CN111545258A - Micro-fluidic chip capable of providing compression deformation and preparation method and application thereof - Google Patents
Micro-fluidic chip capable of providing compression deformation and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a micro-fluidic chip capable of providing compression deformation and a preparation method and application thereof, and the micro-fluidic chip comprises a deformation layer (1), a pre-stretched elastic membrane (2) and a support layer (3), wherein the pre-stretched elastic membrane (2) is arranged between the deformation layer (1) and the support layer (3), the deformation layer (1) comprises a deformation channel (101) and a positive pressure channel, and the support layer (3) comprises a support channel (301). The positive pressure channel makes the channel shape generate elastic deformation under the action of external circulation positive pressure, thereby enabling the elastic membrane at the bottom of the deformation channel to generate the circulation compression action. Compared with the prior art, the invention is based on the micro-fluidic chip technology, realizes different circulation compression modes by optimizing the chip structure, and is easy to manufacture and observe.
Description
Technical Field
The invention belongs to the technical field of micro-fluidic chips capable of providing compression deformation, and particularly relates to a micro-fluidic chip capable of providing compression deformation.
Background
In the research of tissue engineering and regenerative medicine, the interaction between cells and their surrounding microenvironment (such as mechanical stimulation, chemical stimulation, biological material, etc.) is a fundamental issue of guidance. Among them, mechanical transduction (mechanocransduction) of cells, i.e., a process in which cells convert mechanical stimulation of microenvironment into biochemical signals inside cells to further influence signal pathways and final behaviors, is a key point and difficulty of research in biomedicine in recent years. The mechanical signals can affect various functions of cells such as proliferation, differentiation, apoptosis and the like, thereby regulating and controlling important physiological activities such as myocardial cell orientation, osteogenesis, angiogenesis and the like. Moreover, many tissues and organs of the human body are constantly subjected to compressive mechanical stimulation, such as bones, cartilages, skins, blood vessels and the like, so that the research on the reaction of cells under the compressive mechanical stimulation is helpful for researching mechanical conduction and developing related biological materials. And the development of a convenient cell compression device can provide a powerful tool for related research and development.
At present, the cell compression mode is mainly to mechanically press cells or a three-dimensional matrix containing the cells to achieve the effect of compressing and stimulating the cells. Such as (Kim, Kang et al (2007) Microfluidic biological device for computing cell stimulation and lysis. Janet, Cheng et al (2012) Mechanical compression drive cells aware of capacitive compression of capacitive adhesive cell. Ho, Wangt et al (2018) Advanced Microfluidic device consumption for cyclic compression of capacitive adhesive cell. Lee, Erickson et al (2018) pn electrophoretic Microfluidic cell compression device for high-throughput testing of colloidal porosity. The mechanical action of such direct contact may cause cell damage and spatially limit a portion of the cell's vital activities such as orientation, migration, proliferation, etc. In the face of these problems, another way of cell compression provides a solution. It clamps the elastic membrane by a mechanical arm to pre-stretch, then two-dimensionally cultures the cells on the pre-stretched elastic membrane, and makes the elastic membrane perform a rebound action after the cells are attached, so as to achieve the purpose of periodically compressing the cells, such as Wille, Ambrosi et al (2004) Comparison of the effects of cyclic transformation and compression on the elastic cell antigens. Chinese utility model patent using similar principle is such as periodic cell compression and stretching device (application No. 201020595981.6). The disadvantages of this type of approach are the high cost of the device, the large volume, the high cell and culture fluid consumption; and the difficult problems of difficult customization, difficult control of cell environment and the like exist.
The micro-fluidic technology is to control micro-liquid (10)-6-10-9L) of the system. Its main characteristics are miniaturization, which means that it is small and portable in appearance, less in reagent consumption and cost-effective. Microfluidic chips that can provide compression set are easy to customize and can perform many functions such as high throughput, organ chips, digital microfluidics, droplet generators, etc. in different ways. In addition, the microfluidic chip that can provide compression set is generally transparent, and in addition, its small physical size makes it compatible with most microscope viewing platforms and allows real-time viewing.
The invention discloses an arterial blood vessel simulation micro-fluidic device capable of being directly observed under a high-power objective lens, which can simulate physiological and pathological conditions of organs and tissues simultaneously bearing fluid shearing force and mechanical tensile force in vivo and can also be directly observed under the high-power objective lens, thereby realizing real-time observation of fine structures of single cells and dynamic and static changes in micro-fluidic channels. However, these microfluidic devices provide tensile deformation, and no microfluidic technology for providing compression deformation is available at present.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a micro-fluidic chip which has good repeatability and is easy to manufacture and observe and can provide compression deformation, and a preparation method and application thereof.
The purpose of the invention can be realized by the following technical scheme: the microfluidic chip capable of providing compression deformation is characterized by comprising a deformation layer (1), a pre-stretched elastic membrane (2) and a supporting layer (3), wherein the pre-stretched elastic membrane (2) is arranged between the deformation layer (1) and the supporting layer (3), the deformation layer (1) comprises a deformation channel (101) and a positive pressure channel, and the supporting layer (3) comprises a supporting channel (301).
The deformation channel (101) and the positive pressure channel are separated by a thin wall.
The width ratio of the deformation channel (101) to the thin wall to the positive pressure channel is 1: (0.05-0.5): (0.5-5). If the configuration ratio is not in this range, the maximum magnitude of compression is greatly reduced.
The thin wall and the pre-stretching elastic film (2) are both made of elastic polymer materials, including silicon rubber, natural rubber and the like. The elastic modulus should be 0.5-10 MPa.
The height ratio of the supporting channel (301) to the positive pressure channel is 1: (0.1-1). If the configuration ratio is not in this range, the maximum magnitude of compression is greatly reduced.
Two ends of the deformation channel (101) are respectively provided with a fluid inlet (102) and a fluid outlet (103) which are communicated with the deformation channel, and two ends of the positive pressure channel are provided with air passage openings which are communicated with the positive pressure channel.
The positive pressure channel is connected with an external air pressure pump system through an air passage opening, and under the action of external circulating positive pressure, the shape of the positive pressure channel is elastically deformed, so that the pre-stretched elastic membrane (2) at the bottom of the deformation channel is subjected to circulating compression. The cycle number exceeds 20000 times, thereby ensuring the service life of the chip.
Different deformation modes are realized by configuring the positions and the sizes of the deformation channel (101) and the positive pressure channel, and the deformation modes comprise uniaxial compression or biaxial compression.
The preparation method of the micro-fluidic chip capable of providing compression deformation comprises the following steps:
step (1): preparing a template with patterns on the surface by an etching technology, then casting a prepolymer on the template, and obtaining a deformation layer (1) and a supporting layer (3) after curing, demolding and punching;
step (2): spin-coating prepolymer on the surface of a silicon wafer at a high speed, and curing to obtain an elastic film;
and (3): manufacturing an elastic film pre-stretching clamp, transferring the elastic film onto the clamp and pre-stretching the elastic film, wherein the pre-stretching amplitude is 10-20%, so as to obtain a pre-stretched elastic film (2);
and (4): the deformation layer (1) and the pre-stretched elastic film (2) are joined and then joined with the support layer (3). The combination mode is the combination of plasma treatment and hot pressing technology, and specifically comprises the following steps: and (3) putting the deformation layer (1) and the pre-stretched elastic film (2) together in a plasma treatment instrument, setting the power at 100W for 90s, immediately taking out after treatment, butting and pressing the surface of the deformation layer (1) containing the deformation channel shape with the pre-stretched elastic film, and baking at 60-80 ℃ for 10-20 min.
The prepolymer in the step 1 and the step 2 is obtained by uniformly mixing PDMS prepolymer and a cross-linking agent in a mass ratio of 10:1 and removing bubbles in vacuum. The curing condition is heating curing at 60-80 ℃ for 6-12 h.
The application of the micro-fluidic chip capable of providing compression deformation is to use the micro-fluidic chip capable of providing compression deformation for the relevant research on the influence of mechanical stimulation on cell behaviors; and the related research of the physiological and pathological environments of the organs and tissues of the human body under the mechanical stimulation is simulated; application of mechanical property test and research of thin layer materials.
Compared with the prior art, the invention has the beneficial effects that:
(1) the prior art has not yet developed a compression chip based on microfluidic technology.
(2) By optimizing the structural design, the micro-fluidic chip of the deformation channel module and the positive pressure channel module is integrated, and the compression deformation mode is realized.
(3) By changing the mask design and the elastic film pre-stretching mode, various compression deformation modes such as uniaxial compression and biaxial compression can be realized.
(4) The existing three-layer cell stretching device has the advantages that the connecting pipelines are complicated during experiments, and the problems of liquid leakage, air leakage and the like are easily caused.
(5) The micro-fluidic chip has good repeatability and is easy to manufacture and observe.
(6) The invention adopts three layers of materials, the middle of which is a pre-stretched elastic film which is a super-elastic body and has the advantage of large stretching amplitude, and the cyclic compression action is skillfully realized by virtue of the stretching and rebounding characteristics of the elastic film.
Drawings
Fig. 1 is a schematic structural diagram of a microfluidic chip according to the present invention, wherein:
1 is a deformation layer, 101 is a deformation channel, 102 is a fluid inlet, 103 is a fluid outlet, 104 is a positive pressure channel a, 105 is a positive pressure channel b, 106 is an air channel opening a, 107 is an air channel opening b, and 108 is a thin wall a, 109 is a thin wall b;
2 is a pre-stretched elastic membrane, 3 is a support layer, and 301 is a support channel.
Fig. 2 is a schematic diagram of a method for preparing the microfluidic chip according to the present invention.
Fig. 3 is a schematic diagram of the principle of the microfluidic chip in the flat state and the compressed state.
Fig. 4 is an experimental test chart of compression using the microfluidic chip of the present invention: (a) control group of pre-stretched elastic film when not stretched; (b) the pre-stretched elastic film was uniaxially compressed at a level of 12%.
FIG. 5 is a graph of lateral and longitudinal amplitude versus input pressure using the microfluidic chip of the present invention.
Detailed Description
The invention is described in detail below with reference to the figures and specific embodiments.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1, a method of preparing a microfluidic compressed chip, as shown in fig. 2:
(1) manufacturing of mask plate
And designing and drawing the structure of the micro-channel of the micro-fluidic chip by using Computer Aided Design (CAD) software, and manufacturing a mask plate by using high-precision printing equipment.
(2) Making SU-8 template
Soaking a 3-inch silicon wafer in a Piranha solution (98% concentrated sulfuric acid: 30% hydrogen peroxide: 3:1) for 1h, cleaning the silicon wafer for 3 times by using ultrapure water, purging the silicon wafer by using nitrogen, and then putting the silicon wafer into an oven to be dried for later use; placing the silicon wafer in a vacuum drier, and carrying out gas phase surface treatment for 10min by using 200 mu L of hexamethyldisiloxane; spin-coating a certain amount of SU-82150 photoresist on the silicon wafer, wherein the thickness of the film layer is about 300 μm; and pre-baking the silicon wafer coated with the photoresist at 95 ℃. Then clinging to a mask plate with a micro-channel shape, and carrying out exposure treatment by using high-intensity ultraviolet light. Then, placing the silicon wafer on a glue drying table for post-drying, wherein the temperature is set to 95 ℃; then, immersing the silicon wafer by using a photoresist developing solution (propylene glycol-methyl ether acetate), slightly shaking the crystallization vessel for 20-30min, and removing the photoresist of the unexposed part; and finally, washing the mixture by using isopropanol and ultrapure water in sequence, drying the mixture by using nitrogen, naturally cooling the mixture, and storing the mixture for later use.
(3) Manufacturing method of deformation layer of micro-fluidic chip
Uniformly mixing a certain amount of PDMS prepolymer (Sylgard 184 silicon Elastomer Base) and a crosslinking Agent (Sylgard 184 silicon Elastomer Curing Agent) in a mass ratio of 10:1, putting the mixture into a vacuum drier to remove bubbles, pouring the mixture into a culture dish provided with a micro-channel layer template, heating and Curing at 70 ℃ for 12 hours, namely stripping a PDMS thick layer containing a micro-channel shape from the silicon wafer template, and then punching holes at two ends of a deformation channel and corresponding positions of a positive pressure channel by using a puncher.
(4) Manufacturing method of support layer of micro-fluidic chip
Uniformly mixing a certain amount of PDMS prepolymer in a mass ratio of 10:1, putting the mixture into a vacuum drier to remove bubbles, pouring the mixture into a culture dish provided with a supporting layer template, and heating and curing the mixture at 70 ℃ for 12 hours to strip PDMS containing the supporting layer shape from the silicon wafer template.
(5) Manufacture of elastic membrane of micro-fluidic chip
Uniformly mixing a certain amount of PDMS prepolymer and a crosslinking agent (Sylgard 184 Silicone Elastomer curing agent) in a mass ratio of 10:1, removing bubbles under a vacuum condition, uniformly coating the mixture on a silicon wafer subjected to hydrophobic treatment by using a spin coater, and heating and curing at 70 ℃ for 6h after the spin coating is finished.
(6) Making pre-stretched frames
Uniformly mixing a certain amount of PDMS prepolymer and a cross-linking agent (Sylgard 184 Silicone Elastomer Current) in a mass ratio of 10:1, removing bubbles in vacuum, pouring the mixture into a culture dish, heating and curing at 70 ℃ for 12h, naturally cooling, peeling the obtained PDMS glue layer from the culture dish, and cutting the PDMS glue layer into a rectangular frame by using a cutting tool, wherein the length of the inner side of the frame is 30mm, the width of the inner side of the frame is 20mm, and the thickness of the frame is 5 mm.
(7) Bonding of elastic membranes to frames
And (3) putting the silicon wafer with the elastic membrane prepared in the step (5) and the PDMS frame prepared in the step (6) into a plasma processor together, setting the power and the time to be 100W and 90s respectively, immediately taking out after the processing is finished, butting and pressing, heating and curing at 70 ℃ for 15min, then carving on the outer edge of the frame by using a blade, and slowly removing the frame and the elastic membrane together.
(8) Bonding of frame to pre-stretched elastic film
Clamping a PDMS frame by using a clamp, pulling the frame open to enable the stretching amplitude of an elastic film attached to the frame to reach 15%, placing the pre-stretched elastic film prepared in the step 7 and the deformation layer prepared in the step 3 into a plasma treatment instrument together, setting the power to be 100W and the time to be 90s, immediately taking out after the treatment is finished, butting and pressing the frame and the elastic film, baking for 15min at 70 ℃, then engraving by using the edge of the micro-channel layer of the blade, and slowly taking off the deformation layer and the elastic film together.
(9) Bonding of the deformation layer to the supporting layer
PDMS prepolymer was mixed with toluene in a 2: 8, uniformly mixing and spin-coating on a glass sheet, imprinting the support layer prepared in the step 4 with a PDMS-toluene solution, butting and pressing the deformation layer-elastic membrane prepared in the step 8 with the support layer under a body type microscope, heating and curing at 70 ℃ for 3 hours, and finishing the preparation of the microfluidic compression chip.
The obtained micro-fluidic chip structure is shown in fig. 1, and comprises a deformation layer 1, a pre-stretched elastic membrane 2 and a support layer 3 which are sequentially arranged from top to bottom, wherein a deformation channel 101, a positive pressure channel a104 and a positive pressure channel b105 are arranged in the deformation layer 1, the positive pressure channel a104 and the deformation channel 101 are separated by a thin wall a108, the air pressure channel a105 and the deformation channel 101 are separated by a thin wall b109, a fluid inlet 102 and a fluid outlet 103 which are communicated with the deformation channel 101 are respectively arranged at two ends of the deformation channel 101, and during detection, fluid can enter from the fluid inlet 102 and flow out from the fluid outlet 103. The positive pressure channel a104 is provided with an air channel opening a106 communicated with the positive pressure channel a, the positive pressure channel b105 is provided with an air channel opening b107 communicated with the positive pressure channel b, the positive pressure channel is connected with an external air pressure pump system through the air channel opening, and the positive pressure channel cavity structure is elastically deformed through external air pressure, so that acting force is applied to the deformation channel 101 and the pre-stretched elastic membrane 2 at the bottom.
The width ratio of the deformation channel 101 to the thin wall to the positive pressure channel is 1: 0.05-0.5: 0.5-5. The height ratio of the supporting channel 301 to the positive pressure channel is 1: 0.1-1.
Example 2 compression testing of microfluidic compressed chips
Rhodamine dye was ultrasonically sprayed on the surface of the above-described transferable elastic membrane (the pre-stretched elastic membrane 2 prepared by the same method as in example 1), after the dye was dried, the transferable elastic membrane was joined to a deformation layer containing a microchannel to prepare a microfluidic compression chip, the chip was connected to a fluid controller and a gas pressure pump system, and the amount of deformation of the elastic membrane was measured under a positive pressure of 100mbar, with the result shown in fig. 4. Compared with the prior art, the compression amplitude of the elastic membrane after positive pressure compression is 12%, the elastic membrane can immediately recover after long-time compression after positive pressure deformation is removed, the principle schematic diagram of the flat recovery state and the compression state of the microfluidic chip is shown in figure 3, and the requirements of a compression experiment can be completely met. When the positive pressure is varied, the amplitude varies both laterally and longitudinally, with the amplitude being related to the input positive pressure as shown in fig. 5. It can be seen that the longitudinal diastolic amplitude is 0 with increasing pressure and the transverse compressive amplitude grows linearly with increasing pressure.
Example 3 Effect of compaction on cell behavior
(1) Cell seeding
Firstly, the micro-fluidic chip is sterilized, and the sterilization steps are as follows: placing the micro-fluidic compressed chip into a super clean bench for ultraviolet irradiation for 30min, and then sequentially washing the deformation channel 101 of the micro-fluidic chip with 75% alcohol, sterilized PBS and cell culture medium for 3 times each time; taking cells cultured in a cell culture bottle until the fusion degree is about 80%, digesting and centrifuging, injecting cell suspension into the deformation channel 101 of the microfluidic chip through the fluid inlet 102 of the deformation channel at the cell density of 2.5 multiplied by 105/ml, putting the chip into a cell culture box, culturing for 4 hours at the temperature of 37 ℃ and the carbon dioxide concentration of 5%, and connecting the fluid inlet 102 and the fluid outlet 103 of the deformation channel 101 with a fluid controller after the cells are stably adhered to the elastic membrane 2 at the bottom of the deformation channel 101 to provide a fresh culture medium for continuous culture of the cells.
(2) Cell compression and Observation
Starting a living cell workstation, and setting the concentrations of CO2 and O2 in the adapter to be 5 percent and 20 percent respectively; starting a heating module, wherein the temperatures of the adapter and the cover plate are respectively set to be 37 ℃ and 38 ℃; and taking out the microfluidic chip in the cell incubator, and placing the microfluidic chip on an objective table of a living cell workstation. Selecting a phase difference mode for observation, and setting a proper shooting site, the total long-time shooting time and a time interval; opening control software of the air pressure pump system, and setting output positive pressure to achieve that the compression deformation is 10% (the positive pressure is about +90mbar), and the frequency is 1 Hz; connecting the air passage openings (an air passage opening a106 and an air passage opening b107) of the positive pressure passage with the pneumatic pump system, starting the pneumatic pump system, and simultaneously starting a long-term shooting mode of living cell workstation software to perform in-situ dynamic monitoring on cells under periodic compressive stimulation.
Example 4 micro-fluidic chip to simulate the physiological environment of human skin tissue under the stimulation of periodic compressive stress
(1) Production of the same microfluidic chip as in example 1
(2) Human Epidermal Stem Cells (ESCs) were seeded into microfluidic chips and cell culture was performed under continuous perfusion and periodic compressive stress, the seeding and culture methods being the same as described in example 3. Wherein, according to different considered periodic mechanical stress conditions, the perfusion speed is set to be 1-15 muL/min, the compression amplitude is 3-10%, the compression frequency is 0.1-5Hz, and the culture time is 7 days to 4 weeks.
(3) During the culture process, the continuous perfusion of the culture solution ensures the nutrient supply of the skin stem cells, and the regularly applied compression gives continuous and periodic mechanical stress stimulation to the epidermal stem cells, which is similar to the mechanical stress stimulation of the epidermal stem cells caused by skin expansion. Therefore, the microfluidic chip can simulate partial physiological environment of skin expansion.
(4) The influence of various mechanical stress stimuli on the epidermal stem cells and the mechanism thereof are not completely clear as the epidermal stem cells are specific stem cells in skin tissues. The micro-fluidic chip can be used as a compressive mechanical stress cell culture system device, has adjustable compressive stress stimulation frequency and amplitude, and can be applied to investigation of proliferation and differentiation and mechanism research of epidermal stem cells under different mechanical stress effects.
Claims (10)
1. The microfluidic chip capable of providing compression deformation is characterized by comprising a deformation layer (1), a pre-stretched elastic membrane (2) and a supporting layer (3), wherein the pre-stretched elastic membrane (2) is arranged between the deformation layer (1) and the supporting layer (3), the deformation layer (1) comprises a deformation channel (101) and a positive pressure channel, and the supporting layer (3) comprises a supporting channel (301).
2. A microfluidic chip capable of providing compression set according to claim 1, wherein the deformation channel (101) and the positive pressure channel are separated by a thin wall.
3. A microfluidic chip capable of providing compression set according to claim 2, wherein the width ratio of the deformation channel (101), the thin wall and the positive pressure channel is 1: (0.05-0.5): (0.5-5).
4. A microfluidic chip capable of providing compression set according to claim 2, wherein the thin wall and the pre-stretched elastic membrane (2) are made of elastic polymer material.
5. A microfluidic chip capable of providing compression set according to claim 1, wherein the ratio of the height of the supporting channel (301) to the height of the positive pressure channel is 1: (0.1-1).
6. The microfluidic chip capable of providing compression deformation according to claim 1, wherein a fluid inlet (102) and a fluid outlet (103) are respectively disposed at two ends of the deformation channel (101), and an air passage opening is disposed at two ends of the positive pressure channel.
7. The microfluidic chip capable of providing compression deformation according to claim 1, wherein the positive pressure channel is connected to an external air pressure pump system through an air channel opening, and under the action of external cyclic positive pressure, the shape of the positive pressure channel is elastically deformed, so that cyclic compression is performed on the pre-stretched elastic membrane (2) at the bottom of the deformation channel.
8. The microfluidic chip capable of providing compression set according to claim 1, wherein different deformation modes are realized by configuring the positions and sizes of the deformation channel (101) and the positive pressure channel, and the deformation modes include uniaxial stretching or biaxial stretching.
9. The method for preparing the micro-fluidic chip capable of providing compression set according to claim 1, comprising the following steps:
step (1): preparing a template with patterns on the surface by an etching technology, then casting a prepolymer on the template, and obtaining a deformation layer (1) and a supporting layer (3) after curing, demolding and punching;
step (2): spin-coating prepolymer on the surface of a silicon wafer at a high speed, and curing to obtain an elastic film;
and (3): manufacturing an elastic film pre-stretching clamp, transferring the elastic film to the clamp and pre-stretching to obtain a pre-stretched elastic film (2);
and (4): the deformation layer (1) and the pre-stretched elastic film (2) are joined and then joined with the support layer (3).
10. Use of the microfluidic chip capable of providing compression set according to claim 1, wherein the microfluidic chip capable of providing compression set is used for research on influence of mechanical stimulation on cell behavior; and the related research of the physiological and pathological environments of the organs and tissues of the human body under the mechanical stimulation is simulated; and the application of the mechanical property test research of the thin layer material.
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| CN108761600A (en) * | 2018-05-04 | 2018-11-06 | 西安交通大学 | A kind of method that prestressing force aided nano press makes high density diffraction grating |
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