Bioelectronic Sensor Nodes for Internet of Bodies

Energy-efficient sensing with Physically-secure communication for bio-sensors on, around and within the Human Body is a major area of research today for development of low-cost healthcare, enabling continuous monitoring and/or secure, perpetual operation. These devices, when used as a network of nodes form the Internet of Bodies (IoB), which poses certain challenges including stringent resource constraints (power/area/computation/memory), simultaneous sensing and communication, and security vulnerabilities as evidenced by the DHS and FDA advisories. One other major challenge is to find an efficient on-body energy harvesting method to support the sensing, communication, and security sub-modules. Due to the limitations in the harvested amount of energy, we require reduction of energy consumed per unit information, making the use of in-sensor analytics/processing imperative. In this paper, we review the challenges and opportunities in low-power sensing, processing and communication, with possible powering modalities for future bio-sensor nodes. Specifically, we analyze, compare and contrast (a) different sensing mechanisms such as voltage/current domain vs time-domain, (b) low-power, secure communication modalities including wireless techniques and human-body communication, and (c) different powering techniques for both wearable devices and implants.Comment: 30 pages, 5 Figures. This is a pre-print version of the article which has been accepted for Publication in Volume 25 of the Annual Review of Biomedical Engineering (2023). Only Personal Use is Permitte

Fluorescence and Diffuse Reflectance Spectroscopy and Endoscopy for Tissue Analysis

Biophotonics techniques are showing great potential for practical tissue diagnosis, capable of localised optical spectroscopy as well as wide field imaging. Many of those are generally based on the same concept: the spectral information they enable to acquire encloses clues on the tissue biochemistry and biostructure and these clues carry diagnostic information. Biophotonics techniques present the added advantage to incorporate easily miniaturisable hardware allowing several modalities to be set up on the same systems and authorizing their use during minimally invasive surgery (MIS) procedures. The work presented in this thesis aims to build on these advantages to design biophotonics instruments for tissue diagnosis. Fluorescence and diffuse reflectance, the two modalities of interest in this work, were implemented in their single point spectroscopic and imaging declinations. Two “platforms”, a spectroscopic probe setup and an optical imaging laparoscope, were built; they included either one of the two aforementioned modalities or the two of them together. The spectroscopic probe system was assembled to detect lesions in the digestive tract. In its first version, the setup included a dual laser illumination system to carry out an ex vivo fluorescence study of non-alcoholic fatty liver diseases (NAFLD) in the mouse model. Outcomes of the study demonstrated that healthy livers could be distinguished from NAFLD livers with high classification accuracy. Then, the same fluorescence probe inserted in a force adaptive robotic endoscope was applied on a fluorescence phantom and a liver specimen to prove the feasibility of recording spectra at multiple points with controlled scanning pattern and probe/sample pressure (known to affect the spectra shape). This approach proposed therefore a convincing method to perform intraoperative fluorescence measurements. The fluorescence setup was subsequently modified into a combined fluorescence/diffuse reflectance spectroscopic probe and demonstrated as an efficient method to separate normal and diseased tissue samples from the human gastrointestinal tract. Following the single point spectroscopy work, imaging studies were conducted with a spectrally resolved laparoscope. The system, featuring a CCD/filter wheel unit clipped on a traditional laparoscope was validated on fluorescence phantoms and employed in two experiments. The first one, building on the spectroscopy study of the gastrointestinal tract, was originally aimed at locating tumour in the oesophagus but a lack of tissue availability prevented us from doing so. The system design and validation on fluorophores phantoms were nevertheless described. In the second one, the underarm of a pig was imaged after injection of a nerve contrast agent in order to test the feasibility of in vivo nerve delineation. Fluorescence was detected from the region of interest but no clear contrast between the nerve and the surrounding muscle tissue could be detected. Finally, the fluorescence imaging laparoscope was modified into a hyperspectral reflectance imaging laparoscope to perform tissue vasculature studies. It was first characterized and tested on haemoglobin phantoms with varying concentrations and oxygen saturations and then employed in vivo to follow the haemoglobin concentration and oxygen saturation temporal evolutions of a porcine intestine subsequently to the pig’s termination. A decrease in oxygen saturation was observed. The last experiment consisted in monitoring the tissue re-oxygenation of a rabbit uterus transplant on the recipient animal, a successful tissue re-perfusion after the graft was highlighted

Doctor of Philosophy

dissertationAtrial fibrillation (AF) is the leading cause of ischemic stroke and is the most commonly observed arrhythmia in clinical cardiology. Catheter ablation of AF, in which specific regions of cardiac anatomy associated with AF are intenionally injured to create scar tissue, has been honed over the last 15 years to become a relatively common and safe treatment option. However, the success of these anatomically driven ablation strategies, particularly in hearts that have been exposed to AF for extended periods, remains poor. AF induces changes in the electrical and structural properties of the cardiac tissue that further promotes the permanence of AF. In a process known as electroanatomical (EAM) mapping, clinicians record time signals known as electrograms (EGMs) from the heart and the locations of the recording sites to create geometric representations, or maps, of the electrophysiological properties of the heart. Analysis of the maps and the individual EGM morphologies can indicate regions of abnormal tissue, or substrates that facilitate arrhythmogenesis and AF perpetuation. Despite this progress, limitations in the control of devices currently used for EAM acquisition and reliance on suboptimal metrics of tissue viability appear to be hindering the potential of treatment guided by substrate mapping. In this research, we used computational models of cardiac excitation to evaluate param- eters of EAM that affect the performance of substrate mapping. These models, which have been validated with experimental and clinical studies, have yielded new insights into the limitations of current mapping systems, but more importantly, they guided us to develop new systems and metrics for robust substrate mapping. We report here on the progress in these simulation studies and on novel measurement approaches that have the potential to improve the robustness and precision of EAM in patients with arrhythmias. Appropriate detection of proarrhythmic substrates promises to improve ablation of AF beyond rudimentary destruction of anatomical targets to directed targeting of complicit tissues. Targeted treatment of AF sustaining tissues, based on the substrate mapping approaches described in this dissertation, has the potential to improve upon the efficacy of current AF treatment options

Human Body–Electrode Interfaces for Wide-Frequency Sensing and Communication: A Review

Several on-body sensing and communication applications use electrodes in contact with the human body. Body–electrode interfaces in these cases act as a transducer, converting ionic current in the body to electronic current in the sensing and communication circuits and vice versa. An ideal body–electrode interface should have the characteristics of an electrical short, i.e., the transfer of ionic currents and electronic currents across the interface should happen without any hindrance. However, practical body–electrode interfaces often have definite impedances and potentials that hinder the free flow of currents, affecting the application’s performance. Minimizing the impact of body–electrode interfaces on the application’s performance requires one to understand the physics of such interfaces, how it distorts the signals passing through it, and how the interface-induced signal degradations affect the applications. Our work deals with reviewing these elements in the context of biopotential sensing and human body communication

Novel Tools to Investigate Cortical Activity in Paroxysmal Disorders

This PhD project is at the interface between academic research and industry, and is jointly sponsored by the BBSRC and the industrial partner– Scientifica UK. The goal of this research is the development of new instruments and approaches to monitor and manipulate neuronal network activity in disease states. Firstly, (I) I collaborated with Scientifica to develop and utilise the newly developed Laser Applied Stimulation and Uncaging (LASU) system. The combined usage of the LASU system, alongside novel spatially-targeted channelrhodopsin variants, has al- lowed me to test the limits of single-photon optogenetic stimulation in achieving specific activation of targeted neurons. The presented findings demonstrate that, al- though high-resolution stimulation is achievable in the rodent cortex, single-photon stimulation is insufficient to achieve single-cell resolution stimulation. Secondly, (II) I have combined the high temporal resolution of novel, transparent 16-channel epicortical graphene solution-gated field effect transistor (gSGFET) arrays with the large spatial coverage of bilateral widefield Ca2+ fluorescence imaging; to per- form investigations of the relationship between spreading depolarisation (SD) and cortical seizures in awake head-fixed mouse models of epilepsy. To analyse these complex datasets, I developed a bespoke, semi-automated analysis pipeline to pro- cess the data and probe the seizure-SD relationship. I present the advantages of this dual-modality approach by demonstrating the strengths and weaknesses of each recording method, and how a synergistic approach overcomes the limitations of each technique alone. I utilise widefield imaging to perform systematic classification of SD and seizures both temporally and spatially. Detailed electrophysiological anal- ysis of gSGFET data is then performed on extracted time periods of interest. This work demonstrates the complex interaction between seizures and SD, and proposes several mechanisms describing these interactions. The technological and analytical tools presented here lay the groundwork for insightful and flexible experimental paradigms; altogether, able to probe paroxysmal activity in profound detail

Atrial Arrhythmogenic Substrates: The Role of Structure and Molecular Remodeling

Atrial tachyarrhythmias, specifically atrial flutter: AFl) and fibrillation: AF), affect over 2.2 million Americans, leading to more hospitalizations than any other cardiac arrhythmia. These arrhythmias are defined by the presence of reentrant circuits of excitation leading to high atrial rates and uncoordinated activation of the ventricles. The underlying mechanisms of AFl/AF have proven complex and, despite a century of research, no one effective treatment has been developed. Surgical ablation and pharmacological therapies are both fraught with risks and potential pro-arrhythmic side effects. Electrical cardioversion, on the other hand, is extremely effective in terminating these arrhythmias, but the high-energy shocks required for termination cause substantial pain to the patient. In this dissertation, we first investigate the underlying molecular and structural mechanisms of AF in two clinically-relevant models - the human and canine hearts. We identify structural and molecular substrates responsible for the generation and maintenance of AFl/AF. We then explore the application of a novel low-voltage defibrillation therapy to a rabbit model of atrial tachyarrhythmias and show significant reductions in the defibrillation threshold for both AF and AFl. We utilize a variety of experimental techniques, such as high throughput quantitative PCR, optical coherence tomography, and optical mapping. Only truly integrative approaches to arrhythmia research, combining a variety of experimental models and techniques, can continue to unravel the complexities of underlying molecular, structural, and electrophysiological mechanisms and develop effective, safe therapies, as we demonstrate in this dissertation with regards to atrial tachyarrhythmias

Design and development of optical reflectance spectroscopy and optical coherence tomography catheters for myocardial tissue characterization

Catheter ablation therapy attempts to restore sinus rhythm in arrhythmia patients by producing site-specific tissue modification along regions which cause abnormal electrical activity. This treatment, though widely used, often requires repeat procedures to observe long-term therapeutic benefits. This limitation is driven in part by challenges faced by conventional schemes in validating lesion adequacy at the time of the procedure. Optical techniques are well-suited for the interrogation and characterization of biological tissues. In particular, optical coherence tomography (OCT) relies on coherence gating of singly-scattered light to enable high-resolution structural imaging for tissue diagnostics and procedural guidance. Alternatively, optical reflectance spectroscopy (ORS) is a point measurement technique which makes use of incoherent, multiply-scattered light to probe tissue volumes and derive important data from its optical signature. ORS relies on the fact that light-tissue interactions are regulated by absorption and scattering, which directly relate to the intrinsic tissue biochemistry and cellular organization. In this thesis, we explore the integration of these modalities into ablation catheters for obtaining procedural metrics which could be utilized to guide catheter ablation therapy. We first present the development of an accelerated computational light transport model and its application for guiding ORS catheter design. A custom ORS-integrated ablation catheter is then implemented and tested within porcine specimens in vitro. A model is proposed for real-time estimation of lesion size based on changes in spectral morphology acquired during ablation. We then fabricated custom integrated OCT M-mode RF catheters and present a model for detecting contact status based on deep convolutional neural networks trained on endomyocardial images. Additionally, we demonstrate for the first time, tracking of RF-induced lesion formation employing OCT Doppler micro-velocimetry; this response is shown to be commensurate with the degree of treatment. We further demonstrate for the first time spectroscopic tracking of kinetics related to the heme oxidation cascade during thermal treatment, which are linked to tissue denaturation. The pairing of these modalities into a single RF catheter was also validated for guiding lesion delivery in vitro and within live pigs. Finally, we conclude with a proof-of-concept demonstration of ORS as a mapping tool to guide epicardial ablation in human donor hearts. These results showcase the vast potential of ORS and OCT empowered RF catheters for aiding intraprocedural guidance of catheter ablation procedures which could be utilized alongside current practices