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Magnetic fluid hyperthermia (MFH) has been widely investigated as a treatment tool for cancer and other diseases. However, focusing traditional MFH to a tumor deep in the body is not feasible because the in vivo wavelength of 300 kHz very low frequency (VLF) excitation fields is longer than 100 m. Recently we demonstrated that millimeter-precision localized heating can be achieved by combining magnetic particle imaging (MPI) with MFH. In principle, real-time MPI imaging can also guide the location and dosing of MFH treatments. Hence, the combination of MPI imaging plus real time localized MPI–MFH could soon permit closed-loop high-resolution hyperthermia treatment. In this review, we will discuss the fundamentals of localized MFH (e.g. physics and biosafety limitations), hardware implementation, MPI real-time guidance, and new research directions on MPI–MFH. We will also discuss how the scale up to human-sized MPI–MFH scanners could proceed.

Magnetic nanoparticles have many advantages in medicine such as their use in non-invasive imaging as a Magnetic Particle Imaging (MPI) tracer or Magnetic Resonance Imaging contrast agent, the ability to be externally shifted or actuated and externally excited to generate heat or release drugs for therapy. Existing nanoparticles have a gentle sigmoidal magnetization response that limits resolution and sensitivity. Here we show that superferromagnetic iron oxide nanoparticle chains (SFMIOs) achieve an ideal step-like magnetization response to improve both image resolution & SNR by more than 10-fold over conventional MPI. The underlying mechanism relies on dynamic magnetization with square-like hysteresis loops in response to 20 kHz, 15 kAm(−1) MPI excitation, with nanoparticles assembling into a chain under an applied magnetic field. Experimental data shows a ‘1D avalanche’ dipole reversal of every nanoparticle in the chain when the applied field overcomes the dynamic coercive threshold of dipole-dipole fields from adjacent nanoparticles in the chain. Intense inductive signal is produced from this event resulting in a sharp signal peak. We demonstrate novel MPI imaging strategies to harness this behavior towards order-of-magnitude medical image improvements. SFMIOs could provide a breakthrough in noninvasive imaging of cancer, pulmonary embolism, gastrointestinal bleeds, stroke, and inflammation imaging.

Magnetic Particle Imaging is an emerging tracer imaging modality with zero background signal and zero ionizing radiation, high contrast and high sensitivity with quantitative images. While there is recent work showing that the low amplitude or low frequency drive parameters can improve MPI’s spatial resolution by mitigating relaxation losses, the concomitant decrease of the MPI’s tracer sensitivity due to the lower drive slew rates was not fully addressed. There has yet to be a wide parameter space, multi-objective optimization of MPI drive parameters for high resolution, high sensitivity and safety. In a large-scale study, we experimentally test 5 different nanoparticles ranging from multi to single-core across 18.5 nm to 32.1 nm core sizes and across an expansive drive parameter range of 0.4 – 416 kHz and 0.5 – 40 mT/ $\mu _{0}$ to assess spatial resolution, SNR, and safety. In addition, we analyze how drive-parameter-dependent shifts in harmonic signal energy away and towards the discarded first harmonic affect effective SNR in this optimization study. The results show that when optimizing for all four factors of resolution, SNR, discarded-harmonic-energy and safety, the overall trends are no longer monotonic and clear optimal points emerge. We present drive parameters different from conventional preclinical MPI showing ~ 2-fold improvement in spatial resolution while remaining within safety limits and addressing sensitivity by minimizing the typical SNR loss involved. Finally, validation of the optimization results with 2D images of phantoms was performed.

Magnetic fluid hyperthermia (MFH) treatment makes use of a suspension of superparamagnetic iron oxide nanoparticles, administered systemically or locally, in combination with an externally applied alternating magnetic field, to ablate target tissue by generating heat through a process called induction. The heat generated above the mammalian euthermic temperature of 37°C induces apoptotic cell death and/or enhances the susceptibility of the target tissue to other therapies such as radiation and chemotherapy. While most hyperthermia techniques currently in development are targeted towards cancer treatment, hyperthermia is also used to treat restenosis, to remove plaques, to ablate nerves and to alleviate pain by increasing regional blood flow. While RF hyperthermia can be directed invasively towards the site of treatment, non-invasive localization of heat through induction is challenging. In this review, we discuss recent progress in the field of RF magnetic fluid hyperthermia and introduce a new diagnostic imaging modality called magnetic particle imaging that allows for a focused theranostic approach encompassing treatment planning, treatment monitoring and spatially localized inductive heating.

Magnetic particle imaging (MPI) is a promising new tracer-based imaging modality. The steady-state, nonlinear magnetization physics most fundamental to MPI typically predicts improving resolution with increasing tracer magnetic core size. For larger tracers, and given typical excitation slew rates, this steady-state prediction is compromised by dynamic processes that induce a significant secondary blur and prevent us from achieving high resolution using larger tracers. Here, we propose a new method of excitation and signal encoding in MPI we call pulsed MPI to overcome this phenomenon. Pulsed MPI allows us to directly encode the steady-state magnetic physics into the time-domain signal. This in turn gives rise to a simple reconstruction algorithm to obtain images free of secondary relaxation-induced blur. Here, we provide a detailed description of our approach in 1D, discuss how it compares with alternative approaches, and show experimental data demonstrating better than 500- $\mu \text{m}$ resolution (at 7 T/m) with large tracers. Finally, we show experimental images from a 2D implementation.

The success of cancer immunotherapy has driven the rapid growth of research into immuno-oncology, which in turn has fueled the need to be able to determine the location of a variety of immune cells in solid tumors and systemically over time. There is a strong association between response to the new checkpoint inhibitor treatments and the immune status of a tumor, and new methods to determine or modify that status are needed. Magnetic particle imaging (MPI) is a novel preclinical molecular imaging technique that can be used to noninvasively track iron oxide-tagged immune (and other) cells in vivo. By combining accurate quantitation, specificity, and depth-independent 3D imaging, MPI can provide information on macrophage and other cellular biodistributions over time, for weeks or even months. In addition to being an imaging modality, MPI can be used for localized theragnostics and drug delivery. The same or similar nanoparticles that are used for imaging can also be used to generate heat for localized magnetic hyperthermia. Imaging is used to determine the distribution and amount of iron in a sample, then MPI-based magnetic gradients are used to limit the hyperthermia to only a small, adjustable “field-free region” in the sample. Heating can be severe, until the start of apoptosis, or mild, to promote a localized immune response, which can be beneficial as an adjunct to both radiation and immune therapies, improving radiation therapy efficacy and potentially turning “cold,” immunologically unresponsive tumors “hot.” The nanoparticles used for both imaging and hyperthermia are superparamagnetic iron-oxide, with considerable differences in imaging sensitivity and resolution and hyperthermia efficiency possible depending on the size, shape, and composition of the particles. Unlike many other molecular imaging modalities, resolution for MPI depends strongly on the nanoparticle being imaged, with resolutions from 100 um to nearly 2 mm being possible with the same imaging system simply by using different particles. In addition, the design and development of heat-sensitive nanoparticles and liposomes for use with mild hyperthermia is an important aspect of MPI development. MPI is a rapidly growing molecular imaging technique, with applications across many biomedical fields, including oncology. The noninvasive, 3D tracking of immune cell distributions systemically in vivo is an important aspect of understanding immune-tumor interactions, and the combination of imaging nanoparticles along with using them for localized mild or severe RF hyperthermia is a powerful addition to the toolkit for oncology research. Results and instrumentation for both immune cell tracking and localized magnetic hyperthermia will be discussed. Citation Format: James R. Mansfield, Jeffrey M. Gaudet, Gang Ren, Daniel Hensley, Patrick Goodwill, Max Wintermark. Changing the field: Magnetic particle imaging and localized RF hyperthermia in cancer immunology [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B7.

Magnetic particle imaging (MPI), introduced at the beginning of the twenty-first century, is emerging as a promising diagnostic tool in addition to the current repertoire of medical imaging modalities. Using superparamagnetic iron oxide nanoparticles (SPIOs), that are available for clinical use, MPI produces high contrast and highly sensitive tomographic images with absolute quantitation, no tissue attenuation at-depth, and there are no view limitations. The MPI signal is governed by the Brownian and Neel relaxation behavior of the particles. The relaxation time constants of these particles can be utilized to map information relating to the local microenvironment, such as viscosity and temperature. Proof-of-concept pre-clinical studies have shown favourable applications of MPI for better understanding the pathophysiology associated with vascular defects, tracking cell-based therapies and nanotheranostics. Functional imaging techniques using MPI will be useful for studying the pathology related to viscosity changes such as in vascular plaques and in determining cell viability of superparamagnetic iron oxide nanoparticle labeled cells. In this review article, an overview of MPI is provided with discussions mainly focusing on MPI tracers, applications of translational capabilities ranging from diagnostics to theranostics and finally outline a promising path towards clinical translation.

Magnetic particle imaging (MPI) is an emerging ionizing radiation-free biomedical tracer imaging technique that directly images the intense magnetization of superparamagnetic iron oxide nanoparticles (SPIOs). MPI offers ideal image contrast because MPI shows zero signal from background tissues. Moreover, there is zero attenuation of the signal with depth in tissue, allowing for imaging deep inside the body quantitatively at any location. Recent work has demonstrated the potential of MPI for robust, sensitive vascular imaging and cell tracking with high contrast and dose-limited sensitivity comparable to nuclear medicine. To foster future applications in MPI, this new biomedical imaging field is welcoming researchers with expertise in imaging physics, magnetic nanoparticle synthesis and functionalization, nanoscale physics, and small animal imaging applications.

Background Islet transplantation (Tx) represents the most promising therapy to restore normoglycemia in type 1 diabetes (T1D) patients to date. As significant islet loss has been observed after the procedure, there is an urgent need for developing strategies for monitoring transplanted islet grafts. In this report we describe for the first time the application of magnetic particle imaging (MPI) for monitoring transplanted islets in the liver and under the kidney capsule in experimental animals. Methods Pancreatic islets isolated from Papio hamadryas were labeled with superparamagnetic iron oxides (SPIOs) and used for either islet phantoms or Tx in the liver or under the kidney capsule of NOD scid mice. MPI was used to image and quantify islet phantoms and islet transplanted experimental animals post-mortem at 1 and 14 days after Tx. Magnetic resonance imaging (MRI) was used to confirm the presence of labeled islets in the liver and under the kidney capsule 1 day after Tx. Results MPI of labeled islet phantoms confirmed linear correlation between the number of islets and the MPI signal (R2=0.988). Post-mortem MPI performed on day 1 after Tx showed high signal contrast in the liver and under the kidney capsule. Quantitation of the signal supports islet loss over time, which is normally observed 2 weeks after Tx. No MPI signal was observed in control animals. In vivo MRI confirmed the presence of labeled islets/islet clusters in liver parenchyma and under the kidney capsule one day after Tx. Conclusions Here we demonstrate that MPI can be used for quantitative detection of labeled pancreatic islets in the liver and under the kidney capsule of experimental animals. We believe that MPI, a modality with no depth attenuation and zero background tissue signal could be a suitable method for imaging transplanted islet grafts.

Image guided treatment of cancer enables physicians to localize and treat tumors with great precision. Here, we present in vivo results showing that an emerging imaging modality, Magnetic Particle Imaging (MPI), can be combined with Magnetic Hyperthermia into a image-guided theranostic platform. MPI is a noninvasive 3D tomographic imaging method with high sensitivity and contrast, zero ionizing radiation, and is linearly quantitative at any depth with no view limitations. The same superparamagnetic iron oxide nanoparticle (SPIONs) tracers imaged in MPI can also be excited to generate heat for magnetic hyperthermia. In this study, we demonstrate a theranostic platform, with quantitative MPI image-guidance for treatment planning and use of the MPI gradients for spatial localization of magnetic hyperthermia to arbitrarily selected regions. This addresses a key challenge of conventional magnetic hyperthermia - SPIONs delivered systemically accumulate in off-target organs (e.g., liver and spleen), and difficulty in localizing hyperthermia results in collateral heat damage to these organs. Using a MPI-magnetic hyperthermia workflow, we demonstrate image-guided, spatial localization of hyperthermia to the tumor while minimizing collateral damage to the nearby liver (1 – 2 cm distant). Localization of thermal damage and therapy was validated with luciferase activity and histological assessment. Apart from localizing thermal therapy, the technique presented here can also be extended to localize actuation of drug release and other biomechanical-based therapies. With high contrast and high sensitivity imaging combined with precise control and localization of the actuated therapy, MPI is a powerful platform for magnetic-based theranostics.

Magnetic fluid hyperthermia (MFH) is a promising avenue for noninvasive or minimally invasive therapies including tissue ablation, hyperthermia, and drug delivery. Magnetic particle imaging (MPI) is a promising new medical imaging modality with wide-ranging applications including angiography, cell tracking, and cancer imaging. MFH and MPI are kindred technologies leveraging the same physics: Both MFH and MPI function by exciting iron oxide magnetic nanoparticles with AC magnetic fields. In this manuscript, we show that this can be leveraged for combined MPI-MFH. The gradient fields employed in MPI can benefit MFH by providing high resolution targeting anywhere in the body, and a dual system provides opportunities for real-time diagnostic imaging feedback. Here we experimentally quantify the spatial localization of MFH using MPI gradient fields with a custom MPI-MFH system, demonstrating approximately 3 mm heating resolution in phantoms. We show an ability to precisely target phantom components as desired and provide heating of approximately 150 W g-1. We also show preliminary simultaneous MPI-MFH data.

Magnetic Particle Imaging (MPI) is a new molecular imaging technique that directly images superparamagnetic tracers with high image contrast and sensitivity approaching nuclear medicine techniques - but without ionizing radiation. Since its inception, the MPI research field has quickly progressed in imaging theory, hardware, tracer design, and biomedical applications. Here we describe the history and field of MPI, outline pressing challenges to MPI technology and clinical translation, highlight unique applications in MPI, and describe the role of the WMIS MPI Interest Group in collaboratively advancing MPI as a molecular imaging technique. We invite interested investigators to join the MPI Interest Group and contribute new insights and innovations to the MPI field.

Magnetic particle imaging (MPI) is a rapidly developing molecular and cellular imaging modality. Magnetic fluid hyperthermia (MFH) is a promising therapeutic approach where magnetic nanoparticles are used as a conduit for targeted energy deposition, such as in hyperthermia induction and drug delivery. The physics germane to and exploited by MPI and MFH are similar, and the same particles can be used effectively for both. Consequently, the method of signal localization through the use of gradient fields in MPI can also be used to spatially localize MFH, allowing for spatially selective heating deep in the body and generally providing greater control and flexibility in MFH. Furthermore, MPI and MFH may be integrated together in a single device for simultaneous MPI-MFH and seamless switching between imaging and therapeutic modes. Here we show simulation and experimental work quantifying the extent of spatial localization of MFH using MPI systems: we report the first combined MPI-MFH system and demonstrate on-demand selective heating of nanoparticle samples separated by only 3 mm (up to 0.4 °C s-1 heating rates and 150 W g-1 SAR deposition). We also show experimental data for MPI performed at a typical MFH frequency and show preliminary simultaneous MPI-MFH experimental data.

Molecular imaging has been instrumental for unraveling the mystery of biological processes and for diagnosing disease with more accuracy than ever before. The existing repertoire of molecular imaging techniques has been exceedingly fruitful for both preclinical applications and clinical diagnosis, but to date, no technique combines exquisite tracer detection sensitivity with quantitativeness for longitudinal, months-long in vivo imaging deep in tissue. Magnetic particle imaging (MPI) is an emerging technique that directly images the strong electronic magnetization of clinically safe superparamagnetic iron oxide (SPIO) tracers. Because biological tissues do not produce signals detectable in MPI scanners, MP images have high contrast and sensitivity for SPIO tracers, comparable to nuclear medicine techniques. The MPI signal is also robust and linearly quantitative of SPIO tracers anywhere in the body. Hence, MPI may be useful in applications ranging from coronary angiography to stem cell tracking and has potential for human translation. In this chapter, we describe the differences between MPI and MRI physics, since most MRI-tailored SPIOs are not effective as MPI tracers. This chapter is designed so nanoparticle scientists can design ideal MPI-tailored SPIOs.

Magnetic Particle Imaging (MPI) is an emerging tomographic imaging technology that detects magnetic nanoparticle tracers by exploiting their non-linear magnetization properties. In order to predict the behavior of nanoparticles in an imager, it is possible to use a non-imaging MPI relaxometer or spectrometer to characterize the behavior of nanoparticles in a controlled setting. In this paper we explore the use of ferrohydrodynamic magnetization equations for predicting the response of particles in an MPI relaxometer. These include a magnetization equation developed by Shliomis (Sh) which has a constant relaxation time and a magnetization equation which uses a field-dependent relaxation time developed by Martsenyuk, Raikher and Shliomis (MRSh). We compare the predictions from these models with measurements and with the predictions based on the Langevin function that assumes instantaneous magnetization response of the nanoparticles. The results show good qualitative and quantitative agreement between the ferrohydrodynamic models and the measurements without the use of fitting parameters and provide further evidence of the potential of ferrohydrodynamic modeling in MPI.

Magnetic Particle Imaging (MPI) is a promising new tracer modality with zero attenuation deep in tissue, high contrast and sensitivity, and an excellent safety profile. However, the spatial resolution of MPI is limited to around 1 mm currently and urgently needs to be improved for clinical applications such as angiography and brain perfusion. Although MPI resolution is highly dependent on tracer characteristics and the drive waveforms, optimization is limited to a small subset of possible excitation strategies by current MPI hardware that only does sinusoidal drive waveforms at very few frequencies. To enable a more comprehensive and rapid optimization of drive waveforms for multiple metrics like resolution and signal strength simultaneously, we demonstrate the first untuned MPI spectrometer/relaxometer with unprecedented 400 kHz excitation bandwidth and capable of high-throughput acquisition of harmonic spectra (100 different drive-field frequencies in only 500 ms). It is also capable of arbitrary drive-field waveforms which have not been experimentally evaluated in MPI to date. Its high-throughput capability, frequency-agility and tabletop size makes this Arbitrary Waveform Relaxometer/Spectrometer (AWR) a convenient yet powerfully flexible tool for nanoparticle experts seeking to characterize magnetic particles and optimize MPI drive waveforms for in vitro biosensing and in vivo imaging with MPI.

This paper investigates thermal ablation of cancer tissue as a controls problem. The objective is to deliver a lethal dose of thermal energy to the cancer tissue without damaging critical nearby healthy tissue. This paper proposes a model predictive controller (MPC) to regulate thermal dose. The model predictive controller guarantees the safety of the healthy tissue surrounding the tumor. The cost function rewards killing cancer cells. Simulations comparing the proposed controller with the bang-bang controller used in practice demonstrate that the MPC controller kills more of the cancer tissue and requires less time than the bang-bang controller, while damaging less healthy tissue.

Developing tracers for MPI and related applications requires a thorough understanding of underlying relaxation processes. In X-Space MPI reconstruction, relaxation has a profound impact on the image through a decrease in SNR and direction-dependent blurring. To probe the relaxation of potential MPI tracers, Goodwill et al., have developed an X-Space Relaxometer that measures the MPI point spread function and accurately predicts image quality.[1,2] The present work introduces a new relaxometer with improved eddy current shielding to achieve a significant gain in sensitivity. A simulation of the enhanced shielding has shown to attenuate external interference by more than 40dB in the detection bandwidth.

MPI resolution and SNR are driven by the magnetic response of the iron oxide nanoparticles. Prior work has shown that magnetic nanoparticles respond differently to a wide range of excitation frequencies and amplitudes. Most prior work on MPI spectrometers and relaxometers have tuned the transmit coil at a single frequency.1-3 In contrast, in this work, we have constructed an agile frequency and amplitude relaxometer capable of reaching excitation fields of 0–60 mTpp across a continuous frequency range of DC-150 kHz without requirement of capacitors for tuning to discrete frequencies.

Magnetic Particle Imaging (mpi) is a promising new modality that images only a magnetic tracer, commonly super-paramagnetic iron oxide (spio) nanoparticles [1, 2]. During data acquisition information about the dc component of the native image is lost, and must be recovered using some a priori knowledge such as image continuity and positivity [3,4]. One method of recovery uses convex optimization techniques to determine the dc offsets that match the a priori knowledge. This method produces excellent images but significant time and memory resources to perform.

Previous work has explored the effects of nanoparticle relaxation from the system matrix and x-space reconstruction points of view [1-8]. Here we demonstrate how relaxation can be used to “colorize” an image based on relaxation mechanisms using x-space reconstruction [9] and a pixel-wise linear model.

MPI shows great promise for safe angiography, blood pool, and perfusion imaging. MPI images have unprecedented contrast that enables unambiguous measurements of tracer quantity and location [1-4]. At present, pre-clinical MPI resolution does not compare with pre-clinical MRI and CT, which routinely achieve better than 100-micron resolution. MPI's low resolution is primarily due to limitations in MPI hardware and magnetic nanoparticles. To begin to close this resolution gap, we are developing higher-field MPI gradients [3] and specialized MPI magnetic nanoparticles [4]. Since MPI resolution improves with stronger selection field gradients, we recently completed construction of a high-field MPI imager with a 7 T/m × 3.5 T/m × 3.5 T/m magnetic field gradient. Further, magnetic nanoparticles developed specifically for MPI show dramatic improvements in resolution and SNR over commercially available nanoparticles such as Resovist (BayerSchering) [4]. In this work, we demonstrate that combining these two breakthroughs enable improvements in MPI angiography images that begin to close the gap between MPI and pre-clinical MRI and CT.

An MPI spectrometer [1-3] measures the harmonics generated when a nonlinear SPIO is excited by a sinusoidal field. The harmonic peak spectrum allows for comparing SPIOs spatial resolution, since the harmonics are related to the modulation transfer function of the MPI imaging PSF [4-5]. It is also powerful to directly measure the point-spread function (PSF) by using the x-space MPI image reconstruction method [5-6], which has been shown to be equivalent to System Matrix reconstruction [7]. Here we describe a new design for an x-space relaxometer to increase sensitivity.

Magnetic particle imaging (MPI) is a promising new tracer modality with zero attenuation in tissue, high contrast and sensitivity, and an excellent safety profile. However, the spatial resolution of MPI is currently around 1 mm in small animal scanners. Especially considering tradeoffs when scaling up MPI scanning systems to human size, this resolution needs to be improved for clinical applications such as angiography and brain perfusion. One method to improve spatial resolution is to increase the magnetic core size of the superparamagnetic nanoparticle tracers. The Langevin model of superparamagnetism predicts a cubic improvement of spatial resolution with magnetic core diameter. However, prior work has shown that the finite temporal response, or magnetic relaxation, of the tracer increases with magnetic core diameter and eventually leads to blurring in the MPI image. Here we perform the first wide ranging study of 5 core sizes between 18 and 32 nm with experimental quantification of the spatial resolution of each. Our results show that increasing magnetic relaxation with core size eventually opposes the expected Langevin behavior, causing spatial resolution to stop improving after 25 nm. Different MPI excitation strategies were experimentally investigated to mitigate the effect of magnetic relaxation. The results show that magnetic relaxation could not be fully mitigated for the larger core sizes and the cubic resolution improvement predicted by the Langevin was not achieved. This suggests that magnetic relaxation is a significant and unsolved barrier to achieving the high spatial resolutions predicted by the Langevin model for large core size superparamagnetic iron oxides.

This paper presents an updated and augmented version of the Wissler human thermoregulation model that has been developed continuously over the past 50 years. The existing Fortran code is translated into C with extensive embedded commentary. A graphical user interface (GUI) has been developed in Python to facilitate convenient user designation of input and output variables and formatting of data presentation. Use of the code with the GUI is described and demonstrated. New physiological elements were added to the model to represent the hands and feet, including the unique vascular structures adapted for heat transfer associated with glabrous skin. The heat transfer function and efficacy of glabrous skin is unique within the entire body based on the capacity for a very high rate of blood perfusion and the novel capability for dynamic regulation of blood flow. The model was applied to quantify the absolute and relative contributions of glabrous skin flow to thermoregulation for varying levels of blood perfusion. The model also was used to demonstrate how the unique features of glabrous skin blood flow may be recruited to implement thermal therapeutic procedures. We have developed proprietary methods to manipulate the control of glabrous skin blood flow in conjunction with therapeutic devices and simulated the effect of these methods with the model.

The development of magnetic particle imaging (MPI) has created a need for optimized magnetic nanoparticles. Magnetic particle relaxometry is an excellent tool for characterizing potential tracers for MPI. In this paper, we describe the design and construction of a high-throughput tabletop relaxometer that is able to make sensitive measurements of MPI tracers without the need for a dedicated shield room.

Glabrous (hairless) skin found on the hands, feet, face, and ears is a unique component of the thermoregulatory system. Its anatomy and control physiology differ markedly from those of the rest of the skin. Glabrous regions contain vascular networks capable of supporting large blood flows due to the presence of highly tortuous and densely packed arteriovenous anastomoses (AVAs) and associated venous collecting networks [1]. When dilated, these vessels bring large volumes of blood close to the body surface where they function as highly efficient heat exchangers. Furthermore, the manner in which this blood flow is controlled is very unique, exhibiting, for example, rapid and high-magnitude responses, as well as a greater sensitivity to central core signals [1]. In this light, glabrous skin is an important but often overlooked tool the body uses to rapidly and finely adjust energy balance to maintain thermal equilibrium.Copyright © 2012 by ASME

Localized cooling is commonly used after orthopedic surgery and in sports medicine to reduce bleeding, inflammation, metabolism, muscle spasm, pain, and swelling following musculoskeletal trauma and injury. The therapeutic application of cold therapy has a long history dating from the time of Hippocrates and has been widely documented in the literature1–3. Nonetheless, there remains to the present time considerable controversy over the appropriate protocol for application of cryotherapy. One extreme camp advocates continuous use of cryotherapy to a treatment site with no break in cooling for days or even weeks4–5, whereas other practitioners recommend a maximum application duration of 20 to 30 minutes followed by a cessation period of about 2 hours6–7. Although continuous cooling appears to be tolerated by many patients, there has been a large number of reported incidences in which continuous application of cryotherapy device led directly to extensive tissue necrosis and/or nerve injury in the treatment area, sometimes with dire medical consequences6,8.Copyright © 2011 by ASME

The ability to easily manipulate body temperature would impact a number of fields. While perfusion with externally cooled or warmed blood is effective due to the thermoregulatory power of the circulatory system and its diffuse microcirculation, this process is particularly invasive. Noninvasive techniques to date mostly utilize body surface applications that rely on relatively inferior conduction heat transfer.

Ultrasound devices are being investigated for endoluminal and intraductal access for targeted thermal ablation or hyperthermia of pancreas under MR guidance and temperature monitoring. Simulations using patient-specific 3D models were developed for applicator design and development of treatment delivery strategies. MR-compatible devices were constructed for endoluminal (3-5 MHz planar or lightly focused rectangular elements, 12-mm OD assembly, expandable balloon), transgastric interstitial and intraductal (6-8 MHz multi-sectored tubular elements, 2-mm catheter) deployment. Micro-coils were integrated for active MR tracking of position and alignment. The proof-of-concept devices were tested in phantoms, ex vivo tissues, cadaveric porcine models, and in vivo animal models under 3T MR temperature imaging (MRTI). Results indicate endoluminal devices could ablate 2-2.5 cm depth from gastric wall for tumors of the pancreatic head, and multi-sectored tubular intraductal and interstitial applicators could ablate 2.3-3.4 cm diameter targets with directional control. Intraductal applicators could produce effective hyperthermia (>40 C) extending 15 mm radial. Customized tracking sequences could be used to locate 3D position of the applicators. Endoluminal, interstitial, and intraductal ultrasound applicators show promise for ablation or hyperthermia of pancreatic tumors. MR guidance can be employed for positioning these devices with active tracking coils and real time temperature monitoring. (NIH-P01CA159992.)