Magnetic Resonance Thermometry at 7T for Real-Time Monitoring and Correction of Ultrasound Induced Mild Hyperthermia

While Magnetic Resonance Thermometry (MRT) has been extensively utilized for non-invasive temperature measurement, there is limited data on the use of high field (≥7T) scanners for this purpose. MR-guided Focused Ultrasound (MRgFUS) is a promising non-invasive method for localized hyperthermia and drug delivery. MRT based on the temperature sensitivity of the proton resonance frequency (PRF) has been implemented in both a tissue phantom and in vivo in a mouse Met-1 tumor model, using partial parallel imaging (PPI) to speed acquisition. An MRgFUS system capable of delivering a controlled 3D acoustic dose during real time MRT with proportional, integral, and derivative (PID) feedback control was developed and validated. Real-time MRT was validated in a tofu phantom with fluoroptic temperature measurements, and acoustic heating simulations were in good agreement with MR temperature maps. In an in vivo Met-1 mouse tumor, the real-time PID feedback control is capable of maintaining the desired temperature with high accuracy. We found that real time MR control of hyperthermia is feasible at high field, and k-space based PPI techniques may be implemented for increasing temporal resolution while maintaining temperature accuracy on the order of 1°C

The Generation and Control of Ultrasonic Waves in Nonlinear Media

The objective of this thesis is to utilise modern open-design ultrasound research platforms to develop new and advance several existing techniques that incorporate nonlinear phenomena. Acoustically, nonlinearity refers to changes in speed of sound, attenuation or elasticity that vary with frequency, temperature or pressure. These effects cannot be linearised by the wave equation and require fluid dynamics and elasticity equations to be fully understood. While this is a hindrance and source of error in many areas of ultrasound such as high-intensity focused ultrasound (HIFU) and medical imaging, nonlinearities do have uses in non-destructive guided wave (GW) testing. These effects are influenced greatly by the transducer surface pressure, and so precise control of the excitation is necessary to achieve the desired nonlinear effect, if any, in the medium. In this thesis, aided by the use of two new research platforms, several new ultrasound techniques were developed. It was shown the frequency content in the electrical waveform is pertinent and so distortion must be minimised. This requirement conflicts with several hardware limitations, however. Accordingly, a genetic algorithm was applied to find novel switched waveform designs. It was found to achieve a 2% granularity in amplitude control with harmonic reduction, where existing waveform designs could not produce any. This fine amplitude control is a requirement for array applications. Following this, a technique to control the direction of GWs without knowledge of the waveguide was devised. Recordings of a propagating GW, induced by the first element of an array transducer, were re-transmitted in a recursive fashion. The effect was that the transducer's transmissions constructively interfered with the transverse wave, causing most of the guided wave energy to travel in the direction of the transducer's spatial influence. Experimental results show a 34 dB enhancement in one direction compared with the other. GWs were then applied to bone for two purposes: for assessment of osteoporosis and for measurement of skull properties to assist transcranial therapy. It was shown that existing methods for obtaining dispersion curves are ineffectual due to limitations in the available sampling area. A signal processing scheme was devised to temporally align transverse dispersive waves so that beamforming style techniques could be applied to prove or disprove the existence of certain modes. The technique in combination with multiplication was applied to numerical, ex vivo and in vivo experiments. It was found to improve the contrast of the higher order modes. The technique could improve the reliability of osteoporosis diagnosis with ultrasound, but may also prove useful for acquiring dispersion images in NDT. Numerically the technique was shown to improve the S3 and A3 mode intensity by 6 dB and 13 dB respectively compared with an existing Fourier method. In skull, a relationship was found between the curved therapeutic array geometry and the delay profile necessary to form GWs in skull. Several numerical models were tested and it was shown that the thickness could be obtained from the group velocity. The estimated maximum error using this technique was 0.2 mm. Since the data is co-registered with the therapeutic elements, this method could be used to improve the accuracy of thermal treatments in the brain. Finally, the application of switched excitation for HIFU was considered. To improve on cost, efficiency and size, alternative excitation methods have the potential to replace the linear amplifier circuitry currently used in HIFU. In this final study, harmonic reduction pulse width modulation (HRPWM) was proposed as an algorithmic solution to the design of switched waveforms. Its appropriateness for HIFU was assessed by design of a high power 5 level unfiltered amplifier and subsequent thermal-only lesioning of ex vivo chicken breast. HRPWM produced symmetric, thermal-only lesions that were the same size as their linear amplifier equivalents (p > 0.05). These results demonstrate that HRPWM can minimise HIFU drive circuity size without the need for filters to remove harmonics or adjustable power supplies to achieve array apodisation. Overall it has been shown in this thesis that precise control of the nonlinear wave phenomena can be afforded when using open-platform ultrasound research hardware. The methods described within may reduce the cost and increase the efficacy of future commercial systems

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

In-Suit Doppler Technology Assessment

The objective of this program was to perform a technology assessment survey of non-invasive air embolism detection utilizing Doppler ultrasound methodologies. The primary application of this technology will be a continuous monitor for astronauts while performing extravehicular activities (EVA's). The technology assessment was to include: (1) development of a full understanding of all relevant background research; and (2) a survey of the medical ultrasound marketplace for expertise, information, and technical capability relevant to this development. Upon completion of the assessment, LSR was to provide an overview of technological approaches and R&D/manufacturing organizations

Development of a medical imaging-based technology for cancer treatment

The Electrical Impedance Mammography (EIM) device is an imaging system developed at the University of Sussex for the detection of breast lesions in vivo using quadrature detection of impedance. The work describes a novel technique to integrate Ultrasound-guided Focused Ultrasound Surgery (USgFUS) with the existing EIM system. The benefits that such a system could provide include the possibility of non-invasive detection, diagnosis and treatment of breast cancer all within a single device and involving no radiation. Furthermore the timescales involved would allow the process to be considered an outpatient procedure such that a patient can be diagnosed and treated on the same day using the same device. Various geometries of transducer were investigated for physical compatibility as well as the ability to target the entire specified volume, based on the dimensions of the existing system. Simulations were performed using a custom written code based on Huygen’s principle, allowing minimum surface area and power requirements to be determined and feasibility of designs to be evaluated. The use of phase differences in the excitation signals applied to individual elements was also investigated, thus the effect of steering the simulated focus could be observed, an important factor to consider when attempting to incorporate a transducer into a device with restricted dimensions. Resulting simulated pressure fields were used to obtain acoustic intensity fields, which could then be used as inputs in the Pennes Bio-Heat Transfer Equation (BHTE) allowing temperature distributions to be observed. Preliminary studies proved the feasibility of using the suggested transducer design in conjunction with the existing EIM system. Pressure fields and heating patterns were all within acceptable limits, confirming the ability of the device to effectively ablate cancerous tissue. Additionally the capability to steer the resultant focal point was validated, and a thermal dose model was implemented allowing different heating patterns to be quantitatively compared

Modal analysis and nonlinear characterization of an airborne power ultrasonic transducer with rectangular plate radiator

Some industrial processes like particle agglomeration or food dehydration among others can be enhanced by the use of power ultrasonic technologies. These technologies are based on an airborne power ultrasonic transducer (APUT) constituted by a pre-stressed Langevin-type transducer, a mechanical amplifier and an extensive plate radiator. In order to produce the desired effects in industrial processing, the transducer has to vibrate in an extensional mode driving an extensive radiator in the desired flexural mode with high amplitude displacements. Due to the generation of these high amplitude displacements in the radiator surfaces, non-linear effects like frequency shifts, hysteresis or modal interactions, among others, may be produced in the transducer behavior. When any nonlinear effect appears, when applying power, the stability and efficiency of this ultrasonic technology decreases, and the transducer may be damaged depending on the excitation power level and the nature of the nonlinearity. In this paper, an APUT with flat rectangular radiator is presented, as the active part of an innovative system with stepped reflectors. The nonlinear behavior of the APUT has been characterized numerically and experimentally in case of the modal analysis and experimentally in the case of dynamic analysis. According to the results obtained after the experiments, no modal interactions are expected, nor do other nonlinear effects