Ultrasonic electric field coupling treatment flexible device and preparation method thereof

Abstract

The invention provides an ultrasonic electric field coupling treatment flexible device and a preparation method thereof. An ultrasonic signal is transmitted to the head of a wearer through the piezoelectric module in the flexible ultrasonic patch, and an alternating electric field is fed into the head of the wearer through the electric field treatment patch, so that a blood brain barrier is opened by focused ultrasound, and an anti-tumor drug effectively enters a target area; and meanwhile, the growth of tumor cells is further inhibited by using an alternating electric field. In the application, the mechanical action of ultrasound and the heat effect of the alternating electric field can further promote the flow permeation of the medicine, accelerate the medicine effect taking process and shorten the treatment process. According to the application, inhibition on tumors can be effectively promoted through interpenetration and influence of an ultrasonic field and an electric field, so that the treatment effect on the tumors is remarkably improved. The ultrasonic electric field coupling treatment flexible device provided by the invention is simple to operate, convenient and effective to use, easy to carry and easy to wear for a long time.

Description

Technical Field

[0001] The present application relates to the field of medical detection technology, and in particular to an ultrasonic electric field coupled treatment flexible device and a preparation method thereof. Background Art

[0002] Effective treatment of brain diseases such as recurrent gliomas has always been a technical challenge in the biomedical field. Currently, the most commonly used treatment methods are drug therapy, but due to the existence of the blood-brain barrier, it is difficult for therapeutic drugs to effectively penetrate into the target area, so the treatment effect is often greatly reduced. Research in recent years has found that ultrasound irradiation can effectively open the blood-brain barrier, and the opening of the barrier is reversible and has no obvious side effects on the human body. The development of this technology provides a new way to transport therapeutic drugs for gliomas, that is, after injecting therapeutic drugs, ultrasound irradiation is used in the target area of ​​the brain to open the blood-brain barrier and allow the drug to penetrate into the tumor area, greatly improving the treatment effect of brain tumors.

[0003] Another effective method for recurrent brain glioma is electric field therapy, which applies an alternating electric field to tumor cells, thereby interfering with the mitosis of cancer cells, inhibiting cell growth and causing apoptosis. Cancer cells are a group of cells that undergo rapid mitosis and uncontrolled malignant proliferation. Cell division relies on the spindle to pull the chromosomes to both ends, splitting them in two, and then splitting into two cells. The spindle relies on microtubules to gather into clusters according to their own polarity rules. Once there is interference from an external electric field, the spindle is difficult to form, and the cancer cells cannot undergo mitosis, thus leading to apoptosis.

[0004] However, both methods have certain limitations. (1) Currently, the ultrasound devices used to open the blood-brain barrier are made of hard materials, large in size, and difficult to conform to the human body, resulting in poor ultrasound coupling, unstable treatment effects, and inconvenience in use. (2) Electric field therapy devices currently use hard electrodes, which are made of hard materials and have poor adhesion to the human body. They are unstable in contact when worn, have unstable treatment effects, are less comfortable when worn, are easily prone to allergic reactions, and are not suitable for long-term wear. Summary of the invention

[0005] In view of the shortcomings of the existing technology, this application provides a design and preparation method of a flexible device for ultrasound electric field coupling therapy. In view of the problem of brain tumors such as recurrent glioma, this application designs a portable flexible ultrasound field and electric field coupling therapy device that is soft, light, and can fit tightly with the cerebral cortex, solving the problems of existing devices that are difficult to conformally adhere to the human body, have unstable effects, and cannot be worn for a long time. This application specifically adopts the following technical solutions.

[0006] Firstly, to achieve the above-mentioned purpose, a flexible device for ultrasonic electric field coupling therapy is proposed, which includes: a flexible ultrasonic patch, which is fitted on the top of the wearer's head, and a piezoelectric module is arranged in the flexible ultrasonic patch. The piezoelectric module is triggered by an electrical signal to emit an ultrasonic signal to the wearer's head; an electric field therapy patch, which is connected to the outside of the flexible ultrasonic patch, including a positive electrode sheet and a negative electrode sheet arranged in pairs, and the positive electrode sheet and the negative electrode sheet are fitted on the wearer's head and are triggered by the electrical signal to feed an alternating electric field to the wearer's head.

[0007] Optionally, a flexible device for ultrasonic electric field coupling therapy as described in any of the above is characterized in that the flexible ultrasonic patch includes an upper and lower flexible substrate and arranged between the upper and lower flexible substrates: a positive electrode pattern layer, which is adhered to one of the flexible substrates and is used to feed positive electrical signals to the piezoelectric module; a negative electrode pattern layer, which is adhered to the other flexible substrate and is used to feed negative electrical signals to the piezoelectric module; a piezoelectric module, which is adhered and arranged between the positive electrode pattern layer and the negative electrode pattern layer, and is used to emit ultrasonic signals to the outside in response to positive and negative electrical signals; wherein flexible packaging layers corresponding to the electrode patterns are respectively arranged between the positive electrode pattern layer and the piezoelectric module and between the negative electrode pattern layer and the piezoelectric module, and the flexible packaging layers limit the positive electrode pattern layer and the negative electrode pattern layer to be arranged on both sides of the piezoelectric module respectively.

[0008] Optionally, a flexible device for ultrasonic electric field coupling therapy as described above is characterized in that the flexible packaging layer is a PDMS film with a hollow structure, and the positive and negative electrode patterns and the piezoelectric module are respectively embedded in the hollow positions of the PDMS film and maintain a tight fit.

[0009] Optionally, the ultrasonic electric field coupled therapy flexible device as described above is characterized in that the positive and negative electrode patterns and the piezoelectric modules are arranged in arrays, and adjacent negative electrode patterns and adjacent positive electrode patterns are connected with serpentine curved wiring structures to realize power feeding.

[0010] Optionally, the ultrasonic electric field coupling therapy flexible device as described above is characterized in that the piezoelectric module is a piezoelectric ceramic unit.

[0011] Optionally, a flexible ultrasonic electric field coupling therapy device as described in any of the above is characterized in that the electric field therapy patch includes: a flexible base patch, which is fitted on the wearer's head; an electrode sheet, which is arranged on the flexible base patch and is triggered by an electrical signal to feed an alternating electric field to the wearer's head; a flexible packaging sheet, which is a PDMS film with a hollow structure, used to embed the electrode sheet in the hollow position of the PDMS film and keep it tightly fitted on the flexible base patch; the electrode sheets in each electric field therapy patch are arranged in an array, and the electrode sheets are electrically connected by serpentine connecting lines to form an electrical signal path.

[0012] Optionally, a flexible device for ultrasonic electric field coupling therapy as described in any of the above is characterized in that the electric field therapy patch and the flexible ultrasonic patch are electrically connected by a flexible connecting wire; a lead interface is also provided at the edge of the flexible ultrasonic patch, and the lead interface is electrically connected to the ultrasonic electric field coupling control unit through a lead, and the ultrasonic control unit and the electric field control unit in the ultrasonic electric field coupling control unit respectively adjust the ultrasonic wave and the alternating electric field fed into the wearer's head.

[0013] At the same time, in order to achieve the above-mentioned purpose, the present application also provides a method for preparing a flexible device for ultrasonic electric field coupling therapy, the steps of which include: uniformly spin-coating PMMA on a silicon wafer substrate, drying the PMMA and then uniformly spin-coating a layer of PI thereon to obtain a corresponding flexible substrate patch or a flexible substrate; electron beam evaporating a metal film on the silicon wafer on which PMMA and PI are spin-coated, and after the coating is completed, photolithography is performed using a corresponding mask to obtain a corresponding electrode pattern and circuit connection structure; after the photolithography is completed, the above-mentioned silicon wafer is developed, and after the development is completed, it is washed with deionized water and blown dry; after drying, it is continuously placed in a gold etching solution for etching to remove excess metal structure, and after completion, it is washed with deionized water and blown dry to obtain a corresponding positive electrode pattern layer, a negative electrode pattern layer or an electrode sheet; the aforementioned positive electrode pattern layer, negative electrode pattern layer or electrode sheet is transferred to a flexible PDMS substrate, and then a packaging layer of a piezoelectric module and / or a PDMS film is superimposed on the electrode pattern accordingly; the flexible connecting line between the electric field therapy patch and the flexible ultrasonic patch is connected, and a lead interface is assembled on the edge of the flexible ultrasonic patch.

[0014] Optionally, a method for preparing a flexible device for ultrasonic electric field coupling therapy as described in any of the above is characterized in that the ultrasonic control unit connected to the lead interface pre-determines the delay parameters of each unit in the piezoelectric module array through the following steps, and modulates the sound waves of each piezoelectric module to reach the target area at the same time to form a focused sound beam: first, the brain skull and brain tissue parameters are obtained in the form of computer tomography, and the brain is three-dimensionally modeled, and the lesion area is set as a virtual point source, and ultrasonic waves are emitted here, and the time when each array element in the piezoelectric module attached to the brain surface receives the sound wave is recorded; the interval time of receiving the sound wave corresponding to each piezoelectric module is time-reversed, and the piezoelectric module that receives the sound wave first is set to excite the ultrasonic wave later, and the piezoelectric module that receives the sound wave later is set to excite the ultrasonic wave first, so that the sound waves excited by the array formed by each piezoelectric module according to the preset interval rule reach the target area at the same time, forming a focused sound beam to open the blood-brain barrier.

[0015] Optionally, a method for preparing a flexible device for ultrasonic electric field coupling therapy as described above is characterized in that the electric field control unit connected to the lead interface controls the electrode sheet to generate an alternating electric field of 10KHz-1MHz in two directions perpendicular to each other after opening the blood-brain barrier, and controls the voltage amplitude within 36V, thereby accelerating the flow and penetration of anti-tumor drugs. Beneficial Effects

[0016] The present application provides a flexible device for ultrasonic electric field coupling therapy and a preparation method thereof, which transmits ultrasonic signals to the wearer's head through a piezoelectric module in a flexible ultrasonic patch, and feeds an alternating electric field to the wearer's head through an electric field therapy patch, thereby first using focused ultrasound to open the blood-brain barrier, allowing anti-tumor drugs to effectively enter the target area, and at the same time using the alternating electric field to further inhibit the growth of tumor cells. In the present application, the mechanical action of ultrasound and the thermal effect of the alternating electric field can further promote the flow and penetration of drugs, accelerate the drug onset process, and shorten the treatment process. In the present application, the mutual penetration and influence of the ultrasonic field and the electric field can effectively promote the inhibition of tumors, thereby significantly improving the therapeutic effect on tumors. The flexible device for ultrasonic electric field coupling therapy provided by the present application is simple to operate, convenient and effective to use, and easy to carry and wear for a long time.

[0017] Other features and advantages of the present application will be set forth in the following description, and in part will become apparent from the description, or may be understood by practicing the present application. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The accompanying drawings are used to provide a further understanding of the present application and constitute a part of the specification. Together with the embodiments of the present application, they are used to explain the present application and do not constitute a limitation of the present application. In the accompanying drawings: Figure 1A schematic diagram of the structure of an ultrasonic patch of an embodiment of a flexible device for ultrasonic electric field coupling therapy according to the present invention Figure 2 A schematic diagram of device focusing of an embodiment of a flexible device for ultrasound electric field coupling therapy according to the present invention Figure 3 A schematic diagram of the structure of an electrode sheet of an embodiment of a flexible device for ultrasonic electric field coupling therapy of the present invention Figure 4 A schematic diagram of device connection of an embodiment of a flexible device for ultrasound electric field coupling therapy according to the present invention Figure 5 A schematic diagram of a circuit principle of an ultrasonic electric field coupling control unit of an embodiment of an ultrasonic electric field coupling treatment flexible device of the present invention Figure 6 This is a schematic diagram of wearing a flexible device for ultrasound electric field coupling therapy according to an embodiment of the present invention.

[0019] In the figure, 1 represents an upper flexible substrate, 2 represents a positive electrode pattern layer, 3 represents a positive electrode flexible packaging layer, 4 represents a piezoelectric ceramic unit, 5 represents a negative electrode flexible packaging layer, 6 represents a negative electrode pattern layer, 7 represents a lower flexible substrate, 8 represents a serpentine curved wiring structure of the positive electrode of the device, 9 represents a serpentine curved wiring structure of the negative electrode of the device, 10 represents a flexible packaging sheet, 11 represents an electrode sheet, 12 represents a flexible substrate patch, 13 represents a serpentine connection line, 14 represents a positive electrode sheet, 15 represents another positive electrode sheet, 16 represents a negative electrode sheet, 17 represents another negative electrode sheet, 18 represents a flexible connection line, 19 represents a flexible ultrasonic patch, 20 represents an ultrasonic control unit lead A end, 21 represents an electric field control unit lead A end, 22 represents an ultrasonic control unit lead B end, 23 represents an electric field control unit lead B end, 24 represents an ultrasonic control unit, 25 represents an electric field control unit, 26 2 represents an ultrasonic electric field coupling control unit, 27 represents a positive electrode sheet of an electric field therapy patch, 28 represents a negative electrode sheet of an electric field therapy patch, and 29 represents a flexible ultrasonic patch. DETAILED DESCRIPTION

[0020] In order to make the purpose and technical solution of the embodiment of the present application clearer, the technical solution of the embodiment of the present application will be clearly and completely described in conjunction with the drawings of the embodiment of the present application. Obviously, the described embodiment is a part of the embodiment of the present application, not all of the embodiments. Based on the described embodiment of the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of this application.

[0021] It will be understood by those skilled in the art that, unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as generally understood by those skilled in the art to which this application belongs. It should also be understood that terms such as those defined in common dictionaries should be understood to have meanings consistent with the meanings in the context of the prior art, and will not be interpreted with idealized or overly formal meanings unless defined as herein.

[0022] The meaning of "and / or" described in this application means that the situations where each exists alone or both exist at the same time are included.

[0023] The meaning of "inside" and "outside" in this application refers to the direction pointing to the internal circuit structure between the flexible substrate and the package itself, and the opposite direction is outside; it is not a specific limitation on the device mechanism of this application.

[0024] The meaning of "left and right" mentioned in this application refers to that when the user wears the ultrasonic electric field coupling therapy flexible device, the user's left side is the left and the user's right side is the right, rather than a specific limitation on the device mechanism of this application.

[0025] The term “connection” as used in this application may mean a direct connection between components or an indirect connection between components via other components.

[0026] The meaning of "up and down" mentioned in this application refers to that when a user wears the ultrasonic electric field coupling therapy flexible device, the direction from the flexible ultrasonic patch on the top of the user's head to the excitation electrode of the alternating electric field is down, and vice versa, rather than a specific limitation on the device structure of this application.

[0027] Figure 6 A flexible device for ultrasonic electric field coupling therapy according to the present application comprises: A flexible ultrasonic patch 29 is fitted on the top of the wearer's head. A piezoelectric module is provided in the flexible ultrasonic patch. The piezoelectric module is triggered by an electrical signal to emit an ultrasonic signal to the wearer's head. The electric field therapy patches 27 and 28 are connected to the outside of the flexible ultrasonic patch 29, and include a positive electrode sheet and a negative electrode sheet arranged in pairs. The positive electrode sheet and the negative electrode sheet are fitted on the wearer's head and are triggered by an electrical signal to feed an alternating electric field into the wearer's head.

[0028] The ultrasonic electric field coupled treatment flexible device of the present application first realizes the focusing of the ultrasonic signal through the electric field treatment patch, and opens the blood-brain barrier by focusing the ultrasound excited by each piezoelectric module to the target position on the wearer's head, so that the anti-tumor drug can effectively enter the target area. At the same time, the alternating electric field excited by the electric field treatment patch further inhibits the growth of tumor cells. In the present application, the mechanical action of ultrasound and the thermal effect of the alternating electric field can be further coupled and work together to promote the flow and penetration of drugs, accelerate the drug onset process, and shorten the treatment process. In terms of therapeutic effect, the ultrasonic field and electric field provided by the device of the present application are not a simple functional superposition, but mutual penetration and influence, which further promotes the inhibition of tumors, thereby significantly improving the therapeutic effect on tumors. In terms of system control, such as Figure 6 As shown, both are controlled by a main control system and powered by a common power supply. The signals can be displayed separately on the same display terminal. The operation is simple, the use is convenient and effective, and it is easy to carry and wear for a long time.

[0029] The ultrasonic electric field coupling treatment flexible device of the present application can be referred to Figure 4 As shown, electrical connection is achieved between the electric field therapy patch and the flexible ultrasound patch 29 through a flexible connecting line 18; The edge of the flexible ultrasonic patch 29 is also provided with a lead interface, and the lead interface is electrically connected to the ultrasonic electric field coupling control unit 26 through a lead. The ultrasonic control unit 24 and the electric field control unit 25 in the ultrasonic electric field coupling control unit 26 respectively adjust the ultrasonic wave and the alternating electric field fed into the wearer's head.

[0030] During specific control, the ultrasonic control unit 24 connected to the lead interface determines the delay parameters of each unit in the piezoelectric module array in advance through the following steps, and then drives each piezoelectric module accordingly according to the delay parameters, so that the sound waves generated by the piezoelectric modules in various parts can be modulated to reach the target area at the same time to form a focused sound beam: first, the brain skull and brain tissue parameters are obtained in the form of computer tomography, and the brain is three-dimensionally modeled, and the lesion area is set as a virtual point source, and ultrasonic waves are emitted here, and the time when each array element in the piezoelectric module attached to the surface of the brain receives the sound wave is recorded; the interval time of receiving the sound wave corresponding to each piezoelectric module is time-reversed, and the piezoelectric module that receives the sound wave first is set to excite the ultrasonic wave later, and the piezoelectric module that receives the sound wave later is set to excite the ultrasonic wave first, so that the sound waves excited by the array formed by each piezoelectric module according to the preset interval rule reach the target area at the same time, forming a focused sound beam to open the blood-brain barrier.

[0031] The electric field control unit 25 connected to the above-mentioned lead interface is used to control the electrode sheet 11 to generate an alternating electric field of 10KHz-1MHz in two perpendicular directions after opening the blood-brain barrier, and control its voltage amplitude within 36V, so as to accelerate the flow and penetration of anti-tumor drugs through the alternating effect of the electric field and the physical oscillation of ultrasound.

[0032] Combine the following Figures 1 to 3 The example illustrates the preparation process of the ultrasonic electric field coupling therapy flexible device.

[0033] The flexible ultrasound patch 29 in this application comprises Figure 1 The upper and lower flexible substrates 1 and 7 shown and the following disposed between the upper and lower flexible substrates: A positive electrode pattern layer 2, which is attached to one of the flexible substrates and is used to feed a positive electrode electrical signal to the piezoelectric module; A negative electrode pattern layer 5, which is attached to another layer of flexible substrate and is used to feed negative electrode electrical signals to the piezoelectric module; A piezoelectric module is laminated between the positive electrode pattern layer and the negative electrode pattern layer and is used to emit ultrasonic signals in response to positive and negative electrical signals; Among them, flexible packaging layers corresponding to the electrode patterns are respectively arranged between the positive electrode pattern layer and the piezoelectric module and between the negative electrode pattern layer and the piezoelectric module. The flexible packaging layers restrict the positive electrode pattern layer and the negative electrode pattern layer to be arranged on both sides of the piezoelectric module respectively.

[0034] Its 7-layer structure from top to bottom includes: upper surface flexible substrate layer, positive electrode pattern layer, positive electrode flexible packaging layer, piezoelectric ceramic unit layer, negative electrode flexible packaging layer, negative electrode pattern layer, and lower surface flexible substrate layer. The circular electrodes in the electrode pattern layer are arranged into a 8×8 two-dimensional plane array, and 64 piezoelectric ceramic array units are bonded to the corresponding circular electrodes. The upper and lower surfaces of the piezoelectric ceramic array unit are divided into positive and negative poles, which are connected to the electrode pattern. Each array element is connected by the serpentine wire shown in the electrode pattern to form an "island-bridge" structure, which makes the entire device stretchable. A layer of PDMS film is covered on the entire electrode pattern surface for packaging, that is, a flexible packaging layer. The packaging layer is a hollow structure, which only wraps the serpentine wire in the electrode pattern. The circular electrode sheet is exposed and is subsequently directly bonded to a piezoelectric ceramic unit of the same size. Corresponding to each piezoelectric ceramic unit, the corresponding ultrasonic wave generating excitation circuit is matched: a pulse resonant circuit design is adopted to generate a high-frequency oscillation in the circuit, which is connected to the piezoelectric ceramic sheet after amplification of power and amplitude, and ultrasonic waves are generated by the vibration of the piezoelectric ceramic sheet. The circuit can be powered by a battery, thereby realizing portability. Each piezoelectric ceramic unit can be independently controlled, that is, each channel can excite, receive and process ultrasonic signals separately without interfering with each other. For each piezoelectric ceramic sheet unit, it mainly has the following functions: excitation of a single array element, isolation of transceiver signals, and processing of received signals. The specific implementation process is: through the digital circuit drive, a high-voltage square wave pulse signal is generated to excite the piezoelectric ceramic sheet, and high-frequency oscillation is generated due to the inverse piezoelectric effect, that is, ultrasonic signals are emitted. The ultrasonic signal propagates in the medium and is reflected back and received by the piezoelectric ceramic sheet. Due to the piezoelectric effect, the ultrasonic signal is converted into an electrical signal, that is, an echo is received. The received signal and the transmitted signal are separated by an isolation circuit and do not interfere with each other. The received signal voltage is low, and it needs to be processed by a filter and an amplifier during reception to extract useful signals for analysis. The control forms of multiple piezoelectric ceramic units are exactly the same, and the control of each unit is programmable and adjustable, that is, the emission time of each array unit can be controlled so that each array element reaches the target position at the same time, and the ultrasonic beam is focused in the target area to obtain ultrasonic waves with sufficient energy, thereby achieving the opening of the blood-brain barrier in the target area.

[0035] In the process of focusing the sound waves, due to the complex structure of the skull inside the brain, it is difficult for conventional ultrasonic phased array focusing laws to achieve effective focusing of the sound waves. Therefore, the present invention innovatively uses the time reversal focusing law: when using an ultrasonic patch, the ultrasonic array units are first simultaneously excited to emit ultrasonic waves, and then the return time of the reflected signal of each array element in the target area is extracted, and the time value is recorded. When transmitting for the second time, the just recorded time is used as the time delay to control the transmission of each array element, and finally the ultrasonic waves emitted by all array elements reach the target area at the same time, thereby achieving the focusing of the ultrasonic waves. However, in the specific implementation, since the reflected signal received by each array element during the first transmission is relatively complex and it is difficult to distinguish the reflected signal at the target position, the virtual point source-time reversal focusing law is used to implement it. The specific operation is as follows: first, the relevant parameters of the brain skull and brain tissue are obtained through computer tomography, and the brain is three-dimensionally modeled. According to the actual situation, a virtual point source is set in the lesion area model, such as Figure 2 As shown, ultrasound waves are emitted here, and the time when each array element in the ultrasound patch attached to the surface of the brain receives the sound waves is recorded, and time reversal processing is performed, that is, delay processing is performed according to the time of reception, and the first to arrive is sent later, and the last to arrive is sent first. Finally, during the second emission, the sound waves of each array element reach the target area at the same time, forming a focused sound beam, and the calculated focusing law is applied to the actual treatment. The focusing law is generated by modeling the actual target and then calculating, and the calculation result is directly applied when used. In this method, the above process needs to be repeated according to the changes in the patient and the lesion area to calculate and generate a new focusing law. Since the opening of the blood-brain barrier requires a certain ultrasound threshold, that is, when the focused ultrasound reaches a certain energy threshold, the blood-brain barrier can be opened. Even if other interference signals appear, due to the low energy of the scattered signal, there will be no obvious impact and interference on the target area.

[0036] In view of the limitations of current ultrasound and electric field treatments for recurrent brain gliomas, the soft, lightweight, and conformally attached ultrasound field and electric field coupled treatment device provided in the present application not only solves the problems of difficulty in conformally attaching the device to the human body, unstable effects, and inability to be worn for a long time, but also couples electric field therapy with ultrasound to open the blood-brain barrier in the device, thereby achieving dual treatment at the same time, further improving the treatment effect on recurrent brain gliomas.

[0037] Specific reference Figure 3 , the electric field therapy patch provided in this application includes: A flexible base patch 12, which is fitted on the wearer's head; The electrode sheet 11 is arranged on the flexible base patch 12 and is triggered by the electrical signal to feed an alternating electric field to the wearer's head; The flexible packaging sheet 10 is configured as a PDMS film with a hollow structure, and is used to embed the electrode sheet 11 in the hollow position of the PDMS film and keep it closely attached to the flexible base patch 12; The electrode sheets in each electric field therapy patch are arranged in an array, and the electrode sheets 11 are electrically connected by serpentine connection lines 13 to form an electrical signal path.

[0038] The above-mentioned bottom-up: flexible substrate layer, electrode pattern layer, flexible packaging layer, the entire electrode pattern is supported by a flexible substrate, connected to each other through serpentine wires to form an "island-bridge" structure, and a layer of PDMS film is covered on the surface of the electrode for packaging. The packaging film is a hollow layer, only wrapping the serpentine wire, and the circular electrode sheet is exposed, which can be in direct contact with the skin when used. The functional areas in the electric field therapy module are symmetrically distributed around the ultrasonic therapy module. The four treatment patches are evenly distributed in four directions with the ultrasonic therapy module as the center, and are connected to the central ultrasonic therapy area through flexible materials. The pair of electrode sheets facing each other are respectively the positive electrode patch and the negative electrode patch. The positive and negative electrode patches have the same structure, except that they are connected to the positive and negative poles of the power supply respectively when connected to the power supply. The four electrode sheets can be attached to the front, back, left and right positions of the brain respectively. When powered on, alternating electric fields are generated in two directions perpendicular to each other. Each electrode sheet is composed of 9 circular electrode units arranged in a two-dimensional array, and the units are connected in series. The frequency range of alternating electric field therapy is 10KHz-1MHz, which fully covers the medium frequency electric field frequency range. At the same time, in order to ensure the safe tolerance range of the human body, the voltage amplitude is designed not to exceed the human body safety voltage of 36V.

[0039] Therefore, the present invention uses the coupling effect of electric field therapy and ultrasonic therapy to Figure 5 The circuit principle block diagram divides the ultrasonic control unit into ultrasonic transmitting and receiving circuits. The ultrasonic transmitting circuit is controlled by a digital circuit and driven by a MOSFET circuit to generate 64 ultrasonic transmitting signals. The transmitting time can be programmably controlled. The signal received by the device can be processed by the receiving circuit (limiting, isolation, analog-to-digital conversion). The electric field control unit is an alternating electric field excitation circuit. The electric field frequency band covers the full band of the intermediate frequency electric field. The corresponding functions can be opened and closed according to the corresponding buttons.

[0040] The specific process of preparing the above-mentioned ultrasonic electric field coupling therapy flexible device is as follows (the preparation process of the electrode patch substrate is the same as that of the ultrasonic patch, except that the corresponding mask plates are used): First, evenly spin-coat PMMA on the silicon wafer substrate. After evenly spin-coating, dry the PMMA on a drying table at a temperature of about 180 ˚C for about 10 minutes. Then, evenly spin-coat a layer of PI on it and dry it by step heating. The purpose of spin-coating PMMA is to reduce the adhesion between PI and the silicon wafer substrate, so as to facilitate the subsequent transfer of the electrode pattern to the flexible substrate to obtain the corresponding flexible substrate patch 12 or flexible substrate 1, 7; Then, electron beam evaporation of metal film (E-beam) is performed on the silicon wafer on which PMMA and PI are spun, that is, the original metal film is prepared on the silicon wafer on which PMMA and PI are spun. The device of the present invention uses evaporation of gold and chromium, and gold has good conductivity. Electron beam evaporation coating equipment is used for coating. First, a layer of metal chromium with a thickness of about 10nm is plated on the PI of the silicon wafer, and then a layer of gold with a thickness of about 150nm is plated to increase the adhesion between gold and PI by chromium plating. After the coating is completed, photolithography is performed using the corresponding mask to obtain the corresponding electrode pattern and circuit connection structure. The specific steps are: before photolithography, the silicon wafer coated with the metal film is first spin-coated with photoresist. After the spin coating is uniform, it is also necessary to dry it in a drying table at a temperature of about 110 ˚C for about 90 seconds. After the drying is completed, the silicon wafer is placed in the exposure position of the photolithography machine, and the mask is placed in the corresponding position. After adjustment, it is fixed, and then the exposure source is moved to the top of the silicon wafer substrate for about 8-9 seconds of exposure, and then taken out; After the photolithography is completed, the silicon wafer is developed again. The silicon wafer is placed in the developer for 40 seconds. During the development, it needs to be gently shaken to ensure uniform development. After the development is completed, it is washed with deionized water and blown dry. After drying, continue to etch in the gold etching solution for 60 seconds to remove the excess metal structure. After etching, wash with deionized water and blow dry. Repeat the same steps to etch and remove the metal chromium. The etching time is about 10 seconds to obtain the corresponding positive electrode pattern layer 2, negative electrode pattern layer 5 or electrode sheet 11. Rinse the sheet with gold and chromium removed with acetone to remove the photoresist on the surface. After complete removal, rinse with ethanol and blow dry. At this point, the flexible electrode pattern of the device of the present invention is completed. At this time, the electrode pattern is still on the PI of the silicon wafer, so it is necessary to transfer the aforementioned positive electrode pattern layer 2, negative electrode pattern layer 5 or electrode sheet 11 to the flexible PDMS substrate, and then superimpose the packaging layer of the piezoelectric module and / or PDMS film on the electrode pattern accordingly; for example, for the electrode patch part, only packaging is required, and the packaging uses a PDMS film with a thickness of about 200µm, and the circular electrode part corresponding to the packaging layer is hollow, such as Figure 3As shown in the mark 10, the purpose is to isolate and insulate the leads at the flexible substrate, leaving only the circular electrode part exposed. For the ultrasonic patch part, the PDMS film is also used for encapsulation, with a thickness of about 200µm. The encapsulation layer corresponds to the electrode pattern, the functional unit part is hollowed out, and the piezoelectric ceramic sheets are pasted here one by one. The piezoelectric ceramic sheets prepared previously are selected as the piezoelectric module, and are bonded to the reserved positions of the functional units in the flexible substrate with conductive silver glue according to the corresponding positions for connection. Since piezoelectric ceramics have positive and negative poles, two flexible electrodes are required to be connected accordingly, one on the top and one on the bottom to wrap the piezoelectric ceramic unit, such as Figure 1 shown.

[0041] After bonding is completed, the flexible connecting line 18 is connected between the electric field therapy patch and the flexible ultrasonic patch 29, and the ultrasonic patch and the four electrode patches are directly connected at the prefabricated wiring point with ACF soft wires. The A ends of the ultrasonic control unit and the electric field control unit leads are respectively led out on one side of the flexible ultrasonic patch, and the corresponding lead B ends are set in the module part of the ultrasonic and electric field control units. The two ends are also connected with ACF soft wires, and the lead interface is assembled on the edge of the flexible ultrasonic patch 29 for signal testing. After the test is passed, the entire device is completed.

[0042] Therefore, this application can be Figure 5 The circuit schematic diagram shown realizes the control of the above-mentioned ultrasonic electric field coupling therapy flexible device: In this device, a circular piezoelectric ceramic sheet with a diameter of 4 mm is selected, and the piezoelectric ceramic material model is PZT-4. It is arranged in a rectangular matrix in the form of 8×8 in the flexible ultrasonic patch 19. The interval between each circular piezoelectric ceramic sheet is 2 mm, and the size of the entire electrode sheet is 70 mm×70 mm. The piezoelectric ceramic sheet electrode is divided into two sides, one side is the positive electrode and the other side is the negative electrode, so a double-sided electrode pattern needs to be designed for connection, such as Figure 1 As shown in 2 and 6, the electrode patterns on both sides are connected to the positive and negative electrodes of the piezoelectric ceramic unit respectively. Each circular electrode sheet is connected with a serpentine wire to form an "island-bridge" structure with the functional unit, such as Figure 1As shown in 8 and 9, they correspond to the positive and negative parts of each piezoelectric ceramic unit respectively. Each piezoelectric ceramic unit corresponding to the positive part corresponds one by one to the 64 transmitting circuits driven by MOSFET in the control system, while the negative parts are directly connected to the ground wire, that is, they share a ground wire. In this way, each transmitting circuit controls each piezoelectric ceramic unit, so that each unit can be controlled individually through the control system. In this embodiment, the center frequency of the ultrasonic array unit is 4MHz. Each piezoelectric ceramic unit can be used as a sensor for transmitting ultrasonic waves or as a sensor for receiving ultrasonic waves. The ultrasonic echo is monitored through a limiting circuit, an isolation circuit and an analog-to-digital conversion circuit, and the output timing of the driving signal of each piezoelectric ceramic unit is adjusted by analyzing the received ultrasonic signal. Both the transmitting and receiving units require external ultrasonic excitation circuits and signal receiving circuits. The specific circuit principle block diagram is shown in the figure. Figure 5 shown.

[0043] The electric field therapy patch structure of the device is as follows Figure 3 As shown in FIG. 1 , a corresponding photolithography mask is made according to the flexible substrate electrode pattern. Each circular electrode unit in the pattern is connected by a serpentine wire, as shown in FIG. Figure 3 As shown in Figure 13, the serpentine wire width is 125µm, the diameter of a single circular electrode is 5mm, and they are arranged in a 3×3 rectangular form. The interval between each circular electrode sheet is 3mm, and each circular electrode is directly connected in series. The size of the entire electrode sheet is 30mm×30mm.

[0044] In the above-mentioned flexible ultrasound patch 29 and electric field therapy patches 27 and 28, the flexible packaging layer can adopt a hollow structure PDMS film, and its positive and negative electrode patterns and piezoelectric modules can be correspondingly embedded in the hollow position of the PDMS film and maintain a close fit to achieve sound and electrical output to the human body.

[0045] In summary, the ultrasonic electric field coupling treatment flexible device provided in this application is designed for brain tumors such as recurrent gliomas. Its overall structure is soft and thin, and it can fit tightly to the curved surface of the human brain. Figure 6 As shown. Each unit is independently controlled, and the ultrasonic electric field can be used simultaneously and coupled with each other, significantly improving the therapeutic effect on tumors.

[0046] The above is only an implementation method of the present application, and its description is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present application. It should be pointed out that for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present application, which all belong to the protection scope of the present application.

Claims

1. A flexible device for ultrasonic electric field coupling therapy, characterized in that: include: A flexible ultrasonic patch (29) is arranged to fit on the top of the wearer's head, wherein a piezoelectric module is arranged in the flexible ultrasonic patch, and the piezoelectric module is triggered by an electrical signal to emit an ultrasonic signal to the wearer's head; The electric field therapy patch is connected to the outside of the flexible ultrasonic patch (29), and comprises a positive electrode sheet and a negative electrode sheet arranged in pairs. The positive electrode sheet and the negative electrode sheet are arranged to fit the head of the wearer and are triggered by an electrical signal to feed an alternating electric field to the head of the wearer.

2. The ultrasonic electric field coupling therapy flexible device according to claim 1, characterized in that: The flexible ultrasonic patch (29) comprises an upper and lower flexible substrate (1, 7) and a flexible substrate disposed between the upper and lower flexible substrates: A positive electrode pattern layer (2), which is attached to one of the flexible substrate layers and is used to feed a positive electrode electrical signal to the piezoelectric module; A negative electrode pattern layer (5), which is attached to another layer of flexible substrate and is used to feed a negative electrode electrical signal to the piezoelectric module; A piezoelectric module is laminated between the positive electrode pattern layer and the negative electrode pattern layer and is used to emit ultrasonic signals in response to positive and negative electrical signals; Among them, flexible packaging layers corresponding to the electrode patterns are respectively arranged between the positive electrode pattern layer and the piezoelectric module and between the negative electrode pattern layer and the piezoelectric module. The flexible packaging layers restrict the positive electrode pattern layer and the negative electrode pattern layer to be arranged on both sides of the piezoelectric module respectively.

3. The ultrasonic electric field coupling therapy flexible device according to claim 2, characterized in that: The flexible encapsulation layer is a PDMS film with a hollow structure, and the positive and negative electrode patterns and the piezoelectric module are respectively embedded in the hollow positions of the PDMS film and kept in close contact.

4. The ultrasonic electric field coupling therapy flexible device according to claim 2, characterized in that: The positive and negative electrode patterns and the piezoelectric modules are arranged in arrays, and adjacent negative electrode patterns and adjacent positive electrode patterns are respectively connected with serpentine curved connection structures (8, 9) to realize power feeding.

5. The ultrasonic electric field coupling therapy flexible device according to claim 2, characterized in that: The piezoelectric module is a piezoelectric ceramic unit (4).

6. The ultrasonic electric field coupling therapy flexible device according to claim 1, characterized in that: The electric field therapy patch comprises: A flexible base patch (12) which is fitted on the head of the wearer; An electrode sheet (11) is arranged on a flexible base patch (12) and is triggered by an electrical signal to feed an alternating electric field to the head of a wearer; A flexible packaging sheet (10) is provided as a PDMS film with a hollow structure, and is used to embed the electrode sheet (11) in the hollow position of the PDMS film and keep it closely attached to the flexible base patch (12); The electrode sheets in each electric field therapy patch are arranged in an array, and the electrode sheets (11) are electrically connected by serpentine connection lines (13) to form an electrical signal path.

7. The flexible device for ultrasound electric field coupling therapy as described in claims 1 to 6, characterized in that: The electric field therapy patch and the flexible ultrasound patch (29) are electrically connected via a flexible connecting line (18); The edge of the flexible ultrasonic patch (29) is also provided with a lead interface, the lead interface is electrically connected to the ultrasonic electric field coupling control unit (26) via a lead, and the ultrasonic control unit (24) and the electric field control unit (25) in the ultrasonic electric field coupling control unit (26) respectively adjust the ultrasonic wave and the alternating electric field fed into the wearer's head.

8. A method for preparing a flexible device for ultrasonic electric field coupling therapy, characterized in that the steps include: Evenly spin-coating PMMA on a silicon wafer substrate, drying the PMMA and then evenly spin-coating a layer of PI thereon to obtain a corresponding flexible substrate patch (12) or a flexible substrate (1, 7); Electron beam evaporation of metal film is performed on the silicon wafer with spin-coated PMMA and PI. After the coating is completed, photolithography is performed using the corresponding mask to obtain the corresponding electrode pattern and circuit connection structure; After the photolithography is completed, the silicon wafer is developed, and after the development is completed, it is cleaned with deionized water and blown dry; After drying, continue to place in gold etching solution for etching to remove excess metal structure, and after completion, use deionized water to wash and dry to obtain the corresponding positive electrode pattern layer (2), negative electrode pattern layer (5) or electrode sheet (11); Transferring the aforementioned positive electrode pattern layer (2), negative electrode pattern layer (5) or electrode sheet (11) onto a flexible PDMS substrate, and then stacking a packaging layer of a piezoelectric module and / or a PDMS film on the electrode pattern accordingly; A flexible connecting line (18) is connected between the electric field therapy patch and the flexible ultrasonic patch (29), and a lead interface is assembled on the edge of the flexible ultrasonic patch (29).

9. The method for preparing a flexible device for ultrasound electric field coupling therapy as claimed in claim 8, characterized in that: The ultrasonic control unit (24) connected to the lead interface determines the delay parameters of each unit in the piezoelectric module array in advance through the following steps, modulates the sound waves of each piezoelectric module to reach the target area at the same time, and forms a focused sound beam: First, the parameters of the brain skull and brain tissue are obtained through computer tomography, and the brain is modeled in three dimensions. The lesion area is set as a virtual point source, and ultrasound is emitted there. The time when each array element in the piezoelectric module attached to the brain surface receives the sound wave is recorded. The interval time of receiving sound waves corresponding to each piezoelectric module is time-reversed, and the piezoelectric module that receives the sound wave first is set to excite ultrasound later, and the piezoelectric module that receives the sound wave later is set to excite ultrasound first. This makes the sound waves excited by the array composed of each piezoelectric module according to the preset interval rule reach the target area at the same time, forming a focused sound beam to open the blood-brain barrier.

10. The method for preparing a flexible device for ultrasound electric field coupling therapy as described in claims 8-9, characterized in that: The electric field control unit (25) connected to the lead interface controls the electrode sheet (11) to generate an alternating electric field of 10 kHz-1 MHz in two mutually perpendicular directions after opening the blood-brain barrier, and controls the voltage amplitude within 36 V, thereby accelerating the flow and penetration of anti-tumor drugs while inhibiting the proliferation of tumor cells.

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