CN112691191A - Temperature photoacoustic imaging and accurate control method and system based on nano photothermal preparation - Google Patents
Temperature photoacoustic imaging and accurate control method and system based on nano photothermal preparation Download PDFInfo
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Abstract
The invention relates to a temperature photoacoustic imaging and accurate control method and system based on a nano photothermal preparation. The photoacoustic ultrasonic temperature multi-modal imaging system comprises: the system comprises a laser, a coupling light path, an annular light-emitting optical fiber, an ultrasonic transducer, image acquisition and processing equipment, an upper computer and a lower computer; the laser emits pulse laser, enters the annular light-emitting optical fiber through the coupling optical path, excites human tissues to generate ultrasonic signals, and simultaneously changes the temperature of the human tissues through laser energy; the change of the temperature causes the ultrasonic signal to change, and the ultrasonic transducer captures the ultrasonic signal; transmitting the ultrasonic signals to image acquisition and processing equipment, and carrying out temperature pseudo-color image reconstruction work through a photoacoustic temperature image sensitive factor extraction algorithm; and the upper computer extracts the temperature information in the ultrasonic signal and continuously regulates and controls the power of the laser through a control algorithm. The invention is based on nano photothermal preparations, adopts photoacoustic imaging technology, and can realize real-time, accurate and efficient deep tissue temperature imaging and accurate control.
Description
Technical Field
The invention belongs to the field of biomedical engineering, and particularly relates to a temperature photoacoustic imaging and accurate control method and system based on a nano photothermal preparation.
Background
The tumor photothermal therapy utilizes the targeted photothermal preparation to convert absorbed near infrared light energy into heat energy under the irradiation of a light source with a specific wavelength, so that the temperature of a tumor part is quickly raised to be higher than 42 ℃ to generate local high temperature to kill tumor cells, thereby achieving the purpose of treating tumors. The tumor photothermal therapy is rapidly developed due to the advantages of non-invasiveness, no ionization radiation, high detection sensitivity, good treatment selectivity and the like, and becomes a new field of cancer treatment.
Currently, the clinical temperature measurement technology is mainly divided into contact and non-contact measurement technologies. Contact temperature measurement such as a thermocouple or a temperature measurement optical fiber is seriously applied in clinic due to the limitation of probe invasion. The infrared imaging non-contact temperature measurement technology can only measure the temperature of the surface of the tissue. The development of the technology capable of generating local high temperature at the tumor focus part and monitoring the temperature in real time has very important significance for the photothermal treatment of the tumor.
Disclosure of Invention
The invention firstly provides a nano photothermal preparation which can be used for temperature triggering and temperature imaging. The nano photothermal preparation can be used for temperature photoacoustic imaging of deep tissues by adopting a temperature imaging algorithm of a photoacoustic image.
A nano photothermal preparation comprises a shell membrane and contents, wherein the shell membrane is albumin, and the contents are indocyanine green.
Specifically, in the nano photothermal preparation, the weight ratio of albumin to indocyanine green is 200:1-1.5, such as 200: 1.25.
Specifically, the nano photothermal preparation is nano spherical particles formed by coating indocyanine green by using albumin as a shell membrane.
Specifically, the nano photothermal preparation is nano spherical particles. Further, the nano-scale spherical particles have a particle size ranging from 20 to 400 nm.
Specifically, the nano photothermal preparation can generate high temperature under the excitation of near infrared laser at 808 nm; the temperature photoacoustic imaging can be carried out on deep tissues by adopting a temperature imaging algorithm of the photoacoustic image.
The invention also provides a preparation method of the nano photothermal preparation, which comprises the following steps:
providing an indocyanine green solution, wherein the solvent of the indocyanine green solution is a mixed solution of chloroform and ethanol;
providing an aqueous albumin solution;
injecting the indocyanine green solution into the albumin aqueous solution, homogenizing under high pressure, and emulsifying; and (4) centrifugal ultrafiltration washing.
Specifically, the concentration of the indocyanine green solution is 0.08-0.12mg/mL, such as 0.1 mg/mL.
Specifically, the solvent of the indocyanine green solution is a mixed solution of chloroform and ethanol, wherein the volume ratio of chloroform to ethanol is 10: 0.1-1.
In particular, the concentration of the aqueous albumin solution is 1-10% (w/w), for example 5% (w/w).
In particular, the pressure for high-pressure homogenization is 250-700bar, for example 500 bar.
In particular, the time of emulsification is 2-10min, for example 4 min.
In some embodiments, the method for preparing a nano photothermal formulation comprises:
1) weighing 1-1.5mg of indocyanine green, and dissolving the indocyanine green in a mixed solvent of chloroform and ethanol to prepare an indocyanine green solution with the concentration of 0.08-0.12 mg/mL;
2) preparing albumin aqueous solution with the concentration of 5% (w/w) by adopting 160-240mg of human albumin and water for injection,
3) and (3) under the action of a high-pressure homogenizer, adjusting the pressure to 500bar, injecting the indocyanine green solution into the albumin aqueous solution, emulsifying for 4min, and carrying out centrifugal ultrafiltration and washing for three times to obtain the indocyanine green albumin-coated nano photothermal preparation.
The invention also discloses a nano photothermal preparation prepared by the method.
The invention also comprises the application of the nano photothermal preparation in preparing a reagent for temperature photoacoustic imaging.
The invention also provides a reagent for temperature photoacoustic imaging, which comprises the nano photothermal preparation.
The invention also provides a human tumor phantom which comprises the nano photothermal preparation, carbon powder and a coagulant.
Specifically, the coagulating agent is agar.
Specifically, the nano photothermal preparation can be prepared into a solution, and the solution is uniformly mixed with carbon powder and a coagulant to prepare the human tumor mimic.
The human tumor phantom provided by the invention can be used for photo-thermal treatment simulation experiments.
The invention also provides a photoacoustic ultrasonic temperature multi-modal imaging system, comprising: the system comprises a laser, a coupling light path, an annular light-emitting optical fiber, an ultrasonic transducer, image acquisition and processing equipment, an upper computer and a lower computer;
the laser can emit pulse laser, the pulse laser enters the annular light-emitting optical fiber through the coupling optical path, the pulse laser emitted from the annular light-emitting optical fiber excites human tissues to generate ultrasonic signals, and meanwhile, the laser energy changes the temperature of the human tissues; the change in temperature causes a change in an ultrasonic signal that is captured by the ultrasonic transducer; transmitting the ultrasonic signals to the image acquisition and processing equipment, and carrying out temperature pseudo-color image reconstruction work by the image acquisition and processing equipment through a photoacoustic temperature image sensitive factor extraction algorithm; and the upper computer extracts temperature information in the ultrasonic signal and continuously regulates and controls the power of the laser through a control algorithm.
Specifically, the laser is an OPO laser capable of emitting OPO laser with the wavelength of 808 nm.
Specifically, the coupling optical path comprises a diaphragm, a filter plate, an attenuation plate, a focusing lens and a coupler.
In particular, the ultrasound transducer is a linear array ultrasound transducer.
Specifically, the image acquisition and processing device comprises a multi-channel parallel acquisition data acquisition card (hardware); and a temperature image reconstruction algorithm (software) based on the photoacoustic temperature image sensitivity factor is also installed.
Specifically, the lower computer 170 is an STM32 single chip microcomputer.
Specifically, the photoacoustic ultrasonic temperature multi-modal imaging system further comprises the nano photothermal preparation. When the photoacoustic ultrasonic temperature multi-modal imaging system is actually applied, human tissues contain the nano photothermal preparation. By introducing the nano photothermal preparation, the excitation of ultrasonic signals and the targeted heating of tumor areas can be greatly improved.
The invention also provides a temperature photoacoustic imaging and accurate control method, which comprises the following steps: enabling a laser to emit pulse laser, enabling the pulse laser to enter an annular light-emitting optical fiber through a coupling optical path, enabling the pulse laser emitted from the annular light-emitting optical fiber to excite human tissues to generate ultrasonic signals, and enabling laser energy to change the temperature of the human tissues; the change in temperature causes the ultrasonic signal to change, which is captured by the ultrasonic transducer; transmitting the ultrasonic signals to image acquisition and processing equipment, and carrying out temperature pseudo-color image reconstruction work by the image acquisition and processing equipment through a photoacoustic temperature image sensitive factor extraction algorithm; and the upper computer extracts the temperature information in the ultrasonic signal and continuously regulates and controls the power of the laser through a control algorithm.
Specifically, the temperature photoacoustic imaging and accurate control method can be realized by adopting the photoacoustic ultrasonic temperature multi-mode imaging system.
Specifically, the laser emits OPO laser with the wavelength of 808 nm.
Specifically, the human tissue contains the nano photothermal preparation.
The nano photothermal preparation of the invention has the following characteristics:
1. the indocyanine green and the albumin have good biocompatibility, can be biodegraded and are discharged out of the body through normal physiological pathways.
2. After the albumin is wrapped in the indocyanine green, the light stability of the indocyanine green is improved; meanwhile, the albumin carrier has the tumor targeting capacity.
3. The photoacoustic temperature measurement adopts a non-invasive imaging mode, so that the temperature of deep tissues can be quickly and accurately detected, and the treatment effect of the nano photothermal preparation can be fed back and controlled in real time.
The invention is based on an indocyanine green albumin nano photothermal preparation, and can realize real-time, accurate and efficient deep tissue temperature imaging and accurate control by adopting a temperature photoacoustic imaging technology.
The photoacoustic ultrasonic temperature multi-modal imaging system provided by the invention contains the nano photothermal preparation, is combined by a medical instrument, is based on the indocyanine green nano photothermal preparation wrapped by albumin, and can realize real-time, accurate and efficient deep tissue temperature imaging and accurate control by adopting a photoacoustic imaging technology.
Drawings
Fig. 1 is a schematic structural diagram of a photoacoustic ultrasonic temperature multi-modal imaging system according to an embodiment of the present invention.
Fig. 2 shows the result of photoacoustic ultrasound temperature multi-modal imaging according to an embodiment of the present invention. In fig. 2, (a) photoacoustic imaging results; (b) an ultrasonic imaging result; (c) temperature imaging results; (d) ultrasound/photoacoustic multi-modal imaging results.
FIG. 3 is a temperature profile of a tumor phantom in accordance with an embodiment of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Fig. 1 shows a schematic structural diagram of a photoacoustic ultrasonic temperature multi-modal imaging system according to an embodiment of the present invention, and arrows represent signal paths.
As shown in fig. 1, the photoacoustic ultrasonic temperature multi-modality imaging system of the present embodiment includes: the system comprises a laser 110, a coupling optical path 120, an annular light-emitting optical fiber 130, an ultrasonic transducer 140, an image acquisition and processing device 150, an upper computer 160 and a lower computer 170.
In some embodiments, the laser 110 is an OPO laser.
In some embodiments, the coupling optical path 120 includes a diaphragm, a filter, an attenuator, a focusing lens, and a coupler. In some embodiments, the ultrasound transducer 140 is a linear array ultrasound transducer.
In some embodiments, the image acquisition and processing device 150 comprises a multi-channel parallel acquisition data acquisition card (hardware); and a temperature image reconstruction algorithm (software) based on the photoacoustic temperature image sensitivity factor is also installed.
In some embodiments, the lower computer 170 is an STM32 single chip microcomputer.
In some embodiments, the photoacoustic ultrasound temperature multimodal imaging system further comprises a nano-photothermal formulation of the present invention (see example 1 below).
The working process of the photoacoustic ultrasonic temperature multi-mode imaging system of the embodiment is as follows: the laser 110(OPO laser) emits pulse laser (OPO laser with wavelength of 808 nm), enters the annular light-emitting fiber 130 through the coupling optical path 120, the pulse laser emitted from the annular light-emitting fiber excites human tissue to generate ultrasonic signals, and simultaneously, the laser energy changes the temperature of the human tissue; the change in temperature causes the ultrasonic signal to change, which is captured by the ultrasonic transducer 140; the ultrasonic signal is transmitted to the image acquisition and processing device 150, and the image acquisition and processing device 150 performs temperature pseudo-color image reconstruction work through a photoacoustic temperature image sensitive factor extraction algorithm; the upper computer 160 extracts temperature information in the ultrasonic signal and continuously regulates and controls the power of the laser 110 through a control algorithm. Wherein, the human tissue contains the nano photothermal preparation of the invention, and the specific preparation method can be seen in example 1 below.
It was found that the introduction of the nano photothermal formulation of the present invention (see example 1 below) can greatly enhance the excitation of the ultrasound signal and the targeted heating of the tumor region.
EXAMPLE 1 preparation of nano photothermal formulations
1.25mg of indocyanine green is weighed and dissolved in a mixed solvent of chloroform and ethanol (the volume ratio of chloroform to ethanol is 20:1) to form a solution containing the indocyanine green, and the concentration of the solution is 0.1 mg/mL. 200mg of human serum albumin was diluted with water for injection to a 5% (w/w) albumin aqueous solution. And (3) under the action of a high-pressure homogenizer, adjusting the pressure to 500bar, injecting the indocyanine green solution into the albumin aqueous solution, emulsifying for 4min, and carrying out centrifugal ultrafiltration and water washing for three times to obtain the indocyanine green nano photothermal preparation wrapped with albumin. The particle size range of 20-400nm is detected by a Delsa (TM) Nano C particle size distribution tester.
Example 2 temperature photoacoustic imaging
The indocyanine green nano photothermal preparation coated with albumin prepared in example 1 was prepared into 540 μ g/ml aqueous solution, and 1mg of agar and 0.5mg of carbon powder were added to 0.5ml of photothermal preparation solution to prepare a human tumor phantom having a height of 10mm and a bottom diameter of 8 mm. And then preparing a pure agar imitation with the mass fraction of 2%. The human tumor mimetibody was placed 18mm below the surface of the pure agar mimetibody.
The photoacoustic ultrasonic temperature multi-mode imaging system shown in the figure 1 is adopted to carry out imaging and temperature control experiments on the phantom. The temperature at the start of the experiment was 32.8 ℃ at room temperature, and the desired temperature was 42 ℃.
In the experimental process, OPO laser with the wavelength of 808nm generated by the laser is used as a simulation body heating and photoacoustic signal excitation source, the frequency is 20Hz, the simulation body is excited by photoacoustic signals, the temperature information carried in the photoacoustic signals is extracted and analyzed by the system, and the temperature information is used as a feedback signal of the whole control system to regulate and control the power of the heating laser in real time. The system sets the desired control temperature to 42 ℃. After the start of the operation, the continuous laser was driven to heat the phantom from 21s through a constant temperature control process for 20 s. The final simulation results are shown in fig. 2 and 3, and in terms of transient performance, the phantom temperature remained stable (39.9 ℃) in the 5% error band at which the 74 th cycle reached the desired temperature over the 54 th cycle, with no overshoot. In the aspect of steady-state performance, the steady-state error of the final temperature control of the system is always within 1 ℃. Therefore, the method of temperature triggering and temperature imaging using indocyanine green albumin nanoparticles can ultimately achieve stable control of the phantom temperature and multi-modal imaging of ultrasound/photoacoustic/temperature.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. The nano photothermal preparation is characterized by comprising a shell membrane and contents, wherein the shell membrane is albumin, and the contents are indocyanine green.
2. The nano photothermal preparation according to claim 1, wherein the weight ratio of albumin to indocyanine green in the nano photothermal preparation is 200:1-1.5, and optionally 200: 1.25.
3. The nano photothermal formulation according to claim 1 or 2, wherein the nano photothermal formulation is nano spherical particles; optionally, the nanoscale spherical particles have a particle size in the range of 20-400 nm.
4. A preparation method of a nano photothermal preparation is characterized by comprising the following steps:
providing an indocyanine green solution, wherein the solvent of the indocyanine green solution is a mixed solution of chloroform and ethanol;
providing an aqueous albumin solution;
injecting the indocyanine green solution into the albumin aqueous solution, homogenizing under high pressure, and emulsifying; and (4) centrifugal ultrafiltration washing.
5. The method according to claim 4, wherein the pressure for the high-pressure homogenization is 250-700bar, optionally 500 bar; and/or the presence of a gas in the gas,
the emulsifying time is 2-10min, optionally 4 min.
6. A human tumor mimic, which comprises the nano photothermal preparation, carbon powder and a coagulant according to any one of claims 1 to 3; optionally, the coagulating agent is agar.
7. Use of a nano-photothermal formulation according to any of claims 1-3 for the preparation of a reagent for temperature photoacoustic imaging.
8. A photoacoustic ultrasound temperature multimodal imaging system, comprising: the system comprises a laser, a coupling light path, an annular light-emitting optical fiber, an ultrasonic transducer, image acquisition and processing equipment, an upper computer and a lower computer;
the laser can emit pulse laser, the pulse laser enters the annular light-emitting optical fiber through the coupling optical path, the pulse laser emitted from the annular light-emitting optical fiber excites human tissues to generate ultrasonic signals, and meanwhile, the laser energy changes the temperature of the human tissues; the change in temperature causes a change in an ultrasonic signal that is captured by the ultrasonic transducer; transmitting the ultrasonic signals to the image acquisition and processing equipment, and carrying out temperature pseudo-color image reconstruction work by the image acquisition and processing equipment through a photoacoustic temperature image sensitive factor extraction algorithm; the upper computer extracts temperature information in the ultrasonic signal and continuously regulates and controls the power of the laser through a control algorithm;
preferably, the photoacoustic ultrasound temperature multimodal imaging system further comprises the nano-photothermal formulation of any one of claims 1-3.
9. The photoacoustic ultrasound temperature multi-modal imaging system of claim 8, wherein the laser is an OPO laser capable of emitting OPO laser light having a wavelength of 808 nm; and/or the presence of a gas in the gas,
the coupling optical path comprises a diaphragm, a filter plate, an attenuation plate, a focusing lens and a coupler; and/or the presence of a gas in the gas,
the ultrasonic transducer is a linear array ultrasonic transducer.
10. A temperature photoacoustic imaging and precise control method is characterized by comprising the following steps: enabling a laser to emit pulse laser, enabling the pulse laser to enter an annular light-emitting optical fiber through a coupling optical path, enabling the pulse laser emitted from the annular light-emitting optical fiber to excite human tissues to generate ultrasonic signals, and enabling laser energy to change the temperature of the human tissues; the change in temperature causes the ultrasonic signal to change, which is captured by the ultrasonic transducer; transmitting the ultrasonic signals to image acquisition and processing equipment, and carrying out temperature pseudo-color image reconstruction work by the image acquisition and processing equipment through a photoacoustic temperature image sensitive factor extraction algorithm; the upper computer extracts temperature information in the ultrasonic signal and continuously regulates and controls the power of the laser through a control algorithm; the human tissue contains a photothermal preparation comprising the nanoparticles of any one of claims 1-3;
optionally, the laser emits OPO laser with wavelength of 808 nm.
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