Simulation study on acousto-optics sensing of focused ultrasound

Abstract. The acousto-optics (AO) technique can provide a good contrast with high penetration depth (up to 5 cm) and can be potentially utilized in real time monitoring of the focused ultrasound (FUS) therapies. This work presents the AO simulation study on the interaction of light and FUS in the single-layer brain (SLB) medium and four-layer brain (FLB) medium. FUS pressure distribution at 0.5 MHz and 0.9 MHz frequency was simulated on k-Wave toolbox and the AO Monte Carlo (MC) algorithm was developed on MATLAB to simulate the AO effect in both mediums. The result for the SLB for both ultrasound (US) frequencies suggests that the modulation depth (MD) is high in the region of US focus with a magnitude of 2%-3% and <1% at 0.5 MHz and 0.9 MHz, respectively. Moreover, the MD decreases to 5 orders of magnitude at the source region. In the FLB, the MD decreased to 4–4.5 orders at the source and was present in the skull and US focus region with a magnitude of <1% at both US frequencies. These results suggest that AO can be utilized in sensing FUS effects on brain tissue and the AO signal-to-noise ratio (SNR) depends not only on the MD but also on the level of light intensity interacting with the US pressure

Effects of Compression on the Temperature Distribution of a Tissue-Mimicking Material During High-Intensity Focused Ultrasound (HIFU) Ablation

Local blood flow near a high-intensity focused ultrasound (HIFU) target has been shown to decrease ablation effectiveness and predictability, creating a barrier to clinical use for breast cancer treatment. This study investigated the effects of compression on HIFU ablation of a perfused tissue-mimicking material. Gellan gum-based phantoms, with thermal and acoustic properties similar to those of soft tissue, were ablated with a 1.13 MHz HIFU transducer while being subjected to varying levels of external compression. Phantoms were designed with an embedded 6 mm diameter vessel meant to mimic a thermally significant blood vessel near a breast tumor. The internal temperature profile was measured using T-type thin-wire thermocouples embedded in the phantom along the transverse axis. The temperature distributions on opposing lateral sides of the HIFU focal point were measured to determine the effects of compression on heating symmetry. After heating with 30 W for 30 s, the maximum discrepancy between a pair of thermocouples located 2 mm left and right of centerline, respectively, was 40 °C. This maximum discrepancy was observed at a fluid flow rate of 38 mL/min. With applied compression reducing flow to between 28 mL/min and 25 mL/min, the discrepancy between left and right thermocouples was reduced to as low as 5.7 °C. Numerical predictions revealed an agreement with experimental results in the reduction of heating asymmetry as the flow rate decreased from 40 mL/min to 20 mL/min

Development of Novel Energy-based Musculoskeletal Therapies

Back pain is the most common musculoskeletal condition, affecting 80% of Americans at some point in their lifetimes. Intervertebral disc (IVD) pathologies, such as annular tears and herniated discs, are the most common source of low back pain and account for more than 40% of cases. Current treatment options, including discectomy and intradiscal injections, involve invasive procedures and are limited to short-term symptom relief without repairing damaged IVDs. This dissertation explores the stimulatory effects and dose-response relationships of low-intensity pulsed ultrasound (LIPUS) and pulsed electromagnetic fields (PEMF), with the goal of advancing the development of these energy-based therapies for the noninvasive treatment of low back pain. Towards this goal, this dissertation is broken into 4 studies. In the first study, we demonstrate the technical feasibility of targeted, noninvasive delivery of acoustic energy to rat-tail IVDs and evaluate gene expression changes in injured IVDs in response to LIPUS exposure. We found that LIPUS exposure regulates extracellular matrix and inflammatory gene expression in rats with increased proinflammatory gene expression. In the second study, we design, fabricate, characterize, and validate an in-vitro LIPUS exposimetry system for delivering uniform acoustic energy to cells while removing potentially confounding factors including beam reflections and sample heating. We demonstrate that far-field LIPUS exposure upregulates collagen synthesis in annulus fibrosus cells and is equivalent to growth factor treatment. In the third study, we present the use and validation of design of experiments (DOE) for LIPUS parameter exploration, response prediction, and optimization. We discovered that pulse repetition frequency is the most significant factor for modulating catabolic and proinflammatory gene expression while peak intensity is most significant for modulating anabolic gene expression, and that both factors interact with treatment duration to influence extracellular matrix gene expression in inflammatory annulus fibrosus cells. In the last study, we show that magnetic nano-bone substitutes (MNBS) synergize with PEMF to stimulate in-vitro osteogenesis. We found that the combination of PEMF and MNBS accelerates osteogenesis by stimulating early alkaline phosphatase activity and increasing mineralization over time in mesenchymal stem cells. Collectively, the work presented in this dissertation represents significant contributions to the development of two novel energy-based therapies for painful spine conditions. These findings will motivate the use of noninvasive, biologically active treatments for repairing damaged IVDs and alleviating low back pain

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

Modelling, Simulation and Data Analysis in Acoustical Problems

Modelling and simulation in acoustics is currently gaining importance. In fact, with the development and improvement of innovative computational techniques and with the growing need for predictive models, an impressive boost has been observed in several research and application areas, such as noise control, indoor acoustics, and industrial applications. This led us to the proposal of a special issue about “Modelling, Simulation and Data Analysis in Acoustical Problems”, as we believe in the importance of these topics in modern acoustics’ studies. In total, 81 papers were submitted and 33 of them were published, with an acceptance rate of 37.5%. According to the number of papers submitted, it can be affirmed that this is a trending topic in the scientific and academic community and this special issue will try to provide a future reference for the research that will be developed in coming years

Magneettikuvauksella ohjattu korkean intensiteetin kohdennettu ultraääniteknologia syöpätautien liitännäishoidoissa ja syöpälääkkeiden annostelussa

Ablative hyperthermia (more than 55 °C) has been used as a stand-alone treatment for accessible solid tumors not amenable to surgery, whereas mild hyperthermia (40-45 °C) has been shown effective as an adjuvant for both radiotherapy and chemotherapy. An optimal mild hyperthermia treatment is noninvasive and spatially accurate, with precise and homogeneous heating limited to the target region. High-intensity focused ultrasound (HIFU) can noninvasively heat solid tumors deep within the human body. Magnetic resonance imaging (MRI) is ideal for HIFU treatment planning and monitoring in real time due to its superior soft-tissue contrast, high spatial imaging resolution, and the ability to measure temperature changes. The combination of MRI and HIFU therapy is known as magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU). Low temperature-sensitive liposomes (LTSLs) release their drug cargo in response to heat (more than 40 °C) and may improve drug delivery to solid tumors when combined with mild hyperthermia. MR-HIFU provides a way to image and control content release from imageable low-temperature sensitive liposomes (iLTSLs). This ability may enable spatiotemporal control over drug delivery - a concept known as drug dose painting. The objectives of this dissertation work were to develop and implement a clinically relevant volumetric mild hyperthermia heating algorithm, to implement and characterize different sonication approaches (multiple foci vs. single focus), and to evaluate the ability to monitor and control heating in real time using MR-HIFU. In addition, the ability of MR-HIFU to induce the release of a clinical-grade cancer drug encapsulated in LTSLs was investigated, and the potential of MR-HIFU mediated mild hyperthermia for clinical translation as an image-guided drug delivery method was explored. Finally, drug and contrast agent release of iLTSLs as well as the ability of MR-HIFU to induce and monitor the content release were examined, and a computational model that simulates MR-HIFU tissue heating and drug delivery was validated. The combination of a multifoci sonication approach and the mild hyperthermia heating algorithm resulted in precise and homogeneous heating limited to the targeted region both in vitro and in vivo. Heating was more spatially confined compared to the use of single focus sonication method. The improvement in spatial control suggests that multifoci heating is a useful tool in MR-HIFU mediated mild hyperthermia applications for clinical oncology. Using the mild hyperthermia heating algorithm, LTSL + MR-HIFU resulted in significantly higher tumor drug concentrations compared to free drug and LTSL alone. This technique has potential for clinical translation as an image-guided drug delivery method. MR-HIFU also enabled real-time monitoring and control of iLTSL content release. Finally, computational models may allow quantitative in silico comparison of different MR-HIFU heating algorithms as well as facilitate therapy planning for this drug delivery technique.Ablatiivista hypertermiaa (yli 55 °C) on perinteisesti käytetty leikkauksiin soveltumattomien kasvainten hoitoon. Lievän hypertermian (40-45 °C) on sen sijaan todettu olevan tehokas liitännäishoito syöpätautien säde- ja lääkehoidoille. Suotuisa hypertermiahoito on kajoamatonta ja täsmällisesti kohdistettua. Lämmityksen tulisi lisäksi olla tarkkaa, tasalaatuista ja kohdealueeseen rajoittunutta. Korkean intensiteetin kohdennettu ultraääni (HIFU) -hoito mahdollistaa kasvainten kajoamattoman lämmityksen. Magneettikuvauksen (MK) etuina ovat erinomainen pehmytkudoskontrasti, korkea paikkaresoluutio ja kyky mitata lämpötilan muutoksia. Näin ollen MK soveltuu erinomaisesti HIFU -hoitojen suunnitteluun ja seurantaan. MK:n ja HIFU:n yhdistelmää kutsutaan magneettikuvauksella ohjatuksi korkean intensiteetin kohdennetuksi ultraääniteknologiaksi (MR-HIFU). Lämpötilaherkät liposomit ovat suunniteltuja vapauttamaan lääkeainesisältönsä hieman normaalia ruumiinlämpötilaa korkeammissa lämpötiloissa (yli 40 °C). Yhdessä lievän hypertermian kanssa tämänkaltaiset liposomit voivat mahdollistaa kohdistetun lääkeaineen vapauttamisen. Liposomien sisällön vapautumisen tarkkailu voi myös mahdollistaa tarkan lääkemäärän kohdistetun annostelun kasvaimessa. Väitöskirjatyössä kehitettiin kliinisesti merkittävä lämmitysalgoritmi lievän hypertermian aikaansaamiseksi, toteutettiin usean samanaikaisen kohteen sonikaatio (ultraäänialtistus) menetelmä sekä arvioitiin algoritmin ja menetelmän kykyä kontrolloida kudoksen lämpötilaa käyttäen kliinistä MR-HIFU laitetta. Lisäksi tutkittiin HIFU:n kykyä vapauttaa lääkeaine lämpötilaherkistä liposomeista, karakterisoitiin lääke- ja kontrastiaineen vapautuminen kuvannettavissa olevista lämpötilaherkistä liposomeista sekä tarkasteltiin MR-HIFU:lla aikaansaadun lievän hypertermian potentiaalia kohdentaa lääkeaineen vapautuminen kasvaimeen. Tässä työssä myös validoitiin laskennallinen malli, joka simuloi MR-HIFU:lla aikaansaatua lämmitystä ja siitä johtuvaa lääkeaineen vapautumista, sekä todennettiin MR-HIFU:n sopivuus lämpöablaatioon perustuvaan kohdun pehmytkudoskasvainten hoitomenelmään kliinisessä käytössä. Lievän hypertermian lämmitysalgoritmi yhdessä usean kohteen sonikaatiomenetelmän kanssa tuotti täsmällisen, tasalaatuisen sekä paikallisesti rajoitetun lämmityksen kohdealueessa. Usean kohteen sonikaatiomenetelmä voi siis olla hyödyllinen työkalu MR-HIFU:n lievän hypertermian syöpähoidon sovelluksissa. MR-HIFU yhdessä lämpötilaherkkien liposomien kanssa sai aikaan merkittävästi korkeamman kasvaimen lääkeainekonsentraation verrokkiryhmiin nähden, ja saattaa siten soveltua kliiniseen käyttöön kuvantamisavusteisena lääkehoitona. Liposomien sisällön (lääkeaine + MK-kontrastiaine) vapautumisen kuvannettavuus merkitsee, että MR-HIFU saattaa lisäksi mahdollistaa tarkan lääkeannoksen kohdistetun vapauttamisen

Development of a 1D phased ultrasonic array for intravascular sonoporation

Error on title page – year of award is 2021.Sonoporation represents a promising approach to increase targeted drug delivery efficiency by facilitating transport of therapeutic agents to the target tissue with the use of ultrasound. However, most of the current research in sonoporation is performed with external ultrasonic transducers, which hinders the applicability of the therapeutic procedure for treatment of conditions situated deeper into the patient’s body, such as liver or intestinal tumours. This Thesis presents the development process of a miniature-sized 1-3 connectivity piezocomposite 1D phased array for intracorporeal sonoporation. The device was to be incorporated into a capsule or catheter and hence the primary design constraint was the reduced size of the piezoelectric element, which was limited to 2.5 mm in width and 12 mm in length. To meet the needs of the intended application, resonance frequencies of 1.5 MHz and 3.0 MHz were considered. A simulation framework was developed for optimization of the miniature array in relation to the peak negative pressure attained at the focus to mitigate the low power output associated with the limited device dimensions. This was implemented through a multiparametric sweep of the 1-3 piezocomposite geometry-related parameters. Devices made with PZT-5H and PMN-29%PT were evaluated. The optimization algorithm was used to determine specifications for phased array designs based on the two materials and the two resonance frequencies. The 1.5 MHz devices comprised 24 elements and the 3.0 MHz ones had 32 elements. The piezocomposites were manufactured using the dice and fill technique and electroded using a novel method of electrode deposition employing spin coating of Ag ink. Subsequently, the prototype devices were driven with a commercial array controller and characterized with a calibrated needle hydrophone in a scanning tank. Two simulation profiles based on finite element analysis and time extrapolation were developed to model the acoustic beams from the arrays, which were compared and calibrated with experimental data for focal distances between 5 mm and 10 mm and beam steering angles from 0° to 40°. The results showed that modelling could be employed reliably for therapeutic planning. Both the 1.5 MHz and the 3.0 MHz, PZT-5H arrays were tested in vitro and shown to induce and control sonoporation of a human epithelial colorectal adenocarcinoma cell layer. Finally, a 24 element, 1.5 MHz, PZT-5H array was implemented in a 40 mm long by 11 mm diameter tethered, biocompatible capsule intended for in vivo operation. The device was characterized in the scanning tank for steering angles in the range 0° to 56° and focal distances between 4.0 mm and 5.7 mm, and the measured beam profiles were correlated with the simulation framework. The capsule will be tested in future ex-vivo and in-vivo experiments on insulin absorption through porcine small bowel by means of sonoporation.Sonoporation represents a promising approach to increase targeted drug delivery efficiency by facilitating transport of therapeutic agents to the target tissue with the use of ultrasound. However, most of the current research in sonoporation is performed with external ultrasonic transducers, which hinders the applicability of the therapeutic procedure for treatment of conditions situated deeper into the patient’s body, such as liver or intestinal tumours. This Thesis presents the development process of a miniature-sized 1-3 connectivity piezocomposite 1D phased array for intracorporeal sonoporation. The device was to be incorporated into a capsule or catheter and hence the primary design constraint was the reduced size of the piezoelectric element, which was limited to 2.5 mm in width and 12 mm in length. To meet the needs of the intended application, resonance frequencies of 1.5 MHz and 3.0 MHz were considered. A simulation framework was developed for optimization of the miniature array in relation to the peak negative pressure attained at the focus to mitigate the low power output associated with the limited device dimensions. This was implemented through a multiparametric sweep of the 1-3 piezocomposite geometry-related parameters. Devices made with PZT-5H and PMN-29%PT were evaluated. The optimization algorithm was used to determine specifications for phased array designs based on the two materials and the two resonance frequencies. The 1.5 MHz devices comprised 24 elements and the 3.0 MHz ones had 32 elements. The piezocomposites were manufactured using the dice and fill technique and electroded using a novel method of electrode deposition employing spin coating of Ag ink. Subsequently, the prototype devices were driven with a commercial array controller and characterized with a calibrated needle hydrophone in a scanning tank. Two simulation profiles based on finite element analysis and time extrapolation were developed to model the acoustic beams from the arrays, which were compared and calibrated with experimental data for focal distances between 5 mm and 10 mm and beam steering angles from 0° to 40°. The results showed that modelling could be employed reliably for therapeutic planning. Both the 1.5 MHz and the 3.0 MHz, PZT-5H arrays were tested in vitro and shown to induce and control sonoporation of a human epithelial colorectal adenocarcinoma cell layer. Finally, a 24 element, 1.5 MHz, PZT-5H array was implemented in a 40 mm long by 11 mm diameter tethered, biocompatible capsule intended for in vivo operation. The device was characterized in the scanning tank for steering angles in the range 0° to 56° and focal distances between 4.0 mm and 5.7 mm, and the measured beam profiles were correlated with the simulation framework. The capsule will be tested in future ex-vivo and in-vivo experiments on insulin absorption through porcine small bowel by means of sonoporation

Design of a Fast, Efficient and Controlled DNA Shearing System Based on Lateral Acoustic Waves

With the continuous research and advances in Deoxyribonucleic acid (DNA) sequencing technologies, the need for an efficient DNA shearing system has increased more than ever before. In this thesis, we propose a fast, efficient and controlled DNA shearing system based on a uniquely designed ultrasonic transducer, called Fresnel Annular Sector Actuator (FASA). Based on the simulation and experimental results, a circular array of four 90°-FASA elements is chosen as the basic unit for the proposed shearing system. DNA is successfully sheared from 300 to 1500 base-pair lengths. The shearing performance of the system is independent of the source of DNA over a large range of concentrations of the DNA. Finally, multiple FASA elements, excited by separate BF-signals, are used to increase the throughput of the proposed shearing system