CN103257213B - A kind of fully integrated high-flux cell horizontal micro-fluidic chip drug evaluation system - Google Patents
A kind of fully integrated high-flux cell horizontal micro-fluidic chip drug evaluation system Download PDFInfo
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- CN103257213B CN103257213B CN201210038546.7A CN201210038546A CN103257213B CN 103257213 B CN103257213 B CN 103257213B CN 201210038546 A CN201210038546 A CN 201210038546A CN 103257213 B CN103257213 B CN 103257213B
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Abstract
A kind of fully integrated high-flux cell horizontal micro-fluidic chip drug evaluation system, this system take micro-fluidic chip as core technology, start with from integrated, high flux, the overall design of robotization micro-fluidic chip system, one of structure integrates the multi-functional cellular level drug evaluation system of cell function chip module, stream control module, cell chulture microenvironment module and cellular response real time monitoring signals module.This system has fully integrated, and flux is high, and sample consumption is few, totally-enclosed operation, can carry out the features such as multi-parameters real-time monitoring, have very strong original creativity, is significant for large-scale medicine research and development.
Description
Technical field
The invention belongs to cellular level drug evaluation technical field, specifically provide a kind of fully integrated high-flux cell horizontal micro-fluidic chip drug evaluation system.
Background technology
Evaluating drug effect and Study on mechanism are the important steps of New drug discovery, namely by determining its therapeutic action and general pharmacological action, for Clinical Trials provides reliable basis to the observation of the compound candidate mechanism of action and research.Conventional medicament evaluation method is because of animal and animal, and the limitation of the attribute difference between animals and human beings body and assessment technique means and cause the poor efficiency in new drug development and high cost, this is one of bottleneck becoming medicament research and development.Existing multi-medicament evaluation model at present, because cellular level evaluation is closer to physiological condition, accuracy rate is high, and disturbing factor is few, is the main models of carrying out drug evaluation.At present, the Major Technology that cellular level drug evaluation adopts is array microwell plate, microwell plate carries out cell chulture, applies medicine irritation, and be aided with automation equipment and high resolving power fluorescence digital image system and carry out experimental implementation and data acquisition, analysis.Cellular level drug evaluation based on this form remains in many technical matterss, as plate size is fixed, only can operate in a static mode, the automatic control of convection cell cannot be realized, simultaneously automatic operation equipment supporting with it and detection system pattern single, the feature cannot tested for various cell function carries out flexible transformation, is more difficult to realize the Real-Time Monitoring of cell to outside stimuli responsive process.Therefore, the end results of cellular response information can only be obtained in principle, and be difficult to obtain cell to the Real-time dynamics response message of drug response and other biological information.What is more important, apparatus used at present mostly depends on import, although its automaticity makes moderate progress, reagent consumption is comparatively large, equipment volume is huge, and expensive, defines external businessman and enterprise to the monopolization situation of this market segment.Therefore, constantly occur at new drug target, the new drug kinds such as biotech drug constantly increase, new drug development field competition under the new situation, foundation and development have independent intellectual property right, have integrated, high flux, in real time detection, robotization feature the horizontal drug evaluation systems face of novel cell very exigence, this field problem demanding prompt solution such as Ye Shi China new drug development and medical judgement.
Microfluidic system, refer to integrated for the basic operation unit such as sample preparation, reaction, separation, detection involved in the fields such as biological and chemical or be substantially integrated on the chip of a piece several square centimeters (even less), network is formed by microchannel, whole system is run through, in order to replace a kind of technology of the various functions of standard biologic or chemical laboratory with controlled fluid.Its essential characteristic and sharpest edges are that the flexible combination of multiple monotechnics on small platform and scale are integrated.Specific to micro-fluidic chip, micro-dimension feature and cell size match, and chip designs and scale integration characteristic flexibly in addition, are applicable to very much carrying out cell function research.Particularly, due to the multidimensional network Characteristic and function integration characteristic of micro-fluidic chip, conventional evaluating drug effect and Study on mechanism process integration has likely been made to complete on the chip of a piece very little.With cell be object micro-fluidic chip research developed in recent years very fast, show as on the one hand and variously on chip manipulate relevant monotechnics such as Micropump, micro-valve, light tweezer, electrophoresis etc. to cell and reach its maturity, on the other hand then be embodied in the core technologies relevant to cell research such as cell chulture, cell sorting, lysis substantially to have grasped, completely likely make the cell chulture of routine, cell is excited, the process integration such as cell marking and detection completes on the chip of a piece very little.The scale of various monotechnics is integrated makes dozens or even hundreds of group to test parallel carrying out, to obtain large number of biological information.
So far, international pharmaceutical industry has recognized the great potential that microflow control technique contains, and microflow control technique can occupy very important status undoubtedly in future drugs discovery field to have people in the industry to foretell.Existing researcher attempts being combined with patch clamp technique by micro-fluidic chip, for taking ion channel as the drug research of action target spot.Also there is researcher to concentrate on the research in chip stream controlling party face, and attempt solving actual biological question.But generally speaking, micro-fluidic chip system is used for evaluating drug effect and Study on mechanism and is still in the starting stage, also really do not launch the work of the aspects such as the selection of chip platform, Design and optimization and practical application, detected object is relatively scattered and single.Particularly the multi-functional integrated micro-flow control drug evaluation systematic study such as fluid control module, cell chulture microenvironment module is comprised for development and there is not yet report, also there are no related application.
Based on above-mentioned present situation, inventor take micro-fluidic chip as core technology, build an Integrated automation cellular level drug evaluation system integrating cell function chip module, stream control module, cell chulture microenvironment module and cellular response real time monitoring signals module to have important practical significance, this, for towards great actual demand, solves with medical Disciplinary Frontiers closely-related critical bottleneck problem significant.Compared with prior art, microenvironment in the body that this system can not only provide closer to physiological condition for Growth of Cells, and can be integrated by different operating unit flexible combination, scale, computer programming auxiliary under realize full automatic working, shorten evaluation time, reduce the actual consumption of cell.In addition, by changing functionalization micro-flow control chip module, this system also can realize multiparameter, high-throughput drug evaluation, and the real-time tracing analysis to cellular response signal, and the various real-time cell response messages that its expection may be collected are that prior art and instrument cannot obtain.
Summary of the invention
The object of this invention is to provide a kind of fully integrated high-flux cell horizontal micro-fluidic chip drug evaluation system, this system has fully integrated, and flux is high, and sample consumption is few, totally-enclosed operation, can carry out the features such as multi-parameters real-time monitoring.
The invention provides a kind of fully integrated high-flux cell horizontal micro-fluidic chip drug evaluation system, this system is made up of drug evaluation function chip module, drug evaluation fluid control module, cell chulture micro environment control module, cell fluorescence response signal Real-Time Monitoring module four modules.
Fully integrated high-flux cell provided by the invention horizontal micro-fluidic chip drug evaluation system, described drug evaluation function chip module is a kind of micro-fluidic chip based on PDMS polymeric material and soft etching technique, be made up of 1 ~ 10 (preferably 4) identical structural unit, each structural unit can detect the effect of 1 ~ 10 kind of (preferably 3 kinds) medicine, controlled by accurate pump valve, the combination of multi-medicament concentration gradient or different pharmaceutical can be formed.
Fully integrated high-flux cell provided by the invention horizontal micro-fluidic chip drug evaluation system, described drug evaluation fluid control module is the fluid control systems of micro-fluidic chip, be made up of the micro-valve/Micropump on array micro syringe pump and chip, computer programming auxiliary under realize Automatic Control, its function be realize the liquid such as nutrient culture media, medicine on chip interpolation, transport and control with the stream such as concentration adjustment.
Fully integrated high-flux cell provided by the invention horizontal micro-fluidic chip drug evaluation system, described cell chulture micro environment control module by the cell culture chamber of microscope stage can be fixed on, gas control system, temperature humidity control system form, chip is placed in this culturing room, maintains cell culture temperature, humidity and CO stable in it by a series of sensor and control module
2gas concentration, makes continuous print cell cultivate online and is achieved with cell signal Real-Time Monitoring.
Fully integrated high-flux cell provided by the invention horizontal micro-fluidic chip drug evaluation system, described cell fluorescence response signal Real-Time Monitoring module adopts the confocal fluorescent detection technique of automatically controlled scanning to realize, and this module mainly comprises automatically controlled fluorescence imaging platform, ccd signal acquisition system, data handling system three part.
Tool of the present invention has the following advantages:
1. can realize the real-time tracing analysis to cellular response signal.
2. cell and reagent consumption few, multiparameter, high-throughput drug evaluation can be realized.
3. can computer programming auxiliary under realize full-automatic, totally-enclosed operation, shorten evaluation time, reduce cell contamination probability.
Accompanying drawing explanation
The composition of Fig. 1 fully integrated high flux micro-fluidic chip drug evaluation system;
Fig. 2 drug evaluation function chip design schematic diagram, wherein, a chip schematic diagram, b partial enlarged drawing;
Fig. 3 cell chulture microenvironment module diagram, wherein, a module diagram, the micro-objective table schematic diagram of b cell chulture;
Fig. 4 fully integrated high flux micro-fluidic chip drug evaluation system schematic.
Embodiment
Following examples will be further described the present invention, but not thereby limiting the invention.
Embodiment
According to building fully integrated high flux micro-fluidic chip drug evaluation system shown in Fig. 1, this system is made up of four modules.First, according to making drug evaluation functional chip shown in Fig. 2, chip divides fluid path layer, PDMS thin layer, gas circuit layer and glass from top to bottom.Three first layers is PDMS material, and between each layer, using plasma carries out sealing-in, by micro-valve on specific design forming chip.Secondly, the fluid control module be made up of the micro-valve on array micro syringe pump and chip is built.Build cell chulture microenvironment module.This module by the cell culture chamber of microscope stage can be fixed on, gas control system, temperature humidity control system form (as shown in Figure 3).Build cellular response real time monitoring signals module, mainly comprise automatically controlled fluorescence imaging platform, ccd signal acquisition system, data handling system three part.Finally, four modules are integrated into a complete system (as shown in Figure 4) by coupling arrangement
Maintain the temperature of cell chulture indoor at 37 DEG C, CO
2level is 5%, keeps higher relative saturation humidity (95%).Put into cell chulture indoor by after the chip ultraviolet irradiation sterilizing made, cell culture chamber is fixed within cellular response real time monitoring signals module.Hepatocellular carcinoma H22 cell suspension (about 10 is injected from the cell inoculation path of chip center by syringe pump
7/ ml), spend the night.Inject support platinum glycosides by syringe pump by medicine 1 entrance, medicine 2 entrance injects carboplatin, and medicine 3 entrance injects mitomycin, by regulating the On/Off of each micro-valve on chip, obtains variable concentrations and the different pharmaceutical combination of three kinds of medicines.After 24 hours, inject 4 μ g/mlHoechst33342 and 2 μ g/mlRh123 by syringe pump from the cell inoculation path of chip center, after 20 minutes, inject PBS damping fluid and clean, reinject 2 μ g/mlPI, adopts cellular response real time monitoring signals module to carry out detecting and taking pictures.
Claims (1)
1. a fully integrated high-flux cell horizontal micro-fluidic chip drug evaluation system, is characterized in that: this system is made up of drug evaluation function chip module, drug evaluation fluid control module, cell chulture micro environment control module, cell fluorescence response signal Real-Time Monitoring module four modules;
Described drug evaluation function chip module is made up of 1 ~ 10 identical structural unit, and each structural unit can detect the effect of 1 ~ 10 kind of medicine, is controlled by accurate pump valve, can form the combination of multi-medicament concentration gradient or different pharmaceutical;
Described drug evaluation fluid control module is the fluid control systems of micro-fluidic chip, is made up of the micro-valve/Micropump on array micro syringe pump and chip;
Described cell chulture micro environment control module by the cell culture chamber of microscope stage can be fixed on, gas control system, temperature humidity control system form, chip is placed in this culturing room, maintains cell culture temperature, humidity and CO stable in it by a series of sensor and control module
2gas concentration, makes continuous print cell cultivate online and is achieved with cell signal Real-Time Monitoring;
Described cell fluorescence response signal Real-Time Monitoring module adopts the confocal fluorescent detection technique of automatically controlled scanning to realize, and this module mainly comprises automatically controlled fluorescence imaging platform, ccd signal acquisition system, data handling system three part.
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| CN114438161A (en) * | 2022-01-30 | 2022-05-06 | 华中科技大学同济医学院附属协和医院 | Method and system for monitoring influence of drugs on biological sample and radioactive probe |
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