Detection of breast cancer with electrical impedance mammography

Electrical Impedance Tomography (EIT) is a medical imaging technique that reconstructs internal electrical conductivity distribution of a body from impedance data that is measured on the body surface, and Electrical Impedance Mammography (EIM) is the technique that applies EIT in breast cancer detection. The use of EIM for breast cancer identification is highly desirable because it is a non-invasive and low-cost imaging technology. EIM has the potential in detecting early stage cancer, however there are still challenges that hindering EIM to be provided as a routine health care system. There are three major groups of obstacles. One is the hardware design, which includes the selection of electronic components, electrode-skin contacting methods, etc. Second is theoretical problems such as electrode configurations, image reconstruction and regularization methods. Third is the development of analysis methods and generation of a cancerous tissue database. Research reported in this thesis strives to understand these problems and aims to provide possible solutions to build a clinical EIM system. The studies are carried out in four parts. First the functionalities of the Sussex Mk4 EIM system have been studied. Sensitivity of the system was investigated to find out the strength and weakness of the system. Then work has been made on image reconstruction and regularization methods in order to enhance the system’s endurance to noise, also to balance the reconstruction conductivity distribution throughout the reconstructed object. Then a novel cancer diagnosis technique was proposed. It was developed based on the electrical property of human breast tissue and the behaviour or systematic noise, to provide repeatable results for each patient. Finally evaluation has been made on previous EIM systems to find out the major problems. Based on sensitivity analysis, an optimal combined electrode configuration has been proposed to improve sensitivity. The system has been developed and produced meaningful clinical images. The work makes significant contributions to society. This novel cancer diagnosis method has high accuracy for cancer identification. The combined electrode configuration has also provided flexibilities in the designing of current driving and voltage receiving patterns, thus sensitivity of the EIM system can be greatly improved

Electrical Impedance Tomography: From the Traditional Design to the Novel Frontier of Wearables

Electrical impedance tomography (EIT) is a medical imaging technique based on the injection of a current or voltage pattern through electrodes on the skin of the patient, and on the reconstruction of the internal conductivity distribution from the voltages collected by the electrodes. Compared to other imaging techniques, EIT shows significant advantages: it does not use ionizing radiation, is non-invasive and is characterized by high temporal resolution. Moreover, its low cost and high portability make it suitable for real-time, bedside monitoring. However, EIT is also characterized by some technical limitations that cause poor spatial resolution. The possibility to design wearable devices based on EIT has recently given a boost to this technology. In this paper we reviewed EIT physical principles, hardware design and major clinical applications, from the classical to a wearable setup. A wireless and wearable EIT system seems a promising frontier of this technology, as it can both facilitate making clinical measurements and open novel scenarios to EIT systems, such as home monitoring

Graphene Quantum Dot-Based Electrochemical Immunosensors for Biomedical Applications

In the area of biomedicine, research for designing electrochemical sensors has evolved over the past decade, since it is crucial to selectively quantify biomarkers or pathogens in clinical samples for the efficacious diagnosis and/or treatment of various diseases. To fulfil the demand of rapid, specific, economic, and easy detection of such biomolecules in ultralow amounts, numerous nanomaterials have been explored to effectively enhance the sensitivity, selectivity, and reproducibility of immunosensors. Graphene quantum dots (GQDs) have garnered tremendous attention in immunosensor development, owing to their special attributes such as large surface area, excellent biocompatibility, quantum confinement, edge effects, and abundant sites for chemical modification. Besides these distinct features, GQDs acquire peroxidase (POD)-mimicking electro-catalytic activity, and hence, they can replace horseradish peroxidase (HRP)-based systems to conduct facile, quick, and inexpensive label-free immunoassays. The chief motive of this review article is to summarize and focus on the recent advances in GQD-based electrochemical immunosensors for the early and rapid detection of cancer, cardiovascular disorders, and pathogenic diseases. Moreover, the underlying principles of electrochemical immunosensing techniques are also highlighted. These GQD immunosensors are ubiquitous in biomedical diagnosis and conducive for miniaturization, encouraging low-cost disease diagnostics in developing nations using point-of-care testing (POCT) and similar allusive techniques.TU Berlin, Open-Access-Mittel - 201

Discrete mathematical models for electrical impedance tomography

Electrical Impedance Tomography (EIT) is a non-invasive, portable and low-cost medical imaging technique. Different current patterns are injected to the surface of a conductive body and the corresponding voltages are measured also on the boundary. These mea-surements are the data used to infer the interior conductivity distribution of the object. However, it is well known that the reconstruction process is extremely ill-posed due to the low sensitivity of the boundary voltages to changes in the interior conductivity distribution. The reconstructed images also suffer from poor spatial resolution. In tomographic systems, the spatial resolution is related to the number of applied current patterns and to the number and positions of electrodes which are placed at the surface of the object under examination. Two mammographic sensors were recently developed at the University of Mainz in collaboration with Oxford Brookes University. These prototypes consist of a planar sensing head of circular geometry with twelve large outer (active) electrodes arranged on a ring of radius 4.4cm where the external currents are injected and a set of, respectively thirty six and fifty four point-like high-impedance inner (passive) electrodes arranged in a hexagonal pattern where the induced voltages are measured. Two 2D reconstruction methods were proposed for these devices, one based on resistor network models and another one which uses an integral equation formulation. The novelty of the device and hence of these imaging techniques consists exactly in the distinct use of active and passive electrodes. The 2D images of the conductivity distribution of the interior tissue of the breast provide only information about the existence and location of the tumour. In this thesis different circular designs for the sensing head of this EIT device were analysed. The 2D resistor network approach was adapted to the different data collection geometries and the sensitivity of the reconstructions with respect to errors in the simulate data were investigated before any modifications to the original design were made. A novel 3D reconstruction algorithm was also developed for a simpler geometry of the sensing head which consisted of a rectangular array of thirty six electrodes (twenty active+ sixteen passive). This electrode configuration as well as the proposed imaging technique are intended to be used for breast cancer detection. The algorithm is based on linearizing the conductivity about a constant value and allows real-time reconstructions. The perfor-mance of the algorithm was tested on numerically simulated data and small inclusions with conductivities three or four times the background lying beneath the data collection surface were successfully detected. The results were fairly stable with respect to the noise level in the data and displayed very good spatial resolution in the plane of electrodes

A MEMS BASED MICROWAVE PIXEL FOR UWB RADAR BASED 3-D DIAGNOSTIC IMAGING

A MEMS-based microwave Pixel has been developed for use with an Ultra-wideband (UWB) radar probe for high-resolution 3-D non-contact, non-ionizing tomographic diagnostic imaging of the thorax. In the proposed system, an UWB radar transmits a 400 ps duration pulse in the frequency range of 3.1 GHz to 5.1 GHz. The transmitted pulse penetrates through the tissues and is partially reflected at each tissue interface characterized by a complex permittivity change. A suitable microwave lens focuses the reflected wavefront on a 2-D array of MEMS-based microwave Pixels to illuminate each Pixel to a tiny 2-D section of the reflected wavefront. Each Pixel with a footprint area of 595 x 595 μm2 is designed to have 144 parallel connected microfabricated inductors, each with an inductance of 12.439 nH, and a single 150 μm×150 μm microfabricated deformable diaphragm based variable capacitor to generate a voltage which is the dielectric signature of the respective tissue section. A 2-D array of such Pixels can be used to generate a voltage map that corresponds to the dielectric property distribution of the target area. The high dielectric contrast between the healthy and diseased tissues, enable a high precision diagnostics of medical conditions in a non-invasive non-contact manner. This thesis presents the analytical design, 3-D finite element simulation results, and a fabrication process to realize the proposed microwave imaging Pixel. The proposed Pixel with total inductance of 86.329 pH and capacitance tuning range of 1.68:1, achieved a sensitivity of 4.5 aF/0.8 μA.m-1 to generate tomographic coronal imaging slices of human thorax deep upto 4.2 cm enabling a theoritical lateral resolution of 0.59 mm

Nerve localization techniques for peripheral nerve block and possible future directions

Ultrasound guidance is now a standard nerve localization technique for peripheral nerve block (PNB). Ultrasonography allows simultaneous visualization of the target nerve, needle, local anesthetic injectate and surrounding anatomical structures. Accurate deposition of local anesthetic next to the nerve is essential to the success of the nerve block procedure. Unfortunately, due to limitations in the visibility of both needle tip and nerve surface, the precise relationship between needle tip and target nerve is unknown at the moment of injection. Importantly, nerve injury may result both from an inappropriately placed needle tip and inappropriately placed local anesthetic. The relationship between the block needle tip and target nerve is of paramount importance to the safe conduct of peripheral nerve block. This review summarizes the evolution of nerve localization in regional anesthesia, characterizes a problem faced by clinicians in performing ultrasound guided nerve block and explores the potential technological solutions to this problem

Proactive Management of Acute Oedema Following Hand and Minor Burn Injury

Burn injury is a unique trauma. The inflammatory process initiated with burn injury adversely influences all of the Starling equation variables, resulting in increased transvascular fluid filtration, so that oedema as a product of burn injury is more readily formed than in other forms of trauma. Localised wound oedema forms due to minor burn injury, with increasing systemic oedema associated with increased size of burn. It is now recognised that a marked inflammatory and immune response is created with non-severe burn injury, indicating a systemic component with all burns. The effect of oedema formation on the course of the burn healing is well described in the literature, due to its impact on the zone of stasis in the wound and its potential to result in progressive tissue loss or conversion if poorly managed. Burn conversion leads to an increase in the area and depth of the burn wound, necessitating surgical intervention, which increases the risk of scarring. Burn scarring may lead to altered function and poor aesthetic outcomes, which have the potential to adversely affect patient psychological well-being. Despite the influence of oedema on the healing of the burn wound and therefore the scar worn for life, there is little evidence to guide clinicians who aim to proactively manage this oedema, with only two published, controlled trials investigating methods to improve peripheral oedema in burn injury. The aim of the series of studies described in this thesis is to provide a holistic approach to the management of oedema following acute burn injury. To be able to effectively treat oedema, the clinician needs to be able to accurately assess the affected limb and wound for oedema. Oedema management in burn injury is often based on the clinicians’ preference of intervention, without good understanding of the optimal parameters of application or efficacy. Therefore, evidence is required for optimising the management of oedema in the acute burn injured patient. Furthermore, the hand’s unique anatomical structure that produces functional dexterity adds complexity to the assessment and management of oedema formation in the hand. Burn injury to the hand is common, as hands provide interaction with the world, and are generally vulnerable during activities of daily living. In the event of major accidents, the hands are reflexively used to protect the face and body, further predisposing them to significant injury. The ability to accurately measure oedema guides clinicians in their treatment of acute burn wound oedema. Current objective measures of oedema often lack sensitivity, increase pain, introduce a risk of infection from equipment contact with open wounds, or are cumbersome for repeated use in the clinical environment. They are also influenced by the cooperation of the patient, and burn injury often results in significant pain, impaired movement, and may require the use of medications that modify behaviour. As a result, oedema is usually assessed visually or through palpation of the tissue, noting the loss of skin creases or pitting of soft tissue. These assessments are subjective based on the clinician’s experience and do not provide objective measures that can be repeated between testers or between sessions. Demonstrating the effectiveness of proactive oedema management following acute burn injury is therefore dependent on the ability to accurately assess the oedema using a valid, reliable and sensitive objective measure. There is a lack of high-quality prospective studies investigating oedema management techniques in burn injury populations. In a 2011 systematic review, there was only one published randomised control trial, which investigated the use of electrical stimulation in addition to standard interventions for managing hand burn oedema, while a second conference presentation was reported as part of the review. There have been no further published studies in this space, providing clinicians with little guidance as to the optimal parameters to manage oedema in this challenging injury cohort. Measuring oedema in this patient group is similarly challenging. The study series in this thesis addresses the challenge of measuring hand burn oedema and wound healing. Bioimpedance spectroscopy (BIS) is a technology that has demonstrated reliability and validity for measuring whole body and limb oedema in burns patients during fluid resuscitation, and is sufficiently sensitive to measure oedema change with wound healing. Another BIS variable, Phase Angle, is validated to be a measure of cell health, as it measures the flow of current across the cell with respect to the voltage. Increased lag in the current is the result of increased cell mass and cell wall integrity (a healthier cell), resulting in an increased Phase Angle. This has been demonstrated to increase with healing in chronic wound populations, but has not been validated in acute burn injury. The first study in this thesis is a method validation study, investigating the measurement of hand volumes using a novel application of BIS. A technique to measure hand volumes using BIS has been described previously, however the burn injured hand is compromised by wounds. The guidelines for the use of BIS require that electrodes are placed on intact skin. The study compared different electrode configurations on the hand and arm to the previously described configuration in a non-injured population, to determine if different electrode configurations are valid for measuring hand volumes. The key findings of this study were that, when compared to previously described electrode positions on the dorsum of the hand and forearm, alternative electrode combinations on the volar surface of the hand and forearm, and an electrode array on the palm of the hand and the dorsum of the forearm, were both valid for measuring hand oedema volumes in an uninjured population. These outcomes provide novel evidence to guide electrode placements to measure hand volume using BIS where wounds precluded the use of standard electrode arrays. The second study in this series is a validation study, informed by and used the electrode positions assessed in the first study, to determine the validity and reliability of BIS for measuring hand (oedema) volumes in a burn injured population. Repeated hand volume measures were obtained in 100 patients presenting with hand burn injury with BIS, and with water displacement volumetry as a gold standard comparison. The results of this study demonstrated that the electrode positions assessed as valid for measuring hand volumes in an uninjured population in the first study, were valid, reliable and sensitive for measuring oedema in the hand following burn injury, showing high correlation with the gold standard comparator. This technique was used to assess the primary outcome – oedema volume change – in the third study of this series. The following studies in this thesis are intervention research, investigating techniques designed to proactively manage oedema in acute burn injury. The third study described in this thesis is the first randomised controlled trial to investigate different methods of applying compression to the hand to manage acute burn oedema. Compression is a commonly used technique to control oedema, reported to be applied based on clinician preference, which is dependent on the way each clinician was taught. In this study, 100 patients (the largest of its kind to the best of my knowledge), presenting with burn injury involving a portion of the hand were randomised to receive one of three commonly used methods of applying compression, to provide evidence as to which is the most effective at controlling acute burn wound oedema in the hand. In this study, the two most common methods of fabricating a custom compression glove using cohesive bandage were shown to be both equally effective at reducing post burn oedema in the hand, and both were more effective for reducing hand burn oedema than the control condition being an off the shelf compression glove. The patients in this study were also provided education regarding exercise to maintain function and promote oedema reduction, oedema management advice including elevation of the hand above the level of the heart at rest, and ensuring normal use of the hand while respecting the wound environment to minimise the risk of infection. These interventions resulted in significantly greater hand range of movement between test sessions, and a significant improvement in the QuickDASH (Disability of Arm, Shoulder and Hand) patient reported outcome measure. The effect of a low energy, long duration electrical stimulation on the acute burn wound was investigated in study four. Electrical stimulation has been demonstrated to improve the rate of healing of chronic wounds, and aid the reduction of oedema in a number of populations, including patients with hand burn injury when used in addition to standard physiotherapy. The novel application of electrical stimulation in this study utilised a small patient applied stimulation device for more than 20 hours per day for a period of up to 14 days, with the current applied across the wound with electrodes placed either side of the injured tissue on intact skin. This was designed as a within-patient control, randomised trial. Patients with similar size and similar depth burns to multiple limbs participated in this study. Electrical stimulation was applied to one wound, with the contralateral wound serving as the control wound. The outcomes investigated were change in oedema, as measured by the BIS variable R0, measuring the impedance of the extra-cellular fluid; and wound healing, measured by the BIS variable Phase Angle, and compared to clinical photography of the wounds, which were assessed by a consultant burns surgeon to determine wound re-epithelialisation, or healing. Phase Angle and wound impedance were demonstrated to be associated with wound healing. Electrical stimulation applied to a minor burn was shown to increase the rate of oedema reduction in the wound compared to the control wound, and increased Phase Angle at a faster rate than in the control wound, indicating an increase in cell and tissue health. This thesis presents a study series whereby the first two studies validated a new method of measuring hand burn oedema quickly, with minimal imposition on the patient. This method was demonstrated as viable and applicable in acute burn patients, in both research and clinical practice contexts, and informed the ensuing studies in this series. The final two studies presented in this thesis are randomised controlled trials investigating the proactive management of oedema in acute burn injury, and contribute significant new knowledge to the literature, providing guidance to the burn clinician who manages acute oedema to prevent conversion of the burn wound and deterioration in function. When presented with a hand burn injury, the clinician will be able to appropriately manage the ensuing oedema with a custom compression glove fabricated using a cohesive bandage with either of the most common methods therapists are taught. In addition, in minor burn wounds, the use of a small, easy to use, low energy long duration electrical stimulation device as an adjunct to standard burn wound care, will increase oedema reduction and improve the rate of wound healing compared to standard wound care alone

Impedance Sensing of Cancer Cells Directly on Sensory Bioscaffolds of Bioceramics Nanofibers

Cancer cell research has been growing for decades. In the field of cancer pathology, there is an increasing and long-unmet need to develop a new technology for low-cost, rapid, sensitive, selective, label-free (i.e. direct), simple and reliable screening, diagnosis, and monitoring of live cancer and normal cells in same shape and size from the same anatomic region. For the first time on using an impedance signal, the breast cancer and normal cells have been thus screened, diagnosed and monitored on a smart bioscaffold of entangled nanowires of bioceramics titanate grown directly on the surface of implantable Ti-metal and characterized by SEM, XRD, etc. following a technology patented by Tian-lab. In experiment in the aqueous solution of phosphate buffer saline (PBS), human breast benign (MCF7) and aggressive (MDA-MB231) cancer cells, normal (MCF10A) cells, and colon cancer cells (HCT116) showed characteristic impedance spectrum highly different than that of the blank sensor (i.e. no cells on the bioscaffold surface). For two sets of mixtures each containing the normal and cancer cells over a wide range of mixing ratios, the shift of impedance signals has been linearly correlated with the mixing ratios which supports the biosensor’s selectivity and reliability. After being treated with pure glucose and chemotherapeutic drug (i.e. doxorubicin of DOX) and with one after the other, the breast cancer cells showed different impedance signals corresponding to their difference in glucose metabolisms (i.e. Warburg Effect) and resistances to the Dox, thus-fingerprinting the cells easily. Based on the nanostructure chemistry, impedance equivalent circuitry and cancer cell biology, it’s the different cells surface binding on the nanowires, and different cancer cells metabolic wastes from the different treatments on the nanowires that changed the charge density on the scaffolding nanowire surface and in turn changed the impedance signals. This new method is believed expandable to quantifying and characterizing live cells and even biological tissues of different types in general

Investigation of 3D electrical impedance mammography systems for breast cancer detection

Breast cancer is a major disease in women worldwide with a high rate of mortality, second only to lung cancer. Hence, there is considerable interest in developing non-invasive breast cancer detection methods with the aim of identifying breast cancer at an early stage, when it is most treatable. Electrical impedance mammography (EIM) is a relatively new medical imaging method for breast cancer detection. It is a safe, painless, non-invasive, non-ionizing imaging modality, which visualizes the internal conductivity distribution of the breast under investigation. Currently some EIM systems are in clinical trials but not commercialized, as there are still many challenges with sensitivity, spatial resolution and detectability. The research in this thesis aims to enhance and optimize EIM systems in order to address the current challenges. An enhanced image reconstruction algorithm using the duo-mesh method is developed. Both in simulations and real cases of phantoms and patients, the enhanced algorithm has proven more accurate and sensitive than the former algorithm and effective in improving vertical resolution for the EIM system with a planar electrode array. To evaluate the performance of the EIM system and the image reconstruction algorithms, an image processing based error analysis method is developed, which can provide an intuitive and accurate method to evaluate the reconstructed image and outline the shape of the object of interest. Two novel EIM systems are studied, which aim to improve the spatial resolution and the detectability of a tumour deep in the breast volume. These are: rotary planar-electrode-array EIM (RPEIM) system and combined electrode array EIM (CEIM) system. The RPEIM system permits the planar electrode array to rotate in the horizontal plane, which can dramatically increase the number of independent measurements, hence improving the spatial resolution. To support the rotation of the planner electrode array, a synchronous mesh method is developed. The CEIM system has a planar electrode array and a ring electrode array operated independently or together. It has three operational modes. This design provides enhanced detectability of a tumour deep within the tissue, as required for a large volume breast. The studies of the RPEIM system and the CEIM system are based on close-to-realistic digital breast phantoms, which comprise of skin, nipple, ducts, acini, fat and tumour. This approach makes simulations very close to a clinical trial of the technology

The Investigation and Implementation of electrical Impedance Tomography Hardware System

Electrical impedance tomography (EIT) is a medical imaging technology that provides a tomographic representation of the distribution of electrical impedance within the body. As the electrical impedance varies for different body tissues, it is possible to characterize tissues from the images and to detect physiological events. EIT systems have been developed from applying a single signal frequency to a range of frequencies. Imaging at multiple frequencies significantly improves the ability to characterize and differentiate heterogeneity within the region of interest. Applications of EIT are limited by its poor resolution as a consequence of limited number of electrodes and lack of independently published measurements. In a practical EIT system design the parallel structure is normally adopted as it provides a real time monitoring structure. However, there is a difficulty in expanding to a 2-dimensitional or 3-dimensitional high resolution imaging system, as the number of electrodes increase. In this thesis, a serial structure spectrum EIT system has been investigated and developed. Modelling of the electrical circuit has shown that the system bandwidth is degraded primarily by the signal transmission in the coaxial cable and multiplexer. To remove the capacitive effect of these components, a distribute system concept has been developed. The concept uses active electrodes in which a current source and a front end amplifier are embedded in the electrode which makes direct contact with the tissue being measured. The active electrode is based on the Howland current source. The required high output impedance of Howland current source can be realised by matching the two resistor arms. However, from the electrical equivalent circuit analysis the actual output impedance of this circuit was found to be degraded by the op-amp' s limited open loop gain, especially at higher frequencies. To solve the problem, the author describes in detail a novel method of compensating for the above effects. Subsequent circuit tests showed significant improvement after the compensation. Further, to improve the small signal noise ratio a programmable gain amplifier to adapt the frame data measurement was developed. These developments have led to the feasibility of active electrodes. The thesis describes in detail the development, of the MK2 EIT system which is presented as the output of this research