KR102247512B1 - Three dimension biomimetic structure with function for adjusting blood brain barrier opening and closing and apparatus of drug delivery test including the structure - Google Patents

Abstract

Opening and closing of the blood-brain barrier (BBB) to control the opening and closing function of the blood-brain barrier (BBB) of the microstructure in a non-invasive manner by constructing a three-dimensional microstructure of a channel-laminated structure that simulates brain tissue. Disclosed is a three-dimensional biomimetic structure capable of controlling functions.

Description

A three-dimensional biomimetic structure capable of controlling the opening and closing function of the cerebrovascular barrier, and a drug delivery experiment device including the same.

The present invention relates to a 3D biomimetic structure capable of controlling the opening and closing function of the cerebral vascular barrier, and a drug delivery experiment device including the same, and more particularly, a 3D living body implementing the opening and closing function of the cerebral vascular barrier through focused ultrasound stimulation. It relates to a simulated structure and a drug delivery test apparatus including the same.

The capillaries in the brain have a structure different from that of ordinary capillaries because the endothelial cells are tightly bound. Therefore, the capillaries in the brain can transmit small molecules through active transport when the endothelial cells are briefly opened, but large molecules have low permeability.

This brain's capillary structure is called a blood-brain barrier (BBB). The cerebral vascular barrier (BBB) can protect the brain from toxic substances or other pathogens, but there is a problem in that brain-related drugs cannot be penetrated.

Globally, degenerative brain diseases such as Alzheimer's, Parkinson, and Huntington are on the rise in tandem with the aging population. Currently, various treatments for brain diseases have entered the clinical stage, but due to the function of the cerebral vascular barrier (BBB) in which 99% of the drugs are not delivered to the brain, they are not able to pass the third stage of clinical trials. In addition, due to the problem of efficiency of drug delivery for treating brain diseases, the concentration of drugs prescribed to patients is inevitably increased, and the drug side effects may cause serious problems. In addition, most of the drugs for treating brain diseases degenerate the brain vascular barrier (BBB) intrinsic properties, increase immune cells, and worsen the treatment of brain diseases.

Accordingly, recently, in animal models, it has been shown that the opening and closing function of the cerebral vascular barrier (BBB) can be controlled through physical stimulation using focused ultrasound, and thus the possibility of treating brain diseases through drug delivery has emerged. However, since many animal experiments are required to predict efficacy and side effects in the human body from the experiment for controlling the opening and closing function of the cerebral vascular barrier (BBB) using an animal model, ethical issues have been raised accordingly. In addition, since expensive imaging equipment such as MRI is required to study the control of the opening and closing function of the cerebral vascular barrier (BBB), a long time and a lot of cost are required.

One aspect of the present invention is to construct a three-dimensional microstructure of a channel stacked structure that simulates brain tissue, and non-invasively using ultrasound to control the opening and closing function of the brain vascular barrier (BBB) of the microstructure. It provides a 3D biomimetic structure capable of controlling the opening and closing function.

Another aspect of the present invention provides a drug delivery experiment device comprising a three-dimensional biomimetic structure capable of controlling the opening and closing function of the cerebral blood vessel barrier.

The technical problem of the present invention is not limited to the technical problem mentioned above, and other technical problems that are not mentioned will be clearly understood by those skilled in the art from the following description.

The three-dimensional biomimetic structure capable of controlling the opening and closing function of the vascular barrier of the brain according to the present invention for solving the above problems simulates astrocytes, but the first PDMS channel layer in which the brain tissue chamber is formed in the first direction, the brain A second PDMS channel layer in which a cerebrovascular tissue chamber is formed in a second direction orthogonal to the first direction on the membrane layer is a substrate that simulates a membrane layer and a neurovascular endothelial cell covering the tissue chamber. At least one blood-brain barrier organ chip (Blood-Brain Barrier Organ-On-a-chip) stacked in order on the brain and the brain tissue chamber and the cerebrovascular vessel are arranged to correspond to the at least one cerebral vascular barrier organ chip. A brain tissue chamber and a cerebrovascular vessel of the at least one cerebral vascular barrier organ chip by controlling the ultrasonic generation of the at least one ultrasonic device, including at least one ultrasonic element that generates an ultrasonic wave capable of controlling the opening and closing function between the tissue chambers It includes an ultrasonic generating module that selectively controls the opening and closing function between tissue chambers.

Meanwhile, in the cerebral blood vessel barrier organ chip, a separation distance between the first PDMS channel layer and the second PDMS channel layer may be formed to be 0.001 μm or more and 50 μm or less.

In addition, the cerebral blood vessel barrier organ chip may include the first PDMS channel layer and the second PDMS channel layer in which the brain tissue chamber and the cerebrovascular tissue chamber each having a channel structure having a width of 10 μm to 1000 μm are formed.

In addition, the ultrasonic wave generating module may include a charged layer of a constituent material and a thickness determined to generate ultrasonic waves having a frequency, length, and size capable of controlling the opening/closing function between the brain tissue chamber and the cerebrovascular tissue chamber, and an acoustic matching layer. And the ultrasonic device configured as a rear layer.

In addition, when a plurality of the cerebral vascular barrier organ chips are provided, they may be arranged in an array to form a blood-brain barrier (BBB) structure.

In addition, the ultrasound generating module is disposed to correspond to at least a part of the array-type arrangement of the plurality of brain vascular barrier organ chips, and can be moved in a column direction or a row direction of the array-type arrangement of the plurality of cerebral vascular barrier organ chips. It may include the at least one ultrasonic element configured to be.

In addition, when a drug is injected into the cerebral vascular barrier organ chip using a passive acoustic mapping (PAM) technology, the ultrasound generating module may be configured according to the permeability of the drug between the brain tissue chamber and the cerebral vascular tissue chamber. Can control the generation of ultrasonic waves.

In addition, in the case where a plurality of brain vascular barrier organ chips are provided, the ultrasonic generator module requires an opening and closing function between the brain tissue chamber and the cerebrovascular tissue chamber among the plurality of brain vascular barrier organ chips. It may include a control module for moving so as to be positioned to correspond to the brain vascular barrier organ chip and remotely controlling the ultrasound generation of the at least one ultrasound element.

In addition, the ultrasound generation module may control the generation of ultrasound of the at least one ultrasound element so that the between the brain tissue chambers and the cerebrovascular tissue chambers of each of the at least one cerebral vascular barrier organ chip are opened for 100us to 1hr.

In addition, the cerebral blood vessel barrier organ chip may include the membrane layer coated with a biomaterial on its surface.

On the other hand, the drug delivery experiment apparatus of the present invention constructs a three-dimensional microstructure of a channel stacked structure that simulates brain tissue, and uses ultrasound to non-invasively of the blood-brain barrier (BBB) of the microstructure. A three-dimensional biomimetic structure capable of controlling the opening and closing function of the cerebral vascular barrier that controls the opening and closing function, a microfluidic valve for injecting a drug solution into the microstructure, and a screening device for real-time monitoring of a drug solution injected into the microstructure. do.

According to the present invention, the ethical problem of animal experiments can be solved through the brain vascular barrier (BBB) structure having the same living environment as the animal model, and drug delivery experiments can be conducted at low cost.

1 and 2 are diagrams schematically showing a 3D biomimetic structure capable of controlling the opening and closing function of the cerebral blood vessel barrier according to an embodiment of the present invention.
3 is a diagram schematically showing a 3D biomimetic structure capable of controlling the opening and closing function of the cerebral blood vessel barrier according to another embodiment of the present invention.
FIG. 4 is a diagram specifically showing the brain vascular barrier organ chip shown in FIG. 1.
5 is a view for explaining the arrangement of the ultrasound device on the cerebral vascular barrier organ chip shown in FIG. 4.
6 is a control block diagram of the ultrasonic generator module shown in FIG. 1.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The detailed description of the present invention described below refers to the accompanying drawings, which illustrate specific embodiments in which the present invention may be practiced. These embodiments are described in detail sufficient to enable a person skilled in the art to practice the present invention. It should be understood that the various embodiments of the present invention are different from each other, but need not be mutually exclusive. For example, specific shapes, structures, and characteristics described herein may be implemented in other embodiments without departing from the spirit and scope of the present invention in connection with one embodiment. In addition, it should be understood that the location or arrangement of individual components within each disclosed embodiment may be changed without departing from the spirit and scope of the present invention. Accordingly, the detailed description to be described below is not intended to be taken in a limiting sense, and the scope of the present invention, if appropriately described, is limited only by the appended claims, along with all ranges equivalent to those claimed by the claims. Like reference numerals in the drawings refer to the same or similar functions over several aspects.

Hereinafter, preferred embodiments of the present invention will be described in more detail with reference to the drawings.

1 and 2 are diagrams schematically showing a 3D biomimetic structure capable of controlling the opening and closing function of the cerebral blood vessel barrier according to an embodiment of the present invention.

1 and 2, the 3D biomimetic structure 1 capable of controlling the opening and closing function of the cerebral vascular barrier according to an embodiment of the present invention is a blood-brain barrier (BBB) structure 100 And an ultrasonic generator module 200.

The brain vascular barrier (BBB) structure 100 may include at least one blood-brain barrier organ-on-a-chip 101.

The cerebral vascular barrier organ chip 101 is a three-dimensional microstructure that mimics brain tissue, and is composed of two or more types of cell tumors including astrocytes and neurovascular endothelial cells. ) Function can be implemented.

The brain vascular barrier (BBB) is the capillary structure of the brain. Unlike general capillaries, endothelial cells are tightly bound, so small molecules can be transmitted to the brain through active transport, but large molecules have low permeability. Due to the function of the cerebral vascular barrier (BBB), it is required to regulate the opening and closing function of the cerebral vascular barrier (BBB) when administering a brain-related drug. According to the present embodiment, an organ chip that simulates brain tissue may be constructed, and the opening and closing function of the brain vessel barrier (BBB) of the organ chip may be non-invasively controlled using ultrasound.

When a plurality of brain vascular barrier organ chips 101 are provided, they may be arranged in an array form to form a brain vascular barrier (BBB) structure 100. 1 and 2 illustrate an example in which a plurality of brain vascular barrier organ chips 101 are arranged in a 4x4 2D array. The two-dimensional array can be designed from 1x1 to 100x100. A detailed description of the cerebral blood vessel barrier organ chip 101 will be described later with reference to FIG. 4.

The ultrasound generation module 200 may be provided on the brain blood vessel barrier (BBB) structure 100 to control the opening and closing function of the brain blood vessel barrier (BBB) using focused ultrasound.

For example, the ultrasound generation module 200 may control the cerebral vascular barrier (BBB) simulated by the cerebral vascular barrier (BBB) structure 100 to be temporarily opened for 100us to 1hr.

The ultrasonic generation module 200 may include at least one ultrasonic element 201. Each of the ultrasonic devices 201 may generate ultrasonic waves capable of controlling the opening and closing function of the brain blood vessel barrier (BBB). That is, the ultrasound element 201 may generate ultrasound of sufficient energy to open the brain blood vessel barrier (BBB) simulated by the brain blood vessel barrier (BBB) structure 100.

For example, the ultrasound element 201 may generate focused ultrasound (FUS). Focused ultrasound (FUS) is an ultrasound in which an energy focusing area can be selectively distributed within approximately 500 μm by focusing on a desired location.

At least one ultrasound element 201 may be disposed on the brain vascular barrier organ chip 101. The arrangement of the at least one ultrasound element 201 may correspond to at least a portion of the arrangement of the plurality of brain vascular barrier organ chips 101. Accordingly, it is possible to selectively control the opening and closing function of the cerebral vascular barrier (BBB) of each of the plurality of cerebral vascular barrier organ chips 101 by controlling the generation of ultrasonic waves of the at least one ultrasound element 201, respectively.

According to the present embodiment, in the arrangement of the plurality of cerebral vascular barrier organ chips 101 in the form of an array, the at least one ultrasound element 201 is provided as many as the number corresponding to at least one row and may be disposed to correspond to at least one row. I can. In FIG. 1, as an example, four ultrasound elements 201 are provided and arranged to correspond to one row in a 4X4 two-dimensional array of a plurality of cerebrovascular barrier organ chips 101.

Alternatively, the ultrasonic element 201 may be arranged in a polygonal, circular or elliptical shape.

According to the present embodiment, the ultrasound device 201 may be configured to be movable on the brain blood vessel barrier (BBB) structure 100. For example, as shown in FIG. 2, the ultrasound device 201 may be configured to be movable in the column direction of the arrangement of a plurality of brain vascular barrier organ chips 101 on the brain vascular barrier (BBB) structure 100. The ultrasound element 201 may be positioned to correspond to each row while moving from row 1 to row 4 in a 4X4 2D array of a plurality of brain vascular barrier organ chips 101.

Alternatively, the ultrasound element 201 may be configured to be movable in the row direction of the arrangement of the plurality of cerebrovascular barrier organ chips 101, or may be configured to be movable in both the row direction and the column direction. Alternatively, the ultrasonic element 201 is based on the ultrasonic element 201 arranged to correspond to 1X1 in a 4X4 two-dimensional array of a plurality of cerebrovascular barrier organ chips 101, and the remaining ultrasonic elements 201 are clockwise or It may be configured to be rotatable counterclockwise.

When a plurality of ultrasonic elements 201 are provided, they may be integrated into a single structure to form a single structure. The ultrasonic generation module 200 may further include a configuration of a motor device for moving the plurality of ultrasonic elements 201 and a control module for controlling the movement of the plurality of ultrasonic elements 201.

Meanwhile, FIG. 3 is a diagram schematically showing a 3D biomimetic structure capable of controlling the opening and closing function of the cerebral blood vessel barrier according to another embodiment of the present invention.

Referring to FIG. 3, according to another embodiment of the present invention, the ultrasound generation module 200 includes the same number of ultrasound elements 201 as the number of the plurality of brain vascular barrier organ chips 101, and includes a plurality of ultrasound waves. The device 201 may be formed by arranging the device 201 in the same array shape as the plurality of cerebral blood vessel barrier organ chips 101.

The ultrasonic generation module 200 remotely controls the generation of ultrasonic waves of each of the ultrasonic devices 201 using PAM (Passive Acoustic Mapping) technology to open and close the cerebral vascular barrier (BBB) of each of the plurality of cerebral vascular barrier organ chips 101 You will be able to selectively adjust the function.

The three-dimensional biomimetic structure capable of controlling the opening and closing function of the cerebral vascular barrier of the present invention constitutes an organ chip that simulates brain tissue, and non-invasive opening and closing of the cerebral vascular barrier (BBB) of the organ chip using ultrasound Function can be adjusted.

Accordingly, the 3D biomimetic structure capable of controlling the opening and closing function of the cerebral blood vessel barrier of the present invention can be applied to a drug delivery experiment.

For example, the drug delivery experimental apparatus may include a three-dimensional biomimetic structure capable of controlling the opening and closing function of the cerebral blood vessel barrier, a microfluidic valve, and a screening device of the present invention.

The microfluidic valve is a valve that can selectively control the flow of fluid in a chamber in a three-dimensional environment, and can inject and control fluid into the brain vascular barrier (BBB) structure 100 of the present invention. Here, the fluid may be a drug solution for treating degenerative brain diseases, for example, it corresponds to donepezil, rivastigmine, galantamine, and the like.

The screening device can monitor the effect of the drug solution in real time using electrochemical measurement and liquid chromatography mass spectroscopy (LC-MS).

Briefly describing a drug delivery experiment using such a drug delivery experiment device, a drug is injected into the brain vascular barrier (BBB) structure 100 using a microfluidic valve, and a cerebral blood vessel using the ultrasound generating module 200 It controls the opening and closing function of the barrier (BBB), and a screening device can be used to analyze the permeability of the drug to the cerebral vascular barrier (BBB). In this case, the ultrasound generation module 200 may control the ultrasound generation of the ultrasound element 201 based on the penetration of the drug into the brain blood vessel barrier (BBB).

In the case of a drug delivery experiment using a three-dimensional biomimetic structure capable of controlling the opening and closing function of the cerebral vascular barrier of the present invention, the drug delivery efficiency can be maximized by artificially controlling the opening and closing function of the cerebral vascular barrier (BBB), and an animal model Through the brain vascular barrier (BBB) structure 100 having the same biological environment as, it is possible to solve the ethical problem of animal experiments and conduct a drug delivery experiment at low cost.

4 is a diagram showing in detail the brain vascular barrier organ chip shown in FIG. 1.

4, the cerebral blood vessel barrier organ chip 101 includes a substrate 110, a first PDMS channel layer 130, a membrane layer 150, a second PDMS channel layer 170, and a cover layer ( 190).

The substrate 110 is a material on which the first PDMS channel layer 130, the membrane layer 150, and the second PDMS channel layer 170 can be stacked. Although shown, it is not limited thereto, and transparent ceramics including glass, silicone rubbers including at least one of polydimethylsiloxane (PDMS) and ecoflex, polystyrene, and polymethyl Engineering plastics containing at least one of methacrylate, polypropylene, polycarbonate and polyurethane, transparent ceramics, silicone rubber, and engineering plastics at least two It contains at least two of a mixture, a chemically modified product of transparent ceramics, a chemically modified product of silicone rubber, a chemically modified product of engineering plastics, or a chemically modified product of transparent ceramics, a chemically modified product of silicone rubber and a chemically modified product of engineering plastics. It can be implemented including a mixture.

The substrate 110 may include electrodes 111 for culturing the first PDMS channel layer 130 and the second PDMS channel layer 170.

The first PDMS channel layer 130 is a channel layer containing organic organs of a living body, and is a channel layer that simulates cerebral glial cells.

The first PDMS channel layer 130 may be implemented using PDMS as a material. PDMS is a material with excellent biocompatibility and is widely used to make fluid channels because it can implement cell substrates identically or similarly.

The first PDMS channel layer 130 mimics cerebral glial cells, but the brain tissue chamber 131 may be formed in the first direction. The brain tissue chamber 131 may be formed in a channel structure having a width of 10 to 1000 μm, for example. A drug solution may be injected into the brain tissue chamber 131.

The second PDMS channel layer 170 is a channel layer containing organic organs of a living body, and is a channel layer that simulates cerebrovascular cells.

The second PDMS channel layer 170 may be implemented using PDMS as a material.

The second PDMS channel layer 170 mimics cerebral glial cells, but the cerebrovascular tissue chamber 171 may be formed in a second direction orthogonal to the first direction. The cerebrovascular tissue chamber 171 constitutes a chamber separated from the brain tissue chamber 131, and a drug solution may be injected. The cerebrovascular tissue chamber 171 may be formed in, for example, a channel structure having a width of 10 to 1000 μm.

For example, the second PDMS channel layer 170 may be manufactured within a range of 24 to 96 hours by culturing blood vessel cells for 1 day and then adjusting the shear stress level to 0 to 25 dyne/cm ^2.

In this embodiment, a separation distance between the first PDMS channel layer 130 and the second PDMS channel layer 170 may be formed to be 0.001 um or more and 50 um or less.

The membrane layer 150 is inserted between the brain tissue chamber 131 and the cerebrovascular tissue chamber 171 to separate the brain tissue chamber 131 and the cerebrovascular tissue chamber 171, and from the cerebrovascular tissue chamber 171 Diffusion of fluid to the brain tissue chamber 131 may be restricted. That is, the membrane layer 150 covers the brain tissue chamber 131, and the cerebrovascular tissue chamber 171 may be formed on the membrane layer 150.

The membrane layer 150 may be composed of one or more layers, and in this case, each layer may have an arbitrary thickness and the thicknesses of the layers may be the same or different.

The membrane layer 150 may be implemented with polysiloxane, specifically polydimethylsiloxane (PDMS), or, a copolymer of dimethylvinylsiloxane, an ethylene/vinyl acetate copolymer (EVA), polyethylene, polypropylene, ethylene/propylene Copolymer, acrylic acid polymer, ethylene/ethyl acrylate copolymer, polytetrafluoroethylene (PTFE), polyurethane, thermoplastic polyurethane, polyurethane elastomer, polybutadiene, polyisoprene, poly(methacrylate), polymethyl meth Crylate, styrene-butadiene-styrene block copolymer, styrene-isobutylene-styrene copolymer, poly(hydroxyethyl methacrylate) (pHEMA), polyvinyl chloride, polyvinyl acetate, polyether, polyacrylonitrile , Polyethylene glycol, polymethylpentene, polybutadiene, polyhydroxy alkanoate, poly(lactic acid), poly(glycolic acid), polyanhydride, polyorthoester, hydrophilic polymer such as hydrophilic hydrogel, crosslinked poly Vinyl alcohol, neoprene rubber, butyl rubber, a room temperature vulcanized type of hydroxyl-terminated organopolysiloxane cured with an elastomer at room temperature after addition of a crosslinking agent in the presence of a curing catalyst, one-cured by hydrosilylation at room temperature or high temperature Or a two-component dimethylpolysiloxane composition, and a mixture thereof, but is not limited thereto.

The membrane layer 150 may be coated with a biomaterial on its surface.

The biomaterial may be composed of a sol-gel, an inorganic material, an organic polymer, or an organic-inorganic composite material, and may be Matrigel, collagen, cellulose and derivatives thereof, or chitin, alginate, and limited thereto. It doesn't work.

The cover layer 190 covers the second PDMS channel layer 170, and the electrode 191 is formed, and as in the substrate 110, FIG. 4 shows an example implemented with polycarbonate. Without limitation, transparent ceramics including glass, silicone rubbers including at least one of polydimethylsiloxane (PDMS) and ecoflex, polystyrene, polymethylmethacrylate ( Polymethylmethacrylate), polypropylene, engineering plastics containing at least one of polycarbonate and polyurethane, transparent ceramics, mixtures containing at least two of silicone rubber and engineering plastics, transparent Including a mixture containing at least two of a chemical variant of ceramics, a chemical variant of silicone rubber, a chemical variant of engineering plastics, or a chemical variant of transparent ceramics, a chemical variant of silicone rubber and a chemical variant of engineering plastics. Can be implemented.

Such a cerebral vascular barrier organ chip 101 adopts a channel stacking structure that simulates cerebral glial cells and cerebrovascular cells, but by separating the brain tissue chamber 131 and the cerebrovascular tissue chamber 171, the cerebral vascular barrier (BBB) ) Function can be implemented.

The cerebrovascular barrier organ chip 101 may be manufactured by applying a microstructure layer stacking technique. Briefly explaining the microstructure layer stacking technology, a 3D design of a brain tissue consisting of two or more types of cell tumors including cerebral glial cells and cerebrovascular cells using a 3D CAD tool is converted into simulation data for 3D printer application. It can be transformed. In addition, it is possible to manufacture a mold for cell culture chamber process using a 3D printer capable of 30um resolution process. In addition, by applying the SU8 process technique on the surface of the 3 inch silicon wafer, microvascular channel structures within 10 μm resolution can be manufactured. Using such a shear flow-based device, multiple droplets can be created without a separate surface treatment, and precise control of the size and number of droplets formed by controlling the flow velocity of each continuous phase and the dispersed phase is possible. _{In addition, the O 2} plasma surface processing technique may be applied to the surface treatment of the cerebral blood vessel barrier organ chip 101, and accurate positioning of each layer is possible through the alignment mark alignment plasma bonding method.

5 is a view for explaining the arrangement of the ultrasound device on the cerebral vascular barrier organ chip shown in FIG. 4.

5, the ultrasound element 201 is disposed on the brain vascular barrier organ chip 101, specifically, the membrane layer 150 so as to be disposed on the brain tissue chamber 131 and the cerebrovascular tissue chamber 171. ) Can be placed in the corresponding position.

The ultrasound element 201 may generate ultrasonic waves by the cerebral vascular barrier organ chip 101 to control the opening/closing function of the cerebral vascular barrier (BBB) implemented by the cerebral vascular barrier organ chip 101. That is, the ultrasound element 201 may control an opening/closing function between the brain tissue chamber 131 and the cerebrovascular tissue chamber 171.

The ultrasonic element 201 is a piezoelectric element that generates ultrasonic waves of approximately 500 kHz to 20 MHz, and may include a charged layer, an acoustic matching layer, and a back layer. The ultrasonic device 201 is manufactured using PiezoCAD and PZFlex, a finite element method software, so as to generate ultrasonic waves of an energy level capable of controlling the opening and closing function between the brain tissue chamber 131 and the cerebrovascular tissue chamber 171. I can. That is, the ultrasonic element 201 predicts the change in the sound field according to the size and shape of each component, the length of the focusing area, etc. using PiezoCAD and PZFlex, and opens and closes the brain tissue chamber 131 and the cerebrovascular tissue chamber 171 It can be manufactured by calculating each constituent material and thickness such as a charged layer, an acoustic matching layer, and a back layer capable of generating ultrasonic waves having an energy level capable of controlling functions.

6 is a control block diagram of the ultrasonic generator module shown in FIG. 1.

Referring to FIG. 6, the ultrasonic generation module 200 may further include a separate control module for controlling the ultrasonic element 201, and the control module includes a target position calculator 210 and an ultrasonic converter 230 And an ultrasonic element controller 250.

The control module is a device capable of communication and input/output of information, and may be implemented as, for example, a PC, a smartphone, or a tablet. The control module may be implemented by more components than the components illustrated in FIG. 6, and may be implemented by fewer components.

The control module may selectively control a function of opening and closing the cerebral vascular barrier of each of the plurality of cerebral vascular barrier organ chips 101 by controlling the generation of ultrasonic waves of the ultrasonic element 201.

The target position calculation unit 210 selects a cerebral vascular barrier organ chip 101 that is required to control the opening and closing function of the cerebral vascular barrier (BBB) from among the plurality of cerebral vascular barrier organ chips 101, and the corresponding cerebral vascular barrier organ chip The arrangement position of (101) can be calculated.

The three-dimensional biomimetic structure capable of controlling the opening and closing function of the cerebral vascular barrier according to the present invention can be applied to a drug delivery experiment as described above, and the target position calculating unit 210 is configured to provide a plurality of cerebral vascular barrier organs according to the process of the drug delivery experiment. It is possible to select a brain vascular barrier organ chip 101 that is required to control the opening and closing function of the cerebral vascular barrier (BBB) from among the chips 101, and the arrangement position thereof may be calculated.

For example, the target position calculation unit 210 stores the arrangement of the cerebral vascular barrier organ chip 101 of the cerebral vascular barrier (BBB) structure, and the cerebral vascular barrier organ chip 101 according to the process of a drug delivery experiment from the administrator. When) is selected, the arrangement position of the corresponding cerebrovascular barrier organ chip 101 may be calculated according to the previously stored arrangement data.

The target position calculating unit 210 may select an ultrasound element 201 disposed at a position corresponding to an arrangement position of the brain vascular barrier organ chip 101 calculated from among at least one ultrasound element 201. Alternatively, the target position calculating unit 210 may allow the ultrasound element 201 to be disposed at a position corresponding to the arrangement position of the brain vessel barrier organ chip 101 calculated by moving the at least one ultrasound element 201.

The ultrasonic converter 230 may design the ultrasonic frequency, length, and size of the ultrasonic element 201. The ultrasonic converter 230 can design an ultrasonic wave having a frequency, length, and size capable of controlling the opening and closing function between the brain tissue chamber 131 and the cerebrovascular tissue chamber 171, and is based on a passive acoustic mapping (PAM) technique. The design of the ultrasonic wave can be changed accordingly.

For example, the ultrasound transducer 230 may design an ultrasound based on a result of analyzing the brain blood vessel barrier (BBB) permeability of a drug based on analysis of an inertial or non-inertial cavitation signal.

The ultrasonic element controller 250 may transmit design information of ultrasonic waves to the ultrasonic element 201. The ultrasonic element 201 may have a communication function and may be implemented to receive design information of ultrasonic waves from the ultrasonic element controller 250 and generate ultrasonic waves according to the design information of the ultrasonic waves.

The ultrasonic element controller 250 may transmit design information of ultrasonic waves generated by the ultrasonic converter 230 to the ultrasonic element 201 selected by the target position calculator 210 among at least one ultrasonic element 201.

As described above, the ultrasound generation module 200 includes at least one ultrasound element 201, which can remotely control each of the ultrasound elements 201, and controls the generation of ultrasound of the ultrasound element 201 to control a plurality of brain blood vessels. The barrier organ chip 101 may selectively control a function of opening and closing the brain blood vessel barrier.

Although the above has been described with reference to embodiments, those skilled in the art will understand that various modifications and changes can be made to the present invention without departing from the spirit and scope of the present invention described in the following claims. I will be able to.

1: 3D biomimetic structure capable of controlling the opening and closing function of the cerebral blood vessel barrier
100: cerebrovascular barrier structure
101: cerebrovascular barrier organ chip
200: ultrasonic generation module
201: ultrasonic element

Claims (11)

A first PDMS channel layer in which a brain tissue chamber is formed in a first direction, while simulating astrocyte, a membrane layer covering the brain tissue chamber, and a neurovascular endothelial cell, but the membrane layer At least one blood-brain barrier organ chip (Blood-Brain Barrier Organ-On-a) in which a second PDMS channel layer in which a cerebrovascular tissue chamber is formed in a second direction orthogonal to the first direction is sequentially stacked on a substrate. -chip); And
And at least one ultrasonic element that is arranged to correspond to the at least one cerebral vascular barrier organ chip to generate ultrasonic waves capable of controlling an opening/closing function between the brain tissue chamber and the cerebrovascular tissue chamber, and the at least one ultrasonic element An ultrasound generation module for selectively controlling an opening/closing function between the brain tissue chamber and the cerebrovascular tissue chamber of the at least one cerebral vascular barrier organ chip by controlling the generation of ultrasound,
The ultrasonic generator module,
When a drug is injected into the cerebral vascular barrier organ chip using PAM (Passive Acoustic Mapping) technology, a cerebral blood vessel that controls the ultrasound generation of the ultrasound device according to the permeability of the drug between the brain tissue chamber and the cerebrovascular tissue chamber A three-dimensional biomimetic structure capable of controlling the opening and closing function of the barrier. The method of claim 1,
The cerebrovascular barrier organ chip,
A three-dimensional biomimetic structure capable of controlling the opening and closing function of the cerebral blood vessel barrier, wherein a separation interval between the first PDMS channel layer and the second PDMS channel layer is formed to be 0.001um or more and 50um or less. The method of claim 1,
The cerebrovascular barrier organ chip,
A three-dimensional living body capable of controlling the opening and closing function of the cerebral blood vessel barrier, including the first PDMS channel layer and the second PDMS channel layer in which the brain tissue chamber and the cerebrovascular tissue chamber having a channel structure having a width of 10 μm to 1000 μm are respectively formed Mimic structure. The method of claim 1,
The ultrasonic generator module,
The ultrasound consisting of a charged layer, an acoustic matching layer, and a rear layer of a constituent material and thickness determined to generate ultrasound having a frequency, length, and size capable of controlling the opening and closing function between the brain tissue chamber and the cerebrovascular tissue chamber A three-dimensional biomimetic structure capable of controlling the opening and closing function of the cerebral blood vessel barrier, including a device. The method of claim 1,
The cerebrovascular barrier organ chip,
When a plurality of pieces are provided, the three-dimensional biomimetic structure capable of controlling the opening and closing function of the blood-brain barrier (BBB) is arranged in an array form to form a blood-brain barrier (BBB) structure. The method of claim 5,
The ultrasonic generation module,
The at least one ultrasound that is arranged to correspond to at least a part of the array-type arrangement of the plurality of cerebral vascular barrier organ chips, and is configured to be movable in a column direction or a row direction of the array-type arrangement of the plurality of cerebral vascular barrier organ chips A three-dimensional biomimetic structure capable of controlling the opening and closing function of the cerebral blood vessel barrier, including a device. delete The method of claim 1,
The ultrasonic generator module,
When a plurality of the cerebral vascular barrier organ chips are provided, the at least one ultrasound element corresponds to a cerebral vascular barrier organ chip requiring an opening/closing function between a brain tissue chamber and a cerebral vascular tissue chamber among the plurality of cerebral vascular barrier organ chips 3D biomimetic structure capable of controlling the opening/closing function of the cerebral blood vessel barrier, including a control module that is moved to be positioned so as to remotely control the generation of ultrasound of the at least one ultrasound element. The method of claim 1,
The ultrasonic generation module,
3 capable of controlling the opening and closing function of the cerebral vascular barrier by controlling the generation of ultrasound of the at least one ultrasound element so that the brain tissue chamber and the cerebral vascular tissue chamber of each of the at least one cerebral vascular barrier organ chip are opened for 100us to 1hr. Dimensional biomimetic structure. The method of claim 1,
The cerebrovascular barrier organ chip,
A three-dimensional biomimetic structure capable of controlling the opening and closing function of the cerebral blood vessel barrier, comprising the membrane layer coated with a biomaterial on the surface. Opening and closing of the blood-brain barrier (BBB) to control the opening and closing function of the blood-brain barrier (BBB) of the microstructure in a non-invasive manner by constructing a three-dimensional microstructure of a channel layered structure that simulates brain tissue. A three-dimensional biomimetic structure capable of controlling functions;
A microfluidic valve for injecting a drug solution into the microstructure; And
It includes a screening device for real-time monitoring of the drug solution injected into the microstructure,
The three-dimensional biomimetic structure capable of controlling the opening and closing function of the cerebral blood vessel barrier,
When a drug is injected into the cerebral vascular barrier organ chip using PAM (Passive Acoustic Mapping) technology, it is characterized in that the ultrasound generation of the ultrasound element is controlled according to the transmittance between the brain tissue chamber and the cerebral blood vessel tissue chamber of the drug. Experimental device.

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