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Deep-seated tumors of the liver, brain, and other organ systems often recur after initial surgical, chemotherapeutic, radiation, or focal treatments. Repeating these treatments is often invasive and traumatic. We propose an iron oxide nanoparticle (IONP)-enhanced precipitating hydrophobic injectable liquid (PHIL, MicroVention inc.) embolic as a localized dual treatment implant for nutrient deprivation and multiple repeatable thermal ablation. Following a single injection, multiple thermal treatments can be repeated as needed, based on monitoring of tumor growth/recurrence. Herein we show the ability to create an injectable stable PHIL-IONP solution, monitor deposition of the PHIL-IONP precipitate dispersion by μCT, and gauge the IONP distribution within the embolic by magnetic resonance imaging. Once precipitated, the implant could be heated to reach therapeutic temperatures8 °C for thermal ablation (clinical temperature of ∼45 °C), in a model disk and a 3D tumor bed model. Heat output was not affected by physiological conditions, multiple heating sessions, or heating at intervals over a 1 month duration. Further, in ex vivo mice hind-limb tumors, we could noninvasively heat the embolic to an "ablative" temperature elevation of 17 °C (clinically 54 °C) in the first 5 min and maintain the temperature rise over +8 °C (clinically a temperature of 45 °C) for longer than 15 min.

To extend the preservation of donor hearts beyond the current 4-6 h, this paper explores heart cryopreservation by vitrification-cryogenic storage in a glass-like state. While organ vitrification is made possible by using cryoprotective agents (CPA) that inhibit ice during cooling, failure occurs during convective rewarming due to slow and non-uniform rewarming which causes ice crystallization and/or cracking. Here an alternative, "nanowarming", which uses silica-coated iron oxide nanoparticles (sIONPs) perfusion loaded through the vasculature is explored, that allows a radiofrequency coil to rewarm the organ quickly and uniformly to avoid convective failures. Nanowarming has been applied to cells and tissues, and a proof of principle study suggests it is possible in the heart, but proper physical and biological characterization especially in organs is still lacking. Here, using a rat heart model, controlled machine perfusion loading and unloading of CPA and sIONPs, cooling to a vitrified state, and fast and uniform nanowarming without crystallization or cracking is demonstrated. Further, nanowarmed hearts maintain histologic appearance and endothelial integrity superior to convective rewarming and indistinguishable from CPA load/unload control hearts while showing some promising organ-level (electrical) functional activity. This work demonstrates physically successful heart vitrification and nanowarming and that biological outcomes can be expected to improve by reducing or eliminating CPA toxicity during loading and unloading.

Vitrification can dramatically increase the storage of viable biomaterials in the cryogenic state for years. Unfortunately, vitrified systems ≥3 mL like large tissues and organs, cannot currently be rewarmed sufficiently rapidly or uniformly by convective approaches to avoid ice crystallization or cracking failures. A new volumetric rewarming technology entitled “nanowarming” addresses this problem by using radiofrequency excited iron oxide nanoparticles to rewarm vitrified systems rapidly and uniformly. Here, for the first time, successful recovery of a rat kidney from the vitrified state using nanowarming, is shown. First, kidneys are perfused via the renal artery with a cryoprotective cocktail (CPA) and silica‐coated iron oxide nanoparticles (sIONPs). After cooling at −40 °C min−1 in a controlled rate freezer, microcomputed tomography (µCT) imaging is used to verify the distribution of the sIONPs and the vitrified state of the kidneys. By applying a radiofrequency field to excite the distributed sIONPs, the vitrified kidneys are nanowarmed at a mean rate of 63.7 °C min−1. Experiments and modeling show the avoidance of both ice crystallization and cracking during these processes. Histology and confocal imaging show that nanowarmed kidneys are dramatically better than convective rewarming controls. This work suggests that kidney nanowarming holds tremendous promise for transplantation., Vitrification dramatically increases organ storage times in the cryogenic state beyond current storage limits. However, vitrified kidneys cannot currently be rewarmed sufficiently rapidly or uniformly to avoid ice crystallization or cracking failures. A new radiofrequency rewarming technology called “nanowarming” addresses this problem by exciting magnetic nanoparticles to rewarm vitrified kidneys rapidly and uniformly.

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.

Aggregation is a known consequence of nanoparticle use in biology and medicine; however, nanoparticle characterization is typically performed under the pretext of well-dispersed, aqueous conditions. Here, we systematically characterize the effects of aggregation on the alternating magnetic field induced heating and magnetic resonance (MR) imaging performance of iron oxide nanoparticles (IONPs) in non-ideal biological systems. Specifically, the behavior of IONP aggregates composed of ~ 10 nm primary particles, but with aggregate hydrodynamic sizes ranging from 50 nm to 700 nm, was characterized in phosphate buffered saline and fetal bovine serum suspensions, as well as in gels and cells. We demonstrate up to a 50% reduction in heating, linked to the extent of aggregation. To quantify aggregate morphology, we used a combination of hydrodynamic radii distribution, intrinsic viscosity, and electron microscopy measurements to describe the aggregates as quasifractal entities with fractal dimensions in the 1.8–2.0 range. Importantly, we are able to correlate the observed decrease in magnetic field induced heating with a corresponding decrease in longitudinal relaxation rate (R1) in MR imaging, irrespective of the extent of aggregation. Finally, we show in vivo proof-of-principle use of this powerful new imaging method, providing a critical tool for predicting heating in clinical cancer hyperthermia.

While vitrified cryopreservation holds great promise, practical application has been limited to smaller systems (cells and thin tissues) due to diffusive heat and mass transfer limitations, which are typically manifested as devitrification and cracking failures during thaw. Here then we describe a new approach for rapidly and uniformly heating cryopreserved biospecimens with radiofrequency (RF) excited magnetic nanoparticles (mNPs). Importantly, heating rates can be increased several fold over conventional boundary heating techniques and are independent of sample size. Initial differential scanning calorimetry studies indicate that the addition of the mNPs has minimal impact on the freeze-thaw behavior of the cryoprotectant systems themselves. Then proof-of-principle experiments in aqueous and cryoprotectant solutions demonstrate the ability to heat at rates high enough to mitigate or eliminate devitrification (hundreds of °C/min) and scaled heat transfer modeling is used to illustrate the potential of this innovative approach. Finally, X-ray micro-computed-tomography (micro-CT) is investigated as a planning and quality control tool, where the density-based measurements are able to quantify changes in cryoprotectant concentration, mNP concentration, and the frozen state (i.e. crystallized versus vitrified).

Purpose Iron-oxide nanoparticles (IONPs) have proven utility as contrast agents in many MRI applications. Previous quantitative IONP mapping has been performed using mainly T2* mapping methods. However, in applications requiring high IONP concentrations, such as magnetic nanoparticles based thermal therapies, conventional pulse sequences are unable to map T2* because the signal decays too rapidly. In this article, sweep imaging with Fourier transformation (SWIFT) sequence is combined with the Look-Locker method to map T1 of IONPs in high concentrations. Methods T1 values of agar containing IONPs in different concentrations were measured with the SWIFT Look-Locker method and with inversion recovery spectroscopy. Precisions of Look-Locker and variable flip angle (VFA) methods were compared in simulations. Results The measured R1 (=1/T1) has a linear relationship with IONP concentration up to 53.6 mM of Fe. This concentration exceeds concentrations measured in previous work by almost an order of magnitude. Simulations show SWIFT Look-Locker method is also much less sensitive to B1 inhomogeneity than the VFA method. Conclusion SWIFT Look-Locker can accurately measure T1 of IONP concentrations ≤53.6 mM. By mapping T1 as a function of IONP concentration, IONP distribution maps might be used in the future to plan effective magnetic nanoparticle hyperthermia therapy. Magn Reson Med 71:1982–1988, 2014. © 2014 Wiley Periodicals, Inc.

Developments in nanomedicine are expected to provide solutions to many of modern medicine's unsolved problems, so it is no surprise that the literature contains many articles discussing the subject. However, existing reviews tend to focus on specific sectors of nanomedicine or to take a very forward-looking stance and fail to provide a complete perspective on the current landscape. This article provides a more comprehensive and contemporary inventory of nanomedicine products. A keyword search of literature, clinical trial registries, and the Web yielded 247 nanomedicine products that are approved or in various stages of clinical study. Specific information on each was gathered, so the overall field could be described based on various dimensions, including FDA classification, approval status, nanoscale size, treated condition, nanostructure, and others. In addition to documenting the many nanomedicine products already in use in humans, this study indentifies several interesting trends forecasting the future of nanomedicine.

Magnetic nanoparticles (mNPs) are known to heat and produce contrast for magnetic resonance imaging (MRI) in response to varying magnetic fields. These phenomena are being clinically applied in the detection and treatment of diseases such as cancer. However, one important factor that has been largely overlooked in the field is the effect of aggregation on the mNPs’ performance once they are delivered into target cells and tissues. Specifically, nanoparticle aggregation caused by protein interactions and cellular uptake can lead to shifts in their behavior due to increases in the interparticle magnetic interactions and changes to Brownian motion. This will affect both the mNPs’ ability to heat and to be imaged by MRI.

While cryosurgery has proven capable in treating of a variety of conditions, it has met with some resistance among physicians, in part due to shortcomings in the ability to predict treatment outcomes. Here we attempt to address several key issues related to predictive modeling by demonstrating methods for accurately characterizing heat transfer from cryoprobes, report temperature dependent thermal properties for ultrasound gel (a convenient tissue phantom) down to cryogenic temperatures, and demonstrate the ability of convective exchange heat transfer boundary conditions to accurately describe freezing in the case of single and multiple interacting cryoprobe(s). Temperature dependent changes in the specific heat and thermal conductivity for ultrasound gel are reported down to −150 °C for the first time here and these data were used to accurately describe freezing in ultrasound gel in subsequent modeling. Freezing around a single and two interacting cryoprobe(s) was characterized in the ultrasound gel phantom by mapping the temperature in and around the “iceball” with carefully placed thermocouple arrays. These experimental data were fit with finite-element modeling in COMSOL Multiphysics, which was used to investigate the sensitivity and effectiveness of convective boundary conditions in describing heat transfer from the cryoprobes. Heat transfer at the probe tip was described in terms of a convective coefficient and the cryogen temperature. While model accuracy depended strongly on spatial (i.e., along the exchange surface) variation in the convective coefficient, it was much less sensitive to spatial and transient variations in the cryogen temperature parameter. The optimized fit, convective exchange conditions for the single-probe case also provided close agreement with the experimental data for the case of two interacting cryoprobes, suggesting that this basic characterization and modeling approach can be extended to accurately describe more complicated, multiprobe freezing geometries. Accurately characterizing cryoprobe behavior in phantoms requires detailed knowledge of the freezing medium's properties throughout the range of expected temperatures and an appropriate description of the heat transfer across the probe's exchange surfaces. Here we demonstrate that convective exchange boundary conditions provide an accurate and versatile description of heat transfer from cryoprobes, offering potential advantages over the traditional constant surface heat flux and constant surface temperature descriptions. In addition, although this study was conducted on Joule–Thomson type cryoprobes, the general methodologies should extend to any probe that is based on convective exchange with a cryogenic fluid.

Cryosurgery has demonstrated significant capabilities as a minimally invasive technique for treating cancer and other conditions [1], but has been limited by the ability to accurately predict treatment outcome and damage to surrounding tissues. Contributing to this problem has been the accuracy of predictive modeling and translating this to effective pretreatment planning. The two key factors in accurately modeling cryosurgical freezing are the temperature-dependent thermal properties of the freezing medium and cryoprobe boundary conditions. Both of these issues are considered in this study.

Magnetic nanoparticle (MNP) based thermal therapies are currently approved in Europe and poised for clinical translation in the US. The main benefits include the ability to focally and repeatedly treat tissues, including cancers, with a minimally-invasive platform. Nevertheless, a more complete understanding and control of MNP heating is necessary to effectively translate the approach to treat different sizes and geometries of cancer (See Figure 1). The present work discusses contrasts in heating between superparamagnetic and ferromagnetic nanoparticles (sMNP and fMNP), electromagnetic field-dependant MNP response, scaling of MNP volumetric heating, and the ability of theory to predict this behavior.Copyright © 2012 by ASME

Magnetic nanoparticle (mNP) based thermal therapies have demonstrated relevance in the clinic, but effective application requires an understanding of both its strengths and limitations. This study explores two critical limitations for clinical use: (1) maximizing localized mNP heating, while avoiding bulk heating due to inductive coupling of the applied field with the body and (2) the limits of treatable volumes, related to basic heat transfer. Two commercially available mNPs are investigated, one superparamagnetic and one ferromagnetic, thereby allowing a comparison between the two fundamental types of mNPs (both of which are being evaluated for clinical use). Important results indicate that in dispersed solutions, the superparamagnetic mNPs outperform on a per mass basis (2× better), but the ferromagnetic mNPs outperform on a per nanoparticle basis (170× better), at the fields of highest clinical relevance (approximately 100 kHz and 20 kA/m). We also demonstrate a new method of observing heating in microliter droplets of mNP solution, leading to scaling analyses that suggest treatable tumor volumes should be ≥2 mm in diameter (for mNP loading of ≥10 mg Fe/g tumor), to achieve therapeutic temperatures ≥43 °C. This technique also provides a novel platform for quantifying heating from microgram quantities of mNPs.

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

While cryopreservation through vitrification holds great promise, practical application has been limited to smaller systems (cells and thin tissues) due to diffusive transfer and phase-change limitations, which are typically manifested as devitrification and cracking failures during thaw. Here we describe a new approach for rapidly and uniformly heating cryopreserved biospecimens with radiofrequency (RF) excited magnetic nanoparticles (mNPs). Importantly, heating rates can be increased several fold over conventional boundary heating and are independent of sample size and dielectric properties, overcoming the inhomogeneity associated with microwave thawing. Proof-of-principle experiments in aqueous and cryoprotectant solutions are presented and then modeling is used to further illustrate the potential of this innovative approach. Three embodiments of mNP suspensions are studied – aqueous, 6 M glycerol in phosphate buffered saline, and 8.4 M VS55 cryoprotectant solution (Mehl, Cryobiology 30 (1993) 509–518). The iron oxide mNPs used are commercially available (Ferrotec, Inc.) and have been previously shown to produce significant heating in aqueous suspensions (Etheridge and Bischof, ABME 41 (2013) 78–88). Nanoparticle concentrations up to 10 mg Fe/ml are shown to have negligible impact on the freezing behavior of these solutions, including the glass transition, critical cooling/warming rates, and specific heat, as measured by differential scanning calorimetry. One milliliter mNP suspensions at 5 and 10 mg Fe/ml in water and cryoprotectant solution were frozen in liquid nitrogen (at sufficient rates to achieve vitrification in the cryoprotectant samples) and then reheated in an insulated, 370 kHz and 20 kA/m RF coil. Sample temperatures were monitored with 40-gauge thermocouples embedded prior to cooling. RF fields can produce interference in metallic thermocouples, but this was characterized and found to be negligible for the fine gauge thermocouples used. Heating rates at the glass transition of approximately 200 ° C/min were achieved in the 10 mg Fe/ml samples, avoiding devitrification in the cryoprotectant solutions. Since RF fields at frequencies Source of funding: This work was supported by the Minnesota Futures Grant Program, NSF/CBET #1066343, and the University of Minnesota Institute for Engineering Seed Grant Program. Conflict of interest: None declared. bischof@umn.edu

Cryoablation for atrial fibrillation is a clinically approved technique used to control irregular heart rhythms due to abnormal electrical signals conducted from the pulmonary veins to the atria. The ablation catheter rapidly cools the cardiac tissue to freezing temperatures creating a discrete lesion which terminates these abnormal electrical pulses. Benefits of this approach include decreased risk of thrombus formation, well demarcated lesions, and preservation of extracellular matrix and endothelial integrity. However, possible complications include phrenic nerve injury and pulmonary vein stenosis (although these are not unique to the cryoablative approach). Therefore, further understanding of the mechanisms and thresholds of cryoinjury are required. This study begins to address these issues by improving predictive model accuracy through demonstrating the importance of accurate, temperature-dependent tissue properties. The direct relationship between thermal history and treatment outcome, combined with the difficulties of realtime, clinical thermometry, make heat transfer modeling and numerical predictions important aspects of cryoablation studies. The accuracy of the models depends on numerous factors including the kinetics and energy release during phase change phenomena and knowledge of thermal properties as a function of temperature. However, insufficient data for tissue thermal properties in the subzero domain results in a reliance on property estimations, generally based on water–ice data or weight averaged values from known materials. This study focused on expanding the thermal properties database for biological tissue in the subzero regime for use in cryoablation modeling. Results for porcine myocardium as well as ultrasound gel (a substitute phantom used for cryoprobe characterization) are reported. A differential scanning calorimeter was used to measure the specific heat and to observe latent heat effects. The thermal conductivity was measured using self-heating thermistors, employing both transient pulse decay and quasi-steady constant power methods. Specific heats in porcine myocardium were slightly less than those for ice, ranging from 0.93 J/gK at −150 °C to 2.35 J/gK at −21 °C. Specific heat behavior for ultrasound gel could be bracketed into two ranges, in which the values measured were less than those for ice at temperatures below the glass transition temperature (around −110 °C), and progressively higher than those for ice with temperatures above the glass transition. Thermal conductivities of porcine myocardium rose gradually at lower temperatures, ranging from 1.52 W/mK at −10 °C to 2.31 at −148 °C, and were about 50% less than those values for ice. Thermal conductivities of ultrasound gel were similar to those of porcine myocardium, but with an inflection point at the glass transition temperature after which the rise in thermal conductivity was attenuated. The importance of accurate, temperature-dependent thermal properties is demonstrated by comparing the predicted thermal history versus those estimated from constant property values.