Electric field mediated gene delivery modalities have preferable safety profiles with the ability to rapidly transfect cells in vitro and in vivo with high efficiency. However, the current state of the art has relied on trial and error studies that target the average cell within a population present in treated tissue to derive electric pulse parameters. This results in fixed gene electrotransfer (GET) parameters that are not universally optimum. Slow progress towards the validation of a mechanism that explains this phenomena has also hindered its advancement in the clinic. To date, GET methods utilizing feedback control as a means to optimize doses of electric field stimulation have not been investigated. However, with modern electric components the electric characteristics of tissue exposed to electric pulses can be measured in very short time scales allowing for a near instantaneous assessment of the effect these pulses have on cells and tissue. This information is ideal for use in optimizing GET parameters to ensure the conditions necessary for gene delivery can be created regardless of anisotropic tissue architecture and electrode geometry. Bioimpedance theory draws parallels between cell structures and circuit components in an attempt to use circuit theory to describe changes occurring at a cellular and tissue level. In short, a reduction in tissue impedance indicates a reduction to the opposition of current flow in a volume conductor indicating new pathways for current. It has been purported these new pathways exist in the cell membrane and indicate a degree of membrane permeability/destabilization that either indicates or facilitates the uptake of exogenous molecules, such as nucleic acids or plasmid DNA. This study evaluated the use of relative impedance changes from 10 Hz – 10 kHz that occur in tissue before and after GET to indicate relative increase in tissue and membrane permeability. An optimum reduction in impedance was then identified as an indicator of the degree of membrane permeability required to significantly enhance exogenous DNA uptake into cells. This study showed the use of impedance-based feedback control to optimize GET pulse number in real time to target 80% or 95% reduction in tissue impedance resulted in an 12 and 14 fold increase in transgene expression over controls and a 6 and 7 fold increase in transgene expression over fixed pulse open loop protocols.

Stroke is amongst the leading causes of death and disability worldwide. Today diagnosis of Stroke is restricted to fixed imaging facilities which do not provide a rapid diagnostic. A portable device which could provide a non invasive assessment of stroke would therefore decrease the time of diagnosis and increase the chance of survival. Recent studies have confirmed that Implementing Electrical Bioimpedance in a portable device could provide a reliable means for Stroke diagnostic. However in order to be able to use the brain impedance as an indicator of Stroke, the invariance of brain impedance with time in healthy individuals should be studied first. Experimental Bioimpedance Spectroscopy (BIS) measurements from a healthy control group of 10 subjects have been used in this study to inspect the variation of brain impedance in the span of two weeks. The results of this study suggest that the cap which was used for brain impedance measurements together with  the available device have not been an optimal way of measuring the brain impedance and therefore have affected the data by causing artifacts for the results. With the artifacts available in the data acquired in this study it is not possible to make any statements about the variation of brain impedance and therefore a deeper analysis of collected data using descriptive analysis is required in order to be able to judge on the significance of the obtained errors. In the future a larger study group should be considered in order to increase the predictive power of the observations. / Stroke är bland de ledande orsakerna till död och funktionshinder i  hela världen.I dagsläget är diagnos av stroke begränsad till fasta bildenheter som inte möjliggör en snabb diagnos. En bärbar enhet som möjliggör en icke invasiv bedömning av sjukdomen skulle minska diagnos tiden och följaktligen öka chansen att överleva sjukdomen. Genomförda studier i ämnet har bekräftat att implementering av  Electrical Bioimpedance i en bärbar enhet kan räknas som ett effektivt sätt för Stroke diagnostik. För att kunna använda hjärnans impedans för Stroke diagnostik, bör först en studie av hjärnans impedans på friska individer utföras för att kunna visa att impedansen är oförändrad med tiden. Experimentell Bioimpedans Spektroskopi (BIS) mätningar från en frisk kontrollgrupp av 10 försökspersoner har utförts i denna studie för att inspektera variationen av hjärnans impedans under två veckor. Resultaten från denna studie tyder på att sättet av impedans mätningen i dagsläget är inte optimalt. Artefakter presenterad i resultatet gör det omöjligt för att kunna komma till ett beslut om hjärnans impedans variation . För fortsätta studier bör man överväga en större kontrollgrupp och även en analysering av data med hjälp av t-statistik som var inte inom ramen av denna studie.

Síndrome nefrótica é definida pela presença simultânea de edema sistêmico, hipoalbuminemia e proteinúria intensa. Vários componentes da composição corporal, principalmente relacionados à água corporal, sofrem rápidas e frequentes alterações nessa síndrome. A espectroscopia por bioimpedância (BIS) é um método de fácil execução, baixo custo, que pode ser repetido e praticamente isento de riscos que permite avaliar água corporal, massa magra e gordura corporal e tem sido pouco utilizado na síndrome nefrótica. Objetivo. Avaliar as alterações da água e de outros componentes da composição corporal através da BIS em pacientes com síndrome nefrótica. Métodos. Pacientes foram avaliados na ocasião da biópsia renal e no desfecho com ou sem remissão do edema. Foram medidos o peso corporal, albumina sérica e proteinúria de 24 h e, pela BIS, variáveis relacionadas à água corporal e a outros parâmetros de composição corporal. Resultados. Foram estudados 17 pacientes (idade: 51,1 + 17,4 anos) com síndrome nefrótica. Dez pacientes obtiveram remissão do edema (grupo R), sendo que em nove ocorreu também remissão da síndrome nefrótica. Em sete pacientes o edema permaneceu presente, sem remissão (grupo SR). A variação entre a primeira e a segunda medida para a sobrecarga hídrica foi de -5,4 L (-8,5 L; -1,8 L) no grupo R e de 0,0 L (-1,1 L; 1,2 L) no grupo SR (p < 0,05). A água corporal total variou de -4,75 L (- 10,20 L; -2,50 L) e de 4,80 L (-1,30 L; 6,10 L) nos grupos R e SR, respectivamente (p < 0,05), e a água extracelular variou de -5,90 L (-10,10 L; -0,42 L) e de 1,20 L (-0,80 L; 2,70 L) nos mesmos grupos (p < 0,05). Não houve diferença estatisticamente significante na variação entre as duas avaliações nos grupos R e SR para a água intracelular, massa de tecido magro, massa de tecido adiposo, massa gorda total e massa celular corporal. A variação do ângulo de fase entre as avaliações foi de 1,55° (0,41°; 2,24°) no grupo R e 0,10° (-0,28°; 0,46°) no grupo SR (p < 0,05). Houve correlação estatisticamente significante entre cada variável definidora da síndrome nefrótica (peso corporal, proteinúria e albumina sérica) versus sobrecarga hídrica, água corporal total, água extracelular e ângulo de fase, mas não versus as demais medidas de composição corporal obtidas pela BIS. Conclusão. A espectroscopia por bioimpedância mostrou-se eficiente em detectar mudanças da água corporal e do ângulo de fase em pacientes com síndrome nefrótica, mas não para identificar variações relacionadas à massa de tecido magro, massa de tecido adiposo, massa gorda total e massa celular corporal. . / Nephrotic syndrome is established by the simultaneous presence of systemic edema, hypoalbuminemia, and severe proteinuria. Several components of the body composition, mainly related to the body fluid, undergo to rapid and frequent changes in this syndrome. Spectroscopy by bioimpedance (BIS) is a reliable, cost-effective and easy-to-perform method to evaluate body water, adipose tissue mass, and body cell mass. Despite these advantages, BIS has barely been used to evaluate patients with nephrotic syndrome. Aims. To evaluate body fluid variable changes and other components of the body composition in patients with nephrotic syndrome by bioimpedance spectroscopy. Methods. Patients were studied in two moments: at the occasion of the renal biopsy (1st evaluation), and at the end-point (2nd evaluation). Patients were grouped according to they reached remission (Group R) or remained without remission (Group WR) of the edema at the 2nd evaluation. Body weight, serum albumin and 24 hours proteinuria were measured at the two time-points, as well as other variables associated with body fluid and other components of the body composition obtained by the BIS. Results. Seventeen patients (age: 51,1 + 17,4 years-old) with nephrotic syndrome were studied. Ten patients reached remission of the edema while nine of them were also in remission of the nephrotic syndrome. Seven patients remained with edema at the end-point. The variation between the 1st and the 2nd measurement for the overhydration was of -5,4 L (-8,5L; -1,8L) at the group R and of 0,0 (-1,1 L; 1,2 L) at the group NR (p < 0,05). Total body water changes were of -4,75 L (-10,20 L; -2,50 L) and of 4,80 L (-1,30 L; 6,10 L) at the groups R and WR, respectively (p < 0,05), and the extracellular water changed of the -5,90 L (-10,10 L; -0,42 L) and of 1,20 L (-0,80 L; 2,70 L) at the same groups, respectively (p < 0,05). There was no statistically significant difference in the variation between the two evaluations for the groups R and NR for intracellular water, lean tissue mass, fat mass, adipose tissue mass, and body cell mass. The variation of the phase angle between the two evaluations was of the 1,55° (0,41°; 2,24°) at the group R and 0,10° (-0,28°; 0,46°) at the group WR (p < 0,05). There was a statistically significant correlation between each related nephrotic syndrome variable compared with overhydration, total body water, extracellular water, and phase angle, but no difference when compared with the other variables related to the body composition measured by the BIS. Conclusion. The spectroscopy by bioimpedance was efficient to measure body water changes and the phase angle in patients with nephrotic syndrome. However, the BIS could not detect changes related to the intracellular water, lean tissue mass, fat mass, adipose tissue mass, and body cell mass.

Síndrome nefrótica é definida pela presença simultânea de edema sistêmico, hipoalbuminemia e proteinúria intensa. Vários componentes da composição corporal, principalmente relacionados à água corporal, sofrem rápidas e frequentes alterações nessa síndrome. A espectroscopia por bioimpedância (BIS) é um método de fácil execução, baixo custo, que pode ser repetido e praticamente isento de riscos que permite avaliar água corporal, massa magra e gordura corporal e tem sido pouco utilizado na síndrome nefrótica. Objetivo. Avaliar as alterações da água e de outros componentes da composição corporal através da BIS em pacientes com síndrome nefrótica. Métodos. Pacientes foram avaliados na ocasião da biópsia renal e no desfecho com ou sem remissão do edema. Foram medidos o peso corporal, albumina sérica e proteinúria de 24 h e, pela BIS, variáveis relacionadas à água corporal e a outros parâmetros de composição corporal. Resultados. Foram estudados 17 pacientes (idade: 51,1 + 17,4 anos) com síndrome nefrótica. Dez pacientes obtiveram remissão do edema (grupo R), sendo que em nove ocorreu também remissão da síndrome nefrótica. Em sete pacientes o edema permaneceu presente, sem remissão (grupo SR). A variação entre a primeira e a segunda medida para a sobrecarga hídrica foi de -5,4 L (-8,5 L; -1,8 L) no grupo R e de 0,0 L (-1,1 L; 1,2 L) no grupo SR (p < 0,05). A água corporal total variou de -4,75 L (- 10,20 L; -2,50 L) e de 4,80 L (-1,30 L; 6,10 L) nos grupos R e SR, respectivamente (p < 0,05), e a água extracelular variou de -5,90 L (-10,10 L; -0,42 L) e de 1,20 L (-0,80 L; 2,70 L) nos mesmos grupos (p < 0,05). Não houve diferença estatisticamente significante na variação entre as duas avaliações nos grupos R e SR para a água intracelular, massa de tecido magro, massa de tecido adiposo, massa gorda total e massa celular corporal. A variação do ângulo de fase entre as avaliações foi de 1,55° (0,41°; 2,24°) no grupo R e 0,10° (-0,28°; 0,46°) no grupo SR (p < 0,05). Houve correlação estatisticamente significante entre cada variável definidora da síndrome nefrótica (peso corporal, proteinúria e albumina sérica) versus sobrecarga hídrica, água corporal total, água extracelular e ângulo de fase, mas não versus as demais medidas de composição corporal obtidas pela BIS. Conclusão. A espectroscopia por bioimpedância mostrou-se eficiente em detectar mudanças da água corporal e do ângulo de fase em pacientes com síndrome nefrótica, mas não para identificar variações relacionadas à massa de tecido magro, massa de tecido adiposo, massa gorda total e massa celular corporal. . / Nephrotic syndrome is established by the simultaneous presence of systemic edema, hypoalbuminemia, and severe proteinuria. Several components of the body composition, mainly related to the body fluid, undergo to rapid and frequent changes in this syndrome. Spectroscopy by bioimpedance (BIS) is a reliable, cost-effective and easy-to-perform method to evaluate body water, adipose tissue mass, and body cell mass. Despite these advantages, BIS has barely been used to evaluate patients with nephrotic syndrome. Aims. To evaluate body fluid variable changes and other components of the body composition in patients with nephrotic syndrome by bioimpedance spectroscopy. Methods. Patients were studied in two moments: at the occasion of the renal biopsy (1st evaluation), and at the end-point (2nd evaluation). Patients were grouped according to they reached remission (Group R) or remained without remission (Group WR) of the edema at the 2nd evaluation. Body weight, serum albumin and 24 hours proteinuria were measured at the two time-points, as well as other variables associated with body fluid and other components of the body composition obtained by the BIS. Results. Seventeen patients (age: 51,1 + 17,4 years-old) with nephrotic syndrome were studied. Ten patients reached remission of the edema while nine of them were also in remission of the nephrotic syndrome. Seven patients remained with edema at the end-point. The variation between the 1st and the 2nd measurement for the overhydration was of -5,4 L (-8,5L; -1,8L) at the group R and of 0,0 (-1,1 L; 1,2 L) at the group NR (p < 0,05). Total body water changes were of -4,75 L (-10,20 L; -2,50 L) and of 4,80 L (-1,30 L; 6,10 L) at the groups R and WR, respectively (p < 0,05), and the extracellular water changed of the -5,90 L (-10,10 L; -0,42 L) and of 1,20 L (-0,80 L; 2,70 L) at the same groups, respectively (p < 0,05). There was no statistically significant difference in the variation between the two evaluations for the groups R and NR for intracellular water, lean tissue mass, fat mass, adipose tissue mass, and body cell mass. The variation of the phase angle between the two evaluations was of the 1,55° (0,41°; 2,24°) at the group R and 0,10° (-0,28°; 0,46°) at the group WR (p < 0,05). There was a statistically significant correlation between each related nephrotic syndrome variable compared with overhydration, total body water, extracellular water, and phase angle, but no difference when compared with the other variables related to the body composition measured by the BIS. Conclusion. The spectroscopy by bioimpedance was efficient to measure body water changes and the phase angle in patients with nephrotic syndrome. However, the BIS could not detect changes related to the intracellular water, lean tissue mass, fat mass, adipose tissue mass, and body cell mass.

Bioimpedance spectroscopy is very useful in biomedical field as a safe and non-invasive technique. A stable and safe excitation current below than 0.5 mA for load impedances changing from 100 Ω to 10 kΩ in the full β-dispersion range from kHz up to 1 MHz is a big challenge for the design of the current source addressed by this thesis. For a good stability and high accuracy, the source should have a high output impedance. Different current source types in “current-mode approach” and “voltage-mode approach” were investigated and compared for usability in bioimpedance measurement systems. The “voltage-mode approach” with grounded load was proven to be more suitable and stable for biomedical measurements. Thereby the Tietze and the Howland circuit in dual configuration with negative feedback have shown the lowest error of the output current and the highest output impedance, where the improved Howland circuit in dual configuration with negative feedback is preferred because it has a simple structure, high accuracy and good stability. We suggest to improve the stability of the Howland circuit in dual configuration with negative feedback by introducing compensated operational amplifiers and to reduce stray capacitances at higher frequencies by adding gain compensation capacitor. We reach thereby an accuracy of 0.5% at low frequency and 0.9% at 1 MHz. With the realized accuracy of the designed voltage controlled current source, one decisive prerequisite for portable bioimpedance measurement system is achieved. In order to select the appropriate excitation signals for short measurement time, a comparative study of signals and their parameters was carried out. It leads to the selection of binary chirp signal as a suitable excitation signal due to its short measurement time about 100 μs, low crest factor lower than 2.8 and an energy efficiency higher than 54% in a very noisy signal. Simulation results show that the designed enhanced Howland current source excited by the binary chirp signal has low error and flatness in the whole range. / Die Bioimpedanzspektroskopie gewinnt aufgrund ihrer besonderen Eigenschaften als nicht-invasive, schonende Messmethode zunehmend an Bedeutung im biomedizinischen Bereich. Dabei ergeben sich besondere erausforderungen für den Entwurf der Stromquelle zur Realisierung eines stabilen und sicheren Anregungsstroms. Gefordert ist eine hohe Genauigkeit bis zu einem Maximalstrom von 0.5 mA in einem Frequenzbereich, der der β-Dispersion entspricht, von wenigen kHz bis hin zu 1 MHz. Die Stabilität muss bei variablen Lastimpedanzen im Bereich von 100 Ω bis 10 kΩ gewährleistet sein. Dafür muss die Stromquelle eine hohe Ausgangsimpedanz aufweisen. Diese Arbeit fokussiert auf den Entwurf von spannungsgesteuerten Stromquellen. Verschiedene Arten von Stromquellen wurden untersucht und verglichen. Der "Voltage-Modus-Ansatz" mit Masse-referenzierter Last hat sich als besser geeignet und stabiler für biomedizinische Messungen erwiesen. Die Tietze-Schaltung und diese Howland-Schaltung zeigen dabei die niedrigsten Fehler des Ausgangsstroms und die höchste Ausgangsimpedanz. Im direkten Vergleich besitzt die verbesserte Howland-Schaltung doch eine einfachere Struktur, höhere Genauigkeit und bessere Stabilität und wird daher gegenüber der Tietze-Schaltung bevorzugt. Um weitere Stabilitätsverbesserungen bei der Howland-Schaltung zu erreichen, werden zwei Maβnahmen vorgeschlagen. Zum einen werden kompensierte Operationsverstärker eingeführt und zum anderen wird der Einfluss von Streukapazitäten bei hohen Frequenzen minimiert indem die Verstärkung mit Kondensatoren kompensiert wird. Durch diese Maβnahmen wird eine Genauigkeit von 0.5% bei niedrigen Frequenzen und 0.9% bei 1 MHz ermöglicht. Mit dem neuen Entwurf der spannungsgesteuerten Stromquelle ist ein entscheidender Meilenstein für die Realisierung tragbarer Messsysteme der Bioimpedanz erreicht. Um eine kurze Messzeit zu realisieren wurde eine vergleichende Studie von Anregungssignalen und deren Signalparameter durchgeführt. Die Ergebnisse zeigen, dass binäre Chirp-Signale aufgrund der reduzierten Messzeit, des niedrigen Crest-Faktors unter 2.8 und hohe Energieeffizienz von mehr als 54% bei hohem Rauschlevel besonders geeignet sind. Simulationsergebnisse zeigen, dass die entwickelte Howland-Stromquelle zusammen mit einem binären Mehrfrequenzsignal den geringsten Amplitudenfehler im gesamten Frequenzbereich realisiert.

Este trabalho consiste no projeto e implementação em CMOS de um circuito integrado digital para geração de sinais, denominado Oscilador Controlado Numericamente. O circuito será aplicado em um sistema de Espectroscopia por Bioimpedância Elétrica, utilizado como método para detecção precoce de câncer do colo do útero. Durante o trabalho, realizou-se o estudo dos requisitos do sistema de espectroscopia e as especificações dos tipos de sinais a serem gerados. Levantou-se, na bibliografia, algumas técnicas de codificação em linguagem de hardware para otimização do projeto nos quesitos área, potência dissipada e frequência máxima de funcionamento. Para implementar o circuito, também se pesquisou o fluxo de projeto de circuitos digitais, focando as etapas de codificação em linguagem de descrição de hardware Verilog e os resultados de síntese lógica e de layout. Foram avaliadas duas arquiteturas, empregando-se algumas das técnicas de codificação levantadas durante o estudo bibliográfico. Estas arquiteturas foram implementadas, verificadas em plataforma programável, sintetizadas e mapeadas em portas lógicas no processo TSMC 180 nm, onde foram comparados os resultados de área e dissipação de potência. Observou-se, nos resultados de síntese lógica, redução de área de 78% e redução de 83% na dissipação de potência total no circuito em que se aplicou uma das técnicas de otimização em comparação com o circuito implementado sem otimização, utilizando uma arquitetura CORDIC do tipo unrolled. A arquitetura com menor área utilizada - 0,017 mm2 - foi escolhida para fabricação em processo mapeado. Após fabricação e encapsulamento do circuito, o chip foi montado em uma placa de testes desenvolvida para avaliar os resultados qualitativos. Os resultados dos testes foram analisados e comparados aos obtidos em simulação, comprovando-se o funcionamento do circuito. Observou-se uma variação máxima de 0,00623% entre o valor da frequência do sinal de saída obtido nas simulações e o do circuito fabricado. / The aim of this work is the design of a digital integrated circuit for signal generation called Numerically Controlled Oscillator, designed in 180 nm CMOS technology. The application target is for Electrical Bioimpedance Spectroscopy system, and can be used as a method for early detection of cervical cancer. Throughout the work, the spectroscopy system requirements and specifications of the types of signals to be generated were studied. Furthermore, the research of some coding techniques in hardware language for design optimization in terms of area, power consumption and frequency operation was conducted looking into the bibliography. The digital design flow was studied focusing on the Verilog hardware description language and the results of logic synthesis and layout, in order to implement the circuit. Reviews of two architectures have been made, using some of the encoding techniques that have been raised during the bibliographical study. These architectures have been implemented, verified on programmable platform, synthesized and mapped to standard cells in TSMC 180 nm process, which compared the area and total power consumption of results. Based on the results of logic synthesis, a 78% area reduction and 83% power consumption reduction were obtained on the implemented circuit with encoding techniques for optimization in comparison with the another circuit using a CORDIC unrolled architecture. The architecture with smaller area - 0.017 mm2 - was chosen for implementation in the mapped process. After the circuit fabrication and packaging, the chip was mounted on an evaluation board designed to evaluate the functionality. The test results were analyzed and compared with the simulation results, showing that the circuit works as expected. The output signals were compared between theoretical and experimental results, showing a maximum deviation of 0.00623%.

Este trabalho consiste no projeto e implementação em CMOS de um circuito integrado digital para geração de sinais, denominado Oscilador Controlado Numericamente. O circuito será aplicado em um sistema de Espectroscopia por Bioimpedância Elétrica, utilizado como método para detecção precoce de câncer do colo do útero. Durante o trabalho, realizou-se o estudo dos requisitos do sistema de espectroscopia e as especificações dos tipos de sinais a serem gerados. Levantou-se, na bibliografia, algumas técnicas de codificação em linguagem de hardware para otimização do projeto nos quesitos área, potência dissipada e frequência máxima de funcionamento. Para implementar o circuito, também se pesquisou o fluxo de projeto de circuitos digitais, focando as etapas de codificação em linguagem de descrição de hardware Verilog e os resultados de síntese lógica e de layout. Foram avaliadas duas arquiteturas, empregando-se algumas das técnicas de codificação levantadas durante o estudo bibliográfico. Estas arquiteturas foram implementadas, verificadas em plataforma programável, sintetizadas e mapeadas em portas lógicas no processo TSMC 180 nm, onde foram comparados os resultados de área e dissipação de potência. Observou-se, nos resultados de síntese lógica, redução de área de 78% e redução de 83% na dissipação de potência total no circuito em que se aplicou uma das técnicas de otimização em comparação com o circuito implementado sem otimização, utilizando uma arquitetura CORDIC do tipo unrolled. A arquitetura com menor área utilizada - 0,017 mm2 - foi escolhida para fabricação em processo mapeado. Após fabricação e encapsulamento do circuito, o chip foi montado em uma placa de testes desenvolvida para avaliar os resultados qualitativos. Os resultados dos testes foram analisados e comparados aos obtidos em simulação, comprovando-se o funcionamento do circuito. Observou-se uma variação máxima de 0,00623% entre o valor da frequência do sinal de saída obtido nas simulações e o do circuito fabricado. / The aim of this work is the design of a digital integrated circuit for signal generation called Numerically Controlled Oscillator, designed in 180 nm CMOS technology. The application target is for Electrical Bioimpedance Spectroscopy system, and can be used as a method for early detection of cervical cancer. Throughout the work, the spectroscopy system requirements and specifications of the types of signals to be generated were studied. Furthermore, the research of some coding techniques in hardware language for design optimization in terms of area, power consumption and frequency operation was conducted looking into the bibliography. The digital design flow was studied focusing on the Verilog hardware description language and the results of logic synthesis and layout, in order to implement the circuit. Reviews of two architectures have been made, using some of the encoding techniques that have been raised during the bibliographical study. These architectures have been implemented, verified on programmable platform, synthesized and mapped to standard cells in TSMC 180 nm process, which compared the area and total power consumption of results. Based on the results of logic synthesis, a 78% area reduction and 83% power consumption reduction were obtained on the implemented circuit with encoding techniques for optimization in comparison with the another circuit using a CORDIC unrolled architecture. The architecture with smaller area - 0.017 mm2 - was chosen for implementation in the mapped process. After the circuit fabrication and packaging, the chip was mounted on an evaluation board designed to evaluate the functionality. The test results were analyzed and compared with the simulation results, showing that the circuit works as expected. The output signals were compared between theoretical and experimental results, showing a maximum deviation of 0.00623%.

Bioimpedance spectroscopy is very useful in biomedical field as a safe and non-invasive technique. A stable and safe excitation current below than 0.5 mA for load impedances changing from 100 Ω to 10 kΩ in the full β-dispersion range from kHz up to 1 MHz is a big challenge for the design of the current source addressed by this thesis. For a good stability and high accuracy, the source should have a high output impedance. Different current source types in “current-mode approach” and “voltage-mode approach” were investigated and compared for usability in bioimpedance measurement systems. The “voltage-mode approach” with grounded load was proven to be more suitable and stable for biomedical measurements. Thereby the Tietze and the Howland circuit in dual configuration with negative feedback have shown the lowest error of the output current and the highest output impedance, where the improved Howland circuit in dual configuration with negative feedback is preferred because it has a simple structure, high accuracy and good stability. We suggest to improve the stability of the Howland circuit in dual configuration with negative feedback by introducing compensated operational amplifiers and to reduce stray capacitances at higher frequencies by adding gain compensation capacitor. We reach thereby an accuracy of 0.5% at low frequency and 0.9% at 1 MHz. With the realized accuracy of the designed voltage controlled current source, one decisive prerequisite for portable bioimpedance measurement system is achieved. In order to select the appropriate excitation signals for short measurement time, a comparative study of signals and their parameters was carried out. It leads to the selection of binary chirp signal as a suitable excitation signal due to its short measurement time about 100 μs, low crest factor lower than 2.8 and an energy efficiency higher than 54% in a very noisy signal. Simulation results show that the designed enhanced Howland current source excited by the binary chirp signal has low error and flatness in the whole range. / Die Bioimpedanzspektroskopie gewinnt aufgrund ihrer besonderen Eigenschaften als nicht-invasive, schonende Messmethode zunehmend an Bedeutung im biomedizinischen Bereich. Dabei ergeben sich besondere erausforderungen für den Entwurf der Stromquelle zur Realisierung eines stabilen und sicheren Anregungsstroms. Gefordert ist eine hohe Genauigkeit bis zu einem Maximalstrom von 0.5 mA in einem Frequenzbereich, der der β-Dispersion entspricht, von wenigen kHz bis hin zu 1 MHz. Die Stabilität muss bei variablen Lastimpedanzen im Bereich von 100 Ω bis 10 kΩ gewährleistet sein. Dafür muss die Stromquelle eine hohe Ausgangsimpedanz aufweisen. Diese Arbeit fokussiert auf den Entwurf von spannungsgesteuerten Stromquellen. Verschiedene Arten von Stromquellen wurden untersucht und verglichen. Der 'Voltage-Modus-Ansatz' mit Masse-referenzierter Last hat sich als besser geeignet und stabiler für biomedizinische Messungen erwiesen. Die Tietze-Schaltung und diese Howland-Schaltung zeigen dabei die niedrigsten Fehler des Ausgangsstroms und die höchste Ausgangsimpedanz. Im direkten Vergleich besitzt die verbesserte Howland-Schaltung doch eine einfachere Struktur, höhere Genauigkeit und bessere Stabilität und wird daher gegenüber der Tietze-Schaltung bevorzugt. Um weitere Stabilitätsverbesserungen bei der Howland-Schaltung zu erreichen, werden zwei Maβnahmen vorgeschlagen. Zum einen werden kompensierte Operationsverstärker eingeführt und zum anderen wird der Einfluss von Streukapazitäten bei hohen Frequenzen minimiert indem die Verstärkung mit Kondensatoren kompensiert wird. Durch diese Maβnahmen wird eine Genauigkeit von 0.5% bei niedrigen Frequenzen und 0.9% bei 1 MHz ermöglicht. Mit dem neuen Entwurf der spannungsgesteuerten Stromquelle ist ein entscheidender Meilenstein für die Realisierung tragbarer Messsysteme der Bioimpedanz erreicht. Um eine kurze Messzeit zu realisieren wurde eine vergleichende Studie von Anregungssignalen und deren Signalparameter durchgeführt. Die Ergebnisse zeigen, dass binäre Chirp-Signale aufgrund der reduzierten Messzeit, des niedrigen Crest-Faktors unter 2.8 und hohe Energieeffizienz von mehr als 54% bei hohem Rauschlevel besonders geeignet sind. Simulationsergebnisse zeigen, dass die entwickelte Howland-Stromquelle zusammen mit einem binären Mehrfrequenzsignal den geringsten Amplitudenfehler im gesamten Frequenzbereich realisiert.

Volume overload is a common feature in patients on haemodialysis (HD). This contributes significantly to the cardiovascular disease burden seen in these patients. Clinical assessments of the volume state are often inaccurate. Techniques such as interdialytic blood pressure, relative blood volume monitoring, bioimpedance are available to improve clinical effectives. However all these techniques exhibit significant shortcomings in their accuracy, reliability and applicability at the bed side. We evaluated the usefulness of a dual compartment monitoring technique using Continuous Segmental Bioimpedance Spectroscopy (CSBIS) and Relative Blood Volume (RBV) as a tool to assess hydration status and determine dry weight. We also sought to evaluate the role of Atrial Natriuretic Peptide (ANP) and B-type Natriuretic Peptide (BNP) as a volume marker in dialysis patients. The Retrospective analysis of a historical cohort (n = 376, 55 Diabetic) showed a significant reduction in post-dialysis weights in the first three months of dialysis (72.5 to 70kg, p<0.027) with a non-significant increase in weight between months 6-12. The use of anti-hypertensive agents reduced insignificantly in the first 3 months, increased marginally between months 3-6 and significantly increased over the subsequent 6 months. The residual urea clearance (KRU) fell and dialysis times increased. The cohort was very different to that dialysing at Tassin and showed a dissociation between weight reduction and BP control. This may relate to occult volume overload. CSBIS-RBV monitoring in 9 patients with pulse ultrafiltration (pulse UF) showed distinct reproducible patterns relating to extra cellular fluid (ECF) and RBV rebound. An empirical Refill Ratio was then used to define the patterns of change and this was related to the state of their hydration. A value closer to unity was consistent with the attainment of best achievable target weight. The refill ratio fell significantly between the first (earlier) and third (last) rebound phase (1.97 ± 0.92 vs 1.32 ± 0.2). CSBIS monitoring was then carried out in 31 subjects, whilst varying dialysate composition, temperature and patient posture to analyse the effects of these changes on the ECF trace and to ascertain whether any of these interventions can trigger a change in the slope of the ECF trace distinct to that caused by UF. Only, isovolemic HD caused a change in both RBV and ECF in some patients that was explained by volume re-distribution due to gravitational shifts, poor vascular reactivity, sodium gradient between plasma and dialysate and the use of vasodilating antihypertensive agents. This has not been described previously. These will need to be explored further. The study did demonstrate a significant lack of comparability of absolute values of RECF between dialysis sessions even in the same patient. This too has not been described previously. This is likely to be due to subtle changes in fluid distribution between compartments. Therefore a relative changes must be studied. This sensitivity to subtle changes may increase the usefulness of the technique for ECF tracking through dialysis. The potential of dual compartment monitoring to track volume changes in real time was further explored in 29 patients of whom 21 achieved weight reductions and were able to be restudied. The Refill Ratio decreased significantly in the 21 patients who had their dry weights reduced by 0.95 ± 1.13 kg (1.41 ± 0.25 vs 1.25 ± 0.31). Blood pressure changes did not reach statistical significance. The technique was then used to examine differences in vascular refill between a 36oC and isothermic dialysis session in 20 stable prevalent patients. Pulse UF was carried out in both these sessions. There were no significant differences in Refill Ratios, energy removed and blood pressure response between the two sessions. The core temperature (CT) of these patients was close to 36oC and administering isothermic HD did not confer any additional benefit. Mean BNP levels in 12 patients during isovolemic HD and HD with UF did not relate to volume changes. ANP concentrations fell during a dialysis session in 11 patients from a mean 249 ± 143 pg/ml (mean ± SD) at the start of dialysis to 77 ± 65 pg/ml at the end of the session (p<0.001). During isolated UF levels did not change but fell in the ensuing sham phase indicating a time lag between volume loss and decreased generation. (136±99 pg/ml to 101±77.2 pg/ml; p<0.02) In a subsequent study ANP concentrations were measured throughout dialysis and in the post-HD period for 2 hours. A rebound in ANP concentration was observed occurring at around 90 min post-HD. The degree of this rebound may reflect the prevailing fluid state and merit further study. We have shown the utility of dual compartment monitoring with CSBIS-RBV technique and its potential in assessing volume changes in real time in haemodialysis patients. We have also shown the potential of ANP as an independent marker of volume status in the same setting. Both these techniques merit further study.