KR101151688B1 - Systems for preparing embolic microsphere - Google Patents

Abstract

The present invention relates to an apparatus for treating a hydrophilic polymer, comprising: (a) a three-dimensional hydrodynamic focusing device for injecting a hydrophilic polymer fluid and a contrast agent fluid to focus the contrast agent on the hydrophilic polymer fluid; And (b) a droplet-forming lab-on-a-chip for injecting hydrophobic fluid and a hydrophilic polymer fluid focused with contrast medium by the three-dimensional hydrodynamic focusing device of (a). It relates to an embolic microsphere prepared using. Embolization, contrast agent or drug delivery system (DDS) applied to blood vessels formed around tumor tissue by encapsulating or / or mounting a contrast agent or / and pharmacologically active substance (anticancer agent) through the system of the present invention. The embolic microspheres for use can be produced simply and efficiently. In addition, the average diameter of the embolic microspheres produced through the system is constant to 400-600 microns to fit the blood vessel size, when the pharmacologically active material is mounted can maximize the efficiency of embolization. On the other hand, the embolic microspheres enclosed with a contrast agent impart ease of treatment.

Description

Embolization microsphere manufacturing system {Systems for Preparing Embolic Microsphere}

The present invention relates to an embolic microsphere production system and to an embolic microsphere produced by the system.

Embolization is a procedure that uses a contrast agent to find an artery that goes to a cancerous site, and then treats cancer by blocking nutrient supply to cancer tissues using anticancer agents and embolic materials.

Representative arterial embolization is hepatic artery embolization, which involves dispersing various anticancer drugs such as doxorubicin (adriamycin), cisplatin, and carboplatin in an oily contrast medium to simultaneously administer embolization and contrast. . In order to achieve embolism, contrast and anti-cancer effects for use in arterial embolization, chemical methods, ie, emulsion, suspension, or liposome formulations are used for embolization.

For example, adriamycin and epirubicin are widely used as anticancer agents for treating liver cancer in the conventional diagnostic radiology. Most anticancer drugs including adriamycin are water soluble and can be directly dissolved in Lipiodol. The method was used in the form of suspension in the absence (Yoshihiro Katagiri et al., Cancer Chemother. Pharmacol 1989, 23, 238-242). However, in the case of the suspension made by this method, since adriamycin particles are aggregated or precipitates are formed, there is a problem of long-term storage, which is why the anticancer agent is dissolved in an aqueous contrast agent and then dispersed in Lipiodol, an oily contrast agent.

That is, just before administration to the patient, the anticancer agent is dissolved in the aqueous contrast agent and mixed with the oily contrast agent by the pumping method. At this time, in order to maximize the stability of the emulsion, an aqueous contrast agent Eurographine (Urografin, 1.328-1.332) or Iopamiro (Iopamiro) having a specific gravity similar to that of Lipiodol (1.275 to 1.290) was used (Takashi Kanematsu et al., Journal of surgical oncology 1984, 25, 218-226, Takafumi Ichida et al., Cancer Chemother.Pharmacol 1994, 33, 74-78).

However, when such a chemical method is used, only a temporary emulsion is formed and the mixed state is unstable, so that separation occurs again in a few minutes, resulting in precipitation of adriamycin.

Thus, the present inventors have devised a method of preparing microspheres for coloration, encapsulating contrast medium, or mounting anticancer agents using a microfluidic system rather than an unstable chemical method.

With the miniaturization of analytical technology, research and development of micro devices that can process or analyze many samples and reagents in small units are being conducted. Biochips, lab-on-a-chips and micro-total analysis systems Techniques belong to this category. Microdevices such as biochips, lab-on-a-chip and micro-composite analysis systems include multiple channels or microstructures so that all the processes required for analysis can be performed on one small chip.

As part of the above technology, the present inventors produce microspheres in a desired size / shape in response to various blood vessel sizes, and in particular, micro-spheres composed of polymer-contrast (SPIO) -anticancer agents in response to a patient's disease Made through.

Throughout this specification many patent documents are referenced and their citations are indicated. The disclosures of the cited patent documents are incorporated by reference herein in their entirety, and the level of the technical field to which the present invention belongs and the contents of the present invention are more clearly described.

The inventors have sought to develop an embolic microsphere production system. As a result, the present inventors can manufacture embolic microspheres in a relatively simple method by combining a spiral lamination chaos micromixer or / and a three-dimensional hydrodynamic focusing device with a droplet-on wrap-on chip, and have a certain specific size The present invention was completed by confirming that it is suitable for the size, and in addition to simply preparing the embolic microspheres, it is easy to perform the procedure by encapsulating a contrast agent, and that the pharmacologically active substance is loaded to maximize the efficiency of embolization.

Accordingly, it is an object of the present invention to provide an embolic microsphere preparation system in which a contrast agent is encapsulated.

Another object of the present invention is to provide an embolic microsphere in which a contrast agent prepared by the above-described system is enclosed.

Still another object of the present invention is to provide an embolic microsphere preparation system on which a pharmacologically active substance is mounted.

Another object of the present invention is to provide an embolic microsphere on which the pharmacologically active material produced by the system is mounted.

Still another object of the present invention is to provide an embolic microsphere manufacturing system in which a contrast agent is encapsulated and a pharmacologically active substance is loaded.

Another object of the present invention is to provide an embolic microsphere in which a contrast agent prepared by the above-described system is enclosed and a pharmacologically active substance is loaded.

Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the invention, the present invention (a) a three-dimensional hydrodynamic focusing device for injecting a hydrophilic polymer fluid and a contrast medium fluid to focus the contrast agent on the hydrophilic polymer fluid; And (b) a droplet-forming lab-on-a-chip for injecting a hydrophobic fluid and a hydrophilic polymer fluid focused with a contrast agent fluid by the three-dimensional hydrodynamic focusing device of (a).

According to another aspect of the invention, the present invention (a) a spiral lamination chaos micro mixer for injecting and mixing the pharmacologically active material and the hydrophilic polymer fluid; (b) a three-dimensional hydrodynamic focusing device for injecting a mixed fluid and a contrast agent fluid of the pharmacologically active substance and the hydrophilic polymer fluid mixed by the micromixer to focus the contrast agent on the mixed fluid; And (c) a droplet-forming lab-on-a-chip for injecting a hydrophobic fluid and a mixed fluid in which the contrast medium is focused by the three-dimensional hydrodynamic focusing device of (b).

According to another aspect of the invention, the present invention (a) a spiral lamination chaos micro mixer for injecting and mixing the pharmacologically active material and the hydrophilic polymer fluid; And (b) a droplet-forming lab-on-a-chip for injecting a hydrophobic fluid and a mixed fluid of the pharmacologically active material and the hydrophilic polymer fluid mixed by the micromixer of (a), respectively.

By combining the spiral lamination chaos micromixer or / and three-dimensional hydrodynamic focusing device with a droplet-on-a-chip for droplet formation, the present inventors can produce embolic microspheres in a relatively simple manner, and have a certain specific size to fit a blood vessel size. In addition to the preparation of embolic microspheres, the contrast agent is encapsulated to facilitate the procedure, and the pharmacologically active material is mounted to maximize the efficiency of embolization.

The embolic microsphere preparation system of the present invention is largely (A) embolic microspheres with contrast agent, (B) embolic microspheres with pharmacologically active substance and (C) embolic microspheres with contrast agent and pharmacologically active substance loaded Can be prepared.

(A) The contrast agent Enclosed Embolism Microspheres  Manufacturing system

The embolic microsphere preparation system in which the contrast agent is encapsulated includes (a) a three-dimensional hydrodynamic focusing device for injecting a hydrophilic polymer fluid and a contrast agent fluid to focus the contrast agent on the hydrophilic polymer fluid; And (b) a droplet-form wrap-on-a-chip for injecting a hydrophobic fluid and a hydrophilic polymer fluid in which a contrast agent fluid is focused by the three-dimensional hydrodynamic focusing device of (a).

According to a preferred embodiment of the present invention, the (a) three-dimensional hydrodynamic focusing apparatus included in the system of the present invention includes a main inlet having an inlet for injecting a hydrophilic polymer fluid and an outlet for outflowing a hydrophilic polymer fluid in which a contrast agent is concentrated. channel; And subchannels 1 to 3 communicating with the main channel at regular intervals between the inlet and the outlet of the main channel and being formed to cross each other and having a pair of inlets, and arranged at regular intervals from the inlet of the main channel.

The subchannels 1 and 2 are disposed on a lower layer of the main channel, and the widths of the subchannels 1, 2 and the main channel are locally reduced in the intersected portion to form a vertical focusing portion, and the subchannel 3 is the same layer as the main channel. The horizontal focusing portion is formed in the portion arranged and intersected in the subchannel 3 and the main channel without changing the width.

According to another preferred embodiment of the present invention, the droplet forming wrap-on chip included in the system of the present invention includes a pair of side channels having an inlet through which a hydrophobic fluid is introduced, The confluence point has an inlet through which a hydrophilic polymer fluid condensed with the contrast agent fluid is introduced, and an outlet through which the hydrophilic polymer fluid with which the hydrophobic fluid and the contrast agent fluid is condensed is discharged, and the outlet is in communication with the outlet and has a locally reduced diameter. A hydrophilic polymer fluid comprising a channel, a confluence channel and a tube of which the diameter increases rapidly and forms a constant diameter, and the contrast agent fluid flowing through the condensation channel through the outlet is condensed with the hydrophobic fluid to form a microfluidic fluid due to a difference in surface tension. Enemies are formed.

According to another preferred embodiment of the present invention, the same or different hydrophilic polymer fluid in the inlet of the main channel and the inlet of the subchannels 2 and 3 of the (a) three-dimensional hydrodynamic focusing apparatus included in the system of the present invention The subchannel 1 is injected with a contrast agent.

According to another preferred embodiment of the present invention, the hydrophilic polymer fluid used in the system of the present invention is poly N-isopropylacrylamide (PNIPam), polyethylene glycol (PEG), chitosan, alginate, chitin, poly (L-lactic acid). (PLLA), poly (D, L-lactic acid) (PDLLA), poly (glycolic acid) (PGA), poly (caprolactone) (PCL), poly (hydroxyalkanoate), polydioxanone (PDS), Polytrimethylene carbonate, poly (lactic acid-co-glycolic acid) (PLGA), poly (L-lactic acid-co-caprolactone) (PLCL), poly (glycolic acid-co-caprolactone) (PGCL), hyaluronic acid , Chondroitin sulfate, dermatan sulfate, carboxymethylcellulose, heparan sulfate, heparin, keratan sulfate, carboxymethylhydroxyethylcellulose, cellulose sulfate, cellulose phosphate, carboxymethylgua, carboxymethylhydroxypropylguar , Carboxy Tylhydroxyethylguar, xanthan gum, gellan gum, welan gum, rhamsan gum, agarose, furcellaran, pectin, gum arabic, tragacanth rubber (gum tragacanth), carrageenans, starch phosphate, starch succinate, glycoaminoglycans, polysaccharides, polypeptides, acrylamides, N-vinylpyrrolidone, dimethylacrylamide, acrylic acid, methacrylic acid At least 1 from the group consisting of maleic anhydride, vinylsulfonic acid, styrenecarboxylic 2-acrylamido-2-methyl-propanesulfonic acid, vinylphosphonic acid, 2-methylacryloyloxyethylsulfonic acid, gelatin and collagen It is a biodegradable polymer selected from more than one species.

According to another preferred embodiment of the present invention, the hydrophilic polymer fluid used in the present invention further includes a crosslinking agent, a curing agent, and one selected from the group consisting of a crosslinking agent and a curing agent.

According to another preferred embodiment of the present invention, the contrast agent encapsulated by the system of the present invention, magnetic resonance imaging (MRI) contrast agent, computed tomography (CT) contrast agent, single photon emission computed tomography (SPECT) contrast agent, positron emission tomography ), BL (bioluminescence) contrast agent, optical contrast agent, X-ray contrast agent and ultrasound contrast agent.

According to another preferred embodiment of the present invention, the hydrophobic fluid injected into the droplet-on wrap chip of the present invention is hexadecane, paraffin oil, isopropyl myristate, silicone oil, sunflower oil, corn oil, soybean oil, avocado oil , Sesame oil, jojoba oil, olive oil, nut oil, squalane, fish oil, ethoxylated alkyl ether oil, propoxylated alkyl ether oil, phytosphingosine, sphingosine, sphinginine, cerebrose, is selected from cholesterol, campesterol, beta-sitosterol, sterol fucoidan, cholesteryl sulfate, cholesteryl sulfate, cytokines, the group consisting of C _{10 -40} fatty alcohol and ceramides.

According to another preferred embodiment of the present invention, the fluid passing through the vertical focusing portion of subchannel 1 of the three-dimensional hydrodynamic focusing device of the present invention is transferred to the main channel and the hydrophilic polymer fluid layer introduced from the top into the main channel by laminar flow. A double layer is formed of the introduced contrast agent layer, and the fluid passing through the vertical focusing part of the subchannel 2 flows into the hydrophilic polymer fluid layer introduced into the main channel from the top by laminar flow, the contrast agent layer introduced into the subchannel 1, and the subchannel 2. A triple layer is formed of the introduced hydrophilic polymer fluid layer, and the fluid passing through the horizontal focusing portion of the subchannel 3 is concentrically transferred from the center to the subchannel 1 to the contrast agent layer, the main channel, the subchannel 2, and the subchannel 3. It is formed into the introduced hydrophilic polymer fluid layer.

According to another preferred embodiment of the present invention, UV is irradiated to the microdroplets formed in the confluence channel of the lab-on-a-chip of the present invention to cure the hydrophilic polymer fluid.

According to another aspect of the present invention, the present invention provides an embolic microsphere in which a contrast agent is encapsulated using the above-described embolic microsphere production system of the present invention.

According to a preferred embodiment of the present invention, the embolic microspheres in which the contrast agent of the present invention is encapsulated have a diameter of 400-600 microns.

(B) embolism with pharmacologically active substance Microsphere Manufacturing System

The embolic microsphere manufacturing system equipped with the pharmacologically active material may be configured by combining a spiral lamination chaos micro mixer and a lab-on-a-chip for droplet formation.

The system of the present invention comprises: (a) a spiral lamination chaos micromixer for injecting and mixing a pharmacologically active substance and a hydrophilic polymer fluid; And (b) a droplet-forming wrap-on chip for injecting a hydrophobic fluid and a mixed fluid of the pharmacologically active material and the hydrophilic polymer fluid mixed by the micromixer of (a), respectively.

According to a preferred embodiment of the present invention, (a) the spiral lamination chaos micromixer included in the system of the present invention includes (i) at least one pair of inlets into which the pharmacologically active substance and the hydrophilic polymer fluid are injected, and the injected fluid is Inflow channel passing through; (Ii) an outlet channel through which the injected fluid is mixed and discharged to the droplet-on-a-chip; (Iii) a mixing part including a first mixing unit and a second mixing unit for mixing the injected fluid while being arranged in series with each other while being connected between the inflow channel and the outflow channel to form a three-dimensional spiral flow path,

The first mixing unit may include at least a pair of primary split channels branched from the inflow channel and extending toward the first side with respect to the direction of fluid flow in the inflow channel, through which the joined fluid is repartitioned; And a primary confluence channel disposed in a different layer from the primary partition channel and communicating with each end of the primary partition channel to allow the divided fluid to join.

The second mixing unit includes at least one pair of secondary split channels branched from the primary confluence channel and extending toward the second side piece in a direction opposite to the first side piece, through which the joined fluid is subdivided. And a secondary confluence channel disposed in a different layer from the secondary partition channel and communicating with each end of the secondary partition channel to allow the divided fluid to join, and the secondary confluence channel to the outlet channel. Subsequently, the injected fluid is transported through a three-dimensional spiral flow path and combined to combine the split and rearrangement and the chaotic mixing mechanism of the chaotic advection.

According to a more preferred embodiment of the present invention, the primary split channel is a main channel extending in a direction parallel to the inflow channel, and is bent in a direction substantially perpendicular to the traveling direction of the main channel toward the first side piece. A branch channel is formed.

According to another preferred embodiment of the present invention, the secondary divided channel, the main channel leading in a direction parallel to the inflow channel, and the second side to the direction substantially perpendicular to the direction of travel of the main channel toward the second side And branching channels formed.

According to still another preferred embodiment of the present invention, the mixing portion is provided with a plurality of first and second mixing units alternately arranged alternately.

According to another preferred embodiment of the present invention, the primary splitting channel of the first mixing unit is formed in a different layer from the secondary splitting channel of the second mixing unit, and the primary confluence channel of the first mixing unit Is formed in a different layer from the secondary confluence channel of the second mixing unit.

According to another preferred embodiment of the present invention, the primary confluence channel of the first mixing unit is formed in the same layer as the secondary division channel of the second mixing unit.

According to another preferred embodiment of the present invention, the primary and secondary split channel and the primary and secondary confluence channel, the fluid divided through the respective divided channel is transferred to the recombination point through the respective confluence channel Are formed to move by the same distance each.

According to another preferred embodiment of the present invention, a constriction is formed in the confluence channel of the mixing unit, even more preferably the constriction is formed at the point where the confluence channel of the mixing unit meets the split channel. Preferably, a constriction is formed at the end of the split channel that meets the confluence channel.

In addition, the droplet-forming wrap-on-a-chip which (b) the hydrophobic fluid and the pharmacologically active material and hydrophilic polymer fluid mixed by the micromixer of (a) included in the system of the present invention are respectively injected is (A). The same contents are omitted to avoid the complexity of the specification, except that the contrast agent is encapsulated by the droplet-forming wrap-on-a-chip included in the system and the three-dimensional hydrodynamic focusing device.

According to another preferred embodiment of the invention, the pharmacologically active substance to be loaded by the system in the present invention is an anticancer agent.

According to another aspect of the present invention, the present invention provides embolic microspheres on which the pharmacologically active substance prepared by the above-described system of the present invention is mounted.

According to a preferred embodiment of the present invention, the embolic microspheres on which the pharmacologically active substance of the present invention is mounted have a diameter of 400-600 microns.

(C) The contrast agent Being enclosed  With pharmacologically active substance Embolism Microspheres  Manufacturing system

The embolic microsphere preparation system in which the contrast agent of the present invention is encapsulated and the pharmacologically active substance is loaded includes: (a) a spiral lamination chaos micromixer injecting and mixing the pharmacologically active substance and the hydrophilic polymer fluid; (b) a three-dimensional hydrodynamic focusing apparatus for injecting a mixed fluid and a contrast agent fluid of the pharmacologically active substance and the hydrophilic polymer fluid mixed by the micromixer to focus the contrast agent on the mixed fluid; And (c) a droplet-forming lab-on-a-chip for injecting a hydrophobic fluid and a mixed fluid in which the contrast medium is focused by the three-dimensional hydrodynamic focusing device of (b).

To avoid duplication of specification for the same content as (a) the helical lamination chaos micromixer injecting and mixing the pharmacologically active substance and the hydrophilic polymer fluid included in the system of the present invention and the micromixer included in the system (B) described above. Omitted for this purpose.

According to a preferred embodiment of the present invention, (a) the spiral lamination chaos micromixer included in the system of the present invention includes (i) at least one pair of inlets into which the pharmacologically active substance and the hydrophilic polymer fluid are injected, and the injected fluid is Inflow channel passing through; (Ii) an outlet channel through which the injected fluid is mixed and discharged to a three-dimensional hydrodynamic focusing device; (Iii) a mixing part including a first mixing unit and a second mixing unit for mixing the injected fluid while being arranged in series with each other while being connected between the inflow channel and the outflow channel to form a three-dimensional spiral flow path,

The first mixing unit may include at least a pair of primary split channels branched from the inflow channel and extending toward the first side with respect to the direction of fluid flow in the inflow channel, through which the joined fluid is repartitioned; And a primary confluence channel disposed in a different layer from the primary partition channel and communicating with each end of the primary partition channel to allow the divided fluid to join.

The second mixing unit includes at least one pair of secondary split channels branched from the primary confluence channel and extending toward the second side piece in a direction opposite to the first side piece, through which the joined fluid is subdivided. And a secondary confluence channel disposed in a different layer from the secondary partition channel and communicating with each end of the secondary partition channel to allow the divided fluid to join, and the secondary confluence channel to the outlet channel. Subsequently, the injected fluid is transported through a three-dimensional spiral flow path and combined to combine the split and rearrangement and the chaotic mixing mechanism of the chaotic advection.

The three-dimensional hydrodynamic focusing apparatus included in the system of the present invention is the same as the three-dimensional hydrodynamic focusing apparatus included in the system (A), but the system of the present invention differs in that the pharmacologically active substance is loaded.

According to a preferred embodiment of the present invention, (b) the three-dimensional hydrodynamic focusing device is a mixture of the pharmacologically active material and the hydrophilic polymer fluid in which the inlet and the contrast agent is injected and the fluid mixed with the pharmacologically active material and the hydrophilic polymer fluid A main channel having an outlet for outflowing the fluid; And subchannels 1 to 3 communicating with the main channel at regular intervals between the inlets and the outlets of the main channel and being formed to cross each other, having a pair of inlets, and arranged at regular intervals from the inlet of the main channel.

According to a more preferred embodiment of the present invention, the sub-channels 1 and 2 are disposed on the lower layer of the main channel and the cross-section portion of the sub-channel 1, 2 and the width of the main channel is locally reduced to form a vertical focusing portion, The subchannel 3 is disposed on the same layer as the main channel and forms a horizontal focusing part in the cross-sectioned portion without changing the width of the subchannel 3 and the main channel.

According to another preferred embodiment of the present invention, the droplet forming wrap-on chip included in the system of the present invention includes a pair of side channels having an inlet through which a hydrophobic fluid is introduced, The confluence point includes an inlet through which a mixed fluid of pharmacologically active material and a hydrophilic polymer fluid is concentrated, and an outlet through which a mixed fluid of pharmacologically active material and a hydrophilic polymer fluid, wherein the hydrophobic fluid and a contrast agent fluid are concentrated, flows out. The outlet port includes a confluence channel communicating with the outlet port and having a locally reduced diameter, a conduit channel and tube rapidly increasing in diameter, and forming a constant diameter, and the pharmacologically active substance concentrated with a contrast agent fluid flowing through the conduit channel through the outlet port. And the mixed fluid of the hydrophilic polymer fluid is combined with the hydrophobic fluid to obtain a difference in surface tension. Due to the formation of fine droplets.

According to another preferred embodiment of the present invention, the same or different hydrophilic polymer fluid is injected into the inlet of the main channel and the inlets of the subchannels 2 and 3, and contrast medium is injected into the subchannel 1.

According to another preferred embodiment of the invention, the pharmacologically active substance to be loaded by the system in the present invention is an anticancer agent.

The hydrophilic polymer fluid used in the system (C) of the present invention, the components additionally included in the fluid, the contrast agent and the hydrophobic fluid are the same as those used in the system (A) of the present invention, and thus the same contents are used to avoid the complexity of the specification. Is omitted.

According to another preferred embodiment of the present invention, the fluid passing through the vertical focusing section of subchannel 1 of the system of the present invention is a mixed fluid layer and part of pharmacologically active material and hydrophilic polymer fluid introduced into the main channel from above by laminar flow. A double layer is formed of the contrast agent layer introduced into the channel 1, and the fluid passing through the vertical focusing part of the subchannel 2 is a mixed fluid layer of the pharmacologically active substance and the hydrophilic polymer fluid introduced from the top into the main channel by laminar flow, and the subchannel 1 Contrast layer introduced into the subchannel 2 and the hydrophilic polymer fluid layer introduced into the triple layer is formed, the fluid passing through the horizontal focusing portion of the subchannel 3 is the contrast agent layer introduced into the subchannel 1 from the center, concentrically, the main channel And a mixed fluid layer of the pharmacologically active material and the hydrophilic polymer fluid introduced into the channels, the subchannels 2 and the subchannels 3.

According to a more preferred embodiment of the present invention, the hydrophilic polymer fluid by irradiating UV to the microdroplets of the mixed fluid of the pharmacologically active material and the hydrophilic polymer fluid focused on the contrast agent fluid formed in the confluence channel of the droplet-on-a-chip chip of the present invention Harden.

According to another aspect of the present invention, the present invention provides an embolic microsphere in which a contrast agent prepared by the above-described system of the present invention is enclosed and a pharmacologically active substance is loaded.

According to a preferred embodiment of the present invention, the embolic microspheres encapsulated with the contrast agent of the present invention and loaded with the pharmacologically active substance have a diameter of 400-600 microns.

The features and advantages of the present invention are summarized as follows:

(a) The present invention provides an embolic microsphere production system and an embolic microsphere manufactured using the system.

(b) The embolic microsphere production system of the present invention is an embolization, contrast agent or drug delivery system that is applied to blood vessels formed around tumor tissue by encapsulating or / and mounting a contrast agent or / and pharmacologically active substance (anticancer agent) ( Embolization microspheres for use in drug delivery systems (DDS) can be prepared simply and efficiently.

(c) In addition, the average diameter of the embolic microspheres prepared through the system is constant to 400-600 microns to fit the blood vessel size, and when the pharmacologically active material is loaded can maximize the efficiency of embolization.

(d) On the other hand, the embolic microspheres in which the contrast agent is enclosed provide the ease of the procedure.

(e) The helical micromixer and 3D-HFMD included in the system of the present invention may microfluidically mix or encapsulate a contrast agent or an anticancer agent.

1 is a schematic diagram showing a process of making microdroplets.
2 is a schematic view showing a PDMS casting process for manufacturing a droplet-on wrap chip.
Figure 3 is a photograph showing the microsphere droplet preparation experimental apparatus.
4 is a photograph showing the flow of the confluence channel and the tube after the generation of microsphere droplets.
5 is a photograph showing the process of curing the microsphere droplets with UV lamps at the tube exit through the confluence channel.
6 is a schematic of a three-dimensional hydrodynamic focusing microfluidic device (3D-HFMD).
7 is a schematic diagram of a method for encapsulation of SPIO into a hydrophilic fluid using 3D-HFMD.
8A is a schematic diagram showing a serpentine laminating micromixer (SLM), and FIG. 8B shows a process of dividing and stacking the injected fluid.
Figure 9 is a schematic diagram showing the process of producing a blood vessel tailored functional polymer-contrast agent (SPIO) -pharmacologically active substance (anticancer agent) microspheres.
<Description of the symbols for the main parts of the drawings>
100: lab-on-a-chip for droplet formation;
110, 111: side channel; 120: inlet; 130: outlet; 140; A confluence channel of locally decreasing diameter; 150: a confluence channel in which the diameter rapidly increases and forms a constant diameter; 160: confluence of the side channels;
200: three-dimensional hydrodynamic focusing device;
210: main channel; 220, 230, 240: subchannels 1 to 3;
211: inlet for injecting sheath flow A; 212: an outlet for outflow of the enveloped flows A, B, and C where the core flow is focused; 221, 222: inlet of subchannel 1; 231, 232: inlet of subchannel 2; 241, 242: inlet of subchannel 3; 250: vertical focusing unit; 260: horizontal focusing unit;
300: spiral micro mixer;
12: inlet channel: 12a, 12b: inlet for fluid; 13: outlet channel; 15: mixing section; 20: first mixing unit; 21, 22: primary split channel; 23: primary joining channel; 30: second mixing unit; 31, 32: secondary split channel; 31, 32: secondary split channel; 33: secondary confluence channel; 34: extension; 51: final confluence channel.

Hereinafter, the present invention will be described in more detail with reference to the accompanying drawings. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not to be construed as limiting the scope of the present invention. It will be self-evident.

Example

1 is a schematic diagram showing a process of making micro droplets, Figure 2 is a schematic diagram showing a PDMS casting process for manufacturing a droplet-on wrap-on chip, Figure 3 is a photograph showing a microsphere droplet manufacturing experiment apparatus. 4 is a photograph showing a process of flowing the confluence channel and the tube after the creation of the microsphere droplets, Figure 5 is a photograph showing the process of curing the microsphere droplets through the UV channel to the tube exit through the confluence channel.

In the present invention, the droplet-on wrap-on chip is commonly used in all three systems.

As can be seen in the schematic diagram of FIG. 1, the droplet-form wrap-on-a-chip 100 included in the system of the present invention includes a pair of side channels 110 and 111 having an inlet through which an oily fluid is introduced. The confluence point 160 of the side channels 110 and 111 includes an inlet port 120 through which a hydrophilic polymer fluid flows in and an outlet port 130 through which the oily fluid and hydrophilic polymer fluid flow out, and the outlet port 130. The conduit includes a confluence channel 140 communicating with the outlet 130 and having a locally reduced diameter, a conduit channel 150 and a tube which rapidly increase in diameter and form a constant diameter, and pass through the outlet 130 to merge. The hydrophilic polymer fluid flowing through the channel 150 joins the oily fluid and hydrophilic polymer fluids form fine droplets due to hydrodynamic instability due to the difference in surface tension.

In addition, as shown in the photograph of FIG. 3, the hydrophobic fluid is introduced into the side channels 110 and 111 of the lab-on-a-chip through the A tube, and the hydrophilic polymer fluid is introduced into the inlet 120 of the lab-on-a-chip through the B tube. Inflow.

Wrap-on-a-chip (100) manufacturing process for droplet formation includes COC (cyclic olefin copolymer), PMMA (polymethylmethacrylate), and PS (polystyrene) through mass production methods such as injection molding, hot embossing, UV-molding, and casting. Polymers such as polycarbonate (PC), polydimethylsiloxane (PDMS), polytetrafluoroethylene (Teflon), and polyvinylchloride (PVC). The lab-on-a-chip may be manufactured using any of the above processes, but in Example 1 of the present invention, the fabrication process is described in a droplet-on-a-lab for forming droplets using UV-molding and PDMS casting. The PDMS casting process for manufacturing the on-chip is shown in FIG. 2.

Hydrophilic polymers used in the system of the present invention may utilize a variety of biodegradable and biocompatible polymers known in the art, preferably poly N-isopropylacrylamide (PNIPam), polyethylene glycol (PEG), chitosan, alginate , Chitin, poly (L-lactic acid) (PLLA), poly (D, L-lactic acid) (PDLLA), poly (glycolic acid) (PGA), poly (caprolactone) (PCL), poly (hydroxyalkanoate ), Polydioxanone (PDS), polytrimethylene carbonate, poly (lactic acid-co-glycolic acid) (PLGA), poly (L-lactic acid-co-caprolactone) (PLCL), poly (glycolic acid-co- Caprolactone) (PGCL), hyaluronic acid, chondroitin sulfate, dermatan sulfate, carboxymethylcellulose, heparan sulfate, heparin, keratan sulfate, carboxymethylhydroxyethylcellulose, cellulose sulfate, cellulose phosphate, carboxymethyl sphere Are, Kar Methylhydroxypropylguar, carboxymethylhydroxyethylguar, xanthan gum, gellan gum, welan gum, rhamsan gum, agarose, furcellaran, Pectin, gum arabic, gum tragacanth, carrageenans, starch phosphate, starch succinate, glycoaminoglycans, polysaccharides, polypeptides, acrylamides, N-vinylpyrrolidone, Dimethylacrylamide, acrylic acid, methacrylic acid, maleic anhydride, vinylsulfonic acid, styrenecarboxylic acid 2-acrylamido-2-methyl-propanesulfonic acid, vinylphosphonic acid, 2-methylacryloyloxyethylsulfonic acid, At least one is selected from the group consisting of gelatin and collagen.

In order to produce microdroplets into embolic microspheres, a curing process is required, and the curing method is different depending on the use of the hydrophilic polymer material. There are various curing methods such as curing by radical or thermal reaction by heat or UV light, curing by chemical action, and physical coagulation. However, polyN-isopropyl is a biodegradable and biocompatible polymer. Acrylamide (PNIPam), Polyacrylamide (PAAm), Polyacrylic Acid (PAA), Polyethylene Glycol (PEG), Polyethylene Glycol Dimethacrylate (PEGDM), Polyethylene Glycol Dimethacrylic Acid (PEGDMA), Polyglycoaminoglycans , Polysaccharides, polypeptides, poly N-vinylpyrrolidone, maleic anhydride, polyvinylsulfonic acid, polystyrenecarboxylic acid, 2-acrylamido-2-methyl-propanesulfonic acid, polyvinylphosphonic acid, 2- Methylacryloyloxyethylsulfonic acid, gelatin or collagen can be cured using UV light.

Among the biocompatible polymers mentioned above, the materials cured by chemical action include aminobenzoic acid, chitosan, alginate, carboxymethyl cellulose, heparan sulfate, heparin, keratan sulfate, carboxymethylhydroxyethyl cellulose, cellulose Sulfate, cellulose phosphate, xanthan gum, gellan gum, welan gum, rhamsan gum, agarose, furcellaran, pectin, gum arabic, tragacanth gum tragacanth, carrageenans, starch phosphate, starch succinate, and the like, and the curing method is cured through a chemical reaction that is emulsified with a hydrophilic solvent and a hydrophobic solvent.

Finally, biocompatible polymers cured by physical aggregation include divinylbenzene, polyphenylenevinylene (PPV) series, polylactic acid series-polylactic acid (PLA), and poly (L-lactic acid). ) (PLLA), poly (D, L-lactic acid) (PDLLA), poly (glycolic acid) (PGA), poly (caprolactone) (PCL) and the like.

In addition, the hydrophilic polymer may further include a crosslinking agent, a curing agent or a crosslinking agent and a curing agent, and in the case of curing using UV light, the crosslinking agent may include N, N'-methylenebisacrylamide (MBA), Bis-succinimide ester-activated PEG (PEG), ethylene glycol bis (succinimidylsuccinate), ethylene glycol bis (sulfosuccinimidylsuccinate) ( ethylene glycol bis (sulfosuccinimidylsuccinate), bis [2- (succinimidooxycarbonyloxy) ethyl] sulfone (bis [2- (succinimidooxycarbonyloxy) ethyl] sulfone), dithiobis (succinimidyl propionate) succinimidyl propionate)), 3,3'-dithiobis [sulfosuccinimidylpropionate), dimethyl 3,3'-dithiobispropionimate 2 HCl (dimethyl 3,3´) -dithiobispropionimidate 2 HCl), Succinimidyl suberate, bis (sulfosuccinimidyl) suberate, dimethyl suberimidate 2 HCl, dimethyl adipimidate 2 dimethyl adipimidate 2 HCl), disuccinimidyl glutarate, disuccinimidyl tartarate, 1,5-difluoro-2,4-dinitrobenzene (1,5-difluoro-2 , 4-dinitrobenzene), 1,4-di- [3 '-(2'-pyridyldithio) -propionamido] butane (1,4-Di- [3'-(2'-pyridyldithio) -propionamido butane), 1,6-hexane-bis-vinylsulfone, 1,8-bis-maleimidodiethyleneglycol, dithio- Dithio-bismaleimidoethane, bis-maleimidohexane, 1,4-bismaleimidobutane, 1,4-bismaleimidobutane, 1,4-bismaleimidobutane Dihydroxybutane (1,4-bismaleimidyl-2, 3-dihydroxybutane) and bis- [b- (4-azidosalicylamido) ethyl] disulfide (bis- [b- (4-azidosalicylamido) ethyl] disulfide) are preferable, and as a curing agent, α-hydroxykenone (α-Hydroxyketone), phenylglyoxylate, benzyldimethyl-ketal, α-aminoketone, mono acryl phosphine; MAPO), bis acryl phosphine (BAPO), BAPO / α-hydroxyketone, phosphine oxide, metallocene, 4- (2-hydroxyethoxy) phenyl- (2-hydroxy-2-propyl) ketone) (4- (2-hydroxyethoxy) phenyl- (2-hydroxy-2-propyl) ketone), an iodonium salt, and the like are preferable.

Hydrophobic fluids used in the present invention affect only the viscosity of the fluids and their mutual reactivity with the hydrophilic fluids at the interface and can utilize various oily fluids known in the art, preferably hydrocarbons such as hexadecane and paraffin oils. Oil; Synthetic synthetic oils such as isopropyl myristate; Silicone oils such as dimethicone and cyclomethicone series; Animal and vegetable oils such as sunflower seed oil, corn oil, soybean oil, avocado oil, sesame oil, jojoba oil, olive oil, nut oil, squalane and fish oil; Ethoxylated alkyl ether oils; Propoxylated alkyl ether oils; Sphingoidoid lipids such as phytosphingosine, sphingosine and sphinginine; Cerebroside; cholesterol; Camphorsterol; Beta sitosterol; Fusterol; Cholesteryl sulfate; Cytosteryl sulfate; A C _10-40 fatty alcohol or ceramides.

The ratio of the crosslinking agent and the curing agent included in the hydrophilic polymer may vary depending on the use and the experimental method.

The principle of forming fine droplets using the droplet-on wrap chip of FIG. 1 is to make the hydrophilic polymer fluid into a core / sheath flow with a hydrophobic fluid so that an interfacial tension can be achieved by passing an orifice. The hydrodynamic instability caused by the difference in tension causes the hydrophilic monomer to become fine droplets.

In the present invention, the two dimensionless numbers governing the system, Reynolds number (ratio of inertia and viscous force) and capillary number (ratio of viscosity and surface tension), are considered to be 100-1000 microns in size. In order to produce uniform microspheres, a lab-on-a-chip was manufactured using the experimental apparatus as shown in FIG. 3 through a UV etching process and a PDMS replica molding process. In particular, the sphere size (sphere size) was aimed at 400-600 microns, because the size is suitable for the vessel size to serve as a microsphere for color.

As described above, the lab-on-a-chip can be manufactured through various processes, but it is made using PDMS casting, which is less easy to manufacture and less expensive than other processes, and the manufacturing method is relatively easy. However, in order to satisfy the desired size of the microspheres, a large channel cross section is required, which makes it difficult to make the device high in the process. Therefore, in order to satisfy the condition, the size of the channel was increased by overlapping two PDMS sheets during the experiment. In addition, the size of the orifice and the width of the channel involved in the size of the drop was also adjusted.

FIG. 6 is a schematic diagram of a three-dimensional hydrodynamic focusing microfluidic device (3D-HFMD), and FIG. 7 is a diagram illustrating a method of encapsulating SPIO inside a hydrophilic fluid using 3D-HFMD. Schematic.

As can be seen in the panel (a) of FIG. 6, the three-dimensional hydrodynamic focusing device 200 is configured to discharge the inlet 211 for injecting the sheath flow A and the sheath flows A, B, and C where the core flow is focused. A main channel 210 having an outlet 212; And a pair of inlets 221 222, 231 232, and 241 242 communicating with the main channel 210 at regular intervals between the inlet 211 and the outlet 212 of the main channel 210 to form a cross. Sub-channels 1 to 3 (220, 230, 240) arranged at regular intervals from the inlet 211 of the main channel 210,

The subchannels 1 220 and 2 230 are disposed on the lower layer of the main channel 210, and the widths of the subchannels 1 220, 2 230, and the main channel 210 are locally formed at the intersections. Is reduced to form a vertical focusing unit 250, and the subchannel 3 240 is disposed on the same layer as the main channel 211, and crosses the widths of the subchannel 3 240 and the main channel 211 at the cross section. The horizontal focusing part 260 is formed without change.

The 3D-HFMD 200 is composed of two layers without other dividing walls, and the width of the channel in the two vertical focusing units 250 is locally reduced to obtain a high aspect ratio. The core fluid and the other three sheath fluids A, B and C are injected into the 3D-HFMD 200 as in the panel of FIG. Referring to the panel (b) of FIG. 6, it can be seen that the two envelope flows A and B are made through an aspect ratio in which the vertical focusing of the core flow is locally increased. The vertically focused core flow is finally three-dimensional focused by the horizontal envelope flow (C).

The advantage of conventional devices and devices with locally increased aspect ratios is that conventional hydrodynamic focusing devices must maintain an aspect ratio (AR) of more than 1.0 to achieve vertical focusing. Considering the width of the microchannel (eg 300 μm), there is a process limitation because the height to be implemented is too high, and there is a disadvantage in that the pressure loss is increased when the channel width is reduced by the height limit. If the device has a locally increased aspect ratio, 3D-HFMD can be manufactured in a simple process without pressure loss, and stable 3D focusing can be achieved.

The reason for including the 3D-HFMD 200 in the system of the present invention is that embolism microspheres are produced and injected into the body, because without the contrast agent (eg, MRI), effective embolism becomes difficult. Accordingly, if an MRI contrast agent such as SPIO is encapsulated, embolization can be performed effectively. In order to make microspheres containing SPIO-encapsulated microspheres, contrast medium should be encapsulation inside the polymer. Prior to the above-described droplet-on-a-chip, droplet inlet and core flow of 3D-HFMD By producing an embolic microsphere manufacturing system capable of encapsulating the contrast agent by connecting (3-dimensional hydrodynamic focusing device), it is possible to obtain an embolic polymer microsphere in which the contrast agent is encapsulated.

7 is a schematic diagram of a method of encapsulating a contrast agent (SPIO) inside a hydrophilic fluid using 3D-HFMD.

Contrast agent that can be used in the present invention can use a variety of contrast agents known in the art, if the embolic microspheres can be identified in the body, preferably MRI (magnetic resonance imaging) contrast agent, CT (computed tomography) contrast agent, SPECT (single photon emission computed tomography) contrast agent, positron emission tomography (PET), bioluminescence (BL) contrast agent, optical contrast agent, X-ray contrast agent and ultrasound contrast agent.

Magnetic resonance imaging (MRI) contrast agents that can be encapsulated in embolic microspheres can include various contrast agents known in the art, including magnetic materials, and are preferably paramagnetic or superparamagnetic. ) Consists of a material containing a metal component. Exemplary paramagnetic metal components suitable for the present invention include stable free radicals (eg, stable nitroxides), transition elements, lanthanide elements, and actinides. Preferred elements are Gd (III), Mn (II), Cu (II), Cr (III), Fe (II), Fe (III), Co (II), Er (II), Ni (II), Eu (III) and Dy (III). Exemplary superparamagnetic metal components suitable for the present invention include ferro- or ferrimagnetic compounds such as pure iron, magnetic iron oxides (eg magnetite, Fe ₃ O ₄ ), γ-Fe ₂ O ₃ , Manganese ferrite, cobalt ferrite and nickel ferrite.

It is a complex compound which consists of the said core metal and a coordination ligand using the said metal as a center metal. Ligands constituting the metal complex include chelate ligands that form a bond with the central metal at the same time with two or more functional groups. Preferably, the chelating ligand is ethylenediaminotetracetic acid (EDTA), diethylenetriaminopentaacetic acid (DTPA), EOB-DTPA (N- [2- [bis (carboxymethyl) amino] -3- (4-ethoxyphenyl) propyl] -N- [2- [ bis (carboxymethyl) amino] ethyl] -L-glycine), DTPA-GLU (N, N-bis [2- [bis (carboxymethyl) amino] ethyl] -L-glutamic acid), DTPA-LYS (N, N- bis [2- [bis (carboxymethyl) amino] ethyl] -L-lysine), DTPA-BMA (N, N-bis [2- [carboxymethyl [(methylcarbamoyl) methyl] amino] ethyl] glycine), BOPTA (4- carboxy-5,8,11-tris (carboxymethyl) -1-phenyl-2-oxa-5,8,11-triazatridecan-13-oic acid), DOTA (1,4,7,10-tetraazacyclododecan-1,4 , 7,10-tetraacetic acid), DO3A (1,4,7,10-tetraazacyclododecan-1,4,7-triacetic acid), HPDO3A (10- (2-hydroxypropyl) -1,4,7,10-tetraazacyclododecan -1,4,7-triacetic acid) MCTA (2-methyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTMA ((α, α ′, α ″, α ′ ″) -Tetramethyl-1,4,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid), PCTA (3,6,9,15-tetraazabicyclo [9.3.1] pentadeca-1 (15) , 11,13-triene-3,6,9-tri acetic acid), BOPTA (4-carboxy-5,8, 11-bis (carboxymethyl) -1-phenyl-12- (phenylmethoxy) methyl-8-phosphomethyl-2-oxa-5,8,11-triazatridecan-12- oid acid), N, N ′-[(phosphonomethylimino) di-2,1-ethananediyl] bis [N- (carboxymethyl) glycine] (N, N'-phosphonomethylimino-di-2,1 -ethanediyl-bis (N-carboxymethylglycine)), N, N '-[(phosphonomethylimino) di-2,1-ethananediyl] bis [N- (phosphonomethyl) glycine] (N, N' -phosphonomethylimino-di-2,1-ethanediyl-bis (n-phosphonomethylglycine)), N, N '-[(phosphinomethylimino) di-2,1-ethananediyl] bis [N- (carboxymethyl) Glycine] (N, N '-(phosphinomethylimino-di-2,1-ethanediyl-bis- (N- (carboxymethyl) glycine), DOTP (1,4,7,10-tetraazacyclodecane-1,4,7,10- tetrakis (methylphosphonic acid), DOTMP (1,4,7,10-tetraazacyclodecane-1,4,7,10-tetrakis methylene (methylphosphinic acid), or derivatives thereof, including but not limited to.

CT (computed tomography) contrast agents that can be encapsulated in embolic microspheres can include iodine-based contrast agents such as ultravist or gold nanoparticle-based contrast agents.

It can also be encapsulated with a radioactive isotope and used for Single Photon Emission Computed Tomography (SPECT) or Positron Emission Tomography (PET). Examples of preferred radioisotopes are ¹⁰ C, ¹¹ C, ¹³ O, ¹⁴ O, ¹⁵ O, ¹² N, ¹³ N, ¹⁵ F, ¹⁷ F, ¹⁸ F, ³² Cl, ³³ Cl, ³⁴ Cl, ⁴³ Sc, ⁴⁴ Sc, ⁴⁵ Ti, ⁵¹ Mn, ⁵² Mn, ⁵² Fe, ⁵³ Fe, ⁵⁵ Co, ⁵⁶ Co, ⁵⁸ Co, ⁶¹ Cu, ⁶² Cu, ⁶² Zn, ⁶³ Zn, ⁶⁴ Cu, ⁶⁵ Zn, ⁶⁶ Ga, ⁶⁶ Ge, ⁶⁷ Ge, ⁶⁸ Ga, ⁶⁹ Ge, ⁶⁹ As, ⁷⁰ As, ⁷⁰ Se, ⁷¹ Se, ⁷¹ As, ⁷² As ⁷³ Se, ⁷⁴ Kr, ⁷⁴ Br, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ⁷⁷ Kr, ⁷⁸ Br, ⁷⁸ Rb, ⁷⁹ Rb, ⁷⁹ Kr, ⁸¹ Rb, ⁸² Rb, ⁸⁴ Rb, ⁸⁴ Zr, ⁸⁵ Y, ⁸⁶ Y, ⁸⁷ Y, ⁸⁷ Zr, ⁸⁸ Y, ⁸⁹ Zr, ⁹² Tc, ⁹³ Tc, ⁹⁴ Tc, ⁹⁵ Tc , ⁹⁵ Ru, ⁹⁵ Rh, ⁹⁶ Rh, ⁹⁷ Rh, ⁹⁸ Rh, ⁹⁹ Rh, ¹⁰⁰ Rh, ¹⁰¹ Ag, ¹⁰² Ag, ¹⁰² Rh, ¹⁰³ Ag, ¹⁰⁴ Ag, ¹⁰⁵ Ag, ¹⁰⁶ Ag, ¹⁰⁸ In, ¹⁰⁹ In, ¹¹⁰ In, ¹¹⁵ Sb, ¹¹⁶ Sb, ¹¹⁷ Sb, ¹¹⁵ Te, ¹¹⁶ Te, ¹¹⁷ Te, ¹¹⁷ I, ¹¹⁸ I, ¹¹⁸ Xe, ¹¹⁹ Xe, ¹¹⁹ I, ¹¹⁹ Te, ¹²⁰ I, ¹²⁰ Xe, ¹²¹ Xe, ¹²¹ I, ¹²² I, ¹²³ Xe, ¹²⁴ I, ¹²⁶ I, ¹²⁸ I, ¹³¹ I, ¹²⁹ La, ¹³⁰ La, ¹³¹ La, ¹³² La, ¹³³ La, ¹³⁵ La, ¹³⁶ La, ¹⁴⁰ Sm, ¹⁴¹ Sm, ¹⁴² Sm, ¹⁴⁴ Gd , ¹⁴⁵ Gd, ¹⁴⁵ Eu, ¹⁴⁶ Gd, ¹⁴⁶ Eu, ¹⁴⁷ Eu, ¹⁴⁷ Gd, ¹⁴⁸ Eu, ¹⁵⁰ Eu, ¹⁹⁰ Au, ¹⁹¹ Au, ¹⁹² Au, ¹⁹³ Au, ¹⁹³ Tl, ¹⁹⁴ Tl, ¹⁹⁴ Au, ¹⁹⁵ Tl, ^{1 96} Tl, ¹⁹⁷ Tl, ¹⁹⁸ Tl, ²⁰⁰ Tl, ²⁰⁰ Bi, ²⁰² Bi, ²⁰³ Bi, ²⁰⁵ Bi, ²⁰⁶ Bi, or derivatives thereof.

If the contrast agent contains fluorescent and optical materials, optical or bioluminescence (BL) images can be obtained. Examples of the fluorescent substance include fluorosane, rhodamine, lucifer yellow, B-phytoerythrin, 9-acridine isothiocyanate, lucifer yellow VS, 4-acetamido-4'-isothio-cya Natostilbene-2,2'-disulfonic acid, 7-diethylamino-3- (4'-isothiocyatophenyl) -4-methylcoumarin, succinimidyl-pyrenebutyrate, 4-acetamido -4'-isothiocyanatostilbene-2,2'-disulfonic acid derivative, LC ™ -Red 640, LC ™ -Red 705, Cy5, Cy5.5, lysamine, isothiocyanate, erythro Shin isothiocyanate, diethylenetriamine pentaacetate, 1-dimethylaminonaphthyl-5-sulfonate, 1-anilino-8-naphthalene sulfonate, 2-p-touidiyl-6-naphthalene sulfonate , 3-phenyl-7-isocyanatocoumarin, 9-isothiocyanatoacridine, acridine orange, N- (p- (2-benzoxazoylyl) phenyl) melimide, benzoxadiazole , Stilben, pyrene, these Including derivatives, silica nano particles containing a fluorescent substance, II / VI group semiconductor QD, III / V-group semiconductor quantum dot, a Group IV semiconductor quantum dots, or a multi-component hybrid structure, but not limited thereto it. In addition, the optical material includes, but is not limited to, gold nanoparticles, silver nanoparticles, or multicomponent hybrid structures thereof.

X-ray contrast agents preferably include barium sulphate, iodine, derivatives comprising iodine, or multicomponent hybrid structures thereof. In addition, when a contrast agent including a diagnostic agent (eg, a microbubble) for an ultrasound test is encapsulated in an embolic microsphere, it may be used in an ultrasound test.

The most preferred contrast agent that can be encapsulated in the embolic microspheres of the present invention is Gd-diethylenetriaminepentaacetic acid (gadopentate dimeglumine, Gd-DTPA), Gd-1,4,7,10-tetraazacyclododecane-1, 4,7,10-tetraacetic acid (Gd-OTA), Gd-1,4,7,10-tetraazacyclododecane- (2-hydroxypropyl) -4,7,10-triacetic acid (Gd-PDO3A ), Gd-DOTA (gadoterate meglumine), Gd-DTPA-BMA (gadodiamide), Gd-HP-DO3A (gadoteridol), Gd-BOPTA (gadobenate di-meglumine), Gd-EOB-DTPA (gadoxetic acid), MS 325 (diphenylcyclohexyl phosphodiester-Gd-DTPA), MP 2269 (4-pentyl-bicyclo [2.2.2] octan-1-carboxyl-di-L-aspartyllysine-DTPA), Gd-DTPA-PEG polymer, (Gd-DTPA) n -Albumin, (Gd-DTPA) n-polylysine, (Gd-DTPA) n-dextran, Fe-HBED, Fe-EHPD, SPIO (supermagnetic iron oxide), SHU 555A (ferrixan, carboxy-dextran coated iron oxide nanoparticle ), Ultrasmall super paramagnetic iron oxide (USPIO), FeO-BPA USPIO, monocrystalline iron oxide nanoparticles (MION), polycrystalline iron oxi de nanoparticles), MnHA PEG-APD (manganese substituted hydroxylapatite PEG-APD), Dy-DTPA-BMA (sprodyamide), Dy-DTPA, albumin- (Dy-DTPA) x.

By using the contrast agent-encapsulated embolism microsphere manufacturing system as shown in FIG. 7, the contrast medium is injected into the core flow and the hydrophilic polymer fluid is injected into the envelope flow to create a flow in which the contrast agent is enclosed within the hydrophilic polymer fluid. This is injected into the hydrophilic fluid inlet of the droplet-on-a-chip for droplet formation and combined with the oily fluid to produce contrast-encapsulated fine droplets. Subsequently, as described above, when the curing, washing, and drying process are performed, the embolical microspheres in which the contrast agent is encapsulated may be manufactured.

8 is a schematic diagram showing a serpentine laminating micromixer (SLM).

Pharmacologically active substances for effective embolism Preferably doxorubicin (doxorubicin) or paclitaxel (paclitaxel) and the like, if mounted on the microspheres, the effect is incomparably higher compared to normal embolism. In microchannels, however, the low Re inside the channel prevents the effective mixing of two injected fluids. In existing large-scale systems, it is possible to induce turbulent flow with a large enough Reynolds number if the propeller is turned in the fluid or moving parts such as magnetic beads are introduced into the fluid. Thus, a mixture of fluids was obtained.

However, in the case of microfluidic systems, since the Reynolds number is greatly reduced, turbulence is formed in addition to the laminar flow, so that only mixing by diffusion can be expected, and as a result, it is difficult to obtain a uniform mixture of fluids. . Therefore, it can be seen that the micromixer is an essential device in the microchannel for the production of microspheres equipped with pharmacologically active materials. In the present invention, the SLM is used.

Referring to FIG. 8A, the micromixer 300 included in the system of the present invention includes a pair of inlets 12a and 12b through which different fluids are introduced, and an inlet channel 12 through which the injected fluids are joined. And an outlet channel 13 through which the injected fluid is mixed and discharged, and a mixing unit 15 formed between the inlet channel 12 and the outlet channel 13 to connect the injected fluids while mixing the injected fluid. . The mixing unit 15 includes a first mixing unit 20 and a second mixing unit 30 which are arranged successively.

The first mixing unit 20 includes a pair of primary split channels 21 and 22 branched from the inlet channel 12, and ends of the primary split channels 21 and 22. And a primary confluence channel 23 in communication. The primary split channels 21 and 22 extend toward the first side with respect to the flow direction of the inflow channel 12, and the fluid joined in the inflow channel 12 is repartitioned. The primary confluence channel 23 is disposed in a different layer from the primary split channels 21 and 22, and the fluid divided in the primary split channels 21 and 22 passes through.

The second mixing unit 30 includes a pair of secondary split channels 31 and 32 branched from the primary joining channel 23 and each of the secondary split channels 31 and 32. And a secondary confluence channel 33 in communication with the end. The secondary divided channels 31 and 32 extend toward the second side opposite to the first side, and the fluid joined in the primary confluence channel 23 is repartitioned. The secondary confluence channel 33 is disposed in a different layer from the secondary partition channels 31 and 32 while the fluid divided in the secondary partition channels 31 and 32 joins.

In the present exemplary embodiment, the primary divided channels 21 and 22 are formed to face the left side with respect to the advancing direction of the inflow channel 12, and the secondary divided channels 31 and 32 are the inflow channel 12. It is formed to face the right side with respect to the traveling direction of. In this case, the primary divided channels 21 and 22 are formed by being bent in a direction substantially perpendicular to the traveling direction of the inflow channel 12, and the secondary divided channels 31 and 32 are also formed in the inflow channel ( It is formed by bending in a direction substantially perpendicular to the traveling direction of 12). However, the present invention is not limited thereto, and the first divided channels 21 and 22 may face the right side, and the second divided channels 31 and 32 may face the left side.

The primary split channels 21 and 22 are main channels extending in a direction parallel to the inflow channel 12 and branch channels formed to be substantially perpendicular to the traveling direction of the main channel toward the first side. Can be divided into By providing a pair of branching channels, the splitting channel of this embodiment has an F-shape. When the number of split channels increases, the main channel has a longer length, and the number of branch channels increases. Similarly, the secondary divided channels 31 and 32 also have a main channel extending in a direction parallel to the inflow channel 12 and a branch formed to be bent in a direction substantially perpendicular to the traveling direction of the main channel toward the second side. Can be divided into channels.

The mixing unit 15 may be provided with a plurality of repeated alternating structures of the first mixing unit 20 and the second mixing unit 30 arranged in succession. As shown in FIG. 8B, the structures of the first mixing unit 20 and the second mixing unit 30 are repeated two times until the outlet channel 13 is formed. At this time, the final confluence channel 51 is connected to the outlet channel 13 to flow out the homogeneously mixed fluid.

On the other hand, in the mixing unit arranged in succession, the split channel and the confluence channel are formed by changing the layers. That is, the primary splitting channels 21 and 22 of the first mixing unit 20 are formed in different layers from the secondary splitting channels 31 and 32 of the second mixing unit 30 and the first mixing unit 20. The primary confluence channel 23 of) is formed in a different layer from the secondary confluence channel 33 of the second mixing unit 30. The primary confluence channel 23 is formed on the same layer as the secondary division channels 31 and 32 and connected to each other, and the secondary confluence channel 33 is connected to the primary division channels 21 and 22. Is formed on the same layer. The three-dimensional spiral flow path is formed by the first mixing unit 20 and the second mixing unit 30 provided as described above, and the injected different fluids are transferred through the chaotic mixing mechanism and the chaotic advection of splitting and rearranging. The chaotic mixing mechanism of the chaotic advection can be combined and mixed homogeneously.

At this time, the primary, secondary split channels (21, 22, 31, 32) and the primary, secondary confluence channels (23, 33), the fluid divided through the respective divided channels through the respective confluence channels They are formed to travel substantially the same distance each while being conveyed to the recombination point.

In addition, the expansion part 33 may be formed at the time points of the primary confluence channel 23 and the secondary division channels 31 and 32 branched therefrom to facilitate fluid flow.

Any fluid flow drive source, such as a pressure driven flow using pressure or an electric osmotic flow through an electric field, may be applied through the selection of the micro channel material for the flow driving of the fluids inside the micro channel as described above.

Hereinafter, a process of dividing the injected fluid will be described with reference to FIG. 8B.

The fluid flow injected through the pair of inlets 12a and 12b and joined in the inlet channel 12 is divided into two flows through the primary split channels 21 and 22 when it meets the first mixing unit 20. Then, combine again in the primary joining channel (23). That is, the first fluid 17 and the second fluid 18 injected through the injection holes 12a and 12b respectively meet as shown in FIG. 8B in section A of FIG. 8A, and the primary split channels 21 and 22. Are divided into B and C of FIG. 8B, respectively. The divided two fluids 17 and 18 are combined in the thickness direction due to the arrangement of the first mixing unit 20 according to the present embodiment in the primary confluence channel 23 so that the recombination aspect is stacked as shown in FIG. 8B. This is done. This mixing mechanism causes stacking in the thickness direction in D, G, J, and K of FIG. 8A to increase the interface of the fluid exponentially to induce chaotic mixing.

The pharmacologically active substance mixed with the hydrophilic polymer through the above-described micromixer is preferably an anticancer agent, more preferably paclitaxel, cisplatin, carboplatin, procarbazine, and memethol. Mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bisulfan, nitrosourea, diactino Mycin (dactinomycin), daunorubicin, doxorubicin, bleomycin, bleomycin, plicomycin, mitomycin, etoposide, tamoxifen, tamoxifen, Transplatinum, 5-fluorouracil, adriamycin, vincristin, vinblastin or methotrexate.

Figure 9 is a schematic diagram showing the process of producing a blood vessel tailored functional polymer-contrast agent (SPIO) -pharmacologically active substance (anticancer agent) microspheres.

Referring to Figure 9 through the embolic microspheres manufacturing system of the present invention to describe the embolic microspheres manufacturing process encapsulated with a pharmacologically active material (eg, anticancer agent), using a spiral micro mixer (SLM) (300) The anticancer agent and the hydrophilic polymer fluid are mixed and injected into the inlet 211 of the 3D-HFMD 200, and only the hydrophilic polymer fluid is introduced into the shell flow 231, 232, 241 and 242, and the SPIO in the core flow 221 and 222. Injecting a contrast agent, such as SPIO is made into a hydrophilic polymer loaded with an anticancer agent.

When the hydrophilic polymer loaded with the anticancer agent is injected with a hydrophobic fluid corresponding to oil on a shell fluid (110, 111) by using a droplet-forming wrap-on-a-chip (100), the SPIO-encapsulated microsphere droplets When the resulting droplets are cured using photopolymerization or chemical reactions, SPIO-enclosed anticancer loaded microspheres are produced.

These microspheres can be made in a relatively simple manner and have a constant size close to monodispersion. In addition, the size of the microspheres is 400-600 microns, suitable for blood vessel size, the contrast agent is encapsulated, the procedure is easy, and the anti-cancer agent is mounted to greatly increase the efficiency of embolization.

Example  One: Droplets  Forming Lab on a chip (LOC) 100  making

UV-molding and PDMS casting were used to fabricate LOC for droplet formation. In summary, the negative photoresist was coated onto the substrate and subjected to two soft baking processes. The photosensitive material was exposed to UV light through the manufactured mask. After UV exposure, a post exposure baking (PEB) process was performed. The patterned silicon substrate was developed to pattern the LOC master for microsphere fabrication.

Droplet-forming LOC was manufactured by casting polydimethylsiloxane (PDMS) on the silicon substrate master. PDMS casting was the first to silanize a silicon substrate to the surface, making it hydrophobic, making it easier to remove PDMS. In summary, PDMS consists of prepolymers and hardeners of Sylgard 184 (Dow Corning) and mixed at a ratio of 10: 1. The mixed PDMS was poured slowly into the silicon substrate and vacuumed to prevent the formation of air bubbles during casting. The silicon substrate and PDMS from which bubbles were removed in a vacuum state were thermosetted using a heating apparatus, and after curing, the PDMS was removed from the silicon substrate. 2 is a schematic showing the PDMS casting process described above.

Since only one cured PDMS could not be a microchannel, another PDMS was bonded to a glass plate or another PDMS. An oxidative plasma method was used for the conjugation of PDMS. In summary, the PDMS surface becomes hydrophilic when the plasma is oxidized. In order to increase the adhesion of PDMS, a plasma was applied to the PDMS surface so that all surfaces of the PDMS were hydrophilic, and then the two PDMS layers were directly bonded to each other, thereby preparing a wrap-on-a-chip having an inlet and an outlet as shown in FIG. .

Example  2: Wrap on a chip (100)  By using blank Microspheres  Produce

3 is a photograph showing a microsphere droplet manufacturing apparatus including the lab-on-a-chip 100 manufactured in Example 1. The material to be flowed into the hydrophilic fluid is a hydrophilic polymer, which is dissolved in a solvent (DI water) at a ratio of 10 w / w% (the weight of the solute / the weight of the solvent) of polyN-isopropylacrylamide (PNIPam) (Sigma-Aldrich). After dissolving, the crosslinking agent N, N'-methylenebisacrylamide (Sigma-Aldrich) was added at 0.3 mol% (relative molar ratio) of the hydrophilic polymer to dissolve, and finally the curing agent 4- (2-hydride). Hydroxyethoxy) phenyl- (2-hydroxy-2-propyl) ketone) (4- (2-hydroxyethoxy) phenyl- (2-hydroxy-2-propyl) ketone) (Irgacure 2959, Ciba Specialty Chemicals) Mix at 10 wt% (weight ratios) of the polymer.

As shown in FIG. 3, a hydrophilic fluid including a hydrophilic monomer PNIPam is introduced into the inlet B using a syringe pump to inject the silicone oil into the hydrophobic fluid such that the inlet A has a sheath flow. Injection was performed to prepare W / O microsphere droplets.

As can be seen in Figures 4 and 5, the microsphere droplets exiting the outlet of the confluence channel 150 of the lab-on-a-chip 100 continuously irradiated with UV lamps for several seconds using a UV lamp to cure the droplets to polymer Microspheres were prepared. Subsequently, the polymer microspheres were placed in an ethanol bath to remove the oil phase fluid, and the polymer microspheres were collected by filtering and drying.

Example  3: SPIO  Enclosed Microsphere  Produce

Superparamagnetic iron oxide (SPIO) was purchased from Sigma-Aldrich as a magnetic resonance imaging (MRI) contrast medium. In order to manufacture SPIO-encapsulated microspheres for encapsulating the microspheres for use in embolization, 3-D hydrodynamic focusing device (3D-HFMD) 200 of FIG. The lab-on-a-chip 100 was connected to the inlet B of FIG. 3 to form an embolic microsphere manufacturing system of FIG. 7 integrally formed.

As shown in FIG. 6 (a) panel and 7, SPIO is injected into the core flow, and the core fluid and three envelope fluids (hydrophilic fluid including PNIPam, crosslinking agent and curing agent) are injected to the inside of the hydrophilic fluid. SPIO-encapsulated droplets were prepared. In the same manner as in Example 2, the SPIO-encapsulated microsphere droplets exiting from the outlet of the lab-on-a-chip 100 and continuously flowing are irradiated with UV light and cured, and the oil phase fluid is removed. The SPIO is then filtered and dried. The enclosed microspheres were collected.

Example  4: anticancer Microsphere  Produce

In order to mount doxorubicin or paclitaxel, which is an anticancer agent for effective embolization, onto the microspheres, the serpentine laminating micromixer 300 of FIG. 8 is wrapped on the inlet B of FIG. 3. In connection with the anticancer agent-mounted microsphere manufacturing system was formed integrally.

Example  5: SPIO  Encapsulation and Anticancer material  Mount Microsphere  Produce

The microfluidic system was used to encapsulate and mount the contrast agent and the anticancer agent in the embolic microspheres to prepare embolic microspheres for embolization, contrast agent, and drug delivery system applied to blood vessels formed around tumor tissue.

As can be seen in Figure 9, in order to manufacture SPIO-encapsulated and anticancer loading microspheres, doxorubicin and PNIPam are mixed with a spiral laminating micromixer (SLM) 300, and the mixture is shown in (a) panel 3D- of FIG. Inject into HFMD 200 in sheath flow A (main channel inlet: 211), sheath flow B (inlet of subchannel 2: 231, 232) and sheath flow C (inlet of subchannel 3: 241, 242). SPIO, which is an MRI contrast agent, was injected into the core flow (inlets of the subchannel 1, 221 and 222) to create a flow in which the SPIO was encapsulated in a polymer loaded with an anticancer agent. Subsequently, the microspheres were prepared by injecting the silicone oil into the envelope flow (side channels 110 and 111) using the droplet-on wrap-on chip 100 while injecting the flow into the core flow, and applying UV light to the droplet. It irradiated and hardened | cured and the anticancer drug loading microspheres in which SPIO was enclosed was produced.

The microspheres thus made can be made in a relatively simple manner and have a constant size close to monodispersion. In addition, the size of the microspheres is 400-600 microns, suitable for blood vessel size, MRI contrast agent is encapsulated, the procedure is easy, and the anticancer agent is mounted, the efficiency of embolization can be greatly improved.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Thus, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

Claims (29)

(a) a three-dimensional hydrodynamic focusing device for injecting a hydrophilic polymer fluid and a contrast agent fluid to focus the contrast agent on the hydrophilic polymer fluid; And (b) a droplet-forming lab-on-a-chip for injecting a hydrophobic fluid and a hydrophilic polymer fluid in which a contrast agent fluid is concentrated by the three-dimensional hydrodynamic focusing device of (a).
2. The apparatus of claim 1, wherein (a) the three-dimensional hydrodynamic focusing device comprises: a main channel having an inlet for injecting a hydrophilic polymer fluid and an outlet for outflowing a hydrophilic polymer fluid focused with a contrast agent; And subchannels 1 to 3 communicating with the main channel at regular intervals between the inlet and the outlet of the main channel and being formed to cross each other, having a pair of inlets, and arranged to cross at regular intervals from the inlet of the main channel.
The subchannels 1 and 2 are disposed on a lower layer of the main channel, and the widths of the subchannels 1, 2 and the main channel are locally reduced in the intersected portion to form a vertical focusing portion, and the subchannel 3 is the same layer as the main channel. The embolic microspheres manufacturing apparatus, characterized in that the horizontal converging portion is formed on the cross-formed portion without changing the width of the subchannel 3 and the main channel.
The method of claim 1, wherein (b) the droplet-on wrap-on chip comprises a pair of side channels having an inlet for the hydrophobic fluid is introduced, the hydrophilic polymer fluid in which the contrast medium is concentrated at the confluence of the side channels An inlet for inflow and an outlet for outflow of a hydrophilic polymer fluid in which the hydrophobic fluid and the contrast medium are concentrated, and the outlet is in communication with the outlet and has a locally reduced diameter, a rapidly increasing diameter and forming a constant diameter. And a hydrophilic polymer fluid condensed with a contrast channel fluid passing through the confluence channel and the tube through the outlet, wherein the hydrophilic polymer fluid is combined with the hydrophobic fluid to form microdroplets due to a difference in surface tension. .
According to claim 2, The fluid passing through the vertical focusing portion of the sub-channel 1 forms a double layer of a hydrophilic polymer fluid layer introduced into the main channel from the top by laminar flow and a contrast agent layer introduced into the sub-channel 1, the sub-channel The fluid passing through the vertical focusing portion of 2 forms a triple layer with a hydrophilic polymer fluid layer introduced from the top into the main channel by laminar flow, a contrast agent layer introduced into the subchannel 1, and a hydrophilic polymer fluid layer introduced into the subchannel 2, The fluid passing through the horizontal focusing portion of the subchannel 3 is formed of a hydrophilic polymer fluid layer introduced into the contrast medium layer flowing from the center of the subchannel 1, the main channel, the subchannel 2 and the subchannel 3 in a concentric circle. Embolic microsphere manufacturing apparatus.
(a) a spiral lamination chaotic micromixer for injecting and mixing a pharmacologically active substance and a hydrophilic polymer fluid; And (b) a droplet-forming lab-on-a-chip for injecting a hydrophobic fluid and a mixed fluid of the pharmacologically active material and the hydrophilic polymer fluid mixed by the micromixer (a).
6. The apparatus of claim 5, wherein (a) the spiral lamination chaos micromixer comprises: (i) an inlet channel having at least one pair of inlets through which the pharmacologically active material and the hydrophilic polymer fluid are injected; (Ii) an outlet channel through which the injected fluid is mixed and discharged to the droplet-on-a-chip; (Iii) a mixing part including a first mixing unit and a second mixing unit for mixing the injected fluid while being arranged in series with each other while being connected between the inflow channel and the outflow channel to form a three-dimensional spiral flow path,
The first mixing unit may include at least a pair of primary split channels branched from the inflow channel and extending toward the first side with respect to the direction of fluid flow in the inflow channel, through which the joined fluid is repartitioned; And a primary confluence channel disposed in a different layer from the primary partition channel and communicating with each end of the primary partition channel to allow the divided fluid to join.
The second mixing unit is divided into at least a pair of secondary splitting from the primary confluence channel and extending toward the second side piece in a direction opposite to the first side piece. A channel and a secondary confluence channel disposed in a different layer from the secondary partition channel and communicating with each end of the secondary partition channel to allow the divided fluid to join, and the secondary confluence channel is the outlet channel. Continued in the transfer, the injected fluid through a three-dimensional spiral flow path and embossed microspheres manufacturing apparatus characterized in that the mixing and combining the chaotic mixing mechanism of the split and rearrangement and chaotic advection.
(a) a spiral lamination chaotic micromixer for injecting and mixing a pharmacologically active substance and a hydrophilic polymer fluid; (b) a three-dimensional hydrodynamic focusing apparatus for injecting a mixed fluid and a contrast agent fluid of the pharmacologically active substance and the hydrophilic polymer fluid mixed by the micromixer to focus the contrast agent on the mixed fluid; And (c) a droplet-forming lab-on-a-chip for injecting a hydrophobic fluid and a mixed fluid in which the contrast medium is focused by the three-dimensional hydrodynamic focusing device of (b).
The method of claim 7, wherein the (a) spiral lamination chaos micromixer comprises: (i) an inlet channel having at least a pair of inlets through which the pharmacologically active material and the hydrophilic polymer fluid are injected; (Ii) an outlet channel through which the injected fluid is mixed and discharged to a three-dimensional hydrodynamic focusing device; (Iii) a mixing part including a first mixing unit and a second mixing unit for mixing the injected fluid while being arranged in series with each other while being connected between the inflow channel and the outflow channel to form a three-dimensional spiral flow path,
The first mixing unit may include at least a pair of primary split channels branched from the inflow channel and extending toward the first side with respect to the direction of fluid flow in the inflow channel, through which the joined fluid is repartitioned; And a primary confluence channel disposed in a different layer from the primary partition channel and communicating with each end of the primary partition channel to allow the divided fluid to join.
The second mixing unit is divided into at least a pair of secondary splitting from the primary confluence channel and extending toward the second side piece in a direction opposite to the first side piece. A channel and a secondary confluence channel disposed in a different layer from the secondary partition channel and communicating with each end of the secondary partition channel to allow the divided fluid to join, and the secondary confluence channel is the outlet channel. Continued in the transfer, the injected fluid through a three-dimensional spiral flow path and embossed microspheres manufacturing apparatus characterized in that the mixing and combining the chaotic mixing mechanism of the split and rearrangement and chaotic advection.
The method according to claim 6 or 8, wherein the primary divided channel, the main channel extending in a direction parallel to the inflow channel, and is formed to be bent in a direction perpendicular to the traveling direction of the main channel toward the first side. An embolic microsphere manufacturing apparatus comprising a branch channel.
The method of claim 6 or 8, wherein the secondary divided channel is formed in a direction perpendicular to the traveling direction of the main channel toward the second side and the main channel extending in the direction parallel to the inflow channel. An embolic microsphere manufacturing apparatus comprising a branch channel.
The apparatus of claim 6 or 8, wherein the mixing part is provided with a plurality of first and second mixing units arranged in succession alternately.
The method according to claim 6 or 8, wherein the primary splitting channel of the first mixing unit is formed in a different layer from the secondary splitting channel of the second mixing unit, and the primary joining channel of the first mixing unit is Apparatus for producing a microemulsion sphere formed of a different layer from the secondary confluence channel of the second mixing unit.
The apparatus of claim 6 or 8, wherein the primary confluence channel of the first mixing unit is formed on the same layer as the secondary division channel of the second mixing unit.
10. The method of claim 6 or 8, wherein the primary and secondary split channel and the primary and secondary confluence channel, the fluid divided through each of the divided channels are transferred to the recombination point through the respective confluence channels. Embossed microspheres manufacturing apparatus is formed so as to move by the same distance each.
9. The embolic microspheres manufacturing apparatus according to claim 6 or 8, wherein a constriction is formed in a confluence channel of the mixing unit.
16. The apparatus of claim 15, wherein the constriction part is formed at a point where the confluence channel of the mixing unit meets the division channel.
17. The embolic microspheres manufacturing apparatus according to claim 16, wherein a constriction portion is formed at an end of the split channel that meets the confluence channel.
The method of claim 5, wherein (b) the droplet-on wrap-on chip comprises a pair of side channels having an inlet for the introduction of hydrophobic fluid, the confluence of the pharmacologically active material and the hydrophilic polymer fluid An inlet through which the fluid is introduced and an outlet through which the mixed fluid of the hydrophobic fluid, the pharmacologically active substance, and the hydrophilic polymer fluid flows out, and the outlet port communicates with the outlet and has a locally decreased diameter, and the diameter rapidly increases. The mixed fluid of the pharmacologically active material and the hydrophilic polymer fluid, which includes a tube having a constant diameter, and focuses the contrast channel fluid flowing through the confluence channel and the conduit through the outlet, joins the hydrophobic fluid to form fine droplets due to the difference in surface tension. Embossed microsphere manufacturing apparatus characterized in that it is formed.
The method of claim 7, wherein the (b) three-dimensional hydrodynamic focusing device flows out the inlet for injecting a mixed fluid mixed with the pharmacologically active material and the hydrophilic polymer fluid and the mixed fluid of the pharmacologically active material and the hydrophilic polymer fluid is concentrated contrast medium A main channel having an outlet; And subchannels 1 to 3 communicating with the main channel at regular intervals between the inlet and the outlet of the main channel and being formed to cross each other, having a pair of inlets, and arranged to cross at regular intervals from the inlet of the main channel.
The subchannels 1 and 2 are disposed on a lower layer of the main channel, and the widths of the subchannels 1, 2 and the main channel are locally reduced in the intersected portions to form a vertical focusing portion, and the subchannel 3 is the same layer as the main channel. The embolic microspheres manufacturing apparatus, characterized in that the horizontal converging portion is formed on the cross-formed portion without changing the width of the subchannel 3 and the main channel.
8. The method of claim 7, wherein (c) the droplet-on wrap-on chip comprises a pair of side channels having an inlet for the introduction of hydrophobic fluid, the confluence of the pharmacologically active material and the contrast agent fluid at the confluence of the side channels; An inlet through which a mixed fluid of a hydrophilic polymer fluid flows in and an outlet through which a mixed fluid of a hydrophilic polymer fluid and a pharmacologically active substance concentrating the hydrophobic fluid and a contrast agent fluid flows out, and the outlet port communicates with the outlet and has a local diameter. A mixed fluid of pharmacologically active material and hydrophilic polymer fluid comprising a decreasing confluence channel, a tube of rapidly increasing diameter and forming a constant diameter, wherein the pharmacologically active material and the hydrophilic polymer fluid condensed with the contrast channel fluid passing through the confluence channel and the tube are joined with a hydrophobic fluid. Embolism microspheres characterized in that the fine droplets are formed due to the difference in surface tension Manufacturing device.
20. The embolic microspheres of claim 2 or 19, wherein the same or different hydrophilic polymer fluid is injected into the inlet of the main channel and the inlets of the subchannels 2 and 3, and a contrast agent is injected into the subchannel 1. Manufacturing device.
8. The embolic microsphere production apparatus according to claim 5 or 7, wherein the pharmacologically active substance is an anticancer agent.
8. The hydrophilic polymer fluid of claim 1, wherein the hydrophilic polymer fluid is poly N-isopropylacrylamide (PNIPam), polyethylene glycol (PEG), chitosan, alginate, chitin, poly (L-). Lactic acid) (PLLA), poly (D, L-lactic acid) (PDLLA), poly (glycolic acid) (PGA), poly (caprolactone) (PCL), poly (hydroxyalkanoate), polydioxanone (PDS ), Polytrimethylene carbonate, poly (lactic acid-co-glycolic acid) (PLGA), poly (L-lactic acid-co-caprolactone) (PLCL), poly (glycolic acid-co-caprolactone) (PGCL), Hyaluronic acid, chondroitin sulfate, dermatan sulfate, carboxymethylcellulose, heparan sulfate, heparin, keratan sulfate, carboxymethylhydroxyethylcellulose, cellulose sulfate, cellulose phosphate, carboxymethylguar, carboxymethylhydroxypropyl Guar, carboxymethyl hydroxy Guar, xanthan gum, gellan gum, welan gum, rhamsan gum, agarose, furcellaran, pectin, gum arabic, gum tragacanth , Carrageenans, starch phosphate, starch succinate, glycoaminoglycans, polysaccharides, polypeptides, acrylamide, N-vinylpyrrolidone, dimethylacrylamide, acrylic acid, methacrylic acid, maleic anhydride, At least one selected from the group consisting of vinylsulfonic acid, styrenecarboxylic acid 2-acrylamido-2-methyl-propanesulfonic acid, vinylphosphonic acid, 2-methylacryloyloxyethylsulfonic acid, gelatin and collagen Embolism microsphere manufacturing apparatus, characterized in that the biodegradable polymer.
8. The embolic microsphere manufacturing apparatus according to any one of claims 1, 5 and 7, wherein the hydrophilic polymer fluid further comprises a crosslinking agent, a curing agent, and a crosslinking agent and a curing agent.
The method of claim 1 or 7, wherein the contrast agent is a magnetic resonance imaging (MRI) contrast medium, a computed tomography (CT) contrast agent, a single photon emission computed tomography (SPECT) contrast agent, a positron emission tomography (PET), a bioluminescence (BL) contrast agent And an optical contrast agent, an X-ray contrast agent, and an contrast agent selected from the group consisting of ultrasonic contrast agents.
8. The hydrophobic fluid of claim 1, wherein the hydrophobic fluid is hexadecane, paraffin oil, isopropyl myristate, silicone oil, sunflower oil, corn oil, soybean oil, avocado oil, sesame oil, Jojoba oil, olive oil, nut oil, squalane, fish oil, ethoxylated alkyl ether oil, propoxylated alkyl ether oil, phytosphingosine, sphingosine, sphinginine, cerebroside, cholesterol, camphorsterol , Beta sitosterol, fusterol, cholesteryl sulfate, cytosteryl sulfate, C _10-40 fatty alcohol and ceramide is selected from the group consisting of emulsified microspheres production apparatus.
20. The method of claim 19, wherein the fluid passing through the vertical focusing portion of the subchannel 1 is a double layer into the mixed fluid layer of the pharmacologically active material and the hydrophilic polymer fluid introduced into the main channel from the top by laminar flow and the contrast agent layer introduced into the subchannel 1 And a fluid passing through the vertical focusing part of the subchannel 2 is a mixed fluid layer of the pharmacologically active material and the hydrophilic polymer fluid introduced into the main channel from the top by laminar flow, the contrast agent layer introduced into the subchannel 1, and the subchannel 2 A triple layer is formed of a hydrophilic polymer fluid layer introduced into the channel, and the fluid passing through the horizontal focusing portion of the subchannel 3 is concentric in the contrast medium layer injected into the subchannel 1 from the center, and the pharmacologically active substance introduced into the main channel and hydrophilicity. An embolic microsphere manufacturing apparatus, characterized in that formed of a hydrophilic polymer fluid layer introduced into the mixed fluid layer, subchannel 2 and subchannel 3 of the polymer fluid.
21. The embolic microsphere manufacturing apparatus according to any one of claims 3, 18 and 20, wherein the microdroplets are irradiated with UV to cure a hydrophilic polymer fluid. delete

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