WO2021190215A1 - Système de circulation extracorporelle de niveau de puce microfluidique de mécanique des cellules endothéliales vasculaires et de recherche biologique - Google Patents

Système de circulation extracorporelle de niveau de puce microfluidique de mécanique des cellules endothéliales vasculaires et de recherche biologique Download PDF

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WO2021190215A1
WO2021190215A1 PCT/CN2021/077159 CN2021077159W WO2021190215A1 WO 2021190215 A1 WO2021190215 A1 WO 2021190215A1 CN 2021077159 W CN2021077159 W CN 2021077159W WO 2021190215 A1 WO2021190215 A1 WO 2021190215A1
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cell culture
pressure
microfluidic chip
mechanics
fluid
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覃开蓉
那景童
王宇
李泳江
薛春东
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大连理工大学
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    • 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
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/49—Blood
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip

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  • the present invention belongs to the technical field of cell mechanics biology experimental devices for health and rehabilitation engineering. It is designed based on the principles of hemodynamics, microfluidic chips and electronic information technology, and consists of microfluidic chips, peripheral fluid loading devices, and signal acquisition and processing.
  • the microfluidic chip-level extracorporeal circulatory system is used to study the quantitative relationship between hemodynamic signals caused by different physiological and pathological conditions and mechanical treatments and the mechanical and biological effects of vascular endothelial cells.
  • the arterial vessel wall is composed of three layers of tissues: intima, media and adventitia.
  • the intima refers to the single-layer structure of endothelial cells located in the innermost layer of the artery wall, also known as the endothelium.
  • vascular endothelial cells are in a complex hemodynamic microenvironment.
  • the microenvironment also has hemodynamic signals such as wall shear stress caused by blood flow, blood pressure, and blood vessel circumferential stress (strain) caused by blood pressure.
  • Vascular endothelial cells can recognize different forms of extracellular hemodynamic signals and their changes through receptors and receptors on the cell membrane surface, and transmit mechanical signals to the inside of the cell through a series of signal pathway cascade reactions to cause changes in gene and protein expression , That is, the mechanism of mechanobiology, which ultimately affects the functions and behaviors of cell proliferation, migration, and apoptosis.
  • the laminar flow microenvironment in the physiological range can promote the secretion of nitric oxide (NO), prostacyclin (PGI 2 ) and other vasodilation factors by vascular endothelial cells, which play a role in anti-inflammatory, anti-oxidative stress, and anti-inflammatory properties.
  • NO nitric oxide
  • PKI 2 prostacyclin
  • other vasodilation factors by vascular endothelial cells, which play a role in anti-inflammatory, anti-oxidative stress, and anti-inflammatory properties.
  • Severe arterial stenosis lesions caused by atherosclerosis are generally treated by endovascular/surgical procedures such as endarterectomy, stent intervention, bypass grafting, etc. to achieve revascularization; mild or moderate lesions can be treated
  • Artificial heart assist devices, external counterpulsation (ECP), exercise intervention and other methods are used to regulate the hemodynamic microenvironment of the arterial endothelium, and improve endothelial function through mechanobiological mechanisms, thereby preventing or reversing arterial dysfunction.
  • ECP external counterpulsation
  • exercise intervention are used to regulate the hemodynamic microenvironment of the arterial endothelium, and improve endothelial function through mechanobiological mechanisms, thereby preventing or reversing arterial dysfunction.
  • mechanical therapies such as artificial heart assist devices, external counterpulsation, and exercise intervention have become important entry points for the treatment and rehabilitation of cardiovascular diseases.
  • microfluidic chip technology provides an effective experimental platform for accurately simulating the microenvironment of extracellular hemodynamics, observing and detecting the interaction between the microenvironment of the cell and the cell.
  • the microfluidic chip has the advantages of small sample volume, easy integration, easy optical detection, and good biocompatibility. It has also become an ideal experimental platform to reproduce the microenvironment of arterial hemodynamics in the body blood circulation system.
  • the existing microfluidic system can realize simple hemodynamic signals in the circulatory system, there is still a lack of accurate simulation of the target artery endothelial hemodynamic microenvironment under different physiological, pathological conditions and mechanical therapy intervention conditions.
  • Systematic theory and method At the same time, the fluid mechanics circuit used to characterize the hemodynamic characteristics of the downstream afterload of the target artery at the periphery of the cell culture cavity all use off-chip large-scale centralized parameter components, and there is still room for improvement in integration and consumables.
  • the dynamic loading of hemodynamic signals in the simulated circulatory system mostly adopts open-loop control technology, which fails to achieve closed-loop control of pressure or flow signals; moreover, the detection of endothelial cell function in the cell culture cavity is mostly offline Sampling for analysis failed to achieve online, real-time quantitative monitoring of endothelial cell mechanics and biological responses.
  • the chip-level extracorporeal circulatory system can not only realize the precise loading control of hemodynamic signals, but also perform online and real-time quantitative monitoring of the mechanical and biological effects of vascular endothelial cells in the cell culture cavity for the study of different physiology and pathology State and the quantitative relationship between hemodynamic signals and endothelial cell mechanobiological effects under the intervention of mechanical therapy and its molecular biological mechanism.
  • the purpose of the present invention is to simulate the blood pressure, wall shear stress and circumferential stretch strain (stress) signals in the microenvironment of target artery endothelial hemodynamics in the body, based on the flat cube geometry of the "sandwich" structure cell culture cavity
  • the size and multi-element hemodynamic intensive parameter model establishes a set of theoretical methods that accurately simulate the target artery endothelial hemodynamic microenvironment signals under different physiological, pathological conditions and mechanical therapy intervention conditions; further based on the established theoretical method design and Build a microfluidic chip-level extracorporeal circulatory system with higher integration and less consumables; this system can not only achieve precise loading control of hemodynamic signals, but also have mechanical and biological effects on vascular endothelial cells in the cell culture cavity Online, real-time quantitative monitoring is used to study the quantitative relationship between hemodynamic signals and endothelial cell mechanical and biological effects and their molecular biological mechanisms under different physiological, pathological conditions and mechanical therapy intervention conditions.
  • a microfluidic chip-level extracorporeal circulation system for the study of vascular endothelial cell mechanics and biology (as shown in Figure 1).
  • the microfluidic chip-level extracorporeal simulated circulation system includes three basic units: the first basic unit is a multi-element hydrodynamic circulation loop including a microfluidic chip; wherein the microfluidic chip includes a cell culture chamber R c , Elastic cavity C, flu channel L and resistance channel R f , the microfluidic chip is used in the cell culture cavity R c to simulate blood pressure, wall shear stress and circumferential stretch in the microenvironment of body target artery endothelial hemodynamics Strain (stress) signal.
  • the first basic unit is a multi-element hydrodynamic circulation loop including a microfluidic chip
  • the microfluidic chip includes a cell culture chamber R c , Elastic cavity C, flu channel L and resistance channel R f
  • the microfluidic chip is used in the cell culture cavity R c to simulate
  • the second basic unit is the peripheral equipment that provides pulsating flow for the microfluidic chip, including a liquid reservoir, an air pump, and a fluid loading device (i).
  • the liquid storage tank is connected with the inlet and outlet of the microfluidic chip to form a hydrodynamic circulation loop
  • the air pump is connected with the liquid storage tank through the fluid loading device (i).
  • the third basic unit is the acquisition and processing system (ii) and feedback control system (iii) of hemodynamic signals and intracellular biological and chemical signals on the microfluidic chip, including sensors, fluorescence microscopes, CCD cameras and industrial computers.
  • the hemodynamic signals and intracellular biological and chemical signals on the microfluidic chip enter the industrial computer through the sensor, or fluorescence microscope and CCD camera, and are processed by the industrial computer to form control instructions to precisely control the fluid loading device (i) in the micro
  • the blood pressure, wall shear stress, and stretch strain (stress) signals in the target artery endothelial hemodynamic microenvironment are generated in the cell culture cavity on the fluid control chip.
  • the "sandwich” structure cell culture chamber on the microfluidic chip is shown in Figure 2 (a).
  • the upper and lower layers of PDMS with flat cube channels are separated by an elastic film to form a cell culture chamber, the upper layer is directly exposed to atmospheric pressure, and the lower layer cell culture chamber is connected to the circulation path.
  • the selection of the elastic modulus of the elastic film needs to be based on the principle of elastic mechanics to accurately simulate the arterial pressure p(t) waveform and the circumferential strain ⁇ (t) waveform in the body target artery endothelial microenvironment.
  • the upper elastic membrane of the culture chamber Under the condition of no pressure load, the upper elastic membrane of the culture chamber is not deformed, and its length L c , width W c and height H c satisfy: H c ⁇ W c and H c ⁇ L c .
  • the elastic membrane When the fluid is driven by pressure, the elastic membrane is stretched, and the endothelial cells cultured on the top membrane of the lower cell culture chamber are simultaneously subjected to arterial pressure p(t), wall shear stress ⁇ w (t) and tensile strain ⁇ (t) The combined effect of (stress). Since the height of the cell culture chamber is much smaller than its width and length, the flow Reynolds number Re and Womersley number ⁇ in the cell culture chamber satisfy Re ⁇ 1 and ⁇ 1, which satisfies the quasi-steady assumption. It is further assumed that the elastic film is stretched. For small deformation, the wall shear stress ⁇ w (t) borne by endothelial cells should satisfy:
  • ⁇ is the viscosity of the cell culture fluid
  • ⁇ p(t) is the pressure drop generated by the fluid passing through the cell culture chamber
  • q(t) is the volume flow rate through the cell culture chamber.
  • the design of the hydrodynamic circuit on the microfluidic chip requires that the endothelial cells cultured on the elastic film on the top of the cell culture cavity bear the pressure, wall shear stress and the arterial pressure p(t) and wall shear of the target artery endothelial microenvironment.
  • the stress ⁇ w (t) (corresponding to the flow rate q(t) in equation (2a)) has the same waveform. Since the input impedance of the hydrodynamic circuit downstream of the cell culture cavity can reflect the hemodynamic characteristics of the target artery afterload, a lumped parameter model can be designed by simulating the input impedance of the target artery.
  • the input impedance represents the relationship between the pulsating pressure p(t) and the flow rate q(t) waveform in the frequency domain.
  • the Fourier series of arterial pressure p(t) waveform and flow rate q(t) waveform after Fourier decomposition can be expressed as:
  • j is the imaginary number
  • ⁇ n is the circular frequency
  • the pressure is equivalent to the voltage in the circuit
  • the flow rate is equivalent to the current in the circuit
  • the compliance, resistance, and inertial elements are equivalent to the capacitance and resistance in the circuit.
  • inductance can build a multi-element lumped parameter circuit network model (as shown in (b) in Figure 2), and it is easy to know the equivalent impedance of the designed circuit network It is a complex function represented by one or more compliance C, flu L and flow resistance R f.
  • circuit equivalent impedance The amplitude and phase values of is fitted to the amplitude and phase of the target arterial input impedance Z( ⁇ n ), so that the sum of square residuals RSS (Residual Sum of Squares):
  • Arterial compliance C can be simulated by a hollow cylindrical cylinder filled with a certain volume of gas.
  • the compressibility of the gas represents the elasticity of the artery.
  • the calculation formula is as follows:
  • V represents the volume of the air column
  • P represents the air pressure in the air column
  • a c represents the hollow part of the cylinder
  • the cross-sectional area, h represents the height of the air column
  • P o is the atmospheric pressure
  • P a is the pressure of the liquid in the elastic cavity acting on the air column in the elastic cavity. Therefore, the compliance C is known height h and a pressure P a, the equation (6) to calculate the elastic air chamber of the column, as the elastic Reference chamber size.
  • Influenza L is simulated by a section of connected pipeline, which can be calculated by the following formula:
  • ⁇ is the density of the fluid
  • l' is the length of the pipe
  • A' is the internal cross-sectional area of the pipe. Therefore, if the value of influenza L is known, and the internal cross-sectional area A'of the pipeline is known, the pipeline length l'can be calculated by formula (7).
  • a f is the cross-sectional area of the channel
  • L f and P f are the length and circumference of the channel
  • ⁇ is the aspect ratio and satisfies:
  • the input impedance characteristics of the downstream afterload system are determined. Once the input arterial pressure p(t) waveform of the cell culture chamber is known, the flow rate q(t) waveform, that is, the wall shear stress ⁇ w (t) waveform, can be uniquely determined; and vice versa.
  • the fluid loading device (i) adopts a programmable air pump manufactured by Elveflow, and compiles related programs based on the Labview platform to generate target arterial endothelial microarrays in the chip cell culture cavity that simulate different physiological and pathological conditions and mechanical therapy intervention conditions.
  • the environmental blood pressure p(t) waveform is adjusted to load the hydrodynamic component value, so that the flow rate waveform through the cell culture chamber is q(t), so according to formula (1), it can be seen that the endothelial cells on the top membrane of the cell culture chamber bear wall shear The effect of stress ⁇ w (t).
  • the signal acquisition and processing system (ii) and the feedback control system (iii) are shown in Figure 1.
  • the signal acquisition and processing system (ii) includes an inverted fluorescence microscope, a CCD industrial camera, a pressure sensor and a flow sensor for real-time monitoring and collection of the input pressure p 1 (t) and output pressure p 2 (t) of the cell culture chamber.
  • the flow waveform q(t) is the actual state of the cell mechanics and biological response in the cell culture chamber of the chip.
  • the collected signal is fed back to the PID control device (iii), and the loading device (i) is further adjusted to quantitatively regulate the changes in the pressure, flow signal amplitude and frequency of the multi-element cycle simulation system, and finally generated in the microfluidic chip cell culture chamber
  • the cavity geometry is calculated by formula (1); and for the stretch strain ⁇ (t) of the elastic film in the chip under different pressure p(t), the laser induced fluorescence (LIF) method can be used to pass Fluorescence microscope performs pre-measurement.
  • LIF laser induced fluorescence
  • Step 1 Culture of vascular endothelial cells
  • Step 2 Load the blood pressure, wall shear stress and vascular circumferential strain signal stimulation in the target artery endothelial microenvironment under different physiological and pathological conditions and mechanical therapy intervention conditions, and carry out real-time monitoring of the biological response of cell mechanics.
  • the present invention can conveniently carry out experiments of interaction between hemodynamic signals and vascular endothelial cells under different extracellular physiological and pathological states and mechanical therapy intervention conditions, and accurately and completely replicates the real target artery vascular endothelium Extracellular hemodynamic microenvironment, with higher integration, fewer consumables, and real-time observation and collection of cell mechanics and biological responses, providing efficient and powerful for studying the quantitative relationship between hemodynamic signals and the mechanical and biological mechanisms of vascular endothelial cells Experimental platform.
  • Figure 1 is a structure diagram of a microfluidic chip-level extracorporeal circulatory system.
  • Fig. 2 is a schematic diagram of a microfluidic chip cell culture chamber and a general fluid circuit
  • (a) is a schematic diagram of a microfluidic chip cell culture chamber with a "sandwich” structure
  • (b) is a schematic diagram of a general fluid circuit.
  • Figure 3 is a schematic diagram of the blood pressure, wall shear stress and circumferential stretch strain waveforms of the human common carotid artery endothelial hemodynamic microenvironment before and after exercise intervention.
  • (a) is a schematic diagram of human carotid artery endothelial hemodynamic microenvironment blood pressure waveform before and after exercise intervention
  • (b) is a schematic diagram of human carotid artery endothelial hemodynamic microenvironment wall shear stress waveform before and after exercise intervention
  • (c) is Schematic diagram of the circumferential stretch strain waveform of the human common carotid artery endothelial hemodynamic microenvironment before and after exercise intervention.
  • FIG. 4 Input impedance curve before and after exercise intervention, (a-1) is the amplitude-frequency curve of resting state input impedance before exercise intervention, (a-2) is the phase-frequency curve of resting state input impedance before exercise intervention, ( b-1) is the amplitude-frequency curve of the input impedance after exercise intervention, (b-2) is the phase-frequency curve of the input impedance after exercise intervention.
  • Fig. 5 is a schematic diagram of a five-element lumped parameter model and a microfluidic chip, (a) is an equivalent circuit diagram of the microfluidic chip, and (b) is a schematic diagram of the microfluidic chip.
  • (i) is the fluid loading device;
  • (ii) is the signal acquisition and processing system;
  • (iii) is the feedback control system;
  • I(ii) is the pressure and flow sensor at the input of the cell culture chamber on the chip;
  • O(ii) It is a pressure and flow sensor located at the output end of the cell culture chamber;
  • F(ii) is a fluorescent probe;
  • R c is a "sandwich" structure of the cell culture chamber designed as a rectangular flat channel;
  • R f is a curved channel;
  • C 1 , C 2 It is an elastic air cavity;
  • L is a long rectangular channel.
  • R c , R f1 , R f2 simulate the flow resistance of the target artery segment and the total flow resistance of the vascular bed downstream of the target artery
  • L is the flow inertia value
  • C 1 and C 2 simulate the compliance between the heart and the target artery, respectively The value of the total compliance of the vascular bed downstream of the target artery
  • Each channel and chamber structure of the microfluidic chip are manufactured using standardized micromachining methods.
  • the chip material uses PDMS material and is bonded and sealed with a clean glass sheet to form a transparent glass-PDMS chip with good biocompatibility.
  • the geometric dimensions of the specific channel and chamber structure are determined according to the above-mentioned parameters.
  • the selection of the elastic modulus of the film on the top of the “sandwich” cell culture cavity needs to be based on the principle of elasticity to accurately simulate the blood pressure waveform p(t) ((a) in Figure 3) and week in the microenvironment of the target artery endothelium in the body. Calculate and analyze the direction strain waveform ⁇ (t) ((c) in Figure 3);
  • Step 1 The primary cultured arterial endothelial cells were subcultured with EGM medium (Lonza Benelux) for endothelial cells, and passages 2-5 were used for experiments. During the experiment, endothelial cells were planted on the lower surface of the elastic film in the cell culture chamber R c coated with Fibronection to make the cells adhere to the wall and the degree of fusion reached more than 90% as shown in Figure 2 (a).
  • EGM medium Loza Benelux
  • Step 2 Load the blood pressure, wall shear stress, and vascular circumferential strain stimulation at the common carotid artery under different physiological, pathological and mechanical intervention conditions, and conduct real-time monitoring of the biological response of cell mechanics.
  • the invention can successfully realize the real-time monitoring of the dynamic behavior of the calcium ion response in the cultured arterial endothelial cells.

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Abstract

Est divulgué un système de circulation extracorporelle de niveau de puce microfluidique de mécanique des cellules endothéliales vasculaires et de recherche biologique, ledit système se rapportant au domaine technique de la mécanique cellulaire et des dispositifs d'expérience biologique. Le système comprend trois parties : 1) une puce microfluidique, composée d'une cavité de culture de cellules à structure "en sandwich" et d'une boucle de mécanique de fluide à éléments multiples permettant de simuler des caractéristiques hémodynamiques; 2) un dispositif de chargement de fluide (i), qui est combiné à un système de commande de rétroaction (iii), des signaux hémodynamiques tels que la pression artérielle, la contrainte de cisaillement de paroi et la force de tension circonférentielle portés par différents endothéliums vasculaires cibles pouvant être produits dans la cavité de culture cellulaire; 3) un système d'acquisition et de traitement de signaux (ii), pouvant être utilisé pour observer une mécanique cellulaire et une réponse biologique en temps réel et fournir des données de détection en retour au système de commande (iii) de façon à régler également le dispositif de chargement de fluide (i). Le système simule avec précision un microenvironnement réel hémodynamique extracellulaire endothélial vasculaire de l'artère cible, et fournit une plateforme expérimentale miniaturisée, objective, standardisée et quantifiée permettant de rechercher une relation quantitative entre des signaux hémodynamiques et une mécanique des cellules endothéliales vasculaires et un mécanisme biologique.
PCT/CN2021/077159 2020-03-24 2021-02-22 Système de circulation extracorporelle de niveau de puce microfluidique de mécanique des cellules endothéliales vasculaires et de recherche biologique WO2021190215A1 (fr)

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