Computer simulations of an irrigated radiofrequency cardiac ablation catheter and experimental validation by infrared imaging.

PURPOSE: To develop and validate a three-dimensional (3-D) computer model based on accurate geometry of an irrigated cardiac radiofrequency (RF) ablation catheter with microwave radiometry capability, and to test catheter performance. METHODS: A computer model was developed based on CAD geometry of a RF cardiac ablation catheter prototype to simulate electromagnetic heating, heat transfer, and computational fluid dynamics (blood flow, open irrigation, and natural convection). Parametric studies were performed; blood flow velocity (0-25 cm/s) and irrigation flow (0-40 ml/min) varied, both with perpendicular (PE) and parallel (PA) catheter orientations relative to tissue. Tissue Agar phantom studies were performed under similar conditions, and temperature maps were recorded via infrared camera. Computer model simulations were performed with constant voltage and with voltage adjusted to achieve maximum tissue temperatures of 95-105 °C. RESULTS: Model predicted thermal lesion width at 5 W power was 5.8-6.4 mm (PE)/6.5-6.6 mm (PA), and lesion depth was 4.0-4.3 mm (PE)/4.0-4.1 mm (PA). Compared to phantom studies, the mean errors of the computer model were as follows: 6.2 °C(PE)/4.3 °C (PA) for maximum gel temperature, 0.7 mm (10.9%) (PE)/0.1 mm (0.8%) (PA) for lesion width, and 0.3 mm (7.7%)(PE)/0.7 mm (19.1%) (PA) for lesion depth. For temperature-controlled ablation, model predicted thermal lesion width was 7-9.2 mm (PE)/8.6-9.2 mm (PA), and lesion depth was 4.3-5.5 mm (PE)/3.4-5.4 mm (PA). CONCLUSIONS: Computer models were able to reproduce device performance and to enable device evaluation under varying conditions. Temperature controlled ablation of irrigated catheters enables optimal tissue temperatures independent of patient-specific conditions such as blood flow.

Real-time fluorescence imaging for visualization and drug uptake prediction during drug delivery by thermosensitive liposomes.

Objective: Thermosensitive liposomal doxorubicin (TSL-Dox) is a promising stimuli-responsive nanoparticle drug delivery system that rapidly releases the contained drug in response to hyperthermia (HT) (>40 °C). Combined with localized heating, TSL-Dox allows highly localized delivery. The goals of this study were to demonstrate that real-time fluorescence imaging can visualize drug uptake during delivery, and can predict tumor drug uptake. Methods: Nude mice carrying subcutaneous tumors (Lewis lung carcinoma) were anesthetized and injected with TSL-Dox (5 mg/kg dose). Localized HT was induced by heating tumors for 15, 30 or 60 min via a custom-designed HT probe placed superficially at the tumor location. In vivo fluorescence imaging (excitation 523 nm, emission 610 nm) was performed before, during, and for 5 min following HT. After imaging, tumors were extracted, drug uptake was quantified by high-performance liquid chromatography, and correlated with in vivo fluorescence. Plasma samples were obtained before and after HT to measure TSL-Dox pharmacokinetics. Results: Local drug uptake could be visualized in real-time during HT. Compared to unheated control tumors, fluorescence of heated tumors increased by 4.6-fold (15 min HT), 9.3-fold (30 min HT), and 13.2-fold (60 min HT). HT duration predicted tumor drug uptake (p = .02), with tumor drug concentrations of 4.2 ± 1.3 µg/g (no HT), 7.1 ± 5.9 µg/g (15 min HT), 14.1 ± 6.7 µg/g (30 min HT) and 21.4 ± 12.6 µg/g (60 min HT). There was good correlation (R2 = 0.67) between fluorescence of the tumor region and tumor drug uptake. Conclusions: Real-time in vivo fluorescence imaging can visualize drug uptake during delivery, and can predict tumor drug uptake.

Temperature sensitive liposomes combined with thermal ablation: Effects of duration and timing of heating in mathematical models and in vivo.

BACKGROUND: Temperature sensitive liposomes (TSL) are nanoparticles that rapidly release the contained drug at hyperthermic temperatures, typically above ~40°C. TSL have been combined with various heating modalities, but there is no consensus on required hyperthermia duration or ideal timing of heating relative to TSL administration. The goal of this study was to determine changes in drug uptake when heating duration and timing are varied when combining TSL with radiofrequency ablation (RF) heating. METHODS: We used computer models to simulate both RF tissue heating and TSL drug delivery, to calculate spatial drug concentration maps. We simulated heating for 5, 12 and 30 min for a single RF electrode, as well as three sequential 12 min ablations for 3 electrodes placed in a triangular array. To support simulation results, we performed porcine in vivo studies in normal liver, where TSL filled with doxorubicin (TSL-Dox) at a dose of 30 mg was infused over 30 min. Following infusion, RF heating was performed in separate liver locations for either 5 min (n = 2) or 12 min (n = 2). After ablation, the animal was euthanized, and liver extracted and frozen. Liver samples were cut orthogonal to the electrode axis, and fluorescence imaging was used to visualize tissue doxorubicin distribution. RESULTS: Both in vivo studies and computer models demonstrate a ring-shaped drug deposition within ~1 cm of the visibly coagulated tissue. Drug uptake directly correlated with heating duration. In computer simulations, drug concentration increased by a factor of 2.2x and 4.3x when heating duration was extended from 5 to either 12, or 30 minutes, respectively. In vivo, drug concentration was by a factor of 2.4x higher at 12 vs 5 min heating duration (7.1 µg/g to 3.0 µg/g). The computer models suggest that heating should be timed to maximize area under the curve of systemic plasma concentration of encapsulated drug. CONCLUSIONS: Both computer models and in vivo study demonstrate that tissue drug uptake directly correlates with heating duration for TSL based delivery. Computational models were able to predict the spatial drug delivery profile, and may serve as a valuable tool in understanding and optimizing drug delivery systems.

Long-term Survival of Straumann Dental Implants with TPS Surfaces: A Retrospective Study with a Follow-up of 12 to 23 Years.

PURPOSE: The aim of this study was to evaluate the long-term dental implant survival rates of Straumann dental implants in a university hospital environment over 12 to 23 years. MATERIALS AND METHODS: A total of 388 Straumann dental implants with titanium-sprayed surfaces (TPS) were inserted in 92 patients between 1988 and 1999 in the Department of Oral and Maxillofacial Surgery of the University Hospital Schleswig-Holstein in Kiel, and they were reevaluated with standardized clinical and radiological exams. Kaplan-Meier analyses were performed for individual factors. Cox proportional hazard regression analysis was used to detect the factors influencing long-term implant failure. RESULTS: The long-term implant survival rate was 88.03% after an observation time of 12.2 to 23.5 years. Cox regression revealed statistically significant influences of the International Team for Implantology (ITI) implantation type (p = .00354) and tobacco smoking (p = .01264) on implant failure. A proportion 82.8% of the patients with implant losses had a medical history of periodontitis. Peri-implantitis was diagnosed in 9.7% of the remaining implants in the long-term survey. CONCLUSIONS: This study emphasized the long-term rehabilitation capabilities of Straumann dental implants in complex cases. The survival rates after several years constitute important information for patients, as well as for clinicians, in deciding about different concepts of tooth replacement. Patient-related and technical factors - determined before implant placement - could help to predict the risk of implant loss.

Review of temperature dependence of thermal properties, dielectric properties, and perfusion of biological tissues at hyperthermic and ablation temperatures.

The application of supraphysiological temperatures (>40°C) to biological tissues causes changes at the molecular, cellular, and structural level, with corresponding changes in tissue function and in thermal, mechanical and dielectric tissue properties. This is particularly relevant for image-guided thermal treatments (e.g. hyperthermia and thermal ablation) delivering heat via focused ultrasound (FUS), radiofrequency (RF), microwave (MW), or laser energy; temperature induced changes in tissue properties are of relevance in relation to predicting tissue temperature profile, monitoring during treatment, and evaluation of treatment results. This paper presents a literature survey of temperature dependence of electrical (electrical conductivity, resistivity, permittivity) and thermal tissue properties (thermal conductivity, specific heat, diffusivity). Data of soft tissues (liver, prostate, muscle, kidney, uterus, collagen, myocardium and spleen) for temperatures between 5 to 90°C, and dielectric properties in the frequency range between 460 kHz and 3 GHz are reported. Furthermore, perfusion changes in tumors including carcinomas, sarcomas, rhabdomyosarcoma, adenocarcinoma and ependymoblastoma in response to hyperthmic temperatures up to 46°C are presented. Where appropriate, mathematical models to describe temperature dependence of properties are presented. The presented data is valuable for mathematical models that predict tissue temperature during thermal therapies (e.g. hyperthermia or thermal ablation), as well as for applications related to prediction and monitoring of temperature induced tissue changes.

Dynamics of tissue shrinkage during ablative temperature exposures.

There is a lack of studies that examine the dynamics of heat-induced shrinkage of organ tissues. Clinical procedures such as radiofrequency ablation, microwave ablation or high-intensity focused ultrasound, use heat to treat diseases such as cancer and cardiac arrhythmia. When heat is applied to tissues, shrinkage occurs due to protein denaturation, dehydration and contraction of collagen at temperatures greater 50 °C. This is particularly relevant for image-guided procedures such as tumor ablation, where pre- and post-treatment images are compared and any changes in dimensions must be considered to avoid misinterpretations of the treatment outcome. We present data from ex vivo, isothermal shrinkage tests in porcine liver tissue, where axial changes in tissue length were recorded during 15 min of heating to temperatures between 60 and 95 °C. A mathematical model was developed to accurately describe the time and temperature-dependent shrinkage behavior. The shrinkage dynamics had the same characteristics independent of temperature; the estimated relative shrinkage, adjusted for time since death, after 15 min heating to temperatures of 60, 65, 75, 85 and 95 °C, was 12.3, 13.8, 16.6, 19.2 and 21.7%, respectively. Our results demonstrate the shrinkage dynamics of organ tissues, and suggest the importance of considering tissue shrinkage for thermal ablative treatments.

Cytotoxicity of hepatocellular carcinoma cells to hyperthermic and ablative temperature exposures: in vitro studies and mathematical modelling.

PURPOSE: Image-guided ablative therapies use temperatures greater than 45 °C to kill abnormal cells. There is limited published data of cell survival after ablative temperature exposures, which is of importance to predict ablation zone dimensions. The objective of this study was to determine and mathematically model survival of hepatocellular carcinoma cells following ablative temperature exposures (45-60 °C). MATERIALS AND METHODS: Hepatocellular carcinoma (HCC) cell lines were plated in 96-well plates, and heated between 45 and 60 °C for 0-32 min. Heating was applied by a rapid media exchange with heated Hank's balanced salt solution (HBSS) in a temperature-controlled water bath. Cell viability was determined by MTS assay. Survival data was modelled by the Arrhenius model, and the thermal isoeffective dose (TID) model where kinetic parameters were determined via non-linear optimisation. RESULTS: Results suggest that the thermal dose based on cumulative equivalent minutes and parameters as used for hyperthermia exposures (<43 °C) is not applicable for ablative exposures. We found R = 0.72 for temperatures between 45-60°C for the TID model. The Arrhenius parameters were frequency factor A = 3.25E43 1/s, and activation energy Ea = 281 kJ/mol. These parameters correlate well with a prior study in the same cell line, and with threshold temperatures for necrosis from in vivo studies. CONCLUSIONS: Our results suggest that standard TID model kinetic parameters based on hyperthermia studies, often also used at ablation temperatures, are not applicable at these higher temperatures for HCC cells.