Theoretical Basis for Controlling Minimal Tumor Temperature During Interstitial Conductive Heat Therapy

This paper describes simulation of steady-state intratumoral temperatures achieved by a simple modality of local heat therapy: interstitial treatment with parallel arrays of warmed, conductive heating elements. During “conductive heating” power is directly deposited only in the interstitial probes. Adjacent tissue is warmed by heat conduction. Simulations of interstitial conductive heating involved solution of the bioheat transfer equation on a digital computer using a finite difference model of the treated tissue. The simulations suggest that when the complete temperature distributions for conductive interstitial hyperthermia are examined in detail, substantial uniformity of the temperature distributions is evident. Except for a thin sleeve of tissue surrounding each heating element, a broad, flat central valley of temperature elevation is achieved, with a well defined minimum temperature, very close to modal and median tissue temperatures. Because probes are inserted directly in tumor tissue, the thin sleeve of overheated tissue would not be expected to cause normal tissue complications. The temperature of the heated probes must be continuously controlled and increased in the face of increased blood flow in order to maintain minimum tumor temperature. However, correction for changes in blood flow is possible by adjusting probe temperature according to a feedback control scheme, in which power dissipation from each probe is the sensed input variable. Conductive interstitial heating with continually controlled probe temperature deserves investigation as a technique for local hyperthermia therapy

Scalable strategies for tumour targeting of magnetic carriers and seeds

With the evolving landscape of medical oncology, focus has shifted away from nonspecific cytotoxic treatment strategies toward therapeutic paradigms more characteristic of targeted therapies. These therapies rely on delivery vehicles such as nano-carriers or micro robotic devices to boosts the concentration of therapeutics in a specific targeted site inside the body. The use of externally applied magnetic field is suggested to be a predominant approach for remote localisation of magnetically responsive carriers and devices to the target region that could not be otherwise reached. However, the fast decline of the magnetic fields and gradients with increasing distances from the source is posing a major challenge for its clinical application. The aim of this thesis was to investigate potential magnetic delivery strategies which can circumvent some of the typical limitations of this technique. Two different approaches were explored to this end. The first approach was to characterise the ability of a conventional permanent magnet on targeting individual nano-carriers and develop novel magnetic designs which improve the targeting efficiency. The second approach was evaluating the feasibility of a magnetic resonance imaging system to move a millimetre-sized magnetic particle within the body. Phantom and in vivo magnetic targeting experiments illustrated the significant increase in effective targeting depth when our novel magnetic design was used for targeting nano-carriers compared with conventional magnets. In the later part of the thesis, the proof of concept and characterisation experiments showed that a 3 mm magnetic particle can be moved in ex vivo brain tissue using a magnetic resonance imaging system using clinically relevant gradient strengths. The magnetic systems introduced in this thesis provide the potential to target nano-carriers and millimetre-sized thermoseeds to tumours located at deep regions of human body through vasculature and soft tissue respectively

Simulation of Magnetic Nanoparticle Hyperthermia in Prostate Tumors

In clinical studies, it is difficult to determine the temperature distribution throughout both tumor and normal tissue during hyperthermia treatment, since temperatures are sampled at only a limited number of locations with conventional sensors. Simulation studies can help physicians understand better the effects of the treatment. In this study, three 2D tumor models are built in the COMSOL software environment based on the images of nanoparticle distributions in sliced PC3, DU145 and LAPC4 tumors. The images are pre-processed in MATLAB before being imported into COMSOL. A uniform distribution model is added as a control group. Temperature distribution, maximum temperature, time to reach steady state, CEM43, iso-effective dose and heat flux at tumor-tissue boundary are analyzed to evaluate the effect of the nanoparticle distribution on hyperthermia treatment. The results indicate that a more concentrated nanoparticle distribution is better in damaging diseased tissue than the uniform distribution under low heating power. A more uniform distribution is better than the concentrated distribution under high heating power. For concentrated nanoparticle distributions, the location where the nanoparticles are concentrated influences tissue damage: a more centered one has a better effect

マイクロ波温熱と放射線近接照射の組み合わせによる、乳がん向け治療法の検討

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 上坂 充, 東京大学教授 高橋 浩之, 東京大学准教授 関野 正樹, 東京医科歯科大学教授 中島 義和, 千葉大学准教授 齊藤 一幸, 千葉大学客員教授 伊藤 公一University of Tokyo(東京大学

Magnetic Nanomaterials

The constant search for innovative magnetic materials increasingly leads to the creation of highly engineered systems built in different forms (films, wires, particles), structured on the nanoscale in at least one spatial direction, and often characterized by the coexistence of two or more phases that are magnetically and/or structurally different. In magnetic systems, the nanometric structural characteristics of the constituent elements, together with the type and strength of the magnetic interactions between them, determine the overall magnetic behavior and can lead to the appearance of unexpected and amazing magnetic phenomena. Indeed, the study of the magnetic properties of nanomaterials continues to arouse great interest for their intriguing fundamental properties and prospective technological applications. This Special Issue contributes to broadening the knowledge on magnetic nanomaterials, demonstrating the breadth and richness of this research field as well as the growing need to address it through an interdisciplinary approach. The papers collected in this book (two reviews and eight regular articles) report cutting-edge studies on the production and characterization of a variety of novel magnetic nanomaterials (nanoparticles, nanocomposites, thin films and multilayers), which have the potential to play a key role in different technologically advanced sectors, such as biotechnology, nanomedicine, energy, spintronics, data storage, and sensors

Magnetically induced localized on-demand drug delivery

Externally triggered on-demand drug release from an implant can significantly improve the efficiency of the drug therapy since it enables the patient or physician to control the dosing to the patient’s needs and releases the drug only at the required location in the human body. Therefore, patient compliance and efficacy will increase and toxic side effects decrease as untargeted locations are not exposed to significant drug levels as is often the case in systemic drug administration. In this work, the externally triggered drug delivery system is a thermoresponsive polymeric implant triggered using an alternating magnetic field. The thermal switch is based on a significant change in diffusivity of a solute around the glass transition temperature (Tg) of a polymer. At a temperature below the glass transition temperature of the polymer (TTg), the polymer becomes rubbery. This significantly increases the flexibility and free volume of the polymer resulting in release of the active. Since the glass transition is a reversible transition, subsequent lowering of the temperature significantly decreases the drug release rate from the implant, enabling pulsatile drug administration. The temperature of the implant is increased using an externally applied alternating magnetic field. In order to increase the temperature of the implant using a magnetic field, the use of superparamagnetic iron oxide nanoparticles (SPION) is explored. These nanoparticles are used as MRI contrast agents and to locally increase the temperature in hyperthermia treatment, the destruction of tumors by elevated temperature. The particles have no remanent magnetization, are biocompatible and are able to generate thermal energy using an alternating magnetic field because of N´eel and Brown relaxation. N´eel relaxation is the reorientation of the magnetic moment within the particles, generating thermal energy by crossing an anisotropy barrier, and Brown relaxation the reorientation of the magnetic particles itself, generating thermal energy by viscous friction with the carrier fluid. Since the nanoparticles are used for heating a polymer implant, different preparation methods for an iron oxide - polymer nanocomposite have been investigated. Freeze drying a mixture of a ferrofluid with a poly(methyl methacrylate) (p(MMA)) latex and subsequent compounding, results in an optimal distribution of the particles. It is expected that the particles do not agglomerate because of the combination of stabilization of both the iron oxide particles and polymer latex by surfactants, and the lack of mobility during freeze drying. Other methods used, e.g. solvent casting and direct injection of the ferrofluid into the compounder, result in significant agglomeration of the particles. Subsequently, the particle distribution has been shown to have a significant effect on the heating of the particle. An optimal distribution of the particles results in the highest specific absorption rate (SAR), the amount of thermal energy generated per gram of iron oxide, because of a minimum in interparticle interactions. Since the nanoparticles incorporated in a polymer are immobilized, the particles are not able to generate thermal energy by Brown relaxation. By a direct comparison of the specific absorption rate of particles suspended in liquid and incorporated in p(MMA) using the optimal freeze drying method, the contribution of both N´eel and Brown relaxation to the heating of SPION has been investigated. Since the observed SAR is identical in both situations, it is concluded that at the frequency used (745 kHz), N´eel relaxation is the only relaxation process that contributes to the heating of the particles in ferrofluid, because of the significantly shorter relaxation time for N´eel relaxation. Using a cylindrical core of iron oxide - p(MMA) nanocomposite, coated with a thermoresponsive poly(butyl methacrylate-stat -methyl methacrylate) (p(BMAMMA)) layer, externally triggered on-demand drug release has been investigated. A model drug, ibuprofen, has been incorporated in the thermoresponsive p(BMAMMA) coating. Upon exposure of the sample to an alternating magnetic field (on situation), the drug release rate is significantly increased compared to the release rate without the magnetic field (off situation). After the magnetic field is removed, the release rate decreases back to the rate prior to the exposure, demonstrating the reversibility of the system. Multiple consecutive exposures to the external trigger result in similar increases of the release rate. Increasing the iron oxide concentration in the core of the device increases the release rate upon exposure, whereas the release rate without exposure is not influenced, therefore increasing the on/off ratio, because of a higher temperature increase upon exposure. Even though externally triggered pulsatile drug release has been shown, the maximum on/off ratio obtained is only 16.5. This relatively low ratio is primarily due to the suboptimal nature of the used commercially available iron oxide and the relative high off release rate of ibuprofen from p(BMA-MMA). In order to increase the on/off ratio, a cylindrical iron core has been used, coated with an ibuprofen incorporated poly(styrene-stat -butyl methacrylate) (p(S-BMA)) layer. The heat generated in the iron core upon exposure to the magnetic field is due to induction heating. Externally triggered pulsatile drug release has been shown using this concept with on/off ratios exceeding 2000, where both the on/off ratio and the release rate are affected by the concentration of ibuprofen. Generally, decreasing the base temperature of the release experiments from 37 to 25 ¿C significantly increases the on/off ratio. The effect of the orientation of the cylindrical iron rod with respect to the direction of the magnetic field on the heating of the device has been investigated using a Comsol model. Even though the effect of orientation is limited at small angles, a significantly lower surface temperature has been shown for larger angles, up to ~20 ¿C. This can result in a several orders of magnitude difference for the diffusion coefficient of ibuprofen in the polymer. Subsequently, the requirement of alignment between the sample and the magnetic field has been circumvented by the use of a macroscopic spherical iron core, coated with ibuprofen incorporated p(S-BMA). The absence of an alignment effect has been shown using 1 sample and 2 samples in line with the magnetic field, as this does not influence the release rate and on/off ratio, normalized to the surface area available for release in on-demand release experiments. Therefore, it is possible to use multiple samples to increase the attainable drug dose. Increasing the size of the spherical iron core and, therefore, decreasing the polymer thickness, only increases the release rate upon exposure, resulting in higher on/off ratios. In the case of a thinner polymer layer, the distance between the heating core and the outer surface of the polymer is smaller, resulting in a higher temperature of the outer layer. The solubility of a solute in a polymer is predominantly important for the release characteristics of that solute from the polymer. Therefore, the solubility of ibuprofen in p(S-BMA) has been investigated. Even though samples of p(S-BMA) with an ibuprofen concentration above 31 wt% show a clear phase separation, indicating maximum solubility at 31 wt% ibuprofen, measurement of the glass transition temperature of composites show that the system of p(S-BMA) with ibuprofen concentrations below 31 wt% is in a meta-stable state. In conclusion, repetitive on-demand drug release from a polymeric implant can be externally triggered using an alternating magnetic field. Due to their biocompatibility and the absence of an alignment effect, superparamagnetic iron oxide nanoparticles are preferable for the required heat generation. However, more optimal nanoparticles are required for high on/off ratios, as has been shown using another material for heat generation

Materials Science and Technology

Materials are important to mankind because of the benefits that can be derived from the manipulation of their properties, for example electrical conductivity, dielectric constant, magnetization, optical transmittance, strength and toughness. Materials science is a broad field and can be considered to be an interdisciplinary area. Included within it are the studies of the structure and properties of any material, the creation of new types of materials, and the manipulation of a material's properties to suit the needs of a specific application. The contributors of the chapters in this book have various areas of expertise. therefore this book is interdisciplinary and is written for readers with backgrounds in physical science. The book consists of fourteen chapters that have been divided into four sections. Section one includes five chapters on advanced materials and processing. Section two includes two chapters on bio-materials which deal with the preparation and modification of new types of bio-materials. Section three consists of three chapters on nanomaterials, specifically the study of carbon nanotubes, nano-machining, and nanoparticles. Section four includes four chapters on optical materials