Hyperthermia and smart drug delivery systems for solid tumor therapy.

Chemotherapy is a cornerstone of cancer therapy. Irrespective of the administered drug, it is crucial that adequate drug amounts reach all cancer cells. To achieve this, drugs first need to be absorbed, then enter the blood circulation, diffuse into the tumor interstitial space and finally reach the tumor cells. Next to chemoresistance, one of the most important factors for effective chemotherapy is adequate tumor drug uptake and penetration. Unfortunately, most chemotherapeutic agents do not have favorable properties. These compounds are cleared rapidly, distribute throughout all tissues in the body, with only low tumor drug uptake that is heterogeneously distributed within the tumor. Moreover, the typical microenvironment of solid cancers provides additional hurdles for drug delivery, such as heterogeneous vascular density and perfusion, high interstitial fluid pressure, and abundant stroma. The hope was that nanotechnology will solve most, if not all, of these drug delivery barriers. However, in spite of advances and decades of nanoparticle development, results are unsatisfactory. One promising recent development are nanoparticles which can be steered, and release content triggered by internal or external signals. Here we discuss these so-called smart drug delivery systems in cancer therapy with emphasis on mild hyperthermia as a trigger signal for drug delivery.

An Electrode Array for Limiting Blood Loss During Liver Resection: Optimization via Mathematical Modeling.

Liver resection is the current standard treatment for patients with both primary and metastatic liver cancer. The principal causes of morbidity and mortality after liver resection are related to blood loss (typically between 0.5 and 1 L), especially in cases where transfusion is required. Blood transfusions have been correlated with decreased long-term survival, increased risk of perioperative mortality and complications. The goal of this study was to evaluate different designs of a radiofrequency (RF) electrode array for use during liver resection. The purpose of this electrode array is to coagulate a slice of tissue including large vessels before resecting along that plane, thereby significantly reducing blood loss. Finite Element Method models were created to evaluate monopolar and bipolar power application, needle and blade shaped electrodes, as well as different electrode distances. Electric current density, temperature distribution, and coagulation zone sizes were measured. The best performance was achieved with a design of blade shaped electrodes (5 x 0.1 mm cross section) spaced 1.5 cm apart. The electrodes have power applied in bipolar mode to two adjacent electrodes, then switched sequentially in short intervals between electrode pairs to rapidly heat the tissue slice. This device produces a ~1.5 cm wide coagulation zone, with temperatures over 97 masculineC throughout the tissue slice within 3 min, and may facilitate coagulation of large vessels.

Estimating the probability that the Taser directly causes human ventricular fibrillation.

This paper describes the first methodology and results for estimating the order of probability for Tasers directly causing human ventricular fibrillation (VF). The probability of an X26 Taser causing human VF was estimated using: (1) current density near the human heart estimated by using 3D finite-element (FE) models; (2) prior data of the maximum dart-to-heart distances that caused VF in pigs; (3) minimum skin-to-heart distances measured in erect humans by echocardiography; and (4) dart landing distribution estimated from police reports. The estimated mean probability of human VF was 0.001 for data from a pig having a chest wall resected to the ribs and 0.000006 for data from a pig with no resection when inserting a blunt probe. The VF probability for a given dart location decreased with the dart-to-heart horizontal distance (radius) on the skin surface.

A surgical device for radiofrequency ablation of large liver tumors.

Radiofrequency ablation has become an accepted treatment option of patients with primary and metastatic liver tumors. We propose an ablation electrode array consisting of 4-8 blade shaped electrodes arranged in a circular geometry for the treatment of large liver tumors. We developed a 3D code based on the finite difference method for evaluating the effect of different numbers of electrodes (4, 6 and 8) and electrode distance on lesion size. The configuration with six electrodes can ablate a volume of 70 x 70 x 40 mm(3) in approximately 5 min, with tissue temperature above 50 degrees C throughout the treatment volume. We then performed an experimental study in polyacrylamide gel in order to validate the theoretical results. The average temperature error between the simulation and the experiment was 3.8% at the center of the electrode array. This study shows that the proposed device potentially allows more rapid treatment of large tumors than current radiofrequency ablation devices.

An electrode array that minimizes blood loss for radiofrequency-assisted hepatic resection.

Hepatic resection is currently the standard treatment for liver cancer. During hepatic resection part of the liver containing the tumor is surgically removed. This type of surgery is accompanied by high blood loss of approximately 0.6-1.35 L. Blood loss is associated with increased complication rates, prolonged hospital stay, and reduced patient survival, especially when transfusion is required. Other researchers have suggested using radiofrequency (rf) or microwave ablation to coagulate a tissue slice before resection to reduce blood loss, but conventional devices typically take several hours. We developed a device consisting of a linear array of blade-shaped, 1 cm wide radiofrequency (rf) electrodes 1.5 cm apart. Bipolar rf power is applied between pairs of adjacent electrodes, leading to high tissue temperatures between the electrodes that promote coagulation of large vessels (>3 mm) in the resection plane. Rapid switching of applied power between pairs of adjacent electrodes allows simultaneous heating and coagulation of the entire resection plane within 3-6 min. In seven in vivo trials in a porcine model, resection along a plane pre-coagulated with the device resulted in little (<20 mL) to no blood loss, while coagulating all vessels (up to 4.5 mm diameter in this study). Average treatment time (from placement of the device to transection) was 6.8+/-0.5 min when four electrodes were used, and 11.3+/-1.2 min when 5-7 electrodes were used. This device may reduce blood loss related morbidity during resection and reduce treatment time by coagulating all vessels in the resection plane.

Sequential activation of multiple grounding pads reduces skin heating.

Radio frequency (RF) tumor ablation has become an accepted treatment modality for tumors not amenable to surgery. The need for larger ablation zones has required increase in RF generator power, with current generation devices delivering 200-250 W. Skin burns due to ground pad heating have become a common complication and are now a limiting factor for further increase in ablation zone and generator power. We performed ex vivo experiments with three ground pads (5 x 5 cm) placed on a tissue phantom. We applied 100 W of power for 12 min between the pads, and an RF electrode while we measured leading edge temperature below each pad, and temperature profile on the pads using temperature-sensitive LCD-paper. We compared conventional operation (i.e. simultaneous connection of all three pads) to sequential activation of the pads where each pad is only active for approximately 0.5 s. The timing during sequential activation was adjusted to keep leading edge temperature equal between the pads. Temperature rise below the leading edge for proximal, middle and distal ground pad was 10.7 +/- 1.04, 1.0 +/- 0.15 and 0.3 +/- 0.07 degrees C for conventional operation, and 4.8 +/- 0.16, 4.4 +/- 0.20 and 4.5 +/- 0.35 degrees C for sequentially activated operation. The maximum leading edge temperature rise was more than twice as high for conventional compared to switched operation (p<0.001). Sequential activation of multiple ground pads resulted in reduced maximum leading edge temperature, and allows control of each pad such that leading edge temperature of all pads is the same. This may reduce the incidence of ground pad burns by allowing each pad to reach same temperatures independent of location, and may allow higher power RF generators due to reduced skin heating.

Quantification of local convectional cooling during cardiac radiofrequency catheter ablation.

Radiofrequency (RF) catheter ablation is an effective, minimally invasive treatment method in clinical use for treatment of different cardiac arrhythmia. Studies have shown that lesion dimensions strongly depend on blood flow mediated convective cooling at the ablation site. We present a simple method to quantify convective cooling. A brief pulse of RF energy (10 W for 5 s) is applied, and catheter tip temperature is measured during and after energy application. Two parameters are extracted: 1) maximum tip temperature increase, and 2) slope of temperature decay 8 degree C above initial temperature. We tested whether these parameters can quantify convective cooling in ex vivo experiments. A RF catheter was inserted into a tissue phantom placed in a saline bath. Flow at different rates of 0, 1, 2 and 3 L/min was injected towards the catheter, and the parameters were extracted. Both parameters correlated with flow rate. Slope of temperature decay showed linear dependence on flow rate, maximum temperature increase showed exponential dependence. The parameters are potentially useful in quantifying convective cooling before ablation to predict lesion dimensions.

Contribution of direct heating, thermal conduction and perfusion during radiofrequency and microwave ablation.

Heat based tumor ablation methods such as radiofrequency (RF) and microwave (MW) ablation are increasingly accepted treatment methods for tumors not treatable by traditional surgery. Typically, an interstitial applicator is introduced under imaging guidance into the tumor, and tissue is destroyed by heating to above approximately 50 degrees C, with maximum tissue temperatures over 100 degrees C. Since high thermal gradients occur during the procedure, thermal conduction contributes significantly towards tissue heating. We created finite element method (FEM) computer models of RF and MW applicators, and determined the thermal conduction term, the resistive (for RF) or dielectric (for MW) loss term, and perfusion term. We integrated these terms over the heating period to obtain relative contribution towards tissue temperature rise (in degrees C) as a function of distance from the applicator. We performed simulations without and with perfusion, where perfusion was assumed to stop above 50 degrees C. During the first 6 minutes, direct heating by RF and MW were dominating throughout the tissue. Over the treatment period (12 min for RF, and 6 min for MW), thermal conduction was dominating at distances between than 12 and 19 mm from the RF electrode, while for MW ablation direct heating dominated everywhere. Even though thermal conduction significantly contributes towards tissue heating during ablative therapies, direct heating by RF or MW is dominating throughout most of the tissue volume. Tissue cooling due to perfusion is more significant during RF heating, in part due to the longer treatment times.

Thermal tumour ablation: devices, clinical applications and future directions.

Tumour ablation is clinically applied mainly for non-operable liver tumours, with increasing application to other organ sites like kidney, lung, adrenal gland and bone. Most current devices use radiofrequency (RF) current to heat tumour tissue surrounding the applicator, which is introduced into the tumour under imaging guidance. Tissue temperatures in excess of 100 degrees C are achieved, with cell death due to coagulative necrosis occurring above 50 degrees C. Limitations of current ablation devices include inadequate imaging, limited size of coagulation zone and reduced performance next to large vessels. This paper reviews current interstitial RF and microwave devices, clinical applications and future research directions in the field of high-temperature tumour ablation.

Instrument to measure the heat convection coefficient on the endothelial surface of arteries and veins.

The primary objective of the paper was to present the design and analysis of an instrument to measure the heat convection coefficient h on the endothelial surfaces of arteries and veins. An invasive thermistor probe was designed to be inserted through the vessel wall and positioned on the endothelial surface. Electrical power was supplied to the thermistor by a constant temperature anemometry circuit. Empirical calibrations were used to relate electrical measurements in the thermistor to the h at the endothelial surface. As the thermal processes are strongly dependent on baseline blood temperature, the instrument was calibrated at multiple temperatures to minimise this potentially significant source of error. Three different sizes of thermistor were evaluated to optimise accuracy and invasiveness, and the smallest thermistors provided the best results. The sensitivity to thermistor position was evaluated by testing the device at multiple locations, varying both depth of thermistor penetration and position along the vessel. Finally, the measurement accuracy of the instrument was determined for the range of h from 430 to 4200 W m(-2)K, and the average error of the reading was 4.9% for the smallest thermistor. Although the instrument was designed specifically for measurements in the portal vein to obtain useful data for current numerical modelling, the device can be used in any large vessel.

Multiple applicator approaches for radiofrequency and microwave ablation.

Treatment of tumours greater than 2 cm by radiofrequency (RF) or microwave ablation typically use multiple sequential applications, since most currently available ablation devices are limited to use of a single applicator at a time. A major focus of current ablation research is on methodologies that allow increasing the coagulation zone to more rapidly treat large tumours. The ability to use multiple applicators simultaneously would satisfy this need. It would significantly reduce treatment time and may lead to a reduction in local tumour progression, especially in perivascular locations. Several methods have been suggested that potentially allow simultaneous use of multiple applicators, both with radiofrequency (RF) and microwave (MW) ablation. This review compares the different methods of multiple applicator use, investigating advantages and disadvantages of each modality.

A device for radiofrequency assisted hepatic resection.

Hepatic resection is the current standard treatment for hepatic malignancies. During hepatic resection part of the liver containing the tumor is surgically removed. This type of surgery is associated with high blood loss of approximately 1 L. Blood loss is associated with increased complication rates, prolonged hospital stay and reduced patient survival, especially when transfusion is required. We present a device that allows coagulation of a plane of tissue 1 to 2 cm wide, including coagulation of large vessels. This enables reduction of blood loss to a minimum by performing surgery along the coagulated tissue plane. The device consists of a linear array of radiofrequency (RF) electrodes 1.5 cm apart. By application of RF current in bipolar mode between two adjacent electrodes, temperatures close to 100 degrees C are obtained in-between electrodes enabling coagulation of large vessels. Rapid switching of applied current between all adjacent electrode pairs enables rapid heating of a tissue slice. We present a prototype device including results from ex vivo and in vivo experiments.

Hepatic radiofrequency ablation--an overview from an engineering perspective.

Radiofrequency (RF) ablation is receiving increasing attention as treatment for primary and metastatic liver cancer. RF ablation can be performed during open surgery, or minimally invasive through a small incision. An electrode is introduced into the liver tumor, and RF energy is applied. Tissue surrounding the electrode heats up, and is killed above approximately 50 degrees C, where tissue coagulation occurs. Ultrasound imaging is typically used to place the electrode, and monitor the ablation procedure; the exact dimension of the coagulation zone is not visible under ultrasound. Current devices can create coagulation zones between 4 and 7 cm diameter. For large tumors often multiple sequential applications are required, since current devices can only use a single electrode at a time. Current limitations include inadequate imaging modalities, uncontrolled shapes and size of coagulation zones, and inability to reach adequate temperatures close to large vessels. When future devices are available that improve upon these shortcomings, RF ablation may replace classical surgery as the standard treatment for liver cancer.

Hepatic bipolar radiofrequency ablation creates coagulation zones close to blood vessels: a finite element study.

Radiofrequency (RF) ablation has become an important means of treatment of non-resectable primary and metastatic liver tumours. Recurrence of treated tumours is associated with cancer cell survival next to blood vessels. The paper examines the performance of classical monopolar, and two configurations of bipolar, RF ablation using a LeVeen ten-prong catheter. Finite element method models of monopolar and bipolar configurations were created at 5 mm distance from a vessel of the size of a typical portal vein (10 mm diameter). In one bipolar configuration, the probes were oriented in the same axial direction (asymmetric configuration); in the second bipolar configuration, the two probes were facing each other (symmetric configuration). The distribution of temperature and current density was analysed for three different flow conditions: normal flow, reduced flow due to portal hypertension and high flow. For normal flow, the distance between the formed coagulation zone and the blood vessel was 1.8 mm for monopolar, 1 mm for asymmetric bipolar, and 0.2 mm for symmetric bipolar, configurations. Symmetric bipolar RF ablation creates coagulation zones significantly closer to blood vessels compared with monopolar RF ablation. This may reduce tumour cell survival next to blood vessels and reduce recurrence rates.

Changes in electrical resistivity of swine liver after occlusion and postmortem.

The resistivity of swine liver tissue was measured in vivo, during induced ischaemia and post-mortem, so that associated changes in resistivity could be quantified. Plunge electrodes, the four-terminal method and a computer-automated measurement system were used to acquire resistivities between 10Hz and 1 MHz. Liver resistivity was measured in vivo in three animals at 11 locations. At 10 Hz, resistivity was 758 +/- 170 ohm x cm. At 1 MHz, the resistivity was 250 +/- 40 ohm x cm. The resistivity time course was measured during the first 10 min after the liver blood supply in one animal had been occluded. Resistivity increased steadily during occlusion. The change in resistivity of an excised tissue sample was measured during the first 12h after excision in one animal. Resistivity increased during the first 2h by 53% at 10 Hz and by 32% at 1 MHz. After 2h, resistivity decreased, probably owing to membrane breakdown. The resistivity data were fitted to a Cole-Cole circle, from which extracellular resistance Re, intracellular resistance Ri and cell membrane capacitance Cm were estimated. Re increased during the first 2h by 95% and then decreased, suggesting an increase in extracellular volume. Cm increased during the first 4 h by 40%, possibly owing to closure of membrane channels, and then decreased, suggesting membrane breakdown. Ri stayed constant during the initial 6h and then increased.

Hepatic bipolar radio-frequency ablation between separated multiprong electrodes.

Radio-frequency (RF) ablation has become an important means of treatment of nonresectable primary and metastatic liver tumors. Major limitations are small lesion size, which make multiple applications necessary, and incomplete killing of tumor cells, resulting in high recurrence rates. We examined a new bipolar RF ablation method incorporating two probes with hooked electrodes (RITA model 30). We performed monopolar and bipolar in vivo experiments on three pigs. The electrodes were 2.5 cm apart and rotated 45 degrees relative to each other. We used temperature-controlled mode at 95 degrees C. Lesion volumes were 3.9+/-1.8 cm3 (n=7) for the monopolar case and 12.2 +/- 3 cm3 (n=10) for the bipolar case. We generated finite-element models (FEMs) of monopolar and bipolar configurations. We analyzed the distribution of temperature and electric field of the finite element model. The lesion volumes for the FEM are 7.95 cm3 for the monopolar and 18.79 cm3 for the bipolar case. The new bipolar method creates larger lesions and is less dependent on local inhomogenities in liver tissue-such as blood perfusion-compared with monopolar RF ablation. A limitation of the new method is that the power dissipation of the two probes cannot be controlled independently in response to different conditions in the vicinity of each probe. This may result in nonuniform lesions and decreased lesion size.

Flow effect on lesion formation in RF cardiac catheter ablation.

This study investigated the flow effect on the lesion formation during radio-frequency cardiac catheter ablation in temperature-controlled mode. The blood flow in heart chambers carries heat away from the endocardium by convection. This cooling effect requires more power from the ablation generator and causes a larger lesion. We set up a flow system to simulate the flow inside the heart chamber. We performed in vitro ablation on bovine myocardium with three different flow rates (0 L/min, 1 L/min and 3 L/min) and two target temperatures (60 degrees C and 80 degrees C). During ablation, we also recorded the temperatures inside the myocardium with a three-thermocouple temperature probe. The results show that lesion dimensions (maximum depth, maximum width and lesion volume) are larger in high flow rates (p<0.01). Also, the temperature recordings show that the tissue temperature rises faster and reaches a higher temperature under higher flow rate.