KR20010081939A - synchronized medical device - Google Patents

Abstract

PURPOSE: Provided is a medical instrument synchronous to a physiological electric signal which applies electric/magnetic stimulus to transmit treatment materials to a target cell and insert into the cell so that it raises efficiency in transmitting the treatment materials. CONSTITUTION: The medical instrument synchronous to the physiological electric signal comprises the parts of: a transmission part which is composed of a proximal end and a distal end with providing a fluid transmission tool between both ends to transmit the treatment materials through the transmission tool; an electric/magnetic generation part which is placed in the distal end of the transmission part to generate one among electric and magnetic field; and a control part which controls the electric/magnetic generation part to generate electric/magnetic field synchronous to part of physiological signal related to the target cell by time.

Description

Medical device synchronized with physiological electrical signal

With the advent of life sciences and medical technology, many devices are being used to deliver genes as well as various therapeutic agents to target cells. In particular, genetic engineering and gene therapy are developing rapidly. In general, the purpose of gene therapy is to treat genetic and acquired diseases by delivering useful genes to the body cells of a patient to obtain a therapeutic effect from the expression of the delivered genes. The delivered genes or genetic material can produce a genetic product that replaces a damaged gene in the case of a genetic disease, or attenuates or converts the progress of a neoplasia or infectious disease.

Many other methods have been developed for injecting genes or genetic material into body cells. One of them is the ex vivo approach, which involves separating a cell from a patient's body, injecting a gene or genetic material into the cell, and putting it back into the body. The ex vivo approach has been particularly successful in injecting genes or genetic material into lymphocytes. However, this method cannot be used unless the cells to be genetically modified are of a type that can be cultured in vitro and transplanted back into suitable body tissues.

Another method for gene delivery in the body is a direct in vivo approach, in which genes are injected into the appropriate cell type without the need to remove and culture the cells from the patient. Direct gene transfer is particularly suitable for treating a variety of acquired diseases in which the course of the disease is anatomically localized, such as malignant or inflammatory progression.

Numerous methods have been developed for delivering foreign DNA into cells. Methods such as microinjection, electroporation and particle bombardment use physical methods to deliver DNA to cells. However, other methods use agents such as calcium phosphate to cause changes in cell membranes to allow DNA to diffuse into the cytoplasm. Foreign DNA can also be injected into cells by carriers such as liposome-DNA complexes and recombinant viral vectors.

Although the methods described above are particularly effective for in vivo gene transfer, they still present many problems. One is that in vivo gene transfer has an adverse impact on the physiological function of cells. For example, if in vivo gene transfer, such as electroporation, is applied to an important organ cell of the body, the electric or magnetic field involved in the process may interfere with or disrupt the electrical signaling mechanisms of that cell and organ, As the strength of the magnetic field increases, the innate signaling mechanisms can rupture severely, causing cells or organs to stop working. If the intensity of the electric field or magnetic field is lowered or the electric or magnetic field is generated far from the target cell, the characteristics of the method are deteriorated, and a problem that DNA, gene or genetic material does not reach the target cell accurately. In particular, the electric or magnetic field can stimulate the heart, arrhythmia can cause serious damage to the body.

Accordingly, the present invention has been made to solve the above-mentioned problems, medical devices and methods of manufacturing the same, which can minimize interference with the physiological function of cells or organs during the intended medical or pharmaceutical adjustment The purpose is to provide a method.

1 is a block diagram of a medical device according to the present invention.

2 is a perspective view showing a medical device according to a first embodiment of the present invention.

3 is a perspective view illustrating a delivery unit and a magnetic field generating unit of a medical device according to a second embodiment of the present invention.

4 is a cross-sectional view showing another form of delivery device and the electromagnetic field generating unit of the medical device according to the second embodiment of the present invention.

FIG. 5A is a cross-sectional view illustrating another form of delivery unit and an electromagnetic field generating unit of the medical device according to the second embodiment of the present invention.

5B and 5C are longitudinal cross-sectional views of the transmission unit and the magnetic field generating unit shown in FIG. 5A.

Explanation of symbols on the main parts of the drawings

100: medical device according to the present invention 200: storage unit

300: transmission unit 400: discharge unit

410: fluid passage 420: pumping unit

500: electric / magnetic field generator 600: power supply

700: control unit

In order to achieve the above object, the present invention relates to a medical device for injecting therapeutic substances into a target cell in synchronization with a physiological signal associated with the target cell, a method of use and a manufacturing method thereof. The instrument includes a delivery section having a proximal end and a distal end. By providing fluid delivery means between the proximal and distal ends, the delivery portion moves material through the fluid delivery means. The device also includes an electric / magnetic field generating unit which is disposed adjacent to the distal end of the delivery unit and can generate an electric or magnetic field (hereinafter referred to as an electric / magnetic field) in the vicinity thereof. Furthermore, the device includes a control unit that can control the electric / magnetic field generating unit to generate an electric / magnetic field by synchronizing with a unique physiological signal associated with the target cell.

Here, the term 'pharmaceutical substances' refers to any form of active, pseudo-active or non-active that, when injected into a subject cell, can directly or indirectly induce or produce a desired result. It refers to an active molecule or substance. Examples of such therapeutic agents include, but are not limited to, genes, transfer vectors, drugs, anti-sense molecules, oligo-nucleotides, ribozymes, DNA enzymes and other common pharmaceutical or biological agents used in gene therapy. It doesn't work.

A 'gene' generally refers to any biological or pharmaceutical substance that can be found in an iocus or chromosome or made artificially in a laboratory. Examples of such genes include, but are not limited to, angiogenic genes, cell-cycle regulatory genes, cell-contractility modifying genes, cytokines and DNA vaccines. Does not.

'Target cell' means any cell, tissue or organ that is to be intervened or treated by a therapeutic substance injected into the device according to the invention. Depending on the purpose of the modulation or treatment, the subject cell may mean a single or multiple cells of organs such as cardiomyocytes, brain cells, endothelial cells. Also, the target cells make up a large part of the organs, and almost all organs can be manipulated or treated. Alternatively, coordination or treatment may be applied to 'target cells' that do not form organs such as connective tissue, cartilage, and the like.

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

1 is a block diagram of a medical device according to the present invention. The medical device 100 generally includes a storage unit 200 for storing a therapeutic substance, a delivery unit 300 installed to deliver a substance to a target cell (not shown), and a delivery unit 300 from the storage unit 200. Power supply unit 600 is installed to supply power to the discharge unit 400 for transferring the material to the furnace, the electric / magnetic field generating unit 500, the electric / magnetic field generating unit 500 can generate an electric / magnetic field around And a control unit 700 capable of controlling and manipulating the electric / magnetic field generating unit 500 and a method of generating power. Each part of the device 100 is described in more detail below.

The storage unit 200 is generally configured to store a predetermined amount of therapeutic substance. The interior of the storage unit 200 is made of or coated with an inert material so as not to react with or dilute the material to be stored. The storage unit 200 may be integrally formed with the rest of the medical device 100 of the present invention, or may be formed as a separate element and attached to the rest of the device.

The delivery unit 300 is generally disposed at the end of the reservoir 200 and includes at least one end (not shown) as well as at least one end (not shown). The proximal end of the delivery part 300 becomes a fluid delivery means with the storage part 200 directly or through the discharge part 400. Since the shape and size of the podium depends on the shape and size of the storage unit 200 or the discharge unit 400, it can be produced by selecting the base of the appropriate shape and size. The distal end of the delivery unit 300 is connected to a structure capable of delivering a substance to or near the target cell. Thus, the exact shape and size of the terminally linked structure is determined by the location and nature of the target cell, the pharmaceutical and biological mechanisms of treatment, and other factors related to the purpose of infusion. Detailed embodiments of the proximal and distal ends of the delivery unit 300 are described below.

Generally, the discharge unit 400 includes the fluid passage 410 as well as the pumping unit 420. The fluid passageway 410 extends from the reservoir 200 to the delivery part 300 and provides fluid delivery means between the proximal and distal ends. Fluid passageway 410 may include conventional flow control elements to adjust the flow rate as well as the direction of material to be moved through it. For example, the fluid passage 410 may comprise a flow regulating valve or a one-way valve, respectively, to regulate the amount of material and prevent the material from going back. The interior of the fluid passage 410 may also be made or coated with an inert material so as not to react with or dilute the material being carried. The pumping unit 420 is generally adapted to mechanically convey the material from the base end to the end of the fluid passage 410. The pumping unit 420 may be operated electrically or manually. Any existing pump can be employed as the pumping unit 420 as long as it does not affect the pharmacological or biological intact of the material.

The storage unit 200 and the delivery unit 300 may be integrally configured. For example, conventional syringes can be used to store material therein and to manually deliver the drug substance to a subject cell. Furthermore, not only the discharge part 400 but also the storage part 300 may be integrally formed with or separately from the rest of the device 100 so as to be connected or fastened to other parts of the device.

The electromagnetic field generating unit 500 is generally configured to generate an electromagnetic field around it. Typically, the magnetic field generating unit 500 is configured to include at least one electrode disposed in or near the target cell so that the magnetic field surrounds the target cell. The electrode may be placed outside the target cell or cells surrounding the target cell, or may penetrate into the target cell or other peripheral cells. The electrodes can be shaped to be deformable so that they can be unfolded to generate a magnetic field in a wider area while maintaining a minimum volume during transport. The shape and size of the electrode and the former / magnetic field generating unit 500 are determined by the location and nature of the target and surrounding cells, the required intensity and duration of the generated electric / magnetic field, the pharmacological and biological mechanisms of the treatment, and the purpose of the injection. Depends on other factors involved. Embodiments of the electric / magnetic field generating unit 500 and the electrode will be described in more detail below.

Electromagnetic field generator 500 may also be installed at the distal end of transfer unit 300. For example, the electrodes of the magnetic field generating unit 500 may be installed around the end of the delivery unit 300 to surround the target cell and its surrounding cells. Wires may be connected along the fluid passage 410 of the discharge unit 400. Such a configuration allows the medical device 100 of the present invention to have a compact structure and can be inserted into the patient's body even with a small incision, and more easily manipulated when approaching a target cell.

The power supply unit 600 is connected to the electric / magnetic field generator 500 to supply power to generate an electric / magnetic field. The power supply unit 600 may be configured as an internal or external device of the medical device 100 of the present invention. However, the power supply unit 600 may be configured as an external device in order to minimize the size and to facilitate the manipulation thereof. Any conventional power supply can be used in the present invention.

The control unit 700 may control and control the operation of the discharge unit 400, the electromagnetic field generator 500 or other elements of the medical device 100 of the present invention. However, the main function of the control unit 700 is to synchronize the operation of the pre / magnetic field generating unit 500 with a unique physiological signal associated with the action or metabolism of the target cell to harmonize with the slight physiological signal to the electro / magnetic field. Is to make this happen. For this purpose, the control unit 700 generally determines a measurement unit for measuring a physiological signal and a timing of generation of the magnetic field, and a logic unit for operating the magnetic field generator 500 with the signal. It includes.

2 is a perspective view showing a first embodiment of the medical device 100 according to the present invention, where the operation of the device 100 is synchronized with an electrocardiogram (ECG), and the target cell is a cardiomyocyte.

In general, the therapeutic material is stored in a container 200 in the form of a syringe, to which a plunger-type pumping unit 420 is connected to constitute a piston-injector type device. By manually pushing the plunger of the pumping unit 420 may move the drug substance out of the vessel 200. A one-way valve (not shown) or a flow control valve (not shown) is installed in the vessel 200 or the pumping unit 420 to prevent blood and other body fluids from flowing back into the vessel 200, and The amount can be precisely controlled.

The fluid passage 410 has a bendable tube 411 mounted with an internal lumen through which the therapeutic material can be moved. The fluid passage includes a proximal end 413 and a distal end 412, and is configured to be in fluid communication with the reservoir 200 through the proximal end 413 and the delivery unit 300 through the distal end 413. At least a portion of the fluid passageway 410 can be bent to bend the steering ability. For example, the distal end 414 of the fluid passage 410 may be made of a flexible material or may be equipped with a bellow-type structure to move along a curved path such as a blood vessel. By installing a conventional steering mechanism 415, the operator can easily steer the end of the fluid passage 410 toward the target cell 800.

The delivery unit 300 is disposed to contact the target cell 800 or to contact other cells surrounding the target cell 800. In general, the delivery unit 300 is determined in shape and size to perform various functions, for example, by contacting the material to the outside of the target cell, or to limit or maintain the material around the target cell material The blood or other body fluids are not washed away from the target cells or functions to provide a fluid passage into the organ. In the embodiment shown in Figure 2, the delivery unit 300 is inserted into the heart through the blood vessel to supply the therapeutic material to the target cells, such as endocardium (endocardium). Another embodiment of the delivery unit 300 is described in more detail below in conjunction with FIGS. 3, 4, and 5.

At the distal end 412 of the discharge unit 400, an electric / magnetic field generating unit 500 having an electrode rod 501 is installed to generate an electric / magnetic field around the target cell 800. In the embodiment shown in FIG. 2, the electrode 501 in the form of a thin wire is arranged to surround the target cell 800 so that a substantial portion of the target cell is placed in the magnetic field. An electric wire (not shown) is installed to supply electric power to the electric / magnetic field generating unit 500. In consideration of ease of operation and space, the wire moves along the fluid passage 410 to the base end 413 and is connected to the actuation switch 705 there. The actuation switch 705 is described together with the control 700 below.

In the above embodiment, the control unit 700 is also provided as an external module. The control unit 700 generally includes a measuring unit 701 which is arranged to measure an electrocardiogram of a heart, which is measured by a conventional sensor 702. The sensor 702 or the controller 700 itself may be grounded to the ground or directly to the body through an external wire (not shown). The control unit 700 also includes a logic unit 703, which analyzes the electrocardiogram, finds pre-input instructions or information input by the operator regarding the generation of the electromagnetic field, and determines the correct sequence. For example, the logic unit 703 determines an intermittent and periodic ignition sequence that is synchronized with the electrocardiogram so that the electro / magnetic field generator 500 generates the electro / magnetic field, for example, initiation of the T wave of the electrocardiogram. Immediately before the start of the T wave, immediately after the start of the T wave, before the start of the Q wave, immediately before the start of the P wave, immediately after the start of the P wave, immediately after the start of the P wave, or after the start of the P wave And before the start of. Logic unit 703 is also adapted to generate an electromagnetic field based on a predetermined intensity, duration or other criterion. Optionally, the logic unit 703 may determine or change such variables to optimally deliver the therapeutic material to the subject cell 800. In addition, the logic unit 703 may not generate an electric / magnetic field for a period of time, for example, from the start of the R wave of the electrocardiogram to the start of the T wave.

The control switch 700 may be provided with an operation switch 705, which is preferably disposed close to the steering mechanism 415 to facilitate operation. The operation switch 705 may be provided with a flashing device (on and off mode) to operate or stop the operation of the magnetic field generating unit 500. However, more preferably, the operation switch 705 is synchronized with the logic unit 703 so that the operation of the electric / magnetic field generator 500 is synchronized with the above-described electrocardiogram. Optionally, the actuation switch 705 may be installed to allow the operator to manually generate the electro / magnetic field.

In the case of implementation, the medical device 100 according to the present invention is a conventional catheter by arranging the delivery unit 300 and the pre / magnetic field generating unit 500 at or near the end of the catheter. Means can be provided. The catheter is then inserted into the patient's body through an artery or vein. Then, the catheter is carefully advanced along the blood vessel and toward the target cell using the steering mechanism 415 of the medical device 100. When the end of the catheter reaches the target cell, the delivery unit 300 and the pre / magnetic field generating unit 500 are appropriately located in or near the target cell 800.

Both the transmission unit 300 and the magnetic field generating unit 500 may be configured to have an expandable structure having a fully expanded form and a retracted form. When the medical device 100 is inserted into the body of the patient, both the delivery unit 300 and the magnetic field generating unit 500 is retracted, so that the medical device 100 maintains a small appearance. This configuration provides the advantage of making a compact medical device 100, it can be inserted into the body with a smaller incision, and only a minimal wound on the blood vessel to which the medical device 100 is delivered.

When the medical device 100 is properly positioned at or near the target cell 800, the operator manipulates the delivery unit 300 or the discharge unit 400 so that the therapeutic substance comes out of the storage unit 200, and the fluid It moves along the passage 410 to make contact with the cell membrane of the target cell 800. In general, since the molecular size of the material is larger than the size of the hole or inlet of the target cell 800, in this state, the material cannot be effectively transferred therein. The controller 700 measures the electrocardiogram, determines the ignition sequence of the electric / magnetic field generator 500, and supplies a predetermined current or voltage to the electric / magnetic field generator 500. Then, the electrode rod 501 connected to the end of the front / magnetic field generating unit 500 is subjected to osmotic so that the target cell receives a short pulse of a high-intensity front / magnetic field, the therapeutic material is injected without killing the target cell 800 Make it.

3 is a perspective view of a second embodiment of the transfer unit 300 and the electric / magnetic field generating unit 500 according to the present invention. The delivery unit 300 and the magnetic field generating unit 500 are integrally formed and positioned in the target cell 800. The distal end of the delivery unit 300 is inserted into the epicardium, and the electrode rod 501 of the electric / magnetic field generating unit 500 is disposed inside the myocardium and around the distal end of the delivery unit 300. At this time, half of the even electrodes have a (+) pole and the other half has a (-) pole.

4 is a cross-sectional view showing another embodiment of the delivery unit 300 and the magnetic / magnetic field generating unit 500 of the medical device according to the second embodiment of the present invention. Although the transmission unit 300 and the magnetic field generator 500 are integrally formed, the magnetic field generator 500 is located in the endocardium. The electric / magnetic field generating unit 500 includes an electrode rod 501 having a flat end, which is in contact with the pericardium and allows electricity to flow therethrough. The distal end of the delivery unit 300 forms the needle shape 301 and is inserted into the myocardium. The needle 301 has a structure capable of moving forward and backward, and can be manipulated to move forward toward the target cell 800 only when the operator needs it. At this time, if the electrode 501 is a (+) pole, the (-) pole is attached to the epicardium or the body surface in the form of a ground.

Figure 5a is a cross-sectional view showing another embodiment of the transmission device 300 and the magnetic field generating unit 500 of the medical device according to the second embodiment of the present invention. Here, the electrode rod 501 of the magnetic field generating unit 500 has a structure that can be retracted, so that the operator can be manipulated to move forward toward the target cell 800 only when necessary. The shape, size, number and arrangement pattern of the electrode 501 is based on various design criteria such as the shape and size of the catheter, the shape and size of the target cell 800, the required strength of the electric field and magnetic field to be generated. Therefore, the selection of an appropriate electrode is generally a matter of choice of the manufacturing engineer.

5B and 5C are longitudinal cross-sectional views of the transmitter 300 and the electric / magnetic field generator 500 shown in FIG. 5A. 5B shows two electrodes 501, and FIG. 5C shows four electrodes 501. An appropriate number of electrodes 501 can be selected according to the purpose. At this time, half of the even electrodes have a (+) pole and the other half has a (-) pole.

The drawings and the descriptions thus far have been mainly limited to the medical device 100 applied to cardiac cells and synchronized with the electrocardiogram, but the present invention can be applied to other cells or organs, and can also be synchronized with other physiological signals. . For example, it may be synchronized with signals such as electromyogram (EMG), eletro-gastrogram (EGG), electromysterogram (EHG) and electro-encephalogram (EEG). It may also be synchronized with other physiological electrical or non-electrical signals that indicate the physiological activity of the target cell or organ.

The invention may also be applied to other conventional medical devices used for the treatment of other pharmaceutical, medical infusions or diseases of various etiological and pathological organs. For example, the device 100 of the present invention may be incorporated with conventional in vitro or in vivo devices for electroporation or particle bombardment.

While the various embodiments of the present invention have been described with a detailed description, the foregoing descriptions illustrate the invention and are not intended to limit the scope thereof, the scope of the invention being defined by the appended claims. Other embodiments, appearances, advantages and modifications are included in the following claims.

The medical device tuned to the physiological signal according to the present invention facilitates intracellular injection by applying electrical / magnetic stimulation in delivering a therapeutic substance to the target cell, and the electrical / magnetic stimulation by the target cell. By generating in synchronization with the signal, there is an effect of increasing the transmission efficiency and enhancing its safety.

In particular, the device is relatively low cost, there is an effect that can be provided to various kinds of conventional medical devices without significant modification.

In addition, there is an effect that can be used for the prevention, diagnosis, treatment of various diseases by delivering genes, vectors, etc. as well as therapeutic substances.

Claims (20)

A delivery unit comprising at least one proximal end and a distal end, providing a fluid delivery means between the proximal end and the distal end, the delivery unit capable of transferring a therapeutic material through the fluid delivery means; An electric / magnetic field generating unit installed adjacent to the distal end of the transmitting unit and capable of generating any one of an electric field and a magnetic field (electric / magnetic field) around the transmission unit; And A control unit for manipulating the electro / magnetic field generating unit for generating an electro / magnetic field in time synchronized with at least a portion of the physiological signal associated with the subject cell A medical device configured to include, injecting a therapeutic substance into a target cell. The method of claim 1, wherein the therapeutic material, A medical device comprising at least one of a gene, a transfer vector, a drug, an antisense molecule, an oligo-nucleotide, a ribozyme, and a DNA enzyme. The method of claim 2, wherein the gene is Medical devices comprising at least one of angiogenic genes, cell-cycle regulatory genes, cell-contractility modifying genes, cytokines and DNA vaccines . The method of claim 2, wherein the transfer vector is A medical device comprising at least one of DNA itself, DNA-liposomal complex, adeno-virus, adeno-combined virus, RNA tumor virus, and lentivirus. The medical device of claim 1, further comprising a storage unit connected to the proximal end of the delivery unit to form a fluid delivery unit and storing the therapeutic material therein. The medical device of claim 1, further comprising a power supply unit for supplying power to the electric / magnetic field generating unit. The medical device of claim 1, wherein the target cell is a heart cell of a mammalian heart. The magnetic field generating unit of claim 7, A medical device comprising at least one electrode rod capable of passing electricity to a target area including at least one of the target cells and its vicinity. The medical device of claim 7, wherein the physiological signal associated with the target cells is an electro-cardiogram (ECG) of the heart. The method of claim 9, wherein the control unit, Medical device for manipulating the electric / magnetic field generating unit for generating the electric / magnetic field intermittently, periodically. The method of claim 10, wherein the electric / magnetic field, Of the ECG Just before the start of the T wave; At the beginning of the T wave; Immediately after initiation of the T wave; After the start of the T wave and before the start of the P wave; Immediately before the start of the P wave; At the beginning of the P wave; Immediately after the start of the P wave; And After the start of the P wave and before the start of the Q wave A medical device occurring during the period from the time point containing at least one of to an endpoint. The method of claim 10, wherein the control unit, A medical device for manipulating the electric / magnetic field generating unit so as not to generate the electric / magnetic field from the start of the R wave to the start of the T wave of the electrocardiogram. Delivering a therapeutic substance near a target cell; Synchronizing in time with at least a portion of a physiological signal associated with the subject cell, generating either an electric field or a magnetic field (electromagnetic field) around the subject cell; And Injecting the therapeutic material to the target cell comprising the step of injecting the therapeutic material into the target cell. The method of claim 13, further comprising inducing the expression of a desired gene in the target cell. The method of claim 13, wherein the injecting step, And making at least a portion of the cell membrane of the subject cell permeable to allow the therapeutic material to permeate at least instantaneously. The method of claim 13, wherein the delivering step, the generating step and the injection step, respectively, Delivering the therapeutic material near cardiac cells of a mammalian heart; Generating a pre / magnetic field around the heart cells of the mammalian heart; The therapeutic material injection method comprising the step of injecting the therapeutic material into the heart cells of the mammalian heart. The method of claim 16, wherein the generating step, A method of injecting a therapeutic material further comprising the step of supplying the electric / magnetic field intermittently and periodically in synchronization with the electrocardiogram of the heart. Providing a fluid delivery means capable of delivering a therapeutic material to a subject cell; Providing an electric / magnetic field generator capable of generating any one of an electric field and a magnetic field in the vicinity of the target cell; And Providing a controller capable of manipulating a pre / magnetic field generator for generating the pre / magnetic field in time to synchronize with at least a portion of the physiological signal associated with the target cell Comprising a method for providing a medical device that can inject a therapeutic material into the target cell. The method of claim 18, wherein the first providing step, A function disposed outside the target cell; And A function that penetrates the outside of the target cell And forming one end of the fluid delivery means to perform at least one of the following. The method of claim 18, wherein the second providing step, A function disposed outside the target cell; And A function that penetrates the outside of the target cell Forming one end of the electromagnetic field generator for performing at least one of the medical device providing method.