Michal Tepper

Thermographic investigation of tumor size, and its correlation to tumor relative temperature, in mice with transplantable solid breast carcinoma

Abstract. Treating cancer is one of the major challenges of modern medicine. Since mice models are an important tool in cancer treatment research, it is required to assess murine tumor development. Existing methods for investigating tumor development are either high cost and limited by their availability or suffer from low accuracy and reproducibility. In order to overcome these drawbacks, thermography may be used. DA3 breast cancer carcinoma tumors in 12  Balb/c mice were thermally imaged and monitored for a period of several weeks. Eight mice were treated with diffusing alpha emitters radiation therapy (DaRT) wires, while four were treated with inert wires. For large tumors, the area was estimated by analyzing thermal images and was found to be in correlation with manual caliper measurements. In addition, the correlation between tumor area and relative temperatures was calculated and compared to previous works. Temperature differences were larger for tumors treated with DaRT wires than tumors with inert wires. These correlations can be used to assist in tumor size estimation and reveal information regarding its metabolic state. Overall, thermography was shown to be a promising tool for assessing tumor development with the additional advantages of being nonradiative and potentially providing indication of intratumoral biological processes.

Monitoring tumor state from thermal images in animal and human models

PURPOSE Thermography is a potentially useful method for tumor progress monitoring since it is noninvasive, nonradiative, low-cost, and rapid. Perfusion and metabolism are dominant factors for determining tumor temperature difference and are also correlated to the tumors growth rate. Therefore, estimating them from the tumor thermal image can be a very useful tumor monitoring method, since thermal changes occur before physical changes. The goal of this work was to study the effect of tumor state on the thermal image in different tumor types, using simulations and measurements. METHODS Simulated tumor models, representing flat and extruding tumors, typical to transplantable and natural tumors, respectively, were simulated and the effects of tumor metabolism and perfusion on the temperature difference were analyzed. Data regarding tumor size and measured temperature differences were obtained from the literature, discussing five types of transplantable tumors in mice and rats. The growth rates of all tumors were calculated by fitting tumor size measurements to a tumor growth model and were used as an indicator to tumor aggressiveness. Tumor temperature difference was calculated by taking the effect of its extruding shape into account, according to a previously published method. Tumor state was estimated from the normalized temperature differences using simulations and compared to the calculated aggressiveness rates. Computational models of human breast cancers, both in round and flat breast models, were recreated using a finite-element-method heat transfer simulation. Tumor size and state were simulated according to the results obtained from the animal tumor analysis, representing two different tumor aggressiveness levels. The calculated temperature difference as a function of tumor size was calculated for each test case. RESULTS Perfusion was shown to be highly dominant in determining the tumors temperature difference. Since both metabolism and perfusion were shown to have a linear effect on the temperature difference, a conversion value was defined between them. The analysis of the animal experimental results showed correlations between tumor aggressiveness and the following factors: the normalized temperature difference, the estimated tumor state, and the temperature difference change rate. The simulated human breast cancer models analysis showed highly varying temperature differences between the simulated models. Although for each model there is a clear difference between the temperature differences of the test cases simulated, the large differences between the results might make tumor state estimation difficult. However, reviewing the gradient of the tumor temperature change as a function of tumor size showed that the ratio between the gradients of both test cases was similar for all models. Therefore, the effect of model errors and differences in the simulated tissue structure and properties and the environmental conditions between the different models, can be mitigated. This pattern may be used to estimate tumor state in in vivo experiments. CONCLUSIONS Continuous monitoring of tumor temperature difference produces valuable information on tumor state and aggressiveness that can be used both in the clinic and in the laboratory. Monitoring can be either performed on a single image, or continuous on multiple images, revealing changes in tumor state.

Thermal imaging method for estimating oxygen saturation

The objective of this study is to develop a minimal invasive thermal imaging method to determine the oxygenation level of an internal tissue. In this method, the tissue is illuminated using an optical fiber by several wavelengths in the visible and near-IR range. Each wavelength is absorbed by the tissue and thus causes increase in its temperature. The temperature increase is observed by a coherent waveguide bundle in the mid-IR range. The thermal imaging of the tissue is done using a thermal camera through the coherent bundle. Analyzing the temperature rise allows estimating the tissue composition in general, and specifically the oxygenation level. Such a system enables imaging of the temperature within body cavities through a commercial endoscope. As an intermediate stage, the method is applied and tested on exposed skin tissue. A curve-fitting algorithm is used to find the most suitable saturation value affecting the temperature function. The algorithm is tested on a theoretical tissue model with various parameters, implemented for this study, and on agar phantom models. The calculated saturation values are in agreement with the real saturation values.

Parametric study of different contributors to tumor thermal profile

Treating cancer is one of the major challenges of modern medicine. There is great interest in assessing tumor development in in vivo animal and human models, as well as in in vitro experiments. Existing methods are either limited by cost and availability or by their low accuracy and reproducibility. Thermography holds the potential of being a noninvasive, low-cost, irradiative and easy-to-use method for tumor monitoring. Tumors can be detected in thermal images due to their relatively higher or lower temperature compared to the temperature of the healthy skin surrounding them. Extensive research is performed to show the validity of thermography as an efficient method for tumor detection and the possibility of extracting tumor properties from thermal images, showing promising results. However, deducing from one type of experiment to others is difficult due to the differences in tumor properties, especially between different types of tumors or different species. There is a need in a research linking different types of tumor experiments. In this research, parametric analysis of possible contributors to tumor thermal profiles was performed. The effect of tumor geometric, physical and thermal properties was studied, both independently and together, in phantom model experiments and computer simulations. Theoretical and experimental results were cross-correlated to validate the models used and increase the accuracy of simulated complex tumor models. The contribution of different parameters in various tumor scenarios was estimated and the implication of these differences on the observed thermal profiles was studied. The correlation between animal and human models is discussed.

Magnetic nanoparticles-based acoustical detection and hyperthermic treatment of cancer, in vitro and in vivo studies

Abstract. This paper describes a minimally invasive method for detection and growth inhibition of tumors that utilizes the unique properties of super paramagnetic nanoparticles. To demonstrate the feasibility of this method, dimercaptosuccinic acid-coated magnetite nanoparticles were successfully fabricated and used. Those nanoparticles were simultaneously used for magnetoacoustic detection of tumors and for specific hyperthermia treatment in C57BL/J mice injected with Lewis lung carcinoma cells. The in vivo acoustic signal attributed to the nanoparticles was 4.4 dB, while the single session hyperthermia treatment caused a reduction of 50% in tumor growing rate. In addition, a thermography-based method was applied to monitor the efficacy of the hyperthermia treatment. The presented method has the potential to revolutionize current cancer treatment by enabling diagnosis and treatment under real-time feedback in one session.

The effect of geometry on tumor thermal profile and its use in tumor functional state estimation

Thermal differences between transplanted tumors and tumors in humans prevent the implementation of thermographic methods developed in mice models to human models and vise-versa. Transplantable tumors tend to have an extruding shape, which may affect the thermal patterns. This hypothesis was studied in phantom experiments and simulations. A correlation between tumor dimensions and relative temperature was found and used to estimate tumor functional state from previously published in vivo experiments. A correlation was found between temperature differences and tumor growth rates (tumor aggressiveness) and the effect of tumor treatment was demonstrated, showing the potential for in vivo, non-invasive tumor monitoring.

Photothermal bundle measurement of phantoms and blood as a proof of concept for oxygenation saturation measurement.

This studys objective is to validate a method for the measurement of two compound phantoms as a proof of concept for oxygen saturation level measurement via a thermal imaging bundle. The method consists of a thermal imaging system and an algorithm which estimates the compound concentration according to temperature rise. A temperature rise is obtained by illuminating the tissue with a laser with different wavelengths in the NIR range and measured using a thermal camera. A coherent thermal imaging bundle was used for image transmittance for minimal invasive transendoscopic use. The algorithms estimation ability was evaluated using agar phantoms of varying Methylene Blue and ICG ratios as well as blood samples The Methylene Blue ratio in each phantom was estimated and the calculated average RMS of the error was 9.38%, a satisfying value for this stage, verifying the algorithms and bundles suitability for the use in a minimal invasive system.

Proposed method for internal electron therapy based on high-intensity laser acceleration

Abstract. Radiotherapy is one of the main methods to treat cancer. However, due to the propagation pattern of high-energy photons in tissue and their inability to discriminate between healthy and malignant tissues, healthy tissues may also be damaged, causing undesired side effects. A possible method for internal electron therapy, based on laser acceleration of electrons inside the patient’s body, is suggested. In this method, an optical waveguide, optimized for high intensities, is used to transmit the laser radiation and accelerate electrons toward the tumor. The radiation profile can be manipulated in order to create a patient-specific radiation treatment profile by changing the laser characteristics. The propagation pattern of electrons in tissues minimizes the side effects caused to healthy tissues. A simulation was developed to demonstrate the use of this method, calculating the trajectories of the accelerated electron as a function of laser properties. The simulation was validated by comparison to theory, showing a good fit for laser intensities of up to 2×1020  (W/cm2), and was then used to calculate suggested treatment profiles for two tumor test cases (with and without penetration to the tumor). The results show that treatment profiles can be designed to cover tumor area with minimal damage to adjacent tissues.

Photothermal imaging through coherent infrared bundles

This study aims to develop a photothermal imaging system through a coherent infrared bundle. This system will be used to determine the oxygenation level of various tissues, suspected malignant tissues in particular. The oxygenation estimation is preformed using a computerized algorithm. In order to evaluate the system, different bundle configurations were used for the determination of the optimal one. Bundle transmittance and the algorithms estimation ability were measured, measurements were performed using agar phantoms consisting of varying ratios of Methylene Blue and ICG. A bundle consisting of 19 Teflon waveguides with a of 1.1mm was found to be the optimal configuration with an RMS of the error of 9.38%. At a second stage the system was validated on blood samples with varying oxygenation levels and there oxygenation levels were estimated. This stage had an RMS of the error of 10.16% for the oxygenation level estimation for samples with a 50% oxygenation level and higher. Once the basic system was validated successfully on agar phantoms and blood samples a portable system was designed and built in order to fit the system for portable use. The portable system consists of a white light illuminating source followed by filters transmitting certain wavelengths, a transmitting fiber, a thermal imaging bundle and a portable thermal camera. This portable system will be evaluated in order to have an adequate portable system for implementing the method out of the lab.

Simulation and algorithm for photothermal imaging of tissue oxygen saturation

This study aims to develop a minimal invasive photothermal imaging method to determine the oxygenation level of an internal tissue. In this method, the tissue is illuminated using an optical fiber by several wavelengths in the visible and the near IR range. The absorption of the illuminated radiation causes an increase in the tissues temperature which is observed by a thermal camera through a coherent waveguide bundle in the mid-IR range. Analyzing the temperature rise allows estimating the tissue composition in general, and specifically the oxygenation level. This system will enable to measure the saturation on superficial tissues as well as within body cavities through a commercial endoscope. A theoretical model of this problem was implemented to help design the experimental setup and develop the experimental procedures. A curve-fitting algorithm is used to find the most suitable saturation value affecting the temperature function. The estimated saturation was calculated on different simulated model parameters and was in good agreement with the simulated saturation value.