This PDF file contains the front matter associated with SPIE Proceedings Volume 8584, including the Title Page, Copyright information, Table of Contents, and the Conference Committee listing.

Medically useful nanoparticles measure 1-100 nm in at least one dimension and are engineered and manufactured for specific diagnostic and treatment applications. Most nanoparticles used currently used in medicine are engineered and manufactured for specific purposes. Medically significant nanoparticles are composed of a 1) central core that is usually the medically active component, 2) one or more layers of organic or inorganic materials that forms a capsule (corona) covering the core and 3) an outer surface layer that interacts with the environment and/or targeted cells and tissues. Effective nanoparticle function in the living, intact animal or human requires electrochemical stability necessary to bypass the reticuloendothelial system (RES) and avoid filtration through the renal glomerulus into the urine. Nanoparticles are present in ” natural” as well as the manufacturing and clinical environments thus could pose as significant toxins because of their small sizes, their chemical and drug content and potential effect of causing long term disease including allergies, chronic inflammation and cancer. Currently published studies have focused on the effects of nanoparticles on cells in the extremely artificial environments of cell cultures. More clinical and preclinical studies documenting the short term and long term effects nanoparticle in the intact experimental animal and human are needed.

The predicted success of nanoparticle based cancer therapy is due in part to the presence of the inherent leakiness of the tumor vascular barrier, the so called enhanced permeability and retention (EPR) effect. Although the EPR effect is present in varying degrees in many tumors, it has not resulted in the consistent level of nanoparticle-tumor uptake enhancement that was initially predicted. Magnetic/iron oxide nanoparticles (mNPs) have many positive qualities, including their inert/nontoxic nature, the ability to be produced in various sizes, the ability to be activated by a deeply penetrating and nontoxic magnetic field resulting in cell-specific cytotoxic heating, and the ability to be successfully coated with a wide variety of functional coatings. However, at this time, the delivery of adequate numbers of nanoparticles to the tumor site via systemic administration remains challenging. Ionizing radiation, cisplatinum chemotherapy, external static magnetic fields and vascular disrupting agents are being used to modify the tumor environment/vasculature barrier to improve mNP uptake in tumors and subsequently tumor treatment. Preliminary studies suggest use of these modalities, individually, can result in mNP uptake improvements in the 3-10 fold range. Ongoing studies show promise of even greater tumor uptake enhancement when these methods are combined. The level and location of mNP/Fe in blood and normal/tumor tissue is assessed via histopathological methods (confocal, light and electron microscopy, histochemical iron staining, fluorescent labeling, TEM) and ICP-MS. In order to accurately plan and assess mNP-based therapies in clinical patients, a noninvasive and quantitative imaging technique for the assessment of mNP uptake and biodistribution will be necessary. To address this issue, we examined the use of computed tomography (CT), magnetic resonance imaging (MRI), and Sweep Imaging With Fourier Transformation (SWIFT), an MRI technique which provides a positive iron contrast enhancement and a reduced signal to noise ratio, for effective observation and quantification of Fe/mNP concentrations in the clinical setting.

Magnetic nanoparticle hyperthermia (mNHP) is regarded as a promising minimally invasive procedure. These nanoparticles generate heat when exposed to alternating magnetic fields (AMFs) and thus have shown a potential for selective delivery of heat to a target such as a cancer cell. Despite the great promise however, successful clinical translation has been limited in part by technical challenges of selectively delivering heat only to the target tissue. Interaction of AMF with tissues also deposits heat through Joule heating via eddy currents. Considerations of patient safety thus constrain the choice of AMF power and frequency to values that are insufficient to produce desirable heating from available nanoparticle formulations. Therefore, considerable effort must be directed to the design of particles and the AMF device to maximize the specific delivery of heat to the intended target while minimizing the unintended and non-specific heating. We have recently developed new iron-oxide nanoparticles (IONPs) having much higher heating capability at the clinically relevant amplitudes and frequencies than other formulations. Here, we utilize a new rectangular coil designed for treating multi well tissue culture plate and show that these particles are superior to two commercially available IONPs for hyperthermia of DU145 prostate cancer cells in culture. We report results of pilot in-vivo experiments using the DU145 human prostate xenograft model in nude male mouse. AMF treatment yielded an intratumor temperature rise > 10 °C in <10 min heating (AMF amplitude 29 kA/m @160 kHz) with ~4 mg nanoparticle /g tumor while maintaining rectal (core) temperature well within physiological range.

Microwave tumor ablation continues to evolve into a viable treatment option for many cancers. Current systems are poised to supplant radiofrequency ablation as the dominant percutaneous thermal therapy. Here is provided an overview of technical details and early clinical results with a high-powered, gas-cooled microwave ablation system. The system was developed with academic-industry collaboration using federal and private funding. The generator comprises three synchronous channels that each produce up to 140W at 2.45GHz. A mountable power distribution module facilitates CT imaging guidance and monitoring and reduces clutter in the sterile field. Cryogenic carbon-dioxide cools the coaxial applicator, permitting a thin applicator profile (~1.5 mm diameter) and high power delivery. A total of 106 liver tumors were treated (96 malignant, 10 benign) from December 2010 to June 2012 at a single academic institution. Mean tumor size ± standard deviation was 2.5±1.3cm (range 0.5-13.9cm). Treatment time was 5.4±3.3min (range 1-20min). Median follow-up was 6 months (range 1-16 months). Technical success was reported in 100% of cases. Local tumor progression was noted in 4/96 (4.3%) of malignancies. The only major complication was a pleural effusion that was treated with thoracentesis. Microwave ablation with this system is an effective treatment for liver cancer. Compared to previous data from the same institution, these results suggest an increased efficacy and equivalent safety to RF ablation. Additional data from the lung and kidney support this conclusion.

Endometrial ablation has gained significant clinical acceptance over the last decade as a minimally invasive treatment for abnormal uterine bleeding. To improve upon current thermal injury modeling, it is important to better characterize the myometrium’s thermotolerance. The extent of myometrial thermal injury was determined across a spectrum of thermal histories/doses (time-temperature combinations). Fresh extirpated human myometrium was obtained from 13 subjects who underwent a previous scheduled benign hysterectomy. Within two hours of hysterectomy, the unfixed myometrium was treated in a stabilized saline bath with temperatures ranging from 45-70 °C and time intervals from 30- 150 seconds. The time-temperature combinations were selected to simulate treatment times under 2.5 minutes. A total of six such thermal matrices, each comprised of 45 time-temperature combinations, were prepared for evaluation. The treated myometrium was cryosectioned for nitro blue tetrazolium (NBT) staining to assess for thermal respiratory enzyme inactivation. Image analysis was subsequently used to quantitatively assess the stained myometrium’s capacity to metabolize the tetrazolium at each time-temperature combination. This colorimetric data was then used as marker of cellular viability and determine survival parameters with implications for developing minimally invasive uterine therapies.

The aim of this study was to investigate the relation between ablation efficiency and temperature increase during laser ablation by 1940-nm Tm:fiber laser. The thermal effects of the Tm:fiber laser on the brain tissue was also investigated. The laser beam (200-1000 mW) was delivered from a distance of 0.5 mm to cortical and subcortical regions of the ex vivo ovine brain tissue samples via 400 μm optical fiber. A total of 560 brain samples were irradiated at different settings in continuous-mode or pulsed-mode. In continuous-mode and pulsed-modulated-mode doses were changed with exposure time and on-off cycles respectively, in order to achieve the tissue to absorb the same energy. During lasing temperature changes of the irradiated tissue were recorded by a thermoprobe (thermoprobe is a system which an optical fiber was embedded into a thermocouple). The radiuses of ablation and coagulation zones were measured under microscope. The ablation efficiencies (100xablation/coagulation radius) and rates of temperature change were calculated. A strong correlation between the ablation efficiency and rate of temperature change was presented.

Lasers of different wavelengths are being used in oral surgery for incision and excision purposes with minimal bleeding and pain. Among these wavelengths, those close to 2μ yield more desirable results on oral soft tissue due to their strong absorption by water. The emission of 1940 nm Thulium fiber laser is well absorbed by water which makes it a promising tool for oral soft tissue surgery. This study was conducted to investigate the potential of thulium fiber laser as an incisional and excisional oral surgical tool. Ovine tongue has been used as the target tissue due to its similarities to human oral tissues. Laser light obtained from a 1940 nm Thulium fiber laser was applied in contact mode onto ovine tongue completely submerged in saline solution in vitro, via a 600)μm fiber moved with a velocity of 0.5 mm /s to form incisions. There were a total of 9 groups determined by the power (2,5-3- 3,5 W), and number of passes (1-3-5). The samples were stained with HE for microscopic evaluation of depth of ablation and extent of coagulation. The depth of incisions produced with 1940 nm Thulium fiber laser increased with increasing power and number of passes, however an increase in the width of the coagulation zone was also observed.

Radio frequency (RF) is used clinically to treat unresectible tumors. Finite element modeling has proven useful in treatment planning and applicator design. Typically isotherms in the middle 50s °C have been used as the parameter of assessment in these models. We compare and contrast isotherms for multiple known Arrhenius thermal damage predictors including collagen denaturation, vascular disruption, liver coagulation and cell death. Models for RITA probe geometries are included in the study. Comparison to isotherms is sensible when the activation time is held constant, but varies considerably when heating times vary. The purpose of this paper is to demonstrate the importance of looking at specific processes and keeping track of the methods used to derive the Arrhenius coefficients in order to study the extremely complex cell death processes due to thermal therapies.

When using simulations to determine electrode geometry and energy deposition patterns for TURP devices, a dominating factor for consideration is the tissue resection rate of the proposed system. While it is well understood that the vaporization of biological tissue is the mechanism of tissue division, previous models have been unable to match experimental results for a given applied power. Whether modeled as direct tissue/electrode contact or through the spatial transform of arcing, the predicted division rate was significantly lower than that observed though experiment. For the present study, heating rate was again used to determine the vaporization rate during the resection. This model assumes that in order for the wire loop to advance not all of the tissue in front of the electrode must be vaporized but the centerline of the advance must have sufficient energy deposited to divide the tissue. Integrating the volumetric energy deposition rate along this centerline in front of the advancing electrode provides a comparison to the required vaporization energy density resulting in a predicted time necessary for reaching the tissue division threshold. Using the simulation results for a standard TURP electrode and various power settings, five cases were compared to experimental results using in vitro bovine prostate tissue. Each tested at three cutting rates, evaluating the ability to advance through the tissue. The simulation predicted tissue division rates in good agreement with those seen via experiment, although the predicted values biased slightly higher suggesting that further mathematical model refinements are necessary.

One of the greatest challenges of nanoparticle cancer therapy is the delivery of adequate numbers of nanoparticles to the tumor site. Iron oxide nanoparticles (IONPs) have many favorable qualities, including their nontoxic composition, the wide range of diameters in which they can be produced, the cell-specific cytotoxic heating that results from their absorption of energy from a nontoxic, external alternating magnetic field (AMF), and the wide variety of functional coatings that can be applied. Although IONPs can be delivered via an intra-tumoral injection to some tumors, the resulting tumor IONP distribution is generally inadequate; additionally, local tumor injections do not allow for the treatment of systemic or multifocal disease. Consequently, the ultimate success of nanoparticle based cancer therapy likely rests with successful systemic, tumor-targeted IONP delivery. In this study, we used a surface-based, bilateral, noninvasive static magnetic field gradient produced by neodymiumboron- iron magnets (80 T/m to 130 T/m in central plane between magnets), a rabbit ear model, and systemicallydelivered starch-coated 100 nm magnetic (iron oxide) nanoparticles to demonstrate a spatially-defined increase in the local tissue accumulation of IONPs. In this non-tumor model, the IONPs remained within the local vascular space. It is anticipated that this technique can be used to enhance IONP delivery significantly to the tumor parenchyma/cells.

Background Despite positive efficacy, thermotherapy is not widely used in clinical oncology. Difficulties associated with field penetration and controlling power deposition patterns in heterogeneous tissue have limited its use for heating deep in the body. Heat generation using iron-oxide super-paramagnetic nanoparticles excited with magnetic fields has been demonstrated to overcome some of these limitations. The objective of this preclinical study is to investigate the feasibility of treating bladder cancer with magnetic fluid hyperthermia (MFH) by analyzing the thermal dosimetry of nanoparticle heating in a rat bladder model. Methods The bladders of 25 female rats were injected with 0.4 ml of Actium Biosystems magnetite-based nanoparticles (Actium Biosystems, Boulder CO) via catheters inserted in the urethra. To assess the distribution of nanoparticles in the rat after injection we used the 7 T small animal MRI system (Bruker ClinScan, Bruker BioSpin MRI GmbH, Ettlingen, Germany). Heat treatments were performed with a small animal magnetic field applicator (Actium Biosystems, Boulder CO) with a goal of raising bladder temperature to 42°C in <10min and maintaining for 60min. Temperatures were measured throughout the rat with seven fiberoptic temperature probes (OpSens Technologies, Quebec Canada) to characterize our ability to localize heat within the bladder target. Results The MRI study confirms the effectiveness of the catheterization procedure to homogenously distribute nanoparticles throughout the bladder. Thermal dosimetry data demonstrate our ability to controllably raise temperature of rat bladder >1°C/min to a steady-state of 42°C. Conclusion Our data demonstrate that a MFH system provides well-localized heating of rat bladder with effective control of temperature in the bladder and minimal heating of surrounding tissues.

The use of magnetic nanoparticles (mNP’s) to induce local hyperthermia has been emerging in recent years as a promising cancer therapy, in both a stand-alone and combination treatment setting. Studies have shown that cancer cells associate with, internalize, and aggregate mNP’s more preferentially than normal cells. Once the mNP’s are delivered inside the cells, a low frequency (30 kHz-300 kHz) alternating electromagnetic field is used to activate the mNP’s. The nanoparticles absorb the applied field and provide localized heat generation at nano-micron scales. It has been shown experimentally that mNP’s exhibit collective behavior when in close proximity. Although most prevailing mNP heating models assume there is no magnetic interaction between particles, our data suggests that magnetic interaction effects due to mNP aggregation are often significant; In the case of multi-crystal core particles, interaction is guaranteed. To understand the physical phenomena responsible for this effect, we modeled electromagnetic coupling between mNP’s in detail. The computational results are validated using data from the literature as well as measurements obtained in our lab. The computational model presented here is based on a method of moments technique and is used to calculate magnetic field distributions on the nanometer scale, both inside and outside the mNP.

Survival of head and neck cancer patients has not improved in several decades despite advances in diagnostic and therapeutic techniques. Tumor hypoxia in head and neck cancers is a critical factor that leads to poor prognosis, resistance to radiation and chemotherapies, and increased metastatic potential. Magnetic nanoparticle hyperthermia (mNPHT) is a promising therapy for hypoxic tumors because nanoparticles (NP) can be directly injected into, or targeted to, hypoxic tumor cells and exposed to alternating magnetic fields (AMF) to induce hyperthermia. Magnetic NPHT can improve therapeutic effectiveness by two modes of action: 1) direct killing of hypoxic tumor cells; and 2) increase in tumor oxygenation, which has the potential to make the tumor more susceptible to adjuvant therapies such as radiation and chemotherapy. Prior studies in breast cancer cells demonstrated that a hypoxic microenvironment diminished NP uptake in vitro; however, mNPHT with intratumoral NP injection in hypoxic tumors increased tumor oxygenation and delayed tumor growth. In this study, head and neck squamous cell carcinoma (HNSCC) cell lines were incubated in normoxic, hypoxic, and hyperoxic conditions with iron oxide NP for 4-72 hours. After incubation, the cells were analyzed for iron uptake by mass spectrometry, Prussian blue staining, and electron microscopy. In contrast to breast cancer cells, uptake of NPs was increased in hypoxic microenvironments as compared to normoxic conditions in HNSCC cells. In future studies, we will confirm the effect of the oxygen microenvironment on NP uptake and efficacy of mNPHT both in vitro and in vivo.

Iron oxide nanoparticle (IONP) hyperthermia is a novel therapeutic strategy currently under consideration for the treatment of various cancer types. Systemic delivery of IONP followed by non-invasive activation via a local alternating magnetic field (AMF) results in site-specific energy deposition in the IONP-containing tumor. Targeting IONP to the tumor using an antibody or antibody fragment conjugated to the surface may enhance the intratumoral deposition of IONP and is currently being pursued by many nanoparticle researchers. This strategy, however, is subject to a variety of restrictions in the in vivo environment, where other aspects of IONP design will strongly influence the biodistribution. In these studies, various targeted IONP are compared to non-targeted controls. IONP were injected into BT-474 tumor-bearing NSG mice and tissues harvested 24hrs post-injection. Results indicate no significant difference between the various targeted IONP and the non-targeted controls, suggesting the IONP were prohibitively-sized to incur tumor penetration. Additional strategies are currently being pursued in conjuncture with targeted particles to increase the intratumoral deposition.

Most nanoparticle-based cancer therapeutic strategies seek to develop an effective individual cancer cell or metastatic tumor treatment. Critical to the success of these therapies is to direct as much of the agent as possible to the targeted tissue while avoiding unacceptable normal tissue complications. In this light, three different cisplatinum/magnetic nanoparticle (mNP) administration regimens were investigated. The most important finding suggests that clinically relevant doses of cisplatinum result in a significant increase in the tumor uptake of systemically delivered mNP. This enhancement of mNP tumor uptake creates the potential for an even greater therapeutic ratio through the addition of mNP based, intracellular hyperthermia.

Iron oxide nanoparticle (IONP) hyperthermia is an emerging treatment that shows great potential as a cancer therapy both alone and in synergy with conventional modalities. Pre-clinical studies are attempting to elucidate the mechanisms of action and distributions of IONP in various in vitro and in vivo models, however these studies would greatly benefit from real-time imaging of IONP locations both in cellular and in mammalian systems. To this end, fluorescently-tagged IONP (fIONP) have been employed for real time tracking and co-registration of IONP with iron content. Starch-coated IONP were fluorescently-tagged, purified and analyzed for fluorescent signal at various concentrations. fIONP were incubated with MTGB cells for varying times and cellular uptake analyzed using confocal microscopy, flow cytometry and inductively-coupled plasma mass spectrometry (ICP-MS). fIONP were also injected into a bilateral mouse tumor model for radiation modification of tumor tissue and enhanced fIONP deposition assessed using a Xenogen IVIS fluorescent imager. Results demonstrated that fIONP concentrations in vitro correlated with ICPMS iron readings. fIONP could be tracked in vitro as well as in tissue samples from an in vivo model. Future work will employ whole animal fluorescent imaging to track the biodistribution of fIONP over time.

Iron oxide nanoparticles (IONPs) have been investigated as a promising means for inducing tumor cell-specific hyperthermia. Although the ability to generate and use nanoparticles that are biocompatible, tumor specific, and have the ability to produce adequate cytotoxic heat is very promising, significant preclinical and clinical development will be required for clinical efficacy. At this time it appears using IONP-induced hyperthermia as an adjunct to conventional cancer therapeutics, rather than as an independent treatment, will provide the initial IONP clinical treatment. Due to their high-Z characteristics, another option is to use intracellular IONPs to enhance radiation therapy without excitation with AMF (production of heat). To test this concept IONPs were added to cell culture media at a concentration of 0.2 mg Fe/mL and incubated with murine breast adenocarcinoma (MTG-B) cells for either 48 or 72 hours. Extracellular iron was then removed and all cells were irradiated at 4 Gy. Although samples incubated with IONPs for 48 hrs did not demonstrate enhanced post-irradiation cytotoxicity as compared to the non-IONP-containing cells, cells incubated with IONPs for 72 hours, which contained 40% more Fe than 48 hr incubated cells, showed a 25% decrease in clonogenic survival compared to their non-IONP-containing counterparts. These results suggest that a critical concentration of intracellular IONPs is necessary for enhancing radiation cytotoxicity.

Apoptosis is an especially important process affecting disease states from HIV-AIDS to auto-immune disease to cancer. A cascade of initiator and executioner capsase functional proteins is the hallmark of apoptosis. When activated the various caspases activate other caspases or cleave structural proteins of the cytoskeleton, resulting in "blebbing" of the plasma membrane forming apoptotic bodies that completely enclose the disassembled cellular components. Containment of the cytosolic components within the apoptotic bodies differentiates apoptosis from necroptosis and necrosis, both of which release fragmented cytosol and other cellular constituents into the intracellular space. Biochemical models of caspase activation reveal the extensive feedback loops characteristic of apoptosis. They clearly explain the failure of Arrhenius models to give accurate predictions of cell survival curves in hyperthermic heating protocols. Nevertheless, each of the individual reaction velocities can reasonably be assumed to follow Arrhenius kinetics. If so, the thermal sensitivity of the reaction velocity to temperature elevation is: ∂k/∂T = E_a [k/RT²]. Particular reaction steps described by higher activation energies, Ea, are likely more thermally-sensitive than lower energy reactions and may initiate apoptosis in the absence of other stress signals. Additionally, while the classical irreversible Arrhenius formulation fails to accurately represent many cell survival and/or dye uptake curves - those that display an early stage shoulder region - an expanded reversible model of the law of mass action equation seems to prove effective and is directly based on a firm theoretical thermodynamic foundation.

Over the last decade, histopathology techniques for evaluating tissue effects associated with minimally invasive energy-based medical devices have substantially progressed. These techniques have evolved from hematoxylin and eosin and collagen staining on fixed tissues to membrane and enzymatic viability staining in fresh tissue. Further, immunohistochemistry has advanced the detection of apoptosis over the TUNEL and FLICA assays in intact tissue samples. As a result, these techniques have enhanced our ability to evaluate tissues following both hyperthermic and cryothermic tissue treatments.

Tissue fusion is a complex, poorly understood process which bonds collagenous tissues together using heat and pressure. The goal of this study is to elucidate the role of hydration in bond efficacy. Hydration of porcine splenic arteries (n=30) was varied by pre-fusion treatments: 24-48 hour immersion in isotonic, hypotonic, or hypertonic baths. Treated arteries were fused in several locations using Conmed's Altrus thermal fusion device and the bursting pressure was then measured for each fused segment. Artery sections were then weighed before and after lyophilization, to quantify water content. Histology (HE, EVG staining) enabled visualization of the bonding interface. Bursting pressure was significantly greater (p=4.17 E-ll) for the hypotonic group (607.6 ± 83.2mmHg), while no significant difference existed between the isotonic (332.6 ± 44.7mmHg) and hypertonic (348.7 ± 44.0mmHg) treatment groups. Total water content varied (p=8.80 E-24) from low water content in the hypertonic samples (72.5% weight ± 0.9), to high water content in the hypotonic samples (83.1% weight ± 1.9), while the isotonic samples contained 78.8% weight ± 1.1. Strength differences between the treated vessels imply that bound water driven from the tissue during fusion may reveal available collagen crosslinking sites to facilitate bond formation during the fusion process. Thus when the tissue contains greater bound water volumes, more crosslinking sites may become available during fusion, leading to a stronger bond. This study provides an important step towards understanding the chemistry underlying tissue fusion and the mechanics of tissue fusion as a function of bound water within the tissue.

Thermal spread (thermal tissue damage) results from heat conduction through the tissues immediately adjacent to a hyperthermic tissue sealing device. The extent of such heat conduction can be assessed by the detection of adventitial collagen denaturation. Several histologic methods have been reported to measure adventitial collagen denaturation as a marker of thermal spread. This study compared hematoxylin and eosin staining, Gomori trichrome staining and loss of collagen birefringence for the detection of collagen denaturation. Twenty-eight ex vivo porcine carotid arteries were sealed with a commercially available, FDA-approved tissue sealing device. Following formalin fixation and paraffin embedding, two 5-micron tissue sections were hematoxylin and eosin and Gomori trichrome stained. The hematoxylin and eosin-stained section was evaluated by routine bright field microscopy and under polarized light. The trichromestained section was evaluated by routine bright field microscopy. Radial and midline adventitial collagen denaturation measurements were made for both the top and bottom jaw sides of each seal. The adventitial collagen denaturation lengths were determined using these three methods and statistically compared. The results showed that thermal spread, as represented by histologically detected collagen denaturation, is technique dependent. In this study, the trichrome staining method detected significantly less thermal spread than the hematoxylin and eosin staining and birefringence methods. Of the three methods, hematoxylin and eosin staining provided the most representative results for true thermal spread along the adjacent artery.

Plasma Medicine is a growing field that is having an impact in several important areas in therapeutic patient care, combining plasma physics, biology, and clinical medicine. Historically, plasmas in medicine were used in electrosurgery for cautery and non-contact hemostasis. Presently, non-thermal plasmas have attained widespread use in medicine due to their effectiveness and compatibility with biological systems. The paper will give a general overview of how low temperature, non-equilibrium, gas plasmas operate, both from physics and biology perspectives. Plasma is commonly described as the fourth state of matter and is typically comprised of charged species, active molecules and atoms, as well as a source of UV and photons. The most active areas of plasma technology applications are in wound treatment; tissue regeneration; inactivation of pathogens, including biofilms; treating skin diseases; and sterilization. There are several means of generating plasmas for use in medical applications, including plasma jets, dielectric barrier discharges, capacitively or inductively coupled discharges, or microplasmas. These systems overcome the former constraints of high vacuum, high power requirements and bulky systems, into systems that use room air and other gases and liquids at low temperature, low power, and hand-held operation at atmospheric pressure. Systems will be discussed using a variety of energy sources: pulsed DC, AC, microwave and radiofrequency, as well as the range of frequency, pulse duration, and gas combinations in an air environment. The ionic clouds and reactive species will be covered in terms of effects on biological systems. Lastly, several commercial products will be overviewed in light of the technology utilized, health care problems being solved, and clinical trial results.

Electrosurgical devices employing plasmas to ablate, cut and otherwise treat tissues have been in widespread use for decades. Following d’Arsonval's 19th century work on the neuromuscular response from high-frequency excitation of tissue, Doyen treated skin blemishes with a spark-gap generator in 1909. In the late 1920’s, physician Harvey Cushing and Harvard physicist William Bovie developed an electrosurgical device and power source that eventually became a standard of care for cutting, coagulating, desiccating, or fulgurating tissue. Beginning in the 1990’s a new class of low-voltage electrosurgical devices employing electricallyconducting saline fluids were developed by ArthroCare Corp. These modern Coblation® devices are now widely used in many different surgical procedures, including those in arthroscopic surgery, otorhinolaryngology, spine surgery, urology, gynecological surgery, and others. This paper summarizes some of the research we have been doing over the last decade to elucidate the physics and chemistry underlying Coblation® electrosurgical devices. Electrical-, thermal-, fluid-, chemicaland plasma-physics all play important roles in these devices and give rise to a rich variety of observations. Experimental techniques employed include optical and mass spectroscopy, fast optical imaging, and electrical voltage and current measurements. Many of the features occur on fast time scales and small spatial scales, making laboratory measurements difficult, so coupled-physics, finite-element-modeling can also be employed to glean more information than has been acquired thus far through physical observation.

Over the past 18 years, several electrosurgical systems generating a low temperature plasma in an aqueous conductive solution have been commercialized for various clinical applications and have been used in over 10 million patients to date. The most popular utilizations are in arthroscopic surgery, otorhinolaryngology surgery, spine and neurosurgery, urology and wound care. These devices can be configured to bring saline to the tip and to have concomitant aspiration to remove by-products and excess fluid. By tuning the electrode geometry, waveform and fluid dynamic at the tip of the devices, tissue resection and thermal effects can be adjusted individually. This allows one to design products that can operate as precise tissue dissectors for treatment of articular cartilage or debridement of chronic wounds, as well as global tissue debulking devices providing sufficient concomitant hemostasis for applications like tonsillectomies. Effects of these plasma based electrosurgical devices on cellular biology, healing response and nociceptive receptors has also been studied in various models. This talk will include a review of the clinical applications, with product descriptions, results and introductory review of some of the research on the biological effects of these devices.

Background: There are numerous clinical applications for non-invasive monitoring of deep tissue temperature. We present the design and experimental performance of a miniature radiometric thermometry system for measuring volume average temperature of tissue regions located up to 5cm deep in the body. Methods: We constructed a miniature sensor consisting of EMI-shielded log spiral microstrip antenna with high gain onaxis and integrated high-sensitivity 1.35GHz total power radiometer with 500 MHz bandwidth. We tested performance of the radiometry system in both simulated and experimental multilayer phantom models of several intended clinical measurement sites: i) brown adipose tissue (BAT) depots within 2cm of the skin surface, ii) 3-5cm deep kidney, and iii) human brain underlying intact scalp and skull. The physical models included layers of circulating tissue-mimicking liquids controlled at different temperatures to characterize our ability to quantify small changes in target temperature at depth under normothermic surface tissues. Results: We report SAR patterns that characterize the sense region of a 2.6cm diameter receive antenna, and radiometric power measurements as a function of deep tissue temperature that quantify radiometer sensitivity. The data demonstrate: i) our ability to accurately track temperature rise in realistic tissue targets such as urine refluxed from prewarmed bladder into kidney, and 10°C drop in brain temperature underlying normothermic scalp and skull, and ii) long term accuracy and stability of +0.4°C over 4.5 hours as needed for monitoring core body temperature over extended surgery or monitoring effects of brown fat metabolism over an extended sleep/wake cycle. Conclusions: A non-invasive sensor consisting of 2.6cm diameter receive antenna and integral 1.35GHz total power radiometer has demonstrated sufficient sensitivity to track clinically significant changes in temperature of deep tissue targets underlying normothermic surface tissues for clinical applications like the detection of vesicoureteral reflux, and long term monitoring of brown fat metabolism or brain core temperature during extended surgery.

Background: Brown adipose tissue (BAT) plays an important role in whole body metabolism and could potentially mediate weight gain and insulin sensitivity. Although some imaging techniques allow BAT detection, there are currently no viable methods for continuous acquisition of BAT energy expenditure. We present a non-invasive technique for long term monitoring of BAT metabolism using microwave radiometry. Methods: A multilayer 3D computational model was created in HFSS^TM with 1.5 mm skin, 3-10 mm subcutaneous fat, 200 mm muscle and a BAT region (2-6 cm³) located between fat and muscle. Based on this model, a log-spiral antenna was designed and optimized to maximize reception of thermal emissions from the target (BAT). The power absorption patterns calculated in HFSS^TM were combined with simulated thermal distributions computed in COMSOL® to predict radiometric signal measured from an ultra-low-noise microwave radiometer. The power received by the antenna was characterized as a function of different levels of BAT metabolism under cold and noradrenergic stimulation. Results: The optimized frequency band was 1.5-2.2 GHz, with averaged antenna efficiency of 19%. The simulated power received by the radiometric antenna increased 2-9 mdBm (noradrenergic stimulus) and 4-15 mdBm (cold stimulus) corresponding to increased 15-fold BAT metabolism. Conclusions: Results demonstrated the ability to detect thermal radiation from small volumes (2-6 cm³) of BAT located up to 12 mm deep and to monitor small changes (0.5 °C) in BAT metabolism. As such, the developed miniature radiometric antenna sensor appears suitable for non-invasive long term monitoring of BAT metabolism.

Extensive surgical procedure or liver transplant still remains the gold standard for treating slow-growing tumors in liver. But only few candidates are suitable for such procedure due to poor liver function, tumors in unresectable locations or presence of other liver diseases. In such situations, minimally invasive surgery may be the best therapeutic procedure. The use of RF, laser and ultrasound ablation techniques has gained considerable interest over the past several years to treat liver diseases. The success of such minimally invasive procedure depends on accurately targeting the desired region and guiding the entire procedure. The purpose of this study is to use ultrasound imaging and GPS tracking system to accurately place a steerable acoustic ablator and multiple temperature sensors in porcine liver in situ. Temperature sensors were place at eight different locations to estimate thermal distribution in the three-dimensional treated volume. Acoustic ablator of center frequency of 7 MHz was used for the experiments. During therapy a maximum temperature of 60-65 °C was observed at a distance 8-10 mm from the center of the ablation transducer. The dose distribution was analyzed and compared with the gross pathology of the treated region. Accurate placement of the acoustic applicator and temperature sensors were achieved using the combined image-guidance and the tracking system. By combining ultrasound imaging and GPS tracking system accurate placement of catheter based acoustic ablation applicator can be achieved in livers in situ.

Feasibility of hyperthermia delivery to the prostate with a commercially available MR-guided endorectal ultrasound (ERUS) phased array ablation system (ExAblate 2100, Insightec, LTD) was assessed through computer simulations and ex vivo experiments. The simulations included a 3D FEM-based biothermal model, and acoustic field calculations for the ExAblate phased array (2.3 MHz, 2.3x4.0 cm²) using the rectangular radiator method. Array beamforming strategies were investigated to deliver 30-min hyperthermia (<41 °C) to focal regions of prostate cancer, identified from MR images in representative patient cases. Constraints on power densities, sonication durations and switching speeds imposed by ExAblate hardware and software were incorporated in the models. T<41 °C was calculated in 14-19 cm³ for sonications with planar or diverging beam patterns at 0.9-1.2 W/cm², and in 3-10 cm3 for curvilinear (cylindrical) or multifocus beam patterns at 1.5-3.3 W/cm², potentially useful for treating focal disease in a single posterior quadrant. Preliminary experiments included beamformed sonications in tissue mimicking phantom material under MRI-based temperature monitoring at 3T (GRE TE=7.0 ms, TR=15 ms, BW=10.5 kHz, FOV=15 cm, matrix 128x128, FA=40°). MR-temperature rises of 2-6 °C were induced in a phantom with the ExAblate array, consistent with calculated values and lower power settings (~0.86 W/cm², 3 min.). Conformable hyperthermia may be delivered by tailoring power deposition along the array length and angular expanse. MRgERUS HIFU systems can be controlled for continuous hyperthermia in prostate to augment radiotherapy and drug delivery. [FUS Foundation, NIH R01 122276, 111981].

Image-guided thermal interventions have been proposed for potential palliative and curative treatments of pancreatic tumors. Catheter-based ultrasound devices offer the potential for temporal and 3D spatial control of the energy deposition profile. The objective of this study was to apply theoretical and experimental techniques to investigate the feasibility of endogastric, intraluminal and transgastric catheter-based ultrasound for MR guided thermal therapy of pancreatic tumors. The transgastric approach involves insertion of a catheter-based ultrasound applicator (array of 1.5 mm OD x 10 mm transducers, 360° or sectored 180°, ~7 MHz frequency, 13-14G cooling catheter) directly into the pancreas, either endoscopically or via image-guided percutaneous placement. An intraluminal applicator, of a more flexible but similar construct, was considered for endoscopic insertion directly into the pancreatic or biliary duct. An endoluminal approach was devised based on an ultrasound transducer assembly (tubular, planar, curvilinear) enclosed in a cooling balloon which is endoscopically positioned within the stomach or duodenum, adjacent to pancreatic targets from within the GI tract. A 3D acoustic bio-thermal model was implemented to calculate acoustic energy distributions and used a FEM solver to determine the transient temperature and thermal dose profiles in tissue during heating. These models were used to determine transducer parameters and delivery strategies and to study the feasibility of ablating 1-3 cm diameter tumors located 2-10 mm deep in the pancreas, while thermally sparing the stomach wall. Heterogeneous acoustic and thermal properties were incorporated, including approximations for tumor desmoplasia and dynamic changes during heating. A series of anatomic models based on imaging scans of representative patients were used to investigate the three approaches. Proof of concept (POC) endogastric and transgastric applicators were fabricated and experimentally evaluated in tissue mimicking phantoms, ex vivo tissue and in vivo canine model under multi-slice MR thermometry. RF micro-coils were evaluated to enable active catheter-tracking and prescription of thermometry slice positions. Interstitial and intraluminal ultrasound applicators could be used to ablate (t₄₃>240min) tumors measuring 2.3-3.4 cm in diameter when powered with 20-30 W/cm² at 7 MHz for 5-10 min. Endoluminal applicators with planar and curvilinear transducers operating at 3-4 MHz could be used to treat tumors up to 20-25 mm deep from the stomach wall within 5 min. POC devices were fabricated and successfully integrated into the MRI environment with catheter tracking, real-time thermometry and closed-loop feedback control.

Magnetic Resonance guided High-intensity Focused Ultrasound (MR-HIFU) can be used to locally heat tissue while non-invasively monitoring tissue temperature via MR-based thermometry. The goal of this study was to investigate the use of a computational technique based on inverse heat-transfer modeling for the non-invasive measurement of thermal tissue properties from data collected using an MR-HIFU system.

We have developed a new approach for modeling the propagation of an ultrasound beam in inhomogeneous tissues such as encountered with high-intensity focused ultrasound (HIFU) for treatment of various diseases. This method, called the hybrid angular spectrum (HAS) approach, alternates propagation steps between the space and the spatial frequency domains throughout the inhomogeneous regions of the body; the use of spatial Fourier transforms makes this technique considerably faster than other modeling approaches (about 10 sec for a 141 x 141 x 121 model). In HIFU thermal treatments, the acoustic absorption property of the tissues is of prime importance since it leads to temperature rise and the achievement of desired thermal dose at the treatment site. We have recently added to the HAS method the capability of independently modeling tissue absorption and scattering, the two components of acoustic attenuation. These additions improve the predictive value of the beam modeling and more accurately describes the thermal conditions expected during a therapeutic ultrasound exposure. Two approaches to explicitly model scattering were developed: one for scattering sizes smaller than a voxel, and one when the scattering scale is several voxels wide. Some anatomically realistic examples that demonstrate the importance of independently modeling absorption and scattering are given, including propagation through the human skull for noninvasive brain therapy and in the human breast for treatment of breast lesions.

Catheter based ultrasound ablation devices have been suggested as the least minimally invasive procedure for thermal therapy. The success of such procedures depends on accurately delivering the thermal dose to the tissue. One of the main challenges of such therapy is to deliver thermal therapy at the target location without damaging the surrounding tissue or major vessels and veins. To achieve such multi-directional capability, a multi-angular beam pattern is required. The purpose of this study was to build a multi-sectored tubular ultrasonic transducer and control the directionality of the acoustic power delivered to the tissue by each sector simultaneously. Multi-zoned tubular ultrasonic transducer arrays with three active sectors were constructed. Using these transducer configurations, a multi-angular ablation pattern was created in ex vivo chicken breast tissue. Experiments were conducted by activating two and three zones separately to investigate the ablation pattern of each case. Simulations results were presented by solving the Penne bio-heat equation using finite element method. The simulation results were compared with ex vivo results with respect to temperature and dose distribution in the tissue. Thermocouples located at 15 mm radially from the applicator indicated a peak temperature of greater than 52-55° C and thermal dose of 10³-10⁴ EQ mins at 43°C. It was observed through visual inspection that the proposed technology could ablate a specific tissue region or multiple regions selectively while not damaging the desired surrounding tissue. Good agreement between experimental and simulation results was obtained.

Preferential heating of bone due to high ultrasound attenuation may enhance thermal ablation performed with cathetercooled interstitial ultrasound applicators in or near bone. At the same time, thermally and acoustically insulating cortical bone may protect sensitive structures nearby. 3D acoustic and biothermal transient finite element models were developed to simulate temperature and thermal dose distributions during catheter-cooled interstitial ultrasound ablation near bone. Experiments in ex vivo tissues and tissue-mimicking phantoms were performed to validate the models and to quantify the temperature profiles and ablated volumes for various distances between the interstitial applicator and the bone surface. 3D patient-specific models selected to bracket the range of clinical usage were developed to investigate what types of tumors could be treated, applicator configurations, insertion paths, safety margins, and other parameters. Experiments show that preferential heating at the bone surface decreases treatment times compared to when bone is absent and that all tissue between an applicator and bone can be ablated when they are up to 2 cm apart. Simulations indicate that a 5-7 mm safety margin of normal bone is needed to protect (thermal dose < 6 CEM43°C and T < 45°C) sensitive structures behind ablated bone. In 3D patient-specific simulations, tumors 1.0-3.8 cm (L) and 1.3-3.0 cm (D) near or within bone were ablated (thermal dose > 240 CEM43°C) within 10 min without damaging the nearby spinal cord, lungs, esophagus, trachea, or major vasculature. Preferential absorption of ultrasound by bone may provide improved localization, faster treatment times, and larger treatment zones in tumors in and near bone compared to other heating modalities.

Magnetic nanoparticle (mNP) hyperthermia is a promising adjuvant cancer therapy. mNP’s are delivered intravenously or directly into a tumor, and excited by applying an alternating magnetic field (AMF). The mNP’s are, in many cases, sequestered by cells and packed into endosomes. The proximity of the mNP’s has a strong influence on their ability to heat due to inter-particle magnetic interaction effects. This is an important point to take into account when modeling the mNP’s. Generally, more mNP heating can be achieved using higher magnetic field strengths. The factor which limits the maximum field strength applied to clinically relevant volumes of tissue is the heating caused by eddy currents, which are induced in the noncancerous tissue. A coupled electromagnetic and thermal model has been developed to predict dynamic thermal distributions during AMF treatment. The EM model is based on the method of auxiliary sources and the thermal modeling is based on the Pennes bioheat equation. The results of our phantom study are used to validate the model which takes into account nanoparticle heating, interaction effects, particle spatial distribution, particle size distribution, EM field distribution, and eddy current generation in a controlled environment. Preliminary in vivo data for model validation are also presented. Once fully developed and validated, the model will have applications in experimental design, AMF coil design, and treatment planning.

Treatments of the post-operative surgical bed have proven appealing as the majority of cancer recurrence following tumor resection occurs at the tumor margin. A novel, biodegradable pullulan-based gel infused with magnetic iron oxide nanoparticles (IONP) is presented here for surgical bed administration followed by hyperthermia therapy via alternating magnetic field (AMF) activation. Pullulan is a water soluble, film-forming starch polymer that degrades at the postoperative wound site to deliver the IONP payload, targeting the remaining cancer cells. Different gel formulations containing various % wt of pullulan were tested for IONP elution. Elution levels and amount of gel degradation were measured by immersing the gel in de-ionized water for one hour then measuring particle concentrations in the supernatant and the mass of the remaining gel formulation. The most promising gel formulations will be tested in a murine model of surgical bed resection to assess in vivo gel dissolution, IONP cell uptake kinetics via histology and TEM analysis, and heating capability of the gel with AMF exposure.

Recently, several treatments for fighting malignant tumors have been designed. However these procedures have well known inconveniences, depending on their applicability, tumor size and side effects, among others. Magnetic hyperthermia is a safe, non-invasive method for cancer therapy. This treatment is applied via elevation of target tissue temperature by dissipation of heat from Magnetic Nanoparticles (MNPs), previously located within the tumor. The induction of heat causes cell death and therefore the removal of the tumor. In this work the thermal diffusion in phantoms of agar loaded with magnetic nanoparticles (MNPs) is studied using the infrared thermography technique, which is widely used in biology/medicine (e.g. skin temperature mapping). Agar is one of the materials used to simulate different types of body tissues, these samples are known as “phantoms”. Agar is of natural origin, low cost and high degree of biocompatibility. In this work the agar gel was embedded with MNPs by coprecipitation and placed in an alternating magnetic field radiation. As a consequence, the energy from the radiation source is dissipated as heat and then transferred from the MNP to the gel, increasing its temperature. For the temperature analysis, the samples of agar gel were stimulated by RF magnetic field generated by coils. Heating was measured with infrared thermography using a Thermovision A20M infrared camera. Thermographic images allowed obtaining the dependence of thermal diffusion in the phantom as a function of the magnitude of the applied RF magnetic field and the load of magnetic particles.