CN118002224B - Automatic drug screening platform adopting multi-microfluidic concentration gradient chip - Google Patents
Automatic drug screening platform adopting multi-microfluidic concentration gradient chip Download PDFInfo
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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
- G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F33/00—Other mixers; Mixing plants; Combinations of mixers
- B01F33/30—Micromixers
- B01F33/301—Micromixers using specific means for arranging the streams to be mixed, e.g. channel geometries or dispositions
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
- B01F35/71—Feed mechanisms
- B01F35/712—Feed mechanisms for feeding fluids
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
- B01F35/71—Feed mechanisms
- B01F35/717—Feed mechanisms characterised by the means for feeding the components to the mixer
- B01F35/7176—Feed mechanisms characterised by the means for feeding the components to the mixer using pumps
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- 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
- B01L3/50273—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 characterised by the means or forces applied to move the fluids
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F2101/00—Mixing characterised by the nature of the mixed materials or by the application field
- B01F2101/23—Mixing of laboratory samples e.g. in preparation of analysing or testing properties of materials
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
- B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/04—Moving fluids with specific forces or mechanical means
- B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
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Abstract
The invention provides an automatic drug screening platform adopting a multi-microfluidic concentration gradient chip, wherein a main channel outlet and an auxiliary channel outlet are respectively communicated with two inlet ends of the concentration gradient chip, a special serpentine arrangement pipe body of a mixing pipe body in the concentration gradient chip and a macroscopic elliptic contour at the outer edge of the mixing pipe body form a cavity effect of local interception and macroscopic capacity increase, the serpentine arrangement pipe body and a V-shaped retrace contour can disturb liquid laminar flow into torsion flow, and then the liquid laminar flow can start stretching from the middle part of the elliptic cavity through the volume amplification effect of the macroscopic elliptic contour of the mixing pipe body, so that laminar flow disturbance is more obvious, the liquid mixing performance is improved, the mixing efficiency of the concentration gradient chip is effectively improved, the mixing pipe body is easy to manufacture and popularize, and the automatic drug screening technology is promoted to realize the application effects of low cost, multiple varieties and large concentration gradient range.
Description
Technical Field
The invention belongs to the technical field of drug screening, and particularly relates to an automatic drug screening platform adopting a multi-microfluidic concentration gradient chip.
Background
The combined drug is the synergistic application of more than two drugs, thereby achieving the effects of increasing the drug effect and relieving the adverse reaction, and the combined drug has been proved to be more effective than single drug in various clinical, inspection or drug experiment processes, and is a treatment way for preventing and treating difficult and complicated diseases at the present stage.
Because the mechanism of pharmacodynamics interaction is complex, in order to optimize the drug effect and avoid side effects, the formula scheme of the combined drug needs to be subjected to a large number of screening test operations, for example, the screening of tumor drug-resistant combined drugs, the initial screening of cell model drug compounds in the drug development process, the selection of antibiotic combination schemes, the screening of the minimum inhibitory concentration of serious infection or drug-resistant bacteria and the like are applied, the screening variety is various, the influence of dose difference is large, and the traditional laboratory drug screening method only carries out inductive screening through porous plates and related devices, so that the manpower cost, flux and period required by the screening mode are high. In the prior art, although the microfluidic drug screening technology is realized by an integrated microminiaturization mode, the existing concentration gradient chip only needs to ensure full mixing by means of a long mixing channel according to the design principle of the existing microminiaturization concentration gradient chip, and most laminar flows in the existing concentration gradient chip are not completely mixed, so that if the existing concentration gradient chip only depends on the diffusion mixing mode, the length of the long mixing channel and the mixing time are required, the complexity of the whole concentration gradient system is determined by the length of the existing micromixing channel, the time for forming gradients is long, the mixing efficiency of the existing concentration gradient chip is low, the formation of drug concentration gradients is slow, and the manufacturing popularization difficulty is high.
The patent publication No. CN112473758A discloses an equivalent circuit microfluidic concentration gradient chip with a simplified channel, which is characterized in that ellipses protruding outwards are distributed at two sides of a mixing channel in a staggered manner to form a micro-mixing channel, a plurality of circular arcs protruding outwards are added at two sides of a tube body channel in a staggered manner, the rapid reduction of speed and the change of direction in the circular arcs can be utilized to achieve the effect of disturbing laminar flow liquid by secondary flow, however, the staggered array manner requires to process a plurality of staggered and parallel micro-ellipse outlines along two sides of the micro tube body channel, the processing manner is difficult to implement in practical application, the staggered array structure of the processing manner leads to large processing errors and long consumption period, and the problem that the concentration gradient chip is difficult to manufacture and popularize still can not be solved.
Therefore, for the reasons, the existing automatic drug screening technology still has the defects of high manufacturing cost, less drug combination, small concentration gradient range and the like, and a new technical scheme is needed to be improved.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides an automatic drug screening platform adopting a multi-microfluidic concentration gradient chip, which effectively improves the mixing efficiency of the concentration gradient chip, is easy to manufacture and popularize, and promotes the automatic drug screening technology to realize the application effects of low cost, multiple drug combination types and large concentration gradient range.
The invention is implemented by the following technical scheme: an automatic drug screening platform adopting a multi-microfluidic concentration gradient chip comprises a main channel component, wherein an auxiliary channel component is arranged beside the main channel component, the main channel component and the auxiliary channel component are infusion tube functional pieces, the main channel component is provided with a main channel inlet and a main channel outlet, and the auxiliary channel component is provided with an auxiliary channel inlet and an auxiliary channel outlet; the main channel inlet is used for inputting a pharmaceutical agent, and the auxiliary channel inlet is used for inputting an auxiliary functional agent or a diluent of the pharmaceutical agent;
the main channel outlet and the auxiliary channel outlet are respectively communicated with two inlet ends of a concentration gradient chip, and the concentration gradient chip has the function of classifying the concentration of the drug reagent;
each concentration gradient chip is provided with a plurality of outlet ends, and each outlet end of each concentration gradient chip is communicated with an inner cavity of a collecting pipe through a conduit;
one inlet end of the concentration gradient chip is communicated with a primary outlet end of the concentration gradient chip through a primary pipeline;
the middle section of the pipe body of the primary pipeline is communicated with a parallel secondary pipeline through a branch pipeline, the middle section of the secondary pipeline is connected in series with a mixed pipe body, and the tail end of the secondary pipeline is the secondary outlet end of the concentration gradient chip;
The pipeline body positioned at the rear section of the mixed pipeline body in the secondary pipeline is communicated with a parallel tertiary pipeline through a branch pipeline, the middle section of the tertiary pipeline is connected in series with a mixed pipeline body, and the tail end of the tertiary pipeline is a tertiary outlet end of the concentration gradient chip;
The pipeline body positioned at the rear section of the mixed pipeline body in the three-stage pipeline is communicated with a four-stage pipeline in parallel through a branch pipeline, the middle section of the four-stage pipeline is connected with a mixed pipeline body in series, and the tail end of the four-stage pipeline is a four-stage outlet end of the concentration gradient chip;
The multi-stage pipelines are formed by arranging the first-stage pipelines to the fourth-stage pipelines in the same way, and the pipeline stages in the multi-stage pipelines are at least four stages;
the other inlet end of the concentration gradient chip is respectively communicated with branch pipelines of each stage of pipelines in the multi-stage pipeline through a plurality of delay pipelines which are arranged in parallel;
the delay tube body forms a delay control function of liquid circulation time through the extension arrangement of the tortuous tube body;
The mixing pipe body is a snake-shaped arrangement pipe body, a macroscopic contour formed by the outer edges of each bending end on the same side in the snake-shaped arrangement pipe body is an arc contour with a raised middle part, the arc contour is respectively arranged on two sides of the snake-shaped arrangement pipe body, the arc contours on the two sides of the snake-shaped arrangement pipe body form an elliptical contour together, and the long axis of the elliptical contour is the same as the conveying direction of the terminal of the mixing pipe body;
The curved inner wall of each tube turn-back portion of the serpentine tube exhibits a V-shaped profile.
Further, the main channel inlet is connected with the electromagnetic valve assembly to form a plurality of main channel outlets, the auxiliary channel inlet is connected with the electromagnetic valve assembly to form a plurality of auxiliary channel outlets, the concentration gradient chip is provided with a plurality of concentration gradient chips, and each concentration gradient chip is at least communicated with one main channel outlet and one auxiliary channel outlet.
Further, at least three concentration gradient chips are arranged, and concentration grading orders of the three concentration gradient chips are respectively an accumulation order, a multiple order and an exponential order.
Furthermore, each branch pipeline is internally and serially provided with a delay pipeline body.
Furthermore, each stage of pipeline in the multistage pipeline is serially connected with a delay pipeline body.
The beneficial effects of the invention are as follows:
1. According to the invention, the concentration gradient chip is arranged in the screening platform, and the serpentine arrangement pipe body and the macroscopic oval outline of the outer edge of the serpentine arrangement pipe body are arranged in the concentration gradient chip, so that the serpentine arrangement pipe body is equivalent to an interception baffle plate, the liquid laminar flow can be disturbed into a twisted flow, the V-shaped retractive outline inhibits the smoothness of the liquid passing through the bent inner cavity, and then the volume amplification effect of the macroscopic oval outline of the mixing pipe body enables the liquid laminar flow to start stretching from the middle part of the oval cavity, so that the laminar flow disturbance is more obvious, the liquid mixing performance is greatly improved, the mixing pipe body can realize a sufficient liquid mixing effect only by a short mixing channel, the mixing efficiency of the concentration gradient chip is effectively improved, the time and the reliability of gradient formation are accelerated, the manufacturing and popularization are easy, and the automatic drug screening technology is promoted to realize the application effects of low cost, multiple drug combination types and large concentration gradient range.
2. The macroscopic contour formed by the outer edges of each bending end on the same side in the pipe body is an arc contour with a raised middle part, and the arc contours on two sides are utilized to form a macroscopic oval contour, so that macroscopic integral ellipses which are different from the 'staggered distribution' ellipses in the prior patent CN112473758A are formed, the macroscopic capacity-increasing cavity effect formed by the macroscopic integral ellipses is better than the prior patent CN112473758A in terms of volume change degree and laminar disturbance mixing efficiency, and the macroscopic integral ellipses are favorable for unified processing on the two sides of the whole contour of the pipe body during manufacturing, so that the macroscopic arc contour formed by the bending end epitaxy together can be quickly obtained, higher processing precision is obtained, better mixing efficiency is obtained on the basis of precision guarantee, processing difficulty and period are effectively reduced (processing difficulty caused by a plurality of staggered and parallel minitype ellipses in the prior patent CN112473758A is avoided), and the manufacturing of concentration gradient chips is further favorable.
Drawings
FIG. 1 is a schematic diagram of an overall system architecture according to an embodiment of the present invention;
FIG. 2 is a schematic diagram of a pre-formulation system according to an embodiment of the present invention;
FIG. 3 is a schematic diagram of a system architecture of a concentration gradient chip according to an embodiment of the invention;
FIG. 4 is a schematic diagram of an equivalent circuit of a concentration gradient chip according to an embodiment of the invention;
FIG. 5 is a schematic view of a mixing tube according to an embodiment of the present invention;
FIG. 6 is a CAE analysis versus cloud for a hybrid tube in accordance with one embodiment of the present invention;
In the figure: 10 a-four-channel injection pump, 10 b-two-channel injection pump, 10 c-pre-assembly, 11-main channel assembly, 12-auxiliary channel assembly, 20-solenoid valve assembly, 30-concentration gradient chip, 31-serpentine arrangement tube, 32-oval profile, 33-V profile;
A C1-agent inlet port, a C0-diluent inlet port;
Q1-a first outlet end, Q2-a second outlet end, Q3-a third outlet end, Q4-a fourth outlet end and Q5-a fifth outlet end;
M1-a first mixing pipe body, M2-a second mixing pipe body, M3-a third mixing pipe body and M4-a fourth mixing pipe body;
R1-first time delay pipe body, R2-second time delay pipe body, R3-third time delay pipe body, R4-fourth time delay pipe body, R5-fifth time delay pipe body, R6-sixth time delay pipe body, R7-seventh time delay pipe body, R8-eighth time delay pipe body, R9-ninth time delay pipe body, R10-tenth time delay pipe body, R11-eleventh time delay pipe body and R12-twelfth time delay pipe body.
Detailed Description
The invention is described in further detail below with reference to the drawings and examples of the specification.
As shown in fig. 1-2, an automatic drug screening platform using a multi-microfluidic concentration gradient chip, wherein a four-channel syringe pump 10a loaded with four drugs and a two-channel syringe pump 10b loaded with one drug and a dilution component are connected to a six-input two-output front-end assembly 10c (to ensure diversity of tested drug types) through a PEP teflon hard tube, one output end of the front-end assembly 10c inputs a formulated anticancer drug reagent to a main channel assembly 11, the other output end inputs a formulated diluent to an auxiliary channel assembly 12, the two assemblies are connected to the input end of a T-type electromagnetic isolation valve through a peristaltic pump silicone tube, and by selecting different options on an LED display screen, the sample and the diluent are respectively introduced into the input ends of three cross-concentration gradient dilution chips under the action of a circuit board controlled by the chip and 4T-type electromagnetic isolation valves, and finally, the diluted product is output to a cell culture porous plate loaded with cells through the PEP teflon hard tube for performing a drug screening experiment.
Specifically, as shown in fig. 1-5, an automatic drug screening platform using a multi-microfluidic concentration gradient chip is disclosed, wherein a mixer includes a main channel component 11, an auxiliary channel component 12 is provided beside the main channel component 11, the main channel component 11 and the auxiliary channel component 12 are both infusion tube functional components, the main channel component 11 is provided with a main channel inlet and a main channel outlet, and the auxiliary channel component 12 is provided with an auxiliary channel inlet and an auxiliary channel outlet; the main channel inlet is used for inputting a pharmaceutical agent, the auxiliary channel inlet is used for inputting an auxiliary functional agent or a diluent of the pharmaceutical agent, in the embodiment, the pharmaceutical agent input by the main channel inlet is an anticancer agent, and the diluent input by the auxiliary channel inlet is a solvent for the anticancer agent, so that research and test are carried out for the anticancer agent concentration experiment;
the main channel outlet and the auxiliary channel outlet are respectively communicated with two inlet ends of the concentration gradient chip 30, specifically, the main channel outlet is communicated with a medicament inlet end C1 of the concentration gradient chip 30 so as to input anticancer medicament components into the chip, and the auxiliary channel outlet is communicated with a diluent inlet end C0 of the concentration gradient chip 30 so as to input solvents into the chip;
the concentration gradient chip 30 has a function of performing concentration classification for the pharmaceutical agent, thereby ensuring that the concentration gradient chip 30 can obtain input supply of the anticancer agent and the diluent;
each concentration gradient chip 30 is provided with a plurality of outlet ends, and each outlet end of each concentration gradient chip 30 is respectively communicated with an inner cavity of a collecting pipe through a conduit, so that various combined medicines are provided by utilizing the concentration grading function of the concentration gradient chip 30;
the reagent inlet end C1 of the concentration gradient chip 30 is communicated with the first-stage first outlet end Q1 of the concentration gradient chip through a first-stage pipeline, so that a pure reagent sample is output at the first outlet end Q1;
The middle section of the pipe body of the first-stage pipeline is communicated with a parallel-connected second-stage pipeline through a branch pipeline, so that the medicine quantity of the first-stage pipeline is split through the branch pipeline; the middle section of the diode is connected in series with a first mixing pipe M1, and the tail end of the diode is a second outlet end Q2 of the concentration gradient chip 30; the medicine split by the first-stage pipeline is sent into the second-stage pipeline through the branch pipeline and then is mixed with the diluting solvent provided by the diluent inlet end C0, and the medicine and the diluent are uniformly mixed through the first mixing pipe body M1, so that a medicine solution sample with the concentration decreasing stepwise is obtained at the second outlet end Q2;
the tube body positioned at the rear section of the mixed tube body in the secondary tube is communicated with a third-stage pipeline connected in parallel through a branch pipeline, so that the medicine quantity of the secondary tube is split through the branch pipeline; the middle section of the three-stage pipeline is connected in series with a second mixing pipe body M2, and the tail end of the three-stage pipeline is a three-stage third outlet end Q3 of the concentration gradient chip 30; the medicine split by the secondary pipeline is sent into the tertiary pipeline through the branch pipeline and then is mixed with the diluting solvent provided by the diluent inlet end C0, and the two (medicine and diluent) are uniformly mixed through the second mixing pipe body M2, so that a medicine solution sample with the concentration decreasing stepwise is obtained at the third outlet end Q3;
The tube body positioned at the rear section of the mixed tube body in the three-stage pipeline is communicated with a four-stage pipeline connected in parallel through a branch pipeline, so that the medicine quantity of the three-stage pipeline is split through the branch pipeline; the middle section of the fourth-stage pipeline is connected in series with a third mixing pipe body M3, and the tail end of the fourth-stage pipeline is a fourth outlet end Q4 of the concentration gradient chip 30; the medicine split by the three-stage pipeline is sent into the four-stage pipeline through the branch pipeline, then is mixed with the diluting solvent provided by the diluent inlet end C0, and the medicine and the diluent are uniformly mixed through the third mixing pipe body M3, so that a medicine solution sample with the concentration decreasing stepwise is obtained at the fourth outlet end Q4;
the tube body positioned at the rear section of the mixed tube body in the four-stage pipeline is communicated with a five-stage pipeline connected in parallel through a branch pipeline, so that the medicine quantity of the four-stage pipeline is split through the branch pipeline; the middle section of the five-stage pipeline is connected in series with a fourth mixing pipe body M4, and the tail end of the five-stage pipeline is a five-stage fifth outlet end Q5 of the concentration gradient chip 30; the medicine split by the four-stage pipeline is sent into the five-stage pipeline through the branch pipeline, then is mixed with the diluting solvent provided by the diluent inlet end C0, and the medicine and the diluent are uniformly mixed through the fourth mixing pipe body M4, so that a medicine solution sample with the concentration decreasing stepwise is obtained at the fifth outlet end Q5;
the diluent inlet end C0 of the concentration gradient chip 30 is respectively communicated with branch pipelines of each stage of pipelines in the multistage pipeline through a plurality of delay pipelines which are arranged in parallel; the fifth delay tube body R5 is communicated with the branch pipeline of the first-stage pipeline, so that the diluent is provided for the second-stage pipeline at a proper time, and the sixth delay tube body R6, the seventh delay tube body R7 and the eighth delay tube body R8 are respectively provided with the diluent at a proper time for the third-stage pipeline, the fourth-stage pipeline and the fifth-stage pipeline, and the medicine and the diluent input by each mixing tube body can enter at the same time point through the fluid delay function of each delay tube body, so that the mixing concentration of the medicine and the diluent in each mixing tube body is not interfered by time difference, and the accuracy of the output medicine concentration of each stage of pipeline is ensured.
The delay tube body forms a delay control function of liquid circulation time through the extension arrangement of the tortuous tube body, so that the fluid delay effect of each delay tube body is finished under reasonable processing conditions, the length and the fluid delay time length of the tortuous tube body are easy to accurately adjust, and the drugs and diluents input by each mixing tube body are further promoted to enter at the same time point.
The mixing pipe body is a snake-shaped arrangement pipe body 31, the macroscopic contour formed by the outer edges of each bending end on the same side in the snake-shaped arrangement pipe body 31 is an arc contour with a raised middle part, the arc contour is respectively arranged on two sides of the snake-shaped arrangement pipe body, the arc contours on the two sides of the snake-shaped arrangement pipe body jointly form an elliptical contour 32, and the long axis of the elliptical contour 32 is the same as the terminal conveying direction of the mixing pipe body. The serpentine arrangement tube body 31 and the macroscopic elliptical profile 32 at the outer edge of the serpentine arrangement tube body are arranged in the concentration gradient chip 30, so that a local interception and macroscopic capacity-increasing cavity effect is formed, the serpentine arrangement tube body 31 is equivalent to an interception baffle plate, liquid laminar flow can be disturbed into a twisted flow, and then the liquid laminar flow can be stretched from the middle part of the elliptical cavity through the volume amplification effect of the macroscopic elliptical profile 32 of the mixing tube body, so that laminar flow disturbance is more obvious, the liquid mixing performance is greatly improved, the mixing tube body can realize a full liquid mixing effect only by a short mixing channel, and the mixing efficiency of the concentration gradient chip 30 is effectively improved.
In this embodiment, the curved inner wall of each of the folded portions of the serpentine arranged tube body 31 presents a V-shaped profile 33, thereby suppressing the smoothness of the liquid passing through the curved inner cavity, and the V-shaped profile 33 of the folded portion of the tube body makes the liquid unable to smoothly transit, and each layer of medium of the liquid can generate a twisting flow, thereby promoting the liquid laminar flow to generate liquid phase medium exchange, and further promoting the liquid mixing effect of the mixing channel.
Meanwhile, the mixing performance advantage of the mixing pipe body in the embodiment can be verified through a comsol finite element analysis report shown in fig. 6, and the mixing pipe body is mixed by a finite element method to be a reference model (such as a common serpentine micromixer of the upper model in fig. 6), and the mixing pipe body is in a conventional tortuous path structure; the hybrid pipe body modification model (e.g., the lower model modification mixer of fig. 6) is then built by the finite element method, and its morphology is modeled with reference to the macroscopic elliptical profile 32 of the present embodiment. Then, two liquid phases are respectively led into inlets of the reference model and the improved model through finite element software comsol to calculate the internal liquid phase mixing state of the two liquid phases, as shown in fig. 6, when the input liquid phases reach a fully mixed state (the liquid colors in the analysis cloud chart are mixed consistently), the whole length and the whole width required by the improved model are less than 1/3 of those of the reference model, namely: the improved model can achieve the same or even better effect of the reference model under the shorter and smaller size path, thus proving that: the special structural arrangement of the mixing tube body in this embodiment can effectively improve the mixing effect of the input liquid, and further improve the mixing efficiency of the concentration gradient chip 30.
In this embodiment, the main channel inlet is connected to the solenoid valve assembly 20 to form a plurality of main channel outlets, the auxiliary channel inlet is connected to the solenoid valve assembly 20 to form a plurality of auxiliary channel outlets, the concentration gradient chip 30 is provided with a plurality of auxiliary channel outlets, and each concentration gradient chip 30 is at least communicated with one main channel outlet and one auxiliary channel outlet, so that it is ensured that the input anticancer agent and the diluent can be split into a plurality of input sources by the solenoid valve and enter different concentration gradient chips 30 to complete multistage separation.
In this embodiment, three concentration gradient chips 30 are provided, and concentration grading orders of the three concentration gradient chips 30 are respectively an accumulation order, a multiple order and an exponential order. The diversity of the concentration grading types of the anticancer drugs is further increased by three grading modes of accumulation grade, multiple grade and exponential grade, and the success rate of the anticancer drug experiments is improved. Meanwhile, different grading modes of the accumulation stage, the multiple stage and the exponential stage can be realized through the different degrees of the delay tube structures of all stages of pipelines in the concentration gradient chip 30 (the delay tube can ensure the storage capacity of the same group of input liquid phases).
In this embodiment, each branch pipeline is serially connected with a delay tube (as shown by a ninth delay tube R9 to a twelfth delay tube R12 in fig. 3), and on the basis of delay regulation and control of the fifth delay tube R5 to the eighth delay tube R8 branched and connected in parallel with the diluent inlet end C0, the added ninth delay tube R9 to twelfth delay tube R12 can further ensure that two liquids (anticancer drugs and diluent) entering each stage pipeline and the mixing tube can be input at the same time point, thereby improving the coincidence ratio of the input times of the two liquids and further improving the accuracy of outputting the concentration of each stage of drugs by the concentration gradient grading chip.
In this embodiment, each stage of pipeline in the multi-stage pipeline is serially connected with a delay tube (as shown in the first delay tube R1 to the fourth delay tube R4 in fig. 3), and by setting the delay function of the delay tube, output samples with different concentrations can be obtained from each output port at the same time point, so that the concentration screening and the unified planning operation of related medical experiments are facilitated.
Preferably, in the embodiment, the macroscopic contour formed by the outer edges of each zigzag end on the same side in the pipe body is an arc contour with a raised middle part in a serpentine arrangement mode, and then the arc contours on two sides are utilized to form a macroscopic oval contour, so that a macroscopic integral oval which is quite different from a 'staggered distribution' oval in the prior patent CN112473758A is formed, the macroscopic capacity-increasing cavity effect formed by the macroscopic integral oval in the embodiment has better volume change degree and laminar disturbance mixing efficiency than those of the prior patent CN112473758A, and the macroscopic integral oval in the embodiment is beneficial to uniformly processing on two sides of the integral contour of the pipe body during manufacturing, so that the macroscopic arc contour formed by extending together at each zigzag end can be quickly obtained, higher processing precision is obtained, better mixing efficiency is obtained on the basis of precision guarantee, processing difficulty and period are effectively reduced (processing difficulty caused by a plurality of staggered and parallel micro ellipses in the prior patent CN112473758A is avoided), and the manufacturing popularization of concentration gradient chips is further facilitated.
The working principle of this embodiment is as follows:
the method comprises the steps of respectively inputting anticancer drugs and diluents into the inlets of a main channel tube assembly and an auxiliary channel assembly 12 of a screening platform, splitting the anticancer drugs and the diluents through an electromagnetic valve assembly 20 shown in fig. 1, respectively inputting the split anticancer drugs and diluents into three concentration gradient chips 30 to respectively obtain a plurality of groups of concentration samples of accumulation level, multiple level and exponential level, and sending the concentration samples into each collecting tube through an output port to perform subsequent drug concentration experiments;
Due to the design of the mixing tube body in the concentration gradient chip 30, the serpentine arrangement tube body 31 and the macroscopic elliptical outline 32 at the outer edge of the serpentine arrangement tube body are arranged by virtue of the special serpentine arrangement tube body 31 of the mixing tube body in the concentration gradient chip 30, so that the serpentine arrangement tube body 31 is equivalent to an interception baffle plate, the liquid laminar flow can be disturbed into a twisted flow, and then the liquid laminar flow can be stretched from the middle part of the elliptical cavity by the volume amplification effect of the macroscopic elliptical outline 32 of the mixing tube body, so that the laminar flow disturbance is more obvious, the liquid mixing performance is greatly improved, and the mixing tube body can realize a sufficient liquid mixing effect by only needing a shorter mixing channel, so that the concentration gradient chip 30 is easy to manufacture and popularize, and the mixing efficiency of the concentration gradient chip 30 can be effectively improved.
Through the principle, three types (accumulation level, multiple level and exponential level) or even more types of grading chips can be arranged in the embodiment or other embodiments, and the automatic drug screening technology can be promoted to realize the application effects of low cost, multiple drug combination types and large concentration gradient range.
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (5)
1. The utility model provides an adopt medicine autofilter platform of many micro-fluidic concentration gradient chips, includes main channel subassembly, its characterized in that: an auxiliary channel component is arranged beside the main channel component, the main channel component and the auxiliary channel component are both infusion tube functional pieces, the main channel component is provided with a main channel inlet and a main channel outlet, and the auxiliary channel component is provided with an auxiliary channel inlet and an auxiliary channel outlet; the main channel inlet is used for inputting a pharmaceutical agent, and the auxiliary channel inlet is used for inputting an auxiliary functional agent or a diluent of the pharmaceutical agent;
the main channel outlet and the auxiliary channel outlet are respectively communicated with two inlet ends of a concentration gradient chip, and the concentration gradient chip has the function of classifying the concentration of the drug reagent;
each concentration gradient chip is provided with a plurality of outlet ends, and each outlet end of each concentration gradient chip is communicated with an inner cavity of a collecting pipe through a conduit;
one inlet end of the concentration gradient chip is communicated with a primary outlet end of the concentration gradient chip through a primary pipeline;
the middle section of the pipe body of the primary pipeline is communicated with a parallel secondary pipeline through a branch pipeline, the middle section of the secondary pipeline is connected in series with a mixed pipe body, and the tail end of the secondary pipeline is the secondary outlet end of the concentration gradient chip;
The pipeline body positioned at the rear section of the mixed pipeline body in the secondary pipeline is communicated with a parallel tertiary pipeline through a branch pipeline, the middle section of the tertiary pipeline is connected in series with a mixed pipeline body, and the tail end of the tertiary pipeline is a tertiary outlet end of the concentration gradient chip;
The pipeline body positioned at the rear section of the mixed pipeline body in the three-stage pipeline is communicated with a four-stage pipeline in parallel through a branch pipeline, the middle section of the four-stage pipeline is connected with a mixed pipeline body in series, and the tail end of the four-stage pipeline is a four-stage outlet end of the concentration gradient chip;
The multi-stage pipelines are formed by arranging the first-stage pipelines to the fourth-stage pipelines in the same way, and the pipeline stages in the multi-stage pipelines are at least four stages;
the other inlet end of the concentration gradient chip is respectively communicated with branch pipelines of each stage of pipelines in the multi-stage pipeline through a plurality of delay pipelines which are arranged in parallel;
the delay tube body forms a delay control function of liquid circulation time through the extension arrangement of the tortuous tube body;
The mixing pipe body is a snake-shaped arrangement pipe body, a macroscopic contour formed by the outer edges of each bending end on the same side in the snake-shaped arrangement pipe body is an arc contour with a raised middle part, the arc contour is respectively arranged on two sides of the snake-shaped arrangement pipe body, the arc contours on the two sides of the snake-shaped arrangement pipe body form an elliptical contour together, and the long axis of the elliptical contour is the same as the conveying direction of the terminal of the mixing pipe body;
The curved inner wall of each tube turn-back portion of the serpentine tube exhibits a V-shaped profile.
2. The automated drug screening platform employing a multi-microfluidic concentration gradient chip according to claim 1, wherein: the main channel inlets are connected with the electromagnetic valve assembly to form a plurality of main channel outlets, the auxiliary channel inlets are connected with the electromagnetic valve assembly to form a plurality of auxiliary channel outlets, the concentration gradient chip is provided with a plurality of concentration gradient chips, and each concentration gradient chip is at least communicated with one main channel outlet and one auxiliary channel outlet.
3. The automated drug screening platform employing a multi-microfluidic concentration gradient chip according to claim 1, wherein: the concentration gradient chips are at least provided with three concentration gradient chips, and the concentration grading orders of the three concentration gradient chips are respectively an accumulation order, a multiple order and an exponential order.
4. The automated drug screening platform employing a multi-microfluidic concentration gradient chip according to claim 1, wherein: and each branch pipeline is internally and serially connected with a delay pipeline body.
5. The automated drug screening platform employing a multi-microfluidic concentration gradient chip according to claim 1, wherein: each stage of pipeline in the multistage pipeline is serially connected with a delay pipeline body.
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