Laser Irradiation of Tumors for the Treatment of Cancer: An Analysis of Blood Flow, Temperature and Oxygen Transport

It has been shown that hypoxic tumor cells are resistant to radiation and that increasing tumor oxygen levels via laser-mediated hyperthermia treatment increases tumor cell radiosensitivity. Hence, studies of the effects of laser irradiation on tumor oxygen levels are of great interest, as they allow for the optimization of hyperthermia treatment. Accordingly, the main purpose of this experiment was to develop a finite element model to simulate the heat transfer due to laser irradiation of tumor tissue, the blood flow through a tumor capillary, and the effect of changing temperature on blood flow rates and oxygen delivery to tumor tissue. This was achieved by using finite element models in COMSOL Multiphysics. We employed two geometries based on those used in a simliar study by He et al. [1]: a tumor-containing breast model to simulate laser heating of the tissue and a capillary and tumor tissue model to simulate the effect of heating on blood flow and tissue oxygen concentration. By plotting partial pressure of oxygen as a function of radius at three different points in the tissue, we observed that the oxygen concentration was greatest near the inlet and lowest near the outlet (as expected), and that at all points in the tissue, heating increased the tissue oxygen partial pressure to about the same extent (0.75 ? 1 mm Hg). Furthermore, sensitivity analyses suggested ambient air cooling at the breast surface to be ideal and a laser intensity of 18000 W/m2 to be optimal for hyperthermia treatment. The model we developed was validated by comparison to a similar model and has potential for use in future studies on optimization of hyperthermia treatment

Development of Temperature Distribution and Light Propagation Model in Biological Tissue Irradiated by 980 nm Laser Diode and Using COMSOL Simulation

Introduction: The purpose of this project is to develop a mathematical model to investigate light distribution and study effective parameters such as laser power and irradiated time to get the optimal laser dosage to control hyperthermia. This study is expected to have a positive impact and a better simulation on laser treatment planning of biological tissues. Moreover, it may enable us to replace animal tests with the results of a COMSOL predictive model.Methods: We used in this work COMSOL5 model to simulate the light diffusion and bio-heat equation of the mouse tissue when irradiated by 980 nm laser diode and the effect of different parameters (laser power, and irradiated time) on the surrounding tissue of the tumor treatment in order to prevent damage from excess heatResults: The model was applied to study light propagation and several parameters (laser power, irradiated time) and their impact on light-heat distribution within the tumor in the mouse back tissueThe best result is at laser power 0.5 W and time irradiation 0.5 seconds in order to get the maximum temperature hyperthermia at 52°C.Conclusion: The goal of this study is to simulate a mouse model to control excess heating of tissue and reduce the number of animals in experimental research to get the best laser parameters that was safe for use in living animals and in human subjects

NANOTECHNOLOGY-BASED CANCER PHOTOTHERAPY AND CIRCULATING TUMOR CELL ANALYSIS

Gold and hybrid gold nanotechnology are uniquely poised to improve the fields of cancer diagnosis and therapy. Modifying gold nanoparticles with biological proteins has been widely used for decades, however, the common carbodiimide technique requires steps that reduce sensitivity and effectiveness in some spectroscopic techniques. We have developed an antibody conjugation protocol which conducts linking first, and then covalently adheres the antibody-linker complex to the nanoparticle surface. The linking polymer N-hydroxysuccinimide-polyethylene glycol-thiol (NHS-PEG-SH) was incubated with a protein overnight and purified by centrifuge filtration before modifying the surface of gold nanoparticles by slow mixing. The method was transferred to antibody conjugation and cell-labeling strength and specificity verified via dark field imaging of cell lines with known expressions. In cancer treatment, nanoparticles have been implemented in promising phototherapeutic strategies. Here, we describe the development of a nanocomplex which augments photothermal therapy via gold nanorods with the addition of a photosensitizer for dual photothermal-photodynamic (PTT/PDT) therapy under a single laser irradiation. Silicon 2,3-napthallocyanine dihydroxide (SiNC) was adsorbed onto gold nanorods and stabilized with alkylthiol-polyethylene glycol. Cytotoxicity was analyzed in vitro under laser treatment. It was found that the nanocomplex produced cell-killing effects with efficiency greater than PTT or PDT alone under low dosage and cell-killing efficiency increased with increasing alkylthiol length. This nanocomplex has potential to non-invasively destroy tumor cells in a localized area, preventing tumor resurgence. In cancer detection, circulating tumor cells (CTCs) are the hallmark of metastasis and an ideal target for liquid biopsies but are exceptionally rare. Here we develop on the previous system by using multiplexed antibody-targeted SERS-active iron oxide-gold core-shell nanopopcorn in conjunction with a miniaturized chip to capture CTCs from whole blood and analyze individual cells to construct a molecular profile of common cancer markers. We demonstrate the capability of the nanoparticles to selectively capture and profile cancer cells individually and with multiplexed labeling with an integrated microfluidic device. Labeled cancer cells spiked into PBS are swiftly captured with high efficiency, and detected nanoparticle ratios agree with cell line expressions. This method provides a rapid integrated method for CTC capture, detection, and profiling of surface markers

Simulation of thermal field distribution in biological tissue and cell culture media irradiated with infrared wavelengths

In recent years, there has been a growing interest in the singlet form of oxygen as a regulator of the physiological functions of cells. One of the ways to generate singlet oxygen is direct optical excitation of the triplet oxygen form. Since molecular oxygen weakly absorbs light, high power is required to obtain sufficient concentrations of singlet oxygen. However, the increase in the radiation power of laser can induce a local temperature increase around the laser spot. This may be critical considering the temperature governs every biological reaction within living cells, in particular. Here, the interaction of laser radiation of infrared wavelengths, generating singlet oxygen, with biological tissues and cell culture media was simulated. Using the COMSOL Multiphysics software, the thermal field distribution in the volume of skin, brain tissue and cell culture media was obtained depending on the wavelength, power and exposure time. The results demonstrate the importance of taking temperature into account when conducting experimental studies at the cellular and organismal levels

SURFACE FUNCTIONALIZATION VIA PHOTOINITIATED RADICAL POLYMERIZATION FOR RARE CELL ISOLATION AND MECHANICAL PROTECTION

Surface functionalization of living cells for cell therapeutics has gained substantial momentum in the last two decades. From encapsulating islets of Langerhans, to cell laden gels for tissue scaffolds, to individual cell encapsulation in thin hydrogels, to surface adhesives and inert surface camouflage, modification of living cell surfaces has a wide array of important applications. Here we use hydrogel encapsulation of individual cells as a mode of protection from mechanical forces for high throughput cell printing, and chemical stimuli for the isolation of rare cells in blood. In the first study, we review methods of surface functionalization and establish a metric of potential target biomarkers for circulating tumor cell (CTC) isolation. For extended applications in cancer detection through a fluid biopsy, common surface antigen densities were quantitatively assessed in relation to peripheral blood mononuclear cells (PBMCs) for potential targets of cell specific encapsulation. We then look to commercialization of our process after considering biopsy volumes and cell therapy dose sizes. Undesired batch-to-batch variation in our in-house synthesized photo-initiator could be eliminated by the use of fluorescein, a commercial fluorochrome of similar initiating power to our current eosin initiating system. Fluorescence and hydrogel generation were compared indicating a fluorescein conjugate has comparable power to that of our in-house conjugated eosin. Parameters involving the number of cells and fluid volumes processed were then analyzed systematically. Key parameters were studied to determine optimal equipment and protocol for clinically relevant batch sizes. The final study looks at the mechanical protection provided by thin hydrogel encapsulation. With growing interests in 3D bioprinting and goals of viable whole organ printing for transplant, high resolution and high throughput printing is a growing need. 3D bioprinting presents intense mechanical stimuli in the process that cells must endure. Here we analyze how hydrogel encapsulation reinforces the cellular membrane allowing cells to withstand the damaging forces associated with bioprinting

Biomedical Photoacoustic Imaging and Sensing Using Affordable Resources

The overarching goal of this book is to provide a current picture of the latest developments in the capabilities of biomedical photoacoustic imaging and sensing in an affordable setting, such as advances in the technology involving light sources, and delivery, acoustic detection, and image reconstruction and processing algorithms. This book includes 14 chapters from globally prominent researchers , covering a comprehensive spectrum of photoacoustic imaging topics from technology developments and novel imaging methods to preclinical and clinical studies, predominantly in a cost-effective setting. Affordability is undoubtedly an important factor to be considered in the following years to help translate photoacoustic imaging to clinics around the globe. This first-ever book focused on biomedical photoacoustic imaging and sensing using affordable resources is thus timely, especially considering the fact that this technique is facing an exciting transition from benchtop to bedside. Given its scope, the book will appeal to scientists and engineers in academia and industry, as well as medical experts interested in the clinical applications of photoacoustic imaging

Nanoprobes for Tumor Theranostics

This book reports cutting-edge technology in nanoprobes or nanobiomaterials used for the accurate diagnosis and therapy of tumors, involving a multidisciplinary of chemistry, materials science, oncology, biology, and medicine

Label-Free Monitoring of Tumor Models by Surface-Enhanced Raman Scattering

184 p.El objetivo general de la presente tesis se ha centrado en la monitorización de modelos celulares mediante la técnica de espectroscopia de Raman aumentada en superficies (SERS). Las tecnologías desarrolladas en la tesis han perseguido, por un lado, mejorar la recreación del ambiente tumoral a escala de laboratorio, y por otra parte, su integración junto con estructuras plasmónicas para el análisis por SERS de los modelos tumorales creados artificialmente. Más en concreto, se han analizado las alteraciones en la concentración relativa de los metabolitos presentes en el medio extracelular como resultado de la reprogramación metabólica característica de los tumores, la cual permite a su vez un crecimiento descontrolado de dichas células.La disposición conjunta de ambas tecnologías (cultivos celulares en 3D y nanoplasmónica) ofrece un marco único para la identificación de aquellos procesos celulares que se encuentran alterados durante el crecimiento de tumores. Hasta la fecha, la mayoría de las técnicas de laboratorio que se habían empleado para caracterizar ambientes celulares en el laboratorio implicaban procesos invasivos, es decir, quemodifican o incluso desintegraban la muestra para poder analizarla. En contraposición, la espectroscopia Raman había permitido adquirir información sobre la composición del medio celular de una manera mínimamente invasiva. Basada en los fenómenos de dispersión inelástica, la técnica de Raman emplea luz monocromática (generalmente de un láser) para irradiar la muestra bajo análisis, de forma que la interacción entre la muestra y el láser provoca un cambio en la energía de los fotones dispersados, específico de los modos vibraciones de las moléculas irradiadas. Por lo tanto, la luz dispersada y recogida por un detector, permite caracterizar el sistema biológico que ha sido previamente iluminado, sin marcaje previo. Sin embargo, las señales detectadas por dispersión Raman son de manera general muy débiles, por lo que se requiere una intensificación de dichas señales para poder detectar la presencia de metabolitos extracelulares (a bajas concentraciones). En esta tesis se decidió implantar la modalidad conocida como SERS, que hace uso de las propiedades plasmónicas de nanopartículas metálicas (principalmente de oro), las cuales dan lugar a campos eléctricos elevados cuando se iluminan en resonancia con los plasmones superficiales. Como resultado, la señal de Raman de las moléculas adsorbidas sobre dichas superficies metálicas se ve amplificada en varios órdenes de magnitud. Sobre esta base, se han desarrollado en la tesis diferentes plataformas destinadas a combinar sustratos plasmónicos, formados por fijación de nanopartículas de oro sobre estructuras rígidas en 2D, o bien embebidas en redes poliméricas, junto con modelos de células tumorales en crecimiento. La finalidad de la tesis ha sido pues, la monitorización de diferentes procesos celulares en dichos dispositivos mediante SERS, y su posterior interpretación biológica en el ámbito del metabolismo tumoral y la mejora del tratamiento.CICbioGUNE; CICbiomaGUN

Photodynamic Therapy utilizing Interstitial Light Delivery Combined with Spectroscopic Methods

Since cancer continues to plague humanity there is large need for development of modalities for both diagnosis and therapy. Most of the currently available methods suffer from serious disadvantages. The treatments, e.g. ionising radiation, chemotherapy, surgery, may themselves induce malignancies or the patient may be physically impaired for a longer period of time. The work presented aims at developing equipment and methods that use light for both detection and treatment of various malignant or pre-malignant conditions. Fundamental knowledge on the interaction between light and tissue is required in order to develop models for the light distribution in tissue. Therefore, basic properties of light-tissue interaction, like refractive index, absorption, scattering, and scattering anisotropy, are introduced. How the physiological status of the tissue affects these properties are discussed. Utilizing the differences in the fluorescence spectra emitted by healthy and malignant tissues, when irradiated with visible light, it is possible to detect and delineate certain lesions. The contrast between diseased and healthy tissue can be further enhanced with the use of a fluorescence tumour marker. The evolution of these tumour markers has been fuelled by the fact that many tumour markers also can be utilized for light therapy. The modality is called photodynamic therapy (PDT) and has now been clinically approved for the treatment of several conditions. The possible indications for this type of treatment are generally limited to thin superficial lesions due to the limited penetration of the light in tissue. The work presented in this thesis mainly relates to overcoming the limited light penetration by leading the light through multiple optical fibres inserted into the tumour. In this way both embedded tumour and/or thick tumours could be an indication for this modality. In addition to that the fibres are used to collect information about relevant parameters of therapeutic interest