Contributions to the measurement of electrical impedance for living tissue ischemia injury monitoring

Aquesta tesi es centra en el desenvolupament i l'ús d'una sonda miniaturitzada de silici per a la mesura de la impedància elèctrica de teixits vius tous. El propòsit d'aquestes mesures d'impedància és la monitorització en temps real del dany isquèmic per a aplicacions com la cirurgia cardíaca o el trasplantament d'òrgans. Actualment, el rang de mètodes aplicables a nivell clínic per tal de detectar l'isquèmia tissular és limitat i no existeix cap mètode pràctic que permeti la quantificació en temps real de l'efecte d'aquesta isquèmia, això és, el dany isquèmic. En aquest sentit, la monitorització de la impedància elèctrica sembla esperançadora i el treball d'aquesta tesi contribueix al camp mitjançant el desenvolupament de nous instruments i mètodes i mitjançant l'aportació de noves dades experimentals i eines per a la comprensió de la relació entre la patofisiologia i la impedància elèctrica. Les principals contribucions d'aquesta tesi es resumeixen a continuació.En aquesta tesi, es descriu el desenvolupament d'una sonda que formada per quatre elèctrodes de platí (300 m  300 m) a sobre d'un substrat de silici en forma d'agulla ( longitud d'inserció = 9 mm i secció de 600 m  500 m). Els elèctrodes estan situats a una distància de separació no constant per tal de millorar la relació senyal-soroll i la resolució espacial. Es realitza una deposició electroquímica de platí negre sobre els elèctrodes per tal de reduir la impedància de la interfície i millorar la qualitat de les mesures. En el cas dels teixits vius, la banda freqüencial de mesura va dels 100 Hz fins als 100 kHz. Un mètode nou per a la mesura d'impedància a cinc elèctrodes es presenta i s'analitza. Amb aquest mètode, es pretén minimitzar l'error a baixes freqüències degut a l'elevada impedància de la interfície elèctrode-electròlit. Malauradament, encara que aquest mètode a cinc elèctrodes funciona, s'han trobat algunes limitacions que el fan quasi impracticable en el cas dels teixits vius.També es presenta el desenvolupament i l'ús d'un paquet de programari per a simular la impedància elèctrica dels teixits vius en les regions de dispersió  i . Aquest programari es basa en la generació d'arxius SPICE a partir de l'especificació d'alguns paràmetres numèrics relacionats amb el teixit i el dibuix d'un mapa bi-dimensional que representa un tall de teixit. El resultat més significatiu d'aquest simulador és que és capaç d'obtenir respostes compatibles amb l'equació de Cole a partir d'un model basat únicament en resistències i capacitats.S'han realitzat diversos estudis experimental fent servir la sonda de silici. En aquesta tesi únicament es presenten els estudis amb ronyons de rata. Els resultats confirmen les principals observacions fetes anteriorment per altres investigadors que han treballat amb diferents animals, òrgans i protocols. Això vol dir, en termes generals, un increment significatiu de la magnitud de la impedància elèctrica a baixes freqüències (Addicionalment, aquesta tesi inclou un annex que tracta de facilitar la comprensió de la monitorització de la bioimpedància elèctrica a aquells amb formació en ciències de la vida.This thesis is focused on the development and use of a miniaturized silicon probe for electrical impedance measurements of soft living tissues. The purpose of those impedance measurements is to monitor the ischemia injury for applications such as cardiac surgery or organ transplantation.Currently, the range of clinically available methods to detect tissue ischemia is limited and there is not any practical method to quantify in an on-line manner the effect of such ischemia, that is, the ischemia injury. In this sense, electrical impedance monitoring seems very promising and this thesis contributes to the field by developing new instruments and methods and by providing novel experimental results and tools to understand the relation between pathophysiology and electrical impedance. The main contributions of this thesis are summarized below.In this thesis, it is presented the development of a silicon probe that consists of four platinum electrodes (300 m  300 m) on a needle shaped silicon substrate (9 mm insertion length, 600 m  500 m cross section). The electrodes are placed at non-constant separation distance in order to enhance signal-to-noise ratio and spatial resolution. An electrochemical deposition of platinum black on the electrodes is performed in order to reduce the interface impedance and improve the quality of the measurements. For living tissue measurements, the useful measurement band goes from 100 Hz to 100 kHz.A novel measurement method based on five electrodes is described and analyzed. It is intended to minimize errors at low frequencies caused by the high electrode-electrolyte interface impedances. Unfortunately, although this five-electrode method works, some limitations have been found that made almost impossible its implementation for living tissue measurements.It is also presented a custom developed software package to simulate the electrical impedance of living tissues at the  and  dispersion regions. It is based on the generation of a SPICE netlist from the specification of some numerical parameters concerning the tissue and a bi-dimensional map representing a slice of tissue. Some examples are provided to demonstrate its feasibility. The most significant result is that the simulator is able to obtain Cole compatible behaviours from models based on simple resistances and capacitances. Several experimental studies have been performed by using the silicon probe. In this thesis only the experiments carried out on rat kidneys are presented. The results confirm the main observations made by previous researchers working with other animals, organs and protocols. That is, in general terms, a significant increase of impedance magnitude at low frequencies (This thesis includes an annex that tries to facilitate the understanding of electrical bioimpedance monitoring for life-sciences practitioners.Another annex describes the instrumentation systems that were developed for electrical impedance measurements based on the four-electrode method

Electrochemical prevention of needle-tract seeding

Needle-tract seeding refers to the implantation of tumor cells by contamination when instruments, such as biopsy needles, are employed to examine, excise or ablate a tumor. The incidence of this iatrogenic phenomenon is low but it entails serious consequences. Here, as a new method for preventing neoplasm seeding, it is proposed to cause electrochemical reactions at the instrument surface so that a toxic microenvironment is formed. In particular, the instrument shaft would act as the cathode and the tissues would act as the electrolyte in an electrolysis cell. By employing numerical models and experimental observations reported by researchers on Electrochemical Treatment of tumors, it is numerically showed that a sufficiently toxic environment of supraphysiological pH can be created in a few seconds without excessive heating. Then, by employing an ex vivo model consisting of meat pieces, validity of the conclusions provided by the numerical model concerning pH evolution is confirmed. Furthermore, a simplified in vitro model based on bacteria, instead of tumor cells, is implemented for showing the plausibility of the method. Depending on the geometry of the instrument, suitable current densities will probably range from about 5 mA/cm2 to 200 mA/cm2 and the duration of DC current delivery will range from a few seconds to a few minutes.AI’s research is currently supported by a Ramón y Cajal fellowship from the Spanish Ministry for Science and Innovation

Remote electrical stimulation by means of implanted rectifiers

Miniaturization of active implantable medical devices is currently compromised by the available means for electrically/npowering them. Most common energy supply techniques for implants – batteries and inductive couplers – comprise bulky/nparts which, in most cases, are significantly larger than the circuitry they feed. Here, for overcoming such miniaturization/nbottleneck in the case of implants for electrical stimulation, it is proposed to make those implants act as rectifiers of high/nfrequency bursts supplied by remote electrodes. In this way, low frequency currents will be generated locally around the/nimplant and these low frequency currents will perform stimulation of excitable tissues whereas the high frequency currents/nwill cause only innocuous heating. The present study numerically demonstrates that low frequency currents capable of/nstimulation can be produced by a miniature device behaving as a diode when high frequency currents, neither capable of/nthermal damage nor of stimulation, flow through the tissue where the device is implanted. Moreover, experimental/nevidence is provided by an in vivo proof of concept model consisting of an anesthetized earthworm in which a commercial/ndiode was implanted. With currently available microelectronic techniques, very thin stimulation capsules (diameter/n,500 mm) deliverable by injection are easily conceivable.This author's research is currently supported by a Ramón y Cajal fellowship from the Spanish Ministry for Science and Innovation (RYC-2009-04271) and a Marie Curie International Reintegration Grant (256376 – “TAMIVIVE”) from the European Commission. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Two-port networks to model galvanic coupling for intrabody communications and power transfer to implants

Comunicació presentada a: BioCAS 2018, celebrada a Cleveland, Ohio, Estats Units d'Amèrica, del 17 al 19 d'octubre de 2018.Galvanic coupling, or more precisely, volume conduction, can be used to communicate with and to transfer power to electronic implants. Since no bulky components for power, such as coils or batteries, are required within the implants, this strategy can yield very thin devices suitable for implantation by injection. To design the circuitry of both the implants and the external systems, it is desirable to possess a model that encompasses the behavior of these circuits and also the volume conduction phenomenon. Here we propose to model volume conduction with a two-port network so that the whole system can be studied in circuit simulators. The two-port network consists only of three impedances whose values can be obtained through simple measurements or through numerical methods. We report a validation of this modeling approach in a geometrically simple in vitro setup that allowed us to determine the impedances of the two-port network not only by performing measurements or through a finite element method study but also through an analytical solution.Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 724244)

Electrochemical prevention of needle-tract seeding

Needle-tract seeding refers to the implantation of tumor cells by contamination when instruments, such as biopsy needles, are employed to examine, excise or ablate a tumor. The incidence of this iatrogenic phenomenon is low but it entails serious consequences. Here, as a new method for preventing neoplasm seeding, it is proposed to cause electrochemical reactions at the instrument surface so that a toxic microenvironment is formed. In particular, the instrument shaft would act as the cathode and the tissues would act as the electrolyte in an electrolysis cell. By employing numerical models and experimental observations reported by researchers on Electrochemical Treatment of tumors, it is numerically showed that a sufficiently toxic environment of supraphysiological pH can be created in a few seconds without excessive heating. Then, by employing an ex vivo model consisting of meat pieces, validity of the conclusions provided by the numerical model concerning pH evolution is confirmed. Furthermore, a simplified in vitro model based on bacteria, instead of tumor cells, is implemented for showing the plausibility of the method. Depending on the geometry of the instrument, suitable current densities will probably range from about 5 mA/cm2 to 200 mA/cm2 and the duration of DC current delivery will range from a few seconds to a few minutes.AI’s research is currently supported by a Ramón y Cajal fellowship from the Spanish Ministry for Science and Innovation

Two-port networks to model galvanic coupling for intrabody communications and power transfer to implants

Comunicació presentada a: BioCAS 2018, celebrada a Cleveland, Ohio, Estats Units d'Amèrica, del 17 al 19 d'octubre de 2018.Galvanic coupling, or more precisely, volume conduction, can be used to communicate with and to transfer power to electronic implants. Since no bulky components for power, such as coils or batteries, are required within the implants, this strategy can yield very thin devices suitable for implantation by injection. To design the circuitry of both the implants and the external systems, it is desirable to possess a model that encompasses the behavior of these circuits and also the volume conduction phenomenon. Here we propose to model volume conduction with a two-port network so that the whole system can be studied in circuit simulators. The two-port network consists only of three impedances whose values can be obtained through simple measurements or through numerical methods. We report a validation of this modeling approach in a geometrically simple in vitro setup that allowed us to determine the impedances of the two-port network not only by performing measurements or through a finite element method study but also through an analytical solution.Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 724244)

Proof of concept of a stimulator based on AC current rectification for neuroprosthetics

Comunicació presentada a: XXX Congreso Anual de la Sociedad Española de Ingeniería Biomédica, CASEIB 2012, celebrat a San Sebastián del 19 al 21 de novembre de 2012For several years, researchers have developed techniques to replace and enhance the capabilities of our neural system by means of implantable electrical stimulation technologies. Even though important work has been done in this field, further progress must be accomplished in terms of miniaturization in order to ensure comfort, simpler surgical implantation procedures, and the capability of using multiple wireless smart stimulators for achieving more muscle recruitment. In the past, with the objective of accomplishing an unprecedented level of miniaturization, we have proposed the development of implantable stimulators that would act as rectifiers of AC current supplied by external electrodes. Here it is described the development and evaluation of an addressable stimulator based on discrete component technology as a proof-of-concept of the proposed method. This macroscopic version of the stimulator is capable of generating magnitude controlled bipolar pulses according to commands modulated in the AC current. Multiple evaluations were done to test the device, including DC current testing, in-vitro and in-vivo testing, concluding that the developed system is an effective proof-of-concept of the method proposed, being able to perform controlled electrical stimulation. Electrical current testing showed that anodal and cathodal currents were generated, and in-vivo testing showed the effective electrical stimulation of an anesthetized earthworm. It is concluded that the idea of developing smart rectifiers as implantable stimulators is feasible. This represents a first step towards the design of an implantable device with a miniaturization level without precedents.LBF’s Master’s degree was supported by Colfuturo - Colombia. AI’s research is currently supported by a Ramón y Cajal fellowship from the Spanish Ministry for Science and Innovation and a Marie Curie International Reintegration Grant (256376) from the European Commission

Bidirectional communications in wireless microstimulators based on electronic rectification of epidermically applied currents

Comunicació presentada a 7th Annual International IEEE/EMBS Conference on Neural Engineering, celebrada a Montpellier, França, del 22 al 24 d'abril de 2015.Functional Electrical Stimulation (FES) has been used in order to restore muscle functions in patients suffering from neurological disorders. This therapeutic approach benefits from technological improvements that yield miniaturization. We previously have proposed and demonstrated an innovative electrical stimulation method in which wireless implants act as rectifiers of innocuous high frequency (HF) currents. These currents are conductively supplied to the tissues where the/nimplants are located through external electrodes. Locally, the implants generate low frequency currents capable of stimulating excitable tissues. The method has the potential to enable unprecedented levels of miniaturization. The implant needs only two peripheral electrodes both for picking-up the HF current and for performing electrical stimulation. In addition, a tiny hybrid microcircuit, or a single integrated circuit, may integrate all the necessary electronic components. No bulky parts such as coils or batteries are required. We have demonstrated a number of circuit architectures for the implants with advanced capabilities such as digital addressability. In/nhere, we demonstrate that the proposed method also allows bidirectional communications between the implants and the external system that powers and governs them, enabling proprioception-like sensing capabilities that may be crucial for closed-loop FES systems. We demonstrate a scheme based on amplitude modulation and Manchester encoding.AI‟s research is supported by a Ramón y Cajal fellowship from the Spanish government and a Marie Curie grant (IRG 256376) from the European Commission. LBF‟s research is supported by a scholarship from the UPF

Towards addressable wireless microstimulators based on electronic rectification of epidermically applied currents

Electrical stimulation has been explored to restore/nthe capabilities of the nervous system in paralysis patients. This/narea of research and of clinical practice, known as Functional/nElectrical Stimulation, would greatly benefit from further/nminiaturization of implantable stimulators. To that end, we/nrecently proposed and demonstrated an innovative electrical/nstimulation method in which implanted microstimulators/noperate as rectifiers of bursts of innocuous high frequency/ncurrent supplied by skin electrodes, thus generating low/nfrequency currents capable of stimulating excitable tissues. A/ndiode could suffice in some applications but, in order to broaden/nthe method’s clinical applicability, we envision rectifiers with/nadvanced capabilities such as current control and/naddressability. We plan flexible thread-like implants (diameters/n< 300 μm) containing ASICs. As an intermediate stage, we are/ndeveloping macroscopic implants (diameters 2 mm) made of/noff-the-shelf components. Here we present a circuit which/nresponds to commands modulated within the high frequency/nbursts and which is able to deliver charge-balanced currents./nWe show that a number of these circuits can perform/nindependent stimulation of segments of an anesthetized/nearthworm following commands from a computer.AI’s research is supported by a Ramón y Cajal fellowship from the Spanish government and a Marie Curie grant (IRG 256376) from the European Commission. LBF’s research is supported by a scholarship from the UPF

Charge counter for performing active charge-balance in miniaturized electrical stimulators

Functional Electrical Stimulation (FES) has been explored in order to restore the capabilities of the nervous system in patients that suffer from paralysis. This area of research and of clinical practice greatly benefits from any technological improvement yielding miniaturization. In this regard, we recently proposed and demonstrated an innovative electrical stimulation method based on implanted microstimulators that operate as rectifiers of bursts of innocu-ous high frequency current supplied by skin electrodes, gener-ating low frequency currents that are capable of stimulating excitable tissues. We envision flexible ultrathin implants (di-ameters < 300 μm) containing ASICs that have advanced ca-pabilities, such as addressability and current control. As min-iaturization is the main aim of this method, the use of bulky DC-blocking capacitors (e.g. 10 μF) to accomplish zero net charge injection and avoid electrochemical tissue and electrode damage is highly inconvenient. As an alternative, here we present an active charge-balance method based on the use of a digital charge quantifier, whose operation is inspired in the functioning of the tipping bucket rain gauge. The system moni-tors the charge injection, matching the charge injected in the cathodal phase, with the charge injected in the anodal phase, generating a biphasic current waveform that adapts itself to possible current source mismatches. We have implemented a prototype built with discrete components which uses a capaci-tor of only 100 pF for the charge counter.AI’s research is supported by a Ramón y Cajal fellowship/nfrom the Spanish government and a Marie Curie grant/n(IRG 256376) from the European Commission. LBF’s research/nis supported by a scholarship from the UPF