KR101991263B1 - Smart tissue mimicking phantom for visulaizing ultrasonic thermal effect - Google Patents

Abstract

TECHNICAL FIELD The present invention relates to a smart tissue phantom for visualizing the thermal effect of ultrasound, and is a transparent gel having acoustic and heat transfer characteristics similar to biological tissue. And a smart tissue phantom that can be used repeatedly to visualize the thermal effect of an ultrasonic wave including NiS (non-ionic surfactant) whose light transmittance is changed by reversible clouding phenomenon depending on the temperature. Measuring a temperature-opacity characteristic curve of the phantom, the transparency of the phantom according to the temperature being represented by a gray scale change; Collecting a thermal image that is visualized as a difference in transparency within the phantom by the thermal effect of the irradiated ultrasonic waves; A method of measuring a temperature distribution formed in a phantom according to an ultrasonic wave irradiation from the thermal image using a temperature-transparency characteristic curve of the phantom, a method of measuring a temperature distribution of a non-ionic surfactant (NiS) Type and amount of addition; Or a method of controlling the kind and amount of the electrolyte to be added.

Description

[0002] Smart tissue mimicking phantom for visulaizing ultrasonic thermal effect,

The present invention relates to a smart tissue phantom for visualizing the thermal effect of ultrasound and a method for measuring the temperature distribution within the phantom using the same.

The ultrasonic wave is a sound wave which can not be heard because it is above the limit frequency that can be heard by the human ear and has a small wavelength and strong directivity and is widely used for medical diagnosis and treatment purposes.

Irradiation of the ultrasound can elevate the tissue temperature and induce a thermal effect that leads to increased blood flow, induction of inflammatory reactions, increased permeability of the biomembrane, and physiological response of increased metabolism. Hyperthermia and HIFU (High intensity focused ultrasound) are treatments for the treatment of cancer using the thermal effect of ultrasound. Hyperthermia is a method of treating cancer with heat at 40-45 ° C. HIFU is a high-temperature heat treatment (over 50 ° C) that causes non-invasive ultrasound to selectively focus on tumor sites in the body to induce thermal necrosis, unlike conventional surgical procedures. The HIFU device is driven to cause a rapid temperature rise above 70 ° C to obtain a local thermal necrosis effect on the cancer tissue. Thermal lesions formed in the tissues due to HIFU exposure correspond to sites of HIFU cancer surgery.

To confirm the safety and clinical effectiveness of the patient in such ultrasound thermal therapy, it is important to perform a routine quality assurance (QA) test as to whether the device produces thermal lesions. It is difficult to observe thermal lesions in visually opaque organisms. In order to guarantee the therapeutic effect and safety of the therapeutic using ultrasound thermal effect, a phantom capable of visualizing the thermal effect of ultrasound on a thermal lesion that is transparent at room temperature and has sound and heat transfer characteristics similar to that of a living tissue (TM) need. Existing phantoms developed for this purpose include protein based phantom, isopropyl acrylamide (NIPA) phantom.

Protein-based phantom is used by many researchers to study the thermal effects of ultrasound on living tissue. This phantom is a phantom constructed by adding protein (bovine serum albumin or egg white) as a temperature sensitive material to visualize HIFU-induced thermal lesions in visually clear polyacrylamide gels at room temperature. When the phantom is irradiated with HIFU, it is possible to visually observe a thermal lesion in which the phantom is turned opaque white in the local region due to the denaturation of the protein, and it is usefully used in research for understanding the correlation between the HIFU condition and the thermal lesion.

However, the protein phantom has many drawbacks. First, denaturation of proteins is irreversible to temperature. Therefore, the once used phantom can not be reused because the thermal lesion caused by thermal denaturation remains in the phantom permanently. Second, the critical temperature at which protein denaturation begins (~ 70 ° C) is fixed. Therefore, visualization through the phantom is possible only for conditions exceeding this temperature. If thermal therapy is considered, the thermal effect of ultrasound should maintain a temperature around 42-45 ° C, which can not be assessed using protein-based phantoms.

Fourth, the acoustic and thermal characteristics of the existing protein - based phantom are significantly different from those of living tissue. For example, the damping coefficient was much smaller (about 60%) than the tissue, and ultrasound was not scattered unlike tissue. Important nonlinear parameters (B / A) in nonlinear fields such as HIFU are different from organization.

Fifth, the protein is expensive, and once it is denatured, it is difficult to reuse it, resulting in low economic efficiency. For reference, the isopropyl acrylamide required to make a 50 ml phantom is about $ 10. The isopropyl acrylamide (NIPA) phantom is patented in the United States as a transparent tissue similar to a gel consisting of a mixture of isopropyl acrylamide, a temperature sensitive polymer (Tian Y, Ye F, US patent, 2009 , the application number being PCT / CN2009 / 000161). Transparent isopropylacrylamide phantom at room temperature is turned white when the temperature rises and is transparent again when the heat disappears, so it can be used repeatedly. The temperature at which the transparency changes can be controlled depending on the selection and content of the material within a limited range. However, the isopropyl acrylamide phantom has the following disadvantages. First, the acrylamide component must be changed to control the temperature range at which the transparency changes. This will also change the phantom's acoustical properties (eg, the attenuation coefficient of the ultrasound), so that the phantom maintains acoustical similarity to tissue It is difficult. Second, in fact, it has not been verified whether the acoustical and thermal properties are similar to those of living tissue. The acoustic and acoustic impedances of isopropylacrylamide phantoms are similar to those of tissue, but the main acoustic properties attenuation, dispersion, nonlinear parameter, and thermal properties are not evaluated. Third, isopropylacrylamide, which is a major component of Phantom, is as expensive as protein BSA. For example, the amount of isopropylacrylamide required to make a 50 ml phantom is about $ 20. Fifth, the preparation process of the profile acrylamide phantom is complicated, and it takes a long time to manufacture a single phantom (48 hours), the conditions for preparing the nitrogen gas are special, a special environment must be created, and a skilled engineer is needed . Therefore, the feasibility is low.

In order to overcome the problems of the conventional phantom, the present inventors have used a non-ionic surfactant (NiS) that exhibits a reversible temperature clouding phenomenon as a material that reacts with temperature, Nonionic surfactant (NiS) biotissue phantom, which has similar characteristics to those of living tissues, is reusable, and has excellent economic properties.

PCT / CN2009 / 000161

An object of the present invention is to provide a transparent gel having acoustic and heat transfer characteristics similar to biological tissue; And a smart tissue phantom for visualizing the thermal effect of ultrasonic waves by mixing NiS (non-ionic surfactant) with the change of light transmittance according to temperature.

Another object of the present invention is to provide a transparent gel having a similar acoustical property and heat transfer characteristic to a living tissue; The changes in light transmittance depending on temperature include non-ionic surfactant (NiS); And a smart tissue phantom that visualizes the thermal effect of the ultrasonic waves including an electrolyte.

It is another object of the present invention to provide a method for measuring the temperature distribution in the phantom by ultrasonic irradiation using the phantom of the present invention.

Another object of the present invention is to provide a non-ionic surfactant (NiS) (Ti) and a clouding termination temperature (Te) in the phantom according to the present invention, comprising the step of controlling the type and the amount of the electrolyte.

In order to achieve the above object, the present invention provides a method of visualizing the thermal effect of ultrasound mixed with a transparent gel having a similar acoustical property and heat transfer characteristic to a living tissue, and a non-ionic surfactant (NiS) Smart organization phantom.

In one embodiment of the present invention, the transparent gel may be a polyacrylamide hydrogel (PHG).

In one embodiment of the present invention, the apparatus may further include a glass bead as an ultrasonic scattering member.

In one embodiment of the present invention, it is desirable to maintain the homogeneity and elasticity of the transparent gel, to increase the attenuation coefficient of the ultrasonic wave, to prevent the deterioration of the light transmittance of the phantom at room temperature so that the solubility of the electrolyte can be maintained high during the polymerization process. Polysaccharides, which may be used in the present invention.

In one embodiment of the present invention, the NiS may exhibit a reversible hysterical clouding depending on the temperature in the temperature interval (Ti to Te) .

The present invention also relates to a transparent gel having a similar acoustical property and heat transfer characteristic to a living tissue; The changes in light transmittance depending on temperature include non-ionic surfactant (NiS); And a smart tissue phantom that visualizes the thermal effect of an ultrasonic wave including an electrolyte.

In one embodiment of the present invention, when KI or NI containing iodine is used as the electrolyte, the lower the concentration of the electrolyte, the lower the temperature at which the clouding starts.

In one embodiment of the present invention, when NaF, NaCl or NaBr containing chloride, bromide or fluoride is used as the electrolyte, the lower the concentration of the electrolyte, the more the clouding occurs. The starting temperature Ti may increase.

Further, according to the present invention,

Measuring a temperature-opacity characteristic curve of the phantom, the transparency of the phantom according to the temperature being represented by a gray scale change; Collecting a thermal image that is visualized as a difference in transparency within a phantom in a temperature range (Te) terminated from a temperature (Ti) by a thermal effect by ultrasonic irradiation; And a temperature distribution formed in the phantom according to the ultrasonic irradiation from the thermal image using the temperature-opacity characteristic curve of the phantom.

In an embodiment of the present invention, the range of the temperature Te to be terminated from the temperature Ti at which the clouding is started may vary depending on the kind or content of the non-ionic surfactant NiS.

In one embodiment of the present invention, the electrolyte can control the temperature (Ti) at which the clouding begins for the same type and the same amount of NiS (non-ionic surfactant).

In one embodiment of the present invention, the clouding of the NiS formed by raising the temperature in the phantom by ultrasonic irradiation may be reversible and hysterical in which the temperature of the NiS is restored transparently when the temperature of the phantom is lowered.

The present invention also relates to a method for producing a non-ionic surfactant, (Ti) and a termination temperature (Te) in the phantom according to the present invention, including the step of adjusting the type and the amount of the electrolyte.

In one embodiment of the present invention, when KI or NI containing iodine is used as the electrolyte, the lower the concentration of the electrolyte, the lower the temperature at which the clouding starts.

In one embodiment of the present invention, when NaF, NaCl or NaBr containing chloride, bromide or fluoride is used as the electrolyte, the lower the concentration of the electrolyte, the more the clouding occurs. The starting temperature Ti may increase.

The smart tissue phantom capable of visualizing the thermal effect of the ultrasonic wave according to the present invention is a polymerized to mix a non-ionic surfactant (NiS) and an electrolyte in a transparent gel, And the change rate of the light transmittance according to the temperature in the phantom can be easily changed by changing the type and content of NiS or the electrolyte. Since the light transmittance of the phantom has a reversible characteristic according to the temperature change, the phantom can be repeatedly used and is very economical because it uses NiS or an electrolyte which is an ultra low-cost material as compared with the conventional phantom. The smart tissue phantom of the present invention can be used as a tool for evaluating medical ultrasound performance utilizing the thermal effect of ultrasonic waves and for evaluating the stability of therapeutic ultrasound such as HIFU surgery.

Figure 1 illustrates a temperature-light transmission measurement system of a phantom with transparency varying with temperature.
FIG. 2 shows an experimental apparatus for visualizing thermal lesions by HIFU using a nonionic surfactant NiS phantom of the present invention and acquiring them as video images.
FIG. 3 shows the result of measurement of temperature-light transmittance according to NiS concentration for an NiS (NP14 series) aqueous solution. Transparency or transparency was converted to 8-bit grayscale (0 to 255) pixels in the phantom video image and quantified as a value.
Figure 4 shows the temperature-photoperiodicity of the NiS phantom (TM PAG) - (1) NiS solution, (2) a NiS phantom without a polysaccharide (PAG) (Hereinafter referred to as " NiS structure phantom of the present invention ") was heated and cooled (NiS is NP14 series).
FIG. 5 shows the result of measuring the temperature-to-light-transparency according to the concentration of the nonionic surfactant (NiS) for the NiS structure phantom of the present invention (corresponding to TM PAG in FIG. 4).
6 is a graph showing attenuation coefficients according to ultrasonic waves in the NiS tissue phantom and liver tissue of the present invention. This data represents the mean ± standard deviation from five repeated measurements of the same sample (NiS uses the NP14 series).
FIG. 7 is a graph showing the results of measurement of the backscattering factor according to the frequency for the NiS tissue phantom of the present invention. The data points and the error bars indicate the mean and standard deviation, respectively. Lt; RTI ID = 0.0 >
FIG. 8 shows a temperature-optical impermeability curve according to a change in the concentration (% in w / v) of the electrolyte (KI) contained in the NiS structure phantom of the present invention (heating: solid line cooling: dotted line).
FIG. 9 shows the definition of the characteristic parameter of the hysteresis curve showing the optical transparency according to the temperature change when heating and cooling the NiS structure phantom of the present invention.
FIG. 10 is a graph comparing images of thermal lesions formed in a phantom according to electrolyte concentration when the NiS tissue phantom of the present invention including an electrolyte for 10 seconds at the same HIFU intensity was irradiated.

Hereinafter, the present invention will be described in detail.

The present invention relates to a smart tissue phantom capable of visualizing the thermal effect of ultrasound, and more particularly, to a smart tissue phantom having a transparent gel having a similar acoustical property and heat transfer characteristic to a living tissue; And a change in light transmittance according to temperature, is characterized by providing a smart tissue phantom that exhibits the thermal effect of ultrasonic waves, including a non-ionic surfactant (NiS).

The present invention also relates to a transparent gel having a similar acoustical property and heat transfer characteristic to a living tissue;

The changes in light transmittance depending on temperature include non-ionic surfactant (NiS); And a smart tissue phantom for visualizing the thermal effect of the ultrasonic waves, including an electrolyte.

The phantom provided in the present invention is for evaluating the performance of an ultrasonic diagnostic apparatus. Unlike the conventional phantom, the thermal distribution or thermal change of the phantom by ultrasonic waves is visualized, and the temperature change (or distribution) There is a feature that can measure accurately.

In the present invention, the transparent gel, which is one of the components of the tissue phantom capable of visualizing the thermal effect of the ultrasonic wave, is used to make the phantom have the same acoustic and heat transfer characteristics as the living tissue. It can be adjusted by varying the concentration of the components of the transparent gel used.

The transparent gel usable in the present invention is preferably polyacrylamide hydrogel (PHG).

In addition, the non-ionic surfactant (NiS), which is one of the other components of the phantom according to the present invention, has a characteristic of varying light transmittance according to temperature, that is, it has a characteristic of clouding at a specific temperature interval, It is characterized by inducing the clouding effect on the transparent gel and visualizing the thermal change by ultrasonic irradiation.

In addition, the NiS (non-ionic surfactant) of the present invention increases the temperature of the phantom structure due to the thermal effect of ultrasonic waves, and when the temperature starts to reach the starting point Ti where NiS is crowded, the clouding effect And reaches the temperature Te at the time when the clouding is terminated, and the opaque phantom becomes transparent again after the temperature is lowered again. Such NiS can change the temperature range of Ti to Te depending on the kind and content to be used, and even if the same type of NiS is used, the temperature range of Ti to Te can be changed according to the content of use.

For example, in the case of NiS used in the present invention, the opacity continuously increases up to a certain temperature in proportion to the temperature. This is because as the temperature increases, the number of micelles (that is, agglomerates) . Conversely, when the temperature falls, the number and size of the micelles decrease, and the opacity again returns to transparency.

Also, as the concentration of NiS used increases, the difference in opacity depending on the temperature increases. That is, as the concentration of NiS increases, the density of the micelles increases and the interaction between them increases so that the phase transition occurs at a lower temperature So the temperature of Ti decreases while Te does not change. Thus, the range of temperatures at which clouding occurs is widened. The mechanism of clouding (or phase transition) by NiS is schematically shown as follows.

In addition, in the present invention, the use of NiS (non-ionic surfactant) has the effect of widening the temperature range of Ti to Te. Therefore, it is easy to obtain a thermal image by clouding according to the temperature change.

The non-ionic surfactant (NiS) that can be used in the present invention can be used as long as it is used and sold in the market, and the following non-limiting examples can be used.

More specifically, there are two mechanisms for controlling the change in the critical temperature (Ti) at which the clouding starts due to the use of the electrolyte. First, when the electrolyte is added, positive ions are surrounded by the oxygen terminal, The negative (-) ion is surrounded by the terminal positive (+) hydrogen of the water molecule (H ₂ O). The negative (-) ion does not retain hydrogen bonds with other water molecules, but makes hydrogen bonds with ether groups of other nonionic surfactants, increasing the starting point of the clouding (see the figure below).

In other mechanisms, the addition of an electrolyte increases the size of the ion and decreases the density of the ion, reducing the affinity for water. However, electrolytes, such as KI, are considered to be the destructors of the water structure, but mixing such KI with NiS will increase the number of Nis bonded molecules between water molecules and increase the starting point of the clouding (see the figure below).

Therefore, in the present invention, when KI or NI containing iodine is used as the electrolyte, Ti, which is the starting temperature for clouding, can be lowered as the concentration of the electrolyte is lower, and chloride as the electrolyte, If NaF, NaCl or NaBr containing bromide or fluoride is used, the lower the concentration of the electrolyte, the higher the starting temperature for clouding, Ti.

In addition, the phantom according to the present invention may further include a glass bead, which is an ultrasonic scattering glass. The phantom according to the present invention may further include a glass bead to maintain the homogeneity and elasticity of the transparent gel and to increase the attenuation coefficient of the ultrasonic wave and maintain the solubility of the electrolyte at room temperature And may further include polysaccharides that prevent deterioration of the light transmittance of the phantom.

In particular, in the present invention, the use of the polysaccharide increases the hydrophilicity, promotes the polymerisation, and increases the hydrogen bonding, thereby lowering the phase transition temperature.

There are four main reasons for the attenuation of ultrasonic waves due to the use of polysaccharides. The first is viscous friction. That is, the viscous effect is the main cause of the viscous liquid absorption in the gel. Attenuation due to viscous friction is molecular scale and is related to changing acoustic energy to heat due to internal friction. Viscous friction also becomes the main mode of reduction at frequencies above 1 MHz. For example, in a polysaccharide corn syrup solution, corn starch acts like an absorbent particle, and fluctuations in the density of the material along the measuring line cause signal changes and energy loss in the profile. The velocity of the particles can vary depending on the surrounding inertia effect. Also, due to the difference in density of the phantom material, the acoustic impedance of the material can be very diverse, affecting the passage of material under supersonic conditions, It happens.

The second is chemicla relaxation. Absorption is due to the energy exchange between molecules, which is related to polysaccharides (polysaccharides) and their concentration. The relaxation process of ions is related to decoupling - recombination of ions due to pressure oscillation by the propagation of sound waves. This phenomenon is due to the association with water, carbon and oxygen molecules in polysaccharides for hydration of molecules in solution.

The third is structural relaxation, a structural relaxation due to the combination of liquids such as water, acrylamide (gel components) and polysaccharides. These molecules have very strong intermolecular forces, so if the viscous liquid with the same viscosity as the polysaccharide is mixed with a liquid of low viscosity such as water or gel (acrylamide), the presence of water weakens the lattice structure which is the cause of the high viscosity of the polysaccharide . Thus, α / f ² decreases at first but cross - linking of polysaccharide and polymer increases with increasing polysaccharide concentration.

Fourth is thermal relaxation, which can be predicted by taking into account the interaction between the internal structure of the molecule and the internal oscillation and the isometric relaxation.

For the above reasons, the polysaccharide used in the present invention plays the role of increasing the damping coefficient of the ultrasonic wave.

Further, the present invention can provide a method of measuring a temperature distribution in a phantom by ultrasonic irradiation using the phantom of the present invention, wherein the method comprises: irradiating the phantom of the present invention with ultrasound; Measuring a temperature (Te) at which the clouding is terminated from a temperature (Ti) at which clouding of the Nis begins by ultrasonic irradiation; Collecting a visible light transmittance thermal image in a range from a temperature Ti at which the clouding is started to an ending temperature Te and graphing the correlation between the light transmittance and the temperature.

Also, the range of the temperature (Te) at which the clouding starts from the temperature Ti may vary depending on the kind or content of NiS (non-ionic surfactant), and the electrolyte may be the same kind and the same amount of NiS the temperature (Ti) at which the clouding is initiated can be controlled.

In addition, the clouding of NiS formed by raising the temperature in the phantom by ultrasonic irradiation has a reversible characteristic in which, when the temperature of the phantom is lowered, it is restored transparently again.

In addition, the present invention relates to a non-ionic surfactant (NiS) (Ti) and a clouding termination temperature (Te) range in the phantom of the present invention, including the step of adjusting the type and the amount of the electrolyte.

As described above, the phantom provided in the present invention can easily and accurately measure the temperature distribution in the phantom by visualizing the thermal effect by the ultrasonic wave. Therefore, the performance evaluation of the medical ultrasound apparatus utilizing the thermal effect of the ultrasonic wave, And can be used as a tool for testing therapeutic ultrasound.

Hereinafter, the present invention will be described in detail with reference to examples. However, these examples are intended to further illustrate the present invention, and the scope of the present invention is not limited to these examples.

< Example  1>

ultrasonic wave Thermal effect  Visualization Phantom's temperature-light transmission measurement system

The present inventors used a tissue-like phantom similar to soft tissue and acoustic characteristics to measure the heat transmitted to the soft tissues of the strong focused ultrasound, and manufactured by the methods of Examples 1 and 2. The temperature- 1.

The phantom of the present invention visualizes the thermal effect of ultrasound by adding a temperature sensitive material (TSA) that changes in light transmittance in a specific temperature range by a clouding effect to a transparent gel having a similar thermal structure to a living tissue and acoustical characteristics. , The range of Ti to Te was broadened by using TSA as a non-ionic surfactant (NiS) having a reversible clouding effect according to heating and cooling. In addition, the component polysaccharide ratio of the polyacrylamide hydrogel (PHG) was modified so that the biocompatibility and acoustic and heat transfer characteristics were similar, and ultrasonic scattering glass beads were added. In the phantom of the present invention described above, the opacity according to temperature was measured in terms of gray scale pixel value of an optical image photographed with an infrared camera (CCD camera).

A phantom sample of 35 x 35 x 12 mm was immersed in a heated water tube heated with a heating plate (PC-420D, Corning, Chelmsford Street, Lowell MA, USA). The temperature of the phantom sample was monitored by a thermocouple of the needle type (HYP 2-EG-48-RP, E type, diameter 0.5 mm, accuracy ± 0.1 ° C Omega, Stamford, The thermocouple was injected near the center of the sample. The thermocouple data can be monitored with a monitor, and the optical image of the PAG sample was measured every 5 seconds as the sample temperature increased, which is stored in the computer.

< Example  2>

Phantom's temperature-to-light measurement

FIG. 2 is a graph showing the relative optical opacity with an 8-bit gray scale (0 to 255) according to the temperature of the drug varying the concentration of NP-14 to 1 to 5% (w / v).

As a result, it was found that the difference in opacity according to temperature increased as the concentration of Nis increased (see FIG. 3).

The temperature - photoperiodicity of the phantom was measured by dividing into (1) tissue imitated PAG phantom (PAG + Polysaccharides + NiS) (2) PAG (PAG + NiS) Compared to the conventional phantom PAG, the phantom of the present invention was found to have a low cloud point by adding a nonionic surfactant (see FIG. 4). The reason is that the cloud point of the nonionic surfactant is highly dependent on the presence of carbon and ethylene oxide groups in the solution or gel, and the property of the hydrophobic part of the charged surfactant lowers the CMC. As the number of carbon atoms in the hydrocarbon chain increases, more carbon atoms increase the surfactant repellency and in this process the CMC shifts to lower values (Mukherjee et al, 2011). The homology of the polymer at the same concentration is more effective in lowering the cloud point with a larger molecular weight.

Finally, in order to examine the temperature-photoperiod permeability according to the NiS concentration of the NiS structure phantom of the present invention, NiS (NP14 series) was treated at a concentration of 1 to 4% , And when cooled, is indicated by a solid line.

As a result, the cloud point decreased in a concentration-dependent manner of the nonionic surfactant (NiS) (see FIG. 5). These results are due to the increase in the density of the micelles. When the number of micelles increases, the interactions between the micelles increase and the phase separation occurs at a lower temperature.

< Example  3>

According to the invention NiS  Manufacturing Method of Tissue Phantom 1

The inventors of the present invention prepared a 50 ml polyacrylamide hydrogel containing a nonionic surfactant (NiS) at a concentration of 4 w / v%, and the compositions and contents therein are shown in Table 2 below. The phantom manufacturing process of the present invention is as follows.

First, a mixture of 4% (w / v) of NP-14 (IC Chemicals, Jeonnam, Korea) and 40% (w / v) of polysaccharide (corn syrup-Chungjungwon, Daesang Corporation, Dongdaemun- Korea) was mixed with distilled water, and the solution was gently agitated until NP-14 and polysaccharide were dissolved in distilled water. A solution of 40% (w / v) acrylamide (A9926, Sigma Chemicals, St Louis, MO, USA) was added to the solution thus obtained and the acrylamide had an acrylamide / bis monomer crosslinking ratio of 19: 1 , And 17.5% (v / v) of water.

Sodium azide, a preservative, was added to the mixture, and ammonium persulfate solution (APS, A7460 Sigma Chemicals, St Louis, MO, USA) was added and the solution was homogenized by gentle stirring. The entire solution was placed in a vacuum chamber (OV-01/02, Jeio Tech, Seoul, Republic of Korea) and vacuumed at 760 mmHg for 60 minutes or more. Several glass beads were added to the solution, So that the glass beads were uniformly dispersed. Finally, the rate of free radical formation from persulfuric acid was accelerated by the addition of a polymerisation solution of N, N, N ', N'-tetramethyl / diamine (TEMED, T2694 Sigma Chemicals, St Louis, MO, USA) The persulfate free radical converts the acrylamide monomer to a free radical and reacts with the inactivated monomer to initiate the polymer chain reaction, which in turn catalyzes the polymer and replenishes 100 ml of degassed water with a deionization machine. The solution obtained in the above procedure is immediately transferred to a vessel and further reaction is carried out at room temperature (25 ° C.) for 20 minutes until the polymerization is completed. The resulting gel phantom was placed in a container and stored at room temperature.

< Example  4>

Method for manufacturing NiS structure phantom 2 according to the present invention

The inventors of the present invention further added an electrolyte to finely adjust the widths of Ti and Ti to Te compared to the phantom manufactured in Example 1. In the present invention, potassium iodide (KI) was added as an electrolyte I put it.

The compositions and contents of Phantom 2 prepared according to the present invention are shown in Table 3 below. Specific methods are as follows.

First, a mixture of 4% (w / v) of NP-14 (IC Chemicals, Jeonnam, Korea) and 40% (w / v) of polysaccharide (corn syrup-Chungjungwon, Daesang Corporation, Dongdaemun- Korea) was mixed with distilled water, and the solution was gently agitated until NP-14 and polysaccharide were dissolved in distilled water. A solution of 40% (w / v) acrylamide (A9926, Sigma Chemicals, St Louis, MO, USA) was added to the solution thus obtained and the acrylamide had an acrylamide / bis monomer crosslinking ratio of 19: 1 , And 17.5% (v / v) of water. Add sodium persulfate, sodium persulfate, and ammonium persulfate solution (APS, A7460 Sigma Chemicals, St. Louis, Mo., USA) into the thermostat and add the electrolyte (potassium iodide, KI) The solution was then homogenized by gentle stirring.

The entire solution was placed in a vacuum chamber (OV-01/02, Jeio Tech, Seoul, Republic of Korea) and vacuumed at 760 mmHg for 60 minutes or more. Several glass beads were added to the solution, So that the glass beads were uniformly dispersed. Finally, the rate of free radical formation from persulfuric acid was accelerated by the addition of a polymerisation solution of N, N, N ', N'-tetramethyl / diamine (TEMED, T2694 Sigma Chemicals, St Louis, MO, USA) The persulfate free radical converts the acrylamide monomer to a free radical and reacts with the inactivated monomer to initiate the polymer chain reaction, which in turn catalyzes the polymer and replenishes 100 ml of degassed water with a deionization machine. The solution obtained in the above procedure is immediately transferred to a vessel and further reaction is carried out at room temperature (25 ° C.) for 20 minutes until the polymerization is completed. The resulting gel phantom was placed in a container and stored at room temperature.

< Experimental Example  1>

The NiS  Acoustic and heat transfer characteristics of tissue phantoms

<1-1> Acoustic characteristics

The tissue mimic phantom of the present invention has an acoustic velocity of 1,595 (± 8) m / s, an acoustic impedance of 1.68 Mrayls, a damping coefficient of 0.49 (± 0.07) dB / cm at 1 MHz, 0.23 ± 0.015 × 10 ^-3 The backscattering coefficient of cm ^-1 sr ^-1 and the nonlinear parameter (B / A) of 6.3 ± 0.2 at room temperature (~ 22 ° C) are shown. Each of the above measured values was found to be very close to the range of values measured in human liver tissue (suitable for use in measuring or calculating potential biological effects of ultrasound devices). All the acoustic parameters measured in the NiS tissue phantom of the present invention are shown in Table 4 below.

<1-2> Decay curve

The attenuation coefficients of the NiS tissue phantom and biological liver of the present invention measured over the 1-5 MHz frequency range are shown in FIG. As shown in FIG. 6, the NiS tissue phantom of the present invention has a damping coefficient very similar to that of liver tissue. It can be seen that the damping coefficient of the NiS tissue phantom of the present invention increases almost linearly with frequency (frequency) as in liver tissue. On the other hand, as the frequency increases, the gap between the NiS structure phantom and the liver tissue of the present invention becomes larger due to the difference in the damping coefficient. Nevertheless, the NiS tissue phantom of the present invention has a damping coefficient of about 0.54 +/- 0.04 dB / cm at a frequency of 1 MHz (typical frequency used in HIFU surgery), which is very close to normal liver tissue.

<1-3> Backward scattering coefficient

7 is a graph showing the backscattering coefficient in the frequency range of 1 to 5 MHz of the NiS tissue phantom of the present invention. To the rear is a scattering coefficient, and with respect to the frequency increases in a nonlinear fashion, which similar to the liver tissue, be the back scattering coefficient of the tissue phantom NiS of the invention 0.00172 (± 0.00012) cm ^-1 sr at 5 MHz ^{- 1,} and which Fei et al. (1985) compared to 0.00178 cm ^-1 sr ^-1 of the bovine liver. Backward scattering coefficient of the liver tissue is at 3MHz 0.5x10 ^-3 cm ^-1 sr ^{- 1} and from ^{1 MHz 0.27x0 -3 cm -1 sr -} 1 and 0.614 ± 0.009x10 ^-3 cm NiS tissue phantom of the present invention is the 3MHz ^-1 sr ^{- 1} , measured at 0.21 +/- 10 ^-3 cm ^-1 sr ^-1 at 1 MHz, and found to be similar.

<1-4> Thermal properties

The thermal parameters measured for the NiS tissue phantom of the present invention are shown in Table 4 together with the liver tissue. Referring to Table 4, it can be seen that the measured values are very similar to liver tissue. Thus, it can be seen that the NiS tissue phantom of the present invention can withstand a temperature of 95 ° C or higher without being melted, which means that HIFU (High-intensity focused ultrasound) can be applied.

&Lt; 1-5 > NiS  Electrolyte added to tissue phantom ( KI ) Temperature-optically opaque curve with concentration variation

As shown in Figs. 8 (a) to 8 (f), the volume of the tissue-mimicking phantom of the present invention at a clouding temperature, that is, a critical temperature, It was confirmed that the slope changes in various ranges within the range. During focused ultrasound radiation, the focal region of the integrated ultrasound in the tissue-mimicking phantom changes from transparent (colorless) to opaque (white) at a temperature of 50 ° C to 90 ° C due to the absorption of ultrasound As the integrated ultrasound emission ceased, the temperature of the integrated ultrasound dropped below the cloud point, and the opaque phase was gradually restored to a transparent phase.

Such a critical temperature can be relatively easily changed by changing the ratio of the electrolyte. As shown in Figs. 8 (a) to (f), the concentration of KI as an electrolyte is changed from 0 to 5% , 52-90 ° C, 55-90 ° C, 61-90 ° C, 64-90 ° C and 67-90 ° C) with a slope of 7.34, 7.98, 8.58, 9.42 and 10.7.

The measured values of the characteristic parameters of the slope for opacity and transparency of the tissue mimetic phantom of the present invention having 0% -5% electrolyte are also shown in Table 6 below. The clouding onset temperature shT increased from 52 to 67 with an isthmus of about 3 as the electrolyte concentration KI in the phantom decreased from 0% to 5% (w / v).

The threshold temperature of the tissue-mimicking phantom of the present invention with 0% -5% electrolyte shows a shift of about 3, which causes hysteresis. On the other hand, a phantom containing 5% electrolyte compared to a phantom containing 0% electrolyte has a large clouding slope. In other words, the opacification process occurs more rapidly in the phantom containing 5% electrolyte compared to the phantom containing 0% electrolyte. The tissue mimic phantom of the present invention containing 5% electrolyte appeared to have the largest slope and showed a clouding slope of 10.7 gs / C and a clearing slope of 8.82 g / C in detail. It can be seen that this slope decreases gradually as the electrolyte concentration decreases from 5% to 0%.

In addition, the meaning of each parameter in the drawing is as follows.

), JND-just noticeable difference hS: Clouding slope (

), JND-just noticeable difference

), JND-just noticeable difference cS: Clearing slope (

), JND-just noticeable difference

hTs: Clouding start temperature

hTe: Closing termination temperature

hTR (= hTs-hTe): temperature range to be crowned

cTs: Clearing start temperature

cTs Clearing end temperature

cTR (= cTs-cTe): temperature range to be cleared

)C: lesion contrast (

)

Xmin: minimum clouding temperature (X = Xmin: transparent)

Xmax: Maximum clouding temperature (X = Xmax: opaque)

XR (Xmax-Xmin): Optical transparent range

parameter unit KI-0% KI-1% KI-2% KI-3% KI-4% KI-5% Clouding
(heating) _hTs 52 55 58 61 64 68 _hTe 85 86 86 86 86 88 _hTR 33 31 28 26 22 20 _hS gs / 5.6 7.34 7.98 8.58 9.42 10.7 Clearing
(cooling) _cTs 90 93 92 92 92 93 _cTe 59 63 65 68 70 71 _cTR 31 30 27 24 22 22 _cS gs / 5.4 7.63 7.84 8.38 8.44 8.82 Optical transparency _Xmin gs 20 0 0 0 0 0 _Xmax gs 199 202 202 202 202 200 _{Xmax - Xmin} gs 179 202 202 202 202 200 _C % 76.2 79.2 79.2 79.2 79.2 78.4

< Experimental Example  2>

The NiS  Visible to the organizational phantom HIFU Thermal lesions by thermal lesion ) Imaging

The optical image of the thermal lesion formed in the NiS tissue phantom of the present invention by focused ultrasound therapy (HIFU) was tested. For this, an experimental HIFU system and an optical image capturing unit configuration were used in this experiment (see FIG. 2).

Experimental HIFU systems used a concave piezoelectric-ceramic transducer (sonic cincepts, Woodinville Inc, WA, USA) with an aperture diameter of 64 mm and a focal point single configuration resonated at 1.1 MHz. This HIFU transducer was mounted inside a tank filled with water. Prior to the measurement, water was filled and deionized and degassed. The RF system generated by the function generator (Agilent 33250 A, Agilent Technologies, Santa Clara, CA) was amplified by a power amplifier (Model 250A250, Amplifier research, Souderton, PA, USA) To the HIFU converter. The forward and reflected RF power was monitored by a watt-hour meter (Model PM 20002, Amplifier research, Souderton, PA, USA) that measures voltage and current (ie, real-time averaged power in a HIFU converter). The experimental HIFU system was controlled on a computer under Lab View (National Instruments, Austin, TX, USA) environment. At 75% full gain, the acoustic emissions were controlled using the function generator output under the same conditions of the power amplifier.

A phantom sample contained in a rectangular hexahedral acrylic chamber was settled into a water tank and positioned to have a phantom center consistent with the focus of the HIFU in accordance with the two CCD cameras. The front and back sides of the acrylic chamber were opened to prevent ultrasound reflection at the surface. For the production of thermal lesions within the phantom, the HIFU system was set to operate in a continuous wave mode and the amount of ultrasound was controlled through exposure time and focus intensity. Visualized thermal lesions within the phantom were recorded in real time using a CCH camera.

As a result, a video image of thermal lesions formed in the NiS tissue phantom of the present invention containing various concentrations of electrolyte KI is shown in FIG.

Figure 10 shows a tissue mimetic phantom of the present invention exposed to a HIFU field having an exposure time of 10 seconds and a focal intensity of 4, 460 W / cm &lt; ^{2 &} gt ;. For each phantom, the frontal image is shown in the left column and the side image is shown in the right column. The HIFU transducer (not shown in the figure) was mounted on the left side of the front image and allowed to operate in continuous wave (CW) mode at a frequency of 1.1MHz.

As shown in FIG. 10, an elliptical thermal lesion in the phantom containing 5% KI as electrolyte was similar in the field of focus HIFU. The size of the thermal lesion in the tissue-mimicking phantom without the electrolyte was found to have a wider clouding region compared to the phantom containing 5% KI electrolyte. This result is due to the increased critical temperature of the phantom having a large slope as shown in Table 5 above.

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (15)

A transparent gel having a similar acoustic and heat transfer characteristics to a living tissue; And
As a smart tissue phantom, which is composed of a temperature sensitive agent (TSA) that mixes with the gel and changes the optical characteristics of the gel according to the temperature,
TSA is a non-ionic surfactant (NiS) that changes optical characteristics of a gel due to clouding phenomenon depending on temperature at a specific temperature range. A smart tissue phantom that visualizes the thermal effect of ultrasound . The method according to claim 1,
Wherein the optical properties of the gel are light transmissive. A smart tissue phantom that visualizes the thermal effect of an ultrasonic wave. 3. The method of claim 2,
Wherein the temperature (Ti) at which the clouding starts and the temperature (Te) at which the clouding starts are changed according to the type and content of the NiS. The method of claim 3,
Smart tissue phantom that visualizes the thermal effect of ultrasonic mixing electrolyte to finely control the clouding temperature interval for the same amount of NiS (non-ionic surfactant). The method according to claim 1,
Wherein the transparent gel is a polyacrylamide hydrogel (PHG). A smart tissue phantom for visualizing a thermal effect of an ultrasonic wave. The method according to claim 1,
A smart tissue phantom for visualizing the thermal effect of an ultrasonic wave, characterized by including an ultrasonic scattering body for causing a scattering effect of an ultrasonic wave. The method according to claim 1,
Polysaccharides which increase the attenuation coefficient of the ultrasonic wave while maintaining the homogeneity and elasticity of the transparent gel and prevent the deterioration of the light transmittance of the phantom at room temperature by allowing the solubility of the electrolyte to be kept high during the process of polymerizing A smart tissue phantom that visualizes the thermal effects of ultrasound. 5. The method of claim 4,
When KI or NI containing iodine is used as the electrolyte, Ti, which is the starting temperature of clouding of the NiS, is lowered as the electrolyte concentration is lower. Smart organization Phantom. 5. The method of claim 4,
When NaF, NaCl, or NaBr containing chloride, bromide, or fluoride is used as the electrolyte, Ti, which is the clouding start temperature of the NiS, increases as the concentration of the electrolyte decreases A smart tissue phantom that visualizes the thermal effect of ultrasound. 3. The method of claim 2,
When the temperature rises due to a reversible clouding effect according to the temperature, the optical opacity of the gel increases in the form of a sigmoid in the Ti-Te section. On the contrary, when the temperature is lowered, A smart tissue phantom that visualizes the thermal effect of ultrasound, characterized in that the transparency is restored hysterically. 3. The method of claim 2,
The NiS is characterized by using nonylphenyl ethoxylates (NP series) in order to change the temperature range of Te 30 to 70 ° C and Te 50 to 90 ° C in evaluating the thermal effect of medical ultrasound waves Smart Phantom to visualize the thermal effects of. Measuring a temperature-opacity characteristic curve of the phantom, the transparency of the phantom according to the temperature being represented by a gray scale change;
Collecting a thermal image that is visualized as a difference in transparency within a phantom from a temperature of Ti to a temperature of thermo-effect by ultrasonic irradiation, A method for measuring a temperature distribution formed in a phantom. Type and amount of non-ionic surfactant (NiS); Or adjusting the type of the electrolyte and the amount of the electrolyte to be added to the phantom of the first aspect of the present invention, and adjusting the range of the clouding start temperature (Ti) and the clouding end temperature (Te). 14. The method of claim 13,
Wherein when the KI or NI containing iodine is used as the electrolyte, the temperature at which the clouding starts is lowered as the concentration of the electrolyte is lowered. In the phantom according to claim 1, (Ti) and cladding termination temperature (Te). 14. The method of claim 13,
When NaF, NaCl or NaBr containing chloride, bromide, or fluoride is used as the electrolyte, the temperature at which the clouding starts is increased as the concentration of the electrolyte is lower (Ti) and the clouding termination temperature (Te) in the phantom according to claim 1,

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