CN114569903A - Pulse ultrasound-medicine-cooperated external noninvasive therapeutic apparatus and operation method thereof - Google Patents
Pulse ultrasound-medicine-cooperated external noninvasive therapeutic apparatus and operation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
- A61B5/0071—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by measuring fluorescence emission
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
- A61B5/0075—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/48—Other medical applications
- A61B5/4836—Diagnosis combined with treatment in closed-loop systems or methods
- A61B5/4839—Diagnosis combined with treatment in closed-loop systems or methods combined with drug delivery
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES 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
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES 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
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0092—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES 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
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M2037/0007—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents
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Abstract
The invention belongs to the technical field of medical equipment, and particularly discloses a pulse ultrasound synergistic drug in-vitro noninvasive therapeutic apparatus and an operation method thereof, wherein the pulse ultrasound synergistic drug in-vitro noninvasive therapeutic apparatus comprises an ultrasound generating system, a drug monitoring system and a drug delivery system, the ultrasound generating system comprises an ultrasound generator and an ultrasound transducer, and the ultrasound transducer is provided with a low frequency gear and a high frequency gear; the drug monitoring system is a reflection type fluorescence imaging system, and detects the fluorescence intensity of the drug-loaded nanoparticles by collecting fluorescence photons reflected by the drug-loaded nanoparticles marked by the fluorescent substance in the skin tissue so as to monitor the enrichment degree of the drug in the focus tissue of the treatment area; the drug delivery system is combined with a drug monitoring system to realize accurate controlled release of the drug. The therapeutic apparatus integrates ultrasonic medicine penetration, acoustic dynamic therapy and the like, realizes the in-vitro non-invasive treatment of tuberculosis focus and the accurate delivery, efficient controlled release and efficient sterilization of medicine through the ultrasonic synergistic medicine, and prevents the formation or the reversal of drug-resistant tubercle bacillus.
Description
Technical Field
The invention relates to the technical field of medical equipment, in particular to the technical field of ultrasonic synergistic drug-penetrating treatment equipment, and particularly relates to a pulse ultrasonic synergistic drug in-vitro noninvasive treatment instrument.
Background
Tuberculosis, a second infectious disease of Mycobacterium Tuberculosis (MTB) worldwide following HIV, is a major public health problem worldwide, with about 1/3 people worldwide having latent MTB infection. The WHO estimates that the multidrug-resistant tuberculosis patients in China occupy about one fourth of the world, and ranks China as one of 25 key prevention and treatment countries of the drug-resistant tuberculosis in the world. According to the statistics of the world health organization, about 17 hundred million tuberculosis latent infection groups and 1010 ten thousand new cases are generated around 2017, wherein the new cases in China account for 8.9 percent of the world, the number of deaths reaches 3.7 ten thousand, and the tuberculosis epidemic situation in China is still severe. Drug resistance remains a major difficulty in treating tuberculosis, including MTB/HIV double-infected tuberculosis. In recent years, with the increase of mobile population, the aging of society, the emergence of HIV infection and MTB multi-drug resistant strains and other reasons, the worldwide epidemic situation of tuberculosis is rising again, and the tuberculosis control still faces a serious challenge.
The tuberculosis pathogenic Mycobacterium Tuberculosis (MTB) has poor cell wall thickness and permeability, takes macrophage (M phi) endoparasite as a main part, and the dual barriers cause that the antituberculosis drug can not reach a target spot to play a bactericidal effect. Meanwhile, MTB easily forms fiber focus and wraps a tubercle ball after infecting organisms, so that a plurality of medicines are difficult to reach the deep part of focus tissues, and the concentration of the medicines in macrophages can not achieve the sterilization effect, thereby causing the natural drug resistance of the medicines to a plurality of antibiotic medicines. In the past 40 years, the world health organization only implemented a few antibiotics against drug-resistant mycobacterium tuberculosis, and there is an urgent clinical need to find new methods for treating tuberculosis infection.
Tuberculosis treatment has the problems of prolonged course of disease, easy relapse and the like, wherein the continuous increase of drug-resistant strains is the main reason of failure of clinical treatment. Tuberculosis patients in China are the third world and are also the countries with high morbidity caused by multi-drug resistant infection. The course of treatment of the drug-resistant tuberculosis is long, the treatment of patients with multiple drug resistance generally needs 18-24 months, the medical cost is about 100 times that of the common patients, and the treatment of the drug-resistant tuberculosis causes great economic pressure on individuals, families and society.
The main possible mechanisms for MTB to develop resistance are: cell wall permeability disorders, which result in slower entry of drugs into highly hydrophobic cell wall gaps; gene mutation, resulting in antibiotic target mutation or medicine in cell inactive state. Among them, low permeability of the MTB cell wall is an important mechanism leading to its natural resistance to various antibiotics, and there is an urgent need to find new therapeutic approaches.
The ultrasonic wave is a mechanical wave, has mechanical effect, thermal effect, cavitation effect and the like, can penetrate through the skin and subcutaneous tissues of a human body, realizes the target point of non-invasive treatment on deep tissues and organs of the human body, can transmit medicines, and has wide application prospect in the field of medicine. Research proves that the ultrasound can improve the permeability of cell membranes in a certain intensity and irradiation time range, promote the exchange of substances inside and outside cells, and has reversible action process.
Compared with traditional medicine treatment or medicinal application, the ultrasonic medicine penetration shortens the time, has small medicine penetration dosage and improves the bioavailability, the medicine dosage is only about 20 percent of the medicine dosage of the whole body, and the ultrasonic medicine penetration is painless, noninvasive, convenient, safe and free of cross infection, has deep medicine delivery, can directly reach the focus, improves the medicine effect and has small side effect. However, the existing ultrasonic medicine guide instrument on the market has some defects, after the medicine penetrates through skin tissues, the position of the medicine action is not clear, the medicine treatment effect is uncertain, and accurate medicine control cannot be realized.
At present, a plurality of medicaments such as isoniazid, rifampicin, ethambutol, pyrazinamide and the like are commonly used for treating tuberculosis clinically, but the treatment course is long (6-24 months), the side effect is large, and the problems of poor patient compliance, easy prolongation of disease course, relapse and the like are caused. The existing ultrasonic medicine penetration equipment only uses the cavitation effect, the thermal effect and other effects of the ultrasonic wave to promote the absorption of the local skin of the focus on the medicine, and does not fundamentally solve the problems of poor cell wall permeability, insensitivity to the medicine and difficult treatment of drug-resistant tuberculosis of the tuberculosis caused by the tuberculosis.
Disclosure of Invention
In view of the above disadvantages of the prior art, the present invention aims to provide a pulsed ultrasound synergistic drug noninvasive external therapeutic apparatus for solving the problems of poor therapeutic effect of an ultrasound drug-permeable device in the prior art and the failure of clinical treatment to achieve effective drug concentration for killing combined mycobacteria due to the hypotonic drug characteristics of Mycobacterium Tuberculosis (MTB) and macrophage (M phi).
In order to achieve the above objects and other related objects, a first aspect of the present invention provides a pulsed ultrasound in combination with a drug in vitro noninvasive therapeutic apparatus, which comprises: the therapeutic apparatus comprises an ultrasonic generating system, a drug monitoring system and a drug delivery system, wherein the ultrasonic generating system comprises an ultrasonic generator and an ultrasonic transducer, the ultrasonic generator is used for generating plane pulse ultrasound, and the ultrasonic transducer is used for emitting low-frequency low-intensity pulse ultrasound and/or high-frequency high-intensity pulse ultrasound; the drug monitoring system is a reflection type fluorescence imaging system, and detects the fluorescence intensity of the drug-loaded nanoparticles by collecting fluorescence photons reflected by the drug-loaded nanoparticles marked by the fluorescent substance in the skin tissue, so as to monitor the enrichment degree of the drug in the focus tissue of the treatment area; the drug delivery system comprises a drug delivery component for absorbing a liquid drug and allowing the drug to be absorbed by skin tissue by contact with the skin under the action of ultrasound, the drug delivery system being combined with the drug monitoring system to achieve accurate controlled release of the drug.
The working principle of the invention is as follows: the therapeutic apparatus realizes the treatment of the focus of the solid tuberculosis by the pulse ultrasound in cooperation with the medicine. The drug delivery system adopts a low-frequency ultrasonic transdermal drug delivery technology, the drug delivery component is injected with liquid drugs in advance, the drug delivery component is directly contacted with the skin in the treatment area, the skin tissue membrane in the treatment area is irradiated to form and enlarge the formed pore canal under the action of low-frequency low-intensity pulse ultrasound emitted by an ultrasonic transducer, so that the permeability of the pore canal is increased, meanwhile, the drugs can obtain the kinetic energy of directional transportation by the ultrasound, the drugs flow out from the drug delivery component, and drug molecules and particles move along the direction of sound waves and are finally absorbed by the skin tissue through the pore canal and enter lesion tissues. The drug-loaded nanoparticles in the skin tissue are marked by fluorescent substances in advance, the drug monitoring system adopts a reflective fluorescence imaging mode, the enrichment degree of the antituberculosis drug in the focus tissue of a treatment area is evaluated by detecting the fluorescence intensity carried by the drug-loaded nanoparticles in the skin tissue, and meanwhile, the drug monitoring system is combined with a drug delivery system to further realize accurate controlled release of the drug. After the medicine concentration is evaluated to reach the standard by a medicine monitoring system, high-frequency high-intensity pulse ultrasound is transmitted by an ultrasonic transducer, under the action of the ultrasound, the permeability of macrophage membranes and cell walls of mycobacterium tuberculosis in focus tissues is increased, the medicine is promoted to be absorbed by cells to reach the threshold concentration for killing the combined mycobacterium, and under the action of an acoustic dynamic therapy and the medicine, the aim of high-efficiency sterilization is finally fulfilled.
Further, the medicine monitoring system comprises a laser generator, a laser leading-in component, a fluorescence detection component, a fluorescence detector and an image processor, wherein the laser generator is used for emitting laser, and the laser leading-in component is used for irradiating the laser generated by the laser generator onto skin tissues in a treatment area so that the medicine-carrying nano-particles marked by fluorescent substances in the skin tissues are irradiated and excited by the laser to reflect fluorescence photons; the fluorescence detection component is used for collecting fluorescence signals and transmitting the fluorescence signals to the fluorescence detector, the fluorescence detector is used for storing the fluorescence signals and converting the fluorescence signals into electric signals, the electric signals are converted into fluorescence signal intensity in lesion tissues after correlation calculation processing, and the image processor is used for processing the fluorescence signal intensity transmitted back by the fluorescence detector and enabling the fluorescence signal intensity to be imaged on the display.
The drug monitoring system of the therapeutic apparatus adopts a reflection type fluorescence imaging mode, a laser emits laser, then the laser is irradiated on skin tissues in a treatment area through a laser introduction part, fluorescent substances on drug-loaded nanoparticles are introduced into the laser for irradiation, then are excited and reflect fluorescence photons, the fluorescence photons are reflected and scattered by biological tissues and then escape from the surface of the skin, are collected by a fluorescence detection part and are transmitted into a fluorescence detector, the fluorescence detector converts fluorescence signals into electric signals, the electric signals are converted into fluorescence signal intensity in focus tissues after relevant calculation processing, finally the fluorescence signal intensity transmitted by the fluorescence detector is imaged on a display after being processed by an image processor, so that the detection of the fluorescence intensity carried by the drug-loaded nanoparticles in the skin tissues is realized, and the enrichment degree of antituberculous drugs in the focus tissues in the treatment area is evaluated.
Further, the therapeutic apparatus comprises an apparatus main body, a therapeutic head and a data signal line, wherein the apparatus main body comprises an outer box, a display, a frequency regulator, a sound intensity regulator, a power switch and an ultrasonic generator arranged in the outer box, the display is used for displaying ultrasonic frequency, sound intensity, irradiation time and fluorescence signal intensity, the frequency regulator and the sound intensity regulator are respectively used for regulating the ultrasonic frequency and the sound intensity, and the power switch is used for controlling the ultrasonic generator to be turned on and off; the ultrasonic transducer, the laser leading-in component, the fluorescence detection component and the drug delivery component are all arranged in the treatment head, and the ultrasonic transducer, the laser leading-in component and the fluorescence detection component are correspondingly connected with the ultrasonic generator, the laser generator and the fluorescence detector through data signal lines.
Further, the laser generator, the fluorescence detector and the image processor are arranged in the outer box.
Further, the data signal line comprises a laser source lead-in optical fiber and a fluorescence probe coupling optical fiber, the laser generator is connected with the laser lead-in component through the laser source lead-in optical fiber and transmits laser, and the fluorescence detector is connected with the fluorescence detector through the fluorescence probe coupling optical fiber and transmits fluorescence signals.
Furthermore, a laser light source leading-in hole is arranged in the treatment head, and the laser light source leading-in hole is a laser leading-in component.
Further, a spectroscope is installed at the front end of the laser light source leading-in hole and used for increasing the laser irradiation range.
Furthermore, a fluorescence detection head is arranged in the treatment head, the fluorescence detection head is a fluorescence detection part, and the fluorescence detection head is an excitation laser guide-in probe with a collimator.
Further, the laser emitted by the laser generator is near infrared light, the fluorescence detector is a near infrared region fluorescence detector, and the fluorescence detector head is a near infrared region fluorescence detector head; preferably, the near-infrared fluorescence detector can adopt an InGaAs charge coupled device detector (InGaAs CCD) with high response in an infrared band, and is used for ultra-sensitive detection of near-infrared fluorescence.
Further, the treatment head comprises a sealed shell, the ultrasonic transducer, the laser leading-in component, the fluorescence detection component and the drug administration component are all arranged in the treatment head shell, the treatment head shell comprises a treatment end used for treatment, the treatment end is provided with a groove used for placing the drug administration component, the ultrasonic transducer emits ultrasonic waves to skin tissues in a treatment area through the drug administration component in the groove of the treatment end, the laser leading-in component irradiates laser to the skin tissues in the treatment area through the drug administration component in the groove of the treatment end, and the fluorescence detection component acquires fluorescence signals through the drug administration component in the groove of the treatment end.
Further, the drug delivery part is a drug-permeable cotton sheet which can absorb liquid drugs. Before treatment, the liquid medicine is filled in the medicine-permeating cotton sheet, and then the cotton sheet is placed in the groove for fixation. The liquid medicine is injected into the medicine-permeable cotton sheet in advance, the exposed part of the medicine-permeable cotton sheet is directly contacted with the skin, and under the action of ultrasonic wave, the medicine in the medicine-permeable cotton sheet flows out and is absorbed by skin tissues through a pore channel.
Further, the laser leading-in component and the fluorescence detection component are positioned in the center position in the treatment head shell.
Furthermore, the laser leading-in component and the fluorescence detection component are positioned in the center of the groove at the end part of the treatment head shell.
Further, the groove is a circular groove. Because the cotton piece of penetrating medicine is mostly circular, therefore be circular with the recess design.
Furthermore, a buckle used for fixing the medicine-permeating cotton piece is arranged in the groove. After the medicine-permeating cotton piece is placed in the groove, the medicine-permeating cotton piece is fixed through the buckle, so that the medicine-permeating cotton piece is prevented from falling off.
Further, the quantity of buckle is 2 ~ 4, preferably 4, and is the symmetric distribution in the recess.
Furthermore, the treatment head is a handle type treatment head so as to be convenient to hold by hand for use.
Furthermore, a therapy head switch is arranged on the therapy head.
Further, the shell of the treatment head comprises a handheld part, and the treatment head switch is arranged on the handheld part of the treatment head, so that a user can conveniently open or close the treatment head.
Further, the shell of the treatment head comprises a shell body and a handheld part, and the groove is formed in the shell body.
Furthermore, the shell main body of the treatment head is cylindrical or cylinder-like, the groove is formed in the front end of the cylindrical or cylinder-like shell main body, and the handheld portion of the treatment head and the shell main body are integrally formed and located at the rear end of the cylindrical or cylinder-like shell main body.
Furthermore, the diameter of the therapeutic head shell main body is 50-100 mm, preferably 50-80 mm, and more preferably 60 mm.
Further, the ultrasonic generator can generate 20KHz-1MHz frequency, 0.05-3W/cm2The ultrasonic sound intensity is plane pulse ultrasonic, and the frequency and the sound intensity are continuously adjustable.
Further, the ultrasonic transducer comprises a low-frequency piezoelectric wafer and a high-frequency piezoelectric wafer, and the low-frequency piezoelectric wafer and the high-frequency piezoelectric wafer are integrated into a whole. The ultrasonic transducer used by the therapeutic apparatus integrates the low-frequency piezoelectric wafer and the high-frequency piezoelectric wafer into a whole by adopting a multi-frequency technology, the two wafers are independently acted and do not influence each other, and when the low-frequency piezoelectric wafer acts to generate low-frequency ultrasound, the high-frequency piezoelectric wafer does not act and serves as a common sound transmission material; when the high-frequency piezoelectric wafer acts to generate high-frequency ultrasound, the low-frequency piezoelectric wafer does not act as a common sound-transmitting material.
In a second aspect, the present invention provides a method for operating the pulsed ultrasound in conjunction with a drug in vitro noninvasive therapeutic apparatus according to the first aspect, comprising the following steps:
before treatment, the drug-loaded nanoparticles in the liquid drug are labeled by fluorescent substances in advance, and the liquid drug is injected into the drug-feeding part;
during treatment, the drug delivery component is directly contacted with the skin in the treatment area, and the ultrasonic transducer emits low-frequency low-intensity pulse ultrasound to irradiate the skin tissue in the treatment area, so that the drugs are absorbed by the skin tissue; a drug monitoring system is adopted to detect the fluorescence intensity carried by the drug-loaded nanoparticles in the skin tissue so as to evaluate the enrichment degree of the antituberculosis drug in the focus tissue of a treatment area, and meanwhile, the drug monitoring system is combined with a drug delivery system to realize accurate controlled release of the drug; after the concentration of the drug is evaluated to reach the standard by the drug monitoring system, the ultrasonic transducer emits high-frequency high-intensity pulse ultrasound to promote the drug to be absorbed by cells so as to kill combined mycobacteria.
Further, before treatment, the liquid medicine is filled in the medicine-permeable cotton sheet, and then the cotton sheet is placed in the groove for fixation.
Furthermore, during treatment, laser is emitted by a laser device, the laser device irradiates skin tissues in a treatment area through a laser introduction part, a fluorescent substance on the medicine-carrying nanoparticles is excited after being introduced into the laser device for irradiation, fluorescence photons are reflected, a fluorescence detection part collects the fluorescence photons and transmits the fluorescence photons into a fluorescence detector, the fluorescence detector stores fluorescence signals and converts the fluorescence signals into electric signals, the electric signals are converted into fluorescence signal intensity in focus tissues after being processed by related calculation, and finally the fluorescence signal intensity transmitted back by the fluorescence detector is imaged on a display after being processed by an image processor, so that the fluorescence intensity carried by the medicine-carrying nanoparticles in the skin tissues is detected, and the enrichment degree of the antituberculosis drugs in the focus tissues in the treatment area is evaluated.
Furthermore, the medicine is an antituberculous medicine with a sonosensitive effect, and the antituberculous medicine is levofloxacin.
Further, the focus of the solid tuberculosis is lymphoid tuberculosis, breast tuberculosis and subcutaneous tuberculosis.
As mentioned above, the pulse ultrasound synergistic drug in-vitro noninvasive therapeutic apparatus of the invention has the following beneficial effects:
the invention provides an instrument for performing in-vitro non-invasive treatment on subcutaneous tuberculosis lesions by using antituberculosis drugs with pulse ultrasound and acoustic sensitivity synergistic effects, which integrates ultrasound drug penetration, acoustic dynamic therapy and the like, and realizes accurate feeding and efficient controlled release of the antituberculosis drugs by the synergistic treatment effect of the ultrasound and the drugs, thereby realizing efficient sterilization of the drugs and further preventing the formation of drug-resistant tubercle bacillus or reversing drug resistance.
(1) The permeability of cell walls and macrophage membranes of Mycobacterium Tuberculosis (MTB) is increased through the mechanical effect, the cavitation effect and the sound flow effect of ultrasound, the concentration of drugs reaching macrophages is improved, the anti-tuberculosis drugs are promoted to efficiently enter the MTB and are combined with the MTB in a targeted mode, the sterilization effect of the anti-tuberculosis drugs is exerted, the targeted therapy of the mycobacterium tuberculosis is realized, and the purpose of efficiently killing the MTB is achieved.
(2) Through the non-thermal effect of pulse ultrasonic irradiation, the action of the sound sensitizer of the antituberculous drug levofloxacin is activated, active oxygen and the like are generated, and the synergistic sterilization effect is increased.
(3) The method adopts low-frequency ultrasonic transdermal drug permeation and near-infrared fluorescence imaging technology to monitor the intensity of fluorescence signals carried by drug-loaded nanoparticles marked by fluorescent substances, thereby realizing accurate controlled release of drug release.
The micro non-invasive treatment is the inevitable direction of medical development, and the invention is expected to provide a novel method and an instrument for the non-invasive treatment of pulse ultrasound synergistic drugs (sound-sensitive agents) for solid tuberculosis focuses such as lymphoid tuberculosis, breast tuberculosis, subcutaneous tuberculosis and the like.
Drawings
Fig. 1 is a schematic structural diagram of an external noninvasive therapeutic apparatus using pulsed ultrasound in combination with drugs in an embodiment of the invention.
Fig. 2 is a schematic structural diagram of a therapy head in the pulsed ultrasound-drug in-vitro noninvasive therapy apparatus according to the embodiment of the invention.
Fig. 3 is a schematic structural view of the detached treatment head of the pulsed ultrasound-drug in-vitro noninvasive treatment apparatus according to the embodiment of the present invention.
Detailed Description
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
It should be noted that the drawings provided in the present embodiment are only for illustrating the basic idea of the present invention, and the components related to the present invention are only shown in the drawings rather than drawn according to the number, shape and size of the components in actual implementation, and the type, quantity and proportion of the components in actual implementation may be changed freely, and the layout of the components may be more complicated. The structures, proportions, sizes, and other dimensions shown in the drawings and described in the specification are for understanding and reading the present disclosure, and are not intended to limit the scope of the present disclosure, which is defined in the claims, and are not essential to the art, and any structural modifications, changes in proportions, or adjustments in size, which do not affect the efficacy and attainment of the same are intended to fall within the scope of the present disclosure. In addition, the terms "upper", "lower", "left", "right", "middle" and "one" used in the present specification are used for clarity of description, and are not intended to limit the scope of the present invention, and the relative relationship between the terms and the terms may be changed or adjusted without substantial change in the technical content.
Description of the reference numerals
The device comprises an outer box 1, a treatment head 2, a data signal line 3, a display 4, a frequency regulator 5, a sound intensity regulator 6, a power switch 7, a data signal line interface 8, a power supply end 9, a medicine-permeable cotton sheet 10, a groove 11, a buckle 12, a laser light source leading-in hole 13, a fluorescent probe 14 and a treatment head switch 15.
Example 1
The embodiment provides a pulse ultrasound-drug cooperation extracorporeal noninvasive therapeutic apparatus, which comprises an ultrasound generating system, a drug monitoring system and a drug delivery system.
The ultrasound generation system is critical to achieving the objectives of the present invention. The ultrasonic generating system comprises an ultrasonic generator and an ultrasonic transducer, wherein the ultrasonic generator is used for generating plane pulse ultrasonic, the ultrasonic transducer comprises a low-frequency piezoelectric wafer and a high-frequency piezoelectric wafer, and the low-frequency piezoelectric wafer and the high-frequency piezoelectric wafer are integrated and are respectively used for transmitting low-frequency low-intensity pulse ultrasonic and high-frequency high-intensity pulse ultrasonic. The ultrasonic generator used by the invention can generate plane pulse ultrasonic with the frequency of 20KHz-1MHz and the sound intensity of 0.05-3W/cm2, and the frequency and the sound intensity are continuously adjustable. The ultrasonic transducer used by the invention adopts a multi-frequency technology to integrate the low-frequency piezoelectric wafer and the high-frequency piezoelectric wafer, the two wafers are independent and do not influence each other, and the ultrasonic transducer has two low-frequency and high-frequency gears, can act on macrophage and MTB in focus tissues, promotes drug-loaded levofloxacin nano-particles to penetrate through macrophage membranes and mycobacterium tuberculosis cell wall double barriers to enter the MTB, and finally realizes the purpose of high-efficiency sterilization.
The drug monitoring system comprises a laser generator, a laser leading-in component, a fluorescence detection component, a fluorescence detector and an image processor, wherein the laser generator is used for emitting laser, and the laser leading-in component is used for irradiating the laser generated by the laser generator onto skin tissues in a treatment area so that drug-loaded nanoparticles marked by fluorescent substances in the skin tissues are excited by the laser irradiation to reflect fluorescence photons; the fluorescence detection component is used for collecting fluorescence signals and transmitting the fluorescence signals to the fluorescence detector, the fluorescence detector is used for storing the fluorescence signals and converting the fluorescence signals into electric signals, the electric signals are converted into fluorescence signal intensity in lesion tissues after correlation calculation processing, and the image processor is used for processing the fluorescence signal intensity transmitted back by the fluorescence detector and imaging the fluorescence signal intensity on the display.
The ultrasonic transducer, the laser leading-in component and the fluorescence detection component are correspondingly connected with the ultrasonic generator, the laser generator and the fluorescence detector through data signal lines 3.
The drug delivery system includes a drug delivery member for absorbing the liquid drug and allowing the drug to be absorbed by skin tissue by contact with the skin under the action of ultrasound, and is combined with a drug monitoring system to achieve precise controlled release of the drug.
The therapeutic apparatus realizes the treatment of the focus of the solid tuberculosis by the pulse ultrasound in cooperation with the medicine. The working principle is as follows: the drug delivery system adopts a low-frequency ultrasonic transdermal drug delivery technology, the drug delivery part is injected with liquid drugs in advance, the drug delivery part is directly contacted with the skin in the treatment area, the skin tissue membrane in the treatment area is irradiated and the formed pore channel is formed and enlarged under the action of low-frequency low-intensity pulse ultrasound emitted by an ultrasonic transducer, so that the permeability of the pore channel is increased, meanwhile, the drugs can obtain the kinetic energy of directional transportation by the ultrasound, the drugs flow out from the drug delivery part, and the drug molecules and particles move along the direction of sound waves and are finally absorbed by the skin tissue through the pore channel to enter the focus tissue. The drug-loaded nanoparticles in the skin tissue are marked with fluorescent substances in advance, a drug monitoring system adopts a reflection type fluorescence imaging mode, a laser emits laser, then the laser is irradiated on the skin tissue in a treatment area through a laser introduction component, fluorescent substances on the drug-loaded nanoparticles are excited after being irradiated by the introduced laser and reflect fluorescence photons, the fluorescence photons are reflected and scattered by biological tissues and then escape from the surface of the skin, the fluorescence photons are collected by a fluorescence detection component and are transmitted to a fluorescence detector, the fluorescence detector converts a fluorescence signal into an electric signal, finally the electric signal is converted into the intensity of the fluorescence signal in the lesion tissue after being processed by relevant calculation, the intensity of the fluorescence signal transmitted by the fluorescence detector is imaged on a display after being processed by an image processor, and the enrichment degree of the antituberculosis drugs in the lesion tissue in the treatment area is evaluated by detecting the intensity of the fluorescence carried by the drug-loaded nanoparticles in the skin tissue, meanwhile, the controlled release tablet is combined with a drug delivery system to realize accurate controlled release of the drug. After the medicine concentration is evaluated to reach the standard by a medicine monitoring system, high-frequency high-intensity pulse ultrasound is transmitted by an ultrasonic transducer, under the action of the ultrasound, the permeability of macrophage membranes and cell walls of mycobacterium tuberculosis in focus tissues is increased, the medicine is promoted to be absorbed by cells to reach the threshold concentration for killing the combined mycobacteria, and under the action of the sonodynamic therapy and the medicine, the aim of high-efficiency sterilization is finally fulfilled.
Fig. 1 shows a schematic structure diagram of a pulsed ultrasound-drug in-vitro noninvasive therapeutic apparatus.
As shown in figure 1, the pulse ultrasound and medicine cooperated in-vitro noninvasive therapeutic apparatus comprises an apparatus main body, a therapeutic head 2 and a data signal line 3. The device main part includes outer container 1, display 4, frequency regulator 5, sound intensity regulator 6, switch 7, ultrasonic generator, laser generator, the fluorescence detector, image processor installs in outer container 1, display 4, frequency regulator 5, sound intensity regulator 6, switch 7 installs at outer container 1 front end (being the front that fig. 1 shows), display 4 is used for showing ultrasonic frequency, the sound intensity, irradiation time and fluorescence signal intensity, frequency regulator 5, sound intensity regulator 6 are used for adjusting ultrasonic frequency and sound intensity respectively, switch 7 is used for controlling ultrasonic generator and opens and close.
As shown in fig. 1, 2 and 3, the therapy head 2 is a handle-type therapy head 2, so as to be convenient for handheld use. The treatment head 2 comprises a sealed shell, and the ultrasonic transducer, the laser leading-in part, the fluorescence detection part and the drug administration part are all arranged in the shell of the treatment head 2; the treatment head 2 shell comprises a treatment end for treatment, and the treatment end is provided with a groove 11 for placing the administration component. Specifically, the shell of the treatment head 2 comprises a shell body and a handheld part, and the groove 11 is formed in the shell body.
In this embodiment, the drug delivery member is a drug permeable cotton sheet 10, and the drug permeable cotton sheet 10 can absorb the liquid drug. Before treatment, the liquid medicine is filled in the medicine-permeating cotton piece 10, and then the cotton piece is placed in the groove 11 for fixation. The liquid medicine is injected into the medicine-permeable cotton sheet 10 in advance, the exposed part of the medicine-permeable cotton sheet is directly contacted with the skin, and under the action of ultrasonic wave, the medicine in the medicine-permeable cotton sheet 10 flows out and is absorbed by skin tissues through pore canals.
Further, a buckle 12 for fixing the drug-permeable cotton piece 10 is arranged in the groove 11. After the medicine-permeating cotton piece 10 is placed in the groove 11, the medicine-permeating cotton piece 10 is fixed through the buckle 12, so that the medicine-permeating cotton piece 10 is prevented from falling off. The quantity of buckle 12 is 2 ~ 4, is equipped with 4 buckles 12 in the recess 11 in this embodiment, and is the symmetric distribution in recess 11.
In this embodiment, the groove 11 on the treatment head 2 is a circular groove 11. Since the tablet 10 is mostly circular, the groove 11 is designed to be circular. Of course, the recess 11 can also be designed in other shapes, such as square.
Furthermore, the casing main body of the treatment head 2 is cylindrical or cylinder-like, the groove 11 is arranged at the front end of the cylindrical or cylinder-like casing main body, and the handheld part of the treatment head 2 and the casing main body are integrally formed and are positioned at the rear end of the cylindrical or cylinder-like casing main body. The diameter of the main body of the shell of the treatment head 2 is 50-100 mm, preferably 50-80 mm, and the diameter of the main body of the shell in the embodiment is 60 mm.
In this embodiment, the laser introducing component and the fluorescence detecting component are located at the center of the bottom of the recess 11 of the housing of the treatment head 2, and the laser source introducing hole 13 and the fluorescence detecting head 14 are integrated at the center of the recess 11 at the bottom of the treatment head 2. The laser light source leading-in hole 13 is a laser leading-in component, and the front end of the laser light source leading-in hole 13 is also provided with a spectroscope which can increase the laser irradiation range. The fluorescence detecting head 14 is a fluorescence detecting component, and further, the fluorescence detecting head 14 may employ an excitation laser introducing head with a collimator. During treatment, the ultrasonic transducer emits ultrasonic waves to skin tissues in a treatment area through the drug administration part in the groove 11, the laser source introduction hole 13 irradiates laser to the skin tissues in the treatment area through the drug-permeable cotton piece 10 in the groove 11, and the fluorescence probe 14 collects fluorescence signals through the drug-permeable cotton piece 10 in the groove 11.
The drug monitoring system of the present invention uses near infrared fluorescence imaging technology. Based on the above, the laser emitted by the laser generator is near infrared light; the fluorescence detector is a near infrared fluorescence detector, and the near infrared fluorescence detector can adopt an InGa As charge coupled element detector (InGaAs CCD) with high response of an infrared band and is used for the ultra-sensitive detection of the near infrared fluorescence; the fluorescent probe 14 employs a near infrared region fluorescent probe 14.
The rear end of the device body (i.e., the rear wall of the outer case 1) is provided with a data signal line interface 8 and a power supply terminal 9. The data signal line 3 comprises a laser source lead-in optical fiber and a fluorescence probe coupling optical fiber, the laser generator is connected with the laser lead-in component through the laser source lead-in optical fiber and transmits laser, and the fluorescence detector is connected with the fluorescence detector through the fluorescence probe coupling optical fiber and transmits fluorescence signals.
In addition, a therapy head switch 15 is arranged on the therapy head 2, and the therapy head switch 15 is arranged on the handheld part of the therapy head 2, so that a user can conveniently open or close the therapy head 2.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (10)
1. A pulsed ultrasound-drug in-vitro noninvasive therapeutic instrument is characterized by comprising an ultrasound generating system, a drug monitoring system and a drug delivery system, wherein the ultrasound generating system comprises an ultrasound generator and an ultrasound transducer, the ultrasound generator is used for generating planar pulsed ultrasound, and the ultrasound transducer is used for emitting low-frequency low-intensity pulsed ultrasound and/or high-frequency high-intensity pulsed ultrasound; the drug monitoring system is a reflection type fluorescence imaging system, and detects the fluorescence intensity of the drug-loaded nanoparticles by collecting fluorescence photons reflected by the drug-loaded nanoparticles marked by the fluorescent substance in the skin tissue, so as to monitor the enrichment degree of the drug in the focus tissue of the treatment area; the drug delivery system comprises a drug delivery component for absorbing a liquid drug and allowing the drug to be absorbed by skin tissue by contact with the skin under the action of ultrasound, the drug delivery system being combined with the drug monitoring system to achieve accurate controlled release of the drug.
2. The apparatus according to claim 1, wherein the apparatus comprises: the drug monitoring system comprises a laser generator, a laser leading-in component, a fluorescence detection component, a fluorescence detector and an image processor, wherein the laser generator is used for emitting laser, and the laser leading-in component is used for irradiating the laser generated by the laser generator onto skin tissues in a treatment area so that drug-loaded nanoparticles marked by fluorescent substances in the skin tissues are irradiated and excited by the laser to reflect fluorescence photons; the fluorescence detection component is used for collecting fluorescence signals and transmitting the fluorescence signals to the fluorescence detector, the fluorescence detector is used for storing the fluorescence signals and converting the fluorescence signals into electric signals, the electric signals are converted into fluorescence signal intensity in lesion tissues after correlation calculation processing, and the image processor is used for processing the fluorescence signal intensity transmitted back by the fluorescence detector and enabling the fluorescence signal intensity to be imaged on the display.
3. The pulsed ultrasound in conjunction with drugs external noninvasive therapeutic apparatus of claim 1 or 2, characterized in that: the therapeutic apparatus comprises an apparatus main body, a therapeutic head and a data signal line, wherein the apparatus main body comprises an outer box, a display, a frequency regulator, a sound intensity regulator, a power switch and an ultrasonic generator arranged in the outer box, the display is used for displaying ultrasonic frequency, sound intensity, irradiation time and fluorescence signal intensity, the frequency regulator and the sound intensity regulator are respectively used for regulating the ultrasonic frequency and the sound intensity, and the power switch is used for controlling the ultrasonic generator to be switched on and off; the ultrasonic transducer, the laser leading-in component, the fluorescence detection component and the drug delivery component are all arranged in the treatment head, and the ultrasonic transducer, the laser leading-in component and the fluorescence detection component are correspondingly connected with the ultrasonic generator, the laser generator and the fluorescence detector through data signal lines.
4. The apparatus according to claim 3, wherein the apparatus comprises: the laser generator, the fluorescence detector and the image processor are arranged in the outer box.
5. The apparatus according to claim 3, wherein the apparatus comprises: the data signal line comprises a laser source lead-in optical fiber and a fluorescence probe coupling optical fiber, the laser generator is connected with the laser lead-in component through the laser source lead-in optical fiber and transmits laser, and the fluorescence detector is connected with the fluorescence detector through the fluorescence probe coupling optical fiber and transmits fluorescence signals.
6. The apparatus according to claim 3, wherein the apparatus comprises: a laser light source leading-in hole is arranged in the treatment head, and is a laser leading-in component;
and/or a fluorescence detection head is arranged in the treatment head and is a fluorescence detection part.
7. The apparatus according to claim 2, wherein the apparatus comprises: the laser emitted by the laser generator is near infrared light, and the fluorescence detector is a near infrared region fluorescence detector.
8. The apparatus according to claim 3, wherein the apparatus comprises: the treatment head comprises a sealed shell, the ultrasonic transducer, the laser guide-in component, the fluorescence detection component and the drug administration component are all arranged in the treatment head shell, the treatment head shell comprises a treatment end used for treatment, the treatment end is provided with a groove used for placing the drug administration component, the ultrasonic transducer emits ultrasonic waves to skin tissues in a treatment area through the drug administration component in the groove of the treatment end, the laser guide-in component irradiates laser to the skin tissues in the treatment area through the drug administration component in the groove of the treatment end, and the fluorescence detection component acquires fluorescence signals through the drug administration component in the groove of the treatment end.
9. The apparatus according to claim 8, wherein the apparatus comprises: the drug delivery part is a drug-permeable cotton piece;
and/or the groove is a circular groove;
and/or a buckle for fixing the drug-permeable cotton sheet is arranged in the groove;
and/or the treatment head is a handle-type treatment head;
and/or a treatment head switch is arranged on the treatment head.
10. The operation method of the pulsed ultrasound and drug in vitro noninvasive therapeutic instrument according to any one of claims 1 to 9, characterized by comprising the following steps:
before treatment, the drug-loaded nanoparticles in the liquid drug are marked by fluorescent substances in advance, and the liquid drug is injected into the drug administration component;
during treatment, the drug delivery component is directly contacted with the skin in the treatment area, and the ultrasonic transducer emits low-frequency low-intensity pulse ultrasound to irradiate the skin tissue in the treatment area, so that the drugs are absorbed by the skin tissue; a drug monitoring system is adopted to detect the fluorescence intensity carried by the drug-loaded nanoparticles in the skin tissue so as to evaluate the enrichment degree of the antituberculosis drug in the focus tissue of a treatment area, and meanwhile, the drug monitoring system is combined with a drug delivery system to realize accurate controlled release of the drug; after the concentration of the drug is evaluated to reach the standard by the drug monitoring system, the ultrasonic transducer emits high-frequency high-intensity pulse ultrasound to promote the drug to be absorbed by cells so as to kill combined mycobacteria.
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