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

Measurement and mathematical modeling of hyperthermia induced bioeffects in pancreatic cancer cells

Doctor of PhilosophyDepartment of Electrical and Computer EngineeringPunit PrakashSurgical resection is the standard of care for pancreatic cancer, although treatment outcomes remain poor, and a large fraction of the patient population are not surgical candidates. Minimally invasive interventions employing non-ionizing energy, such as image-guided thermal ablation, are under investigation for treatment of unresectable tumors and potentially for debulking and downstaging tumors. Tissue regions at the periphery of an ablation zone are exposed to sub-ablative thermal profiles (referred to as “mild hyperthermia”), which may induce a range of bioeffects including change in perfusion, immune modulation, and others. Bioeffects induced by heating are a function of intensity of heating and duration of thermal exposure. This dissertation presents a suite of tools for integrated in vitro experimental studies and modeling for characterizing bioeffects following thermal exposure to pancreatic cancer cells. An instrumentation platform was developed for exposing monolayer cell cultures to temperatures in the range 42–50°C for 3–60 minutes. The platform was employed to determine the Arrhenius kinetic parameters of thermal injury to pancreatic cancer cells (i.e. loss in viability) following heating. When coupled with bioheat transfer models, these parameters facilitate investigations of thermal injury profiles in pancreatic tumors following thermal exposure with practical devices. There has been growing interest in exploring the potential of thermal therapies for modulating tumor—immune system interactions, due in part to release of damage associated molecular patterns (DAMPs) from stressed tumor cells and their role in recruiting and activating antigen presenting cells. The in vitro thermal exposure platform was further expanded to allow for experimental measurement of extracellular DAMPs released from murine pancreatic cancer cells following heating to temperatures in the range 42 – 50°C for 3-60 mins. A model predicting the dynamics of heat-induced DAMPs release was developed and may inform the design of experiments investigating the role of heat in modulating the anti-tumor immune response. While in vitro experiments on monolayers are informative, 3D cell cultures (e.g., spheroid, organoids) provide an experimental platform accommodating multiple cell types in an environment that may be more representative of tumors in vivo. Furthermore, while the water-bath based in vitro platform applied for monolayers is well suited to achieving near-uniform temperature profiles, in vivo delivery of hyperthermia often yields a gradient of temperatures that is not achieved through water-bath based heating. Thus, an in vitro platform for exposing cells in 3D culture (co-culture of multiple cell populations) to 2.45 GHz microwave hyperthermia was developed. The platform includes a printed patch antenna and associated thermal management elements and was applied to study changes in gene expression profile of a 3D culture of pancreatic cancer cells and fibroblasts. This non-contact microwave heating approach may help enable additional studies for exploring the bioeffects of heat on cancer cells

Image-guidance and computational modeling to develop and characterize microwave thermal therapy platforms

Doctor of PhilosophyDepartment of Electrical and Computer EngineeringPunit PrakashThis dissertation focuses on the development of magnetic resonance imaging (MRI)-guided microwave thermal therapy systems for driving experimental studies in small animals, and to experimentally validate computational models of microwave ablation, which are widely employed for device design and characterization. MRI affords noninvasive monitoring of spatial temperature profiles, thereby providing a means to to quantitatively monitor and verify delivery of prescribed thermal doses in experimental studies and clinical use, as well as a means to validate thermal profiles predicted by computational models of thermal therapy. A contribution of this dissertation is the development and demonstration of a system for delivering mild hyperthermia to small animal targets, thereby providing a platform for driving basic research studies investigating the use of heating as part of cancer treatment strategies. An experimentally validated 3D computational model was employed to design and characterize a non-invasive directional water-cooled microwave hyperthermia applicator for MRI guided delivery of hypethermia in small animals. Following a parametric model-based design approach, a reflector aperture angle of 120°, S-shaped monopole antenna with 0.6 mm displacement, and a coolant flow rate of 150 ml/min were selected as applicator parameters that enable conformal delivery of mild hyperthermia to tumors in experimental animals. The system was integrated with real-time high-field 14.1 T MRI thermometry and feedback control to monitor and maintain target temperature elevations in the range of 4 – 5 °C (hypethermic range). 2 - 4 mm diameter targets positioned 1 – 3 mm from the applicator surface were heated to hyperthermic temperatures, with target coverage ratio ranging between 76 - 93 % and 11 – 26 % of non-targeted tissue heated. Another contribution of this dissertation is using computational models to determine how the fibroids altered ablation profile of a microwave applicator for global endometrial ablation. Uterine fibroids are benign pelvic tumors located within the myometrium or endometrium,and may alter the profile of microwave ablation applicators deployed within the uterus for delivering endometrial ablation. A 3D computational model was employed to investigate the effect of 1 – 3 cm diameter uterine fibroids in different locations around the uterine cavity on endometrial ablation profiles of microwave exposure with a 915 MHz microwave triangular loop antenna. The maximum change in simulated ablation depths due to the presence of fibroids was 1.1 mm. In summary, this simulation study suggests that 1 – 3 cm diameter uterine fibroids can be expected to have minimal impact on the extent of microwave endometrial ablation patterns achieved with the applicator studied in this dissertation. Another contribution of this dissertation is the development of a method for experimental validation of 3D transient temperature profiles predicted by computational models of MWA. An experimental platform was developed integrating custom designed MR-conditional MWA applicators for use within the MR environment. This developed platform was employed to conduct 30 - 50 W, 5 - 10 min MWA experiments in ex vivo tissue. Microwave ablation computational models, mimicking the experimental setting in MRI, were implemented using the finite element method, and incorporated temperature-dependent changes in tissue physical properties. MRI-derived Arrhenius thermal damage maps were compared to Model-predicted ablation zone extents using the Dice similarity coefficient (DSC). Mean absolute error between MR temperature measurements and fiber-optic temperature probes, used to validate the accuracy of MR temperature measurements, during heating was in the range of 0.5 – 2.8 °C. The mean DSC between model-predicted ablation zones and MRI-derived Arrhenius thermal damage maps for 13 experimental set-ups was 0.95. When comparing simulated and experimentally (i.e. using MRI) measured temperatures, the mean absolute error (MAE %) relative to maximum temperature change was in the range 5 % - 8.5 %

Thermal dosimetry for bladder hyperthermia treatment. An overview.

The urinary bladder is a fluid-filled organ. This makes, on the one hand, the internal surface of the bladder wall relatively easy to heat and ensures in most cases a relatively homogeneous temperature distribution; on the other hand the variable volume, organ motion, and moving fluid cause artefacts for most non-invasive thermometry methods, and require additional efforts in planning accurate thermal treatment of bladder cancer. We give an overview of the thermometry methods currently used and investigated for hyperthermia treatments of bladder cancer, and discuss their advantages and disadvantages within the context of the specific disease (muscle-invasive or non-muscle-invasive bladder cancer) and the heating technique used. The role of treatment simulation to determine the thermal dose delivered is also discussed. Generally speaking, invasive measurement methods are more accurate than non-invasive methods, but provide more limited spatial information; therefore, a combination of both is desirable, preferably supplemented by simulations. Current efforts at research and clinical centres continue to improve non-invasive thermometry methods and the reliability of treatment planning and control software. Due to the challenges in measuring temperature across the non-stationary bladder wall and surrounding tissues, more research is needed to increase our knowledge about the penetration depth and typical heating pattern of the various hyperthermia devices, in order to further improve treatments. The ability to better determine the delivered thermal dose will enable clinicians to investigate the optimal treatment parameters, and consequentially, to give better controlled, thus even more reliable and effective, thermal treatments

Temperature Distribution Mapping Using an FBG-Equipped Probe for Solid Tumor Laser Ablation

In recent years, laser ablation treatments have become promising therapies for early-stage solid tumors, although the anatomical variability within the irradiated organs (i.e., presence of blood vessels and other inhomogeneities) greatly challenges the control of the tissue temperature throughout the medical procedure and thus the optical therapeutic outcome. To help getting around these limitations, a new fiber optic probe able to both deliver the laser light with optimal irradiation pattern and measure the temperature in the tumor region had been previously developed. This paper, using simulations validated with experimental data, aims at demonstrating how this probe, combined with suitable hyperthermal treatment planning, can be used to overcome the discrepancies between ex-vivo and in-vivo laser ablation procedures

Systematic review of pre-clinical and clinical devices for magnetic resonance-guided radiofrequency hyperthermia

Clinical trials have demonstrated the therapeutic benefits of adding radiofrequency (RF) hyperthermia (HT) as an adjuvant to radio- and chemotherapy. However, maximum utilization of these benefits is hampered by the current inability to maintain the temperature within the desired range. RF HT treatment quality is usually monitored by invasive temperature sensors, which provide limited data sampling and are prone to infection risks. Magnetic resonance (MR) temperature imaging has been developed to overcome these hurdles by allowing noninvasive 3D temperature monitoring in the target and normal tissues. To exploit this feature, several approaches for inserting the RF heating devices into the MR scanner have been proposed over the years. In this review, we summarize the status quo in MR-guided RF HT devices and analyze trends in these hybrid hardware configurations. In addition, we discuss the various approaches, extract best practices and identify gaps regarding the experimental validation procedures for MR - RF HT, aimed at converging to a common standard in this process

Antenna and system design for controlled delivery of microwave thermal ablation

Doctor of PhilosophyDepartment of Electrical and Computer EngineeringPunit PrakashMicrowave ablation is an established minimally invasive modality for thermal ablation of unresectable tumors and other diseases. The goal of a microwave ablation procedure is to deliver microwave power in a manner localized to the targeted tissue, with the objective of raising the target tissue to ablative temperatures (~60 °C). Engineering efforts in microwave applicator design have largely been focused on the design of microwave antennas that yield large, near-spherical ablation zones, and can fit within rigid needles or flexible catheters. These efforts have led to significant progress in the development and clinical application of microwave ablation systems, particularly for treating tumors in the liver and other highly vascular organs. However, currently available applicator designs are ill-suited to treating targets of diverse shapes and sizes. Furthermore, there are a lack of non-imaging-based techniques for monitoring the transient progression of the ablation zone as a means for providing feedback to the physician. This dissertation presents the design, implementation, and experimental evaluation of microwave ablation antennas for site-specific therapeutic applications with these issues in mind. A deployable 915 MHz loop antenna is presented, providing a minimally-invasive approach for thermal ablation of the endometrial lining of the uterus for treatment of heavy menstrual bleeding. The antenna incorporates a radiating loop, which can be deployed to adjustable shapes within the uterine cavity, and a passive element, to enable thermal ablation, to 5.7–9.6 mm depth, of uterine cavities ranging in size from 4–6.5 cm in length and 2.5–4.5 cm in width. Electromagnetic–bioheat transfer simulations were employed for design optimization of the antennas, and proof-of-concept applicators were fabricated and extensively evaluated in ex vivo tissue. Finally, feasibility of using the broadband antenna reflection coefficient for monitoring the ablation progress during the course of ablation was evaluated. Experimental studies demonstrated a shift in antenna resonant frequency of 50 MHz correlated with complete ablation. For treatment of 1–2 cm spherical targets, water-cooled monopole antennas operating at 2.45 and 5.8 GHz were designed and experimentally evaluated in ex vivo tissue. The technical feasibility of using these applicators for treating 1–2 cm diameter benign adrenal adenomas was demonstrated. These studies demonstrated the potential of using minimally-invasive microwave ablation applicators for treatment of hypertension caused by benign aldosterone producing adenomas. Since tissue dielectric properties have been observed to change substantially at elevated temperatures, knowledge of the temperature-dependence of tissue dielectric properties may provide a means for estimating treatment state from changes in antenna reflection coefficient during a procedure. The broadband dielectric properties of bovine liver, an established tissue for experimental characterization of microwave ablation applicators, were measured from room temperature to ablative temperatures. The measured dielectric data were fit to a parametric model using piecewise linear functions, providing a means for readily incorporating these data into computational models. These data represent the first report of changes in broadband dielectric properties of liver tissue at ablative temperatures and should help enable additional studies in ablation system development

암 진단 및 치료에 적용 가능한 마이크로파 능동 집적 탐침에 관한 연구

학위논문 (박사)-- 서울대학교 대학원 : 전기·컴퓨터공학부, 2015. 2. 권영우.본 논문에서는 암 진단 및 치료에 적용 가능한 초소형 마이크로파 능동 집적 탐침에 대해 기술하였다. 생체 조직의 광대역 측정과 저전력 온열 치료에 적용 하기 위해 유전율 측정 회로를 평면형 동축 탐침에 집적하였고, 마이크로파 발생 회로를 어플리케이터에 집적하였다. MEMS 기술과 MMIC 기술을 적용함으로써 단일 플랫폼에 집적된 시스템으로 구현하여 집적도를 향상 시키고, 시스템을 소형화 하였다. 먼저 multi-state reflectometer를 이용하여 암 진단에 활용 가능한복소 유전율 측정 기술에 대해 제안하였다. 2, 16 GHz에서 동작하는 광대역 reflectometer는 이중 대역 위상 고정 루프 (PLL), 임피던스 튜너, RF 전력 검출기 등의 MMIC와 MEMS 기반의 방향성 결합기, 평면형 탐침을 집적하여 구현하였다. 제작한 능동 집적 탐침 시스템을 이용하여 생체 조직과 암 조직 등의 유전율을 측정함으로써 유용함을 확인하였고, 측정된 유전율과 표준값을 비교하여 시스템의 측정 정확도를 검증하였다. 또한 저전력 마이크로파 온열 치료 요법을 위한 능동 집적 탐침을 개발하였다. MEMS 공정을 통해 제작한 평면형 실리콘 탐침에 전압 제어 발진기, 구동 증폭기, 전력 증폭기를 집적하여 능동 집적 탐침 시스템을 제작하였다. 치료를 진행하는 동안, 마이크로파의 전력을 측정할 수 있도록 전력 검출기와 방향성 결합기도 함께 집적하였다. 암, 근육 등 다양한 생체 조직을 이용한 실험의 결과로부터 Ku 대역의 주파수에서 저전력 마이크로파 온열 치료가 가능함을 확인하였다. 마지막으로 자성 나노입자를 이용한 온열 치료에 적용하기 위해 능동 집적 탐침을 개발하였다. 자성 나노입자가 온열 치료 요법에 미치는 영향을 분석하기 위해 전자기-열 결합 해석을 수행하였고, 이로부터 자성 나노입자의 선택도 향상을 위한 최적의 주파수를 결정하였다. 발진기와 전력 증폭기 MMIC와 이중 채널 로그 전력 검출기, 방향성 결합기를 탐침에 집적하여 시스템을 제작하였다. 이를 이용한 실험 결과로부터 능동 집적 탐침의 성능을 확인하였으며, 자성 나노입자가 저전력 및 암 특이 마이크로파 온열 치료의 효율과 선택도를 향상시키는데 유용함을 검증하였다.This thesis presents miniaturized microwave active integrated probe systems applicable to cancer detection and treatment. To realize broadband detection and low-power hyperthermia, planar-type coaxial probes and heat applicators have been integrated with active circuits for permittivity measurement and microwave generation, respectively. Each integrated system is implemented on a single platform using Microelectromechanical Systems (MEMS) and monolithic microwave integrated circuit (MMIC) technologies for miniaturization and integration. First, a complex permittivity measurement technique using an integrated multi-state reflectometer (MSR) is proposed for cancer detection application. The broadband MSR covering both 2 and 16 GHz bands consists of a dual-band phase-locked loop, a directional coupler, an impedance tuner, two RF power detectors, and a micromachined silicon planar probe with an open-ended coaxial aperture. All the active and passive circuit components have been integrated on the micromachined probe platform in a small form factor of 6.8 mm × 50 mm × 0.6 mm. The performance of the fabricated integrated probe has been evaluated by comparing the measured permittivities of 0.9% saline, pork muscle, fat, and xenografted human breast cancer with the reference data. For low-power microwave hyperthermia, a Ku-band active integrated heat applicator is demonstrated. A planar-type coaxial applicator has been fabricated using silicon micromachining technology, on which a Ku-band voltage controlled oscillator (VCO), a driver amplifier, and a power amplifier (PA) have been integrated. A directional coupler and power detectors are employed for power monitoring. The fully integrated heat applicator has been realized in a small footprint of 8 mm × 56 mm. In-vitro and in-vivo ablation experiments on pork muscle, fat, and human-cancer xenografted nude mouse demonstrate the feasibility of low-power hyperthermia using Ku-band microwaves. Finally, an active integrated heat applicator for magnetic nanoparticle (MNP)-assisted hyperthermia is developed. The effect of the MNP on microwave hyperthermia has been analyzed by a coupled electromagnetic-thermal analysis. The optimum frequency for hyperthermia is determined by the coupled analysis. A 2-GHz source module consisting of a VCO and a PA has been implemented in MMICs and integrated on the heat applicator platform. A dual-channel log detector and a directional coupler have been also employed to monitor the power levels during hyperthermia. Experiment results show not only sufficient heating performance of the integrated applicator, but also the effectiveness of the MNP for low-power and cancer-specific microwave hyperthermia.Abstract i Contents iv List of Figures viii List of Tables xv 1. Introduction 1 1.1 Motivation 1 1.2 Microwave Cancer Detection 4 1.3 Microwave Hyperthermia 5 1.4 Outline of Thesis 7 2. Active Integrated Probe for Cancer Detection 9 2.1 Introduction 9 2.2 Principle of Operation 13 2.2.1 Multi-State Reflectometer 14 2.2.2 Governing Equation for Complex Permittivity 15 2.2.3 Determination of Complex Permittivity 17 2.2.4 Calibration 19 2.3 Design and Fabrication 21 2.3.1 Micromachined Planar Coaxial Probe 21 2.3.2 Impedance Tuner 30 2.3.3 Directional Coupler 34 2.3.4 Power Detector 37 2.3.5 Signal Source 39 2.3.6 Active Integrated Probe System 43 2.4 Measurement Results 46 2.5 Summary 52 3. Ku-Band Active Integrated Heat Applicator for Cancer Ablation 54 3.1 Introduction 54 3.2 Design and Fabrication 57 3.2.1 Micromachined Planar Coaxial Applicator 58 3.2.2 Microwave Source 63 3.2.3 Power Monitoring Circuits 67 3.2.4 Ku-Band Active Integrated Applicator System 67 3.3 Experiment Results 70 3.4 Summary 77 4. Active Integrated Heat Applicator for Magnetic Nanoparticle-Assisted Hyperthermia 79 4.1 Introduction 79 4.2 Magnetic Nanoparticle (MNP) 82 4.2.1 Heating mechanism of MNP 83 4.2.2 Permeability of MNP 84 4.3 Coupled Electromagnetic-Thermal Analysis 88 4.3.1 Coupled Electromagnetic-Thermal Problems 88 4.3.2 Electromagnetic Analysis 92 4.3.3 Thermal Analysis 94 4.3.4 Analysis Results 96 4.4 Design and Fabrication 103 4.4.1 Spiral Applicator 104 4.4.2 Microwave Source 107 4.4.3 Power Monitoring Circuits 111 4.4.4 Active Integrated Applicator for MNP-Assisted Hyperthermia 119 4.5 Experiment Results 122 4.6 Summary 132 5. Conclusion 134 Bibliography 137 Abstract in Korean 152Docto