CN215856107U - Micro-miniature parallel biological reaction device for controlling material feeding based on micro-fluidic liquid drops - Google Patents
Micro-miniature parallel biological reaction device for controlling material feeding based on micro-fluidic liquid drops Download PDFInfo
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- CN215856107U CN215856107U CN202121404771.9U CN202121404771U CN215856107U CN 215856107 U CN215856107 U CN 215856107U CN 202121404771 U CN202121404771 U CN 202121404771U CN 215856107 U CN215856107 U CN 215856107U
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Abstract
The utility model discloses a micro-miniature parallel biological reaction device for controlling material feeding based on microfluidic droplets, and belongs to the technical field of biological cell culture and biological catalysis. The device comprises a controller, a parallel micro-bioreactor component, a material storage bottle, a pressure pump and a micro-fluidic chip; the controller is connected to the parallel microminiature bioreactor assembly; the microminiature bioreactor component comprises a plurality of parallel tanks; the material storage bottle and the pressure pump are connected to the microfluidic chip through the microfluidic micro-pipeline and are connected to the plurality of parallel tanks through the multi-way pipe, and the branch pipelines of the multi-way pipe connected to the plurality of parallel tanks are respectively provided with an electromagnetic valve-flow control valve assembly; the parallel microminiature bioreactor component is also provided with an electrode for detecting pH, temperature and dissolved oxygen, and a bracket is arranged on the microminiature parallel bioreactor component and is used for fixing the multi-way pipe and the electromagnetic valve-flow control valve component arranged on the branch pipe; the micro-fluidic micro-pipeline is also provided with a pressure sensor.
Description
Technical Field
The utility model relates to a micro-miniature parallel bioreactor for controlling material feeding based on microfluidic droplets, belonging to the technical field of biological cell culture and biological catalysis.
Background
The bioreactor is a key driving force for promoting the industrial application of biological products. Cell factories that accumulate specific target products by techniques such as random mutagenesis and metabolic engineering often require further improvement of the efficiency of the bioconversion process through bioreactor design and process optimization. In recent years, with the rise of synthetic biotechnology and high-throughput screening technology, traditional laboratory-scale shake flasks and bioreactors have failed to meet the demand for rapid acquisition of superior strains from a large number of strain samples. The advent of highly automated and functionally flexible high throughput mini-bioreactors alleviated this problem to some extent. However, the current micro-miniature bioreactors are not precise in terms of parallelism and pH control, feed control, etc., and have limited application in the fermentative production of bioproducts, particularly microbial fermentation products.
In recent years, microfluidic droplet technology is widely applied to sample preparation, reaction, separation, detection and other works in biological, chemical, medical analysis and other processes. The micro-pipeline adopted by the micro-fluidic technology is usually very small in size and can reach the micron level or the millimeter level, the material feeding speed can be slowly controlled and can reach the pL/s-nL/s level, and the stability and the uniformity of the material feeding are higher. However, there is no apparatus or device that combines microfluidic technology with micro-miniature reactors to improve the repeatability of the bioreactor process and the accuracy of process control.
SUMMERY OF THE UTILITY MODEL
[ problem ] to
The utility model aims to solve the problems that: the volume of the micro bioreactor is reduced, the parallelism of the micro bioreactor is improved, and the accuracy of material feeding is improved.
[ solution ]
The utility model provides a micro-miniature parallel biological reaction device based on micro-fluidic droplet control, which has small volume, high precision of material feeding and good parallelism.
The technical scheme of the utility model is as follows:
the micro-miniature parallel bioreactor device for controlling material feeding based on micro-fluidic droplets comprises a controller, a parallel micro-miniature bioreactor component, a material storage bottle, a pressure pump and a micro-fluidic chip;
the controller is connected to the parallel microminiature bioreactor assembly and is used for controlling the microminiature bioreactor assembly; the microminiature bioreactor component comprises a plurality of parallel tanks; the material storage bottle and the pressure pump are connected to the microfluidic chip through a microfluidic micro-pipeline, the microfluidic chip is connected to a plurality of parallel tanks of the parallel microminiature bioreactor assembly through a multi-way pipe, and branch pipelines of the parallel tanks of the parallel microminiature bioreactor assembly connected to the multi-way pipe are respectively provided with an electromagnetic valve-flow control valve assembly;
the parallel micro bioreactor assembly is also provided with an electrode for detecting pH, temperature and Dissolved Oxygen (DO), and is provided with a bracket for fixing the multi-way pipe and the electromagnetic valve-flow control valve assembly arranged on the branch pipe; and a pressure sensor is arranged on the micro-fluidic micro-pipeline.
According to the device of the utility model, in one embodiment, the material storage bottle and the pressure pump are multiple and used for providing multiple materials, and the multiple material storage bottles and the pressure pump are connected to the microfluidic chip through the microfluidic micro-pipeline.
According to the device, in one embodiment, the microfluidic chip is used for mixing a plurality of materials provided in a plurality of material storage bottles, and the mixed materials are respectively conveyed to a plurality of parallel tanks of the parallel micro-miniature bioreactor assembly through a multi-way pipe.
According to the apparatus of the present invention, in one embodiment, the number of parallel tanks in the microminiature parallel bioreactor assembly is 2, 4, 8, 16 or 32, preferably 2 or 4.
According to the device of the utility model, in one embodiment, the number of the branched ducts of the multi-channel tube corresponds to the number of parallel tanks in the microminiature parallel bioreactor assembly.
According to the apparatus of the present invention, in one embodiment, the volume of the single parallel tank in the parallel micro-miniature bioreactor assembly is 15 mL-100 mL.
According to the apparatus of the present invention, in one embodiment, the volume of the single parallel tank in the parallel micro-miniature bioreactor assembly is 100 mL-500 mL.
According to the device of the present invention, in one embodiment, the microfluidic microchannel has an inner diameter of 0.2 μm to 4 mm.
According to the device of the utility model, in one embodiment, the inner diameter of the branch pipe of the multi-way pipe is 0.2-500 μm.
According to the device of the utility model, in one embodiment, the number of the material storage bottles, the pressure pumps and the microfluidic pipes in the device corresponds to the number of the types of materials to be provided.
[ advantageous effects ]
The utility model provides a micro-miniature parallel biological reaction device for controlling material feeding based on micro-fluidic droplets, which has the following advantages:
1. the device has small volume and large flux, and can be used for realizing the rapid screening of excellent strains for biochemical production; particularly, the method is applied to the screening process of biological cells, the screening efficiency and the process optimization efficiency can be improved, the consumption of materials for culture and the experimental cost are reduced, and the period from the development of a research laboratory to the industrial production of the product is shortened;
2. the device controls material feeding through microfluidic droplets, has high material feeding accuracy and good parallelism and uniformity, can obviously improve the process optimization efficiency of producing target biochemicals by fermenting bacteria, saccharomycetes, moulds and the like, and shortens the period from pilot scale experiments to industrial production;
3. the device can accurately control the material flow acceleration rate based on microfluidic droplet control, can realize accurate feeding of a substrate in the whole cell or enzyme catalysis process, particularly the substrate with a toxic effect on cells or enzymes, and reduces the damage degree of harmful substrates to the cells, thereby obviously improving the catalysis efficiency and product accumulation;
4. the device can realize the feeding of liquid of various materials through a single channel by the micro-fluidic chip of the micro-fluidic technology;
5. the device can more accurately control the amount of the supplementary material needed by the material based on the microfluidic technology;
6. the device of the utility model can make the adopted pipeline smaller than the diameter of the general microorganism based on the microfluidic technology, thereby avoiding the sterilization process of the culture medium.
Drawings
FIG. 1 is an overall schematic diagram of a micro-miniature parallel biological reaction device for controlling material feeding based on micro-fluidic droplets according to the present invention;
FIG. 2 is an enlarged schematic view of a single microminiature bioreactor of the apparatus of the present invention;
FIG. 3 is an enlarged schematic view of a dual material fed microfluidic chip of the device of the present invention;
fig. 4 is a schematic diagram of the operating principle of the controller of the apparatus of the present invention.
Detailed Description
The present invention provides a micro-miniature parallel bioreactor for controlling material feeding based on micro-fluidic droplets, which is further described in detail with reference to the accompanying drawings and specific examples. Advantages and features of the present invention will become apparent from the following description and from the claims. It is to be noted that the drawings are in a very simplified form and are not to precise scale, which is merely for the purpose of facilitating and distinctly claiming the embodiments of the present invention.
Example one
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention.
Fig. 1 is a schematic diagram of a micro-biological reaction device for controlling material feeding based on microfluidic droplets according to this embodiment, in this embodiment, a microfluidic chip for mixing and feeding two materials is used in a microfluidic micro-channel. As can be seen from fig. 1, the micro-miniature parallel bioreactor apparatus for controlling material feeding based on microfluidic droplets of the present embodiment includes a controller 1, a micro-miniature parallel bioreactor assembly 2, wherein the controller 1 is connected to the parallel micro-miniature bioreactor assembly 2 and is used for controlling the micro-miniature bioreactor assembly 2; the microminiature parallel bioreactor assembly 2 comprises 4 parallel tanks; the pressure pump I3 is connected with the material storage bottle I4 through a micro-fluidic micro-pipeline 7, the pressure pump II 5 is connected with the material storage bottle II 6 through a micro-fluidic micro-pipeline 8, the micro-fluidic micro-pipeline 7 and the micro-fluidic micro-pipeline 8 are connected to a micro-fluidic chip 9, and pass through a micro-fluidic pipeline 10 connected with the micro-fluidic chip 9, a material A in the material storage bottle I4 and a material B in the material storage bottle II 6 are mixed through the micro-fluidic chip 9 and enter the micro-fluidic pipeline 10, a pressure sensor 11 is arranged at the port of the micro-fluidic micro-pipeline 10, which is connected into the micro-miniature parallel bioreactor component 2, the micro-fluidic pipeline 10 is connected with a multi-way pipe 12 after being connected into the reactor 2, and the multi-way pipe 12 is respectively connected to branch pipes of 4 parallel tanks; a branch pipeline 18 for the mixed materials to enter the first parallel tank is provided with an electromagnetic valve-flow control valve assembly 14, and the branch pipeline 18 is connected to a feeding port 22 of the first parallel tank; the solenoid valve-flow control valve assembly 15 is arranged on a branch pipeline 19 of the mixed material entering the second parallel tank, and the branch pipeline 19 is connected to a feeding port 23 of the second parallel tank; the solenoid valve-flow control valve assembly 16 is arranged on a branch pipeline 20 of the mixed material entering the third parallel tank, and the branch pipeline 20 is connected to a material supplementing port 24 of the third parallel tank; the solenoid valve-flow control valve assembly 17 is arranged on the branch pipe 21 of the mixed material entering the parallel tank four, and the branch pipe 21 is connected to the feeding port 25 of the parallel tank four.
The parallel microminiature bioreactor component 2 is also provided with electrodes for detecting parameters such as pH, temperature, DO and the like; the support 13 is used for supporting the multi-way pipe 12 and the solenoid valve-flow control valve assembly arranged on each branch pipe. Most preferably 2 or 4 parallel tanks in the mini-parallel reactor assembly.
FIG. 2 is an enlarged view of a single parallel tank-one micro-bioreactor in the parallel micro-bioreactor assembly 2. As can be seen from fig. 2, a first parallel tank connection controller 1 and a first pressure pump 3 in a parallel reactor assembly 2 are connected with a first material storage bottle 4 through a microfluidic micro-pipeline 7, a second pressure pump 5 is connected with a second material storage bottle 6 through a microfluidic micro-pipeline 8, the microfluidic micro-pipeline 7 and the microfluidic micro-pipeline 8 are connected to a microfluidic chip 9, the microfluidic chip 9 is connected to a microfluidic pipeline 10, a material a in the first material storage bottle 4 and a material B in the second material storage bottle 6 are mixed through the microfluidic chip 9 and enter the microfluidic pipeline 10, a pressure sensor 11 is arranged at a port of the microfluidic micro-pipeline 10, the microfluidic pipeline 10 is connected with a multi-channel 12 after being connected to the reactor 2, and the multi-channel 12 is respectively connected to branch channels of the 4 parallel tanks; the solenoid valve-flow control valve assembly 14 is provided on the branch pipe 18 of the mixed material entering the first parallel tank, and the branch pipe 18 is connected to the replenishment port 22 of the first parallel tank.
Fig. 3 shows a microfluidic chip 9 for controlling the feeding of two materials used in this example. As can be seen from fig. 3, the microfluidic chip 9 is connected to the microfluidic pipeline 7 for feeding the material a, the microfluidic pipeline 8 for feeding the material B, and the microfluidic pipeline 10 for feeding the mixed material.
Fig. 4 is a schematic diagram illustrating the working principle of a controller in the device of the present invention, wherein the controller includes a data monitoring module, a real-time control module, a remote control module, and a main server control module; the data monitoring module is used for detecting the pH, DO, temperature and other data of the microminiature parallel bioreactor component 2 and controlling the module in real time; the block is used for controlling the pH, DO, temperature, feeding and the like of the microminiature parallel bioreactor component 2 in real time; the main server control module is a central system of the controller, can control the data monitoring module, the real-time control module and the remote control module, and can carry out remote control in a wireless mode and the like.
When the device is used, fermentation liquor is added into a parallel fermentation tank in the parallel micro bioreactor assembly 2, in the fermentation process, the electrodes for detecting temperature, DO and pH respectively detect the temperature, DO, pH and other indexes in the fermentation process, the detected signals of temperature, DO, pH and the like are transmitted to the controller, and the controller regulates and controls the fermentation tank in real time according to the set target temperature, DO and pH.
Example two:
in this embodiment, the schematic diagram of the apparatus structure is the same as that of the first embodiment, the parallel micro-bioreactor assembly is a 4-parallel small-scale reactor, that is, the parallel micro-bioreactor assembly includes 4 parallel tanks, the volume of a single parallel tank is 150mL, the height-diameter ratio of the parallel tank is 2.5, the parallel tank is equipped with 2-4 pressure pumps and 2-4 material liquid storage bottles, the inner diameter of the microfluidic micro-pipe 7 of the material a is 50 μm, the inner diameter of the microfluidic micro-pipe 8 of the material B is 50 μm, and the inner diameter of the microfluidic micro-pipe 10 formed by mixing the material a and the material B is 30 μm.
The 4-unit micro-miniature parallel bioreactor based on microfluidic droplet control material feeding in the embodiment is used as an implementation device for testing the growth condition of escherichia coli, and is compared with a shake flask culture method and a 5L bioreactor.
500mL of TB medium (Terrific Broth: yeast extract 24g/L, tryptone 12g/L, KH)2PO42.31g/L，K2HPO412.54g/L and 5g/L of glycerol), sterilizing and cooling, adding the split-charging flow into a parallel reactor by using a microfluidic droplet pipeline system, wherein the liquid charging amount is 60%, adding the pre-cultured escherichia coli seed liquid into the split-charging culture medium by using an inoculation amount of 2% through the microfluidic droplet pipeline system, and culturing at 37 ℃ and 600r/min for 16h, wherein the final concentration of 10g/L of glucose solution is added by using the microfluidic droplet system in a constant-speed flow manner within 8-12 h.
250mL shake flasks (3 parallel groups) and 5L bioreactors (3 parallel groups) were used as controls. And subpackaging the prepared culture medium into a shake flask and a 5L fermentation tank, wherein the liquid filling amount of the shake flask is 50mL, the liquid filling amount of the 5L fermentation tank is 60%, and inoculating 2% of the pre-cultured escherichia coli seed liquid. Shaking to culture at 37 deg.C for 16h at 220r/min, wherein the final concentration of 10g/L glucose solution is added for 3 times at 8h, 9.5h, and 11 h. Culturing in a 5L fermentation tank at 37 ℃ and 400r/min for 16h, wherein a glucose solution with the final concentration of 10g/L is added at a constant speed of 8-12 h.
Taking a sample every 2h, and detecting an OD value under a 600nm visible spectrophotometer, wherein the result shows that the growth, the growth stability and the parallelism among data of the escherichia coli cultured by the small parallel reactor are obviously superior to those of a shake flask compared with the shake flask culture condition; compared with a 5L bioreactor, the growth of the thalli of the escherichia coli cultured by the small parallel reactor is equivalent, but the growth stability and the parallelism among data are obviously superior to those of the 5L bioreactor.
The 4-unit small-sized parallel bioreactor for controlling material feeding based on microfluidic droplets in the embodiment is used as an implementation device for testing the synthesis of vanillin by catalyzing isoeugenol through whole cells of escherichia coli, and is compared with a 5L bioreactor.
Preparing a whole-cell catalytic system: 0.1mmol/L of isoeugenol, 0.5% of dimethyl sulfoxide and 20% of wet escherichia coli cells, wherein the pH value is adjusted to 10.0 by a phosphate buffer solution. The 4-unit small parallel bioreactor reacts for 24 hours at 25 ℃ and 200r/min, wherein a microfluidic droplet system is applied for 10-16 hours, the constant-speed feeding final concentration of the isoeugenol is 0.08mmol/L, a 5L bioreactor (3 groups are parallel) is used as a contrast, the isoeugenol is cultured for 24 hours at 25 ℃ and 200r/min, and the constant-speed feeding final concentration of the isoeugenol is 0.08mmol/L after 10-16 hours. Sampling every 2h, detecting the yield of vanillin, and finding that the yield of vanillin obtained by catalytic reaction of a small parallel reactor is higher than that of a 5L bioreactor, and the parallelism of data of the small parallel reactor is obviously better than that of the 5L bioreactor. Observing the shapes of the Escherichia coli cells in different reaction systems after reaction, and finding that the damage degree of the cells in the small parallel reactor by the isoeugenol is lower than that of the cells in the 5L bioreactor.
Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the utility model as defined in the appended claims.
Claims (10)
1. The micro-miniature parallel bioreactor device for controlling material feeding based on micro-fluidic droplets is characterized by comprising a controller, a parallel micro-miniature bioreactor component, a material storage bottle, a pressure pump and a micro-fluidic chip;
the controller is connected to the parallel microminiature bioreactor assembly and is used for controlling the microminiature bioreactor assembly; the microminiature bioreactor component comprises a plurality of parallel tanks; the material storage bottle and the pressure pump are connected to the microfluidic chip through a microfluidic micro-pipeline, the microfluidic chip is connected to the parallel tanks of the parallel microminiature bioreactor assembly through multi-way pipes, and the branch pipelines of the parallel tanks of the parallel microminiature bioreactor assembly to which the multi-way pipes are connected are respectively provided with an electromagnetic valve-flow control valve assembly;
the parallel micro-miniature bioreactor assembly is also internally provided with an electrode for detecting pH, temperature and dissolved oxygen, and is provided with a bracket for fixing the multi-way pipe and the electromagnetic valve-flow control valve assembly arranged on the branch pipe; and a pressure sensor is arranged on the micro-fluidic micro-pipeline.
2. The micro-fluidic droplet-based micro-miniature parallel biological reaction device for controlling material feeding according to claim 1, wherein the number of the material storage bottles and the pressure pumps is multiple, and the material storage bottles and the pressure pumps are used for providing multiple materials; and a plurality of the material storage bottles and the pressure pump are connected to the microfluidic chip through the microfluidic micro-pipeline.
3. The micro-fluidic droplet-based micro-miniature parallel bioreactor apparatus for controlling material feeding according to claim 1, wherein the micro-fluidic chip is configured to mix a plurality of materials provided in a plurality of the material storage bottles, and the mixed materials are respectively transported to a plurality of parallel tanks of the parallel micro-miniature bioreactor assembly through the multi-channel.
4. The micro-fluidic droplet-based micro-miniature parallel bioreactor apparatus for controlling material flow addition according to claim 1, wherein the number of parallel tanks in the micro-miniature parallel bioreactor assembly is 2, 4, 8, 16 or 32.
5. The micro-fluidic droplet-based micro-miniature parallel bioreactor apparatus for controlling material flow addition according to claim 1, wherein the number of the branch channels of the multi-channel corresponds to the number of parallel tanks in the micro-miniature parallel bioreactor assembly.
6. The microfluidic droplet-based micro-miniature parallel bioreactor apparatus for controlling feed flow in accordance with claim 1, wherein the volume of a single parallel tank in the parallel micro-miniature bioreactor assembly is 15mL to 100 mL.
7. The microfluidic droplet-based micro-miniature parallel bioreactor apparatus for controlling feed flow according to claim 1, wherein the volume of a single parallel tank in the parallel micro-miniature bioreactor assembly is 100mL to 500 mL.
8. The micro-miniature parallel biological reaction device for controlling material feeding based on micro-fluidic droplets as claimed in claim 1, wherein the micro-fluidic micro-channel has an inner diameter of 0.2 μm to 4 mm.
9. The micro-miniature parallel biological reaction device for controlling material flow addition based on micro-fluidic droplets as claimed in claim 1, wherein the inner diameter of each branch pipe of the multi-way pipe is 0.2 μm to 500 μm.
10. The micro-miniature parallel biological reaction device for microfluidic droplet-based control of material feeding of claim 1, wherein the number of said material reservoirs, said pressure pumps and said microfluidic channels in said device corresponds to the number of desired material types.
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