JP2015181927A - Method for resonance excitation of nano bubble having high frequency resonance frequency at low frequency - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method of inducing nano bubbles having high natural vibration frequency using ultrasonic wave motion with a low frequency or an ultrasonic pulse equivalent to it.SOLUTION: A pulse with a smooth and wide waveform generating an impulse wave with time evolution or a pulse in a gauss shape whose full width at half maximum has a specific value is used as excitation external force near a nano bubble group being a target, resonance excitation of nano bubbles being a target is performed, an amount of attenuation of attenuating natural vibration obtained is measured and grasped, the resonance vibration of the nano bubbles is separated from the excitation external force pulse, only the excitation external force pulse is subjected to storage, inversion and power amplification and sent to the nano bubbles being the target. This operation is repeated.

Description

According to the present invention, nanobubbles having a high natural vibration frequency in a human body are resonantly excited with a low frequency ultrasonic wave or an ultrasonic pulse equivalent thereto to resonate at the high natural vibration frequency to promote heat generation and collapse.

  Microbubbles and nanobubbles are used as cancer echo contrast agents for ultrasound echo in medical treatment, particularly in cancer diagnosis. However, the size of the bubble is so large that it cannot enter the cancer cell, and the bubble stays around the cancer cell. The situation changes if the bubble size is less than 200 nm in radius. A bubble moves from a blood vessel to a cell by an EPR (Enhanced permeability and retention effect) effect. Various operations can be performed on the bubbles in the cell. One of them is the use of heat by resonating and generating heat from nanobubbles.

The role of nanobubbles in medicine is large and wide. However, the natural vibration frequency of nanobubbles is high. Even if the radius is 200 nm, the upper limit at which the EPR effect can occur, the natural vibration frequency is 20 MHz. However, the natural vibration frequency increases as the radius decreases, but the human body that is an ultrasonic medium increases as the frequency increases. Attenuation increases. Accordingly, when viewed from the medium of the human body, it is desirable that the ultrasonic wave passing through the body has a low frequency of 10 MHz or less. Therefore, the title of resonating nanobubbles at a high natural vibration frequency with an equivalently low frequency ultrasonic wave is born.
It is an object of the present invention to provide a method for causing resonance at a high natural vibration frequency of nanobubbles using a lower frequency ultrasonic wave or a pulse train equivalent to a lower frequency ultrasonic wave as an external input. .

Means to solve the problem

There are two methods for resonating a nanobubble having a high natural vibration frequency with an external force of a low frequency.
One method is a method using a half-frequency of the natural vibration frequency, and the other is a method using intermittent pulses having a wide half-value width.
In the case of using the ½ sub-frequency of the natural vibration frequency, there is a slight frequency pull-in phenomenon and there is a margin, but a strict tuning operation is necessary, and the excitation frequency of the external force is ½ of the bubble natural vibration frequency. It is a condition that is not good to be limited to. FIG. 1 shows a bubble vibration waveform when the excitation frequency of the external force is accurately set to ½ of the bubble natural vibration frequency. In the figure, it can be seen that every other peak of the excitation wave overlaps the peak of the resonance waveform of the bubble. The spectrum is shown in FIG.
Another method is a method using intermittent pulses.
When intermittent pulses are used, the pulses are assumed to be Gaussian (Gaussian). In this case, if the width of the pulse is too small, the equivalent frequency becomes too high, and if the width is too large, the resonance amplitude of the nanobubble becomes small and eventually does not resonate.
Hereinafter, a case where a pulse train is used as an external force will be described.

で、Ｒ＝Ｒ（ｔ）はバブルの半径、Ｒｏは等価半径、ρは液体の密度、ｐ_ｈは静液圧、ｐ_ｖはバブル内の気圧、ｋはポリトロ−プ定数、σは表面張力、μは液体の粘性係数、Ｆ（ｔ）は外力である。
つまり、減衰定数はバブル外部の液体の粘性係数μを含んだ値できまるが、温度など粘性係数μを変える要素は多い。従って現場では、減衰定数は大巾に変化するものと見なければならない。減衰する固有振動を減衰固有振動と呼ぶことにする
従って、共振の減衰の様子を観測して、次の外部励起パルスを送るという操作が必要になる。
外力としてパルス列におけるパルスの形としてはガウシアンと、時間発展をして衝撃波になるように設計した波形がある。When nanobubbles are excited by a pulse train using an external force, the nanobubbles start to vibrate at the natural vibration frequency, but this vibration is attenuated. The attenuation constant is a coefficient of 4 μ / R for the term (dR / dt) in the Rayleigh-Plesset equation. The Rayleigh-Plesset equation is

In, R = R (t) is the radius of the bubble, Ro is the equivalent radius, [rho is the density of the liquid, p _h is Seieki圧, p _v is the air pressure in the bubble, k is Poritoro - flop constant, sigma is the surface tension , Μ is the viscosity coefficient of the liquid, and F (t) is the external force.
That is, the attenuation constant can be a value including the viscosity coefficient μ of the liquid outside the bubble, but there are many factors that change the viscosity coefficient μ such as temperature. Therefore, in the field, the attenuation constant must be viewed as changing greatly. The decaying natural vibration is called a damped natural vibration. Therefore, it is necessary to observe the state of resonance attenuation and send the next external excitation pulse.
As an external force, there are two types of pulses in the pulse train, such as Gaussian, and a waveform that is designed to evolve into a shock wave over time.

A. When using a Gaussian pulse When using a Gaussian pulse, the nanobubble resonates greatly only when the full width at half maximum of the externally excited Gaussian pulse is not less than 2.5 times and not more than 3.6 times the period of the nanobubble. . FIG. 3 shows an externally excited Gaussian pulse train having a full width at half maximum of 2.8 times the period, and FIG. 4 shows resonant vibrations of nanobubbles excited by the pulse train of FIG. The wave head in FIG. 4 is a wave head corresponding to the externally excited Gaussian pulse, followed by the vibration of the nanobubble, but the vibration is attenuated as shown.
In many cases, a Gaussian pulse is sent directly to a target nanobubble group. This is because it is practically simple. At that time, a Gaussian pulse train is used. In order to use it reasonably and efficiently, it is necessary to devise a method of observing the state of resonance attenuation as described above and sending the next external excitation pulse when the amplitude or number of periods becomes a constant value. This contrivance is one point of the present invention.

B, When using a pulse with a waveform that develops over time and becomes a shock wave near the target.
The strength of the external excitation depends on the steepness of the rise of the pulse. A steep rise is obtained with a shock wave. Therefore, although it is a smooth pulse in the middle of propagating the waveform of the excitation pulse, it is advantageous to use a pulse having a waveform that develops in the vicinity of the target nanobubble group and becomes a shock wave. It is difficult to search for such a pulse waveform. The dotted line in FIG. 5 is the product of Gauss and cosine, and the dotted waveform is one of the answers. The solid line in the figure in Burggers equation (∂u / ∂t + u (∂u / ∂x) = c (∂ 2 u / ∂x 2) · u is Fuhaba), the time development after 251 steps waveform. There is no decrease in pulse height. The determination of the pulse height is subtle. If it is too high, the attenuation of the amplitude due to time development is large, and if it is too low, no shock wave is generated.
An appropriate height Gaussian is also an answer. In the example in which a little attenuation is seen in FIG. 5A, in the example in FIG. 5B, a shock wave is first seen in about 3000 steps. The generation time of a Gaussian shock wave depends on the height and width of the pulse.
Since this method uses a shock wave, the pulse width until it becomes a shock wave is arbitrary. That is, a pulse width equivalent to a sufficiently low frequency can be obtained. Such waveforms have solutions other than the above solutions. However, the only way to convert a pulse having a general waveform including Gaussian, Gaussian, and cosine into a shock wave with time evolution at a desired time is to solve the Burggers equation, which is a nonlinear partial differential equation. Since it is not analytical, the solution can only be obtained as a numerical solution. It is necessary to use a computer together to obtain a waveform that satisfies your wishes.

When using an excitation pulse, whether it is a shock wave or not. A phase conjugate wave has many advantages. (A phase conjugate wave has a wavefront that accurately returns to the wave origin.) A phase conjugate wave is obtained by a phase conjugate mirror. A phase conjugate mirror with an amplifying function can be made with a transducer array, a storage / reversing component and an amplifier.
In the case of using a pulse having a waveform that evolves over time to become a shock wave, in the present invention, the pulse having a waveform that evolves over time to become a shock wave is reflected from the target, which is a group of nanobubbles, from the transmitting transducer. Until the transducer array that constitutes the mirror is reached, the pulse waveform is kept low and only the pulse height is lowered. Using a shaper and amplifier, the original designed pulse with a strong waveform is created, and a phase conjugate wavefront of this pulse is created to create an ideal convergence and shock wave at the target.

Effect of the invention

Heat generation and collapse due to natural vibration of nanobubbles are about to be used in the medical field.
An object of the present invention is to provide a method for inducing natural vibrations of nanobubbles.
In the medical and pharmaceutical fields, nanobubble miniaturization is desired and being implemented because of movement from blood vessels to cells due to the EPR effect.
The natural vibration frequency of the nanobubbles increases in inverse proportion to the diameter as the miniaturization proceeds. When the radius is 200 nm, the natural vibration frequency is 20 MHz. On the other hand, the frequency of the ultrasonic wave passing through the human body is 10 MHz in a shallow place. That is, the present invention has made it possible to resonantly excite nanobubbles having a high natural vibration frequency with an external force having a low frequency that can penetrate the human body.
Here, a method using 1/2 frequency division, a Gaussian pulse with a wide half-value width appropriately, and a wide pulse with a shape that becomes a shock wave in the vicinity of the target by time evolution, considering the attenuation state of the natural vibration of the nanobubble The natural vibrations of high-frequency nanobubbles that are sent intermittently at intervals are approximately sustained.
This belongs to the “implementation description”, but it is the phase conjugate mirror that sends a powerful pulse to the target in the system of the device. Therefore, it is the one-way between the phase conjugate mirror and the target that is subject to time evolution.

FIG. 1 shows a vibration waveform of a bubble when excited by a half-harmonic wave.
FIG. 2 is a spectrum of the vibration waveform of FIG.
FIG. 3 shows a pulse train of Gaussian pulses.
FIG. 4 shows the vibration of bubbles excited by the pulse train of FIG.
FIG. 5 is a comparison diagram of a specially shaped pulse and a pulse that has become a shock wave with time evolution.
FIG. 5A is a comparison diagram of a Gaussian pulse and a pulse that has become a shock wave by time evolution.
FIG. 5B shows the time evolution of a Gaussian pulse with a low wave height.
FIG. 6 is a diagram showing the vibration waveform of bubbles excited by a Gaussian pulse for explanation.
FIG. 7 shows an embodiment of the present invention.
FIG. 8 is an explanatory diagram of part of the operation of the embodiment.
FIG. 9 is a detailed view of a part of the embodiment.
FIG. 10 is a time chart of the operation of each block.

As a method of exciting and resonating nanobubbles with a high resonance frequency at a low frequency, there are three methods: a method using 1/2 frequency division, a method using a Gaussian pulse train, and a method using a shock wave. It becomes almost the same shape.
Therefore, a case where excitation is performed with an excitation pulse train will be described as an example, and a description will be given with reference to FIG. Since the operation procedure is complicated, the role of each block in FIG. 7 will be described before the description of the embodiment. When the phase conjugate mirror is not used, the related part may be deleted.

α, the role of the transducer 3 is only to receive a signal from the target. The subsequent role of the waveform observer 8 is to look at the waveform of the received signal (see FIG. 6), and to grasp when the amplitude reduction of the bubble damped vibration is smaller than a predetermined small threshold value. Counting the number of periods T from the start of bubble resonance and grasping when the count reaches a certain number. And, it is to output the D signal delayed for an arbitrary fixed time starting from one of these two time points. As described above, this work is the point of the present invention. I will rewrite it.
β, the transducer array 4 has n elements. Its role is the reception and transmission of signals.
There are n switches 5. Although it is open at the start of operation, it is closed by the F signal (denoted in γ) that comes out after the output signal of the transducer array 4 has passed. Then, it opens with the signal of the point D of the waveform observer 8. The switch is closed while the excitation pulse and subsequent bubble damped oscillations are present.
γ, there are n storage / reversal components. The storage operation starts when a signal arrives at any one of the n, and goes through a time reversal operation. The reversal operation ends when all n components have given time reversal signals. The output signal is sent to the waveform shaper 10. The F signal is output with a delay in the work end time of the storage / reversal component. This signal is also a signal indicating the passage of the excitation pulse wave tail. This γ term will be described in detail in paragraph [0013].
δ and n amplifiers 6 are also provided. The amplifier 6 is a signal amplifier with a high frequency cut filter. The high-frequency cut filter is for removing the natural vibration when the non-convergence excitation pulse excites the bubble to cause the resonance natural vibration of the bubble. The amplifier 7 is a power amplifier.
ε, the function of the excitation pulse generator is to send out a predetermined form of excitation pulse from the transducer 2 when the D signal of the waveform observer 8 comes.
ζ and the waveform shaper 10 will be described in the following text.
The above is an explanation of the role of each block.

  Move on to operation description. A time chart of the operation is shown in FIG. First, an excitation pulse having a low wave height is generated by the pulse generator 9 and sent toward the target 1 by the transducer 2. Consider the case of a Gaussian pulse that does not generate a shock wave and a pulse that becomes a shock wave with time evolution. In the case of a pulse that is changed into a shock wave by time evolution, the shock wave must not be generated except for the target location, so that the wave height needs to be low. At the time when there is no resonance of the bubble, the reflectivity of the target bubble is high (the reflectivity decreases when resonance starts). Scattered and reflected waves at the target 1 are received by the transducer array 4 made of n elements, become electrical signals, enter the storage / reversal component 11 via the switch 5 and the signal amplifier 6, and are time-reversed. The time reversal signal is shaped by a waveform shaper. In the case of Gaussian that does not expect a shock wave, the wave height is the target. However, when the shock wave is expected, the time evolution that becomes a shock wave is a one-way between the transducer array 4 and the target 1, so delicate shaping is required. . After the signal is shaped, the power is amplified, and is sent out as an excitation pulse wave having a phase conjugate wavefront by the transducer array 4, and is accurately converged at the target 1. This process is repeated. This is a loop of operation of only the excitation pulse, and is not involved in the natural vibration of the nanobubbles excited by the excitation pulse.

The transducer 3 and the waveform observer 8 have been described before, but will be described again. The transducer 3 receives all the ultrasonic signals related to the target 1 and sends them to the waveform observer 8. The waveform observer that receives the signal extracts information about the attenuation of the natural vibration of the nanobubbles. When the amplitude of the natural vibration is lower than a predetermined threshold, the A signal is output, or after the natural vibration of the nanobubble starts, the number of the natural vibration period T is started, and the C signal is output when it reaches a certain number. . Next, either the A signal or the C signal is delayed to produce and output the D signal. With the D signal, the switch 5 closed at the wave tail of the excitation pulse is opened. In short, the waveform observer 8 is for preventing a signal of the natural vibration frequency of the nanobubble having a high frequency from entering the storage / reversal component 11. The D signal commands the pulse generator 9 to produce the next excitation pulse. The excitation pulse is circulated by the above procedure, and intermittent nanobubble damped natural oscillation is induced.
The circulation process begins with a manual command causing the pulse generator 9 to create a pulse and ends with a manual command to stop the pulse generation.

In the present invention, the use of the phase conjugate mirror is special, and it is not used as a phase conjugate mirror of a general image, but only an independent pulse having a symmetric and simple form of rising and falling is used. Therefore, the number of elements of the transducer array 4 is not large. There are not many switches, amplifiers, waveform shapers and memory / reversing components connected to it. Since there are not many storage / reversal components used in the present invention and the waveform is simple, the phase conjugate mirror may be the main player in some cases. Components are abbreviated as components.

Time inversion will be described with reference to FIGS. In the present invention, only one mountain corresponding to Gaussian or a similar mountain is used, but for the sake of explanation, a schematic waveform that shows the front and back is used. When the wavefront of an ultrasonic wave that is scattered, reflected by a target nanobubble, distorted due to an inhomogeneous medium, first arrives at any one element of n transducer arrays 1 after a predetermined time delay, n When all the memory / reverse components have been stored (or), and the wave tails of all the elements 1 to n have been cleared (and), the storage is completed after a predetermined time delay. In FIG. 8, the wave front arrives at the j component first, and finally the wave front arrives at the i component. The time from the wave front of the wave of the j component to the wave tail of the wave of the i component is TD, but all the waves that arrive within this time TD are stored. Thereafter, the stored wave is reversed and read out, that is, each component is read from the wave front of the i component, and ends at the wave tail of the wave of the j component. These operations are performed by exchanging digital signals with the clock pulse organizer 12.
The inverted signal is waveform-shaped, power amplified, and sent to the transducer array as a transmitter. The waveform shaping of the waveform in anticipation of the generation of the shock wave needs to be delicate. It is written many times because the time evolution of shock wave generation occurs in one way between the transducer array and the target.

In this embodiment, the transducer arrays are arranged in a line, but a planar shape is preferable, and a spherical surface is more preferable. In this case, the number of elements is k. Further, for the purpose of explanation, the transducer 2 and the transducer 3 are illustrated separately, but actually, the role is used as it is with two elements in the transducer array.
Further, the storage / reversal method may be digital or analog, and both are known.

In some cases, a phase conjugate wave is not used as a method for exciting the nanobubble group. At that time, the transducer array 4, the switch 5, the amplifiers 6 and 7, the storage / reversing component 11 and the waveform shaper in FIG. The excitation pulse of the pulse generator 9 may be sent by the D signal command issued by the waveform observer.
When excitation is performed with a sine and cosine wave having a ½ frequency, the pulse generator 9 may be replaced with an oscillator.

1. Nanobubble group Transmitting transducer 3, receiving transducer 4, transducer array 5, switch 6, amplifier 7, power amplifier 8, waveform observer 9, pulse generator 10, waveform shaper 11, memory / reversing component 12, Clock pulse organizer 13, clock

Claims (6)

Means for generating a smooth waveform excitation pulse SP having a condition that an ultrasonic shock wave is generated by time evolution with a target nanobubble group, that is, a target G, at a distance between the transducer arrays as an excitation force of the nanobubbles The first low-wave height excitation pulse LSP is added from the first transducer to the target G, with the wave height limited to such an extent that no shock wave is generated and excitation of the nanobubble group that is the target G is not performed. A low-wave high-excitation pulse scattered and reflected by the target G is received by a transducer array consisting of k elements and time-reversed as the first electrical signal by k storage / reversal components, then waveform shaping, power amplification And an excitation pulse SP having a phase conjugate wavefront is sent from the transducer array of k elements and converged at the target G. Means for exciting a nanobubble group as a target G to cause a damped natural vibration as a shock wave, and receiving all the ultrasonic waves scattered and reflected by the target G by the second transducer and always converting it to a second electric signal. By observing the waveform of the damped natural vibration of the shock wave scattered and reflected by the target G and the nanobubble excited by the shock wave, the amplitude of the damped natural vibration is small from the time immediately before the generation of the shock wave and the damped natural vibration. Means for shutting off the input / output electric circuit of the transducer array until a virtual end point of vibration smaller than a threshold set in the value or a specific point before and after the virtual end point, and a second low wave height after the shut-off time elapses Natural vibration excitation of nanobubbles characterized in that the means for sending the excitation pulse LSP from the first transducer to the target G is repeated an integer N times Act Means for generating an excitation pulse having a smooth waveform that does not have a condition for generating an ultrasonic shock wave by time evolution, and the excitation pulse is sent from the first transducer to the target G, and is scattered and reflected by the target G. The excitation pulse is received by a transducer array composed of k elements and time-reversed as a first electric signal by k storage / reversal components, and then the waveform shaping, power amplification is performed, and the transducer composed of the k elements. A means for sending an excitation pulse having a phase conjugate wavefront from the array and converging at the target G to excite the nanobubble group which is the target G and causing a damped natural vibration, and all the ultrasonic waves scattered and reflected by the target G A shock wave that is received by the transducer and is always scattered as a second electrical signal by the target G and reflected by the target G and the nanobubbles excited by the shock wave are fixed. By observing the vibration waveform, from the time immediately before the occurrence of the excitation pulse and the damped natural vibration, the virtual end time of the vibration where the amplitude of the damped natural vibration is smaller than the threshold set to a small value, or before and after the virtual end time A means for shutting off the input / output electric circuit of the transducer array until a specific point of time, and a means for sending a second excitation pulse from the first transducer to the target G after the shut-off time has elapsed. Of natural vibration of nanobubbles characterized by A means for sending a Gaussian pulse whose half width is 2.5 times or more and 3.6 times or less of the natural vibration period of the nanobubble to the target G as the first excitation external force of the nanobubble, and is scattered and reflected by the target G All the ultrasonic waves are received by the second transducer and converted into the second electric signal, and the waveform of the damped natural vibration of the nanobubble excited by the excitation wave and the excitation wave always scattered and reflected by the target G is observed. The Gaussian pulse is used as the second excitation external force at the virtual end point of the vibration where the amplitude of the damped natural vibration is smaller than the threshold value set to a small value or at a specific time before and after the virtual end point. Nanobubble natural vibration excitation method characterized in that means for sending from transducer to target G is repeated integer N times Means for generating an excitation pulse SP having a smooth waveform having a condition that an ultrasonic shock wave is generated by time evolution at a distance between a target nanobubble group, that is, a target G and a transducer array, as an excitation force of the nanobubble. , Means for sending the first excitation pulse SP from the first transducer to the target G, and all the ultrasonic waves scattered and reflected by the target G are received by the second transducer and converted into a second electrical signal at all times. Observing the shock wave that is scattered and reflected by the target G and the waveform of the damped natural vibration of the nanobubbles excited by the shock wave, and the virtual end point of the vibration when the amplitude of the damped natural vibration is smaller than a set threshold value, Alternatively, the means for sending the second excitation pulse SP from the first transducer to the target G at a specific time before and after the virtual end time is an integer N times. Natural vibration excitation method nanobubbles, which comprises the The determination of the virtual end point of the damped natural vibration of the nanobubble in claims 1 to 4 is a point where the number of periods of the natural vibration from the start of the damped natural vibration becomes a constant value. The described method Nanobubble natural vibration excitation method characterized by continuously exciting nanobubbles of target G with sine or cosine ultrasonic waves having a frequency half the natural vibration frequency of nanobubbles

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