We present in vivo validation of an automated magnetic hyperthermia therapy (MHT) device that uses real-time temperature input measured at the target to control tissue heating. MHT is a thermal therapy that uses heat generated by magnetic materials exposed to an alternating magnetic field. For temperature monitoring, we integrated a commercial fiber optic temperature probe containing four gallium arsenide (GaAs) temperature sensors. The controller device used temperature from the sensors as input to manage power to the magnetic field applicator. We developed a robust, multi-objective, proportional-integral-derivative (PID) algorithm to control the target thermal dose by modulating power delivered to the magnetic field applicator. The magnetic field applicator was a 20 cm diameter Maxwell-type induction coil powered by a 120 kW induction heating power supply operating at 160 kHz. Finite element (FE) simulations were performed to determine values of the PID gain factors prior to verification and validation trials. Ex vivo verification and validation were conducted in gel phantoms and sectioned bovine liver, respectively. In vivo validation of the controller was achieved in a canine research subject following infusion of magnetic nanoparticles (MNPs) into the brain. In all cases, performance matched controller design criteria, while also achieving a thermal dose measured as cumulative equivalent minutes at 43 °C (CEM43) 60 ± 5 min within 30 min.

Purpose: A proposed mechanism for the enhanced effectiveness of hyperthermia and doxorubicin (Dox) combinations is increased intracellular Dox concentrations resulting from heat-induced cell stress. The purpose of this study was to determine whether specific varied Dox and heat combinations produce measurable effects greater than the additive combination, and whether these effects can be attributed to heat-induced increases in intracellular Dox concentrations. Methods: HCT116, HT29 and CT26 cells were exposed to Dox and water bath heating independently. A clonogenic survival assay was used to determine cell killing and intracellular Dox concentrations were measured in HCT116 cells with mass spectrometry. Cells were exposed to heating at 42 °C (60 min) and 0.5 µg/ml of Dox at varying intervals. Synergy was determined by curve-fitting and isobologram analysis. Results: All cell lines displayed synergistic effects of combined heating and Dox. A maximum synergistic effect was achieved with simultaneous cell exposure to Dox and heat. For exposures at 42 °C, the synergistic effect was most pronounced at Dox concentrations <0.5 µg/ml. Increased intracellular concentrations of Dox in HCT116 cells caused by heat-stress did not generate a concomitant thermal enhancement. Conclusions: Simultaneous exposure of HCT116 cells to heating and Dox is more effective than sequential exposure. Heat-induced cell responses are accompanied by increased intracellular Dox concentrations; however, clonogenic survival data do not support this as the cause for synergistic cytotoxicity.

For patients diagnosed with advanced and unresectable hepatocellular carcinoma (HCC), liver transplantation remains the best option to extend life. Challenges with organ supply often preclude liver transplantation, making palliative non-surgical options the default front-line treatments for many patients. Even with imaging guidance, success following treatment remains inconsistent and below expectations, so new approaches are needed. Imaging-guided thermal therapy interventions have emerged as attractive procedures that offer individualized tumor targeting with the potential for the selective targeting of tumor nodules without impairing liver function. Furthermore, imaging-guided thermal therapy with added standard-of-care chemotherapies targeted to the liver tumor can directly reduce the overall dose and limit toxicities commonly seen with systemic administration. Effectiveness of non-ablative thermal therapy (hyperthermia) depends on the achieved thermal dose, defined as time-at-temperature, and leads to molecular dysfunction, cellular disruption, and eventual tissue destruction with vascular collapse. Hyperthermia therapy requires controlled heat transfer to the target either by in situ generation of the energy or its on-target conversion from an external radiative source. Magnetic hyperthermia (MHT) is a nanotechnology-based thermal therapy that exploits energy dissipation (heat) from the forced magnetic hysteresis of a magnetic colloid. MHT with magnetic nanoparticles (MNPs) and alternating magnetic fields (AMFs) requires the targeted deposition of MNPs into the tumor, followed by exposure of the region to an AMF. Emerging modalities such as magnetic particle imaging (MPI) offer additional prospects to develop fully integrated (theranostic) systems that are capable of providing diagnostic imaging, treatment planning, therapy execution, and post-treatment follow-up on a single platform. In this review, we focus on recent advances in image-guided MHT applications specific to liver cancer

Magnetic particle hyperthermia (MPH) enables the direct heating of solid tumors with alternating magnetic fields (AMFs). One challenge with MPH is the unknown particle distribution in tissue after injection. Magnetic particle imaging (MPI) can measure the nanoparticle content and distribution in tissue after delivery. The objective of this study was to develop a clinically translatable protocol that incorporates MPI data into finite element calculations for simulating tissue temperatures during MPH. To verify the protocol, we conducted MPH experiments in tumor-bearing mouse cadavers. Five 8–10-week-old female BALB/c mice bearing subcutaneous 4T1 tumors were anesthetized and received intratumor injections of Synomag^®-S90 nanoparticles. Immediately following injection, the mice were euthanized and imaged, and the tumors were heated with an AMF. We used the Mimics Innovation Suite to create a 3D mesh of the tumor from micro-computerized tomography data and spatial index MPI to generate a scaled heating function for the heat transfer calculations. The processed imaging data were incorporated into a finite element solver, COMSOL Multiphysics^®. The upper and lower bounds of the simulated tumor temperatures for all five cadavers demonstrated agreement with the experimental temperature measurements, thus verifying the protocol. These results demonstrate the utility of MPI to guide predictive thermal calculations for MPH treatment planning.

Liver transplantation is the only treatment for hepatic insufficiency as a result of acute and chronic liver injuries/pathologies that fail to recover. Unfortunately, there remains an enormous and growing gap between organ supply and demand. Although recipients on the liver transplantation waitlist have significantly higher mortality, livers are often not allocated because they are (i) classified as extended criteria or marginal livers and (ii) subjected to longer cold preservation time (>6 h) with a direct correlation of poor outcomes with longer cold ischemia. Downregulating the recipient’s innate immune response to successfully tolerate a graft having longer cold ischemia times or ischemia-reperfusion injury through induction of immune tolerance in the graft and the host would significantly improve organ utilization and post-transplant outcomes. Broadly, technologies proposed for development aim to extend the life of the transplanted liver through post-transplant or recipient conditioning. In this review, we focus on the potential benefits of nanotechnology to provide unique pre-transplant grafting and recipient conditioning of extended criteria donor livers using immune tolerance induction and hyperthermic pre-conditioning.

High-grade gliomas (HGG) are the most common primary brain malignancy and continue to be associated with a dismal prognosis (median survival rate of 15–18 months) with standard of care therapy. Magnetic hyperthermia therapy (MHT) is an emerging intervention that leverages the ferromagnetic properties of magnetic iron-oxide nanoparticles (MIONPs) to target cancer cells that are otherwise left behind after resection. We report a novel port device to facilitate localization, delivery, and temperature measurement of MIONPs within a target lesion for MHT therapy. We conducted an in-depth literature and intellectual property review to define specifications of the conceived port device. After setting the design parameters, a thorough collaboration with neurological surgeons guided the iterative modeling process. A prototype was developed using Fusion 360 (Autodesk, San Rafael, CA) and printed on a Form 3 printer (Formlabs, Medford, MA) in Durable resin. The prototype was then tested in a phantom skull printed on a Pro-Jet 660Pro 3D printer (3D Systems, Rock Hill, SC) and a brain model based on mechanical and electrochemical properties of native brain tissue. This phantom underwent MHT heating tests using an alternating magnetic field (AMF) sequence based on current MHT workflow. Successful localization, delivery, and temperature measurement were demonstrated. The purpose of this study was twofold: first, to create and validate the procedural framework for a novel device, providing the groundwork for an upcoming comprehensive animal trial and second, to elucidate a cooperative approach between engineers and clinicians that propels advancements in medical innovation.