Title: Biomechanical Assessment and Monitoring of Thermal Ablation Using Harmonic Motion Imaging for Focused Ultrasound (HMIFU)
Description: Cancer remains, one of the major public health problems in the United States as well as many other countries worldwide. According to the World Health Organization, cancer is currently the leading cause of death worldwide, accounting for 7.6 million deaths annually, and 25% of the annual death was due to Cancer during the year of 2011. In the long history of the cancer treatment field, many treatment options have been established up to date. Traditional procedures include surgical procedures as well as systemic therapies such as biologic therapy, chemotherapy, hormone therapy, and radiation therapy. Nevertheless, side-effects are often associated with such procedures due to the systemic delivery across the entire body. Recently technologies have been focused on localized therapy under minimally or noninvasive procedure with imaging-guidance, such as cryoablation, laser ablation, radio‐frequency (RF) ablation, and High Intensity F-ocused Ultrasound (HIFU). HIFU is a non-invasive procedure aims to coagulate tissue thermally at a localized focal zone created with noninvasively emitting a set of focused ultrasound beams while the surrounding healthy tissues remain relatively untreated.

Harmonic Motion Imaging for Focused Ultrasound (HMIFU) is a dynamic, radiation-force-based imaging technique, which utilizes a single HIFU transducer by emitting an Amplitude-modulated (AM) beam to both thermally ablate the tumor while inducing a stable oscillatory tissue displacement at its focal zone. The oscillatory response is then estimated by a cross-correlation based motion tracking technique on the signal collected by a confocally-aligned diagnostic transducer. HMIFU addresses the most critical aspect and one of the major unmet needs of HIFU treatment, which is the ability to perform real-time monitoring and mapping of tissue property change during the HIFU treatment. In this dissertation, both the assessment and monitoring aspects of HMIFU have been investigated fundamentally and experimentally through development of both a 1-D and 2-D based system. The performance assessment of HMIFU technique in depicting the lesion size increase as well as the lesion-to-background displacement contrast was first demonstrated using a 3D, FE-based interdisciplinary simulation framework.

Through the development of 1-D HMIFU system, a multi-parametric monitoring approach was presented where presented where the focal HMI displacement, phase shift (Δφ), and correlation coefficients were monitored along with thermocouple and PCD under the HIFU treatment sequence with boiling and slow denaturation. For HIFU treatments with slow denaturation, consistent displacement increase-then-decrease trend was observed, indicating tissue softening-then-stiffening and phase shift increased with treatment time in agreement with mechanical testing outcomes. The correlation coefficient remained high throughout the entire treatment time under a minimized broadband energy and boiling mechanism. Contrarily, both displacement and phase shift changes lacked consistency under HIFU treatment sequences with boiling due to the presence of strong boiling mechanism confirmed by both PCD and thermocouple monitoring. In order to facilitate its clinical translation, a fully-integrated, clinically 2D real-time HMIFU system was also developed, which is capable of providing 2D real-time streaming during HIFU treatment up to 15 Hz without interruption.

Reproducibility studies of the system showed consistent displacement estimation on tissue-mimicking phantoms as well as monitoring of tissue-softening-then-stiffening phase change across 16 out of 19 liver specimens (Increasing rate in phase shift (Δφ): 0.73±0.69 %/s, Decreasing rate in phase shift (Δφ): 0.60±0.19 %/s) along with thermocouple monitoring (Increasing: 0.84±1.15 %/ °C, Decreasing: 2.03± 0.93%/ °C) and validation of tissue stiffening using mechanical testing. In addition, the 2-D HMIFU system feasibility on preclinical pancreatic tumor mice model was also demonstrated in vivo, where HMI displacement decreases were observed across three of five treatment locations on the kP(f)c model at 20.8±6.84, 18.6±1.46, and 24.0±5.43%, as well as across four of the seven treatment locations on the KPC model at 39.5±2.98%, 34.5±21.5%, 16.0±3.05%, and 35.0±3.12% along with H and E histological confirmation. In order to improve the quantitative monitoring aspect of HMIFU, a novel, model-independent method for the estimating Young's modulus based on strain profile was also implemented, where 1-D HMIFU system showed feasibilities on polyacrylamide phantom (EHMI/E ≈ 2.3) and liver specimen (EHMI/E ≈ 8.1), and 2-D HMIFU system showed feasibilities on copolymer phantom(EHMI/E ≈ 30.4), liver specimen(EHMI/E ≈ 211.3), as well as HIFU treated liver specimen (EHMI,end/EHMI,beginning ≈ 5.96).

In conclusion, the outcomes from the aforementioned studies successfully showed the feasibility of both HMIFU systems in multi-parametric monitoring of HIFU treatment with slow denaturation and boiling, which prepares its stage towards clinical translation.