HIGH INTENSITY FOCUSED ULTRASOUND AND OXYGEN LOAD NANOBUBBLES: TWO DIFFERENT APPROCHES FOR CANCER TREATMENT

The study of applications based on the use of ultrasound in medicine and biology for therapeutic purposes is under strong development at international level and joins the notoriously well-established and widespread use of diagnostic applications [1]. In the past few years, High Intensity Focused Ultrasound (HIFU) has developed from a scientific curiosity to an accepted therapeutic modality. HIFU is a non invasive technique for the treatment of various types of cancer, as well as non-malignant pathologies, by inducing localized hyperthermia that causes necrosis of the tissue. Beside HIFU technology, other innovative therapeutic modalities to treat cancer are emerging. Among them, an extremely innovative technique is represented by oxygen loaded nanobubbles (OLNs): gas cavities confined by an appropriately functionalized coating. This is an oxygenating drugs aimed at re-oxygenation of cancerous tissue. Oxygen deficiency, in fact, is the main hallmark of cancerous solid tumors and a major factor limiting the effectiveness of radiotherapy. In this work, these two approaches to treat tumours are under study from a metrological point of view. In particular, a complete characterization of an HIFU fields regarding power, pressure and temperature is provided while oxygen load nanobubbles are synthesized, characterized and applied in in vitro and in vivo experiments

IDENTIFYING AND MONITORING THE ROLES OF CAVITATION IN HEATING FROM HIGH-INTENSITY FOCUSED ULTRASOUND

For high-intensity focused ultrasound (HIFU) to continue to gain acceptance for cancer treatment it is necessary to understand how the applied ultrasound interacts with gas trapped in the tissue. The presence of bubbles in the target location have been thought to be responsible for shielding the incoming pressure and increasing local heat deposition due to the bubble dynamics. We lack adequate tools for monitoring the cavitation process, due to both limited visualization methods and understanding of the underlying physics. The goal of this project was to elucidate the role of inertial cavitation in HIFU exposures in the hope of applying noise diagnostics to monitor cavitation activity and control HIFU-induced cavitation in a beneficial manner. A number of approaches were taken to understand the relationship between inertial cavitation signals, bubble heating, and bubble shielding in agar-graphite tissue phantoms. Passive cavitation detection (PCD) techniques were employed to detect inertial bubble collapses while the temperature was monitored with an embedded thermocouple. Results indicate that the broadband noise amplitude is correlated to bubble-enhanced heating. Monitoring inertial cavitation at multiple positions throughout the focal region demonstrated that bubble activity increased prefocally as it diminished near the focus. Lowering the HIFU duty cycle had the effect of maintaining a more or less constant cavitation signal, suggesting the shielding effect diminished when the bubbles had a chance to dissolve during the HIFU off-time. Modeling the effect of increasing the ambient temperature showed that bubbles do not collapse as violently at higher temperatures due to increased vapor pressure inside the bubble. Our conclusion is that inertial cavitation heating is less effective at higher temperatures and bubble shielding is involved in shifting energy deposition at the focus. The use of a diagnostic ultrasound imaging system as a PCD array was explored. Filtering out the scattered harmonics from the received RF signals resulted in a spatially- resolved inertial cavitation signal, while the amplitude of the harmonics showed a correlation with temperatures approaching the onset of boiling. The result is a new tool for detecting a broader spectrum of bubble activity and thus enhancing HIFU treatment visualization and feedback.Gordon Center for Subsurface Sensing and Imaging Systems via NSF ERC Award Number EEC-9986821 and the U.S. Army, award number DAMD17-02-2-0014

The Effect of Ultrasonic Vibration on the Solidification of Light Alloys

This exposition presents the novel thermodynamical and microstructural modification to light alloys, such as aluminum alloys and magnesium alloys, by ultrasonic vibrations during their solidification processes. Ultrasonic vibration has proven to be effective in controlling columnar dendritic structure, reducing the size of equiaxed grains, and under some conditions, producing globular non-dendritic grains. Despite this, the solidification process under the effect of ultrasonic vibration was not clear. Not only was there no such research on how ultrasonic vibration affected its solidification thermodynamically, but also its effects on the as-cast microstructure, including the primary fcc phase, the eutectics, and the secondary phases, were not systematically studied. In addition, most studies had been empirical and phenomenological rather than quantitative. Prior to the experiments, thermodynamic simulations were carried out using the Scheil model to determine the temperature versus solid fraction curve of the alloys. The starting temperature for ultrasonic processing and the casting temperature were predetermined according to the simulation result. An experimental apparatus which supplied a powerful 1500 Watts at 20 KHz of ultrasonic power was designed and built. Thermal analysis experiments were performed. The result shows that, with ultrasonic vibration, the steady growth temperature and the minimum supercooling temperature have been elevated; while the recalescence time decreased, which indicates a much slower growth rate of primary fcc aluminum grains. The difference between dendrites nucleation/growth and thickening is not significant in the casting with ultrasonic vibration, which might suggest dendrites formation might not present in this solidification process. The mechanisms for ultrasonic influence on solidification have been discussed. Two types of ultrasonic processing techniques were developed and attempted. The first one related to introducing the vibration into the solidifying specimen through the liquid, while the second through the formally solidified part. For the first ultrasonic processing technique, the treatment was employed isothermally, intermittently, and continuously. In contrast to the fully developed dendrites up to several millimeters in length in untreated A356 alloy, fine globular primary fcc Al grains sized less than 200 mm were obtained in the specimen treated with 5 second intermittent ultrasonic vibrations. However, dendrites were not completely broken down into fine grains in the isothermally or continuously processed specimens. It may imply that there is limited effect of dendrite fragmentation on the formation of globular/non-dendrite microstructure in the acoustically processed melt, and acoustically induced heterogeneous nucleation seems to be the dominant mechanism for the formation of a globular microstructure. For the second approach, ultrasonic treatment was performed continuously. During the treatment, grain refinement reached an unprecedented level. The average grains were globular with size ranges from 20 to 40 mm. Superfine globular grains of size less than 20 mm were obtained in the area near the ultrasonic radiator. Similar grain refinement could only be reached by using a quenching method with a much faster cooling rate. The main parameters of ultrasonic processing, such as casting temperature, ultrasonic intensity, and the distance from the radiator, have been investigated. It is concluded that high acoustic amplitude/intensity favors the formation of small, spherical primary aluminum grains. The casting temperature of 630°C brings about best grain refinement result. The primary aluminum grain size in a casting increases with the increasing distance from the acoustic radiator. In order to examine the feasibility of ultrasonic vibration for SSM processing, high intensity ultrasonic vibration has been applied during the casting of A356 alloy at high volume. Non-dendritic/globular grains have been obtained. Grain refiner can further refine A356 alloy structure, with the combination of ultrasonic vibration. Experiments on the grain refinement of other aluminum alloys have been carried out. Fine globular grains were obtained in various aluminum alloys, including A354, 319, 6063, 6061, 2618 alloys. It was found that 670 °C is the optimum casting temperature for grain refinement of 2618 with the aid of ultrasonic vibration. The effect of ultrasonic vibration on the modification of eutectic silicon in aluminum-silicon alloys has been studied. The introduction of ultrasonic vibration into A356 alloy modified the morphology of eutectic silicon from a coarse acicular plate-like form to a finely dispersed rosette-like form. The length, width, and aspect ratio of eutectic silicon all reduced significantly. This modification is beneficial to the mechanical properties. Ultrasonic grain refinement and secondary phases modification to magnesium AM60B alloy have been examined. With ultrasonic vibration, alloy experienced a reduction in size of primary α-Mg grains from 760 µm to about 25~48 µm in diameter, which is much better than other traditional grain refinement methods. The morphology of eutectic phases was modified from a mainly fully divorced blocky morphology dispersed among dendrite arms, to a mainly lamellar/script morphology across the grain boundaries. Furthermore, the volume fraction of the eutectic morphology is less. Ultrasonic processing of solidifying metals can have a number of applications. Incorporating ultrasonic vibration into a die casting machine would dramatically increase the integrity and properties of die castings. Ultrasonic vibration may be used for producing semisolid feedstock directly from molten metal. Ultrasonic techniques can also find applications in forging industries for processing alloys that are difficult to cast. Ultrasonic treatment has the advantages of being environmentally favorable, cost effective, and ready to be combined with other known physical processing technologies for liquid and solidifying metal. It is expected that the results of this study will impact a wide range of alloy processing including DC casting, continuous casting, vacuum arc remelting, and foundry processing in the areas of grain refinement, semi-solid metalcasting (SSM), and the production of new and novel microstructures. It is highly recommended to continue both the research reported in this study and the application and commercialization of this technology

Arterial Tissue Perforation Using Ultrasonically Vibrating Wire Waveguides

Chronic Total Occlusions (CTOs) are fibrous and calcified atherosclerotic lesions which completely occlude the artery. They are difficult to treat with standard dilation procedures as they cannot be traversed easily. Their treatment is also associated with a high risk of arterial perforation. Low frequency ultrasonic vibrations delivered via wire waveguides represent a minimally invasive treatment for CTOs and other tissue ablation applications. These devices typically operate at 20–50 kHz delivering wire waveguide distal tip amplitudes of vibration of 0-60 μm. The diseased tissue is ablated or disrupted by repetitive direct mechanical contact and cavitation. This research assesses the susceptibility of arterial tissue to perforation and residual damage under the action of ultrasonically energised wire waveguides. Using Finite Element Analysis (FEA), a linear acoustic model of the wire waveguide distal tips can predict the pressures for a range of operating parameters typically used for these devices. High mesh densities (140 EPW) were required to solve the entire acoustic field, including complex wave interactions. The FEA model was used to aid in the further design and modification of an ultrasonic apparatus and wire waveguide (0–34.3 μm at 22.5 kHz). Using a test rig, the effects of distal tip amplitudes of vibration, feedrate and angled entry on the perforation forces, energy and temperature were measured. The perforation forces reduced (≈ 60%, 6.13 N - 2.46 N mean) when the wire waveguide was energised at low amplitudes of vibrations (\u3c 27.8 μm). There were no significant change in tissue perforation forces above this or when the waveguide was operating above the cavitation threshold. Histological analysis also showed tissue removal. While this knowledge is useful in the prediction and avoidance of perforations during CTO operations; it is also envisaged that this information can aid in the design and development of generic ultrasonic wire waveguide tissue cutting tools

Heating technology for malignant tumors: a review

The therapeutic application of heat is very effective in cancer treatment. Both hyperthermia, i.e., heating to 39-45 degrees C to induce sensitization to radiotherapy and chemotherapy, and thermal ablation, where temperatures beyond 50 degrees C destroy tumor cells directly are frequently applied in the clinic. Achievement of an effective treatment requires high quality heating equipment, precise thermal dosimetry, and adequate quality assurance. Several types of devices, antennas and heating or power delivery systems have been proposed and developed in recent decades. These vary considerably in technique, heating depth, ability to focus, and in the size of the heating focus. Clinically used heating techniques involve electromagnetic and ultrasonic heating, hyperthermic perfusion and conductive heating. Depending on clinical objectives and available technology, thermal therapies can be subdivided into three broad categories: local, locoregional, or whole body heating. Clinically used local heating techniques include interstitial hyperthermia and ablation, high intensity focused ultrasound (HIFU), scanned focused ultrasound (SFUS), electroporation, nanoparticle heating, intraluminal heating and superficial heating. Locoregional heating techniques include phased array systems, capacitive systems and isolated perfusion. Whole body techniques focus on prevention of heat loss supplemented with energy deposition in the body, e.g., by infrared radiation. This review presents an overview of clinical hyperthermia and ablation devices used for local, locoregional, and whole body therapy. Proven and experimental clinical applications of thermal ablation and hyperthermia are listed. Methods for temperature measurement and the role of treatment planning to control treatments are discussed briefly, as well as future perspectives for heating technology for the treatment of tumors

Investigations of the Cavitation and Damage Thresholds of Histotripsy and Applications in Targeted Tissue Ablation.

Histotripsy is a noninvasive ultrasound therapy that controls acoustic cavitation to mechanically fractionate soft tissue. This dissertation investigates the physical thresholds to initiate cavitation and produce tissue damage in histotripsy and factors affecting these thresholds in order to develop novel strategies for targeted tissue ablation. In the first part of this dissertation, the effects of tissue properties on histotripsy cavitation thresholds and damage thresholds were investigated. Results demonstrated that the histotripsy shock scattering threshold using multi-cycle pulses increases in stiffer tissues, while the histotripsy intrinsic threshold using single-cycle pulses is independent of tissue stiffness. Further, the intrinsic threshold slightly decreases with lower frequencies and significantly decreases with increasing temperature. The effects of tissue properties on the susceptibility to histotripsy-induced tissue damage were also investigated, demonstrating that stiffer tissues are more resistant to histotripsy. In the second part of this dissertation, the feasibility of using histotripsy for targeted liver ablation was investigated in an intact in vivo porcine model, with results demonstrating that histotripsy was capable of non-invasively creating precise lesions throughout the entire liver. Additionally, a tissue selective ablation approach was developed, where histotripsy completely fractionated the liver tissue surrounding the major hepatic vessels and gallbladder while being self-limited at the boundaries of these critical structures. In the final part of this dissertation, a novel ablation method combining histotripsy with acoustically sensitive nanodroplets was developed for targeted cancer cell ablation, demonstrating the potential of using nanodroplet-mediated histotripsy (NMH) for targeted, multi-focal ablation. Studies demonstrated that lower frequency and higher boiling point perfluorocarbon droplets can improve NMH therapy. The role of positive and negative pressure on cavitation nucleation in NMH was also investigated, showing that NMH cavitation nucleation is caused directly from the peak negative pressure of the incident wave, similar to histotripsy bubbles generated above the intrinsic threshold. Overall, the results of this dissertation provide significant insight into the physical mechanisms underlying histotripsy tissue ablation and will help to guide the future development of histotripsy for clinical applications such as the treatment of liver cancer.PhDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/113591/1/evlaisav_1.pd

\u27Fabrication and Characterization of Polymer Blends and Composites Derived from Biopolymers\u27

This research focuses on fabricating blends and composites from natural polymers especially from proteins and natural epoxy, and describing the properties of plastics made from them. Specifically, plastic samples from partially denatured feathermeal and bloodmeal proteins, derived from the animal co-products (rendering) industry, were successfully produced through a compression molding process. The modulus (stiffness) of the material obtained was found to be comparable with that of commercial synthetic materials, such as polystyrene, but was found to have lower toughness characteristics, which is a common phenomenon among plastics produced from animal and plant proteins. Therefore, this study explored blending methods for improving the toughness. Plastic forming conditions for undenatured animal proteins such as chicken egg whites albumin and whey, used as a model, were established to prepare plastics from their blends with animal co-product proteins. The resultant plastic samples from these biomacromolecular blends demonstrated improved mechanical properties that were also compared with the established theoretical models known for polymer blends and composites. Moreover, plastics from albumin of chicken egg whites and human serum have demonstrated their potential in medical applications that require antibacterial properties. Another natural polymer vegetable oil-based epoxy, especially epoxidized linseed oil, showed significant potential to replace petroleum-derived resins for use as a matrix for composites in structural applications. Moreover, the research showed the benefits of ultrasonic curing, which can help in preparing the out-of-autoclave composites