Application of Signal Advance Technology to Electrophysiology

Medical instrumentation used in diagnosis and treatment relies on the accurate detection and processing of various physiological events and signals. While signal detection technology has improved greatly in recent years, there remain inherent delays in signal detection/ processing. These delays may have significant negative clinical consequences during various pathophysiological events. Reducing or eliminating such delays would increase the ability to provide successful early intervention in certain disorders thereby increasing the efficacy of treatment. In recent years, a physical phenomenon referred to as Negative Group Delay (NGD), demonstrated in simple electronic circuits, has been shown to temporally advance the detection of analog waveforms. Specifically, the output is temporally advanced relative to the input, as the time delay through the circuit is negative. The circuit output precedes the complete detection of the input signal. This process is referred to as signal advance (SA) detection. An SA circuit model incorporating NGD was designed, developed and tested. It imparts a constant temporal signal advance over a pre-specified spectral range in which the output is almost identical to the input signal (i.e., it has minimal distortion). Certain human patho-electrophysiological events are good candidates for the application of temporally-advanced waveform detection. SA technology has potential in early arrhythmia and epileptic seizure detection and intervention. Demonstrating reliable and consistent temporally advanced detection of electrophysiological waveforms may enable intervention with a pathological event (much) earlier than previously possible. SA detection could also be used to improve the performance of neural computer interfaces, neurotherapy applications, radiation therapy and imaging. In this study, the performance of a single-stage SA circuit model on a variety of constructed input signals, and human ECGs is investigated. The data obtained is used to quantify and characterize the temporal advances and circuit gain, as well as distortions in the output waveforms relative to their inputs. This project combines elements of physics, engineering, signal processing, statistics and electrophysiology. Its success has important consequences for the development of novel interventional methodologies in cardiology and neurophysiology as well as significant potential in a broader range of both biomedical and non-biomedical areas of application

LOW POWER AND HIGH SIGNAL TO NOISE RATIO BIO-MEDICAL AFE DESIGN TECHNIQUES

The research work described in this thesis was focused on finding novel techniques to implement a low-power and noise Bio-Medical Analog Front End (BMEF) circuit technique to enable high-quality Electrocardiography (ECG) sensing. Usually, an ECG signal and several bio-medical signals are sensed from the human body through a pair of electrodes. The electrical characteristics of the very small amplitude (1u-10mV) signals are corrupted by random noise and have a significant dc offset. 50/60Hz power supply coupling noise is one of the biggest cross-talk signals compared to the thermally generated random noise. These signals are even AFE composed of an Instrumentation Amplifier (IA), which will have a better Common Mode rejection ratio (CMRR). The main function of the AFE is to convert the weak electrical Signal into large signals whose amplitude is large enough for an Analog Digital Converter (ADC) to detect without having any errors. A Variable Gain Amplifier (VGA) is sometimes required to adjust signal amplitude to maintain the dynamic range of the ADC. Also, the Bio-medical transceiver needs an accurate and temperature-independent reference voltage and current for the ADC, commonly known as Bandgap Reference Circuit (BGR). These circuits need to consume as low power as possible to enable these circuits to be powered from the battery. The work started with analysing the existing circuit techniques for the circuits mentioned above and finding the key important improvements required to reach the target specifications. Previously proposed IA is generated based on voltage mode signal processing. To improve the CMRR (119dB), we proposed a current mode-based IA with an embedded DC cancellation technique. State-of-the-art VGA circuits were built based on the degeneration principle of the differential pair, which will enable the variable gain purpose, but none of these techniques discussed linearity improvement, which is very important in modern CMOS technologies. This work enhances the total Harmonic distortion (THD) by 21dB in the worst case by exploiting the feedback techniques around the differential pair. Also, this work proposes a low power curvature compensated bandgap with 2ppm/0C temperature sensitivity while consuming 12.5uW power from a 1.2V dc power supply. All circuits were built in 45nm TSMC-CMOS technology and simulated with all the performance metrics with Cadence (spectre) simulator. The circuit layout was carried out to study post-layout parasitic effect sensitivity

Neue Methodik zur Optimierung der Energieeffizienz des Künstlichen Akkommodationssystems

Das Künstliche Akkommodationssystem ist ein neuer Ansatz zur Wiederherstellung der Akkommodationsfähigkeit des menschlichen Auges. Das hochintegrierte, gekapselte Mikrosystem soll autonom die Funktion der natürlichen Linse übernehmen. Das Ziel der Arbeit besteht darin, eine neue Methodik zur Optimierung der Energieeffizienz des Künstlichen Akkommodationssystems zu entwickeln. Dazu werden Konzepte zur Optimierung der Spannungswandlung sowie Konzepte zur Reduktion der Leistungsaufnahme und zur Verlängerung der autonomen Betriebsdauer des Implantats vorgestellt

[¹⁸F]fluorination of biorelevant arylboronic acid pinacol ester scaffolds synthesized by convergence techniques

Aim: The development of small molecules through convergent multicomponent reactions (MCR) has been boosted during the last decade due to the ability to synthesize, virtually without any side-products, numerous small drug-like molecules with several degrees of structural diversity.(1) The association of positron emission tomography (PET) labeling techniques in line with the “one-pot” development of biologically active compounds has the potential to become relevant not only for the evaluation and characterization of those MCR products through molecular imaging, but also to increase the library of radiotracers available. Therefore, since the [18F]fluorination of arylboronic acid pinacol ester derivatives tolerates electron-poor and electro-rich arenes and various functional groups,(2) the main goal of this research work was to achieve the 18F-radiolabeling of several different molecules synthesized through MCR. Materials and Methods: [18F]Fluorination of boronic acid pinacol esters was first extensively optimized using a benzaldehyde derivative in relation to the ideal amount of Cu(II) catalyst and precursor to be used, as well as the reaction solvent. Radiochemical conversion (RCC) yields were assessed by TLC-SG. The optimized radiolabeling conditions were subsequently applied to several structurally different MCR scaffolds comprising biologically relevant pharmacophores (e.g. β-lactam, morpholine, tetrazole, oxazole) that were synthesized to specifically contain a boronic acid pinacol ester group. Results: Radiolabeling with fluorine-18 was achieved with volumes (800 μl) and activities (≤ 2 GBq) compatible with most radiochemistry techniques and modules. In summary, an increase in the quantities of precursor or Cu(II) catalyst lead to higher conversion yields. An optimal amount of precursor (0.06 mmol) and Cu(OTf)2(py)4 (0.04 mmol) was defined for further reactions, with DMA being a preferential solvent over DMF. RCC yields from 15% to 76%, depending on the scaffold, were reproducibly achieved. Interestingly, it was noticed that the structure of the scaffolds, beyond the arylboronic acid, exerts some influence in the final RCC, with electron-withdrawing groups in the para position apparently enhancing the radiolabeling yield. Conclusion: The developed method with high RCC and reproducibility has the potential to be applied in line with MCR and also has a possibility to be incorporated in a later stage of this convergent “one-pot” synthesis strategy. Further studies are currently ongoing to apply this radiolabeling concept to fluorine-containing approved drugs whose boronic acid pinacol ester precursors can be synthesized through MCR (e.g. atorvastatin)