Open Access
Issue
Acta Acust.
Volume 6, 2022
Article Number 41
Number of page(s) 8
Section Ultrasonics
DOI https://doi.org/10.1051/aacus/2022036
Published online 23 September 2022

© The Author(s), published by EDP Sciences, 2022

Licence Creative CommonsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1 Introduction

As non-invasive, non-ionizing radiation, non-invasive treatment, high-intensity focused ultrasound (HIFU) has been widely used to treat solid tumors such as uterine fibroids [1], liver cancer [2], bone tumors [3], breast cancer [4] and pancreatic cancer [5] and is an effective complement to traditional surgery. The primary goal of HIFU treatment is to cause instantaneous coagulation and necrosis in the target tissue, which is then absorbed or scarred. HIFU treatment works via a variety of mechanisms, including thermal effect [6], cavitation effect [7, 8], mechanical effect [9], biological effect [10] and so on, with thermal effect and cavitation effect playing a significant role. Due to the complexity and uncontrollability of the mechanisms, it is critical for the demand for safe treatment to have an effective and real-time process monitoring of the thermal damage.

Several methods for monitoring in surgery are currently available, including computed tomography (CT) [11], magnetic resonance imaging (MRI) [12], and B-mode ultrasonography [13]. CT and MRI have a high degree of imaging accuracy but a limited ability to perform in real-time. Meanwhile, the operation is inconvenient, which means it is not conducive to real-time monitoring during surgery but rather to preoperative diagnosis and postoperative evaluation. Ultrasonic imaging collects and analyzes scattered echo waves generated when ultrasound penetrates tissue to characterize the difference in acoustic impedance and generate a gray-scale image. Its advantages include real-time monitoring, complete non-destructive examination, the absence of ionizing radiation, low cost, and ease of integration with treatment equipment. It is widely used in real-time monitoring of HIFU treatment.

Zhao et al. [14, 15] reported the treatment of low-power accumulation. Clinical data demonstrated clear survival benefits and a favorable safety profile in patients with malignant tumors. Among them, the high duty cycle T1/T2 990 ms/10 ms treatment scheme enables clinicians to monitor tumor tissue changes using B-ultrasound only during the treatment’s idle time, as the sound wave irradiated by HIFU will appear as strong background noise on the B-ultrasound image, resulting in low imaging accuracy and inability to meet the requirements of intraoperative real-time monitoring. On the other hand, therapeutic ultrasound does not affect B-ultrasound imaging in treatment schemes with a relatively low duty cycle T1/T2 200 ms/200 ms. It is expected to realize real-time monitoring of the treatment process.

To gain a thorough understanding of the development characteristics of target thermal damage during low-power cumulative treatment and to assess the real-time monitoring effect of B-ultrasound imaging, degassed ex-vivo bovine liver was used as an experimental sample and irradiated with a range of HIFU energies, sound powers, and irradiation durations. A 128-element 7.5 MHz linear array and a receiving transducer were used to collect B-ultrasound images and scattered echo signals, respectively. By analyzing the B-ultrasound images, reflected acoustic spectrum, and thermal damage slice, a correlation between the strong echo of B-ultrasound and the formation process of thermal damage was established. This provides an experimental basis for the effectiveness of B-ultrasound monitoring in clinical HIFU surgery.

2 Materials and methods

The experimental setup is shown in Figure 1. A confocal transducer composed of a transceiver developed by ourself is attached to the sidewall of a plexiglass transparent water tank, whose size is 220 mm × 130 mm × 130 mm. The tank was filled with degassed water within less than 0.3 mg/L gas. The degassed ex-vivo bovine liver was cut into 50 mm × 50 mm × 50 mm segments and placed in a square polycarbonate box with holes on six sides and fixed at the focus of the focusing transducer. A 7.5 MHz B-ultrasound probe (L7.5AS, S-Sharp, Taiwan, China) is placed directly above the bovine liver, parallel to the direction of the acoustic axis, and its position and posture can be adjusted using a 3-D xyz positioner.

thumbnail Figure 1

Experimental setup.

2.1 HIFU transducer and driving system

The aperture of the spherical shell transducer used for transmitting sound waves is 95 mm, with a 22 mm hole in the middle. The resonant frequency is 1.155 MHz, the geometric focal length is 150 mm, the −6dB focus size is 30 mm × 3 mm (axial × radial). Two channels arbitrary signal generator (DG5072, RIGOL, China) is used to generate excitation signal. CH1 generates a gate signal with a period of 400 ms, CH2 generates a continuous sine wave of 1.155 MHz, which is modulated by the gate signal and output to the power amplifier (AR800W, AR, USA), driving the transmitting transducer to irradiate ultrasonic wave. The working sequence is shown in Figure 2.

thumbnail Figure 2

System working sequence.

The spherical shell transducer emits a 200 ms high-intensity sound wave followed by a 30 μs detection sound wave after a 300 μs delay in a 400 ms periodic sequence. For ultrasonic echo signal acquisition and B-ultrasound imaging, the echo signal acquisition system and the B-ultrasound acquisition system are triggered simultaneously. Before the experiment began, the sound power was determined [16], as shown in Table 1.

Table 1

Sound power setting conditions.

2.2 Echo signal acquisition system

A confocal receiving transducer with an aperture of 20 mm and a geometric focal length of 150 mm is installed in the middle of the transmitting transducer. The transducer receives the echo signal, and the NI-DAQ system (PXI-5105, National Instruments, USA) samples the voltage signal at 60 MHz/8 bits. The time-domain echo signal is collected, and the variation of scattering echo with HIFU irradiation is analyzed offline using the power spectrum by LabVIEW (LabVIEW2019, National Instruments, USA).

2.3 B-ultrasound imaging method

During the HIFU irradiation process, a 128-element linear array B-ultrasound probe with a center frequency of 7.5 MHz is placed above the bovine liver and fine-tuned using a 3D xyz positioner to ensure that the B-ultrasound probe is parallel to the sound axis direction. A B-ultrasound imaging system (Prodigy256, S-Sharp, Taiwan, China) set to pulse sequence (PS), and external trigger mode collects, analyzes, displays, and stores the data. It takes approximately 200 ms to image a frame of B-ultrasound sequence that is triggered by the rising edge of the detecting sound wave’s gate signal, as shown in Figure 2. Each subarray is driven by the B-ultrasound imaging system, which transmits a phase-controlled delay signal to focus the ultrasonic wave at a predetermined depth and receives a beamformed signal to determine the gray value of a line. As illustrated in Figure 3, different subarrays are selected in this manner to obtain the entire normalized gray image.

thumbnail Figure 3

Principle of B-ultrasound imaging.

2.4 Experimental arrangement

Fresh bovine liver slaughtered within 6 h was bought from the slaughterhouse and cut into 50 mm × 50 mm × 50 mm regular shape. Homogeneous samples without thick blood vessels or fascia are selected and equally divided into three groups. Repetitive orthogonal experiments are conducted with samples being irradiated by such ultrasonic power as 100 W, 125 W, and 150 W for 10 s, 20 s, and 40 s, respectively. The ultrasonic dose is defined as power × exposure time in this paper. Low power × short exposure time is defined as low dose. In contrast, high power × long exposure time is defined as high dose. The other situation between the two is defined as medium dose. B-ultrasonic image sequence, thermal damage slice image, and the original waveform of scattering echo signal are obtained simultaneously and analyzed offline under each condition of ultrasonic dose.

3 Results

3.1 Result analysis method

The B-ultrasound system triggered by the rising edge presents images in a 400 ms cycle. The resolution of each frame image is 512 × 512. Region of interest (ROI) sequences covering the physical focal region of HIFU of 120 × 400 pixels, as shown in Figure 4a, are selected to observe the changes caused by HIFU irradiation over time.

thumbnail Figure 4

B-ultrasound image and damage slice in 125W20s case (a) B-ultrasound image, with red arrows pointing to such special tissue structure as blood vessels as spatial reference. (b) Damage slice.

As shown in Figure 4b, ex-vivo bovine liver samples are sliced, and the shape, size, and degree of thermal ablation damage are measured compared to the B-ultrasound image. The obvious temporal and spatial characteristics are observed using the specific tissue structure in the bovine liver, blood vessels for example, as a reference mark position and analyzing the relationship between B-ultrasound images and the final morphology and size of bovine liver thermal damage.

The reflected and scattered echo waveforms collected by the NI-DAQ system are shown in Figure 5. The signal components of sections ①–④ of the figure are so complex, including the direct wave irradiated by HIFU, the reflected echo of the multi-layer interface of bovine liver tissue, the scattered echo generated within the tissue, and the vibration signal caused by the radial vibration mode of the transmitting transducer, determining that they cannot be useful for power spectrum analysis. However, the signals in the figure representing segments ⑤–⑦ are pure echo ultrasonic signals. Among them, segment ⑤ represents the reflected wave on the front surface of the bovine liver. Segment ⑥ is the scatter echo caused by the internal structure change of the bovine liver, and segment ⑦ is the reflected wave on the rear surface of the water tank. Thus, the change of scatter echo ⑥ is the focus of our attention in this paper. The power spectrum of the waveform is calculated, and the variation law of the energy of the fundamental frequency component is analyzed.

thumbnail Figure 5

Reflected and scattered echo waveform (frame No. 25 in 125W20s case).

3.2 Low ultrasonic dose irradiation

On B-ultrasound images, 100 W cases with exposure times of 20 s, 30 s, and several 40 s, and 125 W cases with exposure times of 10 s exhibit no significant changes. However, as illustrated in Figure 6, the slices have obvious thermal damage in the shape of a slender jujube nucleus. As shown in Table 2, the ultrasound dose and ablation size were statistically analyzed. As a result, it can be concluded that the ablation first develops axially to the transducer side along the acoustic axis and then gradually expands radially.

thumbnail Figure 6

Thermal damage slices and B-ultrasound images (a) and (e) 100W20s, (b) and (f) 100W30s, (c) and (g) 100W40s, (d) and (h) 125W10s.

Table 2

Low dose ablation size statistics.

The changing curves of the power spectrum of the scattered echo’s 1.155 MHz fundamental frequency component are shown in Figure 7. The time-varying curve demonstrates that when the dose is low, the energy of the echo signal fluctuates gently, exhibiting a trend of periodic oscillations weakening first and then strengthening overall, but never a sudden change.

thumbnail Figure 7

Power spectrum analysis of scattered echo signal with low ultrasonic dose irradiation.

3.3 Medium and high ultrasonic dose irradiation

With low power and a long exposure time in the 100W40s case, as shown in Figure 8b, a large area of bright spots appears suddenly in frame 63 of the B-ultrasound image. It then moves relatively slowly in the direction of the transducer, reaching its maximum size at frame 110. At this point, HIFU ceases irradiation, and the bright spots gradually fade away. The ablation slice is shaped like a “tadpole”, and cavities are located in the spatial distribution’s center and rear. With an increase in ultrasonic dose, as shown in Figure 8d, slender bright spots appeared suddenly in the B-ultrasound image at frame 35, and the bright spots rapidly moved towards the transducer in the 125W20s case. At frame 52, the HIFU irradiation was stopped, and the bright spots gradually disappeared. The ablation shape is slender, and cavities are distributed evenly throughout the spatial distribution. Similarly, in the case of the 150W20s, as shown in Figure 8f, small bright spots appear on B-ultrasound in frame 14 and migrate towards the transducer while maintaining a small area. At frame 50, the HIFU irradiation is stopped, and the bright spots gradually fade away. Thermal damage is shaped like a “tadpole”, with cavities throughout the spatial distribution.

thumbnail Figure 8

Thermal damage slices and B-ultrasound images (a) and (b) 100W40s, (c) and (d) 125W20s, (e) and (f) 150W20s.

The changing curves of the power spectrum of the scattered echo’s 1.155 MHz fundamental frequency component are shown in Figure 9. It is discovered that when a medium or high ultrasonic dose is irradiated, the energy of the echo signal fluctuates gently in the preceding period, similar to the situation when a low ultrasonic dose is irradiated. However, at frame 60 of 100W40s, a sudden increase in energy occurs. Thus, as with frame 31 in the 125W20s case and frame 9 in the 150W20s case, respectively, there is a period of strong discrete fluctuation followed by a period of continuous fluctuation until the end of the exposure.

thumbnail Figure 9

Power spectrum analysis of scattered echo signal with medium and high ultrasonic dose irradiation.

The frame number Necho at which the scattered echo suddenly increases, the frame number NB of the bright spots occurrence on the B-ultrasound image, the final ablation size and the location of the damaged cavity (F-Front, M-Middle, B-Back) are analyzed statistically as Table 3. According to the analysis in low ultrasonic dose irradiation, there will be no bright spots on B-ultrasound in low ultrasonic dose cases. However, it is uncertain in low power × long expose time cases, as shown in Figure 8a, with the ablation shape of which is generally “tadpole”. Additionally, in cases of medium to high ultrasonic dose radiation, there will be obvious bright spots on B-ultrasound images.

Table 3

Medium and high dose ablation statistics.

4 Discussion

The thermal effect is a significant factor in low-dose HIFU radiation therapy. Heat is converted and deposited because of the attenuation of ex-vivo tissue on sound waves in the tissue, resulting in a temperature rise above 65 °C and the formation of permanent protein coagulation necrosis. As shown in Table 1, thermal damage develops rapidly in the axial direction early in the treatment and gradually in the radial direction later in the treatment. This treatment scheme has a lower efficiency but produces more regular “jujube nucleus” shaped thermal ablation, as illustrated in Figure 6. B-ultrasound is ineffective at monitoring the ablative area and its formation during treatment. This requires clinicians to use MRI or contrast-enhanced intraoperative ultrasound to precisely determine the ablated area’s size and precisely control the ultrasonic dose. However, the treatment will become uncontrollable if the exposure time is extended indefinitely in the low ultrasonic power case. When bright spots appear on B-ultrasound images, the resulting damage takes on the shape of a “tadpole” as illustrated in Figure 8a.

The thermal effect is dominant at the early stages of medium-dose HIFU irradiation. Cavitation will occur later, significantly increasing thermal efficiency, as illustrated in Figure 8a and 8b. While B-ultrasound can monitor the cavitation effect, it cannot monitor the thermal effect. Due to the formation of thermal damage during the early stages of treatment, the reflection of a transmitted therapeutic sound wave is enhanced, causing the thermal damage to moving toward the transducer. The temperature rise and the continuous action of high acoustic negative pressure precipitate microbubbles in the ex-vivo tissue, and cavitation occurs when the condition exceeds the cavitation threshold, significantly exacerbating the thermal effect. Simultaneously, the presence of bubble clusters alters the acoustic impedance characteristics of the local tissue, resulting in visible bright spots on B-ultrasound images. For high-dose HIFU irradiation, increasing the ultrasonic power advances both the temporal and spatial location of cavitation occurrence, as illustrated in Figure 8c–8f. Under this treatment scheme, doctors can roughly estimate the shape and size of thermal damage based on bright spots on B-ultrasound images but should keep in mind that the B-ultrasound image is a normalized gray image and thus cannot quantify the size of thermal damage precisely.

When cavitation occurs suddenly during HIFU irradiation, the scattered echo also increases immediately with a large time-varying discreteness, which can be used as important evidence of the cavitation effect. Additionally, this sudden strong oscillation occurs approximately 3–5 frames before the appearance of bright spots on B-ultrasound images, corresponding to an exposure time of 1.2–2.0 s, requiring clinicians to address the cavitation situation as soon as possible when they see bright spots on B-ultrasound images, to avoid uncontrollable terrible consequences.

After HIFU irradiation is stopped, the bright spots on the B-ultrasound images gradually darken until they vanish, as a large number of microbubbles precipitated as a result of cavitation quickly burst and vanish, demonstrating once again that the bright spots observed on the B-ultrasound images are microbubbles generated by cavitation, not thermal damage.

5 Conclusion

B-ultrasound is a critical tool for monitoring the HIFU treatment process in real-time. The following are the major conclusions drawn from this paper’s research:

First, because thermal damage is always directed toward the transducer during HIFU irradiation, clinicians should locate the initial treatment point at the back of the tumor with a certain distance from the transducer rather than in the center. Otherwise, it will lead to incomplete treatment at the bottom of the tumor. In this way, the bottom of the tumor can be ablated by thermal diffusion.

Second, B-ultrasound is ineffective at monitoring thermal ablation because the bright spots visible in B-ultrasound represent the generation of cavitation, not the thermal effect. This means that clinicians should be assisted with intraoperative B-ultrasound angiography or MRI if the size of the total thermal damaged area needs to be precisely determined to avoid terrible accidents such as thermal scald or perforation caused by overtreatment.

Third, thermal damage is primarily caused by thermal effects in low sound power situations and cavitation effects in high sound power situations. In general, for the same ultrasonic dose, the thermal efficiency by low-power × long-time treatment mode is relatively lower, but the controllability is higher, giving physicians a longer response time. On the contrary, the high-power × short-time treatment mode has a higher thermal efficiency but a lower controllability, giving clinicians less response time in the event of an emergency. Therefore, clinicians should select the most appropriate treatment mode for individual patients during clinical treatment.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgments

This work was supported by National Key R&D Program of China (Grants 2018YFC0114902).

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Cite this article as: Zhao P. Wang Y. Wu Y. Hu X. Shen H, et al. 2022. Formation process of thermal damage in a target area of high intensity focused ultrasound and effectiveness analysis of B-ultrasound real-time monitoring. Acta Acustica, 6, 41.

All Tables

Table 1

Sound power setting conditions.

Table 2

Low dose ablation size statistics.

Table 3

Medium and high dose ablation statistics.

All Figures

thumbnail Figure 1

Experimental setup.

In the text
thumbnail Figure 2

System working sequence.

In the text
thumbnail Figure 3

Principle of B-ultrasound imaging.

In the text
thumbnail Figure 4

B-ultrasound image and damage slice in 125W20s case (a) B-ultrasound image, with red arrows pointing to such special tissue structure as blood vessels as spatial reference. (b) Damage slice.

In the text
thumbnail Figure 5

Reflected and scattered echo waveform (frame No. 25 in 125W20s case).

In the text
thumbnail Figure 6

Thermal damage slices and B-ultrasound images (a) and (e) 100W20s, (b) and (f) 100W30s, (c) and (g) 100W40s, (d) and (h) 125W10s.

In the text
thumbnail Figure 7

Power spectrum analysis of scattered echo signal with low ultrasonic dose irradiation.

In the text
thumbnail Figure 8

Thermal damage slices and B-ultrasound images (a) and (b) 100W40s, (c) and (d) 125W20s, (e) and (f) 150W20s.

In the text
thumbnail Figure 9

Power spectrum analysis of scattered echo signal with medium and high ultrasonic dose irradiation.

In the text

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