This PDF file contains the front matter associated with SPIE Proceedings Volume 7901, including the Title Page, Copyright information, Table of Contents, Introduction, and the Conference Committee listing.

Applications of low energy non-ionizing irradiation result in non-lethal and lethal effects in cells, tissues and intact individuals. The effects of these applications depend on the physical parameters of the applied energies, the mechanisms of interaction of these energies on the target and the biologic status of the target. Recently, cell death has been found not to be a random accident of situation or age but a range of complicated physiological responses to various extrinsic and intrinsic events some of which are genetically programmed and/ or physiologically regulated. Therefore, cell death has been classified into three general groups: 1) Programmed cell death including apoptosis and necroptosis, cornefication and autophagy; 2) Accidental (traumatic) cell death due to the direct, immediate effects of the lethal event and 3) Necrotic cell death which is, by default, all cell death not associated with programmed or accidental cell death. Lethal low energy non-ionizing application biologic effects involve mechanisms of all three groups as compared to high energy applications that predominantly involve the mechanisms of accidental cell death. Currently, the mechanisms of all these modes of cell death are being vigorously investigated. As research and development of new low energy applications continues, the need to understand the mechanisms of cell death that they produce will be critical to the rational creation of safe, yet effective instruments.

Currently, hyperthermic-based minimally invasive medical devices are available for the treatment of dysfunctional and neoplastic tissues in a variety of organ systems. These therapies employ a spectrum of modalities for delivering heat energy to the targeted tissue, including radiofrequency/microwave, high intensity focused ultrasound, conductive/convective sources and others. While differences in energy transfer and organ systems exist, hyperthermic treatment sites show a spectrum of changes that intimately correlate with the thermal history generated in the tissue (temperature-time dependence). As a result, these hyperthermic medical technologies can be viewed using a "gradient" approach. First, the thermal applications themselves can be globally categorized along a high-dose ablation to low-dose ablation to lowdose non-ablative rejuvenating slope. Second, the resultant tissue changes can be viewed along a decreasing thermal dose gradient from thermally/heat-fixed tissue necrosis to coagulative tissue necrosis to partial tissue necrosis (transition zone) to subtle non-necrotizing tissue changes. Finally, a gradient of cellular and structural protein denaturation is present, especially within the transition zone and adjacent viable tissue region. A hyperthermic treatment's location along these gradients depends more on the overall thermal history it generates than the amount of energy it deposits into the tissue. The features of these gradients are highlighted to provide a better understanding of hyperthermic device associated tissue changes and their associated healing responses.

Novel non-ablative hyperthermic medical devices are currently being developed, in association with cryogen surface cooling, to rejuvenate tissues without collagen scarring. These devices have been designed to remodel skin, manage urinary stress incontinence, and more recently, treat vaginal laxity. In contrast to the thermal injury and reparative healing associated with higher energy ablation systems, these lower energy non-ablative systems are designed to subtly modify the collagen, stimulate the fibroblasts, and maintain a functional tissue architecture that subsequently promotes tissue rejuvenation and restoration. While these devices have primarily relied on clinical outcome questionnaires and satisfaction surveys to establish efficacy, a physiologic explanation for the induced tissue changes and tightening has not been well documented. Recent histology studies, using the Viveve ovine vaginal treatment model, have identified changes that propose both a mechanism of action and a tissue remodeling timeline for such non-ablative hyperthermic devices. The Viveve model results are consistent with subtle connective tissue changes leading to fibroblast stimulation and subsequent collagen replacement and augmentation. Unlike tissue ablation devices that cause thermal necrosis, these non-ablative devices renew the targeted tissue without dense collagenous scarring over a period of 3 or more months. The spectrum of histologic findings, as illustrated in the Viveve ovine vaginal model, further support the previously documented safety and efficacy profiles for low-dose non-ablative hyperthermic devices that rejuvenate and tighten submucosal tissues.

Electromechanical reshaping (EMR) of cartilage has been suggested as an alternative to the classical surgical techniques of modifying the shape of facial cartilages. The method is based on exposure of mechanically deformed cartilaginous tissue to a low level electric field. Electro-chemical reactions within the tissue lead to reduction of internal stress, and establishment of a new equilibrium shape. The same reactions offset the electric charge balance between collagen and proteoglycan matrix and interstitial fluid responsible for maintenance of cartilage mechanical properties. The objective of this study was to investigate correlation between the electric charge transferred during EMR and equilibrium elastic modulus. We used a finite element model based on the triphasic theory of cartilage mechanical properties to study how electric charges transferred in the electro-chemical reactions in cartilage can change its mechanical responses to step displacements in unconfined compression. The concentrations of the ions, the strain field and the fluid and ion velocities within the specimen subject to an applied mechanical deformation were estimated and apparent elastic modulus (the ratio of the equilibrium axial stress to the axial strain) was calculated as a function of transferred charge. The results from numerical calculations showed that the apparent elastic modulus decreases with increase in electric charge transfer. To compare numerical model with experimental observation we measured elastic modulus of cartilage as a function of electric charge transferred in electric circuit during EMR. Good correlation between experimental and theoretical data suggests that electric charge disbalance is responsible for alteration of cartilage mechanical properties.

Thermal treatment is commonly performed interstitially in either surgical or percutaneous procedures, using microwave antenna sources at 915 or 2540 MHz. There are a number of tools or aids as well as challenges for clinicians performing these procedures in the course of patient treatment. These challenges will be present whether the procedure is surgical, laparoscopic, or percutaneous, and include treatment planning, image guidance, navigation, coregistration in 3D, and treatment assessment. Treatment planning has been used historically in hyperthermia for microwave antenna arrays, but has yet to be properly applied in thermal ablation. Image assessment of thermal treatment is not typically performed in real time, although these tools will provide the clinician with further information to understand the extent of treatment and whether further treatment is needed. 3D imaging is available, but not coregistered to patient space. Navigation has been used in many medical specialties, but is also not in the clinician's toolbox in thermal treatment. Although treatment planning will lay out the skin entry and trajectory for each antenna placed, subsequently, each antenna needs to be tracked to accurately show placement in the patient and overlaid in patient space, along with the tumor target location. Some patient treatments may consist of multiple, but sequential single placements of an antenna, and guidance is even more critical to track positions and plan for the next insertion. Lastly, real-time image assessment will show the extent and shape of the coagulated lesion and which targets may have been undertreated. If used synchronously in arrays, MW power steering may also aid in filling in the ablation as the treatment progresses. This paper will analyze the present state-of-the art as well as a strategy to incorporate the various facets of planning, guidance, and assessment of treatment. The integration of thermal treatment planning, navigation and guidance, robotics, and treatment assessment continues to evolve to provide better assistance for clinicians in order to provide targeting optimization with the goal of improved treatment for the patient. Ultimately, the effect on patient outcomes will determine the value of the technology.

Numerous studies have demonstrated the efficacy of interstitial ablative approaches for the treatment of renal and hepatic tumors. Despite these promising results, current systems remain highly dependent on operator skill, and cannot treat many tumors because there is little control of the size and shape of the zone of necrosis, and no control over ablator trajectory within tissue once insertion has taken place. Additionally, tissue deformation and target motion make it extremely difficult to accurately place the ablator device into the target. Irregularly shaped target volumes typically require multiple insertions and several sequential thermal ablation procedures. This study demonstrated feasibility of spatially tracked image-guided conformal ultrasound (US) ablation for percutaneous directional ablation of diseased tissue. Tissue was prepared by suturing the liver within a pig belly and 1mm BBs placed to serve as needle targets. The image guided system used integrated electromagnetic tracking and cone-beam CT (CBCT) with conformable needlebased high-intensity US ablation in the interventional suite. Tomographic images from cone beam CT were transferred electronically to the image-guided tracking system (IGSTK). Paired-point registration was used to register the target specimen to CT images and enable navigation. Path planning is done by selecting the target BB on the GUI of the realtime tracking system and determining skin entry location until an optimal path is selected. Power was applied to create the desired ablation extent within 7-10 minutes at a thermal dose (>300eqm43). The system was successfully used to place the US ablator in planned target locations within ex-vivo kidney and liver through percutaneous access. Targeting accuracy was 3-4 mm. Sectioned specimens demonstrated uniform ablation within the planned target zone. Subsequent experiments were conducted for multiple ablator positions based upon treatment planning simulations. Ablation zones in liver were 73cc, 84cc, and 140cc for 3, 4, and 5 placements, respectively. These experiments demonstrate the feasibility of combining real-time spatially tracked image guidance with directional interstitial ultrasound ablation. Interstitial ultrasound ablation delivered on multiple needles permit the size and shape of the ablation zone to be "sculpted" by modifying the angle and intensity of the active US elements in the array. This paper summarizes the design and development of the first system incorporating thermal treatment planning and integration of a novel interstitial acoustic ablation device with integrated 3D electromagnetic tracking and guidance strategy.

Advances in medical imaging now provide detailed images of solid tumors inside the body and miniaturized energy delivery systems enable tumor destruction through local heating powered by a thin electrode. We have developed a robot for accurately repositioning the distal tip of a medical instrument such an ablation probe to adjacent points within tissue. The position accuracy in ballistics gelatin was evaluated in a 2D experimental setup with a digital SLR camera that was fixed to a rig that also contained the gelatin. The robot was mounted to the rig in such a way that the stylet was deployed in a plane parallel the camera's lens. A grid paper attached to the back of the box containing the gelatin provided a stationary reference point for each of the pictures taken and also served as a coordinate system for making measurements. The measurement repeatability error was found by taking a stylet tip position measurement five times for two different pictures and found to be 0.26 mm. For a stylet with a radius of curvature of 31.5 mm and a diameter of 0.838 mm, the targeting accuracy was found to be 2.5 ± 1.4 mm at points that were approximately 38 mm lateral from the cannula axis.

The purpose is to develop a patient-specific treatment planning method for a cylindrically-focused (i.e., SonoKnife) ultrasound thermal therapy system to optimize the thermal treatment of locally-advanced head and neck squamous cell carcinomas (HNSCC) and/or positive lymph nodes. To achieve a more efficient and effective treatment, a temperature-based treatment planning was devised, which was composed of : (1) a 3D acoustic-thermal model has been developed to simulate the acoustic field, temperature distribution, and thermal dose coverage induced by the SonoKnife applicator. (2) A 3D relevant anatomical structures (e.g. the H&N tumors, bones and cavities) were reconstructed based on multislice CT scans. A step-and-shoot strategy was devised to perform the treatment, in which the initial applied power levels, placement of the transducers, and sonication times per scan were determined by conducting a temperature-based forward simulation. The maximum temperature, thermal dose coverage of target, and thermal exposure to surrounding tissue were analyzed. For performance evaluation, the treatment planning was applied on representative examples obtained from the clinical radiation therapy of HNSCC and positive lymph nodes. This treatment planning platforms can be used to guide applicator placement, set-up configurations, and applied power levels prior to delivery of a treatment or for post-procedure analysis of temperature distributions.

Essential developments in the reliable and effective use of heat in medicine include: 1) the ability to model energy deposition and the resulting thermal distribution and tissue damage (Arrhenius models) over time in 3D, 2) the development of non-invasive thermometry and imaging for tissue damage monitoring, and 3) the development of clinically relevant algorithms for accurate prediction of the biological effect resulting from a delivered thermal dose in mammalian cells, tissues, and organs. The accuracy and usefulness of this information varies with the type of thermal treatment, sensitivity and accuracy of tissue assessment, and volume, shape, and heterogeneity of the tumor target and normal tissue. That said, without the development of an algorithm that has allowed the comparison and prediction of the effects of hyperthermia in a wide variety of tumor and normal tissues and settings (cumulative equivalent minutes/ CEM), hyperthermia would never have achieved clinical relevance. A new hyperthermia technology, magnetic nanoparticle-based hyperthermia (mNPH), has distinct advantages over the previous techniques: the ability to target the heat to individual cancer cells (with a nontoxic nanoparticle), and to excite the nanoparticles noninvasively with a noninjurious magnetic field, thus sparing associated normal cells and greatly improving the therapeutic ratio. As such, this modality has great potential as a primary and adjuvant cancer therapy. Although the targeted and safe nature of the noninvasive external activation (hysteretic heating) are a tremendous asset, the large number of therapy based variables and the lack of an accurate and useful method for predicting, assessing and quantifying mNP dose and treatment effect is a major obstacle to moving the technology into routine clinical practice. Among other parameters, mNPH will require the accurate determination of specific nanoparticle heating capability, the total nanoparticle content and biodistribution in the target cells/tissue, and an effective and matching alternating magnetic field (AMF) for optimal and safe excitation of the nanoparticles. Our initial studies have shown that appropriately delivered and targeted nanoparticles are capable of achieving effective tumor cytotoxicity at measured thermal doses significantly less than the understood thermal dose values necessary to achieve equivalent treatment effects using conventional heat delivery techniques. Therefore conventional CEM based thermal dose - tissues effect relationships will not hold for mNPH. The goal of this effort is to provide a platform for determining the biological and physical parameters that will be necessary for accurately planning and performing safe and effective mNPH, creating a new, viable primary or adjuvant cancer therapy.

Electromagnetic heating of nanoparticles is complicated by the extremely short thermal relaxation time constants and difficulty of coupling sufficient power into the particles to achieve desired temperatures. Magnetic field heating by the hysteresis loop mechanism at frequencies between about 100 and 300 kHz has proven to be an effective mechanism in magnetic nanoparticles. Experiments at 2.45 GHz show that Fe₃O₄ magnetite nanoparticle dispersions in the range of 10¹² to 10¹³ NP/mL also heat substantially at this frequency. An FEM numerical model study was undertaken to estimate the order of magnitude of volume power density, Q_gen (W m^-3) required to achieve significant heating in evenly dispersed and aggregated clusters of nanoparticles. The FEM models were computed using Comsol Multiphysics; consequently the models were confined to continuum formulations and did not include film nano-dimension heat transfer effects at the nanoparticle surface. As an example, the models indicate that for a single 36 nm diameter particle at an equivalent dispersion of 10¹³ NP/mL located within one control volume (1.0 x 10^-19 m³) of a capillary vessel a power density in the neighborhood of 10¹⁷ (W m^-3) is required to achieve a steady state particle temperature of 52°C - the total power coupled to the particle is 2.44 μW. As a uniformly distributed particle cluster moves farther from the capillary the required power density decreases markedly. Finally, the tendency for particles in vivo to cluster together at separation distances much less than those of the uniform distribution further reduces the required power density.

Biomedical applications of nanoparticle heating range in scale from molecular activation (i.e. molecular beacons, protein denaturation, lipid melting and drug release), cellular heating (i.e. nanophotolysis and membrane permeability control and rupture) to whole tumor heating (deep and superficial). This work will present a review on the heating of two classes of biologically compatible metallic nanoparticles: iron oxide and gold with particular focus on spatial and temporal scales of the heating event. The size range of nanoparticles under discussion will focus predominantly in the 10 - 200 nm diameter size range. Mechanisms of heating range from Néelian and Brownian relaxation due to magnetic susceptibility at 100s of kHz, optical absorption due to VIS and NIR lasers and "Joule" heating at higher frequency RF (13.56 MHz). The heat generation of individual nanoparticles and the thermal responses at nano-, micro-, and macroscales are presented. This review will also discuss how to estimate a specific absorption rate (SAR, W/g) based on individual nanoparticles heating in bulk samples. Experimental setups are designed to measure the SAR and the results are compared with theoretical predictions.

We discuss in this article the implementation of a laser-tissue interaction and bioheat-transfer 2-D finite-element model for Photothermal Therapy assisted with Gold Nanorods. We have selected Gold Nanorods as absorbing nanostructures in order to improve the efficiency of using compact diode lasers because of their high opto-thermal conversion efficiency at 808 and 850 nm. The goal is to model the distribution of the optical energy among the tissue including the skin absorption effects and the tissue thermal response, with and without the presence of Gold Nanorods. The heat generation due to the optical energy absorption and the thermal propagation will be computationally modeled and optimized. The model has been evaluated and compared with experimental ex-vivo data in fresh chicken muscle samples and in-vivo BALB/c mice animal model.

Hyperthermia has been shown to be an effective radiosensitizer. Its utility as a clinical modality has been limited by a minimally selective tumor sensitivity and the inability to be delivered in a tumor-specific manner. Recent in vivo studies (rodent and human) have shown that cancer cell-specific cytotoxicity can be effectively and safely delivered via iron oxide magnetic nanoparticles (mNP) and an appropriately matched noninvasive alternating magnetic field (AMF). To explore the tumor radiosensitization potential of mNP hyperthermia we used a syngeneic mouse breast cancer model, dextran-coated 110 nm hydrodynamic diameter mNP and a 169 kHz / 450 Oe (35.8 kA/m) AMF. Intradermally implanted (flank) tumors (150 ± 40 mm³) were treated by injection of 0.04 ml mNP (7.5 mg Fe) / cm³ into the tumor and an AMF (35.8 kA/m and 169 kHz) exposure necessary to achieve a CEM (cumulative equivalent minute) thermal dose of 60 (CEM 60). Tumors were treated with mNP hyperthermia (CEM 60), radiation alone (15 Gy, single dose) and in combination. Compared to the radiation and heat alone treatments, the combined treatment resulted in a greater than two-fold increase in tumor regrowth tripling time (tumor treatment efficacy). None of the treatments resulted in significant normal tissue toxicity or morbidity. Studies were also conducted to compare the radiosensitization effect of mNP hyperthermia with that of microwave-induced hyperthermia. The effects of incubation of nanoparticles within tumors (to allow nanoparticles to be endocytosed) before application of AMF and radiation were determined. This preliminary information suggests cancer cell specific hyperthermia (i.e. antibody-directed or anatomically-directed mNP) is capable of providing significantly greater radiosensitization / therapeutic ratio enhancement than other forms of hyperthermia delivery.

Low temperature sensitive liposomes (LTSL) are drug delivery vehicles with long plasma half-life, which release the drug upon heating above ~40°C. The combination of LTSL with local heat generated by image-guided focused ultrasound may thus allow non-invasively targeted drug delivery. We combined a heat-transfer model with a drug delivery model to determine temperature-dependent release and tumor tissue accumulation of drug in extravascular-extracellular space, and inside cells. Tissue was heated with a 16 mm focal spot for 7 min at 43°C target temperature. In addition we examined the effect of an additional subsequent high-temperature pulse to eliminate blood flow after drug release. Our results show high local plasma concentration during hyperthermia at the target site, during which drug is taken up by tissue and finally by cells. Following heating, local plasma concentration rapidly drops off and drug not taken up by cells is removed from tissue by blood flow. Elimination of blood flow following hyperthermia by a high-temperature pulse avoided this removal and resulted in ~2x higher intracellular concentration.

Intense, nanosecond-duration electric pulses (nsEP) have been introduced as a novel modality to alter cellular function, with a mechanism of action qualitatively different from micro- and millisecond duration pulses used in electroporation. In this study, we determined the thresholds for plasma membrane injury (within 15 minutes) and cell death (at 24 hours) for 4 different cell types (CHO-K1, HeLa, Jurkat and U937). Plasma membrane injury was measured by flow cytometry using two fluorescent dyes, namely Annexin V-FITC, which binds to phosphatidylserine (PS) upon its externalization (subtle membrane injury), and propidium iodide (PI), which is typically impermeable to the cell, but enters when large pores are formed in the plasma membrane. In all cell types, 10-ns pulses caused phosphatidylserine (PS) externalization at low doses (<150kV/cm and 100 pulses for each cell type) and no PI uptake. Jurkat and U937 cell lines showed substantial cell death without uptake of PI (15 minutes post exposure) suggesting either delayed permeabilization due to swelling, or damage to intracellular components. In CHO-K1 and HeLa cell lines, PI uptake occurred at low doses relative to that necessary to cause cell death suggesting a necrotic death similar to longer pulse exposures. These findings suggest that nanosecond pulses may be beneficial in applications that require selective elimination of specific cell types.

Macrophages create a major danger signal following injury or infection and upon activation release pro-inflammatory cytokines, which in turn help to generate febrile conditions. Thus, like other cells of the body, tissue macrophages are often exposed to naturally occurring elevations in tissue temperature during inflammation and fever. However, whether macrophages sense and respond to temperature changes in a specific manner which modulates their function is still not clear. In this brief review, we highlight recent studies which have analyzed the effects of temperatures on macrophage function, and summarize the possible underlying molecular mechanisms which have been identified. Mild, physiological range hyperthermia has been shown to have both pro- and anti-inflammatory roles in regulating macrophage inflammatory cytokine production and at the meeting presentation, we will show new data demonstrating that hyperthermia can indeed exert both positive and negative signals to macrophages. While some thermal effects are correlated with the induction of heat shock factors/heat shock proteins, overall it is not clear how mild hyperthermia can exert both pro- and anti-inflammatory functions. We also summarize data which shows that hyperthermia can affect other macrophage effector functions, including the anti-tumor cytotoxicity. Overall, these studies may help us to better understand the immunological role of tissue temperature and may provide important information needed to maximize the application of heat in the treatment of various diseases including cancer.

The cellular response to subtle membrane damage following exposure to nanosecond electric pulses (nsEP) is not well understood. Recent work has shown that when cells are exposed to nsEP, ion permeable nanopores (< 2nm) are created in the plasma membrane in contrast to larger diameter pores (> 2nm) created by longer micro and millisecond duration pulses. Macroscopic damage to a plasma membrane by a micropipette has been shown to cause internal vesicles (lysosomes) to undergo exocytosis to repair membrane damage, a calcium mediated process called lysosomal exocytosis. Formation of large pores in the plasma membrane by electrical pulses has been shown to elicit lysosomal exocytosis in a variety of cell types. Our research objective is to determine whether lysosomal exocytosis will occur in response to nanopores formed by exposure to nsEP. In this paper we used propidium iodide (PI) and Calcium Green-1 AM ester (CaGr) to differentiate between large and small pores formed in CHO-K1 cells following exposure to either 1 or 20, 600-ns duration electrical pulses at 16.2 kV/cm. This information was compared to changes in membrane organization observed by increases in FM1-43 fluorescence, both in the presence and absence of calcium ions in the outside buffer. In addition, we monitored the real time migration of lysosomes within the cell using Cellular Lights assay to tag LAMP-1, a lysosomal membrane protein. Both 1 and 20 pulses elicited a large influx of extracellular calcium, while little PI uptake was observed following a single pulse exposure. Statistically significant increases in FM1-43 fluorescence were seen in samples containing calcium suggesting that calcium-triggered membrane repair may be occurring. Lastly, density of lysosomes within cells, specifically around the nucleus, appeared to change rapidly upon nsEP stimulation suggesting lysosomal migration.

In the present work the effects of high-power femtosecond laser irradiation on a functional condition of red blood cells and neutrophils in vitro have been investigated. The data on parameters of the lipid peroxidation - antioxidants system, hemoglobin level and rigidity of red blood cell membranes testify destabilization of the membranes under the influence of the given laser. The study of phagocytic activity, anaerobic and aerobic metabolism of neutrophils, and rigidity of their membranes allows to suppose the dose-dependent effect to be stimulating.

The aim of the study was to investigate the thermal effects of the 1940-nm Tm-fiber laser on the dead brain tissue. 4-5 mm coronal sections were taken from lamb brains. Tm-fiber laser was applied at the back (cortical) and below the cortex (subcortical) of these slices with 0.5 mm distance. At the beginning of the research in order to find appropriate laser parameter to be compared for 1940-nm Tm-fiber laser, the carbonization and coagulation times of the brain slices were recorded for each power value, both for cortical and subcortical tissue. The appropriate laser parameters for lamb brain tissue were selected according to this study. Lasers were applied in both continuous and pulsed modes. In continuous mode, doses were changed with fixed application time. In pulsed mode, doses were modified with the change in pulse width. The lesions were detected with microscope. The radius of ablation and coagulation for each laser application was recorded. By calculating ablation efficiency (100xablation/calculation radius) the aproppriate laser doses were determined for both cortical and subcortical tissue. The maximum ablation efficiency for cortical tissue in continuous mode was 200 mW and 600 mW and in pulsed mode was 600 mW and for subcortical tissue maximum ablation efficiency was found 600 mW in both continuous mode and pulsed mode.

Magnetic resonance guided focused ultrasound surgery (MRgFUS) is an emerging technology that can non-invasively heat and ablate targeted tissue utilizing ultrasound energy. Use of MR imaging for treatment guidance provides several key advantages over more widely used ultrasound guidance for focused ultrasound ablation. MR allows for precise targeting, detailed beam path visualization, real time non-invasive temperature measurement, and treatment feedback to ensure therapeutic goals are achieved. In the realm of oncology, management of painful bone metastases is a common and daunting clinical problem. The Insightec ExAblate System has been shown in phase I/II trials for treatment of bone metastases to have an excellent safety profile and high rates of pain response. An international multi-center phase III trial for patients with painful bone metastases or multiple myeloma who are not candidates for radiation therapy is currently open. Patients are randomized 3:1 to MRgFUS or sham treatment with crossover to study treatment allowed for sham failures. The primary study endpoint is assessment of pain control over 3 months following treatment. In addition safety, quality of life, cost effectiveness analysis, and patient perceived clinical benefit are also being assessed. Details of the MRgFUS system, technical and clinical therapeutic parameters, use of real time non-invasive MR thermometry, and examples of patient treatments with use of MRgFUS to treat bone metastases will be discussed. New directions in use of MRgFUS including an update on development of a new mobile applicator and integration of MRgFUS in multimodality oncologic care will also be presented.

High intensity focused ultrasound (HIFU) uses focused ultrasound beams to ablate localized tumors noninvasively. Multiple clinical trials using HIFU treatment of liver, kidney, breast, pancreas and brain tumors have been conducted, while monitoring the temperature distribution with various imaging modalities such as MRI, CT and ultrasound. HIFU has achieved only minimal acceptance partially due to insufficient guidance from the limited temperature monitoring capability and availability. MR proton resonance frequency (PRF) shift thermometry is currently the most effective monitoring method; however, it is insensitive in temperature changes in fat, susceptible to motion artifacts, and is high cost. Exploiting the relationship between dielectric properties (i.e. permittivity and conductivity) and tissue temperature, in vivo dielectric property distributions of tissue during heating were reconstructed with our microwave tomographic imaging technology. Previous phantom studies have demonstrated sub-Celsius temperature accuracy and sub-centimeter spatial resolution in microwave thermal imaging. In this paper, initial animal experiments have been conducted to further investigate its potential. In vivo conductivity changes inside the piglet's liver due to focused ultrasound heating were observed in the microwave images with good correlation between conductivity changes and temperature.

A clinical treatment delivery platform has been developed and is being evaluated in a clinical pilot study for providing 3D controlled hyperthermia with catheter-based ultrasound applicators in conjunction with high dose rate (HDR) brachytherapy. Catheter-based ultrasound applicators are capable of 3D spatial control of heating in both angle and length of the devices, with enhanced radial penetration of heating compared to other hyperthermia technologies. Interstitial and endocavity ultrasound devices have been developed specifically for applying hyperthermia within HDR brachytherapy implants during radiation therapy in the treatment of cervix and prostate. A pilot study of the combination of catheter based ultrasound with HDR brachytherapy for locally advanced prostate and cervical cancer has been initiated, and preliminary results of the performance and heating distributions are reported herein. The treatment delivery platform consists of a 32 channel RF amplifier and a 48 channel thermocouple monitoring system. Controlling software can monitor and regulate frequency and power to each transducer section as required during the procedure. Interstitial applicators consist of multiple transducer sections of 2-4 cm length × 180 deg and 3-4 cm × 360 deg. heating patterns to be inserted in specific placed 13g implant catheters. The endocavity device, designed to be inserted within a 6 mm OD plastic tandem catheter within the cervix, consists of 2-3 transducers × dual 180 or 360 deg sectors. 3D temperature based treatment planning and optimization is dovetailed to the HDR optimization based planning to best configure and position the applicators within the catheters, and to determine optimal base power levels to each transducer section. To date we have treated eight cervix implants and six prostate implants. 100 % of treatments achieved a goal of >60 min duration, with therapeutic temperatures achieved in all cases. Thermal dosimetry within the hyperthermia target volume (HTV) and clinical target volume (CTV) are reported. Catheter-based ultrasound hyperthermia with HDR appears feasible with therapeutic temperature coverage of the target volume within the prostate or cervix while sparing surrounding more sensitive regions.

Conformable hyperthermia can be administered in the prostate, immediately following radiation, using multiple (2-6) directional ultrasound transducer arrays through previously implanted HDR brachytherapy catheters. These ultrasound devices provided controlled heating in angle and length. To plan a hyperthermia treatment, the patient anatomy and catheter geometry were reconstructed from CT images. Transducer powers were estimated to maximize the heated tumor volume, while sparing the surrounding organs. Fast computation of temperature elevations was performed by approximating the temperature rise induced at a point as the superposition of temperature increases resulting from individual transducers. Steady state temperature increases due to individual transducer elements (90 - 360° sector angles, 0 - 2 W) were precalculated and stored in a lookup table. Instead of using computationally expensive 3D finite element methods (FEM), temperature profiles were generated through interpolation and superposition of the precomputed data. These approximate models were included in a gradient search optimization, reducing the treatment planning time by a factor greater than 4.0 compared to the FE model. For 10 patient cases with dominant intraprostatic lesions, the optimized treatment plans were furnished in 10 - 35 minutes and yielded T₉₀ > 40.0°C in most cases. The corresponding T₉₀ values obtained through rigorous FE modeling were within 0.5 °C.

The SonoKnife is a scan-able high intensity line-focused ultrasound device for thermal ablation (52 - 60°C) of superficially located advanced tumors or nodal disease in the head and neck. Based on preliminary simulation results, a prototype cylindrical section transducer operating at 3.5 MHz, with a 60 mm radius of curvature, an elevation of 30 mm and an aperture of 60 mm, was constructed for laboratory testing. The three-dimensional distribution of the acoustic field was measured in water and compared to preliminary numerical results. Ablation experiments were performed in gel phantoms, in porcine liver ex vivo and in live piglets. The experimental results agreed well with the theoretical simulations and showed that the SonoKnife transducer had a narrow acoustic edge and is able to ablate living biological tissues at practical power levels.

Radiofrequency (RF) ablation has emerged as an effective method for treating liver tumors under 3 cm in diameter. Multiple applicator devices and techniques - using RF, microwave and other modalities - are under development for thermal ablation of large and irregularly-shaped liver tumors. Interstitial ultrasound (IUS) applicators, comprised of linear arrays of independently powered tubular transducers, enable 3D control of the spatial power deposition profile and simultaneous ablation with multiple applicators. We evaluated IUS applicator configurations (parallel, converging and diverging implants) suitable for percutaneous and laparascopic placement with experiments in ex vivo bovine tissue and computational models. Ex vivo ablation zones measured 4.6±0.5 x 4.2±0.5 × 3.3±0.5 cm³ and 5.6±0.5 × 4.9±0.5 x 2.8±0.3 cm³ using three parallel applicators spaced 2 and 3 cm apart, respectively, and 4.0±0.3 × 3.2±0.4 × 2.9±0.2 cm³ using two parallel applicators spaced 2 cm apart. Computational models indicate in vivo ablation zones up to 4.5 × 4.4 × 5.5 cm³ and 5.7 × 4.8 × 5.2 cm³, using three applicators spaced 2 and 3 cm apart, respectively. Converging and diverging implant patterns can also be employed for conformal ablation of irregularly-shaped tumor margins by tailoring power levels along each device. Simultaneously powered interstitial ultrasound devices can create tailored ablation zones comparable to currently available RF devices and similarly sized microwave antennas.

In this paper, we present the design, fabrication and calibration of new micro machined electrical probe and experimental studies on liver tissues using this probe. The probe was fabricated by photolithography and mounted in a catheter with 1.5mm in diameter, which can be used to measure local impedance of the biological tissues. After the calibration of the impedance at 500k Hz against different concentrations of saline water, the electrical conductivity can be obtained from the measured impedance value. The micro electrical probe was first used to investigate the effect of temperature elevation on the electrical conductivity liver tissues by different heating methods. Also, the electrical conductivity change caused by directional placement and perfusion rate was investigated on a perfused pig liver model. The experimental results show that the local electrical conductivity varies location to location and that the electrical conductivity has a strong directional dependence. Also by varying the perfusion rate, the probe shows that the local electrical conductivity varies linearly with the square root of perfusion rate. These results may be of great value to many biomedical applications.

This study presents a prototype design of an ultra-miniature, wireless, battery-less, and implantable temperature-sensor, with applications to thermal medicine such as cryosurgery, hyperthermia, and thermal ablation. The design aims at a sensory device smaller than 1.5 mm in diameter and 3 mm in length, to enable minimally invasive deployment through a hypodermic needle. While the new device may be used for local temperature monitoring, simultaneous data collection from an array of such sensors can be used to reconstruct the 3D temperature field in the treated area, offering a unique capability in thermal medicine. The new sensory device consists of three major subsystems: a temperature-sensing core, a wireless data-communication unit, and a wireless power reception and management unit. Power is delivered wirelessly to the implant from an external source using an inductive link. To meet size requirements while enhancing reliability and minimizing cost, the implant is fully integrated in a regular foundry CMOS technology (0.15 μm in the current study), including the implant-side inductor of the power link. A temperature-sensing core that consists of a proportional-to-absolute-temperature (PTAT) circuit has been designed and characterized. It employs a microwatt chopper stabilized op-amp and dynamic element-matched current sources to achieve high absolute accuracy. A second order sigma-delta (Σ-Δ) analog-to-digital converter (ADC) is designed to convert the temperature reading to a digital code, which is transmitted by backscatter through the same antenna used for receiving power. A high-efficiency multi-stage differential CMOS rectifier has been designed to provide a DC supply to the sensing and communication subsystems. This paper focuses on the development of the all-CMOS temperature sensing core circuitry part of the device, and briefly reviews the wireless power delivery and communication subsystems.

Prostate cancer diagnosis is based solely on biopsy-based findings. Unfortunately, routine biopsy protocols only sample ~0.95% of the entire gland limiting the technique's sensitivity to cancer detection. Previous studies have demonstrated significant electrical property differences between malignant and benign prostate tissues due to their dissimilar morphological architectures. We have taken the important step of translating these findings to the clinic by integrating an electrical property sensor into the tip of a standard biopsy needle. This novel device allows clinicians to simultaneously extract a tissue core and assess the electrical properties around the needle tip in real-time. The expected volume of tissue sensed with this device was estimated using finite-element method (FEM) based simulations to model the potential fields and current distributions. Prototype devices have been constructed and evaluated in a series of saline baths in order to validate the FEM-based findings. Simulations suggest that the electrical property sensor is able to interrogate a tissue volume of ~62.1 mm³ and experimental results demonstrated a volume of sensitivity of ~68.7 mm³. This coupled device is being used to assess the increased sensitivity and specificity to cancer detection when electrical properties are sensed in concert with tissue core extraction in a series of 50 ex vivo prostates. Typical 12-core prostate biopsy protocols extract a total tissue volume of 228 mm³ for histological assessment. Employing this electrical property sensor to gauge electrical properties at both the beginning and end of the needle trajectory will provide pathological assessment of an additional 1648 mm³ of tissue.

Background: Vesicoureteral reflux (VUR) is a serious health problem leading to renal scarring in children. Current VUR detection involves traumatic x-ray imaging of kidneys following injection of contrast agent into bladder via invasive Foley catheter. We present an alternative non-invasive approach for detecting VUR by radiometric monitoring of kidney temperature while gently warming the bladder. Methods: We report the design and testing of: i) 915MHz square slot antenna array for heating bladder, ii) EMI-shielded log spiral microstrip receive antenna, iii) high-sensitivity 1.375GHz total power radiometer, iv) power modulation approach to increase urine temperature relative to overlying perfused tissues, and v) invivo porcine experiments characterizing bladder heating and radiometric temperature of aaline filled 30mL balloon "kidney" implanted 3-4cm deep in thorax and varied 2-6°C from core temperature. Results: SAR distributions are presented for two novel antennas designed to heat bladder and monitor deep kidney temperatures radiometrically. We demonstrate the ability to heat 180mL saline in in vivo porcine bladder to 40-44°C while maintaining overlying tissues <38°C using time-modulated square slot antennas coupled to the abdomen with room temperature water pad. Pathologic evaluations confirmed lack of acute thermal damage in pelvic tissues for up to three 20min bladder heat exposures. The radiometer clearly recorded 2-6°C changes of 30mL "kidney" targets at depth in 34°C invivo pig thorax. Conclusion: A 915MHz antenna array can gently warm in vivo pig bladder without toxicity while a 1.375GHz radiometer with log spiral receive antenna detects ≥2°C rise in 30mL "urine" located 3-4cm deep in thorax, demonstrating more than sufficient sensitivity to detect Grade 4-5 reflux of warmed urine for non-invasive detection of VUR.

Heat therapy has long been used for treatments in dermatology and sports medicine. The use of laser, RF, microwave, and more recently, ultrasound treatment, for psoriasis, collagen reformation, and skin tightening has gained considerable interest over the past several years. Numerous studies and commercial devices have demonstrated the efficacy of these methods for treatment of skin disorders. Despite these promising results, current systems remain highly dependent on operator skill, and cannot effectively treat effectively because there is little or no control of the size, shape, and depth of the target zone. These limitations make it extremely difficult to obtain consistent treatment results. The purpose of this study was to determine the feasibility for using acoustic energy for controlled dose delivery sufficient to produce collagen modification for the treatment of skin tissue in the dermal and sub-dermal layers. We designed and evaluated a curvilinear focused ultrasound device for treating skin disorders such as psoriasis, stimulation of wound healing, tightening of skin through shrinkage of existing collagen and stimulation of new collagen formation, and skin cancer. Design parameters were examined using acoustic pattern simulations and thermal modeling. Acute studies were performed in 201 freshly-excised samples of young porcine underbelly skin tissue and 56 in-vivo treatment areas in 60- 80 kg pigs. These were treated with ultrasound (9-11MHz) focused in the deep dermis. Dose distribution was analyzed and gross pathology assessed. Tissue shrinkage was measured based on fiducial markers and video image registration and analyzed using NIH Image-J software. Comparisons were made between RF and focused ultrasound for five energy ranges. In each experimental series, therapeutic dose levels (60degC) were attained at 2-5mm depth. Localized collagen changes ranged from 1-3% for RF versus 8-15% for focused ultrasound. Therapeutic ultrasound applied at high frequencies can achieve temperatures and dose distributions which concentrate in a depth profile that coincides with the location of maximum structural collagen content in skin tissues. Using an appropriate transducer configuration produces coverage of significant lateral area, thus making this a practical approach for treatment of skin disorders.

Thermal therapy has the potential to provide a nonexcisional alternative to tonsillectomy. Clinical implementation requires that the lymphoid tissue of tonsils is heated homogeneously to produce an amount of primary thermal injury that corresponds to gradual postoperative tonsil shrinkage, with minimal risk of damage to underlying critical blood vessels. Optical constants are derived for tonsils from tissue components and used to calculate the depth of 1/e of irradiance. The 1125 nm wavelength is shown to correspond to both deep penetration and minimal absorption by blood. A probe for tonsil thermal therapy that comprises two opposing light emitting, temperature controlled surfaces is described. For ex vivo characterization of tonsil heating, a prototype 1125 nm diode laser is used in an experimental apparatus that splits the laser output into two components, and delivers the radiation to sapphire contact window surfaces of two temperature controlled cells arranged to irradiate human tonsil specimens from opposing directions. Temperatures are measured with thermocouple microprobes at located points within the tissue during and after irradiation. Primary thermal damage corresponding to the recorded thermal histories are calculated from Arrhenius parameters for human tonsils. Results indicate homogeneous heating to temperatures corresponding to the threshold of thermal injury and above can be achieved in advantageously short irradiation times.

Hyperthermic tissue sealing devices are advancing modern laparoscopy and other minimally invasive surgical approaches. Histopathologic evaluation of thermally sealed vessels can provide important information on their associated tissue effects and reactions. However, a standardized systematic approach has not been historically used in the literature. This paper proposes a histologic approach for the analysis of thermally sealed vessels and their basis of hemostasis, including thermal tissue changes, healing, and thrombosis. Histologic evaluation during the first week (Days 3-7) can assess the seal's primary tissue properties. These parameters include the thermal seal's length, architecture, tissue layers involved, adventitial collagen denaturation length, entrapped vapor or blood pockets, tissue homogenization and thermal tissue injury zones. While the architectural features can be assessed in Day 0-3 specimens, the latter thermal injury zones are essentially not assessable in Day 0-3 specimens. Day 14 specimens can provide information on the early healing response to the sealed vessel. Day 30 and longer specimens can be used to evaluate the seal's healing reactions. Assessment of the healing response should include seal site inflammation, granulation tissue, necrosis resorption, fibroproliferative scar healing, and thrombus organization. In order to accurately evaluate these parameters, careful specimen orientation, embedding and multiple histologic sections across the entire seal width are required. When appropriate in vivo post-treatment times are used, thermal vessel seals can be evaluated with routine light microscopy and common histologic staining methods.

Purpose: Develop a new combination therapy consisting of cryoablation and conductive high-temperature ablation for enhanced thermal ablation of solid tumors. Methods: We have constructed an invasive probe that can be used for consecutive cryoablation and hightemperature ablation (C/HTA), with a single insertion. The C/HTA probe was tested, in Balb/c mice bearing solid 4T1 tumors, in comparison to cryoablation and high temperature ablation, only. Three days after ablation, the diameter of the ablated zone was evaluated with pathological examination. Results: The C/HTA device can be used to induce larger ablation zones, in comparison to high temperature or cryoablation alone, and at lower thermal doses and temperatures than either modality alone. Conclusions: The relatively high thermal conductivity of ice, in comparison to water and native tissue, enables rapid heating of the ice-ball that result in improved conductive high temperature ablation. The new dual thermal modality improves ablation outcomes at lower thermal doses in comparison to a single ablation modality.

Clinical implementation of a thermal therapy requires the ability to predict tissue injury following exposures to specific thermal histories. As part of an effort to develop a nonexcisional alternative to tonsillectomy, the degree of primary hyperthermic tissue injury in human tonsil was characterized. Fifteen fresh pediatric hypertrophic tonsillectomy specimens were sectioned and treated in a NIST-calibrated saline bath at temperatures of 40 to 70°C with hold times of one to seven minutes. The treated tissues were subsequently nitroblue tetrazolium (NBT) stained to assess for thermal respiratory enzyme inactivation as a marker of cellular injury/death. The NBT stains were quantitatively image analyzed and used to calculate Arrhenius parameters for primary thermal injury in human tonsils.

Visualisation of the thermo dynamics of surgical coagulation devices like laser, diathermy and RFA devices in tissue are essential to get better understanding about the principles of operation of these devices. Thermo cameras have the ability to measure absolute temperatures. However, the visualization of temperature fields using thermal imaging has always been limited to the surface of a medium. We have developed a new strategy to look below the surface of biological tissue by viewing through a ZincSelenide window positioned alongside a block of tissue. When exposed from above with an energy source, the temperature distribution below the surface can be observed through the window. To obtain a close-up view, the thermo camera is enhanced with special macro optics. The thermo dynamics during tissue interaction of various electro surgery modes was studied in biological tissues to obtain a better understanding of the working mechanism. Simultaneously with thermal imaging, normal close-up video footage was obtained to support the interpretation of the thermal imaging. For comparison, temperature gradients were imaged inside a transparent tissue model using color Schlieren imaging. The new subsurface thermal imaging method gives a better understanding of interaction of thermal energy of surgical devices and contributes to the safety and the optimal settings for various medical applications. However, the technique has some limitations that have to be considered. The three imaging modalities showed to be both compatible and complementary showing the pro- and cons- of each modality.

Background and Purpose. Determine the efficacy of indocyanine green (ICG) dye in enhancing near infrared (NIR) laser ablation of tumors in a mouse model. Methods. Mammary carcinoma cells of A/J mice were injected subcutaneously in the lower back of female A/J mice (n=6). Five to seven days post inoculation the tumors (7-9 mm) were treated with 755-nm laser using 70 J/cm² radiant exposures and 3-ms pulse time. Epidermal cooling was accomplished by cryogen spray cooling. Two minutes prior to laser irradiation mice were injected, intravenously, with 4 mg/kg body weight of ICG solution. Results. Complete tumor ablation was observed in the tumor region and minor damage was seen in the healthy skin. No major skin damage was observed post treatment. Substantial damage (up to 100% coagulative necrosis) was observed in tissue collected from tumors that were treated with laser/ICG. Conclusions. Intravenous administration of 4 mg/kg ICG significantly enhanced thermal ablation of tumors during NIR laser irradiation while sparing healthy skin.

The effects of sweat gland ducts (SGD) on specific absorption rate and temperatures during millimeter wave irradiation of skin were investigated with a high resolution finite differences time domain model consisting of a 30 μm stratum corneum (SC), a 350 μm epidermis, 1000 μm dermis and five SGD (60 μm radius, 300 μm height, 370 μm separation). The source was a WR-10 waveguide irradiating at 94 GHz. Without SGD, specific absorption rate (SAR) and temperature maximum were in the dermis near epidermis. With SGD, a higher SAR maximum was inside SGD in the epidermis while temperature maximum moved to the epidermis/stratumcorneum junction. SGD significantly affected how GHz waves were absorbed in the skin. Implications of these finding in nociceptive research will be discussed as well as other potential medical applications.

Advances in magnetic nanoparticle hyperthermia are opening new doors in cancer therapy. As a standalone or adjuvant therapy this new modality has the opportunity significantly advance thermal medicine. Major advantages of using magnetic magnetite (Fe₃O₄) nanoparticles are their highly localized power deposition and the fact that the alternating magnetic fields (AMF) used to excite them can penetrate deeply into the body without harmful effect. One limitation, however, which hinders the technology, is the problem of inductive heating of normal tissue by the AMF if the frequency and fields strength are not appropriately matched to the tissue. Restricting AMF amplitude and frequency limits the heat dose which can be selectively applied to cancerous tissue via the magnetic nanoparticle, thus lowering therapeutic effect. In an effort to address this problem, particles with optimized magnetic properties must be developed. Using particles with higher saturation magnetizations and coercivity will enhance hysteresis heating increasing particle power density at milder AMF strengths and frequencies. In this study we used oil in water microemulsions to develop nanoparticles with zero-valent Fe cores and magnetite shells. The superior magnetic properties of zero-valent Fe give these particles the potential for improved SAR over pure magnetite particles. Silane and subsequently dextran have been attached to the particle surface in order to provide a biocompatible surfactant coating. The heating capability of the particles was tested in-vivo using a mouse tumor model. Although we determined that the final stage of synthesis, purification of the dextran coated particles, permits significant corrosion/oxidation of the iron core to hematite, the particles can effectively heat tumor tissue. Improving the purification procedure will allow the generation Fe/Fe₃O₄ with superior SAR values.

This study adapted AuroLase® Therapy, previously reported for the treatment of brain tumors, to the treatment of prostate disease by 1) using normal canine prostate in vivo, directly injected with a solution of nanoparticles as a proxy for prostate tumor and, 2) developing an appropriate laser dosimetry for prostate which is which is subablative in native prostate while simultaneously producing photothermal coagulation in prostate tissue containing therapeutic nanoshells. Healthy, mixed-breed hound dogs were given surgical laparotomies during which nanoshells were injected directly into one or both prostate hemispheres. Laser energy was delivered percutaneously to the parenchyma of the prostate along 1-5 longitudinal tracts via a liquid-cooled optical fiber catheter terminated with a 1-cm isotropic diffuser after which the incision was closed and sutured using standard surgical techniques. The photothermal lesions were permitted to resolve for up to 8 days, after which each animal was euthanized, necropsied, and the prostate taken for histopathological analysis. We developed a laser dosimetry which is sub- to marginally ablative in native prostate and simultaneously ablative of prostate tissue containing nanoshells which would indicate a viable means of treating tumors of the prostate which are known from other studies to accumulate nanoshells. Secondly, we determined that multiple laser treatments of nanoshell-containing prostate tissue could be accomplished while sparing the urethra and prostate capsule thermal damage. Finally, we determined that the extent of damage zone radii correlate positively with nanoshell concentration, and negatively to the length of time between nanoshell injection and laser treatment.

Iron oxide nanoparticles present a promising alternative to conventional energy deposition-based tissue therapies. The success of such nanoparticles as a therapeutic for diseases like cancer, however, depends heavily on the particles' ability to localize to tumor tissue as well as provide minimal toxicity to surrounding tissues and key organs such as those involved in the reticuloendothelial system (RES). We present here the results of a long term clearance study where mice injected intravenously with 2 mg Fe of 100 nm dextran-coated iron oxide nanoparticles were sacrificed at 14 and 580 days post injection. Histological analysis showed accumulation of the nanoparticles in some RES organs by the 14 day time point and clearance of the nanoparticles by the 580 day time point with no obvious toxicity to organs. An additional study reported herein employs 20 nm and 110 nm starch-coated iron oxide nanoparticles at 80 mg Fe/kg mouse in a size/biodistribution study with endpoints at 4, 24 and 72 hours. Preliminary results show nanoparticle accumulation in the liver and spleen with some elevated iron accumulation in tumoral tissues with differences between the 20 nm and the 110 nm nanoparticle depositions.

Magnetic nanoparticles excited by alternating magnetic fields (AMF) have demonstrated effective tumor-specific hyperthermia. This treatment is effective as a monotherapy as well as a therapeutic adjuvant to chemotherapy and radiation. Iron oxide nanoparticles have been shown, so far, to be non-toxic, as are the exciting AMF fields when used at moderate levels. Although higher levels of AMF can be more effective, depending on the type of iron oxide nanoparticles use, these higher field strengths and/or frequencies can induce normal tissue heating and toxicity. Thus, the use of nanoparticles exhibiting significant heating at low AMF strengths and frequencies is desirable. Our preliminary experiments have shown that the aggregation of magnetic nanoparticles within tumor cells improves their heating effect and cytotoxicity per nanoparticle. We have used transmission electron microscopy to track the endocytosis of nanoparticles into tumor cells (both breast adenocarcinoma (MTG-B) and acute monocytic leukemia (THP-1) cells). Our preliminary results suggest that nanoparticles internalized into tumor cells demonstrate greater cytotoxicity when excited with AMF than an equivalent heat dose from excited external nanoparticles or cells exposed to a hot water bath. We have also demonstrated that this increase in SAR caused by aggregation improves the cytotoxicity of nanoparticle hyperthermia therapy in vitro.

Surgery, radiation and chemotherapy are currently the most commonly used cancer therapies. Hyperthermia has been shown to work effectively with radiation and chemotherapy cancer treatments. The major obstacle faced by previous hyperthermia techniques has been the inability to deliver heat to the tumor in a precise manner. The ability to deliver cytotoxic hyperthermia to tumors (from within individual cells) via iron oxide magnetic nanoparticles (mNP) is a promising new technology that has the ability to greatly improve the therapeutic ratio of hyperthermia as an individual modality and as an adjuvant therapy in combination with other modalities. Although the parameters have yet to be conclusively defined, preliminary data suggests mNP hyperthermia can achieve greater cytotoxicity (in vitro) than conventional water bath hyperthermia methods. At this time, our theory is that intracellular nanoparticle heating is more effective in achieving the combined effect than extracellular heating techniques.1 However, understanding the importance of mNP association and uptake is critical in understanding the potential novelty of the heating modality. Our preliminary data suggests that the mNP heating technique, which did not provide time for particle uptake by the cells, resulted in similar efficacy to microwave hyperthermia. mNP hyperthermia/cisplatinum results have shown a tumor growth delay greater than either modality alone at comparable doses.