KR102281610B1 - Microvascular Device, Method for manufacturing the same, and Drug Flow Observation System Including the same - Google Patents

Abstract

The present invention relates to a microvascular mimic device, a method for manufacturing the same, and a system including the same, and it is possible to perform flow tests related to the flow of drugs by reproducing blood vessels in a living body, thereby reducing unnecessary clinical trials, By realizing the blood flow of various blood vessels, it is possible to observe with the naked eye, and precise channel grooves are formed, respectively, and a coating layer is provided on the contact surface of the upper plate member and the lower plate member forming one channel to prevent drug leakage, It relates to a microvascular mimic device that is easy to reuse after washing and can be used repeatedly, a method for manufacturing the same, and a system including the same.

Description

Microvascular Device, Method for manufacturing the same, and Drug Flow Observation System Including the same

The present invention relates to a microvascular mimic device, a method for manufacturing the same, and a system including the same, and it is possible to perform flow tests related to the flow of drugs by reproducing blood vessels in a living body, thereby reducing unnecessary clinical trials, By realizing the blood flow of various blood vessels, it is possible to observe with the naked eye, and precise channel grooves are formed, respectively, and a coating layer is provided on the contact surface of the upper plate member and the lower plate member forming one channel to prevent drug leakage, It relates to a microvascular mimic device that is easy to reuse after washing and can be used repeatedly, a method for manufacturing the same, and a system including the same.

In general, the field of ultra-precision microfluidic research has made great strides in the field of bio-embodied biochips since the Genome project, which acquired a bioreaction algorithm based on DNA in the early 2000s. Since then, in vitro diagnostic techniques such as blood diagnosis based on project data have been developed, and the market demand for self-initiated early diagnosis is continuously increasing.

In addition, when developing a blood-based in vitro diagnostic method, verification is possible mainly at large healthcare companies that have automated systems or large hospitals with expensive precision examination machines, but quantification is difficult at the university lab scale, and it is difficult to quantify at the experimental stage. There is a need to develop a verification device that can be analyzed and verified.

When a new drug is developed, clinical trials are conducted to prove its safety and effectiveness. In particular, in the first phase of clinical trials, safety evaluation is performed to collect data on drug absorption, distribution, metabolism, and excretion. At this time, a quantitative evaluation is made to confirm how much the drug reaches the intended place, and for this, observation of blood flow is essential.

X-ray imaging (X-ray), positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), etc. are used to observe such blood flow. There is a problem of having to inject a contrast agent to take a blood vessel, and it puts a burden on patients with renal failure or drug hypersensitivity, and there is a problem of exposure to radiation.

In order to solve the above problems, in vitro diagnostic techniques such as observing blood flow by making a virtual blood flow model are being introduced, but mainly large healthcare companies that have automated systems or large hospitals that have expensive precision examination machines are being introduced. There are disadvantages that can be implemented in

In addition, the equipment used in the in vitro diagnostic techniques includes a silicone material or a paper material such as polydimethylsiloxane (PDMS), which is vulnerable to thermal deformation and is susceptible to fluid contamination. There is a problem in that it is difficult to reproduce the blood flow of microvessels as they have a structure.

Furthermore, it is difficult to clean, so it is not easy to reuse, such as having to be discarded after one use, and there is a problem in that it is not economical because it is expensive to manufacture it every time blood flow observation is required.

In order to solve the above problems, unnecessary clinical trials can be reduced by reproducing blood vessels in the living body, and by realizing blood flow of various blood vessels, it is possible to observe with the naked eye, and precise channel grooves are formed respectively, and the upper plate forms a single channel. A coating layer is provided on the contact surface of the member and the lower plate member to prevent leakage, and it is easy to reuse after washing and thus can be used repeatedly, a method of manufacturing the same, and a system including the same are introduced. does not exist.

The present invention relates to a microvascular mimic device, a method for manufacturing the same, and a system including the same, and it is possible to perform flow tests related to the flow of drugs by reproducing blood vessels in a living body, thereby reducing unnecessary clinical trials, By realizing the blood flow of various blood vessels, it is possible to observe with the naked eye, and precise channel grooves are formed, respectively, and a coating layer is provided on the contact surface of the upper plate member and the lower plate member forming one channel to prevent drug leakage, An object of the present invention is to provide a microvascular mimic device that is easy to reuse after washing and can be used repeatedly, a method for manufacturing the same, and a system including the same.

In order to solve the above problems, the present invention, in a microvascular simulating device for evaluating the vascular fluidity of drugs, one side of the channel groove, which is made of a light-transmissive material, branches at multiple branch points and decreases in width step by step an upper plate member formed on the; and a lower plate member made of a light-transmitting material and having a channel groove corresponding to the channel groove of the upper plate member formed on one side thereof; It includes, and one side of the upper plate member and the lower plate member is in close contact with a surface contact state to provide a microvascular simulating device, characterized in that the channel groove at a corresponding position forms a channel for simulating a blood vessel.

Here, the flow path grooves formed in the upper plate member and the lower plate member are semicircular or semi-elliptical in shape, and the cross section of the flow path is circular or oval.

In addition, the flow path provides the same as the sum of the area before branching and the area after branching based on the branch point, and the flow passage branched at the branch point is arranged side by side.

Furthermore, the branch point provides a microvascular simulating device, characterized in that at least five or more are provided in the longitudinal direction of the flow path.

On the other hand, it provides a microvascular simulating device, characterized in that the injection port of the drug is formed at the upper end of the flow path, the discharge part is formed at the lower end of the flow path, the drug discharged from the lower ends of the plurality of flow paths converge.

In addition, it provides a microvascular simulating device, characterized in that it further comprises a branch pipe for measuring or controlling the pressure in the flow path in the upper region of the flow path.

Here, the inner diameter of the upper end of the flow path is composed of 2 millimeters (mm) to 4 millimeters (mm) for simulating arterioles or venules, and the inner diameter of the lower end of the flow path is from 10 micrometers (㎛) to 100 for simulating capillaries. It provides a microvascular simulating device, characterized in that it is composed of micrometers (㎛).

In addition, after the polyurethane coating is performed on at least one surface of one side of the upper plate member and the lower plate member, a flow path groove for forming the flow path is provided.

In addition, the thickness of the polyurethane coating provides a microvascular simulator, characterized in that the thickness of 50% or less of the inner diameter of the lower end of the flow path.

In addition, the flow path is a microvascular simulating device, characterized in that a portion having an inner diameter greater than the reference inner diameter is processed by machining with a reference inner diameter of the predetermined passage as a boundary, and a portion smaller than the reference inner diameter is performed by laser processing. to provide.

Here, the reference inner diameter provides a microvascular simulator, characterized in that in the range of 80 micrometers (㎛) to 120 micrometers (㎛).

On the other hand, it provides a microvascular simulating device, characterized in that it is provided with a plurality of positioning jigs on one side of the upper plate member and the lower plate member, respectively, for determining a reference position for forming a flow path groove at corresponding positions.

In addition, a plurality of fastening members fastened through the upper plate member and the lower plate member to fix the upper plate member and the lower plate member in close contact; It further comprises, wherein the process of forming a fastening hole in the upper plate member and the lower plate member for fastening the fastening member is performed after forming a flow path groove in the upper plate member and the lower plate member. provide the device.

On the other hand, the drug to be tested for fluidity by the microvascular mimic device is one of embolics, blood mimicking fluid (BMF), plasma, synthetic drugs, biopharmaceuticals, and compounds or compositions containing radioactive isotopes. It provides a microvascular simulator comprising:

On the other hand, a planarization step of flattening one side of the light-transmitting upper plate member and the lower plate member; a polyurethane coating step of applying polyurethane to one side of the upper plate member and the lower plate member on which the planarization process has been performed; a coating layer forming step of UV curing one side of the upper plate member and the lower plate member coated with polyurethane in the polyurethane coating step to form a polyurethane coating layer; a channel groove forming step of forming a channel groove whose width is gradually reduced by branching at a branching point a plurality of times at positions corresponding to one side of the upper plate member and the lower plate member, respectively, in which the coating layer is formed in the coating layer forming step; an assembling step of penetrating and fastening the upper plate member and the lower plate member in a state in which one side of the upper plate member and the lower plate member are in surface contact using a plurality of fastening members; It provides a method for manufacturing a microvascular mimic device comprising a.

Here, the polyurethane layer forming step includes the steps of applying liquid polyurethane to one side of the upper plate member and the lower plate member, respectively, placing a protective film on the applied liquid polyurethane, and above the protective film A method of manufacturing a microvascular mimic device comprising the steps of flattening the liquid polyurethane by pressing with a roller, curing the flattened liquid polyurethane by UV irradiation, and removing the protective film provides

Here, the planarization step provides a method for manufacturing a microvascular mimic device, characterized in that it is performed a plurality of times until the height deviation of one side of the upper plate member and the lower plate member is 10 micrometers (㎛) or less.

In addition, the thickness of the polyurethane coating layer formed in the polyurethane coating step and the coating layer forming step is 50% or less of the minimum width of the channel groove formed in the channel groove forming step.

In addition, in the channel groove formed in the channel groove forming step, a portion having a width greater than the reference width with respect to the predetermined reference width of the channel groove is machined, and a portion smaller than the reference width is processed by laser processing, The reference width provides a method for manufacturing a microvascular simulator, characterized in that in the range of 80 micrometers (㎛) to 120 micrometers (㎛).

Here, the laser used in the step of forming the channel groove provides a method for manufacturing a microvascular simulating device, characterized in that it is a femtosecond laser.

On the other hand, the microvascular mimic device; a cradle capable of accommodating the microvascular simulator; a drug supply unit connected to a drug inlet provided at the upper end of the flow path of the microvascular simulator and a tube, and supplied with a drug to be tested; a pulsation pump for supplying drugs to the microvascular simulator by pressing the tube connecting the drug supply unit and the microvascular simulator; It provides a drug flow test system comprising a.

In addition, it provides a drug flow test system, characterized in that at least one of a pressure gauge and a pressure control valve is provided in the branch pipe provided in the upper region of the flow path of the microvascular simulator.

Here, the microvascular simulator is mounted to be displaceable in the first axial direction on the cradle, and a vision unit for enlarging or capturing an image of the flow path of the microvascular simulator on the cradle on the upper part of the microvascular simulator It provides a drug flow test system, characterized in that the vision unit is mounted to be displaceable in a first axial direction and a second axial direction perpendicular to the first axis.

According to the microvascular mimic device, the method for manufacturing the same, and the system including the same according to the present invention, in clinical trials performed to prove the safety and effectiveness of drugs, an excellent effect of not performing unnecessary clinical trials is obtained. indicates.

In addition, precise flow path grooves are formed for flow passages corresponding to blood vessels in the living body and micro flow passages corresponding to various micro blood vessels such as arterioles, venules, capillaries, etc., respectively, and a coating layer is formed on the contact surface of the upper plate member and the lower plate member forming one flow path It has an excellent effect to prevent leakage.

In addition, it shows an excellent effect that can be observed with the naked eye by applying the formed microvascular mimic device.

In addition, the microvasculature simulator can be separated, and various blood flow tests can be performed by combining it as needed, and it can be reused after washing, thus exhibiting an excellent effect that enables repeated tests.

1 is a perspective view showing a microvascular simulating device according to the present invention.
2 is a plan view showing the microvascular simulating device according to the present invention.
3 is a cross-sectional view showing a microvascular mimic device according to the present invention.
4 shows a method for manufacturing a microvascular simulating device according to the present invention.
5 (a) to 5 (e) schematically shows the main process of the method for manufacturing a microvascular simulating device according to the present invention.
6 is a detailed view showing a method of forming a polyurethane layer in the method of manufacturing a microvascular simulating device according to the present invention.
7 (a) to 7 (e) shows the main process of whether the polyurethane layer is formed in the method for manufacturing a microvascular simulating device according to the present invention.
8 is a perspective view showing a drug flow test system including a microvascular simulator according to the present invention.

Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the embodiments introduced herein are provided so that the disclosed subject matter may be thorough and complete, and the spirit of the invention may be sufficiently conveyed to those skilled in the art. Like reference numbers refer to like elements throughout.

Figure 1 is a perspective view showing a microvascular simulator according to the present invention, Figure 2 is a plan view showing the microvascular simulator according to the present invention, Figure 3 is a main cross-sectional view showing the microvascular simulator according to the present invention.

1 to 3, the microvascular simulating device 100 according to the present invention is for evaluating the vascular fluidity of a drug, and may include an upper plate member 110a and a lower plate member 110b.

The upper plate member (110a) and the lower plate member (110b) may be made of a transparent light-transmitting material so that the flow of the drug can be observed with the naked eye. For example, polydimethylsiloxane (Poly Di Methyl Siloxane; PDMS), methyl methacrylate (MMA), polymethyl methacrylate (PMMA), polyacrylate (Poly Acrylate), polysilic It may be composed of any one of olefin (Polycyclic olefin), polycarbonate (PC), casting acrylic, and extruded acrylic, and preferably, it may be composed of polymethyl methacrylate (PMMA).

In addition, the upper plate member 110a and the lower plate member 110b may have a flat shape such as a square, a rectangle, a square, a polygon, and the like, and may be applied to various shapes. In addition, it is possible to shape and simulate organs through which blood flows, such as liver, heart, lungs, pancreas, kidneys, or brain.

A flow path groove 140a branching at a branching point 141 a plurality of times and gradually decreasing in width may be formed on one side, preferably the lower surface, of the upper plate member 110a, and one side of the lower plate member 110b , preferably, a channel groove 140b corresponding to the channel groove 140a of the upper plate member 110a may be formed on the upper surface.

Here, one side of the upper plate member 110a, preferably, the lower surface and one side of the lower plate member 110b, preferably, the upper surface is in close contact with the upper surface in contact with the flow path grooves 140a, 140b at corresponding positions. ) may form a flow path 140 simulating a blood vessel.

The channel grooves 140a and 140b formed in the upper plate member 110a and the lower plate member 110b may have a semi-circular or semi-elliptical shape, and the cross-section of the channel 140 may be circular or oval.

The flow path 140 may be manufactured similarly to a blood vessel in the human body, and at least five or more branch points 141 may be provided in the longitudinal direction of the flow path 140 to more specifically simulate this. In addition, a layer simulating the innermost epithelial cell layer of the blood vessel wall may be additionally formed, and an inner elastic plate imitation layer may be additionally formed to simulate the elastic fibers in the artery.

The microvascular simulating device 100 according to the present invention is at least one surface of one side of the upper plate member 110a and the lower plate member 110b so as to prevent the drug from flowing out of the flow path 140, preferably, A material having elasticity, for example, a polyurethane material, may be coated on the lower surface of the upper plate member 110a and the upper surface of the lower plate member 110b. Also, after coating is performed, channel grooves 140a and 140b for forming the channel 140 may be formed.

At least one surface of one side of the upper plate member 110a and the lower plate member 110b, preferably, a lower surface of the upper plate member 110a and a polyurethane layer 111 coated on the upper surface of the lower plate member 110b; 111') is compressed so that there is no gap when in close contact with the upper and lower plate members 110a and 110b due to the elasticity of the member, and the formed grooves are in close contact to correspond to each other to form a circular flow path 140. Accordingly, it is possible to prevent leakage of the injected drug, and it is possible to simulate the blood flow of microvessels having a small inner diameter.

Here, the thickness of the polyurethane layers 111 and 111 ′ may be 50% or less of the inner diameter of the lower end of the flow path 140 . Here, when the thickness of the polyurethane layer (111, 111') is more than 50% of the inner diameter, the polyurethane layer (111, 111') is unnecessarily applied, there is a problem in that the manufacturing cost increases, and the polyurethane layer Due to the elasticity of (111, 111'), when the upper and lower plate members 110a and 110b are in close contact with each other, they are compressed to such an extent that the flow path 140 cannot be formed. It becomes impossible to simulate blood flow.

In addition, in the flow path 140, a portion having an inner diameter greater than the reference inner diameter with the reference inner diameter of the predetermined flow passage 140 as a boundary may be machined, and a portion smaller than the reference inner diameter may be processed by laser processing. there is. Here, the reference inner diameter may be in the range of 80 micrometers (μm) to 120 micrometers (μm). Here, by performing laser processing that has high cutting quality and can obtain a smooth cut surface during processing, microvessels with small internal diameters can be manufactured, thereby simulating the blood flow of microvessels.

Meanwhile, the machining may be NC machining or CNC machining. Here, NC machining or CNC machining is to use a computer to automatically control the machining tool, follow the programmed instructions where the process is controlled by numbers, letters and symbols, and meet the exact specifications without manual operators. It is defined as machining in the form of automation by changing the blank space so that the machining can be performed, and the machining can be performed according to the programmed instructions.

Here, when manufacturing the microvascular simulating device according to the present invention, the diameter of the flow path 140 may be formed differently based on the flow path branch point 141 . In this case, since the respective flow paths having different diameters are combined, there is a problem in that a numerical error occurs in the processing section. In order to solve this problem, the machining operation may be performed in the order of forming a large-diameter flow path, forming a small-diameter flow path, and machining an edge section during NC machining or CNC machining.

Specifically, a flow path having a relatively large diameter may be formed first, and then a flow path having a relatively small diameter may be formed next. After that, an edge (edge) section generated due to a difference in diameter is defined as 'Y' It can be performed in a way that removes the flow vortex section by processing it into a ruler-shaped pattern.

On the other hand, the laser processing may be preferably performed by femtosecond laser processing. Here, when performed by femtosecond laser processing, using the short pulse width and high peak output characteristics of the femtosecond laser, the time of the irradiated laser pulse is shorter than the thermal diffusion time of the upper and lower plate members 110a and 110b. Non-thermal processing without thermal denaturation of the member and lower plate members 110a, 110b is possible, and since it produces a large peak output with relatively less energy than the conventional continuous wave or nanosecond laser, applied to the upper and lower plate members 110a and 110b It is possible to enable high-quality, ultra-precise micro-machining due to its low impact.

The flow path 140 is the inner diameter of the longest line passing through the center of the flow path 140 in any cross section for simulating arterioles or venules in the upper region 140 u. The inner diameter may be of 2 millimeters (mm) to 4 millimeters (mm).

In addition, the flow path 140 is the inner diameter of the longest of countless straight lines passing through the center of the flow path 140 in any cross section to simulate capillaries in the lower region 140 l. The inner diameter may be of 10 micrometers (㎛) to 100 micrometers (㎛).

Here, when the inner diameter of the flow path 140 is less than 10 micrometers (㎛), the inner diameter is smaller than that of the fine capillaries, so that the meaningless micro blood vessel simulating device 100 can be manufactured, and due to the technical limitations, as described above There is a problem in that it is difficult to produce an inner diameter having an inner diameter of less than 10 micrometers (μm). On the other hand, in the case of more than 100 micrometers (㎛), in order to simulate the blood flow of the capillary, the microvascular simulating device 100 according to the present invention has no choice but to be excessively long. That is, in the microvascular simulating device 100 according to the present invention, a drug is injected at the initial injection port 120 to create a flow for simulating blood flow, and the flow flows along the flow path 140 while passing through each branch point 141 . It may be configured to reduce the inner diameter of the branched flow path 140, and it has no choice but to further include an additional branch point 141 until it reaches the inner diameter for implementing fine capillaries, etc., so the overall length of the microvascular simulating device 100 A problem arises that cannot but be extended.

In addition, the flow path 140 may be formed such that the sum of the area before branching and the area after branching is the same with respect to the branch point 141 , and the flow channels 140 branched from the branch point 141 may be arranged side by side. there is. In this case, the sum of the area before branching and the area after branching may be flexibly changed according to the purpose or environment of use of the microvascular simulating device 100 according to the present invention.

On the other hand, the microvascular simulating device 100 according to the present invention may include an injection hole 120 formed at the upper end of the flow path 140 so that a drug can be injected into the flow path 140 , and the flow path 140 . ) may be additionally formed with a discharge unit 150 in which the drug discharged from the lower end is converged.

Here, the drug to be tested for fluidity injected into the injection port 120 is an embolic, a blood mimicking fluid (BMF), plasma from which blood corpuscles contained in blood have been filtered (Plasma), synthetic drugs, and biologics. It may be one of pharmaceuticals, compounds or compositions containing radioactive isotopes, and any fluid that can be observed with the naked eye will be applicable.

Furthermore, reagents may be used directly or indirectly. For example, it may include a chemical synthetic drug, and may include a biopharmaceutical such as protein, nucleic acid (Deoxyribo Nucleic Acid; DNA, Ribo Nucleic Acid; RNA) or metabolite (Metabolite). In addition, it may include a compound or composition that is conjugated or fused to a nucleic acid probe or antibody, and facilitates detection of the conjugated or fused reagent. In this case, the probe itself can be detected or a radioisotope that can be detected using positron emission tomography (PET) or computed tomography (CT) is used. may be labeled.

In addition, the drug may be injected through the injection port 120 included in the microvascular simulation device (100). For example, the drug may be introduced through a dropper, a needle, or a catheter, and may be introduced through a tube connected to the pulsation pump 400 to be described later.

The discharge unit 150 may be formed at the lower end 140 l of the flow path 140 so that the discharged drug may converge, and may be formed to be detachable for repeated use after use.

Meanwhile, the branch pipe 130 may further include a branch pipe 130 in the upper region 140 u of the flow path 140 to measure or control the pressure in the flow path 140 . At this time, the branch pipe 130 may provide information on the pressure by the injected drug, and may provide a portion of the injected drug to the pressure gauge 600 to be described later through the connected tube.

A plurality of positioning jigs 170 may be provided at corresponding positions for determining reference positions for forming flow path grooves 140a and 140b on one side of the upper plate member 110a and the lower plate member 110b, respectively. there is.

The jig 170 may be provided on either the upper plate member 110a or the lower plate member 110b, and may be provided through the upper plate member 110a and the lower plate member 110b. Here, the size, area, or shape of the jig 170 may be determined according to the size, area or shape of the upper and lower plate members 110a and 110b, and the number of the jigs 170 is determined by the fastening member 160 . ) can be provided with less than the number and the fastening position can be varied.

On the other hand, in order to closely fix the upper and lower plate members 110a and 110b, it may further include a plurality of fastening members 160 fastened through the upper and lower plate members 110a and 110b. In the embodiment shown in FIGS. 1 and 2 , the fastening member 160 is shown as an example in which the fastening member 160 is provided through the inside of the upper and lower plate members 110a and 110b, but the fastening position may be changed.

In addition, the process of forming a fastening hole in the upper plate member 110a and the lower plate member 110b for fastening the fastening member 160 is a flow path groove in the upper plate member 110a and the lower plate member 110b ( It may be performed after forming 140a and 140b).

4 shows a method for manufacturing a microvascular simulator according to the present invention, and FIGS. 5(a) to 5(e) schematically show the main steps of the method for manufacturing a microvascular simulator according to the present invention.

As shown in FIG. 4 , the method for manufacturing a microvascular simulating device according to the present invention includes a planarization step (S100) of flattening one side of a light-transmitting upper plate member and a lower plate member; a polyurethane coating step (S200) of applying polyurethane to one side of the upper plate member and the lower plate member on which the planarization process has been performed; A coating layer forming step of forming a polyurethane coating layer by UV curing one side of the upper plate member and the lower plate member coated with polyurethane in the polyurethane coating step (S300); a channel groove forming step (S400) of forming a channel groove having a width gradually reduced by branching at a branching point a plurality of times at positions corresponding to one side of the upper plate member and the lower plate member each having a coating layer formed in the coating layer forming step (S400); Assembling step (S500) of fastening through the upper plate member and the lower plate member in a state in which one side of the upper plate member and the lower plate member are in surface contact using a plurality of fastening members; may include.

Specifically, as shown in Fig. 5(a), the light-transmitting polymer material that can be used as the transparent layers 112 and 112' in the microvascular simulator according to the present invention generally has a rough surface. 112 and 112') are not suitable for direct use as a microvascular simulator for the purpose of the present invention. Therefore, by forming and adhering a polyurethane layer to have a smooth surface, it is tightly adhered to and prevents drug leakage. For this purpose, the upper plate member 110a and the lower plate member 110b of one side of the The planarization step S100 performed a plurality of times until the height deviation becomes 10 micrometers (㎛) or less may be performed.

The planarization step (S100) may be performed by machining, the machining may be NC machining (NC machining) or CNC machining (CNC machining).

Here, the overall shape and thickness of the upper and lower plate members can be machined first. At this time, the polyurethane layer (111, 111') may be machined to match the overall thickness by machining the opposite surface of the surface to be formed.

Thereafter, in order to match the thickness deviation of the polyurethane layers 111 and 111' to within 10 micrometers (μm), the surface on which the polyurethane layers 111 and 111' are formed to have a precision within 10 micrometers (μm). In this case, the transparent polymer material such as the above-mentioned PMMA may cause warping of the material when roughing through a milling machine due to the nature of the material, so finish using an end mill of 3 millimeters (mm) or less. It is preferable to perform the above-mentioned face treatment.

In addition, after the finishing surface treatment, the surface on which the polyurethane layers 111 and 111' are formed can be as flat as possible by performing a mirror surface treatment using a mirror surface treatment agent or the like.

Meanwhile, the planarization step ( S100 ) may be repeatedly performed 3 to 4 times at a predetermined time interval.

This is to prevent thermal deformation. In other words, if a predetermined time interval is not provided during the flattening operation, the upper plate member 110a and the lower plate member 110b, which are materials vulnerable to heat, are thermally deformed by heat generated by friction. Since it may occur, when the upper and lower plate members 110a and 110b are assembled, they are not perfectly in close contact and fixed, so that a drug or blood flow leak may occur. Therefore, when performing a plurality of surface treatment operations, it is possible to prevent deformation such as warpage and distortion due to heat by setting a predetermined time interval until rework after each operation and controlling the working surface not to rise to the thermal deformation temperature of the material.

As shown in FIG. 5(b), the transparent layers 112 and 112' that have undergone the planarization step (S100) may have a height deviation of 10 micrometers (㎛) or less, and thus, It becomes suitable for use as a microvascular simulator.

After the planarization step (S100) is completed, as shown in FIG. 5(c), a poly on one side of the transparent layers 112 and 112' included in the planarized upper and lower plate members 110a and 110b. An application step (S200) of forming the polyurethane layer 111 by applying urethane may be performed.

6 to 7 (e) shows in detail the configuration of the polyurethane layer forming step (S200) in the method for manufacturing a microvascular simulating device according to the present invention.

Referring to this, the step (S200) of forming the polyurethane layer ((111, 111') includes the step (S210) of applying the liquefied polyurethane (P) to one side of the upper and lower plate members (S210), and the application The steps of seating the protective film on the liquid polyurethane (S220), pressing and flattening with a roller (S230), curing by irradiating UV light (S240), and removing the protective film (S250) may include

Each step is explained as follows.

First, in the step (S210) of applying the liquefied polyurethane (P) to one side of the upper and lower plate members (112, 112'), the liquefied polyurethane (P) is a mixture of acrylic, polyurethane, and UV initiator. As shown in Fig. 7(a), after filling the discharge device (D) capable of discharging a certain amount of this liquid, it is discharged to one side of the upper and lower plate members (112, 112'). By doing so, liquid polyurethane (P) can be applied.

Next, the protective film mounting step (S220) is performed, and as shown in FIG. 7(b), the protective film (F) may be seated on the liquid polyurethane (P) applied in this step (S220). This is to allow the liquid polyurethane (P) to be uniformly applied to the upper surfaces of the upper and lower plate members 112 and 112' by pressing the liquid polyurethane (P) using a roller (R) in the next step (S230).

Next, a step (S230) of pressing and flattening with a roller for flattening the liquid polyurethane (P) is performed, and as shown in FIG. 7(c), in this step (S230), the roller on the protective film (F) (R) is pressurized so that the liquid polyurethane (P) is uniformly applied to the upper and lower plate members 112, 112', and at this time, the roller (R) and/or the upper and lower plate members 112 and 112' By constantly pressing the protective film (F) while moving on a horizontal plane, the liquid polyurethane (P) can be spread flat.

Next, a UV curing step (S240) is performed, and as shown in FIG. 7(d), in this step (S240), the liquid polyurethane (P) and the liquid polyurethane (P) uniformly applied and flattened by the roller (R) are protected. By irradiating UV on the film (F) using a UV curing device (U), the liquid polyurethane (P) can be cured and fixed to the upper and lower plate members (112, 112').

Next, a protective film removal step (S250) is performed, and as shown in FIG. 7(e), the protective film (F) is removed in this step (S250), thereby forming the polyurethane layers (111, 111'). (S200) may be finished.

Through this process, the polyurethane layers 111 and 111' are formed, and due to the elasticity of the polyurethane layers 111 and 111', the polyurethane layers 111 and 111' can be closely adhered so that there is no gap when in surface contact with the upper plate member 110a. .

Accordingly, it is possible to prevent leakage (leakage) of the injected drug, and it is possible to simulate the blood flow of microvessels having a small inner diameter.

In this case, the thickness of the polyurethane layers 111 and 111 ′ formed in the polyurethane coating step S200 may be 50% or less of the minimum width of the flow path grooves 140a and 140b to be formed in the future. Here, when the size of the thickness is more than 50% of the inner diameter, the polyurethane layers 111 and 111' are unnecessarily applied, and the polyurethane layers 111 and 111' block the flow path in the surface contact state. because it can happen.

Next, the method of manufacturing a microvascular simulating device according to the present invention will be described next. After the polyurethane layer forming step (S200), the upper plate member and the lower plate member 110a, on which the polyurethane layers 111 and 111' are formed, A channel groove forming step (S300) in which a channel groove 140b is formed on one side of 110b) may be performed.

Specifically, as shown in FIG. 5(d) , the channel grooves 140a and 140b having a semi-circular or semi-elliptical shape corresponding to each other may be formed in the upper and lower plate members 110a and 110b.

Here, the formed channel grooves 140a and 140b have a larger width than the reference width with the reference width of the predetermined channel grooves 140a and 140b as a boundary, such as NC machining or CNC machining. Machining may be performed, and the portion smaller than the reference width may be performed by laser processing, preferably, by femtosecond laser processing. Here, the reference width may be in the range of 80 micrometers (μm) to 120 micrometers (μm). Here, femtosecond laser processing has high cutting quality and can obtain a smooth cut surface during processing, making it possible to fabricate a flow path at the capillary level, thereby simulating the blood flow of microvessels.

Next, an assembly step (S400) of assembling the lower plate member 110b and the upper plate member 110a in close contact with each other so that the channel groove at the corresponding position forms the channel 140 simulating a blood vessel is performed can be

In this step, as shown in FIG. 5(e), the upper plate member and the lower plate member 110a, 110b in which the channel grooves 140a and 140b are formed are made to correspond to the channel grooves 140a and 140b, and there is a defect. By doing so, the blood vessel simulating device 110 for simulating fine blood vessels according to the present invention can be manufactured.

The method for manufacturing the microvascular simulator according to the present invention has been described above. Next, the drug flow test system ( ) including the microvascular simulator according to the present invention will be described.

8 is a diagram showing the configuration of a drug flow test system according to the present invention. Referring to this, the drug flow test system 1 according to the present invention includes the above-described microvascular simulation device 100, a cradle 200 capable of mounting the microvascular simulation device 100, and the microvascular simulation device ( 100) connected to the drug inlet 120 provided at the upper end of the flow path 140 and the tube, the drug supply unit 700 to which the drug to be tested is supplied, the drug supply unit 700 and the microvascular simulation device 100 are connected It may include a pulsation pump 400 for supplying the drug to the microvascular simulating device 100 by pressing the tube.

Here, the cradle 200 may have a plate shape so that the microvascular simulating device 100 and the vision unit 300 to be described later can be stably mounted thereon, and the shape is not particularly limited. For example, it may be a square plate shape, a round square plate shape, a rhombic plate shape, and the like. In addition, the microvascular simulating device 100 may be mounted to be displaceable in the first axial direction on the cradle 200 .

The cradle 200 may include a hard material to physically withstand the load caused by the microvascular simulating device 100, the vision unit 300, etc., and an antibacterial material to protect the fluid from external contamination. may include. For example, it may include at least one composition selected from the group consisting of an antibacterial agent, a lubricant, sodium silicate, potassium silicate, a silane coupling agent, polyethylene oxide, and polyglycidol.

On the other hand, a design pattern, a trademark, etc. may be printed on the upper surface or the side surface of the holder 200 .

The vision unit 300 may be provided on the second surface of the holder 200 , preferably on the top of the holder 200 so that the drug injected into the microvascular simulating device 100 can be observed with the naked eye. In this case, the function of enlarging or capturing the image of the flow path of the microvascular simulating device 100 may be performed. The vision unit 300 may be mounted to be displaceable in a first axial direction and a second axial direction perpendicular to the first axis. Here, it may further include a moving means (not shown) to facilitate movement, it is also possible to further include a height adjustment means.

The vision unit 300 may have a cable connected to an end thereof, and an end of the connected cable may be connected to a PC, a smartphone, a tablet PC, or a mobile terminal to collect observation data. In addition, it is possible to additionally install a camera so that the user can easily collect data.

The pulsation pump 400 may supply a fluid to the inlet 120 through a tube connected to the microvascular simulator 110 according to a preset discharge standard. In particular, in order to simulate a physical stimulus applied to an arterial region of the human body, a discharge standard similar to the human heart may be set and operated.

The pulsation pump 400 may operate in a manner that receives and delivers a drug from the drug supply unit 700 provided outside, and pressurizes a tube that directly connects the drug supply unit 700 and the injection port 120 to It may also operate in a way that supplies the drug to the microvascular simulating device 100 .

On the other hand, at least one of a pressure gauge 600 and a pressure control valve 500 may be provided in the branch pipe 130 provided in the upper region of the flow path 140 of the microvascular simulating device 100 .

The pressure control valve 500 may be provided on the third surface of the holder 200 . The pressure control valve 500 may control the pressure of the drug injected into the microvascular simulating device 100 and may perform a function of preventing backflow.

The pressure gauge 600 may be provided on one side of the cradle 200 and may detect the pressure of the injected drug. Furthermore, it may include a pressure gauge to detect precise pressure, for example, a flexible gauge, a vacuum gauge, a high pressure gauge, a special pressure gauge, a diaphragm pressure gauge, an oil filled pressure gauge, a pulsation resistant pressure gauge, a high temperature diaphragm pressure gauge, for sanitary purposes. It may include a pressure gauge, a twin needle pressure gauge, a three needle pressure gauge, a small pressure gauge, a differential pressure gauge, or a ring diaphragm pressure gauge.

Meanwhile, the vision unit 300 , the pressure control valve 500 , and the pressure gauge 600 may be provided detachably from the cradle 200 , and may be provided integrally.

Although the present specification has been described with reference to preferred embodiments of the present invention, those skilled in the art can variously modify and change the present invention without departing from the spirit and scope of the present invention as set forth in the claims described below. will be able to carry out Therefore, if the modified implementation basically includes the elements of the claims of the present invention, all of them should be considered to be included in the technical scope of the present invention.

1: Drug flow test system
100: microvascular simulator
200: cradle
300: vision unit
400: pulsation pump
500: pressure control valve
600: pressure gauge

Claims (14)

In the microvascular simulator for evaluating the vascular fluidity of a drug,
an upper plate member made of a light-transmitting material and having a flow path groove that is branched at a branching point a plurality of times and whose width is reduced step by step is formed on one side thereof; and,
a lower plate member made of a light-transmitting material and having a channel groove corresponding to the channel groove of the upper plate member formed on one side thereof; including,
One side of the upper plate member and the lower plate member is in close contact with each other to form a flow path through which a flow path groove at a corresponding position simulates a blood vessel, and a drug supplied from the drug supply unit by a pulsating pump flows;
After polyurethane coating is performed on at least one surface of one side of the upper plate member and the lower plate member, a channel groove for forming the channel is formed,
The microvascular simulator further comprises a branch pipe that is branched for measuring the pressure in the flow path in the upper region of the flow path, and is connected to the pressure gauge through the upper plate member through a tube. According to claim 1,
The flow path grooves formed in the upper plate member and the lower plate member have a semicircular or semi-elliptical shape, and the cross section of the flow path is circular or elliptical. According to claim 1,
An injection hole for a drug is formed at an upper end of the flow path, and a discharge part through which the drugs discharged from the lower ends of the plurality of flow paths converge are formed at the lower end of the flow path. delete According to claim 1,
The inner diameter of the upper end of the flow path consists of 2 millimeters (mm) to 4 millimeters (mm) for simulating arterioles or venules, and the inner diameter of the lower end of the flow path is 80 micrometers (μm) to 120 micrometers for capillary imitation. (㎛) microvascular mimic device, characterized in that consisting of. delete According to claim 1,
The thickness of the polyurethane coating is a microvascular simulator, characterized in that the thickness of 50% or less of the inner diameter of the lower end of the flow path. According to claim 1,
The flow path is a microvascular simulating device, characterized in that a portion having an inner diameter greater than the reference inner diameter is processed by machining with a reference inner diameter of the predetermined passage as a boundary, and a portion smaller than the reference inner diameter is performed by laser processing. 9. The method of claim 8,
The reference inner diameter is a microvascular simulator, characterized in that in the range of 80 micrometers (㎛) to 120 micrometers (㎛). According to claim 1,
A microvascular simulating device, characterized in that a plurality of positioning jigs are provided on one side of the upper plate member and the lower plate member, respectively, at corresponding positions for determining a reference position for forming a flow path groove. According to claim 1,
a plurality of fastening members fastened through the upper plate member and the lower plate member in order to closely fix the upper plate member and the lower plate member; further comprising,
The process of forming a fastening hole in the upper plate member and the lower plate member for fastening the fastening member is performed after forming a channel groove in the upper plate member and the lower plate member. According to claim 1,
The drug to be tested for fluidity by the microvascular mimic device is one of embolics, blood mimicking fluid (BMF), plasma, synthetic drugs, biopharmaceuticals, compounds or compositions containing radioactive isotopes microvascular simulator. delete Claims 1 to 3, claim 5, claim 7 to claim 12 of any one of the microvascular simulator;
a cradle capable of mounting the microvascular simulator;
a drug supply unit connected to a drug inlet and a tube provided at the upper end of the flow path of the microvascular mimic device and supplied with a drug to be tested; and,
a pulsation pump for supplying drugs to the microvascular simulator by pressing the tube connecting the drug supply unit and the microvascular simulator; A drug flow test system comprising a.

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