Engineering Magnetic Nanoclusters for Highly Efficient Heating in Radio-Frequency Nanowarming.

Effective thawing of cryopreserved samples requires rapid and uniform heating. This is achievable through nanowarming, an approach that heats magnetic nanoparticles by using alternating magnetic fields. Here we demonstrate the synthesis and surface modification of magnetic nanoclusters for efficient nanowarming. Magnetite (Fe3O4) nanoclusters with an optimal diameter of 58 nm exhibit a high specific absorption rate of 1499 W/g Fe under an alternating magnetic field at 43 kA/m and 413 kHz, more than twice that of commercial iron oxide cores used in prior nanowarming studies. Surface modification with a permeable resorcinol-formaldehyde resin (RFR) polymer layer significantly enhances their colloidal stability in complex cryoprotective solutions, while maintaining their excellent heating capacity. The Fe3O4@RFR nanoparticles achieved a high average heating rate of 175 °C/min in cryopreserved samples at a concentration of 10 mg Fe/mL and were successfully applied in nanowarming porcine iliac arteries, highlighting their potential for enhancing the efficacy of cryopreservation.

On Chip Sorting of Stem Cell-Derived ß Cell Clusters Using Traveling Surface Acoustic Waves.

There is a critical need for sorting complex materials, such as pancreatic islets of Langerhans, exocrine acinar tissues, and embryoid bodies. These materials are cell clusters, which have highly heterogeneous physical properties (such as size, shape, morphology, and deformability). Selecting such materials on the basis of specific properties can improve clinical outcomes and help advance biomedical research. In this work, we focused on sorting one such complex material, human stem cell-derived ß cell clusters (SC-ß cell clusters), by size. For this purpose, we developed a microfluidic device in which an image detection system was coupled to an actuation mechanism based on traveling surface acoustic waves (TSAWs). SC-ß cell clusters of varying size (∼100-500 µm in diameter) were passed through the sorting device. Inside the device, the size of each cluster was estimated from their bright-field images. After size identification, larger clusters, relative to the cutoff size for separation, were selectively actuated using TSAW pulses. As a result of this selective actuation, smaller and larger clusters exited the device from different outlets. At the current sample dilutions, the experimental sorting efficiency ranged between 78% and 90% for a separation cutoff size of 250 µm, yielding sorting throughputs of up to 0.2 SC-ß cell clusters/s using our proof-of-concept design. The biocompatibility of this sorting technique was also established, as no difference in SC-ß cell cluster viability due to TSAW pulse usage was found. We conclude the proof-of-concept sorting work by discussing a few ways to optimize sorting of SC-ß cell clusters for potentially higher sorting efficiency and throughput. This sorting technique can potentially help in achieving a better distribution of islets for clinical islet transplantation (a potential cure for type 1 diabetes). Additionally, the use of this technique for sorting islets can help in characterizing islet biophysical properties by size and selecting suitable islets for improved islet cryopreservation.

CPA toxicity screening of cryoprotective solutions in rat hearts.

In clinical practice, donor hearts are transported on ice prior to transplant and discarded if cold ischemia time exceeds ∼5 h. Methods to extend these preservation times are critically needed, and ideally, this storage time would extend indefinitely, enabling improved donor-to-patient matching, organ utilization, and immune tolerance induction protocols. Previously, we demonstrated successful vitrification and rewarming of whole rat hearts without ice formation by perfusion-loading a cryoprotective agent (CPA) solution prior to vitrification. However, these hearts did not recover any beating even in controls with CPA loading/unloading alone, which points to the chemical toxicity of the cryoprotective solution (VS55 in Euro-Collins carrier solution) as the likely culprit. To address this, we compared the toxicity of another established CPA cocktail (VEG) to VS55 using ex situ rat heart perfusion. The CPA exposure time was 150 min, and the normothermic assessment time was 60 min. Using Celsior as the carrier, we observed partial recovery of function (atria-only beating) for both VS55 and VEG. Upon further analysis, we found that the VEG CPA cocktail resulted in 50 % lower LDH release than VS55 (N = 4, p = 0.017), suggesting VEG has lower toxicity than VS55. Celsior was a better carrier solution than alternatives such as UW, as CPA + Celsior-treated hearts spent less time in cardiac arrest (N = 4, p = 0.029). While we showed substantial improvement in cardiac function after exposure to vitrifiable concentrations of CPA by improving both the CPA and carrier solution formulation, further improvements will be required before we achieve healthy cryopreserved organs for transplant.

Thermal Analyses of Nanowarming-Assisted Recovery of the Heart From Cryopreservation by Vitrification.

This study explores thermal design aspects of nanowarming-assisted recovery of the heart from indefinite cryogenic storage, where nanowarming is the volumetric heating effect of ferromagnetic nanoparticles excited by a radio frequency electromagnet field. This study uses computational means while focusing on the human heart and the rat heart models. The underlying nanoparticle loading characteristics are adapted from a recent, proof-of-concept experimental study. While uniformly distributed nanoparticles can lead to uniform rewarming, and thereby minimize adverse effects associated with ice crystallization and thermomechanical stress, the combined effects of heart anatomy and nanoparticle loading limitations present practical challenges which this study comes to address. Results of this study demonstrate that under such combined effects, nonuniform nanoparticles warming may lead to a subcritical rewarming rate in some parts of the domain, excessive heating in others, and increased exposure potential to cryoprotective agents (CPAs) toxicity. Nonetheless, the results of this study also demonstrate that computerized planning of the cryopreservation protocol and container design can help mitigate the associated adverse effects, with examples relating to adjusting the CPA and/or nanoparticle concentration, and selecting heart container geometry, and size. In conclusion, nanowarming may provide superior conditions for organ recovery from cryogenic storage under carefully selected conditions, which comes with an elevated complexity of protocol planning and optimization.

Kinetics of nonisothermal phase change with arbitrary temperature-time history and initial transformed phase distributions.

This paper describes the extension of the classic Avrami equation to nonisothermal systems with arbitrary temperature-time history and arbitrary initial distributions of transformed phase. We start by showing that through examination of phase change in Fourier space, we can decouple the nucleation rate, growth rate, and transformed fraction, leading to the derivation of a nonlinear differential equation relating these three properties. We then consider a population balance partial differential equation (PDE) on the phase size distribution and solve it analytically. Then, by relating this PDE solution to the transformed fraction of phase, we are able to derive initial conditions to the differential equation relating nucleation rate, growth rate, and transformed fraction.

Imaging the distribution of iron oxide nanoparticles in hypothermic perfused tissues.

PURPOSE: Herein, we evaluate the use of MRI as a tool for assessing iron oxide nanoparticle (IONP) distribution within IONP perfused organs and vascularized composite allografts (VCAs) (i.e., hindlimbs) prepared for cryopreservation. METHODS: Magnetic resonance imaging was performed on room-temperature organs and VCAs perfused with IONPs and were assessed at 9.4 T. Quantitative T1 mapping and T2∗ -weighted images were acquired using sweep imaging with Fourier transformation and gradient-echo sequences, respectively. Verification of IONP localization was performed through histological assessment and microcomputer tomography. RESULTS: Quantitative imaging was achieved for organs and VCAs perfused with up to 642 mMFe (36 mgFe /mL), which is above previous demonstrations of upper limit detection in agarose (35.7mMFe [2 mgFe /mL]). The stability of IONPs in the perfusate had an effect on the quality of distribution and imaging within organs or VCA. Finally, MRI provided more accurate IONP localization than Prussian blue histological staining in this system, wherein IONPs remain primarily in the vasculature. CONCLUSION: Using MRI, we were able to assess the distribution of IONPs throughout organs and VCAs varying in complexity. Additional studies are necessary to better understand this system and validate the calibration between T1 measurements and IONP concentration.

The impact of data selection and fitting on SAR estimation for magnetic nanoparticle heating.

BACKGROUND: Magnetic fluid heating has great potential in the fields of thermal medicine and cryopreservation. However, variations among experimental parameters, analysis methods and experimental uncertainty make quantitative comparisons of results among laboratories difficult. Herein, we focus on the impact of calculating the specific absorption rate (SAR) using Time-Rise and Box-Lucas fitting. Time-Rise assumes adiabatic conditions, which is experimentally unachievable, but can be reasonably assumed (quasi-adiabatic) only for specific and limited evaluation times when heat loss is negligible compared to measured heating rate. Box-Lucas, on the other hand, accounts for heat losses but requires longer heating. METHODS: Through retrospective analysis of data obtained from two laboratories, we demonstrate measurement time is a critical parameter to consider when calculating SAR. Volumetric SAR were calculated using the two methods and compared across multiple iron-oxide nanoparticles. RESULTS: We observed the lowest volumetric SAR variation from both fitting methods between 1-10 W/mL, indicating an ideal SAR range for heating measurements. Furthermore, our analysis demonstrates that poorly chosen fitting method can generate reproducible but inaccurate SAR. CONCLUSION: We provide recommendations to select measurement time for data analysis with either Modified Time-Rise or Box-Lucas method, and suggestions to enhance experimental precision and accuracy when conducting heating experiments.

From Nanowarming to Thermoregulation: New Multiscale Applications of Bioheat Transfer.

This review explores bioheat transfer applications at multiple scales from nanoparticle (NP) heating to whole-body thermoregulation. For instance, iron oxide nanoparticles are being used for nanowarming, which uniformly and quickly rewarms 50-80-mL (≤5-cm-diameter) vitrified systems by coupling with radio-frequency (RF) fields where standard convective warming fails. A modification of this approach can also be used to successfully rewarm cryopreserved fish embryos (∼0.8 mm diameter) by heating previously injected gold nanoparticles with millisecond pulsed laser irradiation where standard convective warming fails. Finally, laser-induced heating of gold nanoparticles can improve the sensitivity of lateral flow assays (LFAs) so that they are competitive with laboratory tests such as the enzyme-linked immunosorbent assay. This approach addresses the main weakness of LFAs, which are otherwise the cheapest, easiest, and fastest to use point-of-care diagnostic tests in the world. Body core temperature manipulation has now become possible through selective thermal stimulation (STS) approaches. For instance, simple and safe heating of selected areas of the skin surface can open arteriovenous anastomosis flow in glabrous skin when it is not already established, thereby creating a convenient and effective pathway to induce heat flow between the body core and environment. This has led to new applications of STS to increase or decrease core temperatures in humans and animals to assist in surgery (perioperative warming), to aid ischemic stress recovery (cooling), and even to enhance the quality of sleep. Together, these multiscale applications of nanoparticle heating and thermoregulation point to dramatic opportunities for translation and impact in these prophylactic, preservative, diagnostic, and therapeutic applications of bioheat transfer.

Engineering T cell response to cancer antigens by choice of focal therapeutic conditions.

Focal thermal therapy (Heat), cryosurgery (Cryo) and irreversible electroporation (IRE) are increasingly used to treat cancer. However, local recurrence and systemic spread are persistent negative outcomes. Nevertheless, emerging work with immunotherapies (i.e., checkpoint blockade or dendritic cell (DC) vaccination) in concert with focal therapies may improve outcomes. To understand the role of focal therapy in priming the immune system for immunotherapy, an in vitro model of T cell response after exposure to B16 melanoma cell lysates after lethal exposures was designed. Exposure included: Heat (50 °C, 30 min), Cryo (-80 °C, 30 min) and IRE (1250 V/cm, 99 pulses, 50 µs pulses with 1 Hz intervals). After viability assessment (CCK-8 assay), cell lysates were collected and assessed for protein release (BCA assay), protein denaturation (FTIR-spectroscopy), TRP-2 antigen release (western blot), and T cell activation (antigen-specific CD8 T cell proliferation). Results showed IRE released the most protein and antigen (TRP-2), followed by Cryo and Heat. In contrast, Cryo released the most native (not denatured) protein, compared to IRE and Heat. Finally, IRE dramatically outperformed both Cryo and Heat in T cell activation while Cryo modestly outperformed Heat. This study demonstrates that despite all focal therapies ability to destroy cells, the 'quantity' (i.e., amount) and 'quality' (i.e., molecular state) of tumor protein (including antigen) released can dramatically change the ensuing priming of the immune system. This suggests protein-based metrics whereby focal therapies can be designed to prime the immune system in concert with immunotherapies to eventually achieve improved and durable cancer treatment in vivo.

The Role of Protein Loss and Denaturation in Determining Outcomes of Heating, Cryotherapy, and Irreversible Electroporation on Cardiomyocytes.

Atrial fibrillation (AF) currently affects millions of people in the U.S. alone. Focal therapy is an increasingly attractive treatment for AF that avoids the debilitating effects of drugs for disease control. Perhaps the most widely used focal therapy for AF is heat-based radiofrequency (heating), although cryotherapy (cryo) is rapidly replacing it due to a reduction in side effects and positive clinical outcomes. A third focal therapy, irreversible electroporation (IRE), is also being considered in some settings. This study was designed to help guide treatment thresholds and compare mechanism of action across heating, cryo, and IRE. Testing was undertaken on HL-1 cells, a well-established cardiomyocyte cell line, to assess injury thresholds for each treatment method. Cell viability, as assessed by Hoechst and propidium iodide (PI) staining, was found to be minimal after exposure to temperatures ≤-40 °C (cryo), ≥60 °C (heating), and when field strengths ≥1500 V/cm (IRE) were used. Viability was then correlated to protein denaturation fraction (PDF) as assessed by Fourier transform infrared (FTIR) spectroscopy, and protein loss fraction (PLF) as assessed by bicinchoninic acid (BCA) assay after the three treatments. These protein changes were assessed both in the supernatant and the pellet of cell suspensions post-treatment. We found that dramatic viability loss (≥50%) correlated strongly with ≥12% protein change (PLF, PDF or a combination of the two) in every focal treatment. These studies help in defining both cellular thresholds and protein-based mechanisms of action that can be used to improve focal therapy application for AF.

The Role of Nanoparticle Design in Determining Analytical Performance of Lateral Flow Immunoassays.

Rapid, simple, and cost-effective diagnostics are needed to improve healthcare at the point of care (POC). However, the most widely used POC diagnostic, the lateral flow immunoassay (LFA), is ∼1000-times less sensitive and has a smaller analytical range than laboratory tests, requiring a confirmatory test to establish truly negative results. Here, a rational and systematic strategy is used to design the LFA contrast label (i.e., gold nanoparticles) to improve the analytical sensitivity, analytical detection range, and antigen quantification of LFAs. Specifically, we discovered that the size (30, 60, or 100 nm) of the gold nanoparticles is a main contributor to the LFA analytical performance through both the degree of receptor interaction and the ultimate visual or thermal contrast signals. Using the optimal LFA design, we demonstrated the ability to improve the analytical sensitivity by 256-fold and expand the analytical detection range from 3 log10 to 6 log10 for diagnosing patients with inflammatory conditions by measuring C-reactive protein. This work demonstrates that, with appropriate design of the contrast label, a simple and commonly used diagnostic technology can compete with more expensive state-of-the-art laboratory tests.

Cryopreservation by vitrification: a promising approach for transplant organ banking.

PURPOSE OF REVIEW: The objective of this review is to describe the physical and biological barriers to organ cryopreservation, historic approaches for conventional cryopreservation and evolving techniques for ice-free cryopreservation by vitrification. RECENT FINDINGS: Vitrification is a process whereby a biologic substance is cooled to cryogenic temperatures without the destructive phase transition of liquid to solid ice. Recent advances in cryoprotective solutions, organ perfusion techniques and novel heating technologies have demonstrated the potential for vitrification and rewarming organs on a scale applicable for human transplantation. SUMMARY: Successful strategies for organ cryopreservation could enable organ banking, which would recast the entire process in which organs are recovered, allocated, stored and prepared for transplant.

Quantification and biodistribution of iron oxide nanoparticles in the primary clearance organs of mice using T1 contrast for heating.

PURPOSE: To use contrast based on longitudinal relaxation times (T1 ) or rates (R1 ) to quantify the biodistribution of iron oxide nanoparticles (IONPs), which are of interest for hyperthermia therapy, cell targeting, and drug delivery, within primary clearance organs. METHODS: Mesoporous silica-coated IONPs (msIONPs) were intravenously injected into 15 naïve mice. Imaging and mapping of the longitudinal relaxation rate constant at 24 h or 1 week postinjection were performed with an echoless pulse sequence (SWIFT). Alternating magnetic field heating measurements were also performed on ex vivo tissues. RESULTS: Signal enhancement from positive T1 contrast caused by IONPs was observed and quantified in vivo in liver, spleen, and kidney at concentrations up to 3.2 mg Fe/(g tissue wt.) (61 mM Fe). In most cases, each organ had a linear correlation between the R1 and the tissue iron concentration despite variations in intra-organ distribution, degradation, and IONP surface charge. Linear correlation between R1 and volumetric SAR in hyperthermia therapy was observed. CONCLUSION: The linear dependence between R1 and tissue iron concentration in major organs allows quantitative monitoring of IONP biodistribution in a dosage range relevant to magnetic hyperthermia applications, which falls into the concentration gap between CT and conventional MRI techniques. Magn Reson Med 78:702-712, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Thermo-mechanical stress analysis of cryopreservation in cryobags and the potential benefit of nanowarming.

Cryopreservation by vitrification is the only promising solution for long-term organ preservation which can save tens of thousands of lives across the world every year. One of the challenges in cryopreservation of large-size tissues and organs is to prevent fracture formation due to the tendency of the material to contract with temperature. The current study focuses on a pillow-like shape of a cryobag, while exploring various strategies to reduce thermo-mechanical stress during the rewarming phase of the cryopreservation protocol, where maximum stresses are typically found. It is demonstrated in this study that while the level of stress may generally increase with the increasing amount of CPA filled in the cryobag, the ratio between width and length of the cryobag play a significant role. Counterintuitively, the overall maximum stress is not found when the bag is filled to its maximum capacity (when the filled cryobag resembles a sphere). Parametric investigation suggests that reducing the initial rewarming rate between the storage temperature and the glass transition temperature may dramatically decrease the thermo-mechanical stress. Adding a temperature hold during rewarming at the glass transition temperature may reduce the thermo-mechanical stress in some cases, but may have an adverse effect in other cases. Finally, it is demonstrated that careful incorporation of volumetric heating by means on nanoparticles in an alternating magnetic field, or nanowarming, can dramatically reduce the resulting thermo-mechanical stress. These observations display the potential benefit of a thermo-mechanical design of the cryopreservation protocols in order to prevent structural damage.

Determination of cryothermal injury thresholds in tissues impacted by cardiac cryoablation.

Despite widespread clinical use of cryoablation, there remain questions regarding dosing and treatment times which may affect efficacy and collateral injury. Dosing and treatment times are directly related to the degree of cooling necessary for effective lesion formation. Human and swine atrial, ventricular, and lung tissues were ablated using two cryoablation systems with concurrent infrared thermography. Post freeze-thaw samples were cultured and stained to differentiate viable and non-viable tissue. Matlab code correlated viability staining to applied freeze-thaw thermal cycles, to determine injury thresholds. Tissue regions were classified as live, injured, or dead based upon staining intensity at the lesion margin. Injury begins at rates of ∼10 °C/min to 0 °C, with non-viable tissue requiring cooling rates close to 100 °C/min to âˆ¼ -22 °C for swine and significantly greater cooling to -26 °C for human tissue (p = 0.041). At similar rates, lung tissue injury began at 0 °C, with human tissue requiring significantly less cooling, to âˆ¼ -15 °C for complete necrosis and -26 °C for swine (p = 0.024). Data suggest that there are no significant differences between swine and human myocardial response, but there may be differences between swine and human lung cryothermal tolerance.

Thermal Contrast Amplification Reader Yielding 8-Fold Analytical Improvement for Disease Detection with Lateral Flow Assays.

There is an increasing need for highly sensitive and quantitative diagnostics at the point-of-care. The lateral flow immunoassay (LFA) is one of the most widely used point-of-care diagnostic tests; however, LFAs generally suffer from low sensitivity and lack of quantification. To overcome these limitations, thermal contrast amplification (TCA) is a new method that is based on the laser excitation of gold nanoparticles (GNPs), the most commonly used visual signature, to evoke a thermal signature. To facilitate the clinical translation of the TCA technology, we present the development of a TCA reader, a platform technology that significantly improves the limit of detection and provides quantification of disease antigens in LFAs. This TCA reader provides enhanced sensitivity over visual detection by the human eye or by a colorimetric reader (e.g., BD Veritor System Reader). More specifically, the TCA reader demonstrated up to an 8-fold enhanced analytical sensitivity and quantification among LFAs for influenza, malaria, and Clostridium difficile. Systematic characterization of the laser, infrared camera, and other components of the reader and their integration into a working reader instrument are described. The development of the TCA reader enables simple, highly sensitive quantification of LFAs at the point-of-care.

Predictable Heating and Positive MRI Contrast from a Mesoporous Silica-Coated Iron Oxide Nanoparticle.

Iron oxide nanoparticles have great potential as diagnostic and therapeutic agents in cancer and other diseases; however, biological aggregation severely limits their function in vivo. Aggregates can cause poor biodistribution, reduced heating capability, and can confound their visualization and quantification by magnetic resonance imaging (MRI). Herein, we demonstrate that the incorporation of a functionalized mesoporous silica shell can prevent aggregation and enable the practical use of high-heating, high-contrast iron oxide nanoparticles in vitro and in vivo. Unmodified and mesoporous silica-coated iron oxide nanoparticles were characterized in biologically relevant environments including phosphate buffered saline, simulated body fluid, whole mouse blood, lymph node carcinoma of prostate (LNCaP) cells, and after direct injection into LNCaP prostate cancer tumors in nude mice. Once coated, iron oxide nanoparticles maintained colloidal stability along with high heating and relaxivity behaviors (SARFe = 204 W/g Fe at 190 kHz and 20 kA/m and r1 = 6.9 mM(-1) s(-1) at 1.4 T). Colloidal stability and minimal nonspecific cell uptake allowed for effective heating in salt and agarose suspensions and strong signal enhancement in MR imaging in vivo. These results show that (1) aggregation can lower the heating and imaging performance of magnetic nanoparticles and (2) a coating of functionalized mesoporous silica can mitigate this issue, potentially improving clinical planning and practical use.

The Grand Challenges of Organ Banking: Proceedings from the first global summit on complex tissue cryopreservation.

The first Organ Banking Summit was convened from Feb. 27 - March 1, 2015 in Palo Alto, CA, with events at Stanford University, NASA Research Park, and Lawrence Berkeley National Labs. Experts at the summit outlined the potential public health impact of organ banking, discussed the major remaining scientific challenges that need to be overcome in order to bank organs, and identified key opportunities to accelerate progress toward this goal. Many areas of public health could be revolutionized by the banking of organs and other complex tissues, including transplantation, oncofertility, tissue engineering, trauma medicine and emergency preparedness, basic biomedical research and drug discovery - and even space travel. Key remaining scientific sub-challenges were discussed including ice nucleation and growth, cryoprotectant and osmotic toxicities, chilling injury, thermo-mechanical stress, the need for rapid and uniform rewarming, and ischemia/reperfusion injury. A variety of opportunities to overcome these challenge areas were discussed, i.e. preconditioning for enhanced stress tolerance, nanoparticle rewarming, cyroprotectant screening strategies, and the use of cryoprotectant cocktails including ice binding agents.

Thermomechanical Stress in Cryopreservation Via Vitrification With Nanoparticle Heating as a Stress-Moderating Effect.

This study focuses on thermomechanical effects in cryopreservation associated with a novel approach of volumetric heating by means on nanoparticles in an alternating electromagnetic field. This approach is studied for the application of cryopreservation by vitrification, where the crystalline phase is completely avoided-the cornerstone of cryoinjury. Vitrification can be achieved by quickly cooling the material to cryogenic storage, where ice cannot form. Vitrification can be maintained at the end of the cryogenic protocol by quickly rewarming the material back to room temperature. The magnitude of the rewarming rates necessary to maintain vitrification is much higher than the magnitude of the cooling rates that are required to achieve it in the first place. The most common approach to achieve the required cooling and rewarming rates is by exposing the specimen's surface to a temperature-controlled environment. Due to the underlying principles of heat transfer, there is a size limit in the case of surface heating beyond which crystallization cannot be prevented at the center of the specimen. Furthermore, due to the underlying principles of solid mechanics, there is a size limit beyond which thermal expansion in the specimen can lead to structural damage and fractures. Volumetric heating during the rewarming phase of the cryogenic protocol can alleviate these size limitations. This study suggests that volumetric heating can reduce thermomechanical stress, when combined with an appropriate design of the thermal protocol. Without such design, this study suggests that the level of stress may still lead to structural damage even when volumetric heating is applied. This study proposes strategies to harness nanoparticles heating in order to reduce thermomechanical stress in cryopreservation by vitrification.

Magneto acoustic tomography with short pulsed magnetic field for in-vivo imaging of magnetic iron oxide nanoparticles.

Nanoparticles are widely used as contrast and therapeutic agents. As such, imaging modalities that can accurately estimate their distribution in-vivo are actively sought. We present here our method Magneto Acoustic Tomography (MAT), which uses magnetomotive force due to a short pulsed magnetic field to induce ultrasound in the magnetic nanoparticle labeled tissue and estimates an image of the distribution of the nanoparticles in-vivo with ultrasound imaging resolution. In this study, we image the distribution of superparamagnetic iron oxide nanoparticles (IONP) using MAT method. In-vivo imaging was performed on live, nude mice with IONP injected into LNCaP tumors grown subcutaneously within the hind limb of the mice. Our experimental results indicate that the MAT method is capable of imaging the distribution of IONPs in-vivo. Therefore, MAT could become an imaging modality for high resolution reconstruction of MNP distribution in the body. FROM THE CLINICAL EDITOR: Many magnetic nanoparticles (MNPs) have been used as contrast agents in magnetic resonance imaging. In this study, the authors investigated the use of ultrasound to detect the presence of MNPs by magneto acoustic tomography. In-vivo experiments confirmed the imaging quality of this new approach, which hopefully would provide an alternative method for accurate tumor detection.