WO2020098601A1 - Percutaneous vaccine delivery device employing acoustically induced micropore array - Google Patents

Percutaneous vaccine delivery device employing acoustically induced micropore array Download PDF

Info

Publication number
WO2020098601A1
WO2020098601A1 PCT/CN2019/117138 CN2019117138W WO2020098601A1 WO 2020098601 A1 WO2020098601 A1 WO 2020098601A1 CN 2019117138 W CN2019117138 W CN 2019117138W WO 2020098601 A1 WO2020098601 A1 WO 2020098601A1
Authority
WO
WIPO (PCT)
Prior art keywords
ultrasonic
monitoring
ultrasonic transducer
skin
signal
Prior art date
Application number
PCT/CN2019/117138
Other languages
French (fr)
Chinese (zh)
Inventor
胡亚欣
杨梅
陈昕
Original Assignee
深圳大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 深圳大学 filed Critical 深圳大学
Publication of WO2020098601A1 publication Critical patent/WO2020098601A1/en

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0061Methods for using microneedles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/05General characteristics of the apparatus combined with other kinds of therapy
    • A61M2205/058General characteristics of the apparatus combined with other kinds of therapy with ultrasound therapy

Definitions

  • the present disclosure belongs to the technical field of transdermal administration and immunity, for example, a vaccine transdermal delivery device based on an acoustically induced micropore array.
  • the skin serves as the body's first line of defense against harmful substances in the external environment.
  • the superficial skin contains many immune cells in the epidermis and dermis, such as dendritic Langerhans cells and dermal dendritic cells. Langerhans cells on the one hand control the formation of keratin, on the other hand participate in skin immune response and are the main antigen presenting cells in the skin epidermis.
  • the epidermal layer of the skin is about 100 microns thick. If the antigen can reach the epidermal layer, it can activate the immune response of immune cells, thereby achieving a local to systemic immune response. Therefore, skin immunity is expected to become an ideal new needleless immunization route.
  • the commonly used stratum corneum permeation techniques include iontophoresis, electroporation, microneedle array technique, and acoustic perforation techniques.
  • the iontophoresis method can only be applied to the transdermal delivery of small-molecule drugs, and cannot deliver large-molecule vaccine antigens;
  • the electroporation technology has a hidden danger of biological safety due to the transient high-voltage pulses during administration, which can cause strong pain and discomfort;
  • the production of microneedle array technology carriers is complicated, and the cost is high, which cannot be promoted on a large scale. Because the delivery probe is a low-frequency, non-focusing probe, the delivery area is large, the delivery position is uncertain, and the consistency of the delivery area is poor.
  • the drug delivery by acoustic perforation technology is a small molecular weight drug, and there is also a delivery effect that cannot achieve the immunity of large molecule antigen.
  • the related transdermal drug delivery technology has problems such as the inability to deliver large-molecule vaccine antigens, painful delivery, complicated and costly process, and poor delivery area accuracy.
  • the present disclosure provides a vaccine transdermal delivery device based on an acoustically induced micropore array, to solve the related transdermal drug delivery technology, there is no delivery of macromolecular vaccine antigens, painful delivery process, complicated process and high cost, delivery Problems such as poor regional accuracy.
  • a vaccine percutaneous delivery device based on an acoustically induced micropore array, including: a main control system, a high-frequency intense focused ultrasound excitation component connected to the main control system, and a device for applying to An acoustically permeable immune patch for drug administration on the skin;
  • the high-frequency strong-focus ultrasound excitation component includes a high-frequency ultrasound signal generating system, a first ultrasound transducer connected to the high-frequency ultrasound signal generating system, and the A conical coupling catheter connected to the first ultrasonic transducer;
  • the conical coupling catheter is placed on the acoustically permeable immune patch during drug administration, and is used to conduct the acoustic energy of the first ultrasonic transducer to The immune patch;
  • the high-frequency ultrasonic signal generating system includes an electrical signal generator, a linear power amplifier, and an impedance matching circuit that are electrically connected in sequence;
  • the main control system sends a pulsed ultrasonic excitation signal to the high
  • the first ultrasonic transducer is a ring-shaped hollow first ultrasonic transducer; the ring-shaped hollow area is provided with a receiving cavity.
  • the ultrasonic echo signal monitoring system also includes an ultrasonic echo signal monitoring system connected to the main control system;
  • the ultrasonic echo signal monitoring system includes a second ultrasonic transducer and a signal monitoring component electrically connected to each other;
  • the outer diameter of the second ultrasonic transducer is not larger than the inner diameter of the accommodating cavity, and is used to be placed in the accommodating cavity during monitoring;
  • the echo signal monitoring component is used to send a signal and then pass the The second ultrasonic transducer converts and monitors the administration process of the vaccine transdermal delivery device based on the acoustically induced micropore array based on the received return signal.
  • the signal monitoring component includes a pulse transceiver connected to the second ultrasonic transducer, and a data acquisition card connected to the pulse transceiver; wherein, the pulse transceiver and the data acquisition The cards are connected to the main control system; when the sound-transmitting immune patch is encountered during the propagation of the monitoring sound signal, the monitoring sound signal is reflected to form a first monitoring echo, and is sent and received through the pulse Instrument amplification, the data acquisition card receives the amplified first monitoring echo and performs analog-to-digital conversion, and the record is stored as the first echo pulse; when the monitoring acoustic signal continues to encounter the skin during the propagation process, the monitoring is reflected The acoustic signal forms a second monitoring echo and is amplified by the pulse transceiver.
  • the data acquisition card receives the amplified second monitoring echo and performs analog-to-digital conversion.
  • the record is stored as a second echo pulse;
  • the first echo pulse and the second echo pulse monitor the administration process of the vaccine transdermal delivery device based on the acoustically induced micropore array.
  • the optical imaging monitoring system also includes an optical imaging monitoring system connected to the main control system;
  • the optical imaging monitoring system includes an imaging probe and an imaging processing unit connected to the imaging probe;
  • the outer diameter of the imaging probe is not greater than The inner diameter of the accommodating cavity is used to be placed in the accommodating cavity during monitoring;
  • the main control system is also used to control the imaging probe to perform on the acoustically permeable immune patch and / or skin Image acquisition, real-time or timing imaging, and imaging processing is performed on the imaging data by the imaging processing unit to perform imaging detection.
  • the imaging probe is placed in the middle of the receiving cavity of the first ultrasonic transducer; and, the imaging probe, the center of the imaging field corresponding to the imaging probe, and the first ultrasonic transducer
  • the relative position of the device is coaxial with the geometric center.
  • the optical imaging monitoring system further includes a probe fixing bracket connected to the imaging probe; and the high-frequency intense focusing ultrasound excitation component further includes A first ultrasonic transducer fixing bracket connected to the first ultrasonic transducer; the ultrasonic echo signal monitoring system further includes a second ultrasonic transducer fixing bracket connected to the second ultrasonic transducer; the probe The fixed bracket, the first ultrasonic transducer fixed bracket, and the second ultrasonic transducer fixed bracket are all connected to the three-dimensional movement controller.
  • the sound-permeable immune patch includes an isolation ring and an adhesive film; the adhesive film covers the isolation ring; and, a drug container is formed between the adhesive film and the isolation ring Cavity; when administering to the skin, use the viscosity of the adhesive film to apply the sound-permeable immune patch to the skin surface, wherein the drug containing cavity is filled with a drug for administration.
  • the isolation ring is a circular rubber isolation ring;
  • the adhesive film is a transparent plastic material adhesive film; the adhesive film faces away from the conical coupling catheter and faces the skin during administration One side is sticky;
  • the outer diameter of the isolation ring is 5-15 mm, the inner diameter is 3-10 mm, and the thickness is 1-3 mm.
  • the present disclosure also provides a method for using a vaccine transdermal delivery device based on an acoustically induced micropore array, which includes: applying an acoustically permeable immune patch and placing it in the cone of the vaccine transdermal delivery device based on an acoustically induced micropore array The lower end of the shape-coupled catheter; spatial positioning through the ultrasonic echo signal monitoring system and optical imaging monitoring system of the vaccine transdermal delivery device based on the acoustically induced micropore array to determine the site of skin administration; through the acoustically induced micropore Array high-frequency focused ultrasound excitation component of vaccine transdermal delivery device performs transdermal immunotherapy on the skin administration site; delivery effect on the skin administration site on the transdermal immunity administration through the optical imaging monitoring system Evaluation.
  • the present disclosure provides a vaccine transdermal delivery device based on an acoustically induced micropore array, which includes a main control system, a high-frequency intense focused ultrasound excitation component connected to the main control system, and a sound applied to the skin for drug administration Permeable immune patch;
  • the high-frequency strong-focus ultrasound excitation component includes a high-frequency ultrasonic signal generating system, a first ultrasonic transducer connected to the high-frequency ultrasonic signal generating system, and a first ultrasonic transducer connected to the first ultrasonic transducer A conical coupling catheter;
  • the conical coupling catheter is placed on the acoustically permeable immune patch during drug administration, and is used to conduct the acoustic energy of the first ultrasonic transducer to the immune patch;
  • the high-frequency ultrasonic signal generating system includes an electrical signal generator, a linear power amplifier, and an impedance matching circuit that are electrically connected in sequence.
  • the present disclosure controls the electrical signal generator in the high-frequency and strong-focus ultrasonic excitation assembly through the main control system to generate ultrasonic electrical signals, and transmits them to the high-intensity ultrasonic transducer through the linear power amplifier amplification and impedance matching circuit, and then uses the high-intensity ultrasonic transducer Acoustic energy conversion is performed to obtain acoustic energy, which is introduced into the skin under the patch through a conical coupling catheter to form skin micropores on the skin, and then delivers the drug through the skin micropores.
  • the present disclosure uses high-frequency high-intensity focused ultrasound technology to form skin micropores with different breadths and depths on the skin (as shown in FIG.
  • the administration method is simple and the administration process is minimally invasive.
  • the pain, delivery and delivery methods are safe and effective, and the delivery efficiency is high, the delivery area has high accuracy and the location is accurate, which greatly improves the user experience.
  • Embodiment 1 is a schematic structural view of Embodiment 1 of a vaccine transdermal delivery device based on an acoustically induced micropore array;
  • FIG. 2 is an XY plane ultrasonic focus measurement diagram of the first embodiment of the vaccine percutaneous delivery device based on an acoustically induced micropore array;
  • FIG. 3 is an XZ plane ultrasonic focus measurement diagram of the first embodiment of the vaccine percutaneous delivery device based on the acoustically induced micropore array;
  • Embodiment 4 is a schematic structural view of Embodiment 2 of a vaccine percutaneous delivery device based on an acoustically induced micropore array;
  • FIG. 5 is a schematic diagram of the second ultrasonic transducer echo monitoring method of the second embodiment of the vaccine transdermal delivery device based on the acoustically induced micropore array;
  • FIG. 6 is a schematic structural view of Embodiment 3 of a vaccine percutaneous delivery device based on an acoustically induced micropore array;
  • FIG. 7 is a diagram showing the delivery effect of the acoustically permeable immune patch of the third embodiment of the vaccine transdermal delivery device based on the acoustically induced micropore array;
  • FIG. 8 is a schematic structural diagram of a three-dimensional mobile controller according to Embodiment 4 of a vaccine percutaneous delivery device based on an acoustically induced micropore array;
  • FIG. 9 is a schematic diagram of the structure of an acoustically permeable immune patch of the fourth embodiment of the vaccine transdermal delivery device based on an acoustically induced micropore array;
  • FIG. 10 is an overall schematic diagram of Embodiment 4 of a vaccine transdermal delivery device based on acoustically induced micropore arrays;
  • FIG. 11 is a schematic flowchart of a method for using a vaccine transdermal delivery device based on an acoustically induced micropore array in Embodiment 5 of the present invention
  • FIG. 12 is another schematic flow chart of a method for using a vaccine percutaneous delivery device based on an acoustically induced micropore array in Embodiment 5 of the present invention.
  • FIG. 13 is an example diagram of different width and depth patterns of skin pores formed after immunization of a vaccine transdermal delivery device based on an acoustically induced pore array (H & E stained slice diagram);
  • FIG. 14 is a diagram showing examples of different array patterns of skin micropores formed in the vaccine transdermal delivery device based on the acoustically induced micropore array.
  • Embodiment 1 discloses a vaccine transdermal delivery device 1 based on an acoustically induced micropore array.
  • the vaccine transdermal delivery device 1 based on an acoustically induced micropore array includes: a master control System 11, a high-frequency intense focused ultrasound excitation assembly 12 connected to the main control system 11, and an acoustically permeable immune patch 13 applied to the skin for drug delivery;
  • the high-frequency intense focused ultrasound excitation assembly 12 includes high Frequency ultrasonic signal generating system 121, a first ultrasonic transducer 122 connected to the high frequency ultrasonic signal generating system 121, a conical coupling conduit 123 connected to the first ultrasonic transducer 122; the conical coupling The catheter 123 is placed on the acoustically permeable immune patch 13 at the time of drug administration, and is used to conduct the acoustic energy of the first ultrasound transducer 122 to the immune patch; the high-frequency ultrasound signal
  • the main control system 11 sends a pulsed ultrasonic excitation signal to the high-frequency ultrasonic signal generation system 121, and then the high-frequency ultrasonic signal generation system 121 generates an ultrasonic electric signal according to the pulsed ultrasonic excitation signal, and passes the first
  • the ultrasonic transducer 122 converts the ultrasonic electrical signal into an acoustic signal, and introduces the acoustic energy of the acoustic signal into the skin under the acoustically permeable immune patch 13 through the conical coupling catheter 123 to facilitate the formation of the skin Micropores in the skin for transdermal delivery of immune antigens.
  • the high-frequency ultrasonic signal generating system 121 includes an electrical signal generator 121a, a linear power amplifier 121b, and an impedance matching circuit 121c that are electrically connected in sequence;
  • the main control system 11 is used to send pulsed ultrasonic excitation signal parameters to the electrical signal generator 121a, and the electrical signal generator 121a generates an ultrasonic electrical signal according to the pulsed ultrasonic excitation signal parameters; through the linear power
  • the amplifier 121b amplifies the ultrasonic electrical signal, and transmits the amplified ultrasonic electrical signal to the first ultrasonic transducer 122 through the impedance matching circuit 121c, and the first ultrasonic transducer 122 performs the ultrasonic electrical signal Conversion to an acoustic signal, and the acoustic energy of the acoustic signal is introduced into the skin under the acoustically permeable immune patch 13 through a conical coupling catheter 123, so as to form skin pores on the skin for the immune antigen to pass through ⁇ DELIVERY.
  • the stratum corneum serves as the outermost shielding protective layer of the skin, and its thickness is 15-20 microns.
  • the complete stratum corneum can well regulate the transdermal absorption of the substance.
  • the rate of transdermal diffusion of a substance is inversely related to its molecular weight. The smaller the molecular weight, the easier it is to pass through the stratum corneum. It is generally believed that only compounds with a molecular weight of less than 500 Daltons can penetrate the stratum corneum. If the skin is damaged, the stratum corneum can lose its shielding effect, thereby greatly increasing the speed and degree of substance absorption, especially for the transdermal delivery of macromolecular proteins such as antigens.
  • the vaccine-derived transdermal delivery device 1 based on the acoustically induced micropore array provided in this embodiment is applied to the transdermal administration of immune antigens of macromolecules, and utilizes the acoustically induced micropore technology to pass the drug through the stratum corneum. Thus delivery achieves immunity.
  • the high-frequency strong-focus ultrasonic excitation assembly 12 is composed of the electric signal generator 121a, the linear power amplifier 121b, the impedance matching circuit 121c, and the first ultrasonic transducer 122.
  • the parameters of the pulsed ultrasonic excitation signal may include, but are not limited to, parameters such as duty cycle, pulse repetition frequency, and peak negative sound pressure.
  • the main control system 11 performs edit control based on this parameter through the electric signal generator 121a, and edits the generated
  • the signal is amplified by the linear power amplifier 121b, and the amplified electrical signal drives the first ultrasonic transducer 122 to output a pulsed ultrasonic excitation signal of high frequency, high intensity, and strong focus.
  • the high-frequency high-intensity focused ultrasound excitation component 12 is a high-frequency high-intensity strong focused ultrasound excitation component, where high frequency, in this embodiment, may refer to a signal with a frequency greater than 1 MHz ; High intensity means that the output ultrasonic peak negative sound pressure is greater than 5MPa; strong focusing means that the lateral diameter of the ultrasonic focus point is less than 0.8mm and the longitudinal diameter is less than 3mm.
  • the first ultrasonic transducer 122 is a high-intensity ultrasonic transducer in this embodiment.
  • the half-height width of the transverse focus of the sound field measured in the XY plane (ie: the corresponding sound field diameter when its negative sound pressure drops to half the peak value) is about 0.76mm.
  • the longitudinal half-height width of this sound field measured in the XZ plane is about 2.4mm.
  • the sound-permeable immune patch 13 is a carrier for applying to the skin for administration, that is, the immune vaccine antigen or the vaccine antigen mixed liquid added with phase-change droplets can be filled into the cavity of the patch , And then apply the patch to the skin surface to complete the preparation of the skin immune patch.
  • the phase-change droplets can be a film-enhanced agent whose original core is liquid.
  • the internal low-boiling liquid such as perfluoropentane with a boiling point of 42 ° C
  • the internal low-boiling liquid such as perfluoropentane with a boiling point of 42 ° C
  • the first ultrasonic transducer 122 can realize the conversion of electrical signals into acoustic signals.
  • the transducer can include a probe whose front end is placed on the sound-transmitting immune patch through a cone-shaped acoustic coupling catheter.
  • the cone-shaped acoustic coupling The catheter is filled with degassed ultrapure water as a sound propagation medium.
  • ultrasonic coupling agents can achieve the acoustic coupling of the cone-shaped acoustic coupling catheter and the acoustically transparent immune patch, thereby introducing the acoustic energy output from the high-intensity transducer into the acoustic permeability
  • the skin under the immune patch creates micropores in the skin, allowing the antigen solution in the acoustically permeable immune patch to diffuse into the skin.
  • the linear power amplifier 121b is used to amplify the ultrasonic electrical signal; that is, the impedance of the matching signal source is equal to the characteristic impedance of the connected transmission line and the phase is the same, or the characteristic impedance of the transmission line and the impedance of the connected load Equivalent in size and phase, the input end or output end of the transmission line is in impedance matching state, referred to as impedance matching; and the impedance matching circuit 121c is mainly used on the transmission line to reach all high-frequency microwave signals. For the purpose of reaching the load point, no signal will be reflected back to the source point, thereby improving energy efficiency.
  • the main control system 11 can be a main control computer to coordinate and control various sub-systems.
  • the main control system 11 controls the electric signal generator 121a in the high-frequency and strong-focus ultrasonic excitation assembly 12 to generate ultrasonic electric signals, which are amplified by a linear power amplifier, and transmitted to a high-intensity ultrasonic transducer by an impedance matching circuit 121c.
  • the intensity ultrasonic transducer converts the acoustic energy to obtain the acoustic energy, which is introduced into the skin under the patch through the conical coupling catheter 123, forms a skin micropore in the skin, and then delivers the drug through the skin micropore (wherein, an array formed on the skin (The model is shown in Figure 14).
  • This embodiment uses high-frequency high-intensity focused ultrasound technology to form skin micropores with different breadths and depths on the skin for the transdermal delivery of immune antigens of large molecules.
  • the method of administration is simple, the process of administration is minimally invasive, painless, and delivered to
  • the medicine method is safe and effective, and the drug delivery efficiency is high, the delivery area accuracy is high, and the location is accurate, which greatly improves the user experience.
  • Embodiment 2 Referring to FIGS. 4-5, based on the foregoing embodiment, this embodiment provides a vaccine percutaneous delivery device 1 based on an acoustically induced micropore array, wherein,
  • the first ultrasonic transducer 122 is a ring-shaped hollow first ultrasonic transducer 122; the ring-shaped hollow region is provided with a receiving cavity 122a.
  • the vaccine transdermal delivery device 1 based on an acoustically induced micropore array further includes an ultrasound echo signal monitoring system 14 connected to the main control system 11;
  • the ultrasonic echo signal monitoring system 14 includes a second ultrasonic transducer 141 and a signal monitoring assembly 142 electrically connected to each other; the outer diameter of the second ultrasonic transducer 141 is not larger than the accommodating cavity 122a The inner diameter of is used to be placed in the accommodating cavity 122a during monitoring;
  • the echo signal monitoring component 142 is used to send a signal, and then converted by the second ultrasonic transducer 141, and according to the received return signal to the acoustically induced micropore array-based vaccine transdermal delivery device 1. Monitor the administration process.
  • the signal monitoring component 142 includes a pulse transceiver 142a connected to the second ultrasonic transducer 141, and a data acquisition card 142b connected to the pulse transceiver 142a; wherein, the pulse Both the transceiver 142a and the data acquisition card 142b are connected to the main control system 11;
  • the main control system 11 controls the pulse transceiver 142a to output an electrical pulse, Exciting the second ultrasonic transducer 141 to emit a monitoring acoustic signal according to the electrical pulse, the monitoring acoustic signal entering the accommodating cavity 122a and propagating through the conical coupling conduit 123;
  • the monitoring sound signal is reflected to form a first monitoring echo, which is amplified by the pulse transceiver 142a, and the data acquisition card 142b receives the amplified first monitoring echo and performs analog-to-digital conversion, and the record is stored as the first echo pulse;
  • the monitoring acoustic signal continues to spread and encounters the skin, the monitoring acoustic signal is reflected to form a second monitoring echo Wave, and amplified by the pulse transceiver 142a, the data acquisition card 142b receives the amplified second monitoring echo and performs analog-to-digital conversion, and the record is stored as a second echo pulse; by the first echo pulse And the second echo pulse to monitor the administration process of the vaccine transdermal delivery device 1 based on the acoustically induced micropore array.
  • the ultrasonic signal echo monitoring system is a low-intensity ultrasonic signal echo system
  • the second ultrasonic transducer 141 in this embodiment, is a low-intensity ultrasonic transducer, low Intensity, in this embodiment, may be a signal whose peak time sound field sound intensity is lower than 720mW and greater than a frequency above 1MHz.
  • the first ultrasonic transducer 122 is a ring-shaped hollow design, wherein the ring-shaped hollow region is provided with a receiving cavity 122a, so that the imaging probe 151 with a smaller diameter can be placed in the receiving cavity 122a inside the first ultrasonic transducer 122 Perform inspection and imaging.
  • the ultrasonic echo signal monitoring system 14 includes the second ultrasonic transducer 141 and the echo signal monitoring component 142, and the echo signal monitoring component 142 includes the pulse transceiver 142a and the data acquisition card 142b.
  • the second ultrasonic transducer 141 mainly emits acoustic signals and receives acoustic echoes, and its diameter is not greater than the inner diameter of the annular first ultrasonic transducer 122, and can be placed in the intermediate space of the annular first ultrasonic transducer 122.
  • the pulse transceiver 142a is a device with dual functions of transmitting and receiving.
  • the pulse transceiver 142a first outputs an electrical pulse to excite the second ultrasonic transducer 141 to emit a monitoring sound signal, and the monitoring sound signal enters the cone-shaped acoustic coupling catheter to propagate, when When the transmission encounters the diaphragm of the sound-transmitting immune patch, it reflects back an echo and enters the pulse transceiver 142a for amplification, and after further undergoing the analog-to-digital conversion of the data acquisition card 142b, it can be recorded as the first echo pulse.
  • the reception time t1 of the first monitoring echo and the reception time t2 of the second monitoring echo are separated by 2 microseconds.
  • the main functions and principles of the ultrasonic echo signal monitoring system 14 include: z-axis positioning of the first ultrasonic transducer 122 assisted by low-intensity ultrasonic echo and microbubble generation and blasting monitoring in enhanced ultrasonic mode.
  • the following implementation method may be included: During the process of the automatic positioning of the first ultrasonic transducer 122 in the z-axis, The ultrasound echo signal monitoring system 14 is activated to calculate, move and determine the position between the first ultrasound transducer 122 and the skin. As shown in Fig.
  • the main functions and principles of microbubble generation and blast monitoring used in enhanced ultrasound mode include: in enhanced ultrasound mode, the phase-change droplets mixed with the vaccine antigen solution in the acoustically permeable immune patch 13 first To achieve gasification at the ultrasound focus. Therefore, in the enhanced ultrasonic mode, after the positioning of the first ultrasonic transducer 122 is completed, the high-intensity excitation pulse is released, first the phase-change activation of the phase-change droplet from the liquid core to the gaseous core is completed, and then the low-intensity ultrasonic pulse signal is released Detection. As shown in Fig.
  • the air core ultrasound intensifier will generate a strong reflection between the diaphragm and the skin, forming a third monitoring echo in the echo waveform. Further release the high-intensity excitation pulse blasting gas nuclear ultrasound enhancer, thereby generating a stronger mechanical effect on the skin and inducing the formation of skin pores. When the gas nuclear ultrasound enhancer blasts, its third monitoring echo will disappear. Therefore, as shown in FIG. 5 (4), the low-intensity ultrasonic pulse signal is released again for detection, it is determined that the third monitoring echo disappears, and the single-shot enhanced ultrasound skin pore induction is completed.
  • an ultrasound echo signal monitoring system 14 connected to the main control system 11 is provided in the vaccine transdermal delivery device 1 based on the acoustically induced micropore array; wherein, the pulse is transmitted and received in the monitoring system
  • the instrument 142a and the data acquisition card 142b based on the second ultrasonic transducer 141 in the detection system, monitor the drug delivery process of the vaccine transdermal delivery device 1 based on the acoustically induced micropore array, which may include
  • the z-axis positioning of the first ultrasonic transducer 122 assisted by low-intensity ultrasonic echo, and for the monitoring and generation of microbubbles in the enhanced ultrasonic mode, through the monitoring of the ultrasonic echo signal monitoring system 1414,
  • the z-axis positioning of the first ultrasound transducer 122 is realized, so that the area of the target skin of the ultrasound percutaneous administration is more accurate, and the accuracy of the administration is improved on the positioning level.
  • Embodiment 3 Referring to FIGS. 6-7, based on the above-mentioned Embodiment 2, this embodiment provides a vaccine transdermal delivery device 1 based on an acoustically induced micropore array, the vaccine transdermal delivery device based on an acoustically induced micropore array 1 also includes an optical imaging monitoring system 15 connected to the main control system 11;
  • the optical imaging monitoring system includes an imaging probe 151, and an imaging processing unit 152 connected to the imaging probe 151;
  • the outer diameter of the imaging probe 151 is not larger than the inner diameter of the accommodating cavity 122a, and is used to be placed in the accommodating cavity 122a during monitoring;
  • the main control system 11 is also used to control the imaging probe 151 to perform image acquisition on the acoustically permeable immune patch and / or skin, perform real-time or timed imaging, and perform imaging data on the imaging processing unit 152 Recognition process for imaging detection.
  • the imaging probe 151 is placed in the middle of the receiving cavity 122a of the first ultrasonic transducer 122; and,
  • the relative positions of the imaging probe 151, the center of the imaging field corresponding to the imaging probe 151, and the first ultrasound transducer 122 are geometric centers coaxial.
  • the optical imaging monitoring system is composed of the imaging probe 151 and the imaging processing unit 152, wherein the imaging probe 151 has zoom and zoom functions, and its diameter is not larger than the inner diameter of the ring-shaped first ultrasonic transducer 122, so that it can be placed in the ring-shaped first
  • An accommodating cavity 122a in an ultrasonic transducer 122 performs imaging monitoring of the acoustically permeable immune patch (rubber ring) and skin damage below the annular first ultrasonic transducer 122.
  • the realized functions include the xy axis positioning of the first ultrasonic transducer 122 assisted by optical imaging, and the quantitative evaluation of skin micropore damage.
  • the working principle includes: 1. When positioning the xy axis of the first ultrasonic transducer 122 with the aid of optical imaging, as shown in FIG. 7 (1), the The isolation ring can be imaged in real time.
  • the imaging probe 151 is placed in the middle of the ring-shaped first ultrasonic transducer 122, and the centers of the two are coaxial, and the center of the imaging field of view is coaxial with the geometric center of the imaging probe 151 and the first ultrasonic transducer 122.
  • the first ultrasound transducer 122 and the imaging probe 151 placed therein can be moved by a three-axis movement control system to isolate the center of the imaging field of view from the acoustically permeable immunopatch
  • the center of the ring is coaxial, so that the acoustic energy focus (located on the center axis of the first ultrasonic transducer 122) and the center of the sound-transmitting immune patch isolation ring are aligned in the xy plane.
  • the imaging probe 151 obtains the vaccine-derived transdermal delivery device 1 based on the acoustically induced micropore array provided in this example to perform acoustic induction
  • the high-definition image of skin damage after micropore immunization passes through the imaging processing unit 152 to perform image processing analysis and calculate the skin damage range. Examples include:
  • the skin damage HD result image is converted to 8-bit grayscale image, and the size is re-set (such as: 600pixels * 600pixels) and the contrast is improved;
  • Threshold screening select the damaged area marked with black biological dye in the skin, and count the sum of its pixels
  • the imaging probe 151 of the optical imaging monitoring system is moved into the accommodating cavity 122 a in the annular hollow first ultrasonic transducer 122 to acquire an image
  • the imaging processing unit 152 Permeable immune patch and / or skin image acquisition to achieve the positioning of the xy axis of the first ultrasound transducer 122 with the aid of optical imaging during the ultrasound transdermal drug delivery through the immune array device, or Quantitative evaluation of skin micropore damage can, on the one hand, improve the positioning accuracy of the drug delivery area by positioning to achieve precise drug delivery; on the other hand, it can be accurately quantified during the drug delivery process to achieve precise delivery of immune antigens control.
  • Embodiment 4 Referring to FIGS. 8-10, based on the foregoing Embodiment 3, this embodiment provides a vaccine transdermal delivery device 1 based on an acoustically induced micropore array, wherein,
  • the vaccine transdermal delivery device 1 based on an acoustically induced micropore array further includes a three-dimensional mobile controller 16 connected to the main control system 11;
  • the optical imaging monitoring system 15 further includes a probe fixing bracket 153 connected to the imaging probe 151;
  • the high-frequency strong-focus ultrasonic excitation assembly 12 further includes a first ultrasonic transducer fixing bracket 124 connected to the first ultrasonic transducer 122;
  • the ultrasonic echo signal monitoring system 14 further includes a second ultrasonic transducer fixing bracket 143 connected to the second ultrasonic transducer;
  • the probe fixing bracket 153, the first ultrasound transducer fixing bracket 124, and the second ultrasound transducer fixing bracket are all connected to the 16.
  • the sound-permeable immune patch 13 includes an isolation ring 131 and an adhesive film 132;
  • the adhesive film 132 covers the isolation ring 131; and, a drug accommodating cavity 133 is formed between the adhesive film 132 and the isolation ring 131;
  • the acoustically permeable immune patch 13 When administering to the skin, using the viscosity of the adhesive film 132, the acoustically permeable immune patch 13 is applied to the surface of the skin, wherein the drug accommodating cavity 133 is filled with a drug for administration.
  • the isolation ring 131 is a circular rubber isolation ring 131; the adhesive film 132 is a transparent plastic adhesive film 132; the adhesive film 132 faces away from the drug during administration
  • the conical coupling catheter 123 has adhesiveness on the side facing the skin; the outer diameter of the isolation ring 131 is 5-15 mm, the inner diameter is 3-10 mm, and the thickness is 1-3 mm.
  • the three-dimensional positioning movement control system uses echo signals to detect the relative position of the skin site and the excitation source, and cooperates with the three-dimensional movement controller 16 to adjust the skin site to the ultrasonic focus point area, and is also used to vaporize the phase change droplets into Bubble detection and process evaluation of ultrasonic cavitation effects, real-time monitoring, is the leading role of the system.
  • the three-dimensional movement control system is connected to the main control system 11, and the probe fixing bracket 153, the first ultrasonic transducer fixing bracket 124, and the second ultrasonic transducer 141 are all connected with the three-dimensional movement
  • the controller 16 is connected.
  • the movement of the three-dimensional positioning movement control system can be controlled by the main control device, that is, the probe fixing bracket 153, the first ultrasonic transducer fixing bracket 124, and the second
  • the ultrasonic transducer 141 controls the spatial orientation of the first ultrasonic transducer 122 and the cone-shaped acoustic coupling catheter, the spatial orientation of the second ultrasonic transducer 141, and the spatial orientation of the imaging probe 151;
  • the spatial orientation of the second ultrasonic transducer 141 and the imaging probe 151 are adjusted separately, and the second ultrasonic transducer 141 or The imaging probe 151 is moved into the annular hollow accommodating cavity 122a of the first ultrasonic transducer 122, respectively to perform the corresponding functions of the immune array device provided in this embodiment, so that When medicine is taken, accurate drug delivery can be achieved by moving the corresponding device, and the corresponding imaging probe 151 or the second ultrasonic transducer 141 can
  • the sound-permeable immune patch 13 is used to apply to the target immunized area of the user or patient, that is, the drug carrier corresponding to the immune array device provided by the present disclosure.
  • the structure of the sound-permeable immune patch 13 may be composed of an isolation ring and a single-sided adhesive transparent plastic film.
  • the outer diameter of the isolation ring is 8 mm
  • the inner diameter is 6.5 mm
  • the thickness is 1.5 mm.
  • the mechanical coefficient is small and the weak reflection can reduce the loss of ultrasonic energy and can Avoid echo energy causing additional damage to the ultrasonic transmitter and echo receiver.
  • the thickness of the single-sided adhesive plastic film is 75 microns or less, and the plastic film in this thickness range has acoustic permeability, that is, more than 80% of the acoustic energy can be transmitted through the film into the skin.
  • Immune patch means that the vaccine antigen, or the vaccine antigen mixed liquid added with phase change droplets can be filled into the annular cavity of the patch, and then the skin surface is applied with a single-sided adhesive transparent film to complete the skin immune patch. ready.
  • the isolation ring By setting the isolation ring, it can be used to locate and administer the target immune area of the skin on the basis of achieving a small mechanical coefficient, if reflecting, reducing energy damage or injury, and to a certain extent, improve the spatial orientation of the administration area Accuracy, and reduce energy damage and mechanical damage to the skin.
  • Embodiment 5 In addition, referring to FIGS. 11-12, this embodiment provides a method for using a vaccine transdermal delivery device 1 based on an acoustically induced micropore array, including:
  • Step S10 applying an acoustically permeable immune patch 13 and placing it on the lower end of the conical coupling catheter 123 of the vaccine percutaneous delivery device 1 based on the acoustically induced micropore array;
  • Step S20 spatial positioning is performed by the ultrasonic echo signal monitoring system 14 and the optical imaging monitoring system 15 of the vaccine-derived transdermal delivery device 1 based on the acoustically induced micropore array to determine the skin administration site;
  • Step S30 Transcutaneous immunization administration to the skin administration site by the high-frequency intensity focused ultrasound excitation assembly 12 of the vaccine transdermal delivery device 1 based on the acoustically induced micropore array;
  • step S40 the delivery effect evaluation is performed on the skin administration site of percutaneous immune administration through the optical imaging monitoring system 15.
  • the present disclosure can provide a method for using a vaccine transdermal delivery device 1 based on an acoustically induced micropore array for transdermal patch administration to a target location of a user's skin to achieve the purpose of transdermal immunity.
  • a vaccine transdermal delivery device 1 based on an acoustically induced micropore array for transdermal patch administration to a target location of a user's skin to achieve the purpose of transdermal immunity.
  • Figure 12 for its workflow, which may include:
  • Mode 1 Skin pore formation and transdermal vaccine delivery:
  • mode two enhanced ultrasound mode.
  • Mode 2 has higher delivery efficiency than Mode 1.
  • the enhanced ultrasound mode first release high-intensity ultrasound pulses to excite the vaporization of liquid-nuclear phase-change droplets, confirm the generation of the gas-nuclear ultrasound enhancer by low-energy ultrasound echoes, and then release the high-energy ultrasound pulses to induce gas-nuclear ultrasound enhancement The agent exploded, and again confirmed the disappearance of the air core ultrasound enhancer by low-energy ultrasound echo, thus completing a single delivery.
  • the width of the skin pores in the width mode 1 is 0.1 ⁇ 0.03 mm2, the area of the skin pores in the width mode 2 is 0.3 ⁇ 0.05, and the width of the skin pores in the width 3 is 0.6 ⁇ 0.1;
  • the depth of the skin micropores in Mode 1 is 100 ⁇ 50 microns, the depth of the skin micropores in Depth Mode 2 is 200 ⁇ 50 microns, and the depth of the skin micropores in Depth Mode 3 is 300 ⁇ 50 microns; where black is marked by Indian ink.
  • the total vaccine delivery dose can be further designed and optimized through the combination of skin micropores, thereby regulating the total transdermal delivery dose.
  • the 1 ⁇ 1 array mode is a single skin micropore
  • the 1 ⁇ 2 array mode is two skin micropores
  • the 2 ⁇ 2 array mode is four skin micropores
  • the 3 ⁇ 3 array mode is nine skin micropores hole.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Medical Informatics (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Media Introduction/Drainage Providing Device (AREA)

Abstract

A percutaneous vaccine delivery device (1) employing an acoustically induced micropore array. The device (1) comprises a main control system (11), a high-frequency intense-focused ultrasonic excitation assembly (12), and an acoustically permeable immunization patch (13). The high-frequency intense-focused ultrasonic excitation assembly (12) comprises a high-frequency ultrasonic signal generation system (121), a first ultrasonic transducer (122) connected to the high-frequency ultrasonic signal generation system (121), and a conical coupling duct (123) connected to the first ultrasonic transducer (122). The conical coupling duct (123) is placed on the acoustically permeable immunization patch (13) during vaccine administration, such that high-frequency intense-focused ultrasonic energy is output from a front end of the duct to induce formation of micropores and micropore arrays on the skin.

Description

一种基于声诱导微孔阵列的疫苗经皮递送装置Transdermal vaccine delivery device based on acoustically induced micropore array
本申请要求在2018年11月12日提交中国专利局、申请号为201811341239.X的中国专利申请的优先权,以上申请的全部内容通过引用结合在本申请中。This application requires the priority of the Chinese patent application with the application number 201811341239.X submitted to the China Patent Office on November 12, 2018. The entire content of the above application is incorporated by reference in this application.
技术领域Technical field
本公开属于经皮给药免疫技术领域,例如是一种基于声诱导微孔阵列的疫苗经皮递送装置。The present disclosure belongs to the technical field of transdermal administration and immunity, for example, a vaccine transdermal delivery device based on an acoustically induced micropore array.
背景技术Background technique
随着皮肤在人体免疫保护方面的重要性逐步揭晓,“皮肤免疫”的概念已经确立。皮肤作为人体抵御外界环境有害物质的第一道防线,浅层皮肤包含表皮层和真皮层均存在许多免疫细胞,比如:树突状朗格汉斯细胞和真皮树突状细胞等。朗格汉斯细胞一方面控制角质的形成,另一方面参与皮肤免疫反应,是皮肤表皮中主要的抗原呈递细胞。通常皮肤的表皮层大约100微米厚度,如果抗原能够抵达表皮层就能激活免疫细胞的免疫应答,从而实现局部到全身的免疫反应。因此,皮肤免疫有望成为理想的新型无针免疫途径。With the gradual disclosure of the importance of skin in human immune protection, the concept of "skin immunity" has been established. The skin serves as the body's first line of defense against harmful substances in the external environment. The superficial skin contains many immune cells in the epidermis and dermis, such as dendritic Langerhans cells and dermal dendritic cells. Langerhans cells on the one hand control the formation of keratin, on the other hand participate in skin immune response and are the main antigen presenting cells in the skin epidermis. Usually the epidermal layer of the skin is about 100 microns thick. If the antigen can reach the epidermal layer, it can activate the immune response of immune cells, thereby achieving a local to systemic immune response. Therefore, skin immunity is expected to become an ideal new needleless immunization route.
目前,通常使用的角质层通透技术包括离子导入法、电致穿孔技术、微针阵列技术和声致穿孔技术等经皮免疫方法。其中,离子导入法,只能应用于小分子药物经皮递送,无法递送大分子疫苗抗原;电致穿孔技术由于给药时产生瞬时高压脉冲存在生物安全隐患,会造成较强痛感和不适感;微针阵列技术载体制作复杂,且成本高昂,无法大规模推广;声致穿孔技术由于递送探头为低频率、非聚焦探头,导致递送面积大、递送位置不确定、递送面积一致性差等 问题,并且声致穿孔技术递送药物为小分子量药物,也存在无法达到大分子抗原免疫的递送效果。At present, the commonly used stratum corneum permeation techniques include iontophoresis, electroporation, microneedle array technique, and acoustic perforation techniques. Among them, the iontophoresis method can only be applied to the transdermal delivery of small-molecule drugs, and cannot deliver large-molecule vaccine antigens; the electroporation technology has a hidden danger of biological safety due to the transient high-voltage pulses during administration, which can cause strong pain and discomfort; The production of microneedle array technology carriers is complicated, and the cost is high, which cannot be promoted on a large scale. Because the delivery probe is a low-frequency, non-focusing probe, the delivery area is large, the delivery position is uncertain, and the consistency of the delivery area is poor. The drug delivery by acoustic perforation technology is a small molecular weight drug, and there is also a delivery effect that cannot achieve the immunity of large molecule antigen.
总之,相关的经皮给药进行免疫的技术,存在无法递送大分子疫苗抗原、递送过程痛苦、工艺复杂成本高昂、递送区域精度差等问题。In short, the related transdermal drug delivery technology has problems such as the inability to deliver large-molecule vaccine antigens, painful delivery, complicated and costly process, and poor delivery area accuracy.
发明内容Summary of the invention
本公开提供一种基于声诱导微孔阵列的疫苗经皮递送装置,以解决相关的经皮给药进行免疫的技术中,存在无法递送大分子疫苗抗原、递送过程痛苦、工艺复杂成本高昂、递送区域精度差等问题。The present disclosure provides a vaccine transdermal delivery device based on an acoustically induced micropore array, to solve the related transdermal drug delivery technology, there is no delivery of macromolecular vaccine antigens, painful delivery process, complicated process and high cost, delivery Problems such as poor regional accuracy.
本公开通过以下技术方案来实现:一种基于声诱导微孔阵列的疫苗经皮递送装置,包括:主控系统、与所述主控系统连接的高频强聚焦超声激励组件,以及用于贴敷至皮肤上用于给药的声透性免疫贴片;所述高频强聚焦超声激励组件包括高频超声信号发生系统、与所述高频超声信号发生系统连接的第一超声换能器、与所述第一超声换能器连接的圆锥形耦合导管;所述圆锥形耦合导管在给药时置于所述声透性免疫贴片上,用于传导所述第一超声换能器的声能量至所述免疫贴片;所述高频超声信号发生系统包括依次电性连接的电信号发生器、线性功率放大器和阻抗匹配电路;所述主控系统发送脉冲超声激励信号至所述高频超声信号发生系统,进而所述高频超声信号发生系统根据所述脉冲超声激励信号产生超声电信号,并通过所述第一超声换能器进行超声电信号到声信号的转换,并将所述声信号的声能量通过圆锥形耦合导管导入所述声透性免疫贴片下方的皮肤中,以便于对皮肤形成皮肤微孔,以供免疫抗原经皮递送。The present disclosure is achieved by the following technical solutions: a vaccine percutaneous delivery device based on an acoustically induced micropore array, including: a main control system, a high-frequency intense focused ultrasound excitation component connected to the main control system, and a device for applying to An acoustically permeable immune patch for drug administration on the skin; the high-frequency strong-focus ultrasound excitation component includes a high-frequency ultrasound signal generating system, a first ultrasound transducer connected to the high-frequency ultrasound signal generating system, and the A conical coupling catheter connected to the first ultrasonic transducer; the conical coupling catheter is placed on the acoustically permeable immune patch during drug administration, and is used to conduct the acoustic energy of the first ultrasonic transducer to The immune patch; the high-frequency ultrasonic signal generating system includes an electrical signal generator, a linear power amplifier, and an impedance matching circuit that are electrically connected in sequence; the main control system sends a pulsed ultrasonic excitation signal to the high-frequency ultrasonic signal Generating system, and the high-frequency ultrasonic signal generating system generates an ultrasonic electrical signal according to the pulsed ultrasonic excitation signal, and converts the ultrasonic electrical signal into an acoustic signal through the first ultrasonic transducer, and converts the acoustic signal The acoustic energy is introduced into the skin under the sound-permeable immune patch through a conical coupling catheter, so as to form skin micropores in the skin for the transdermal delivery of immune antigens.
可选地,所述第一超声换能器为环形中空的第一超声换能器;其中的环形中空的区域设有容置腔。Optionally, the first ultrasonic transducer is a ring-shaped hollow first ultrasonic transducer; the ring-shaped hollow area is provided with a receiving cavity.
可选地,还包括与所述主控系统连接的超声回波信号监测系统;所述超声回波信号监测系统包括互相之间电性连接的第二超声换能器和信号监测组件;所述第二超声换能器的外直径不大于所述容置腔的内直径,用于在监测时放置于所述容置腔中;所述回波信号监测组件用以发送信号,进而通过所述第二超声换能器转换,并根据所接收到的返回的信号对所述基于声诱导微孔阵列的疫苗经皮递送装置的给药过程进行监控。Optionally, it also includes an ultrasonic echo signal monitoring system connected to the main control system; the ultrasonic echo signal monitoring system includes a second ultrasonic transducer and a signal monitoring component electrically connected to each other; the The outer diameter of the second ultrasonic transducer is not larger than the inner diameter of the accommodating cavity, and is used to be placed in the accommodating cavity during monitoring; the echo signal monitoring component is used to send a signal and then pass the The second ultrasonic transducer converts and monitors the administration process of the vaccine transdermal delivery device based on the acoustically induced micropore array based on the received return signal.
可选地,所述信号监测组件包括与所述第二超声换能器连接的脉冲收发仪,以及与所述脉冲收发仪连接的数据采集卡;其中,所述脉冲收发仪和所述数据采集卡均与所述主控系统连接;在所述监测声信号传播过程中遇到所述声透性免疫贴片时,反射所述监测声信号形成第一监测回波,并通过所述脉冲收发仪放大,所述数据采集卡接收放大后的第一监测回波并进行模数转换,记录存储为第一回波脉冲;当所述监测声信号继续传播过程中遇到皮肤,反射所述监测声信号形成第二监测回波,并通过所述脉冲收发仪放大,所述数据采集卡接收放大后的第二监测回波并进行模数转换,记录存储为第二回波脉冲;通过所述第一回波脉冲和所述第二回波脉冲对所述基于声诱导微孔阵列的疫苗经皮递送装置的给药过程进行监控。Optionally, the signal monitoring component includes a pulse transceiver connected to the second ultrasonic transducer, and a data acquisition card connected to the pulse transceiver; wherein, the pulse transceiver and the data acquisition The cards are connected to the main control system; when the sound-transmitting immune patch is encountered during the propagation of the monitoring sound signal, the monitoring sound signal is reflected to form a first monitoring echo, and is sent and received through the pulse Instrument amplification, the data acquisition card receives the amplified first monitoring echo and performs analog-to-digital conversion, and the record is stored as the first echo pulse; when the monitoring acoustic signal continues to encounter the skin during the propagation process, the monitoring is reflected The acoustic signal forms a second monitoring echo and is amplified by the pulse transceiver. The data acquisition card receives the amplified second monitoring echo and performs analog-to-digital conversion. The record is stored as a second echo pulse; The first echo pulse and the second echo pulse monitor the administration process of the vaccine transdermal delivery device based on the acoustically induced micropore array.
可选地,还包括与所述主控系统连接的光学成像监测系统;所述光学成像监测系统包括成像探头,以及与所述成像探头连接的成像处理单元;所述成像探头的外直径不大于所述容置腔的内直径,用于在监测时放置于所述容置腔中;所述主控系统还用于控制所述成像探头对所述声透性免疫贴片和/或皮肤进行图像采集,进行实时或定时成像,并通过所述成像处理单元对成像数据进行识别处理,以进行成像检测。Optionally, it also includes an optical imaging monitoring system connected to the main control system; the optical imaging monitoring system includes an imaging probe and an imaging processing unit connected to the imaging probe; the outer diameter of the imaging probe is not greater than The inner diameter of the accommodating cavity is used to be placed in the accommodating cavity during monitoring; the main control system is also used to control the imaging probe to perform on the acoustically permeable immune patch and / or skin Image acquisition, real-time or timing imaging, and imaging processing is performed on the imaging data by the imaging processing unit to perform imaging detection.
可选地,所述成像探头置于所述第一超声换能器的容置腔的中间;并且, 所述成像探头、所述成像探头对应的成像视野的中心和所述第一超声换能器的相对位置为几何中心同轴。Optionally, the imaging probe is placed in the middle of the receiving cavity of the first ultrasonic transducer; and, the imaging probe, the center of the imaging field corresponding to the imaging probe, and the first ultrasonic transducer The relative position of the device is coaxial with the geometric center.
可选地,还包括与所述主控系统连接的三维移动控制器;所述光学成像监测系统还包括与所述成像探头连接的探头固定支架;所述高频强聚焦超声激励组件还包括与所述第一超声换能器连接的第一超声换能器固定支架;所述超声回波信号监测系统还包括与所述第二超声换能器连接的第二超声换能器固定支架;所述探头固定支架、所述第一超声换能器固定支架以及所述第二超声换能器固定支架均与所述三维移动控制器连接。Optionally, it also includes a three-dimensional movement controller connected to the main control system; the optical imaging monitoring system further includes a probe fixing bracket connected to the imaging probe; and the high-frequency intense focusing ultrasound excitation component further includes A first ultrasonic transducer fixing bracket connected to the first ultrasonic transducer; the ultrasonic echo signal monitoring system further includes a second ultrasonic transducer fixing bracket connected to the second ultrasonic transducer; the probe The fixed bracket, the first ultrasonic transducer fixed bracket, and the second ultrasonic transducer fixed bracket are all connected to the three-dimensional movement controller.
可选地,所述声透性免疫贴片,包括隔离环和粘性薄膜;所述粘性薄膜覆盖于所述隔离环上;并且,所述粘性薄膜与所述隔离环之间形成一药物容置腔体;在对皮肤给药时,利用所述粘性薄膜的粘性,将所述声透性免疫贴片贴敷于皮肤表面,其中,所述药物容置腔体内注有用于给药的药物。Optionally, the sound-permeable immune patch includes an isolation ring and an adhesive film; the adhesive film covers the isolation ring; and, a drug container is formed between the adhesive film and the isolation ring Cavity; when administering to the skin, use the viscosity of the adhesive film to apply the sound-permeable immune patch to the skin surface, wherein the drug containing cavity is filled with a drug for administration.
可选地,所述隔离环为圆形的橡胶材质的隔离环;所述粘性薄膜为透明的塑料材质的粘性薄膜;所述粘性薄膜在给药时背离所述圆锥形耦合导管并且面对皮肤的一面具有粘性;所述隔离环的外径为5-15mm,内径为3-10mm,厚度为1-3mm。本公开还提供一种基于声诱导微孔阵列的疫苗经皮递送装置的使用方法,包括:贴敷声透性免疫贴片,并置于基于声诱导微孔阵列的疫苗经皮递送装置的圆锥形耦合导管下端;通过所述基于声诱导微孔阵列的疫苗经皮递送装置的超声回波信号监测系统和光学成像监测系统进行空间定位,以确定皮肤给药位点;通过基于声诱导微孔阵列的疫苗经皮递送装置的高频强聚焦超声激励组件对所述皮肤给药位点进行经皮免疫给药;通过所述光学成像监测系统对经皮免疫给药的皮肤给药位点进行递送效果评价。Optionally, the isolation ring is a circular rubber isolation ring; the adhesive film is a transparent plastic material adhesive film; the adhesive film faces away from the conical coupling catheter and faces the skin during administration One side is sticky; the outer diameter of the isolation ring is 5-15 mm, the inner diameter is 3-10 mm, and the thickness is 1-3 mm. The present disclosure also provides a method for using a vaccine transdermal delivery device based on an acoustically induced micropore array, which includes: applying an acoustically permeable immune patch and placing it in the cone of the vaccine transdermal delivery device based on an acoustically induced micropore array The lower end of the shape-coupled catheter; spatial positioning through the ultrasonic echo signal monitoring system and optical imaging monitoring system of the vaccine transdermal delivery device based on the acoustically induced micropore array to determine the site of skin administration; through the acoustically induced micropore Array high-frequency focused ultrasound excitation component of vaccine transdermal delivery device performs transdermal immunotherapy on the skin administration site; delivery effect on the skin administration site on the transdermal immunity administration through the optical imaging monitoring system Evaluation.
本公开提供一种基于声诱导微孔阵列的疫苗经皮递送装置,包括:主控系 统、与所述主控系统连接的高频强聚焦超声激励组件,以及贴敷于皮肤上用于给药的声透性免疫贴片;所述高频强聚焦超声激励组件包括高频超声信号发生系统、与所述高频超声信号发生系统连接的第一超声换能器、与所述第一超声换能器连接的圆锥形耦合导管;所述圆锥形耦合导管在给药时置于所述声透性免疫贴片上,用于传导所述第一超声换能器的声能量至所述免疫贴片;所述高频超声信号发生系统包括依次电性连接的电信号发生器、线性功率放大器和阻抗匹配电路。本公开通过主控系统控制高频强聚焦超声激励组件中的电信号发生器产生以超声电信号,并通过线性功率放大器放大、阻抗匹配电路传送至高强度超声换能器,进而利用高强度超声换能器进行声能转换,得到声能量,通过圆锥形耦合导管导入至贴片下皮肤,对皮肤形成皮肤微孔,进而通过皮肤微孔递送药物。本公开利用高频高强度聚焦超声技术在皮肤上形成不同广度和深度的皮肤微孔(如图12),以供大分子的免疫抗原经皮递送,给药方法简易、给药过程微创无痛、递送给药方式安全有效,并且给药效率高、递送区域精度高位置准确,大大提高了用户体验。The present disclosure provides a vaccine transdermal delivery device based on an acoustically induced micropore array, which includes a main control system, a high-frequency intense focused ultrasound excitation component connected to the main control system, and a sound applied to the skin for drug administration Permeable immune patch; the high-frequency strong-focus ultrasound excitation component includes a high-frequency ultrasonic signal generating system, a first ultrasonic transducer connected to the high-frequency ultrasonic signal generating system, and a first ultrasonic transducer connected to the first ultrasonic transducer A conical coupling catheter; the conical coupling catheter is placed on the acoustically permeable immune patch during drug administration, and is used to conduct the acoustic energy of the first ultrasonic transducer to the immune patch; The high-frequency ultrasonic signal generating system includes an electrical signal generator, a linear power amplifier, and an impedance matching circuit that are electrically connected in sequence. The present disclosure controls the electrical signal generator in the high-frequency and strong-focus ultrasonic excitation assembly through the main control system to generate ultrasonic electrical signals, and transmits them to the high-intensity ultrasonic transducer through the linear power amplifier amplification and impedance matching circuit, and then uses the high-intensity ultrasonic transducer Acoustic energy conversion is performed to obtain acoustic energy, which is introduced into the skin under the patch through a conical coupling catheter to form skin micropores on the skin, and then delivers the drug through the skin micropores. The present disclosure uses high-frequency high-intensity focused ultrasound technology to form skin micropores with different breadths and depths on the skin (as shown in FIG. 12) for the transdermal delivery of large molecular immune antigens. The administration method is simple and the administration process is minimally invasive. The pain, delivery and delivery methods are safe and effective, and the delivery efficiency is high, the delivery area has high accuracy and the location is accurate, which greatly improves the user experience.
附图说明BRIEF DESCRIPTION
应当理解的是,以下附图仅示出了本公开的某些实施例,因此不应被看作是对范围的限定,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他相关的附图。It should be understood that the following drawings only show certain embodiments of the present disclosure, and therefore should not be considered as a limitation on the scope. For those of ordinary skill in the art, without paying creative labor, Other related drawings can also be obtained from these drawings.
图1为本公开基于声诱导微孔阵列的疫苗经皮递送装置的实施例一的结构示意图;1 is a schematic structural view of Embodiment 1 of a vaccine transdermal delivery device based on an acoustically induced micropore array;
图2为本公开基于声诱导微孔阵列的疫苗经皮递送装置的实施例一的XY平面超声焦点测量图;2 is an XY plane ultrasonic focus measurement diagram of the first embodiment of the vaccine percutaneous delivery device based on an acoustically induced micropore array;
图3为本公开基于声诱导微孔阵列的疫苗经皮递送装置的实施例一的XZ平面超声焦点测量图;3 is an XZ plane ultrasonic focus measurement diagram of the first embodiment of the vaccine percutaneous delivery device based on the acoustically induced micropore array;
图4为本公开基于声诱导微孔阵列的疫苗经皮递送装置的实施例二的结构示意图;4 is a schematic structural view of Embodiment 2 of a vaccine percutaneous delivery device based on an acoustically induced micropore array;
图5为本公开基于声诱导微孔阵列的疫苗经皮递送装置的实施例二的第二超声换能器回波监测方法的原理示意图;5 is a schematic diagram of the second ultrasonic transducer echo monitoring method of the second embodiment of the vaccine transdermal delivery device based on the acoustically induced micropore array;
图6为本公开基于声诱导微孔阵列的疫苗经皮递送装置的实施例三的结构接示意图;FIG. 6 is a schematic structural view of Embodiment 3 of a vaccine percutaneous delivery device based on an acoustically induced micropore array;
图7为本公开基于声诱导微孔阵列的疫苗经皮递送装置的实施例三的声透性免疫贴片的递送效果图;7 is a diagram showing the delivery effect of the acoustically permeable immune patch of the third embodiment of the vaccine transdermal delivery device based on the acoustically induced micropore array;
图8为本公开基于声诱导微孔阵列的疫苗经皮递送装置的实施例四的三维移动控制器的结构示意图;8 is a schematic structural diagram of a three-dimensional mobile controller according to Embodiment 4 of a vaccine percutaneous delivery device based on an acoustically induced micropore array;
图9为本公开基于声诱导微孔阵列的疫苗经皮递送装置的实施例四的声透性免疫贴片结构示意图;9 is a schematic diagram of the structure of an acoustically permeable immune patch of the fourth embodiment of the vaccine transdermal delivery device based on an acoustically induced micropore array;
图10为本公开基于声诱导微孔阵列的疫苗经皮递送装置的实施例四的整体示意图;FIG. 10 is an overall schematic diagram of Embodiment 4 of a vaccine transdermal delivery device based on acoustically induced micropore arrays;
图11为本发明实施例五中的基于声诱导微孔阵列的疫苗经皮递送装置的使用方法的流程示意图;11 is a schematic flowchart of a method for using a vaccine transdermal delivery device based on an acoustically induced micropore array in Embodiment 5 of the present invention;
图12为本发明实施例五中的基于声诱导微孔阵列的疫苗经皮递送装置的使用方法的又一流程示意图;12 is another schematic flow chart of a method for using a vaccine percutaneous delivery device based on an acoustically induced micropore array in Embodiment 5 of the present invention;
图13为本公开的基于声诱导微孔阵列的疫苗经皮递送装置的免疫后形成的皮肤微孔不同广度与深度模式实例图(H&E染色切片图);13 is an example diagram of different width and depth patterns of skin pores formed after immunization of a vaccine transdermal delivery device based on an acoustically induced pore array (H & E stained slice diagram);
图14为本公开基于声诱导微孔阵列的疫苗经皮递送装置的所形成的皮肤微 孔不同阵列模式实例图。FIG. 14 is a diagram showing examples of different array patterns of skin micropores formed in the vaccine transdermal delivery device based on the acoustically induced micropore array.
附图标号说明:Description of Drawing Symbols:
Figure PCTCN2019117138-appb-000001
Figure PCTCN2019117138-appb-000001
具体实施方式detailed description
为了便于理解本公开,下面将参照相关附图对本公开所提供的基于声诱导微孔阵列的疫苗经皮递送装置和使用方法进行更全面的描述。附图中给出了该装置的实施例。但是,该装置可以通过许多不同的形式来实现,并不限于本文 所描述的实施例。相反地,提供这些实施例的目的是使对该装置的公开内容更加透彻全面。需要说明的是,当元件被称为“固定于”另一个元件,它可以直接在另一个元件上或者也可以存在居中的元件。当一个元件被认为是“连接”另一个元件,它可以是直接连接到另一个元件或者可能同时存在居中元件。相反,当元件被称作“直接在”另一元件“上”时,不存在中间元件。本文所使用的术语“垂直的”、“水平的”、“左”、“右”以及类似的表述只是为了说明的目的。In order to facilitate understanding of the present disclosure, the following will provide a more comprehensive description of the vaccine-derived delivery device and method of use based on the acoustically induced micropore array provided by the present disclosure with reference to related drawings. An example of the device is given in the drawings. However, the device can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the device more thorough and comprehensive. It should be noted that when an element is referred to as being “fixed” to another element, it can be directly on the other element or there can also be a centered element. When an element is considered to be "connected" to another element, it may be directly connected to another element or there may be a center element at the same time. In contrast, when an element is referred to as being "directly on" another element, there are no intervening elements present. The terms "vertical", "horizontal", "left", "right" and similar expressions used herein are for illustrative purposes only.
除非另有定义,本文所使用的所有的技术和科学术语与属于本公开的技术领域的技术人员通常理解的含义相同。本文中在基于声诱导微孔阵列的疫苗经皮递送装置的说明书中所使用的术语只是为了描述实施例的目的,不是旨在限制本公开。本文所使用的术语“及/或”包括一个或多个相关的所列项目的任意的和所有的组合。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field of the present disclosure. The terminology used herein in the specification of a vaccine-derived transdermal delivery device based on an array of acoustically induced micropores is for the purpose of describing examples only, and is not intended to limit the present disclosure. The term "and / or" as used herein includes any and all combinations of one or more related listed items.
实施例1:请结合参阅图1-3,本实施例公开一种基于声诱导微孔阵列的疫苗经皮递送装置1,该基于声诱导微孔阵列的疫苗经皮递送装置1包括:主控系统11、与所述主控系统11连接的高频强聚焦超声激励组件12,以及用于贴敷至皮肤上用于给药的声透性免疫贴片13;所述高频强聚焦超声激励组件12包括高频超声信号发生系统121、与所述高频超声信号发生系统121连接的第一超声换能器122、与所述第一超声换能器122连接的圆锥形耦合导管123;所述圆锥形耦合导管123在给药时置于所述声透性免疫贴片13上,用于传导所述第一超声换能器122的声能量至所述免疫贴片;所述高频超声信号发生系统121包括依次电性连接的电信号发生器121a、线性功率放大器121b和阻抗匹配电路121c;Embodiment 1: Please refer to FIGS. 1-3 together, this embodiment discloses a vaccine transdermal delivery device 1 based on an acoustically induced micropore array. The vaccine transdermal delivery device 1 based on an acoustically induced micropore array includes: a master control System 11, a high-frequency intense focused ultrasound excitation assembly 12 connected to the main control system 11, and an acoustically permeable immune patch 13 applied to the skin for drug delivery; the high-frequency intense focused ultrasound excitation assembly 12 includes high Frequency ultrasonic signal generating system 121, a first ultrasonic transducer 122 connected to the high frequency ultrasonic signal generating system 121, a conical coupling conduit 123 connected to the first ultrasonic transducer 122; the conical coupling The catheter 123 is placed on the acoustically permeable immune patch 13 at the time of drug administration, and is used to conduct the acoustic energy of the first ultrasound transducer 122 to the immune patch; the high-frequency ultrasound signal generating system 121 It includes an electrical signal generator 121a, a linear power amplifier 121b and an impedance matching circuit 121c that are electrically connected in sequence;
所述主控系统11发送脉冲超声激励信号至所述高频超声信号发生系统121,进而所述高频超声信号发生系统121根据所述脉冲超声激励信号产生超声电信 号,并通过所述第一超声换能器122进行超声电信号到声信号的转换,并将所述声信号的声能量通过圆锥形耦合导管123导入所述声透性免疫贴片13下方的皮肤中,以便于对皮肤形成皮肤微孔,以供免疫抗原经皮递送。The main control system 11 sends a pulsed ultrasonic excitation signal to the high-frequency ultrasonic signal generation system 121, and then the high-frequency ultrasonic signal generation system 121 generates an ultrasonic electric signal according to the pulsed ultrasonic excitation signal, and passes the first The ultrasonic transducer 122 converts the ultrasonic electrical signal into an acoustic signal, and introduces the acoustic energy of the acoustic signal into the skin under the acoustically permeable immune patch 13 through the conical coupling catheter 123 to facilitate the formation of the skin Micropores in the skin for transdermal delivery of immune antigens.
此外,所述高频超声信号发生系统121包括依次电性连接的电信号发生器121a、线性功率放大器121b和阻抗匹配电路121c;In addition, the high-frequency ultrasonic signal generating system 121 includes an electrical signal generator 121a, a linear power amplifier 121b, and an impedance matching circuit 121c that are electrically connected in sequence;
所述主控系统11用于发送脉冲超声激励信号参数至所述电信号发生器121a,并且所述电信号发生器121a根据所述脉冲超声激励信号参数生成一超声电信号;通过所述线性功率放大器121b对所述超声电信号放大,并通过所述阻抗匹配电路121c将放大后的超声电信号传送至所述第一超声换能器122,所述第一超声换能器122进行超声电信号到声信号的转换,并将所述声信号的声能量通过圆锥形耦合导管123导入所述声透性免疫贴片13下方的皮肤中,以便于对皮肤形成皮肤微孔,以供免疫抗原经皮递送。The main control system 11 is used to send pulsed ultrasonic excitation signal parameters to the electrical signal generator 121a, and the electrical signal generator 121a generates an ultrasonic electrical signal according to the pulsed ultrasonic excitation signal parameters; through the linear power The amplifier 121b amplifies the ultrasonic electrical signal, and transmits the amplified ultrasonic electrical signal to the first ultrasonic transducer 122 through the impedance matching circuit 121c, and the first ultrasonic transducer 122 performs the ultrasonic electrical signal Conversion to an acoustic signal, and the acoustic energy of the acoustic signal is introduced into the skin under the acoustically permeable immune patch 13 through a conical coupling catheter 123, so as to form skin pores on the skin for the immune antigen to pass through皮 DELIVERY.
需要说明的是,角质层作为皮肤最外层屏蔽保护层,其厚度为15-20微米,完整的角质层可以很好的调节物质的经皮吸收。物质经皮扩散的速度与其分子量呈负相关,分子量越小越容易通过角质层,通常认为只有分子量小于500道尔顿的化合物才能透过角质层。如果皮肤受损可致角质层丧失屏蔽作用,从而使物质吸收的速度和程度大幅度提高,特别是有利于大分子蛋白质如抗原的经皮递送。本实施例中所提供的基于声诱导微孔阵列的疫苗经皮递送装置1,应用于对于大分子的免疫抗原的经皮给药,利用声诱导微孔技术,将药物透过皮肤角质层,从而递送实现免疫。It should be noted that the stratum corneum serves as the outermost shielding protective layer of the skin, and its thickness is 15-20 microns. The complete stratum corneum can well regulate the transdermal absorption of the substance. The rate of transdermal diffusion of a substance is inversely related to its molecular weight. The smaller the molecular weight, the easier it is to pass through the stratum corneum. It is generally believed that only compounds with a molecular weight of less than 500 Daltons can penetrate the stratum corneum. If the skin is damaged, the stratum corneum can lose its shielding effect, thereby greatly increasing the speed and degree of substance absorption, especially for the transdermal delivery of macromolecular proteins such as antigens. The vaccine-derived transdermal delivery device 1 based on the acoustically induced micropore array provided in this embodiment is applied to the transdermal administration of immune antigens of macromolecules, and utilizes the acoustically induced micropore technology to pass the drug through the stratum corneum. Thus delivery achieves immunity.
上述,其中高频强聚焦超声激励组件12由电信号发生器121a、线性功率放大器121b、阻抗匹配电路121c和第一超声换能器122组成。As described above, the high-frequency strong-focus ultrasonic excitation assembly 12 is composed of the electric signal generator 121a, the linear power amplifier 121b, the impedance matching circuit 121c, and the first ultrasonic transducer 122.
其中,脉冲超声激励信号参数可以包括但不限于占空比、脉冲重复频率和 峰值负声压等参数,主控系统11通过电信号发生器121a进行基于该参数的编辑控制,编辑生成的超声电信号,通过线性功率放大器121b放大,放大后的电信号驱动第一超声换能器122,输出高频、高强度和强聚焦的脉冲超声激励信号。The parameters of the pulsed ultrasonic excitation signal may include, but are not limited to, parameters such as duty cycle, pulse repetition frequency, and peak negative sound pressure. The main control system 11 performs edit control based on this parameter through the electric signal generator 121a, and edits the generated The signal is amplified by the linear power amplifier 121b, and the amplified electrical signal drives the first ultrasonic transducer 122 to output a pulsed ultrasonic excitation signal of high frequency, high intensity, and strong focus.
需要说明的是,本实施例中所提供的高频强聚焦超声激励组件12,即为高频高强度强聚焦超声激励组件,其中,高频,在本实施例中可以是指大于1MHz以上频率的信号;高强度,是指输出超声峰值负声压大于5MPa;强聚焦,是指超声聚焦点的横向直径小于0.8mm,纵向直径小于3mm。此外,第一超声换能器122,在本实施例中即为高强度超声换能器。It should be noted that the high-frequency high-intensity focused ultrasound excitation component 12 provided in this embodiment is a high-frequency high-intensity strong focused ultrasound excitation component, where high frequency, in this embodiment, may refer to a signal with a frequency greater than 1 MHz ; High intensity means that the output ultrasonic peak negative sound pressure is greater than 5MPa; strong focusing means that the lateral diameter of the ultrasonic focus point is less than 0.8mm and the longitudinal diameter is less than 3mm. In addition, the first ultrasonic transducer 122 is a high-intensity ultrasonic transducer in this embodiment.
参考图2-3,其中给出了一个强聚焦声场示例,此声场在XY平面测得的横向焦点半高宽(即:其负声压在下降到峰值一半数值时对应的声场直径)约为0.76mm。此声场在XZ平面测得的纵向焦点半高宽约为2.4mm。Referring to Figure 2-3, an example of a strongly focused sound field is given. The half-height width of the transverse focus of the sound field measured in the XY plane (ie: the corresponding sound field diameter when its negative sound pressure drops to half the peak value) is about 0.76mm. The longitudinal half-height width of this sound field measured in the XZ plane is about 2.4mm.
上述,声透性免疫贴片13,是用于贴敷于皮肤,进行给药的载体,即可将免疫疫苗抗原,或添加相变液滴的疫苗抗原混合液注满贴片的空腔内,然后将该贴片贴敷与皮肤表面,即完成皮肤免疫贴片的准备。其中,相变液滴,可以为原本内核为液态的覆膜增强剂,当施加高强度超声能量时,其内部的低沸点液体(如:沸点42℃的全氟戊烷)可以气化从而形成气核超声增强剂。As mentioned above, the sound-permeable immune patch 13 is a carrier for applying to the skin for administration, that is, the immune vaccine antigen or the vaccine antigen mixed liquid added with phase-change droplets can be filled into the cavity of the patch , And then apply the patch to the skin surface to complete the preparation of the skin immune patch. Among them, the phase-change droplets can be a film-enhanced agent whose original core is liquid. When high-intensity ultrasonic energy is applied, the internal low-boiling liquid (such as perfluoropentane with a boiling point of 42 ° C) can be vaporized to form Pneumatic ultrasound enhancer.
上述,第一超声换能器122可实现电信号向声信号转换,该换能器可包括一探头,其探头前端通过圆锥型声耦合导管置于声透性免疫贴片上,圆锥型声耦合导管内注满除气的超纯水作为声传播介质。因高频超声在空气中传播受限,所以进一步应用超声耦合剂可以实现圆锥型声耦合导管与声透性免疫贴片的声耦合,从而将高强度换能器输出的声能量导入声透性免疫贴片下方的皮肤,在皮肤上产生微孔,使得声透性免疫贴片中的抗原溶液进入皮肤扩散。As mentioned above, the first ultrasonic transducer 122 can realize the conversion of electrical signals into acoustic signals. The transducer can include a probe whose front end is placed on the sound-transmitting immune patch through a cone-shaped acoustic coupling catheter. The cone-shaped acoustic coupling The catheter is filled with degassed ultrapure water as a sound propagation medium. Due to the limited propagation of high-frequency ultrasound in the air, further application of ultrasonic coupling agents can achieve the acoustic coupling of the cone-shaped acoustic coupling catheter and the acoustically transparent immune patch, thereby introducing the acoustic energy output from the high-intensity transducer into the acoustic permeability The skin under the immune patch creates micropores in the skin, allowing the antigen solution in the acoustically permeable immune patch to diffuse into the skin.
上述,线性功率放大器121b,用与对超声电信号进行放大;即阻抗匹配 (impedance matching)信号源内阻与所接传输线的特性阻抗大小相等且相位相同,或传输线的特性阻抗与所接负载阻抗的大小相等且相位相同,分别称为传输线的输入端或输出端处于阻抗匹配状态,简称为阻抗匹配;而阻抗匹配电路121c,主要用于传输线上,来达至所有高频的微波信号皆能传至负载点的目的,不会有信号反射回来源点,从而提升能源效益。As mentioned above, the linear power amplifier 121b is used to amplify the ultrasonic electrical signal; that is, the impedance of the matching signal source is equal to the characteristic impedance of the connected transmission line and the phase is the same, or the characteristic impedance of the transmission line and the impedance of the connected load Equivalent in size and phase, the input end or output end of the transmission line is in impedance matching state, referred to as impedance matching; and the impedance matching circuit 121c is mainly used on the transmission line to reach all high-frequency microwave signals. For the purpose of reaching the load point, no signal will be reflected back to the source point, thereby improving energy efficiency.
上述,主控系统11,可以为主控电脑,协调控制各分系统。As mentioned above, the main control system 11 can be a main control computer to coordinate and control various sub-systems.
本实施例通过主控系统11控制高频强聚焦超声激励组件12中的电信号发生器121a产生以超声电信号,并通过线性功率放大器放大、阻抗匹配电路121c传送至高强度超声换能器,进而利用高强度超声换能器进行声能转换,得到声能量,通过圆锥形耦合导管123导入至贴片下皮肤,对皮肤形成皮肤微孔,进而通过皮肤微孔递送药物(其中,在皮肤上形成的阵列模式如图14所示)。本实施例利用高频高强度聚焦超声技术在皮肤上形成不同广度和深度的皮肤微孔,以供大分子的免疫抗原经皮递送,给药方法简易、给药过程微创无痛、递送给药方式安全有效,并且给药效率高、递送区域精度高位置准确,大大提高了用户体验。In this embodiment, the main control system 11 controls the electric signal generator 121a in the high-frequency and strong-focus ultrasonic excitation assembly 12 to generate ultrasonic electric signals, which are amplified by a linear power amplifier, and transmitted to a high-intensity ultrasonic transducer by an impedance matching circuit 121c. The intensity ultrasonic transducer converts the acoustic energy to obtain the acoustic energy, which is introduced into the skin under the patch through the conical coupling catheter 123, forms a skin micropore in the skin, and then delivers the drug through the skin micropore (wherein, an array formed on the skin (The model is shown in Figure 14). This embodiment uses high-frequency high-intensity focused ultrasound technology to form skin micropores with different breadths and depths on the skin for the transdermal delivery of immune antigens of large molecules. The method of administration is simple, the process of administration is minimally invasive, painless, and delivered to The medicine method is safe and effective, and the drug delivery efficiency is high, the delivery area accuracy is high, and the location is accurate, which greatly improves the user experience.
实施例2:参考图4-5,基于上述实施例,本实施例提供一种基于声诱导微孔阵列的疫苗经皮递送装置1,其中,Embodiment 2: Referring to FIGS. 4-5, based on the foregoing embodiment, this embodiment provides a vaccine percutaneous delivery device 1 based on an acoustically induced micropore array, wherein,
所述第一超声换能器122为环形中空的第一超声换能器122;其中的环形中空的区域设有容置腔122a。The first ultrasonic transducer 122 is a ring-shaped hollow first ultrasonic transducer 122; the ring-shaped hollow region is provided with a receiving cavity 122a.
在一实施方式中,所述基于声诱导微孔阵列的疫苗经皮递送装置1还包括与所述主控系统11连接的超声回波信号监测系统14;In an embodiment, the vaccine transdermal delivery device 1 based on an acoustically induced micropore array further includes an ultrasound echo signal monitoring system 14 connected to the main control system 11;
所述超声回波信号监测系统14包括互相之间电性连接的第二超声换能器141和信号监测组件142;所述第二超声换能器141的外直径不大于所述容置腔 122a的内直径,用于在监测时放置于所述容置腔122a中;The ultrasonic echo signal monitoring system 14 includes a second ultrasonic transducer 141 and a signal monitoring assembly 142 electrically connected to each other; the outer diameter of the second ultrasonic transducer 141 is not larger than the accommodating cavity 122a The inner diameter of is used to be placed in the accommodating cavity 122a during monitoring;
所述回波信号监测组件142用以发送信号,进而通过所述第二超声换能器141转换,并根据所接收到的返回的信号对所述基于声诱导微孔阵列的疫苗经皮递送装置1的给药过程进行监控。The echo signal monitoring component 142 is used to send a signal, and then converted by the second ultrasonic transducer 141, and according to the received return signal to the acoustically induced micropore array-based vaccine transdermal delivery device 1. Monitor the administration process.
在一实施方式中,所述信号监测组件142包括与所述第二超声换能器141连接的脉冲收发仪142a,以及与所述脉冲收发仪142a连接的数据采集卡142b;其中,所述脉冲收发仪142a和所述数据采集卡142b均与所述主控系统11连接;In one embodiment, the signal monitoring component 142 includes a pulse transceiver 142a connected to the second ultrasonic transducer 141, and a data acquisition card 142b connected to the pulse transceiver 142a; wherein, the pulse Both the transceiver 142a and the data acquisition card 142b are connected to the main control system 11;
在所述超声回波信号监测系统14中的第二超声换能器141置于所述容置腔122a中进行监测时,所述主控系统11控制所述脉冲收发仪142a输出一电脉冲,激励所述第二超声换能器141根据所述电脉冲发射一监测声信号,所述监测声信号进入所述容置腔122a中并通过所述圆锥形耦合导管123传播;When the second ultrasonic transducer 141 in the ultrasonic echo signal monitoring system 14 is placed in the accommodating cavity 122a for monitoring, the main control system 11 controls the pulse transceiver 142a to output an electrical pulse, Exciting the second ultrasonic transducer 141 to emit a monitoring acoustic signal according to the electrical pulse, the monitoring acoustic signal entering the accommodating cavity 122a and propagating through the conical coupling conduit 123;
在所述监测声信号传播过程中遇到所述声透性免疫贴片13时,反射所述监测声信号形成第一监测回波,并通过所述脉冲收发仪142a放大,所述数据采集卡142b接收放大后的第一监测回波并进行模数转换,记录存储为第一回波脉冲;当所述监测声信号继续传播过程中遇到皮肤,反射所述监测声信号形成第二监测回波,并通过所述脉冲收发仪142a放大,所述数据采集卡142b接收放大后的第二监测回波并进行模数转换,记录存储为第二回波脉冲;通过所述第一回波脉冲和所述第二回波脉冲对所述基于声诱导微孔阵列的疫苗经皮递送装置1的给药过程进行监控。When the sound-transmitting immune patch 13 is encountered during the propagation of the monitoring sound signal, the monitoring sound signal is reflected to form a first monitoring echo, which is amplified by the pulse transceiver 142a, and the data acquisition card 142b receives the amplified first monitoring echo and performs analog-to-digital conversion, and the record is stored as the first echo pulse; when the monitoring acoustic signal continues to spread and encounters the skin, the monitoring acoustic signal is reflected to form a second monitoring echo Wave, and amplified by the pulse transceiver 142a, the data acquisition card 142b receives the amplified second monitoring echo and performs analog-to-digital conversion, and the record is stored as a second echo pulse; by the first echo pulse And the second echo pulse to monitor the administration process of the vaccine transdermal delivery device 1 based on the acoustically induced micropore array.
上述,在本实施例中,所述超声信号回波监测系统,即为低强度超声信号回波系统;第二超声换能器141,在本实施例中即为低强度超声换能器,低强度,在本实施例中,可以为声场峰值时间平局声强低于720mW,大于1MHz以上频率的信号。As mentioned above, in this embodiment, the ultrasonic signal echo monitoring system is a low-intensity ultrasonic signal echo system; the second ultrasonic transducer 141, in this embodiment, is a low-intensity ultrasonic transducer, low Intensity, in this embodiment, may be a signal whose peak time sound field sound intensity is lower than 720mW and greater than a frequency above 1MHz.
上述,第一超声换能器122为环形中空设计,其中,环形中空区域设有一容置腔122a,因此可以将较小直径成像探头151至于第一超声换能器122内部的容置腔122a中进行检测和成像。As mentioned above, the first ultrasonic transducer 122 is a ring-shaped hollow design, wherein the ring-shaped hollow region is provided with a receiving cavity 122a, so that the imaging probe 151 with a smaller diameter can be placed in the receiving cavity 122a inside the first ultrasonic transducer 122 Perform inspection and imaging.
上述,超声回波信号监测系统14包括第二超声换能器141和回波信号监测组件142,而回波信号监测组件142中包括:脉冲收发仪142a和数据采集卡142b。其中第二超声换能器141主要是发射声信号和接受声回波,其直径不大于环形第一超声换能器122的内直径,可以放入环形第一超声换能器122中间空间。As described above, the ultrasonic echo signal monitoring system 14 includes the second ultrasonic transducer 141 and the echo signal monitoring component 142, and the echo signal monitoring component 142 includes the pulse transceiver 142a and the data acquisition card 142b. The second ultrasonic transducer 141 mainly emits acoustic signals and receives acoustic echoes, and its diameter is not greater than the inner diameter of the annular first ultrasonic transducer 122, and can be placed in the intermediate space of the annular first ultrasonic transducer 122.
其中,脉冲收发仪142a为具有发射和接受的双重功能的装置。参考图5(1)所示,在进行工作时,脉冲收发仪142a首先输出一个电脉冲激励第二超声换能器141发射一个监测声信号,该监测声信号进入圆锥型声耦合导管传播,当传播遇到声透性免疫贴片的膜片时,反射回一个回波进入脉冲收发仪142a进行放大,进一步经过数据采集卡142b模数转换后即可记录为第一回波脉冲。当该监测声信号继续传播遇到皮肤,反射回第二监测回波,根据膜片与皮肤间距为1.5mm进行计算(时间T等于间距D的二倍值除以超声声速C,即T=2D/C,超声在介质中的传播速度为C=1480m/s),可知第一监测回波的接收时间t1与第二监测回波的接收时间t2,二者间隔为2微秒。通过回波接收时间,可进一步进行检测和判断。Among them, the pulse transceiver 142a is a device with dual functions of transmitting and receiving. Referring to FIG. 5 (1), during operation, the pulse transceiver 142a first outputs an electrical pulse to excite the second ultrasonic transducer 141 to emit a monitoring sound signal, and the monitoring sound signal enters the cone-shaped acoustic coupling catheter to propagate, when When the transmission encounters the diaphragm of the sound-transmitting immune patch, it reflects back an echo and enters the pulse transceiver 142a for amplification, and after further undergoing the analog-to-digital conversion of the data acquisition card 142b, it can be recorded as the first echo pulse. When the monitoring sound signal continues to propagate and meet the skin, it is reflected back to the second monitoring echo, and the calculation is based on the distance between the diaphragm and the skin being 1.5mm (time T is equal to the double value of the distance D divided by the ultrasonic sound velocity C, that is T = 2D / C, the propagation speed of ultrasound in the medium is C = 1480m / s), it can be known that the reception time t1 of the first monitoring echo and the reception time t2 of the second monitoring echo are separated by 2 microseconds. Through the echo reception time, further detection and judgment can be performed.
超声回波信号监测系统14的主要功能和原理包括:低强度超声回波辅助下的第一超声换能器122的z轴定位和增强超声模式下的微泡生成与爆破监控。The main functions and principles of the ultrasonic echo signal monitoring system 14 include: z-axis positioning of the first ultrasonic transducer 122 assisted by low-intensity ultrasonic echo and microbubble generation and blasting monitoring in enhanced ultrasonic mode.
其中,在用于进行低强度超声回波辅助下的第一超声换能器122的z轴定位时,可以包括如下实现方式:在第一超声换能器122在自动z轴定位的过程中,启动超声回波信号监测系统14对第一超声换能器122与皮肤之间的位置进行计算、移动和确定。如图5(2)所示,当第一监测回波接收时间t1大于67.6 微秒时,减少高强度聚焦换能器与膜片间距;当第一监测回波接收时间t1小于67.6微秒时,增加高强度聚焦换能器与膜片间距;当第一监测回波接收时间t1等于67.6微秒时,高强度聚焦换能器的焦点(50mm)已定位在膜片,其z轴定位完成;其中67.6微秒的计算依据是高强度聚焦换能器的焦点(50mm)乘以二倍再除以声速1480m/s。Wherein, when performing the z-axis positioning of the first ultrasonic transducer 122 assisted by the low-intensity ultrasonic echo, the following implementation method may be included: During the process of the automatic positioning of the first ultrasonic transducer 122 in the z-axis, The ultrasound echo signal monitoring system 14 is activated to calculate, move and determine the position between the first ultrasound transducer 122 and the skin. As shown in Fig. 5 (2), when the first monitoring echo receiving time t1 is greater than 67.6 microseconds, reduce the distance between the high-intensity focusing transducer and the diaphragm; when the first monitoring echo receiving time t1 is less than 67.6 microseconds , Increase the distance between the high-intensity focusing transducer and the diaphragm; when the first monitoring echo reception time t1 is equal to 67.6 microseconds, the focus (50mm) of the high-intensity focusing transducer has been positioned on the diaphragm, and its z-axis positioning is completed ; The calculation of 67.6 microseconds is based on the focal point of the high-intensity focusing transducer (50mm) multiplied by two times divided by the speed of sound 1480m / s.
其中,在用于增强超声模式下的微泡生成与爆破监控时的主要功能和原理包括:在增强超声模式下,声透性免疫贴片13中的混合于疫苗抗原溶液的相变液滴首先要在超声焦点处实现气化。因此,在增强超声模式下,第一超声换能器122定位完成后,释放高强度激励脉冲,首先完成相变液滴由液态内核到气态内核的相变激活,然后释放低强度超声脉冲信号进行检测。如图5(3)所示,如果相变过程已完成,气核超声增强剂将在膜片和皮肤之间产生强反射,在回波波形图形成第三监测回波。进一步释放高强度激励脉冲爆破气核超声增强剂,从而在皮肤上产生更强的机械作用,诱导皮肤微孔形成。当气核超声增强剂爆破以后,其第三监测回波将消失。所以,如图5(4)所示,再次释放低强度超声脉冲信号进行检测,确定第三监测回波消失,完成单次增强超声皮肤微孔诱导。Among them, the main functions and principles of microbubble generation and blast monitoring used in enhanced ultrasound mode include: in enhanced ultrasound mode, the phase-change droplets mixed with the vaccine antigen solution in the acoustically permeable immune patch 13 first To achieve gasification at the ultrasound focus. Therefore, in the enhanced ultrasonic mode, after the positioning of the first ultrasonic transducer 122 is completed, the high-intensity excitation pulse is released, first the phase-change activation of the phase-change droplet from the liquid core to the gaseous core is completed, and then the low-intensity ultrasonic pulse signal is released Detection. As shown in Fig. 5 (3), if the phase transition process has been completed, the air core ultrasound intensifier will generate a strong reflection between the diaphragm and the skin, forming a third monitoring echo in the echo waveform. Further release the high-intensity excitation pulse blasting gas nuclear ultrasound enhancer, thereby generating a stronger mechanical effect on the skin and inducing the formation of skin pores. When the gas nuclear ultrasound enhancer blasts, its third monitoring echo will disappear. Therefore, as shown in FIG. 5 (4), the low-intensity ultrasonic pulse signal is released again for detection, it is determined that the third monitoring echo disappears, and the single-shot enhanced ultrasound skin pore induction is completed.
在本实施例中,通过在基于声诱导微孔阵列的疫苗经皮递送装置1中,设置一与主控系统11连接的超声回波信号监测系统14;其中,通过该监测系统中的脉冲收发仪142a、数据采集卡142b,在基于检测系统中的第二超声换能器141基础上,进行对所述基于声诱导微孔阵列的疫苗经皮递送装置1的给药过程进行监控,可以包括用于进行低强度超声回波辅助下的第一超声换能器122的z轴定位,以及用于在增强超声模式下的微泡生成与爆破监控,通过超声回波信号监测系统1414的监控,实现了对于第一超声换能器122的z轴定位,从而使 超声经皮给药的目标皮肤的区域更加准确,在定位层面上提高了给药的精度。In this embodiment, an ultrasound echo signal monitoring system 14 connected to the main control system 11 is provided in the vaccine transdermal delivery device 1 based on the acoustically induced micropore array; wherein, the pulse is transmitted and received in the monitoring system The instrument 142a and the data acquisition card 142b, based on the second ultrasonic transducer 141 in the detection system, monitor the drug delivery process of the vaccine transdermal delivery device 1 based on the acoustically induced micropore array, which may include For the z-axis positioning of the first ultrasonic transducer 122 assisted by low-intensity ultrasonic echo, and for the monitoring and generation of microbubbles in the enhanced ultrasonic mode, through the monitoring of the ultrasonic echo signal monitoring system 1414, The z-axis positioning of the first ultrasound transducer 122 is realized, so that the area of the target skin of the ultrasound percutaneous administration is more accurate, and the accuracy of the administration is improved on the positioning level.
实施例3:参考图6-7,基于上述实施例2,本实施例提供一种基于声诱导微孔阵列的疫苗经皮递送装置1,所述基于声诱导微孔阵列的疫苗经皮递送装置1还包括与所述主控系统11连接的光学成像监控系统15;Embodiment 3: Referring to FIGS. 6-7, based on the above-mentioned Embodiment 2, this embodiment provides a vaccine transdermal delivery device 1 based on an acoustically induced micropore array, the vaccine transdermal delivery device based on an acoustically induced micropore array 1 also includes an optical imaging monitoring system 15 connected to the main control system 11;
所述光学成像监测系统包括成像探头151,以及与所述成像探头151连接的成像处理单元152;The optical imaging monitoring system includes an imaging probe 151, and an imaging processing unit 152 connected to the imaging probe 151;
所述成像探头151的外直径不大于所述容置腔122a的内直径,用于在监测时放置于所述容置腔122a中;The outer diameter of the imaging probe 151 is not larger than the inner diameter of the accommodating cavity 122a, and is used to be placed in the accommodating cavity 122a during monitoring;
所述主控系统11还用于控制所述成像探头151对所述声透性免疫贴片和/或皮肤进行图像采集,进行实时或定时成像,并通过所述成像处理单元152对成像数据进行识别处理,以进行成像检测。The main control system 11 is also used to control the imaging probe 151 to perform image acquisition on the acoustically permeable immune patch and / or skin, perform real-time or timed imaging, and perform imaging data on the imaging processing unit 152 Recognition process for imaging detection.
在一实施方式中,所述成像探头151置于所述第一超声换能器122的容置腔122a的中间;并且,In one embodiment, the imaging probe 151 is placed in the middle of the receiving cavity 122a of the first ultrasonic transducer 122; and,
所述成像探头151、所述成像探头151对应的成像视野的中心和所述第一超声换能器122的相对位置为几何中心同轴。The relative positions of the imaging probe 151, the center of the imaging field corresponding to the imaging probe 151, and the first ultrasound transducer 122 are geometric centers coaxial.
上述,光学成像监测系统由成像探头151和成像处理单元152组成,其中成像探头151具有变焦和放大功能,其直径不大于环形第一超声换能器122的内直径,从而可以放入环形的第一超声换能器122中的容置腔122a中,对环形第一超声换能器122下方的声透性免疫贴片(橡胶圈)以及皮肤损伤进行成像监测。As described above, the optical imaging monitoring system is composed of the imaging probe 151 and the imaging processing unit 152, wherein the imaging probe 151 has zoom and zoom functions, and its diameter is not larger than the inner diameter of the ring-shaped first ultrasonic transducer 122, so that it can be placed in the ring-shaped first An accommodating cavity 122a in an ultrasonic transducer 122 performs imaging monitoring of the acoustically permeable immune patch (rubber ring) and skin damage below the annular first ultrasonic transducer 122.
其中,实现的功能包括用于光学成像辅助下的第一超声换能器122的xy轴定位,以及用于皮肤微孔损伤定量评价。Among them, the realized functions include the xy axis positioning of the first ultrasonic transducer 122 assisted by optical imaging, and the quantitative evaluation of skin micropore damage.
在一实施方式中,其工作原理包括:1、在用于光学成像辅助下的第一超声 换能器122的xy轴定位时,如图7(1)所示,声透性免疫贴片的隔离环可以实时成像。成像探头151放置于环形第一超声换能器122的中间,并且二者的中心同轴,进一步成像视野中心与成像探头151和第一超声换能器122的几何中心同轴。在第一超声换能器122的xy轴定位过程中,可以通过三轴移动控制系统移动第一超声换能器122和其中放置的成像探头151,实现成像视野中心与声透性免疫贴片隔离环中心共轴,从而实现声能量焦点(位于第一超声换能器122中心轴上)与声透性免疫贴片隔离环中心在xy平面的对准。通过对多点一线的对准,实现在免疫过程中,提高免疫位置的精确性,提高进一步图像识别判别皮肤微损伤的准确性。In one embodiment, the working principle includes: 1. When positioning the xy axis of the first ultrasonic transducer 122 with the aid of optical imaging, as shown in FIG. 7 (1), the The isolation ring can be imaged in real time. The imaging probe 151 is placed in the middle of the ring-shaped first ultrasonic transducer 122, and the centers of the two are coaxial, and the center of the imaging field of view is coaxial with the geometric center of the imaging probe 151 and the first ultrasonic transducer 122. During the xy-axis positioning of the first ultrasound transducer 122, the first ultrasound transducer 122 and the imaging probe 151 placed therein can be moved by a three-axis movement control system to isolate the center of the imaging field of view from the acoustically permeable immunopatch The center of the ring is coaxial, so that the acoustic energy focus (located on the center axis of the first ultrasonic transducer 122) and the center of the sound-transmitting immune patch isolation ring are aligned in the xy plane. Through the alignment of multiple points and one line, the accuracy of the immunization position is improved during the immunization process, and the accuracy of further image recognition and discrimination of skin micro-damage is improved.
2、在用于皮肤微损伤定量评价时,如图7(2)所示,由所述成像探头151获取本实施例所提供的基于声诱导微孔阵列的疫苗经皮递送装置1进行声诱导微孔免疫以后的皮肤损伤高清图像,经过成像处理单元152进行图像处理分析和计算皮肤损伤范围。例如,包括:2. When used for quantitative evaluation of skin microdamage, as shown in FIG. 7 (2), the imaging probe 151 obtains the vaccine-derived transdermal delivery device 1 based on the acoustically induced micropore array provided in this example to perform acoustic induction The high-definition image of skin damage after micropore immunization passes through the imaging processing unit 152 to perform image processing analysis and calculate the skin damage range. Examples include:
(1)损伤图像裁剪,以损伤位点为中心裁剪以隔离环外径大小为边长的正方形图像;(1) Damage image cropping, crop the square image with the outer diameter of the isolation ring as the side length with the damage site as the center;
(2)图像格式转换,皮肤损伤高清结果图像转化为8bit格式的灰度图,并重新设置大小(如:600pixels*600pixels)并提高对比度;(2) Image format conversion, the skin damage HD result image is converted to 8-bit grayscale image, and the size is re-set (such as: 600pixels * 600pixels) and the contrast is improved;
(3)进行阈值筛选,选中皮肤中用黑色生物染料进行标记的损伤区域,并统计其像素点总和;(3) Threshold screening, select the damaged area marked with black biological dye in the skin, and count the sum of its pixels;
(4)面积转换,以黑色标记区域的像素点总和占该图像的总像素点百分比,计算得出的百分比即可计算出染色皮肤区域的实际面积,即为实际皮肤损伤面积。通过系统分析获得实际损伤面积便于生成超声信号参数与皮肤二维损伤对应规律,实现相对定量评估递药效率。(4) Area conversion. The sum of the pixels in the black marked area accounts for the percentage of the total pixels in the image. The calculated percentage can calculate the actual area of the stained skin area, which is the actual skin damage area. Obtaining the actual damage area through system analysis is convenient for generating the correspondence law of the ultrasonic signal parameters and the two-dimensional damage of the skin, so as to realize the relative quantitative evaluation of the drug delivery efficiency.
在本实施例中,通过在环形中空的第一超声换能器122中的容置腔122a中,移入光学成像监测系统的成像探头151,进行采集图像,并且通过成像处理单元152对所述声透性免疫贴片和/或皮肤进行图像采集,以实现在进行通过免疫阵列装置进行超声经皮给药过程中,在光学成像辅助下的第一超声换能器122的xy轴定位,或对皮肤微孔损伤定量评价,一方面可通过定位,提高给药区域的定位精度,实现精准给药;另一方面,可在给药过程中进行精确定量,实现对免疫抗原的给药量的精准控制。In the present embodiment, the imaging probe 151 of the optical imaging monitoring system is moved into the accommodating cavity 122 a in the annular hollow first ultrasonic transducer 122 to acquire an image, and the imaging processing unit 152 Permeable immune patch and / or skin image acquisition to achieve the positioning of the xy axis of the first ultrasound transducer 122 with the aid of optical imaging during the ultrasound transdermal drug delivery through the immune array device, or Quantitative evaluation of skin micropore damage can, on the one hand, improve the positioning accuracy of the drug delivery area by positioning to achieve precise drug delivery; on the other hand, it can be accurately quantified during the drug delivery process to achieve precise delivery of immune antigens control.
实施例4:参考图8-10,基于上述实施例3,本实施例提供一种基于声诱导微孔阵列的疫苗经皮递送装置1,其中,Embodiment 4: Referring to FIGS. 8-10, based on the foregoing Embodiment 3, this embodiment provides a vaccine transdermal delivery device 1 based on an acoustically induced micropore array, wherein,
所述基于声诱导微孔阵列的疫苗经皮递送装置1还包括与所述主控系统11连接的三维移动控制器16;The vaccine transdermal delivery device 1 based on an acoustically induced micropore array further includes a three-dimensional mobile controller 16 connected to the main control system 11;
所述光学成像监控系统15还包括与所述成像探头151连接的探头固定支架153;The optical imaging monitoring system 15 further includes a probe fixing bracket 153 connected to the imaging probe 151;
所述高频强聚焦超声激励组件12还包括与所述第一超声换能器122连接的第一超声换能器固定支架124;The high-frequency strong-focus ultrasonic excitation assembly 12 further includes a first ultrasonic transducer fixing bracket 124 connected to the first ultrasonic transducer 122;
所述超声回波信号监测系统14还包括与所述第二超声换能器连接的第二超声换能器固定支架143;The ultrasonic echo signal monitoring system 14 further includes a second ultrasonic transducer fixing bracket 143 connected to the second ultrasonic transducer;
所述探头固定支架153、所述第一超声换能器固定支架124以及所述第二超声换能器固定支架均与所述16连接。The probe fixing bracket 153, the first ultrasound transducer fixing bracket 124, and the second ultrasound transducer fixing bracket are all connected to the 16.
所述声透性免疫贴片13,包括隔离环131和粘性薄膜132;The sound-permeable immune patch 13 includes an isolation ring 131 and an adhesive film 132;
所述粘性薄膜132覆盖于所述隔离环131上;并且,所述粘性薄膜132与所述隔离环131之间形成一药物容置腔体133;The adhesive film 132 covers the isolation ring 131; and, a drug accommodating cavity 133 is formed between the adhesive film 132 and the isolation ring 131;
在对皮肤给药时,利用所述粘性薄膜132的粘性,将所述声透性免疫贴片 13贴敷于皮肤表面,其中,所述药物容置腔体内133注有用于给药的药物。When administering to the skin, using the viscosity of the adhesive film 132, the acoustically permeable immune patch 13 is applied to the surface of the skin, wherein the drug accommodating cavity 133 is filled with a drug for administration.
在一实施方式中,所述隔离环131为圆形的橡胶材质的隔离环131;所述粘性薄膜132为的透明的塑料材质的粘性薄膜132;所述粘性薄膜132在给药时背离所述圆锥形耦合导管123并且面对皮肤的一面具有粘性;所述隔离环131的外径为5-15mm,内径为3-10mm,厚度为1-3mm。In one embodiment, the isolation ring 131 is a circular rubber isolation ring 131; the adhesive film 132 is a transparent plastic adhesive film 132; the adhesive film 132 faces away from the drug during administration The conical coupling catheter 123 has adhesiveness on the side facing the skin; the outer diameter of the isolation ring 131 is 5-15 mm, the inner diameter is 3-10 mm, and the thickness is 1-3 mm.
上述,三维定位移动控制系统,采用回波信号检测皮肤位点与激励源的相对位置,配合三维移动控制器16进行调整使皮肤位点处于超声聚焦点区域,也用于相变液滴气化成泡检测以及超声空化效应的进程评估,实现实时监测,是系统的前导角色。As mentioned above, the three-dimensional positioning movement control system uses echo signals to detect the relative position of the skin site and the excitation source, and cooperates with the three-dimensional movement controller 16 to adjust the skin site to the ultrasonic focus point area, and is also used to vaporize the phase change droplets into Bubble detection and process evaluation of ultrasonic cavitation effects, real-time monitoring, is the leading role of the system.
上述,三维移动控制系统与主控系统11连接,并且,所述探头固定支架153、所述第一超声换能器固定支架124,以及所述第二超声换能器141均与所述三维移动控制器16连接。在进行免疫经皮给药时,可通过主控装置,控制三维定位移动控制系统的移动,即对所述探头固定支架153、所述第一超声换能器固定支架124,以及所述第二超声换能器141进行控制,进而对第一超声换能器122和圆锥型声耦合导管的空间方位、第二超声换能器141的空间方位和成像探头151的空间方位;其中,可在免疫阵列装置进行对用户进行经皮免疫给药过程中,对所述第二超声换能器141和成像探头151的空间方位进行分别调整,依据免疫要求,分别进行将第二超声换能器141或成像探头151移如所述第一超声换能器122的环形中空的容置腔122a中,分别进行实现本实施例所提供的免疫阵列装置的相应功能,从而可在对用户进行经皮免疫给药时,通过移动相应的装置实现精准给药,并且,可控制相应的成像探头151或第二超声换能器141,分别进行自动检测或图像采集等监控、定位、分析的工作,实现免疫阵列装置的智能化运行和操作,为用户、医务工作者、管理者的相关工作提供了方便。As described above, the three-dimensional movement control system is connected to the main control system 11, and the probe fixing bracket 153, the first ultrasonic transducer fixing bracket 124, and the second ultrasonic transducer 141 are all connected with the three-dimensional movement The controller 16 is connected. When immunizing percutaneously, the movement of the three-dimensional positioning movement control system can be controlled by the main control device, that is, the probe fixing bracket 153, the first ultrasonic transducer fixing bracket 124, and the second The ultrasonic transducer 141 controls the spatial orientation of the first ultrasonic transducer 122 and the cone-shaped acoustic coupling catheter, the spatial orientation of the second ultrasonic transducer 141, and the spatial orientation of the imaging probe 151; During the percutaneous immune administration of the array device to the user, the spatial orientation of the second ultrasonic transducer 141 and the imaging probe 151 are adjusted separately, and the second ultrasonic transducer 141 or The imaging probe 151 is moved into the annular hollow accommodating cavity 122a of the first ultrasonic transducer 122, respectively to perform the corresponding functions of the immune array device provided in this embodiment, so that When medicine is taken, accurate drug delivery can be achieved by moving the corresponding device, and the corresponding imaging probe 151 or the second ultrasonic transducer 141 can be controlled to perform monitoring, positioning, and analysis work such as automatic detection or image acquisition, respectively, to realize the immune array The intelligent operation and operation of the device provides convenience for users, medical workers, and managers.
上述,声透性免疫贴片13,用于与用户或患者的目标免疫的区域进行贴敷,即本公开所提供的免疫阵列装置对应的药物载体。As mentioned above, the sound-permeable immune patch 13 is used to apply to the target immunized area of the user or patient, that is, the drug carrier corresponding to the immune array device provided by the present disclosure.
其中,声透性免疫贴片13的结构可以由隔离环、单面粘性的透明塑料薄膜组成。在一实施方式中,该隔离环外径为8mm、内径为6.5mm、厚度为1.5mm,在该特定尺寸和材质的限定下,其机械系数小、弱反射,可减少超声能量的损耗并能避免回波能量对超声发射装置以及回波接收装置造成额外伤害。The structure of the sound-permeable immune patch 13 may be composed of an isolation ring and a single-sided adhesive transparent plastic film. In one embodiment, the outer diameter of the isolation ring is 8 mm, the inner diameter is 6.5 mm, and the thickness is 1.5 mm. Under the limitation of the specific size and material, the mechanical coefficient is small and the weak reflection can reduce the loss of ultrasonic energy and can Avoid echo energy causing additional damage to the ultrasonic transmitter and echo receiver.
需要说明的是,单面粘性塑料薄膜厚度为75微米及其以下,此厚度范围的塑料薄膜具有声透性,即声能量可以80%以上透过此薄膜传播进入皮肤。免疫贴片是指,可以将疫苗抗原,或添加相变液滴的疫苗抗原混合液注满贴片环形空腔,然后利用单面粘性的透明薄膜贴敷皮肤表面,即完成皮肤免疫贴片的准备。It should be noted that the thickness of the single-sided adhesive plastic film is 75 microns or less, and the plastic film in this thickness range has acoustic permeability, that is, more than 80% of the acoustic energy can be transmitted through the film into the skin. Immune patch means that the vaccine antigen, or the vaccine antigen mixed liquid added with phase change droplets can be filled into the annular cavity of the patch, and then the skin surface is applied with a single-sided adhesive transparent film to complete the skin immune patch. ready.
通过设置隔离环,可在实现机械系数小、若反射、减少能量损害或损伤的基础上,用以对皮肤目标免疫区域进行定位和给药,在一定程度上提高了给药区域在空间方位上的精确度,并且减少能量损害和对皮肤的机械损伤。By setting the isolation ring, it can be used to locate and administer the target immune area of the skin on the basis of achieving a small mechanical coefficient, if reflecting, reducing energy damage or injury, and to a certain extent, improve the spatial orientation of the administration area Accuracy, and reduce energy damage and mechanical damage to the skin.
实施例5:此外,参考图11-12,本实施例提供一种基于声诱导微孔阵列的疫苗经皮递送装置1的使用方法,包括:Embodiment 5: In addition, referring to FIGS. 11-12, this embodiment provides a method for using a vaccine transdermal delivery device 1 based on an acoustically induced micropore array, including:
步骤S10,贴敷声透性免疫贴片13,并置于基于声诱导微孔阵列的疫苗经皮递送装置1的圆锥形耦合导管123下端;Step S10, applying an acoustically permeable immune patch 13 and placing it on the lower end of the conical coupling catheter 123 of the vaccine percutaneous delivery device 1 based on the acoustically induced micropore array;
步骤S20,通过所述基于声诱导微孔阵列的疫苗经皮递送装置1的超声回波信号监测系统14和光学成像监控系统15进行空间定位,以确定皮肤给药位点;Step S20, spatial positioning is performed by the ultrasonic echo signal monitoring system 14 and the optical imaging monitoring system 15 of the vaccine-derived transdermal delivery device 1 based on the acoustically induced micropore array to determine the skin administration site;
步骤S30,通过基于声诱导微孔阵列的疫苗经皮递送装置1的高频强聚焦超声激励组件12对所述皮肤给药位点进行经皮免疫给药;Step S30: Transcutaneous immunization administration to the skin administration site by the high-frequency intensity focused ultrasound excitation assembly 12 of the vaccine transdermal delivery device 1 based on the acoustically induced micropore array;
步骤S40,通过所述光学成像监控系统15对经皮免疫给药的皮肤给药位点 进行递送效果评价。In step S40, the delivery effect evaluation is performed on the skin administration site of percutaneous immune administration through the optical imaging monitoring system 15.
上述,本公开可提供一种对于基于声诱导微孔阵列的疫苗经皮递送装置1的使用方法,用以对用户皮肤的目标位置进行经皮贴片给药,以达到经皮免疫的目的。其工作流程参考图12,可以包括:As mentioned above, the present disclosure can provide a method for using a vaccine transdermal delivery device 1 based on an acoustically induced micropore array for transdermal patch administration to a target location of a user's skin to achieve the purpose of transdermal immunity. Refer to Figure 12 for its workflow, which may include:
(1)免疫贴片准备:将感兴趣皮肤区域消毒,将需递送的疫苗抗原溶液注满贴片空腔。特别的,在增强超声模式下,可将疫苗抗原溶液与相变液滴按一定比例混合。然后,将声透性疫苗免疫贴片贴敷于皮肤。最后,声透性疫苗免疫贴片上面涂层声耦合剂,置于圆锥型声导管尖端下方,开始全自动经皮免疫;(1) Preparation of immune patch: disinfect the skin area of interest and fill the patch cavity with the vaccine antigen solution to be delivered. In particular, in the enhanced ultrasound mode, the vaccine antigen solution and the phase change droplets can be mixed in a certain ratio. Then, apply the sound-permeable vaccine immune patch to the skin. Finally, apply the acoustic coupling agent on top of the sound-permeable vaccine immunization patch and place it under the tip of the cone-shaped sound catheter to start fully automatic percutaneous immunization;
(2)第一超声换能器122空间定位:首先通过成像探头151拍摄画面检测激励源与贴片是否同心,若否,则通过三维移动控制器16调整激励源与贴片的xy平面位置,最终实现激励源与贴片同轴心。然后,调整z轴方向换能器位点,移走成像探头151,移来低声压超声换能器,激励源发射测试信号,如经过回波监测装置接收回波信号并传输数据,回波信号监测系统对皮肤位点是否在声聚焦点进行判断,调整三维移动控制器16使T1=67.6微秒,若否,则通过三维移动控制器16进行z轴方向调整。(2) Spatial positioning of the first ultrasonic transducer 122: first, the imaging probe 151 takes a picture to detect whether the excitation source and the patch are concentric. If not, the xy plane position of the excitation source and the patch is adjusted by the three-dimensional movement controller 16, Finally, the excitation source and the patch are coaxial. Then, adjust the position of the transducer in the z-axis direction, remove the imaging probe 151, move the low-sound pressure ultrasonic transducer, and the excitation source emits the test signal, such as receiving the echo signal and transmitting data through the echo monitoring device, the echo The signal monitoring system judges whether the skin site is at the acoustic focus point, and adjusts the three-dimensional movement controller 16 so that T1 = 67.6 microseconds. If not, the three-dimensional movement controller 16 adjusts the z-axis direction.
(3)皮肤微孔形成与经皮疫苗递送:根据皮肤厚度等参数的不同,可使用两种超声免疫模式:模式一,单独超声模式;模式二,增强超声模式。模式二较于模式一递送效率更高。特别的,在增强超声模式,首先释放高强度超声脉冲激励液核相变液滴气化,通过低能量超声回波确认气核超声增强剂的生成,然后释放高能量超声脉冲诱导气核超声增强剂爆破,并再次通过低能量超声回波确认气核超声增强剂的消失,从而完成单次递送。(3) Skin pore formation and transdermal vaccine delivery: According to different skin thickness and other parameters, two ultrasound immunization modes can be used: mode one, single ultrasound mode; mode two, enhanced ultrasound mode. Mode 2 has higher delivery efficiency than Mode 1. In particular, in the enhanced ultrasound mode, first release high-intensity ultrasound pulses to excite the vaporization of liquid-nuclear phase-change droplets, confirm the generation of the gas-nuclear ultrasound enhancer by low-energy ultrasound echoes, and then release the high-energy ultrasound pulses to induce gas-nuclear ultrasound enhancement The agent exploded, and again confirmed the disappearance of the air core ultrasound enhancer by low-energy ultrasound echo, thus completing a single delivery.
(4)递送效果评价:移走低能量超声探头,移来成像探头151,对皮肤微孔形成情况进行评价,如果微通道已形成,完成此位点递送,若否,再次启动 (3)步骤。(4) Evaluation of delivery effect: Remove the low-energy ultrasound probe, move the imaging probe 151, and evaluate the formation of skin micropores. If microchannels have been formed, complete the site delivery. If not, start again (3) step.
如图13所示,单个皮肤微孔实现疫苗递送时,通过控制高频强聚焦超声激励参数(峰值负声压、脉冲宽度和脉冲重复频率),可以在皮肤上形成不同广度或深度的递送微通道,从而调控经皮递送剂量。As shown in Figure 13, when a single skin micropore achieves vaccine delivery, by controlling high frequency and intense focused ultrasound excitation parameters (peak negative sound pressure, pulse width, and pulse repetition frequency), delivery microchannels of different breadth or depth can be formed on the skin. Thereby regulating the dosage of transdermal delivery.
举例来说,如广度模式1的皮肤微孔面积为0.1±0.03平方毫米,广度模式2的皮肤微孔面积为0.3±0.05,广度三的皮肤微孔为0.6±0.1;举例来说,如深度模式1的皮肤微孔深度为100±50微米,深度模式2的皮肤微孔深度为200±50微米,深度模式3的皮肤微孔深度为300±50微米;其中黑色为印度墨水标记。For example, the width of the skin pores in the width mode 1 is 0.1 ± 0.03 mm2, the area of the skin pores in the width mode 2 is 0.3 ± 0.05, and the width of the skin pores in the width 3 is 0.6 ± 0.1; The depth of the skin micropores in Mode 1 is 100 ± 50 microns, the depth of the skin micropores in Depth Mode 2 is 200 ± 50 microns, and the depth of the skin micropores in Depth Mode 3 is 300 ± 50 microns; where black is marked by Indian ink.
如图14所示,实施过程中,总的疫苗递送剂量可以进一步通过皮肤微孔组合设计和优化,从而调控总的经皮递送剂量。As shown in FIG. 14, during the implementation process, the total vaccine delivery dose can be further designed and optimized through the combination of skin micropores, thereby regulating the total transdermal delivery dose.
举例来说,如1×1阵列模式为单个皮肤微孔,1×2阵列模式为两个皮肤微孔,2×2阵列模式为四个皮肤微孔,3×3阵列模式为九个皮肤微孔。从而,通过控制微通道阵列的数量和布局,进行疫苗总剂量的控制。For example, if the 1 × 1 array mode is a single skin micropore, the 1 × 2 array mode is two skin micropores, the 2 × 2 array mode is four skin micropores, and the 3 × 3 array mode is nine skin micropores hole. Thus, by controlling the number and layout of microchannel arrays, the total dose of vaccine is controlled.
在这里示出和描述的所有示例中,任何具体值应被解释为仅仅是示例性的,而不是作为限制,因此,示例性实施例的其他示例可以具有不同的值。应注意到:相似的标号和字母在下面的附图中表示类似项,因此,一旦某一项在一个附图中被定义,则在随后的附图中不需要再对其进行定义和解释。In all the examples shown and described herein, any specific values should be interpreted as merely exemplary and not as limitations, and therefore, other examples of the exemplary embodiments may have different values. It should be noted that similar reference numerals and letters indicate similar items in the following drawings, therefore, once an item is defined in one drawing, there is no need to define and explain it in subsequent drawings.

Claims (10)

  1. 一种基于声诱导微孔阵列的疫苗经皮递送装置,包括:主控系统、与所述主控系统连接的高频强聚焦超声激励组件,以及用于贴敷至皮肤上用于给药的声透性免疫贴片;A vaccine transdermal delivery device based on an acoustically induced micropore array, comprising: a main control system, a high-frequency intense focused ultrasound excitation component connected to the main control system, and an acoustic penetration for application to the skin for drug delivery Sexual immune patch;
    所述高频强聚焦超声激励组件包括高频超声信号发生系统、与所述高频超声信号发生系统连接的第一超声换能器、与所述第一超声换能器连接的圆锥形耦合导管;所述圆锥形耦合导管在给药时置于所述声透性免疫贴片上,用于传导所述第一超声换能器的声能量至所述免疫贴片;The high-frequency intense focusing ultrasonic excitation component includes a high-frequency ultrasonic signal generating system, a first ultrasonic transducer connected to the high-frequency ultrasonic signal generating system, and a conical coupling catheter connected to the first ultrasonic transducer; The conical coupling catheter is placed on the acoustically permeable immune patch during administration, and is used to transmit the acoustic energy of the first ultrasonic transducer to the immune patch;
    所述主控系统发送脉冲超声激励信号至所述高频超声信号发生系统,进而所述高频超声信号发生系统根据所述脉冲超声激励信号产生超声电信号,并通过所述第一超声换能器进行超声电信号到声信号的转换,并将所述声信号的声能量通过所述圆锥形耦合导管导入所述声透性免疫贴片下方的皮肤中,以便于对皮肤诱导形成微孔及微孔阵列,以供免疫抗原经皮递送。The main control system sends a pulsed ultrasonic excitation signal to the high-frequency ultrasonic signal generation system, and then the high-frequency ultrasonic signal generation system generates an ultrasonic electrical signal according to the pulsed ultrasonic excitation signal, and passes the first ultrasonic energy The device converts ultrasonic electrical signals into acoustic signals, and introduces the acoustic energy of the acoustic signals into the skin under the acoustically transmissive immune patch through the conical coupling catheter, so as to induce the formation of micropores and Microwell array for transdermal delivery of immune antigens.
  2. 如权利要求1所述基于声诱导微孔阵列的疫苗经皮递送装置,其中,所述第一超声换能器为环形中空的第一超声换能器;其中的环形中空的区域设有容置腔。The vaccine percutaneous delivery device based on an acoustically induced micropore array according to claim 1, wherein the first ultrasonic transducer is a ring-shaped hollow first ultrasonic transducer; wherein the ring-shaped hollow region is provided with an accommodation Cavity.
  3. 如权利要求2所述基于声诱导微孔阵列的疫苗经皮递送装置,还包括与所述主控系统连接的超声回波信号监测系统;The vaccine percutaneous delivery device based on an acoustically induced micropore array according to claim 2, further comprising an ultrasonic echo signal monitoring system connected to the main control system;
    所述超声回波信号监测系统包括互相之间电性连接的第二超声换能器和信号监测组件;所述第二超声换能器的外直径不大于所述容置腔的内直径,用于在监测时放置于所述容置腔中;The ultrasonic echo signal monitoring system includes a second ultrasonic transducer and a signal monitoring assembly that are electrically connected to each other; the outer diameter of the second ultrasonic transducer is not greater than the inner diameter of the accommodating cavity. Placed in the accommodating cavity during monitoring;
    所述回波信号监测组件用以发送信号,进而通过所述第二超声换能器转换,并根据所接收到的返回的信号对所述基于声诱导微孔阵列的疫苗经皮递送装置 的给药过程进行监控。The echo signal monitoring component is used to send a signal, and then converted by the second ultrasonic transducer, and according to the received return signal to the acoustically induced micropore array-based vaccine transdermal delivery device The drug process is monitored.
  4. 如权利要求3所述基于声诱导微孔阵列的疫苗经皮递送装置,其中,The vaccine percutaneous delivery device based on an acoustically induced micropore array according to claim 3, wherein
    所述信号监测组件包括与所述第二超声换能器连接的脉冲收发仪,以及与所述脉冲收发仪连接的数据采集卡;其中,所述脉冲收发仪和所述数据采集卡均与所述主控系统连接;The signal monitoring component includes a pulse transceiver connected to the second ultrasonic transducer, and a data acquisition card connected to the pulse transceiver; wherein the pulse transceiver and the data acquisition card are both Describe the connection of the main control system;
    在所述超声回波信号监测系统中的第二超声换能器置于所述容置腔中进行监测时,所述主控系统控制所述脉冲收发仪输出一电脉冲,激励所述第二超声换能器根据所述电脉冲发射一监测声信号,所述监测声信号进入所述容置腔中并通过所述圆锥形耦合导管传播;When the second ultrasonic transducer in the ultrasonic echo signal monitoring system is placed in the accommodating cavity for monitoring, the main control system controls the pulse transceiver to output an electrical pulse to excite the second The ultrasonic transducer emits a monitoring acoustic signal according to the electrical pulse, and the monitoring acoustic signal enters the accommodating cavity and propagates through the conical coupling catheter;
    在所述监测声信号传播过程中遇到所述声透性免疫贴片时,反射所述监测声信号形成第一监测回波,并通过所述脉冲收发仪放大,所述数据采集卡接收放大后的第一监测回波并进行模数转换,记录存储为第一回波脉冲;当所述监测声信号继续传播过程中遇到皮肤,反射所述监测声信号形成第二监测回波,并通过所述脉冲收发仪放大,所述数据采集卡接收放大后的第二监测回波并进行模数转换,记录存储为第二回波脉冲;通过所述第一回波脉冲和所述第二回波脉冲对所述基于声诱导微孔阵列的疫苗经皮递送装置1的给药过程进行监控。When encountering the sound-transmitting immune patch during the propagation of the monitoring sound signal, the monitoring sound signal is reflected to form a first monitoring echo, which is amplified by the pulse transceiver, and the data acquisition card receives the amplification After the first monitoring echo and the analog-to-digital conversion, the record is stored as the first echo pulse; when the monitoring acoustic signal continues to encounter the skin during the propagation process, the monitoring acoustic signal is reflected to form a second monitoring echo, and Amplified by the pulse transceiver, the data acquisition card receives the amplified second monitoring echo and performs analog-to-digital conversion, and the record is stored as a second echo pulse; through the first echo pulse and the second The echo pulse monitors the administration process of the vaccine transdermal delivery device 1 based on the acoustically induced micropore array.
  5. 如权利要求4所述基于声诱导微孔阵列的疫苗经皮递送装置,还包括与所述主控系统连接的光学成像监控系统;The vaccine percutaneous delivery device based on an acoustically induced micropore array according to claim 4, further comprising an optical imaging monitoring system connected to the main control system;
    所述光学成像监测系统包括成像探头,以及与所述成像探头连接的成像处理单元;The optical imaging monitoring system includes an imaging probe and an imaging processing unit connected to the imaging probe;
    所述成像探头的外直径不大于所述容置腔的内直径,用于在监测时放置于所述容置腔中;The outer diameter of the imaging probe is not larger than the inner diameter of the accommodating cavity, and is used to be placed in the accommodating cavity during monitoring;
    所述主控系统还用于控制所述成像探头对所述声透性免疫贴片和/或皮肤进 行图像采集,进行实时或定时成像,并通过所述成像处理单元对成像数据进行识别处理,以进行成像检测。The main control system is also used to control the imaging probe to perform image acquisition on the acoustically permeable immune patch and / or skin, perform real-time or timed imaging, and perform recognition processing on the imaging data through the imaging processing unit For imaging inspection.
  6. 如权利要求5所述基于声诱导微孔阵列的疫苗经皮递送装置,其中,所述成像探头置于所述第一超声换能器的容置腔的中间;并且,The vaccine percutaneous delivery device based on an acoustically induced micropore array according to claim 5, wherein the imaging probe is placed in the middle of the receiving cavity of the first ultrasonic transducer; and,
    所述成像探头、所述成像探头对应的成像视野的中心和所述第一超声换能器的相对位置为几何中心同轴。The relative position of the imaging probe, the center of the imaging field corresponding to the imaging probe, and the first ultrasound transducer is coaxial with the geometric center.
  7. 如权利要求6所述基于声诱导微孔阵列的疫苗经皮递送装置,还包括与所述主控系统连接的三维移动控制器;The vaccine transdermal delivery device based on the acoustically induced micropore array according to claim 6, further comprising a three-dimensional mobile controller connected to the main control system;
    所述光学成像监控系统还包括与所述成像探头连接的探头固定支架;The optical imaging monitoring system further includes a probe fixing bracket connected to the imaging probe;
    所述高频强聚焦超声激励组件还包括与所述第一超声换能器连接的第一超声换能器固定支架;The high-frequency strong-focus ultrasonic excitation assembly further includes a first ultrasonic transducer fixing bracket connected to the first ultrasonic transducer;
    所述超声回波信号监测系统还包括与所述第二超声换能器连接的第二超声换能器固定支架;The ultrasonic echo signal monitoring system further includes a second ultrasonic transducer fixing bracket connected to the second ultrasonic transducer;
    所述探头固定支架、所述第一超声换能器固定支架以及所述第二超声换能器固定支架均与所述三维移动控制器连接。The probe fixing bracket, the first ultrasonic transducer fixing bracket, and the second ultrasonic transducer fixing bracket are all connected to the three-dimensional movement controller.
  8. 如权利要求1所述基于声诱导微孔阵列的疫苗经皮递送装置,其中,所述声透性免疫贴片,包括隔离环和粘性薄膜;The vaccine transdermal delivery device based on an acoustically induced micropore array according to claim 1, wherein the acoustically permeable immune patch includes an isolation ring and an adhesive film;
    所述粘性薄膜覆盖于所述隔离环上;并且,所述粘性薄膜与所述隔离环之间形成一药物容置腔体;The adhesive film covers the isolation ring; and, a drug containing cavity is formed between the adhesive film and the isolation ring;
    在对皮肤给药时,利用所述粘性薄膜的粘性,将所述声透性免疫贴片贴敷于皮肤表面,其中,所述药物容置腔体内注有用于给药的药物。When administering to the skin, using the viscosity of the adhesive film, the acoustically permeable immune patch is applied to the surface of the skin, wherein the drug containing cavity is filled with a drug for administration.
  9. 如权利要求8所述基于声诱导微孔阵列的疫苗经皮递送装置,其中,The vaccine transdermal delivery device based on an acoustically induced micropore array according to claim 8, wherein,
    所述隔离环为圆形的橡胶材质的隔离环;The isolation ring is a circular isolation ring made of rubber material;
    所述粘性薄膜为的透明的塑料材质的粘性薄膜;所述粘性薄膜在给药时背离所述圆锥形耦合导管并且面对皮肤的一面具有粘性;The adhesive film is a transparent plastic material adhesive film; the adhesive film faces away from the conical coupling catheter and is adhesive on the side facing the skin during administration;
    所述隔离环的外径为5-15mm,内径为3-10mm,厚度为1-3mm。The outer diameter of the isolation ring is 5-15 mm, the inner diameter is 3-10 mm, and the thickness is 1-3 mm.
  10. 一种基于声诱导微孔阵列的疫苗经皮递送装置的使用方法,包括:A method for using a vaccine percutaneous delivery device based on an acoustically induced micropore array includes:
    贴敷声透性免疫贴片,并置于基于声诱导微孔阵列的疫苗经皮递送装置的圆锥形耦合导管下端;Apply a sound-permeable immune patch and place it on the lower end of a conical coupling catheter of a vaccine transdermal delivery device based on an acoustically induced micropore array;
    通过所述基于声诱导微孔阵列的疫苗经皮递送装置的超声回波信号监测系统和光学成像监控系统进行空间定位,以确定皮肤给药位点;Spatial positioning is performed by the ultrasonic echo signal monitoring system and optical imaging monitoring system of the vaccine transdermal delivery device based on the acoustically induced micropore array to determine the site of skin administration;
    通过基于声诱导微孔阵列的疫苗经皮递送装置的高频强聚焦超声激励组件对所述皮肤给药位点进行经皮免疫给药;Transcutaneous immune administration to the skin administration site by a high-frequency intense focused ultrasound excitation assembly based on a sound-induced micropore array vaccine transdermal delivery device;
    通过所述光学成像监控系统对经皮免疫给药的皮肤给药位点进行递送效果评价。The optical imaging monitoring system is used to evaluate the delivery effect of the skin administration site of percutaneous immune administration.
PCT/CN2019/117138 2018-11-12 2019-11-11 Percutaneous vaccine delivery device employing acoustically induced micropore array WO2020098601A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811341239.XA CN109513104B (en) 2018-11-12 2018-11-12 Vaccine transdermal delivery device based on sound-induced micropore array
CN201811341239.X 2018-11-12

Publications (1)

Publication Number Publication Date
WO2020098601A1 true WO2020098601A1 (en) 2020-05-22

Family

ID=65774187

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/117138 WO2020098601A1 (en) 2018-11-12 2019-11-11 Percutaneous vaccine delivery device employing acoustically induced micropore array

Country Status (2)

Country Link
CN (1) CN109513104B (en)
WO (1) WO2020098601A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109513104B (en) * 2018-11-12 2020-10-02 深圳大学 Vaccine transdermal delivery device based on sound-induced micropore array
CN112023243B (en) * 2020-09-15 2022-03-25 南京大学 Transdermal drug delivery device with ultrasonic circulating focusing emission and control method
CN113616917B (en) * 2021-07-12 2024-04-09 重庆医科大学 Intelligent percutaneous drug delivery device and method based on ultrasound and micro-flow control

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101466432A (en) * 2006-06-14 2009-06-24 皇家飞利浦电子股份有限公司 Device for transdermal drug delivery and method of operating such a device
CN101698121A (en) * 2009-10-23 2010-04-28 西安交通大学 Conformal ultrasonic system for enforcing medicaments to permeate blood brain barrier
CN102406979A (en) * 2010-09-22 2012-04-11 田德扬 Method and system for leading macromolecule substances into living target cells
CN102755692A (en) * 2012-07-30 2012-10-31 王路 Ultrasonic wave and ion conduction transdermal medicament or cosmetic conduction device
CN103861204A (en) * 2014-03-25 2014-06-18 王安 Modulation ultrasonic wave device and percutaneous administration permeation facilitating method thereof
CN204995996U (en) * 2015-09-29 2016-01-27 广州三得医疗科技有限公司 Height dual -frenquency supersound electric conductance therapeutic instrument
CN106621024A (en) * 2017-01-17 2017-05-10 湖南省健缘医疗科技有限公司 Ultrasonic medication diagnosis and treatment device
US20180071505A1 (en) * 2016-09-13 2018-03-15 National Tsing Hua University Ultrasonic device for transversely manipulating drug delivery carriers and method using the same
CN109513104A (en) * 2018-11-12 2019-03-26 深圳大学 A kind of vaccine transdermal delivery device for leading microwell array based on acousta induction

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110040171A1 (en) * 2003-12-16 2011-02-17 University Of Washington Image guided high intensity focused ultrasound treatment of nerves
CN101920064A (en) * 2009-06-13 2010-12-22 翁春晓 Method and instrument of ultrasonic and electric field superposition target medicine penetration
CN103463732B (en) * 2013-09-18 2015-07-15 北京中美联医学科学研究院有限公司 Ultrasonic target position pore-forming device and method
CN104383646B (en) * 2014-12-12 2020-04-24 黄晶 Ultrasonic interventional therapy system
CN105361904A (en) * 2015-11-25 2016-03-02 青岛金智高新技术有限公司 Hydrogel ultrasonic coupling device
CN206391368U (en) * 2016-10-18 2017-08-11 苏州国科昂卓医疗科技有限公司 A kind of sonicator

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101466432A (en) * 2006-06-14 2009-06-24 皇家飞利浦电子股份有限公司 Device for transdermal drug delivery and method of operating such a device
CN101698121A (en) * 2009-10-23 2010-04-28 西安交通大学 Conformal ultrasonic system for enforcing medicaments to permeate blood brain barrier
CN102406979A (en) * 2010-09-22 2012-04-11 田德扬 Method and system for leading macromolecule substances into living target cells
CN102755692A (en) * 2012-07-30 2012-10-31 王路 Ultrasonic wave and ion conduction transdermal medicament or cosmetic conduction device
CN103861204A (en) * 2014-03-25 2014-06-18 王安 Modulation ultrasonic wave device and percutaneous administration permeation facilitating method thereof
CN204995996U (en) * 2015-09-29 2016-01-27 广州三得医疗科技有限公司 Height dual -frenquency supersound electric conductance therapeutic instrument
US20180071505A1 (en) * 2016-09-13 2018-03-15 National Tsing Hua University Ultrasonic device for transversely manipulating drug delivery carriers and method using the same
CN106621024A (en) * 2017-01-17 2017-05-10 湖南省健缘医疗科技有限公司 Ultrasonic medication diagnosis and treatment device
CN109513104A (en) * 2018-11-12 2019-03-26 深圳大学 A kind of vaccine transdermal delivery device for leading microwell array based on acousta induction

Also Published As

Publication number Publication date
CN109513104A (en) 2019-03-26
CN109513104B (en) 2020-10-02

Similar Documents

Publication Publication Date Title
WO2020098601A1 (en) Percutaneous vaccine delivery device employing acoustically induced micropore array
Child et al. Lung damage from exposure to pulsed ultrasound
US9636083B2 (en) High quality closed-loop ultrasound imaging system
CA2773181C (en) Systems, methods, and computer readable media for high-frequency contrast imaging and image-guided therapeutics
JPH0643242A (en) Ultrasonic wave imaging system
CN101854854A (en) Non-invasive device and method for locating a structure such as a nerve
CN204410838U (en) Ultrasonic probe sterility protection cover
US10271733B2 (en) Photo-acoustic signal enhancement with microbubble-based contrast agents
CN106621024B (en) Ultrasonic medicine-permeable diagnosis and treatment device
Xu et al. Optical and acoustic monitoring of bubble cloud dynamics at a tissue-fluid interface in ultrasound tissue erosion
Pouliopoulos et al. Pulse inversion enhances the passive mapping of microbubble-based ultrasound therapy
EP3326538B1 (en) Ultrasonic energy display device
Rota et al. Detection of acoustic cavitation in the heart with microbubble contrast agents in vivo: A mechanism for ultrasound-induced arrhythmias
US20150351724A1 (en) Real time ultrasound thermal dose monitoring system for tumor ablation therapy
Hu et al. Programmable and monitorable intradermal vaccine delivery using ultrasound perforation array
Yang et al. Photoacoustic imaging of biological tissues based on annular transducer array
Sutin et al. Prospective medical applications of nonlinear time reversal acoustics
Sapozhnikov et al. Ultrasound-guided localized detection of cavitation during, lithotripsy in pig kidney in vivo
Khokhlova et al. The use of twinkling artifact of Doppler imaging to monitor cavitation in tissue during high intensity focused ultrasound therapy
JP4387947B2 (en) Ultrasonic therapy device
US11896253B2 (en) System and method for detecting and aligning acoustic beam in situ to a target using wide-beam, low frequency (<1 mhz) ultrasound
Rich Characterization of cavitation effects in therapeutic ultrasound: Sonophoresis experiments and quantitative emission measurements
Tung et al. Identifying the inertial cavitation pressure threshold and skull effects in a vessel phantom using focused ultrasound and microbubbles
van Blokland Instigating and monitoring transdermal drug delivery using ultrasound-mediated cavitation
Slayton et al. Feasibility of tissue effects produced by noninvasive high frequency intense therapy ultrasound via inertial cavitation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19885061

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19885061

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 23.08.2021)

122 Ep: pct application non-entry in european phase

Ref document number: 19885061

Country of ref document: EP

Kind code of ref document: A1