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

Finite element simulations: computations and applications to aerodynamics and biomedicine.

171 p.Las ecuaciones en derivadas parciales describen muchos fenómenos de interés práctico y sus solucionessuelen necesitar correr simulaciones muy costosas en clústers de cálculo.En el ámbito de los flujos turbulentos, en particular, el coste de las simulaciones es demasiado grande sise utilizan métodos básicos, por eso es necesario modelizar el sistema.Esta tesis doctoral trata principalmente de dos temas en Cálculo Científico.Por un lado, estudiamos nuevos desarrollos en la modelización y simulación de flujos turbulentos;utilizamos un Método de Elementos Finitos adaptativo y un modelo de ¿número de Reynolds infinito¿para reducir el coste computacional de simulaciones que, sin estas modificaciones, serían demasiadocostosas.De esta manera conseguimos lograr simulaciones evolutivas de flujos turbulentos con número deReynolds muy grande, lo cual se considera uno de los mayores retos en aerodinámica.El otro pilar de esta tesis es una aplicación biomédica.Desarrollamos un modelo computacional de Ablación (Cardiaca) por Radiofrecuencia, una terapiacomún para tratar varias enfermedades, por ejemplo algunas arritmias.Nuestro modelo mejora los modelos existentes en varias maneras, y en particular en tratar de obteneruna aproximación fiel de la geometría del sistema, lo cual se descubre ser crítico para simularcorrectamente la física del fenómeno

Real-time modelling and visualization of soft tissue thermomechanical behaviour for radiofrequency thermal ablation

A review of current literature indicates a limited knowledge and documentation of thermomechanical response of soft tissue during Minimally Invasive Surgical (MIS) hyperthermia procedures such as Radiofrequency Thermal Ablation (RFA). Furthermore, current models and simulations have not accounted for the temperature-dependence of the stress-strain behaviour of soft tissue. The only quantified data for temperature-dependent stress-strain relationships in literature is yielded from Xu and Lu (2009) and Xu, Seffen and Lu (2008a). As well as this, hardware-accelerated (by use of Graphics Processing Units (GPUs)) heat transfer simulations of RFA had not been documented prior to commencement of this project, and the first conference paper announcing this achievement was published in April of 2014 following research and implementation by NE Scientific LLC. A computational three-dimensional (3D) simulated virtual model of liver tissue is developed to establish temperature distributions resulting from single point temperature sources in emulation of the RFA heat treatment procedure. The temperature distribution in the virtual tissue domain is produced by Finite Element (FEM) spatial discretization and Finite Difference (FDM) temporal discretization of the Pennes bioheat transfer equation. The modelled temperature distribution is utilized to determine the degree of transient thermal damage to the virtual tissue based on the Arrhenius Burn Integration. Furthermore, the temperature distribution is used in conjunction with linear thermal expansion to model thermal strains and thermal stresses within the virtual tissue, resulting from the heat source. Novel work is undertaken in producing a thermal stress profile of virtual liver tissue under operational temperatures based on temperature-dependent material stress-strain. The simulation of tissue bioheat transfer and thermal damage is developed in C++ and the High-Level Shader Language (HLSL) with Microsoft’s Direct3D11 Application Programming Interface (API), where the numerical solution process is parallelized and accelerated in performance upon an NVIDIA GTX 770M GPU far beyond its performance upon a single thread/core of an Intel® Core™ i7-4700MQ Central Processing Unit (CPU). A maximum mesh resolution is determined for producing visual real-time post-processing output data based on the GPU accelerated simulation performance. A commercial FEM software package (LISA) is used for determining thermal strain and thermal stress distributions from the temperature distribution data. Examination of simulation results when comparing tissue thermomechanical response for temperature-independent and temperature-dependent stress-strain relationships indicates a dramatic difference in magnitude and distribution of the thermally-induced stresses within the soft tissue. The implications are that RFA simulations must account for this stress-strain temperature-dependence in order to produce remotely accurate stress and strain distributions (both thermomechanical and mechanical) due to the behavioural response of the collagenous biological soft tissue. Furthermore, GPU acceleration is highly recommended for RFA simulation, as the visual real-time maximum mesh resolution far surpasses that of real-time performed on a single modern CPU core

Computational Models and Experimentation for Radiofrequency-based Ablative Techniques

Las técnicas ablativas basadas en energía por radiofrecuencia (RF) se emplean con el fin de lograr un calentamiento seguro y localizado en el tejido biológico. En los últimos años ha habido un rápido crecimiento en el número de nuevos procedimientos médicos que hacen uso de dichas técnicas, lo cual ha ido acompañado de la aparición de nuevos diseños de electrodos y protocolos de aplicación de energía. Sin embargo, existen todavía muchas incógnitas sobre el verdadero comportamiento electro-térmico de los aplicadores de energía, así como de la interacción energía-tejido en aplicaciones concretas. El principal propósito de esta Tesis Doctoral es adquirir un mejor conocimiento de los fenómenos eléctricos y térmicos involucrados en los procesos de calentamiento de tejidos biológicos mediante corrientes de RF. Esto permitirá, por un lado, mejorar la eficacia y seguridad de las técnicas actualmente empleadas en la clínica en campos tan diferentes como la cirugía cardiaca, oncológica o dermatológica; y por otro, sugerir mejoras tecnológicas para el diseño de nuevos aplicadores. La Tesis Doctoral combina dos metodologías ampliamente utilizadas en el campo de la Ingeniería Biomédica, como son el modelado computacional (matemático) y la experimentación (ex vivo e in vivo). En cuanto al área cardiaca, la investigación se ha centrado, por una parte, en mejorar la ablación intraoperatoria de la fibrilación auricular por aproximación epicárdica, es decir, susceptible de ser realizada de forma mínimamente invasiva. Para ello, se ha estudiado mediante modelos matemáticos un sistema de medida de la impedancia epicárdica como método de valoración de la cantidad de grasa previo a la ablación. Por otra parte, se ha estudiado cómo mejorar la ablación de la pared ventricular por aproximación endocárdica-endocárdica (septo interventricular) y endocárdica-epicárdica (pared libre del ventrículo). Con este objetivo, se han comparado mediante modelado por computador la eficacia de los modos de ablación bipolar y unipolar en términos de la transmuralidad de la lesión en la pared ventricular. En lo que respecta al área de cirugía oncológica, la investigación se ha centrado en la resección hepática asistida por RF. Las técnicas de calentamiento por RF deberían ser capaces de minimizar el sangrado intraoperatorio y sellar vasos y ductos mediante la creación de una necrosis coagulativa por calentamiento. Si este calentamiento se produce en las cercanías de grandes vasos, existe un problema potencial de daño a la pared de dicho vaso. En este sentido, se ha evaluado con modelos matemáticos y experimentación in vivo si el efecto del flujo de sangre dentro de un gran vaso es capaz de proteger térmicamente su pared cuando se realiza una resección asistida por RF en sus cercanías. Además, se ha realizado un estudio computacional y experimental ex vivo e in vivo del comportamiento electro-térmico de aplicadores de RF bipolares internamente refrigerados, puesto que representan una opción más segura frente a los monopolares en la medida en que las corrientes de RF fluyen casi exclusivamente por el tejido biológico situado entre ambos electrodos. Respecto al área dermatológica, la investigación se ha centrado en mejorar el tratamiento de enfermedades o desórdenes del tejido subcutáneo (tales como lipomatosis, lipedema, enfermedad de Madelung y celulitis) mediante el estudio teórico de la dosimetría correcta en cada caso. Para ello, se han evaluado los efectos eléctricos, térmicos y termo-elásticos de dos estructuras diferentes de tejido subcutáneo durante el calentamiento por RF, y se ha cuantificado el daño térmico producido en ambas estructuras tras dicho calentamientoGonzález Suárez, A. (2014). Computational Models and Experimentation for Radiofrequency-based Ablative Techniques [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/36502TESI

Pacing with restoration of respiratory sinus arrhythmia improved cardiac contractility and the left ventricular output: a translational study

Introduction: Respiratory sinus arrhythmia (RSA) is a prognostic value for patients with heart failure and is defined as a beat-to-beat variation of the timing between the heart beats. Patients with heart failure or patients with permanent cardiac pacing might benefit from restoration of RSA. The aim of this translational, proof-of-principle study was to evaluate the effect of pacing with or without restored RSAon parameters of LV cardiac contractility and the cardiac output

Interrogating the Viscoelastic Properties of Tissue Using Viscoelastic Response (VisR) Ultrasound

Affecting approximately 1 in 3,500 newborn males, Duchenne muscular dystrophy (DMD) is one of the most common lethal genetic disorders in humans. Boys with DMD suffer progressive loss of muscle strength and function, leading to wheelchair dependence, cardiac and respiratory compromise, and death during young adulthood. There are currently no treatments that can halt or reverse the disease progression, and translating prospective treatments into clinical trials has been delayed by inadequate outcome measures. Current outcome measures, such as functional and muscle strength assessments, lack sensitivity to individual muscles, require subjective effort of the child, and are impacted by normal childhood growth and development. The goal of this research is to develop Viscoelastic Response (VisR) ultrasound which can be used to delineate compositional changes in muscle associated with DMD. In VisR, acoustic radiation force (ARF) is used to produce small, localized displacements within the muscle. Using conventional ultrasound to track the motion, the displacement response of the tissue can be evaluated against a mechanical model. In order to develop signal processing techniques and assess mechanical models, finite element method simulations are used to model the response of a viscoelastic material to ARF excitations. Results are then presented demonstrating VisR differentiation of viscoelastic changes with progressive dystrophic degeneration in a dog model of DMD. Finally, clinical feasibility of VisR imaging is demonstrated in two boys with DMD.Doctor of Philosoph

Psr1p interacts with SUN/sad1p and EB1/mal3p to establish the bipolar spindle

Regular Abstracts - Sunday Poster Presentations: no. 382During mitosis, interpolar microtubules from two spindle pole bodies (SPBs) interdigitate to create an antiparallel microtubule array for accommodating numerous regulatory proteins. Among these proteins, the kinesin-5 cut7p/Eg5 is the key player responsible for sliding apart antiparallel microtubules and thus helps in establishing the bipolar spindle. At the onset of mitosis, two SPBs are adjacent to one another with most microtubules running nearly parallel toward the nuclear envelope, creating an unfavorable microtubule configuration for the kinesin-5 kinesins. Therefore, how the cell organizes the antiparallel microtubule array in the first place at mitotic onset remains enigmatic. Here, we show that a novel protein psrp1p localizes to the SPB and plays a key role in organizing the antiparallel microtubule array. The absence of psr1+ leads to a transient monopolar spindle and massive chromosome loss. Further functional characterization demonstrates that psr1p is recruited to the SPB through interaction with the conserved SUN protein sad1p and that psr1p physically interacts with the conserved microtubule plus tip protein mal3p/EB1. These results suggest a model that psr1p serves as a linking protein between sad1p/SUN and mal3p/EB1 to allow microtubule plus ends to be coupled to the SPBs for organization of an antiparallel microtubule array. Thus, we conclude that psr1p is involved in organizing the antiparallel microtubule array in the first place at mitosis onset by interaction with SUN/sad1p and EB1/mal3p, thereby establishing the bipolar spindle.postprin