HYPER: pre-clinical device for spatially-confined magnetic particle hyperthermia.

PURPOSE: Magnetic particle hyperthermia is an approved cancer treatment that harnesses thermal energy generated by magnetic nanoparticles when they are exposed to an alternating magnetic field (AMF). Thermal stress is either directly cytotoxic or increases the susceptibility of cancer cells to standard therapies, such as radiation. As with other thermal therapies, the challenge with nanoparticle hyperthermia is controlling energy delivery. Here, we describe the design and implementation of a prototype pre-clinical device, called HYPER, that achieves spatially confined nanoparticle heating within a user-selected volume and location. DESIGN: Spatial control of nanoparticle heating was achieved by placing an AMF generating coil (340 kHz, 0-15 mT), between two opposing permanent magnets. The relative positions between the magnets determined the magnetic field gradient (0.7 T/m-2.3 T/m), which in turn governed the volume of the field free region (FFR) between them (0.8-35 cm3). Both the gradient value and position of the FFR within the AMF ([-14, 14]x, [-18, 18]y, [-30, 30]z) mm are values selected by the user via the graphical user interface (GUI). The software then controls linear actuators that move the static magnets to adjust the position of the FFR in 3D space based on user input. Within the FFR, the nanoparticles generate hysteresis heating; however, outside the FFR where the static field is non-negligible, the nanoparticles are unable to generate hysteresis loss power. VERIFICATION: We verified the performance of the HYPER to design specifications by independently heating two nanoparticle-rich areas of a phantom placed within the volume occupied by the AMF heating coil.

Magnetic Particle Imaging-Guided Thermal Simulations for Magnetic Particle Hyperthermia.

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.

A new method to measure magnetic nanoparticle heating efficiency in non-adiabatic systems using transient pulse analysis.

Heating magnetic nanoparticles (MNPs) with alternating magnetic fields (AMFs) have applications in biomedical research and cancer therapy. Accurate measurement of the heating efficiency or specific loss power (SLP) generated by the MNPs is essential to assess response(s) in biological systems. Efforts to develop standardized equipment and to harmonize results obtained from various MNP samples and AMF systems have met with little success. Without a standardized magnetic nanoparticle or calorimeter device, objective comparisons of estimated thermal output among laboratories remain a challenge. In addition, the most widely used adiabatic initial slope model fails to account for thermal losses, which are unavoidable. We propose a non-adiabatic method to analyze MNP heating efficiency derived from the Box-Lucas equation, wherein the sample is subjected to several short duration heating pulses. SLP is then estimated from an arithmetic average of the Box-Lucas fitted coefficients obtained from each pulse. Heating experiments were conducted with two identical samples that were placed within vessels having different thermal insulation using the same AMF parameters. Though the samples generated different temperature curves, the pulsed Box-Lucas method produced nearly equivalent SLP estimates. Further, the pulsed test enabled analysis of the heat transfer coefficient providing quantitative measures of sample heat loss throughout the test, with robust statistical confidence. We anticipate this new methodology will aid efforts to standardize measurements of MNP heating efficiency, enabling direct comparison among varied systems.

MONITORING PERFUSION-BASED CONVECTION IN CANCER TUMOR TISSUE UNDERGOING NANOPARTICLE HEATING BY ANALYZING TEMPERATURE RESPONSES TO TRANSIENT PULSED HEATING.

The dynamic nature of perfusion in living tissues, such as solid tumors during thermal therapy, produces challenging spatiotemporal thermal boundary conditions. Changes in perfusion can manifest as changes in convective heat transfer that influence temperature changes during cyclic heating. Herein, we propose a method to actively monitor changes in local convection (perfusion) in vivo by using a transient thermal pulsing analysis. Syngeneic 4T1 tumor cells were injected subcutaneously into BALB/c mice and followed by caliper measurements. When tumor volumes measured 150-400 mm3, mice were randomly divided into one of two groups to receive intratumor injections of one of two iron oxide nanoparticle formulations for pulsed heating with an alternating magnetic field (AMF). The nanoparticles differed in both heating characteristics and coating. Intratumor temperature near the injection site as well as rectal temperature were measured with an optic fiber temperature probe. Following heating, mice were euthanized and tumors harvested and prepared for histological evaluation of nanoparticle distribution. To ascertain the heat transfer coefficient from heating and cooling pulses, we fit a lumped capacitance, Box-Lucas model to the time-temperature data assuming fixed tumor geometry and constant experimental conditions. For the first particle set, the injected nanoparticles dispersed evenly throughout the tumor with minimal aggregation, and with minimal change in convection. On the other hand, heating with the second particle generated a measurable decline in convective performance and histology analysis showed substantial aggregation near the injection site. We consider it likely that though the second nanoparticle type produced less heating per unit mass, its tendency to aggregate led to more intense local heating and tissue damage. Further analysis and experimentation is warranted to establish quantitative correlations between measured temperature changes, perfusion, and tissue damage responses. Implementing this type of analysis may stimulate development of robust and adaptive temperature controllers for medical device applications.

Design of a temperature-feedback controlled automated magnetic hyperthermia therapy device.

Introduction: Magnetic hyperthermia therapy (MHT) is a minimally invasive adjuvant therapy capable of damaging tumors using magnetic nanoparticles exposed radiofrequency alternating magnetic fields. One of the challenges of MHT is thermal dose control and excessive heating in superficial tissues from off target eddy current heating. Methods: We report the development of a control system to maintain target temperature during MHT with an automatic safety shutoff feature in adherence to FDA Design Control Guidance. A proportional-integral-derivative (PID) control algorithm was designed and implemented in NI LabVIEW®. A standard reference material copper wire was used as the heat source to verify the controller performance in gel phantom experiments. Coupled electromagnetic thermal finite element analysis simulations were used to identify the initial controller gains. Results: Results showed that the PID controller successfully achieved the target temperature control despite significant perturbations. Discussion and Conclusion: Feasibility of PID control algorithm to improve efficacy and safety of MHT was demonstrated.

Development of a Treatment Planning Framework for Laser Interstitial Thermal Therapy (LITT).

PURPOSE: Develop a treatment planning framework for neurosurgeons treating high-grade gliomas with LITT to minimize the learning curve and improve tumor thermal dose coverage. METHODS: Deidentified patient images were segmented using the image segmentation software Materialize MIMICS©. Segmented images were imported into the commercial finite element analysis (FEA) software COMSOL Multiphysics© to perform bioheat transfer simulations. The laser probe was modeled as a cylindrical object with radius 0.7 mm and length 100 mm, with a constant beam diameter. A modeled laser probe was placed in the tumor in accordance with patient specific patient magnetic resonance temperature imaging (MRTi) data. The laser energy was modeled as a deposited beam heat source in the FEA software. Penne's bioheat equation was used to model heat transfer in brain tissue. The cerebrospinal fluid (CSF) was modeled as a solid with convectively enhanced conductivity to capture heat sink effects. In this study, thermal damage-dependent blood perfusion was assessed. Pulsed laser heating was modeled based on patient treatment logs. The stationary heat source and pullback heat source techniques were modeled to compare the calculated tissue damage. The developed bioheat transfer model was compared to MRTi data obtained from a laser log during LITT procedures. The application builder module in COMSOL Multiphysics© was utilized to create a Graphical User Interface (GUI) for the treatment planning framework. RESULTS: Simulations predicted increased thermal damage (10-15%) in the tumor for the pullback heat source approach compared with the stationary heat source. The model-predicted temperature profiles followed trends similar to those of the MRTi data. Simulations predicted partial tissue ablation in tumors proximal to the CSF ventricle. CONCLUSION: A mobile platform-based GUI for bioheat transfer simulation was developed to aid neurosurgeons in conveniently varying the simulation parameters according to a patient-specific treatment plan. The convective effects of the CSF should be modeled with heat sink effects for accurate LITT treatment planning.

Design, characterization, and modeling of a chitosan microneedle patch for transdermal delivery of meloxicam as a pain management strategy for use in cattle.

This work describes the formulation and evaluation of a chitosan microneedle patch for the transdermal delivery of meloxicam to manage pain in cattle. Microneedle patches composed of chitosan and chitosan/meloxicam were evaluated regarding their chemical composition, uniformity of physical characteristics, capacity to penetrate the skin, and response to thermal and thermo-mechanical changes. Microneedle patches were prepared by varying the percentage of acetic acid used during solution preparation, including 90% (v/v), 50% (v/v), and 10% (v/v). In addition, drug release was assessed by modeling different percentages of penetration into the skin and the number of microneedles on the microneedle patch. Scanning electron microscopy confirmed the presence of microneedles uniformly organized on the patch surface for each percentage of acetic acid used. Fourier transform infrared spectroscopy revealed that 10% (v/v) of acetic acid in the solution was a suitable condition to preserve the characteristic bands of chitosan (amide I and amide II) and meloxicam (amine NH stretch and CO stretch) as compared to 90% (v/v) and 50% (v/v) of acetic acid used during the solution preparation. The resultant microneedle patches were successful in penetrating the skin in a cow's cadaver ear. Results demonstrated that the average depth penetration measured after complete dehydration of the penetrated skin was approximately 78 ± 1 µm. Chitosan and chitosan/meloxicam microneedle patches with higher acetic acid percentages reflected greater resistance to compressive force as temperature increased. Time-dependent simulation of the transport of diluted species by COMSOL revealed that the transdermal drug delivery increases in function to the increment of the number of microneedles on the surface patch and percentage of penetration per microneedle. One patch released a drug concentration of 3.57 × 10-5 mol/m3 in the skin per week, which represents the 26.2% of what is needed for pain management in cattle, established as 1.43 × 10-4 mol/m3. These results demonstrate that chitosan/meloxicam microneedles patches may be suitable to manage pain in cattle after routine procedures.