理拉伸(2％应变)进行裂纹传感器，(vii)铸造PDMS基础 部件，(viii)PDMS支撑部分和载玻片通过O 2等离子体处理粘合，(ix)一根内径为1.1厘米的1.1厘米玻璃管，(x)PDMS支撑部分、薄膜部分和玻璃管粘合，e用于拉伸Ag/CNT-PDMS裂纹传感器表征的实验平台。
图2为本发明实施例制备的裂纹传感器的表征图；a 0.01％应变下不同CNT重量比的Ag/CNT-PDMS裂纹传感器的噪声和信噪比；b不同CNT重量比的Ag/CNT-PDMS裂纹传感器的ΔR/R0-应变曲线，插图显示了用于拉伸测试的哑铃形Ag/CNT-PDMS裂纹传感器的正面和背面光学图像(比例尺：10mm)；c不同CNT重量比的Ag/CNT-PDMS裂纹传感器在0-1％应变范围内的ΔR/R0应变曲线；d裂纹传感器在0.5％应变下2,000,000次拉伸释放循环期间的稳定性，插图：显示拉伸释放循环的放大响应曲线；e 0.5％应变下0.5％应变下2,000,000次拉伸释放循环的滞后曲线，插图：GF和相关系数平方(R2)随着拉伸释放周期的增加而变化；f裂纹传感器在0.1％、0.2％、0.3％、0.4％和0.5％连续变幅应变下的ΔR/R0响应，重复执行四次；g裂纹传感器在0.5％应变下的ΔR/R0-时间曲线，频率分别为0.5Hz、1Hz、2Hz、3Hz和4Hz；h裂纹传感器的温度漂移测试。
图3为本发明实施例的裂纹传感器测量CM收缩性的结果图；a CM的裂纹传感器和商用硅应变传感器测量14天；b CM在不同成熟阶段的打浆率，从裂纹传感器和硅应变传感器信号统计得出；c从裂纹传感器和商用硅应变传感器在不同日期记录的CM收缩性的波形比较；d、e不同成熟阶段CMs跳动波形的上升和下降时间，统计来自裂纹传感器和商用硅应变传感器；f裂纹传感器和商用硅应变计在第4、7、10和13天的CMs收缩性的ΔR/R0幅度；g气动校准设置；h CMs培养前后ΔR/R0与裂纹传感器压力之间的校准关系；i CMs在不同日子的收缩应力。
图4为本发明实施例裂纹传感器进行药物治疗CM的收缩性变化图；a在0.01nM至1μM的不同浓度下，在裂纹传感器上培养的CMs的ΔR/R0变化；b、c维拉帕米治疗后CM的收缩应力和跳动率；d CMs收缩力的维拉帕米剂量反应曲线，表观EC 50＝8.029×10 -7M；e CMs搏动率的维拉帕米剂量反应曲线，表观EC 50＝9.210×10 -7M；f在0.1nM至1μM不同浓度的异丙肾上腺素治疗CM后裂纹传感器上培养的CMs的变化；g、h异丙肾上腺素处理后CMs的收缩应力和跳动率；i CMs收缩力的异丙肾上腺素剂量反应曲线，表观EC 50＝9262×10 -8M；j异丙肾上腺素CMs搏动率的剂量反应曲线，表观EC 50＝7.144×10 -8M。
具体实施方式
应该指出，以下详细说明都是示例性的，旨在对本发明提供进一步的说明。除非另有指明，本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是，这里所使用的术语仅是为了描述具体实施方式，而非意图限制根据本发明的示例性实施方式。如在这里所使用的，除非上下文另外明确指出，否则单数形式也意图包括复数形式，此外，还应当理解的是，当在本说明书中使用术语“包含”和/或“包括”时，其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
正如背景技术所介绍的，现有裂纹传感器存在裂纹扩展导致稳定性较差等不足，为了解决如上的技术问题，本发明提出了一种裂纹传感器及制备方法与其在收缩力测量中的应用。
本发明的一种典型实施方式，提供了一种裂纹传感器，包括柔性膜，所述柔性膜的一面设置若干线性凸起，所述柔性膜的另一面设置线性结构，所述线性结构由下至上依次包括银层、铬层以及CNT-PDMS层，所述CNT-PDMS层的 材质为掺杂碳纳米管的聚二甲基硅氧烷，所述银层设置裂纹结构，所述裂纹结构是能够随银层的形变产生变化的裂纹。
研究表明，本发明提供的裂纹传感器在检测心肌细胞的收缩力具有稳定性和灵敏度高的优势。
在一些实施例中，所述柔性膜为聚二甲基硅氧烷膜。聚二甲基硅氧烷膜的后的为5～20μm。
在一些实施例中，银层的厚度为90～110nm。
在一些实施例中，铬层的厚度为2～10nm。
在一些实施例中，CNT-PDMS层的厚度为5～20μm。
在一些实施例中，CNT-PDMS层中碳纳米管的添加量为0.01～5wt％。当碳纳米管的添加量为2～4wt％(尤其是2.5～3.5wt％)时，传感效果更好。CNT的直径为8～15nm，长度为3～12μm。
在一些实施例中，CNT-PDMS层连接电极。
线性结构可以为直线形，可以为曲线形等，在一些实施例中，线性结构为U形。U形的线性结构更方便连接电路。
本发明的另一种实施方式，提供了一种上述裂纹传感器的制备方法，将基底表面涂覆光刻胶层，在光刻胶层表面刻蚀若干微通道，在光刻胶层表面涂覆一层聚二甲基硅氧烷，凝固后获得一面有若干线性凸起、另一面光滑的聚二甲基硅氧烷层；在聚二甲基硅氧烷层的光滑面覆盖带有线形通孔的模板，在模板侧依次制备银层、铬层以及CNT-PDMS层，将模板去除，预拉伸后即得。
在一些实施例中，基底为玻璃，在涂覆光刻胶层前，先采用O 2等离子体对基底进行处理。
在一些实施例中，采用真空蒸发法制备银层和铬层。
在一些实施例中，采用丝网印刷法在铬层表面制备CNT-PDMS层。
在一些实施例中，在1.5～2.5％的应变条件下进行预拉伸。
本发明的第三种实施方式，提供了一种裂纹传感装置，包括上述裂纹传感器、支架和细胞培养部件，裂纹传感器位于支架和细胞培养部件之间，支架设置凹槽或通孔，裂纹传感器覆盖凹槽或通孔，裂纹传感器的部分线性结构或全部线性结构位于凹槽或通孔内。
本发明所述的细胞培养部件可以为玻璃管，将玻璃管的一端与粘结在裂纹传感器即可，此时裂纹传感器与玻璃管形成用于培养细胞的腔体。
在一些实施例中，包括玻璃基体，将支架粘结在玻璃基体上。玻璃基体采用O 2等离子体处理。
在一些实施例中，支架采用O 2等离子体处理。
本发明的第四种实施方式，提供了一种上述裂纹传感器或裂纹传感装置在收缩力测量中的应用。
在一些实施例中，在心肌细胞收缩力测量中的应用。
心肌收缩异常可导致心力衰竭、心房颤动和其他心血管疾病，因而本发明所述的应用可以用于疾病的诊断与治疗，也可以以进行科学研究等非疾病的诊断与治疗为目的，还可以用于制备监测心脏的医疗设备。
本发明还将上述裂纹传感器或裂纹传感装置用于药物疗效的分析，研究表明心脏药物能够调节兴奋-收缩耦合过程来影响CM的收缩行为，从而能够量化药物效应方面的有效性，其既可以筛选有效药物，又可以评估药物的计量，从而应用于制备心脏药物的过程中。所以本发明的第五种实施方式，提供了一种上述裂纹传感器或裂纹传感装置在制备心脏药物中的应用。
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案，以下将 结合具体的实施例详细说明本发明的技术方案。
实施例
Ag/CNT-PDMS裂纹传感器的制造：
集成裂纹传感器的收缩力测量装置的制造过程如图1c所示。该装置主要由三部分组成：集成在PDMS薄膜上的裂纹传感器、PDMS支撑部分和用于培养细胞的玻璃管部分。为了制造集成在PDMS薄膜上的裂纹传感器，用无水乙醇清洗2.5cm×2.5cm玻璃，并用O 2等离子体(Zhengzhou Chengyue Science Instruments Co.,Ltd.CY-P2L-B)以100的功率处理120s W。将0.5g光刻胶(AZ-4620)以1400r/min的速度均匀旋涂到载玻片表面1min。在60℃烘烤60分钟并冷却至室温后，在载玻片上涂覆具有微沟道图案的掩模模板，通过光刻曝光3s，然后显影10s。在光刻胶表面形成宽度为3μm、深度为2μm的微沟道。将0.5g PDMS溶液(固化剂与PDMS聚合物(Sylgard 184,Dow Corning)的比例为1:10)以8,500r/min的速度旋涂在微沟道表面上1min，固化2h获得厚度为10μm的薄膜。然后，O 2等离子体处理PDMS膜的背面(120s)，然后将10μm厚“U形”通孔结构的掩膜版覆盖在PDMS膜的背面，通过真空蒸镀机(Angstrom engineering)，将100nm厚和5nm厚的Ag/Cr膜沉积到PDMS膜的背面，这种U形结构可以使电极处在整个测量装置的一端，有利于外接电路的连接。CNT(直径：8-15nm，长度：3-12μm，Tanfeng technology)和PDMS(Sylgard 184，Dow Corning)通过磁力搅拌器(Sedulis 85-2A)以3:97的重量比混合(12h)。在O 2等离子体120s后，通过丝网印刷将10μm厚的CNT-PDMS条丝网印刷在Ag层的表面上。然后移开“U形”通孔结构的掩膜版，使用Ag电极将CNT-PDMS条连接。为了在传感器中产生均匀的银裂纹，薄膜在2％的应变下进行了预拉伸。采用浇注法制备尺寸为2.5cm×2.5cm×2mm的PDMS支架。 底部的5mm×0.5mm×0.5mm气孔设计用于校准具有ΔR/R 0的压力(P)。方形玻璃(2.5cm×2.5cm)和PDMS支撑部分通过O 2等离子体处理密封。最后，集成裂纹传感器的PDMS薄膜通过PDMS黏结到PDMS薄膜支撑部分和玻璃管部分上。
裂纹传感器的校准：
为了检测CMs的收缩应力，需要建立裂纹传感器的相对电阻变化(ΔR/R 0)与薄膜表面压力之间的关系。对于设备校准，使用注射泵(LSP注射泵，LSP02-1B)和1ml注射器施加压力(图4g)。数字压力表(Smart，GM 505)用于测量喷射泵施加的压力。注入泵以5mL/min的注入速率通过单个入口将0.5kPa至5kPa的压力(P)输送到设备通道，使PDMS薄膜鼓起。同时，对每个Ag/CNT-PDMS裂纹传感器施加2.5V的恒定电压，并使用数字万用表(GWINSTEK，GDM-9061)以50Hz的采样率采集电阻信号。在校准之前，Ag/CNT-PDMS裂纹传感器在2％应变下预拉伸24小时，以确保可再现的电阻信号。
将Ag/CNT-PDMS裂纹传感器集成到用于培养CM的薄微沟道PDMS薄膜上(图1a和b)。CMs的收缩和松弛会导致PDMS薄膜的偏转(图1a(i))。传感器中的裂纹相应地打开和关闭，导致电阻变化(图1a(ii))。此外，制造了微沟道(宽度为3m；深度为2m)，以使CM能够模拟体内心肌结构的各向异性生长和心肌细胞一致收缩。
降低PDMS薄膜的亲水角可以提高表面能，增加CM细胞的粘附。O2等离子体经过0s、90s和120s后，微沟道PDMS薄膜的亲水角从122.35°下降到8.17°，证明PDMS亲水性有所提高(图1d)。
裂纹传感器的表征：
1.信噪比(SNR)、灵敏度、工作范围和稳定性
为了最大限度地提高Ag/CNT-PDMS裂纹传感器的传感性能(例如SNR、灵敏度和稳定性)，选择渗流阈值附近的CNT重量比(0-5wt.％CNT)来调整Ag/Cr之间的导电连接裂纹并优化Ag/CNT-PDMS裂纹传感器的压阻性能，采用的实验平台见图1e。如图2a和图2b所示，裂纹传感器的噪声随着碳纳米管的添加而显着降低。与没有碳纳米管的裂纹传感器(Ag-PDMS)相比，Ag/CNT-PDMS裂纹传感器的噪声从0.425Ω下降到0.015Ω(约23倍)，0.01％应变时的SNR从2.5提高到73.4(约28次)，如图2a所示。
不含CNT(0wt.％)的Ag-PDMS的工作范围在0.01％和4％之间。相比之下，掺杂不同CNT重量比的Ag/CNT-PDMS裂纹传感器的工作范围显着提高。例如，Ag/CNT 0.03-PDMS裂纹传感器(掺杂3wt.％CNT)的最大工作范围达到44％，如图2b所示。在小应变范围内(应变<1％，这是CMs跳动的最大范围)，Ag-PDMS裂纹传感器的应变系数为36.01；相比之下，混合Ag/CNT 0.02-PDMS裂纹传感器和Ag/CNT 0.03-PDMS裂纹传感器的应变系数在相同应变下可以达到166,099.0和108,241.7，如图2b所示，混合Ag/CNT 0.02-PDMS裂纹传感器和Ag/CNT 0.03-PDMS裂纹传感器的应变系数在相同应变下可以达到166,099.0和108,241.7，分别为Ag-PDMS的4612倍和3005倍，证明灵敏度有显著提升。
为了实现CM收缩性的长期稳定检测(>14天，即>1,500,000次跳动循环)，有必要确保裂纹传感器不会发生疲劳失效。为此，以50μm/s的速率和0.5％的应变进行了2,000,000次循环拉伸释放测试。对没有CNT的Ag-PDMS裂纹传感器的ΔR/R 0进行监测显示，在20,000次循环后器件不稳定，这可能是由于Ag裂纹沿垂直拉伸方向持续扩展直至疲劳所致。相比之下，由于CNT和Ag岛之 间的桥接效应，Ag/CNT 0.03-PDMS裂纹传感器的ΔR/R 0显示出高稳定性，如图2d所示。
2.连续变化的幅度响应、频率响应和温度响应
由于CMs生长过程中收缩的幅度和频率不断变化，因此有必要验证Ag/CNT 0.03-PDMS裂纹传感器在动态应变和变化频率下的响应。如图2f所示，Ag/CNT 0.03-PDMS裂纹传感器线性响应，应变从0.1％连续逐步增加至0.5％。此外，传感器对相同大小的重复应变具有一致的响应。图2g显示了裂纹传感器对不同频率(0.5-4Hz)的0.5％应变的ΔR/R 0响应。ΔR/R 0的峰值没有明显变化，这表明裂纹传感器可以适用于检测频率变化的CMs的收缩性。为了检查温度变化对裂纹传感器的影响，当温度从30℃以10℃的梯度增加到60℃时，发现ΔR/R 0以0.02的梯度增加，如图2h所示。这表明裂纹传感器的电阻率发生了温度漂移。因此，在恒温箱中(37℃)进行了10小时的电阻稳定性测试，Ag/CNT 0.03-PDMS裂纹传感器的R 0波动小于0.056％，表明稳定性高。
CMs收缩性的测量：
裂纹传感器和商用硅应变计测量了关键参数，包括ΔR/R 0的变化趋势、跳动率、上升和衰减时间。图3a显示了14天培养期间CM的收缩性引起的裂纹传感器和商用硅应变计的ΔR/R 0。在第2天检测到CM的收缩行为，随着CM的生长，收缩力在第8天达到最大值，然后下降到第14天。在搏动率和搏动波形中观察到相同的模式，如图3b和图3c所示。多天的搏动波形比较表明，裂纹传感器测量的搏动波形具有较短的上升时间(第10天：134.91ms与140.15ms)和衰减时间(第10天：294.98ms)与299.82毫秒)，如图3d、图3e所示。此外，ΔR/R 0的幅度对比图显示裂纹传感器的幅度是硅应变计的520倍以上，如图3f所示。
为了探索裂纹传感器在检测CMs收缩性方面的性能稳定性，在实验前后校准了与裂纹传感器集成的收缩性检测装置。使用注射泵施加0到5kPa的气压以使PDMS薄膜中的裂纹传感器膨胀，如图3g所示。ΔR/R 0和压力(P)之间的关系被校准为ΔR/R 0＝0.042×P-0.0015，(R 2＝0.997，n＝5个设备元件)，裂纹传感器在心肌细胞培养14天后反复校准，ΔR/R 0与压力保持良好的线性关系，如图4h所示。根据校准结果，随着CMs的增长，CMs的收缩应力从0.23±0.024kPa(第2天)增加到3.75±0.063kPa(第8天)，并且随着CMs的老化，收缩应力降低，如图4i所示。CM为0.95±0.040kPa(第14天)。
药物评价：
利用裂纹传感器来评估心脏药物效应。测试了两种典型的临床药物，它们通过调节兴奋-收缩耦合过程来影响CM的收缩行为，以证明该装置在量化药物效应方面的有效性，如图4所示。维拉帕米和异丙肾上腺素分别作用于LTCC和β-肾上腺素能受体，影响CM的收缩增强和跳动率。
图4a显示CM用0.01nM至1μM的维拉帕米处理后的ΔR/R 0变化。当浓度为10nM时，CMs的相对收缩力和跳动率开始下降，在10μM或更高浓度时测量到心脏骤停。相应的收缩应力和跳动率如图4b和图4c所示。根据药物剂量反应曲线计算得出的收缩力和跳动率的EC 50值为8.029×10 -7M和9.210×10 -7M，如图4d和图4e所示。
图4f显示了治疗异丙肾上腺素后CM的收缩性引起的ΔR/R 0变化。随着异丙肾上腺素浓度从0.1nM增加到1μM，收缩力和跳动速度缓慢增强。当异丙肾上腺素的浓度达到100nM时，由于CM的收缩性饱和，CM开始出现心动过速的症状。相应的收缩应力和跳动率如图4g和图4h所示。根据药物剂量反应曲线计算得出的收缩力和跳动率的EC 50值为9.262×10 -8M和7.144×10 -8M，如图 4i和图4j所示。这些结果证实，Ag/CNT-PDMS裂纹传感器能够检测不同药物剂量引起的CM收缩性的动态变化。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种裂纹传感器，其特征是，包括柔性膜，所述柔性膜的一面设置若干线性凸起，所述柔性膜的另一面设置线性结构，所述线性结构由下至上依次包括银层、铬层以及CNT-PDMS层，所述CNT-PDMS层的材质为掺杂碳纳米管的聚二甲基硅氧烷，所述银层设置裂纹结构，所述裂纹结构是能够随银层的形变产生变化的裂纹。
  2. 如权利要求1所述的裂纹传感器，其特征是，所述柔性膜为聚二甲基硅氧烷膜；优选地，聚二甲基硅氧烷膜的后的为5～20μm；
    或，CNT-PDMS层中碳纳米管的添加量为0.01～5wt％；优选地，碳纳米管的添加量为2～4wt％；进一步优选地，碳纳米管的添加量为2.5～3.5wt％。
  3. 如权利要求1所述的裂纹传感器，其特征是，银层的厚度为90～110nm；
    或，铬层的厚度为2～10nm；
    或，CNT-PDMS层的厚度为5～20μm；
    或，CNT-PDMS层连接电极；
    或，线性结构为U形。
  4. 一种权利要求1～3任一所述的裂纹传感器的制备方法，其特征是，将基底表面涂覆光刻胶层，在光刻胶层表面刻蚀若干微通道，在光刻胶层表面涂覆一层聚二甲基硅氧烷，凝固后获得一面有若干线性凸起、另一面光滑的聚二甲基硅氧烷层；在聚二甲基硅氧烷层的光滑面覆盖带有线形通孔的模板，在模板侧依次制备银层、铬层以及CNT-PDMS层，将模板去除，预拉伸后即得。
  5. 如权利要求4所述的裂纹传感器的制备方法，其特征是，基底为玻璃，在涂覆光刻胶层前，先采用O 2等离子体对基底进行处理；
    或，采用真空蒸发法制备银层和铬层；
    或，采用丝网印刷法在铬层表面制备CNT-PDMS层；
    或，在1.5～2.5％的应变条件下进行预拉伸。
  6. 一种裂纹传感装置，其特征是，包括权利要求1～3任一所述的裂纹传感器、支架和细胞培养部件，裂纹传感器位于支架和细胞培养部件之间，支架设置凹槽或通孔，裂纹传感器覆盖凹槽或通孔，裂纹传感器的部分线性结构或全部线性结构位于凹槽或通孔内。
  7. 如权利要求6所述的裂纹传感装置，其特征是，包括玻璃基体，将支架粘结在玻璃基体上；优选地，玻璃基体采用O 2等离子体处理；
    或，支架采用O 2等离子体处理。
  8. 一种权利要求1～3任一所述的裂纹传感器或权利要求6或7所述的裂纹传感装置在收缩力测量中的应用。
  9. 如权利要求8所述的应用，其特征是，在心肌细胞收缩力测量中的应用。
  10. 一种权利要求1～3任一所述的裂纹传感器或权利要求6或7所述的裂纹传感装置在制备心脏药物中的应用。
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