High-Frequency Rapid B-Mode Ultrasound Imaging for Real-Time Monitoring of Lesion Formation and Gas Body Activity During High-Intensity Focused Ultrasound Ablation

Abstract: The goal of this study was to examine the ability of high-frame-rate, high-resolution imaging to monitor tissue necrosis and gas-body activities formed during high-intensity focused ultrasound (HIFU) application. Ex vivo porcine cardiac tissue specimens (n = 24) were treated with HIFU exposure (4.33 MHz, 77 to 130 Hz pulse repetition frequency (PRF), 25 to 50% duty cycle, 0.2 to 1 s, 2600 W/cm2). RF data from Bmode ultrasound imaging were obtained before, during, and after HIFU exposure at a frame rate ranging from 77 to 130 Hz using an ultrasound imaging system with a center frequency of 55 MHz. The time history of changes in the integrated backscatter (IBS), calibrated spectral parameters, and echo-decorrelation parameters of the RF data were assessed for lesion identification by comparison against gross sections. Temporal maximum IBS with +12 dB threshold achieved the best identification with a receiver-operating characteristic (ROC) curve area of 0.96. Frame-to-frame echo decorrelation identified and tracked transient gas-body activities. Macroscopic (millimetersized) cavities formed when the estimated initial expansion rate of gas bodies (rate of expansion in lateral-to-beam direction) crossed 0.8 mm/s. Together, these assessments provide a method for monitoring spatiotemporal evolution of lesion and gas-body activity and for predicting macroscopic cavity formation

Monitoring Focal Laser Ablation of Prostate Cancer with Interstitial Thermal and Optical Probes

Prostate cancer is diagnosed in almost 200,000 men in the U.S. annually. With approximately 30,000 deaths, the mortality to incidence ratio is relatively low in comparison to other common cancers. Moreover, the primary treatment modalities, radical prostatectomy and radiation therapy, are associated with a substantial reduction in quality of life. Consequently, there is a growing interest in focal therapy which aims to treat the target tumor while minimizing damage to surrounding tissue.Focal laser ablation (FLA) is a form of focal therapy in which a laser fiber is inserted into a target tumor and oncologic control is achieved through thermally induced coagulative necrosis. Many groups have performed FLA using magnetic resonance imaging (MRI) for laser fiber targeting and real-time feedback. While this approach has shown promise, we contend that the resource intensive nature of MRI will forever preclude widespread adoption of FLA.This thesis presents a concerted effort to translate FLA from the MRI suite to the urology clinic. To this end we performed a clinical trial using magnetic resonance – ultrasound fusion guidance and interstitial thermal probes for treatment targeting and monitoring respectively. This approach proved to be safe and potentially effective; however, the utility of thermal probes was found to be inherently limited due to the need for empirically derived thermal damage models.In an effort to provide an improved monitoring modality we developed an interstitial optical monitoring system that directly assesses the state of tissue based on laser-tissue interaction. To correlate the optical signal and the growth of the coagulation zone we created a tissue mimicking phantom which simulates the thermal and optical response of prostatic tissue and facilitates visualization of the coagulation zone on MRI. FLA was performed in the phantom under MRI surveillance with simultaneous interstitial optical monitoring resulting in the development of a real-time feedback algorithm. The algorithm was subsequently tested in ex vivo bovine tissue and was capable of identifying the coagulation border with a mean absolute error of 0.3�0.1mm. Further work is necessary to demonstrate the utility of interstitial optical monitoring in vivo

Interstitial laser photocoagulation as a treatment for breast cancer

Conservative surgery is a safe alternative to mastectomy for some patients with breast cancer. A survey of surgeons in this thesis has shown that more surgeons would now undertake conservative surgery than they have done in the past. Recently a new technique, interstitial laser photocoagulation(ILP) has been described which is capable of in situ tissue necrosis with safe healing. The idea of ILP takes the concept of conservative surgery for breast cancer a step further. The main purpose of this thesis was to investigate the potential value of ILP as a future method of destroying breast cancers in situ leaving the area to heal via resorption and fibrosis. The aims of this thesis were to study the biology of laser interactions with breast cancers scheduled for surgery(and not to completely destroy the tumour), to optimise the laser parameters of power and exposure for a particular tumour and to find an imaging technique which will accurately predict the extent of laser damage. Forty five patients were treated with ILP prior to surgery(median 7 days). Tumour necrosis varied from 2-25mm. No laser damage was noted in 4 patients. Two patients developed minor complications and treatment was abandoned early due to pain in a further 4 patients. The presence of charring within the tumour was associated with larger diameters of necrosis than when charring was absent(median 13 vs 6 mm, p=0.002) and use of a precharred fibre produced similar lesions(median 14mm) which were more predictable.The histological features in the tumour following ILP were of coagulative necrosis which appeared to heal by the formation of fibrous tissue. An area of heat fixed, morphologically preserved tissue was noted within the zone of coagulative necrosis which was thought to be non-viable. Ultrasonography, Com puterised Tomography(CT) and M agnetic Resonace Imaging(MRI) were all used to monitor necrosis. Ultrasound was unable to predict the extent of necrosis as measured in the resected specimen(r=0.3, p=N.S.) but was reasonable at predicting tumour size(r=0.6, p=0.001). CT and MRI show some promise but were only investigated in small numbers of patients. This study has shown that ILP is simple and safe and when using a pre-charred fibre, predictable. If the initial results of imaging using CT and MRI are confirmed in larger studies then ILP could possibly have a role in the treatment of small breast cancers

Spectral Ultrasound Characterization of Tissues and Tissue Engineered Constructs.

Even though ultrasound imaging is widely used in clinical diagnosis and image-guided interventions, the field is far behind other areas of clinical quantitative image analysis, such as MRI, CT and X-ray mammography. In this thesis, non-destructive and non-invasive ultrasound characterization techniques were developed to study the tissue micro-structural details using high frequency spectral ultrasound imaging (SUSI). The techniques were explored in in-vitro conditions of acellular and cellular tissue engineered constructs and then on ex-vivo tissues for their characterization. SUSI was used to assess the amount of hydroxyl-apatite (HA) mineral, differentiate HA mineral types and study their distribution in acellular tissue engineered constructs. The process of mineral deposition from surrounding mineralizing media onto simple collagen constructs was also studied and characterized with SUSI. 3D morphological changes of the constructs with MC3t3 cells was monitored and characterized for the developmental changes such as net cell proliferation/apoptosis and cell differentiation process through mineral production by the early osteoblastic MC3t3-cell constructs in-situ. A novel method was introduced using SUSI to estimate the amount of mineral secreted by the differentiated osteoblast cells in a non-destructive method. Then, SUSI was investigated in ex-vivo cardiac tissues to monitor and characterize the cellular changes during high-intensity focused ultrasound ablation with high-frame-rate and high-resolution ultrasound imaging. The mechanistic hypotheses behind the improvement in lesion detection were investigated and best identification methods to assess lesion formation and transient gas body activities were proposed to provide a method for visualizing spatiotemporal evolution of lesion and gas–body activity and for predicting macroscopic cavity formation upon its implementation as a real-time monitoring technique with feedback control system for HIFU treatment of atrial fibrillation to improve the ablation process. Even though the results from the developed techniques show great promise in in-vitro and ex-vivo settings, additional work needs to be carried out to demonstrate the applicability of the techniques in in-vivo.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/99788/1/msreddy_1.pd

METHODOLOGY FOR RESEARCH AND DEVELOPMENT OF NOVEL MEDICAL DEVICES FOR MINIMALLY INVASIVE INTERVENTIONS

The design of innovative medical device requires extensive and hard efforts to reach good results in terms of safety, efficacy and cost effectiveness. First of all the idea has to be set and a wide search of state of the art, both technological and academic, has to be developed. Then the materials, manufacturing processes and design constraints have to be understood. In this work three examples of innovative surgical devices for minimally invasive surgery and assistance have been presented. The Muneretto Beam catheter is a new device for atrial defibrillation. Starting from a catheter produced by Estech company for the treatment of atrial fibrillation by ablating cardiac tissue during surgery, a system for the magnetic guidance of the same has been implemented. Thanks to finite element analysis of various configurations of magnets and to several in vitro tests, a final configuration which allows a good balance between the sliding of the catheter on the tissues and the magnetic interaction and adhesion to tissues has been found. Further attention has been taken to the development of the cover and the right configuration and method of use of the device. The VideoDrain system is a new catheter for the monitoring of post-operative wound. After critical surgical procedures it is necessary to monitor the status of the surgical wound for avoiding second look surgical interventions. Therefore a new balloon catheter for allowing the vision of the abdominal cavity has been produced. Several in vitro and in vivo trials have been conducted and the device is at the pre-industrial stage. The FloSeal GI cath. is a new device for the gastrointestinal release of an haemostatic substance of the Baxter company: the Floseal thrombin matrix. It consists in a balloon catheter suited for the use in the lower and upper gastrointestinal tract in the occurrence of bleedings during endoscopic procedures. This device has been CE labelled and is now on the market. All the devices described in this work come from ideas of surgeons leader in innovation in the field of minimally invasive interventions. Their collaboration has been fundamental for the several phases of design and tests of the devices. This Ph.D. thesis is divided into five chapters. In the Introduction chapter the process of research and development of innovative MDs for minimally invasive surgery has been illustrated. The second chapter shows the efforts done to find a working configuration for the Muneretto Beam catheter and the subsequent first prototypes developed. The progress in the design of VideoDrain has been explained in the third chapter; the whole process goes from the idea to the animal test on prototypes and a preliminary risk analysis. The development of the Floseal GI Catheter is depicted in the fourth chapter; all the details of the materials used and tests done to ensure a CE mark have been reported. Finally, in the Conclusion chapter I have reported some lessons learned from the work in the field of MDs, as a student, researcher and engineer at close contact with the world of surgery and minimally invasive technologies. Some papers about a preliminary research activity in the field of minimally invasive surgery and robotic interventions have been also enclosed. These works have been very useful to start the understanding of the complex and amazing world of MIS

Biomechanical Assessment and Monitoring of Thermal Ablation Using Harmonic Motion Imaging for Focused Ultrasound (HMIFU)

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