KR102092725B1 - 3D printed density induced flow focusing device for parallel production of multiple sized droplets - Google Patents

Abstract

The present invention relates to a density difference-fluid direct method using a microfluidic device manufactured by a 3D printer, and a parallel production apparatus for droplets of various sizes using the same. The parallel production apparatus for droplets comprises a plurality of droplet generation units providing an accommodating space that provides a hydrophobic surface to create droplets using a non-mixed first fluid and second fluid supplied, and controlling the size of droplets generated by a flow rate ratio of the first fluid and the second fluid; and a first supply pipe and a second supply pipe that simultaneously supply the first fluid and the second fluid to the droplet generation units, respectively.

Description

Density-fluid direct method using a microfluidic device fabricated in 3D printing and various sized droplet parallel production devices using the same 3D printed density induced flow focusing device for parallel production of multiple sized droplets}

The present invention relates to a density difference-fluid direct method using a microfluidic device manufactured by 3D printing and a parallel production apparatus for droplets of various sizes using the same, and more specifically, to generate droplets of multiple sizes using density-induced flow focusing. The present invention relates to a density difference-fluid direct method using a microfluidic device made of a 3D print capable and a parallel production apparatus for droplets of various sizes using the same.

In general, droplets in microfluidic engineering systems play a large role in academic research and engineering applications such as biology, chemistry, materials science, pharmacy, and medicine. These droplet-based microfluidic engineering systems are used for superior control of the process in terms of isolated partitions of chemical or biological samples, encapsulation of chemical reactions or biological treatments, heat transfer and mass.

 A variety of passive strategies for droplet formation in microfluidic engineering systems have been proposed in order to meet the inherent functions and high processing performance required for engineering applications.

The above strategy is mainly based on the following principles. (i) Deformation and fracture of the liquid-liquid interface by shear forces generated in microfluidic systems having a variety of configurations, including cross flow, simultaneous flow, and flow concentration configurations. (ii) Pressure due to the pinch-off of droplets induced by interfacial tension and changes in capillary change channel confinement (eg, step emulsification configuration), such as a stepwise emulsification arrangement.

In the development of such droplet formation technology, it is very important to precisely control the size and uniformity of droplets. This is because the size and uniformity of the droplets have a decisive effect on the performance and quality of the final product.

In order to control the size and uniformity of droplets, it has been developed by using microchannels of several hundred microns in size through sophisticated microfabrication processes such as poly dimethyl siloxane (PDMS) and soft lithography of glass.

The conventional droplet generation technology is widely used at present, but there is a critical technical limitation that requires skill of workers and sophisticated laboratory infrastructure and complicated processes.

These technical constraints are (i) the difficulty of repetitive and mass production of devices with reproducible precision for industrial applications, and (ii) the flexibility of the size range of the droplets produced because it is difficult to change the design of already manufactured devices. There are limitations.

3D printing technology has emerged as a promising alternative tool to overcome the problems of the prior art, no assembly is required, and thanks to advantages such as rapid prototyping and easy adjustment of device functions, the manufacturing process of microfluidic devices It can provide convenience and flexibility.

For this reason, the incorporation of 3D printing technology into microfluidic research has attracted considerable interest.

There have been reports of droplet formation using conventional 3D printed microfluidic devices.

In the prior art, "Femmer et al . High-Throughput Generation of Emulsions and Microgels in Parallelized Microfluidic Drop-Makers Prepared by Rapid Prototyping.ACS Applied Materials & Interfaces 7 , 12635-12638, doi: 10.1021 / acsami.5b03969 (2015)" A parallel microfluidic flow concentrator has been described so that large-diameter large droplets (500 µm or more in diameter) can be processed in large quantities using a digital light processing 3D printer.

Also, "Kanai et al. Microfluidic devices fabricated using stereolithography for preparation of monodisperse double emulsions. Chemical Engineering Journal 290, 400-404, doi: https: //doi.org/10.1016/j.cej.2016.01.064 (2016) "Is described for a 3D printed microfluidic device in a three-coaxially aligned cylindrical channel cavity flow configuration using a 3D printing process.

These prior art techniques can produce a dual fluid composed of a number of internal droplets (diameter ~ 400 μm) and one external droplet (diameter ~ 1000 μm). Most of the conventional microfabricated or 3D printed droplet generators are typically configured to vary the flow rate of the injected fluid to control the droplet size produced.

However, "Riche et al . Flow invariant droplet formation for stable parallel microreactors. Nature Communications 7, 10780, doi: 10.1038 / ncomms10780""discloses a technique for resizing droplets using the diameter of the outlet tubing regardless of the flow rate. It is done.

Development techniques of the conventional 3D printed droplet generator have the following problems.

First, in the prior art, a stronger tangential or vertical stress must be generated for the production of smaller droplets, so a fine internal channel (or cavity) having a size of several hundred to several tens of micrometers is required.

Therefore, since an expensive high-resolution 3D printer has to be used, the availability and accessibility of end users are reduced, and there is a problem in that the cost is increased.

In addition, conventionally, there is a problem in that a range of droplet sizes that can be produced is very limited because one physical parameter (flow rate or inner diameter of the tubing) is changed to adjust the generated droplet size.

The technical problem to be solved by the present invention is to provide a droplet generating apparatus and method capable of generating fine droplets using a low-resolution 3D printer having a three-dimensional millimeter-sized spatial structure.

In addition, the present invention provides a droplet generating apparatus and method capable of expanding a size range of droplets that can be produced using various parameters.

In order to solve the above problems, the density difference-fluid direct method using a microfluidic device manufactured by 3D printing according to an aspect of the present invention is supplied with a non-mixable fluid to the receiving space, and the outlet on the upper side of the receiving space To be discharged through, the size of the droplets discharged through the outlet can be adjusted by adjusting the flow rate ratio of the fluids and the inclination angle of the inclined surface from the upper side of the receiving space to the outlet.

According to an embodiment of the present invention, it is assumed that the surface defining the accommodation space is hydrophobic.

According to one embodiment of the present invention, the inclination angle may be adjusted to 15 to 60 degrees.

According to an embodiment of the present invention, droplets having different sizes may be generated using a plurality of accommodation spaces having different inclination angles.

In addition, a parallel production apparatus for droplets of various sizes using a density difference-fluid direct using a microfluidic device made of a 3D print according to another aspect of the present invention provides an accommodation space providing a hydrophobic surface, and is supplied with non-mixed A droplet is generated by using the first and second fluids of the castle, but a plurality of droplet generation units for controlling the size of the droplets generated by the flow rate ratios of the first and second fluids, respectively, the first fluid and the second fluid It may include a first supply pipe and a second supply pipe for simultaneously supplying the fluid to the droplet generating portion.

According to an embodiment of the present invention, each of the plurality of the droplet generating parts, the body provided with a receiving space therein, the first supply pipe and the second supply pipe in communication with each of the first fluid and the second fluid in the receiving space It may include supply pipes for supplying, an outlet for communicating with the receiving space on the upper surface of the body to discharge droplets, and an inclined surface for forming a space in the shape of a square pyramid from the upper side of the receiving space to the outlet.

According to an embodiment of the present invention, it is assumed that each of the plurality of droplet generators has a different apex angle that is an inclination angle of the inclined surface.

According to an embodiment of the present invention, the apex angle may be 15 to 60 degrees.

According to an embodiment of the present invention, the body may be hydrophobic.

According to one embodiment of the present invention, the accommodation space, the length of one side of the bottom surface is 8 ~ 12mm, the height of the side portion perpendicular to the bottom surface may be 15 ~ 20mm, the height of the inclined surface may be 14 ~ 18mm .

According to an embodiment of the present invention, the plurality of droplet generating units and the first supply pipe and the second supply pipe may be integrally printed simultaneously with a 3D printer.

The present invention can determine the size of the droplets generated using the flow rate ratio of the fluid to be supplied, the apex angle which is the inclination angle to the outlet, and the hydrophobic surface. It can be easily implemented without a printing device, thereby reducing costs and improving user convenience.

In addition, the present invention can generate droplets having different sizes at the same time by arranging a plurality of droplet generating units having different apex angles in parallel, and thus has an effect applicable to various application fields.

1 is a block diagram of a droplet generating apparatus of a microfluidic engineering system according to a preferred embodiment of the present invention.
2 is a configuration diagram of the first droplet generating unit.
3 is a simulation result of testing the droplet generation principle of the present invention.
4 is a photograph of a droplet generation process over time of an empty droplet generation device having no structure for droplet generation.
5 is a photograph of a droplet generation state at a fluid outlet using a super-speed camera.
6 is a comparison of the droplet size according to the flow rate ratio and the apex angle.
7 is a micrograph of the droplets produced by the present invention and a graph of the results of the analysis.

Hereinafter, a droplet generating apparatus and method of a microfluidic engineering system of the present invention will be described in detail with reference to the accompanying drawings.

The embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art, and the embodiments described below may be modified in various other forms, and The scope is not limited to the examples below. Rather, these examples are provided to make the present invention more faithful and complete and to fully convey the spirit of the present invention to those skilled in the art.

Terms used in this specification are used to describe specific embodiments, and are not intended to limit the present invention. As used herein, singular forms may include plural forms unless the context clearly indicates otherwise. Also, as used herein, “comprise” and / or “comprising” specifies the shapes, numbers, steps, actions, elements, elements and / or the presence of these groups. And does not exclude the presence or addition of one or more other shapes, numbers, actions, elements, elements and / or groups. As used herein, the term “and / or” includes any and all combinations of one or more of the listed items.

Although the terms first, second, etc. are used herein to describe various members, regions, and / or parts, it is obvious that these members, parts, regions, layers, and / or parts are not limited by these terms. . These terms do not imply a specific order, top or bottom, or superiority, and are only used to distinguish one member, region or site from another. Accordingly, the first member, region, or site to be described below may refer to the second member, region, or site without departing from the teachings of the present invention.

Hereinafter, embodiments of the present invention will be described with reference to the drawings schematically showing embodiments of the present invention. In the drawings, deformations of the illustrated shape can be expected, for example, according to manufacturing technology and / or tolerances. Therefore, the embodiments of the present invention should not be interpreted as being limited to a specific shape of the region shown in this specification, but should include, for example, a change in shape caused by manufacturing.

1 is a block diagram of a droplet generating apparatus of a microfluidic engineering system according to a preferred embodiment of the present invention.

Referring to Figure 1, the droplet generation apparatus of the microfluidic engineering system according to a preferred embodiment of the present invention, the first to fourth droplet generation unit (10, 20, 30, 40) having a different apex angle (Apex angle), A first supply pipe (50) for simultaneously supplying a first fluid to the first to fourth droplet generating units (10, 20, 30, 40) and a first to fourth droplet generating unit (10, 20, 30, 40) It comprises a second supply pipe 60 for supplying a second fluid having a different density from the first fluid at the same time.

The first to fourth liquid crystal generating units 10, 20, 30, and 40 are configured in parallel to each other by the first supply pipe 50 and the second supply pipe 60.

It is assumed that the first to fourth liquid crystal generating parts 10, 20, 30, and 40 provide a hydrophobic surface.

In the present invention, in order to solve the conventional problems, the first to fourth liquid crystal generating units 10, 20, 30, and 40 composed of only a millimeter-scale spatial structure are used to generate micro-droplets applicable to microfluidic engineering. Therefore, a high-performance 3D printing device is not required to print the first to fourth droplet generating units 10, 20, 30, and 40.

The first to fourth droplet generating units 10, 20, 30, and 40 have the same composition with different apex angles, and a specific configuration example is illustrated in FIG. 2.

2 is a configuration diagram of the first droplet generating unit 10, FIG. 2 (a) is a perspective view, FIG. 2 (b) is a longitudinal sectional view, and FIG. 2 (c) is a cross-sectional view.

Referring to Figure 2, the first droplet generating unit 10 is provided on the lower side of the body 12 having a receiving space 11 therein, and the side portions opposite to each other of the body 12, the first fluid and the 2 Supply pipes (13, 14) for supplying each of the fluids are provided, and an outlet (15) is formed in the direction of the z-axis, and the exit (15) side of the receiving space (11) is inclined at a predetermined angle to the exit (15) It consists of an inclined surface 16 with a narrowing angle.

The specific shape of the first droplet generating unit 10 has been described above, but the second droplet generating unit 20, the third droplet generating unit 30, and the fourth droplet generating unit 40 also have an inclined surface forming an apex angle. It has the same configuration as the first droplet generating unit 10 only with a difference in angle.

The body 12 is made of a material that provides a hydrophobic surface.

Hereinafter, the principle of droplet generation according to the specific structure of the present invention and the configuration and operation of the present invention will be described in more detail.

The droplet generation device of the microfluidic engineering system of the present invention provides a point in which the heavy fluid sinks to the bottom of the supplied first and second fluids and the lighter fluid rises above the heavy fluid and provides a hydrophobic surface to spread the oily fluid. Use points that cause.

The first and second fluids (for example, low-density oil and heavy water), which are immiscible fluids having different densities, are supplied, and the receiving space 11 has hydrophobic inner side walls perpendicular to the flat surface. When continuously fed into the fluid, the fluid gradually increases in the vertical direction. At this time, the oil tends to flow along the hydrophobic wall of the receiving space 11, and due to the difference in density and preference for the hydrophobic surface, water fills the receiving space 11 and the outlet in the upper center of the receiving space 11 ( 15).

In a typical two-phase flow focusing system, the less viscous flow breaks into smaller droplets due to capillary instability due to the competition between shear stress and capillary pressure due to less viscous flow.

Thus, the vertical flow of oil and water is further concentrated by the inclined surface 16 providing an appropriate tapered structure in the vertical direction, after which the capillary instability at the interface between them is increased.

3 is a simulation result of testing the droplet generation principle of the present invention.

3 (a) is a simulation result when there is a difference in density, in which fluids having different density are initially (0 sec), a fluid having a high density is located at the bottom and a fluid having a low fluid is located at the top, and an inclined surface ( 16). That is, the dispersed phase of the first fluid and the second fluid fills most of the receiving space 11, and the water level is increased.

Over time, a thin stream of a continuous phase flows along the hydrophobic wall (3 sec) along the hydrophobic phase.

When the dispersed phase flow reaches the bottleneck connecting the inclined surface 16 and the outlet 15 (3,9 sec), it is repeatedly due to capillary instability as a result (4.5 sec) due to the shear stress received by the continuous phase. Small droplets are discharged through the outlet 15 in a reliable manner.

On the other hand, if there is no density difference as shown in FIG. 3 (b), the dispersed phase flows to the upper portion without filling the bottom portion of the receiving space portion 11 because the gravitational and buoyancy grades are the same.

Therefore, the dispersed phase flow breaks near the supply line for dispersing the dispersed phase, and as shown in FIG. 3 (a), it produces droplets that are considerably larger than droplet formation considering density.

Hexadecane oil may be used as the continuous phase, and water may be used as the dispersed phase.

As described above, the present invention can form fine droplets using an inclined inclined surface having a difference in density and hydrophobicity of a fluid, and can be easily produced using a commercially available inexpensive 3D printer.

FIG. 4 is a photograph of a droplet generation process over time of an empty droplet generation device having no structure for droplet generation, and FIG. 5 is a photograph of droplet generation at a fluid outlet using a super-speed camera.

As shown in the present invention, the present invention can generate droplets using a fluid focusing method induced by a density difference.

The first to fourth droplet generating units 10 to 40 may be printed with UV curable methacrylate-based resins that provide hydrophobicity, wettability and chemical resistance to hexadecane oil used as a continuous phase.

Thus, the present invention can reduce the manufacturing cost compared to the prior art requiring a high-resolution printer for the production of complex micro-channels (less than 250 μm), and is very advantageous in terms of end-user convenience.

The scale bar SB is illustrated in FIG. 2B, wherein the scale bar is 5 mm. That is, in the first to fourth droplet generating parts 10 to 40 of the present invention, the length of one side of the bottom surface of the receiving space 11 is about 8 to 12 mm, and the height of the vertical side portion of the receiving space 11 is 15. The body 12 having a height of ~ 20 mm and an inclined surface of 14 to 18 mm can be easily manufactured with a conventional 3D printer.

The upper side of the receiving space 11 is a square pyramid or a cone-shaped space.

The physical influencing factors for generating droplets using the first to fourth droplet generating units 10 to 40 are the main factors in which the apex angle is the main factor in the flow velocity ratio of the continuous phase and the dispersed phase and the quadrangular pyramid structure of the receiving space 11. do.

The temporal change of the boundary between the dispersed phase and the continuous phase is continuously observed by a high-speed camera. The influence of the flow rate ratio on the dynamic characteristics of the flow rate distribution can be confirmed by changing the dispersion phase flow rate (Qd) while keeping the continuous phase flow rate (Qc) at 1 ml / min and maintaining the apex angle (α) at 15 degrees.

As shown in Fig. 6, two distinct modes of droplet formation (i.e., narrowing and widening spraying mode) appear depending on the flow rate ratio (Qc / Qd).

In a narrow injection mode with a high flow rate ratio (upper line in Fig. 6 (a)), the dispersed phase initially flows to the top of a square pyramid or cone shape, filling most of the space in the bottom. On the other hand, a thin stream of continuous phase flows along the hydrophobic channel wall together in terms of the flow of the dispersed phase. When the dispersion phase flow is reached at the bottleneck portion connecting the capillary tube, which is the cylindrical outlet 15 and the inclined surface 16 constituting the upper side square pyramid or cone of the receiving space 11, as a result of the shear stress applied by the continuous phase Due to repeated capillary instability, a narrow injection mode is created.

On the other hand, in the wide injection mode (lower row in Fig. 6 (a)) having a low flow rate ratio, the flow of the dispersed phase forms a long liquid chamber inside the capillary because the inertial force is comparable to the capillary force. As a result, droplets are formed far away from the downward flow of the bottleneck position.

In addition, it can be confirmed by changing the apex angle of the square pyramid or conical structure for the dynamic properties of droplet formation in the range of 15 to 60 degrees.

Finally, the size and the rate of formation of the droplets generated in the narrow injection mode capable of producing the droplets stably and uniformly can be expressed as a function of the flow rate ratio and the apex angle (Fig. 6 (b)).

The resulting droplet size decreases with increasing flow rate ratio and increasing vertex angle. This was confirmed to be inversely proportional to the square root of the flow rate ratio.

Consequently, a library of droplets with diameters of 36 μm and 616 μm with very high monodispersity (CV <2%) can be generated by modulating the two parameters mentioned above.

Referring back to FIG. 1, the present invention provides the apex angles of the first to fourth droplet generating units 10, 20, 30, and 40 respectively to enlarge the degree of change in the size of the droplets by 15, 30, and 45 degrees, respectively. We propose a droplet generator arranged at 60 degrees in parallel.

Such a droplet generator can be manufactured in a batch with a low-resolution 3D printer. Parallelized droplet generators can provide more usefulness and flexibility in microfluidic applications in industrial applications involving materials, cosmetics and pharmaceuticals.

Thus, it is possible to simultaneously produce droplets of various sizes through a parallelized device with multiple outlets.

In particular, this can be an important approach in the point-of-care market, which may be possible with a downstream approach to the crystal size and particle shape of the active molecule. Crystallization of the active pharmaceutical ingredient (API) is performed to confirm that the present invention can be applied to pharmaceutical applications. Formation of glycine crystallization in water (W / O) emulsions in oil is tested as a general example of amino acids in APIs for continuous and size distribution processing.

Using the present invention, glycine-loaded emulsions of different diameters can be simultaneously obtained. This is because the sizes of the glycine loaded emulsion droplets generated in each of the first to fourth droplet generating units 10, 20, 30 and 40 are different.

Here, saturated glycine solution and dodecane are used as the dispersed phase and the continuous phase, respectively. Saturated glycine solution is fed and emulsified into spherical aggregates into the next unmixed continuous phase. Smaller droplets (<100 μm) were able to obtain uniform spherical crystals from 45 μm to 134 μm for uniform nucleation on the heated glass slides through evaporation and subsequent nucleation on the heated glass slides (FIG. 7 ( a)).

As described above, droplets of various sizes may be generated due to a difference in apex angles of the first to fourth droplet generating units 10, 20, 30, and 40, and the diameter of the emulsion is about 50% by nucleation in a sealed emulsion. Shrinked (Fig. 7 (b)).

The resulting crystal size has been found to depend on the emulsion size and is controlled by changing the flow rate ratio and vertex angle of a single droplet generation. In addition, the crystallinity of the glycine crystal is confirmed by an X-ray diffractometer (XRD). As a result of XRD pattern analysis (Fig. 7 (c)), the polymorphic form was found to be relatively superior to other forms of 2θ = 15 degrees, 19 degrees, 24 degrees and 30 degrees. These results indicate that continuous production of dispersed API crystals and high efficiency screening of crystal nucleation and growth conditions are possible.

The present invention is not limited to the above embodiments and can be variously modified and modified within a range not departing from the technical gist of the present invention, which is apparent to those skilled in the art to which the present invention pertains. will be.

10: first droplet generation unit 11: accommodation space
12: Body 13, 14: Supply pipeline
15: Exit 16: Slope
20: second droplet generation unit 30: third droplet generation unit
40: fourth droplet generating unit 50: first supply pipe
60: second supply pipe

Claims (11)

Non-mixable fluids are supplied to the receiving space, and discharged through an outlet at the upper side of the receiving space,
Density-fluid direct method using a microfluidic device made of a 3D print that adjusts the flow rate ratio of fluids and the inclination angle of the inclined surface from the upper side of the receiving space to the outlet to adjust the size of droplets discharged through the outlet. According to claim 1,
Density-fluid direct method using a microfluidic device made of a 3D print, characterized in that the surface defining the receiving space is hydrophobic. The method according to claim 1 or 2,
The inclination angle,
Density-fluid direct method using a microfluidic device manufactured by 3D printing, characterized in that it is 15 to 60 degrees. According to claim 3,
Density-fluid direct method using a microfluidic device made of a 3D print that generates droplets of different sizes using a plurality of receiving spaces having different inclination angles. By providing an accommodation space that provides a hydrophobic surface, droplets are generated using the supplied non-mixed first fluid and second fluid, but the size of the droplets generated by the flow rate ratio of the first fluid and the second fluid is controlled. A plurality of droplet generation units;
It includes a first supply pipe and a second supply pipe for supplying the first fluid and the second fluid to the droplet generating units, respectively,
Each of the plurality of the droplet generating portion,
A body having an accommodation space therein;
Supply pipes communicating with each of the first supply pipe and the second supply pipe to supply a first fluid and a second fluid to the accommodation space;
An outlet communicating with the accommodation space on the upper surface of the body to discharge droplets; And
A device for parallel production of droplets of various sizes using a density difference-fluid straightness including an inclined surface forming a square pyramid or cone-shaped space from the upper side of the receiving space to the outlet. delete The method of claim 5,
Each of the plurality of droplet generation units is a droplet size parallel production device using a density difference-fluid direct current, characterized in that the vertex angle is different from the inclination angle of the inclined surface. The method of claim 7,
The apex angle is 15 to 60 degrees, characterized in that the density difference-a liquid droplet parallel production apparatus of various sizes using a fluid direct. The method of claim 5,
The body,
A device for parallel production of droplets of various sizes using density difference-fluid direct, characterized in that they are hydrophobic. The method of claim 5,
The accommodation space,
A device for parallel production of droplets of various sizes using a density difference-fluid straightness, wherein the length of one side of the base is 8 to 12 mm, the height of the side portion perpendicular to the base is 15 to 20 mm, and the height of the slope is 14 to 18 mm. The method of claim 5,
A plurality of droplet generation units and the first supply pipe and the second supply pipe are 3D printers simultaneously printing integrally with a variety of sizes of liquid droplets using a density difference-fluid directivity.

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