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Theoretical And Computational Modeling Of An Implantable Biomedical Device For Localized Hyperthermia And Drug Delivery

Theoretical And Computational Modeling Of An Implantable Biomedical Device For Localized Hyperthermia And Drug Delivery

ABSTRACT

The advent of nanotechnology together with Biomedical Microelectro-Mechanical Systems (BioMEMS) for improved efficacy in treatment of cancer has resulted in the development of an implantable biomedical device for localized hyperthermia and drug delivery. This thesis work develops a mathematical framework based on relaxation losses of heating mechanism of magnetite magnetic nanoparticles synthesized with the Polydimethylsiloxane (PDMS) gel encasement. Numerical solution of the mathematical model developed showed explicit dependence of the temperature rise of the device on frequency and amplitude of the external applied field, relaxation time and volume fraction of the nanoparticles and implicitly on the viscosity of the PDMS gel and radius of the nanoparticles. A linear dependence of the temperature rise on the amplitude and frequency of the field was observed for usable range of values of the Radio Frequency field. Similarly for the viscosity of the gel and volume fraction the nanoparticles, it is approximately linear but saturates at a maximum value and then declines.

This result was found to be in conformity with other predicted theoretical and experimental findings. This research shows that hyperthermia therapeutic temperature of 41-46oC can achieved with frequency and amplitude ranges of 2.16-2.19 kHz and 9.77-9.89 kA/m respectively. Also, that for the range of the viscosity and volume fraction of the nanoparticles are 1.1-1.2 mPa.s and 0.12-0.14 respectively. Simulation of the heat diffusion profile of the implant and its surrounding tumor in 2D and 3D using a finite element simulation package Abaqus/CAE 6.9 showed that for maximum generated heat of 52oC and 55oC maintained the temperature of the tumor within the therapeutic range for more than thirty minutes. However, for a temperature 45oC, the temperature falls a little below the therapeutic range but will be very useful in treatment for longer time periods. The generated heat in these cases is also seen to be enough to serve as the transition temperature for the thermo sensitive drug loaded hydrogel embed in the device with micro channels for release since the drug release kinematic of the gel occurs between 37oC and 45oC.

TABLE OF CONTENTS

ACKNOWLEDGEMENT-iii
ABSTRACT-iv
CHAPTER ONE-1
BACKGROUND AND INTRODUCTION-1
1.1 BACKGROUND AND MOTIVATION-1
1.2 SCOPE OF WORK-3
CHAPTER TWO-4
LITERATURE REVIEW-4
2.1 INTRODUCTION-4
2.2 CANCER AND CANCER TREATMENT-4
2.3 HYPERTHERMIA IN CANCER TREATMENT-5
2.3.1 MAGNETIC FLUID HYPERTHERMIA (MFH)-6
2.3.2 LOW CURIE TEMPERATURE NANOPARTICLES-9
2.4 BIOMEMS FOR HYPERTHERMIA-9
2.5 ELECTROMAGNETIC RADIATION AND ELECTROMAGNETISM-11
2.5.1 ELECTROMAGNETIC RADIATION-11
2.5.2 BASIC LAWS OF ELECTROMAGNETISM-13
2.5.3 MAGNETISATION AND MAGNETISING FIELD-14
2.5.4 MAGNETIC INDUCTION-17
2.5.5 INDUCTANCE AND MAGNETIC ENERGY-19
2.6 MAGNETIC MATERIALS-20
2.6.1 MAGNETIC NANOPARTICLES-23
CHAPTER THREE-26
THEORETICAL AND COMPUTATIONAL MODELS-26
3.1 MAGNETIC NANOPARTICLE HEATING WITH ALTERNATING MAGNETIC FIELD . 26
3.1.1 CONSERVATION OF ENERGY IN ELECTROMAGNETIC FIELDS-26
3.1.2 SPECIFIC ABSORPTION RATE (SAR) OF NANOPARTICLES-28
3.2 HEAT DISSIPATION-29
3.2.1 THEORY OF HEATING WITH TIME DEPENDENT MATERIAL PARAMETER-31
3.2.2 RELAXATION MECHANISMS-31
3.3 MODELLING MAGNETIC FLUID HYPERTHERMIA IN AN IMPLANTABLE DEVICE . 35

CHAPTER ONE

BACKGROUND AND INTRODUCTION

1.1 BACKGROUND AND MOTIVATION

Cancer is identified as the seconding leading course of death by the World Health Organization (WHO). According to GLOBOCAN 2008 of the WHO, about 7.6 million cancer deaths occurred in 2008 and it is expected that there will be more than 13 million cancer deaths and approximately 21 million diagnosis by 2030 as reported by WHO in June 2010. Cancer diagnosis and treatment are of great interest due to the widespread occurrence of the disease, high death rate and reoccurrence after treatment [1]. The disease is widespread regardless of race, and occurs in many sites including lung, breast, kidney, ovary, prostate, colon, bladder, and cervix. With increasing industrialization and other socio-behavioral changes in most developing countries, and Sub-Saharan Africa as a whole, it is projected by the WHO that the rate of incidence of cancer will increase to the leading cause of death by 2030.

There are several conventional approaches to cancer treatment; these include surgery, radiation, hormone, gene, immunotherapy, etc. with radiation, surgery and chemotherapy being the most common [2]. Most widely acknowledged issues with chemotherapy are the exposure of healthy tissues to toxic chemicals and the inefficiency of achieving the therapeutic zone [3]. Among other conventional treatment are hormone therapy, radiation therapy, surgery and thermal therapy. However, an integrated approach to cancer treatment that is promising, and currently at the heart of research, is the combination of radiotherapy, chemotherapy, surgery and hyperthermia.

Electronic devices have now reached a stage of dimensions comparable to those of biological macromolecules. This raises exciting possibilities for combining microelectronic and biotechnology to develop new technologies with unprecedented power and versatility [4]. The plethora of biomedical microelectromechanical systems (BioMEMS) emerging today range from fascinating molecular motors that swim inside a cell utilizing the intercellular energy-rich ATP
molecules to sophisticated point-of-care diagnostic devices [5].

Magnetic nanoparticles (MNPs) mainly magnetic elements of iron, cobalt, nickel and their chemical compounds in recent times have numerous applications in data storage, Magnetic Resonance Imaging (MRI), and Biomedicine especially as agents for heating, temperature censoring and drug delivery in biomedical devices. In general, Nano sized magnetic particles display super paramagnetism with properties dependent on the synthesis and chemical structure.

Shell materials for magnetic nanoparticles used for medical applications include polysaccharides for example dextron or derivatives (carboxymethylated dextran, Poly(ethyleneglycol), Poly(Nisoproply-acrylamide) e.t.c [6]. However, the most commonly used are ferrite nanoparticles which exhibit agglomeration and according to K. Babinch et al [6], iron oxides have known low cytotoxicity and high biocompatibility.

In particular, magnetic nanoparticles can be localized in deep tissue, external static magnetic field can fix them at precise position, gradient fields can move them and alternating (AC) fields lead to local heating. The latter can be utilized for hyperthermia applications which are shown for example by the use of super-paramagnetic nanoparticles for magnetic fluid hyperthermia [7].

A great advantage of magnetic field is their biocompatibility, i.e. they penetrate tissue non-invasively and without known adverse effects and their weak interaction with organic matter so that deep layers of human tissue can be reached [7]. To this end, a magnetic field is applied to the biomedical device and heat induced by the magnetic nanoparticles for localized hyperthermia.

The challenge of targeted drug delivery, coupled with the advent of nanotechnology, has led to the discovery and development of novel biomedical devices for localized hyperthermia and drug delivery. These devices will reduce the effects of bulk systemic treatments and increase the effectiveness of localized treatments by controlling drug release. These devices are currently under intense research by material scientists, engineers and medical practitioners.

In this novel device, thermosensitive drug loaded hydrogel (PNIPA) is encapsulated in a biocompatible gel (Polydimethylsiloxane microfluidic devices, PDMS) [3]. Several thermosensitive polymer hydrogels have proven to be biocompatible. These hydrogels are advantageous in clinical application due to their fluidity below lower critical solution temperature at approximately 33 oC which enable them to be introduced into site-specific organ, tissue or body cavity with improved applicability and comfort of injection [8].

The PDMS gel is synthesized with magnetic nanoparticles which induce heat by hysteresis, when an external alternating (AC) magnetic field is applied. The heat is used for localized hyperthermia for cancer treatment, and also in drug delivery, since the hydrogel is temperature sensitive and shrinks to expel drug, when the temperature of the device is increased. Essentially, this process controls the amount of drug released and to specific or targeted location.

Fig 1.0: Schematic diagram of Hydrogel, PNIPA encapsulated by a biocompatible gel PDMS

1.2 SCOPE OF WORK

This thesis presents a theoretical/computational framework of the modeling of the heating a localized nano-composite gel for the treatment of cancer by hyperthermia. The effects of applied magnetic field are modeled using a combination of electromagnetic theory and thermodynamics concepts. The heat diffusion is also modeled within a computational framework that explores the potential for future application in the localized treatment of breast cancer via hyperthermia.

The thesis is divided into five chapters. Following the introduction, the literature review is presented in chapter two. The theoretical and computational models are then described in chapter three before comparing the predictions to experimental work by Oyku Akkaya. Conclusions will be drawn in chapter four while future work presented in chapter five.


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