40 research outputs found

    Electrical Impedance-Based Characterization of Hepatic Tissue with Early-Stage Fibrosis

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    Liver fibrosis is a key pathological precondition for hepatocellular carcinoma in which the severity is confidently correlated with liver cancer. Liver fibrosis, characterized by gradual cell loss and excessive extracellular matrix deposition, can be reverted if detected at the early stage. The gold standard for staging and diagnosis of liver fibrosis is undoubtedly biopsy. However, this technique needs careful sample preparation and expert analysis. In the present work, an ex vivo, minimally destructive, label-free characterization of liver biopsies is presented. Through a custom-made experimental setup, liver biopsies of bile-duct-ligated and sham-operated mice were measured at 8, 15, and 21 days after the procedure. Changes in impedance were observed with the progression of fibrosis, and through data fitting, tissue biopsies were approximated to an equivalent RC circuit model. The model was validated by means of 3D hepatic cell culture measurement, in which the capacitive part of impedance was proportionally associated with cell number and the resistive one was proportionally associated with the extracellular matrix. While the sham-operated samples presented a decrease in resistance with time, the bile-duct-ligated ones exhibited an increase in this parameter with the evolution of fibrosis. Moreover, since the largest difference in resistance between healthy and fibrotic tissue, of around 2 kW, was found at 8 days, this method presents great potential for the study of fibrotic tissue at early stages. Our data point out the great potential of exploiting the proposed needle setup in clinical applications

    Investigation of Heat Therapies using Multi-Scale Models and Statistical Methods

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    Ph.DDOCTOR OF PHILOSOPH

    Towards Bio-impedance Based Labs: A Review

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    In this article, some of the main contributions to BI (Bio-Impedance) parameter-based systems for medical, biological and industrial fields, oriented to develop micro laboratory systems are summarized. These small systems are enabled by the development of new measurement techniques and systems (labs), based on the impedance as biomarker. The electrical properties of the life mater allow the straightforward, low cost and usually non-invasive measurement methods to define its status or value, with the possibility to know its time evolution. This work proposes a review of bio-impedance based methods being employed to develop new LoC (Lab-on-a-Chips) systems, and some open problems identified as main research challenges, such as, the accuracy limits of measurements techniques, the role of the microelectrode-biological impedance modeling in measurements and system portability specifications demanded for many applications.Spanish founded Project: TEC 2013-46242-C3-1-P: Integrated Microsystem for Cell Culture AssaysFEDE

    Computational Modelling of Electrical Properties of Thyroid and Parathyroid Tissue

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    Parathyroid gland identification is an important consideration in order to decrease the inci- dence of post-surgical complications associated with thyroid surgeries. Electrical Impedance Spectroscopy (EIS) based tissue differentiation recently emerged as a promising non-invasive technique that could enhance the tissues separation, and parathyroid preservation in a surgery setting. The aim of the work presented in this thesis is to implement a computational modelling approach in order to elucidate the differences between healthy thyroid and parathyroid tissue impedance spectra which could permit their differentiation during surgery. Multiscale finite element thyroid and parathyroid models have been constructed with the main objective to investigate the impact of morphology and composition on the bulk electrical behaviour of both tissues. The multiscale pipeline represents the hierarchical tissue structure from cellu- lar to tissue scale including a novel mesoscale for the thyroid follicular arrangements. A comprehensive inter- and intracompartmental sensitivity study provided an insight into the impact of the variations in geometrical and electrical properties of tissue structures on electrical impedance spectra of both tissue types suggesting a successful separability between the computed thyroid and parathyroid impedance spectra indices. Moreover, the modelled results obtained through the variation of geometrical parameters demonstrating the natural variability in tissue morphology provided a good agreement with the in vivo measured data acquired and published by Hillary et al. In addition, the verification of selected homogeneity assumptions and the exploration of measurement accuracy and di↵erent probe configurations provided further recommendations for future work concerning computational modelling, experimental data collection and EIS device design improvements. In particular, the outcomes of this computational study re- vealed the importance of additional experimental work concerning the electrical properties measurements of biological tissue materials, and the significance of tissue preparation and measurement accuracy in obtaining thyroid and parathyroid measurements with a tetrapolar EIS probe

    Entwicklung der multifrequenten Magnetresonanz-Elastographie zur Quantifizierung der biophysikalischen Eigenschaften von menschlichem Hirngewebe

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    Magnetic resonance elastography (MRE) is an emerging technique for the quantitative imaging of the biophysical properties of soft tissues in humans. Following its successful clinical application in detecting and characterizing liver fibrosis, the scientific community is investigating the use of viscoelasticity as a biomarker for neurological diseases. Clinical implementation requires a thorough understanding of brain tissue mechanics in conjunction with innovative techniques in new research areas. Therefore, three in vivo studies were conducted to analyze the inherent stiffness dispersion of brain tissue over a wide frequency range, to investigate real-time MRE in monitoring the viscoelastic response of brain tissue during the Valsalva maneuver (VM), and to study mechanical alterations of small lesions in multiple sclerosis (MS). Ultra-low frequency MRE with profile-based wave analysis was developed in 14 healthy subjects to determine large-scale brain stiffness, from pulsation-induced shear waves (1 Hz) to ultra-low frequencies (5 – 10 Hz) to the conventional range (20 – 40 Hz). Furthermore, multifrequency real-time MRE with a frame rate of 5.4 Hz was introduced to analyze stiffness and fluidity changes in response to respiratory challenges and cerebral autoregulation in 17 healthy subjects. 2D and 3D wavenumber-based stiffness reconstruction of the brain was established for conventional MRE in 12 MS patients. MS lesions were analyzed in terms of mechanical contrast with surrounding tissue in relation to white matter (WM) heterogeneity. We found superviscous properties of brain tissue at large scales with a strong stiffness dispersion and a relatively high model-based viscosity of η = 6.6 ± 0.3 Pa∙s. The brain’s viscoelasticity was affected by perfusion changes during VM, which was associated with an increase in brain stiffness of 6.7% ± 4.1% (p<.001), whereas fluidity decreased by -2.1 ± 1.4% (p<.001). In the diseased brain, the analysis of 147 MS lesions revealed 46% of lesions to be softer and 54% of lesions to be stiffer than surrounding tissue. However, due to the heterogeneity of WM stiffness, the results provide no significant evidence for a systematic pattern of mechanical variations in MS. Nevertheless, the results may explain, for the first time, the gap between static ex vivo and dynamic in vivo methods. Fluidity-induced dispersion provides rich information on the structure of tissue compartments. Moreover, viscoelasticity is affected by perfusion during cerebral autoregulation and thus may be sensitive to intracranial pressure modulation. The overall heterogeneity of stiffness obscures changes in MS lesions, and MS may not exhibit sclerosis as a mechanical signature. In summary, this thesis contributes to the field of human brain MRE by presenting new methods developed in studies conducted in new research areas using state-of-the-art technology. The results advance clinical applications and open exciting possibilities for future in vivo studies of human brain tissue.Die Magnetresonanz-Elastographie (MRE) ist ein Verfahren zur quantitativen Darstellung der viskoelastischen Eigenschaften von Weichgewebe. Nach der erfolgreichen klinischen Anwendung in der Leberdiagnostik wird versucht, Viskoelastizität als Biomarker für neurologische Krankheiten zu nutzen. Hierzu bedarf es einer genauen Analyse der Gewebemechanik und innovativen Anwendungsgebieten. Daher, wurden drei Studien durchgeführt, um die Steifigkeitsdispersion von Hirngewebe zu analysieren, das viskoelastische Verhalten während des Valsalva Manövers (VM) abzubilden, und die mechanischen Veränderungen in Läsionen bei Multipler Sklerose (MS) zu untersuchen. Niedrigfrequenz-MRE mit profilbasierter Wellenanalyse wurde in 14 Probanden entwickelt, um die Steifigkeit des Gesamthirns von pulsationsinduzierten Scherwellen (1 Hz) über ultraniedrige Frequenzen (5 – 10 Hz) bis hin zum konventionellen Bereich (20 – 40 Hz) zu bestimmen. Außerdem wurde die multifrequente Echtzeit-MRE mit einer Bildfrequenz von 6.4 Hz eingeführt, um die viskoelastische Antwort des Gehirns auf respiratorische Herausforderungen bei 17 gesunden Probanden zu untersuchen. Neue 2D- und 3D-Wellenzahl-basierte Steifigkeitsrekonstruktionen für das Gehirn wurden in 12 MS Patienten und konventioneller MRE entwickelt. Die Steifigkeitsänderungen in MS-Läsionen wurden mit umliegender weißer Substanz und dessen Heterogenität verglichen. Wir fanden superviskose Eigenschaften des Hirngewebes mit einer starken Dispersion und relativ hohen, modellbasierten Viskosität von η = 6,6 ± 0,3 Pa∙s. Die mechanischen Gewebeeigenschaften wurden durch Perfusionsänderungen während VM beeinflusst und die Hirnsteifigkeit erhöhte sich um 6,7 ± 4,1% (p<.001) wobei sich die Fluidität um -2,1 ± 1,4% (p<.001) verringerte. Die Analyse von 147 MS-Läsionen ergab, dass 54% bzw. 46% der Läsionen steifer bzw. weicher sind als das umgebende Gewebe. Aufgrund der Heterogenität der WM-Steifigkeit konnte jedoch kein Hinweis auf ein systematisches Muster mechanischer Veränderungen in MS-Läsionen gefunden werden. Die Ergebnisse können zum ersten Mal die Lücke zwischen statischen ex vivo und dynamischen in vivo Methoden erklären. Die fluiditätsinduzierte Dispersion liefert interessante Informationen über die zugrundeliegende Gewebestruktur. Darüber hinaus wird die Viskoelastizität durch die Perfusion während der zerebralen Autoregulation beeinflusst und kann daher empfindlich auf intrakranielle Druckschwankungen reagieren. Die allgemeine Heterogenität der Steifigkeit überschattet die Veränderungen in MS-Läsionen, und somit ist Sklerose möglicherweise kein prominentes Merkmal von MS. Zusammenfassend lässt sich festhalten, dass diese Dissertation einen Beitrag zum Gebiet der MRE leistet, indem neue Methoden und Anwendungen in neuen Forschungsgebieten mit modernster Technologie dargestellt werden. Hierdurch wird die klinische Translation gefördert und spannende Möglichkeiten für zukünftige Studien eröffnet

    Multiscale Modeling of the Ventricles: From Cellular Electrophysiology to Body Surface Electrocardiograms

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    This work is focused on different aspects within the loop of multiscale modeling: On the cellular level, effects of adrenergic regulation and the Long-QT syndrome have been investigated. On the organ level, a model for the excitation conduction system was developed and the role of electrophysiological heterogeneities was analyzed. On the torso level a dynamic model of a deforming heart was created and the effects of tissue conductivities on the solution of the forward problem were evaluated

    Mapping of the electrical activity of human atria. Multiscale modelling and simulations

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    La fibrilación auricular es una de las arritmias cardíacas más comunes observadas en la práctica clínica. Por lo tanto, es de vital importancia desarrollar nuevas tecnologías destinadas a diagnosticar y acabar con este tipo de arritmia, para mejorar la calidad de vida de los pacientes y reducir los costes de los sistemas nacionales de salud. En los últimos años ha aumentado el uso de las nuevas técnicas de mapeo auricular, basadas en sistemas multi-electrodo para mapear la actividad eléctrica en humanos. Dichas técnicas permiten localizar y ablacionar los impulsores de la fibrilación auricular, como son las fuentes focales o los rotores. Sin embargo, todavía existe incertidumbre sobre su precisión y los procedimientos experimentales para su análisis están limitados debido a su carácter invasivo. Por lo tanto, las simulaciones computacionales son una herramienta muy útil para superar estas limitaciones, al permitir reproducir con fidelidad las observaciones experimentales, dividir el problema bajo estudio en sub-estudios más simples, y realizar investigaciones preliminares imposibles de llevar a cabo en el práctica clínica. Esta tesis doctoral se centra en el análisis de la precisión de los sistemas de mapeo multi-electrodo a través de modelos y simulaciones computacionales. Para ello, desarrollamos modelos realistas multi-escala con el objetivo de simular actividad eléctrica auricular reentrante, en primer lugar en una lámina de tejido auricular, y en segundo lugar en las aurículas completas. Posteriormente, analizamos los efectos de las configuraciones geométricas multi-electrodo en la precisión de la localización de los rotores, mediante el uso de agrupaciones multi-electrodo con distancias inter-electrodo equidistantes, así como a través de catéteres de tipo basket con distancias inter-electrodo no equidistantes. Después de calcular los electrogramas unipolares intracavitarios, realizamos mapas de fase, detecciones de singularidad de fase para rastrear los rotores, y mapas de frecuencia dominantes. Finalmente, descubrimos que la precisión de los sistemas de mapeo multi-electrodo depende de su posición dentro de la cavidad auricular, de la distancia entre los electrodos y el tejido, de la distancia inter-electrodo, y de la contribución de las fuentes de campo lejano. Además, como consecuencia de estos factores que pueden afectar a la precisión de los sistemas de mapeo multi-electrodo, observamos la aparición de rotores falsos que podrían contribuir al fracaso de los procesos de ablación de la fibrilación auricular.Atrial fibrillation is one of the most common cardiac arrhythmias seen in clinical practice. Therefore, it is of vital importance to develop new technologies aimed at diagnosing and terminating this kind of arrhythmia, to improve the quality of life of patients and to reduce costs to national health systems. In the last years, new atrial mapping techniques based on multi-electrode systems are increasingly being used to map the atrial electrical activity in humans and localise and target atrial fibrillation drivers in the form of focal sources or rotors. However, significant concerns remain about their accuracy and experimental approaches to analyse them are limited due to their invasive character. Therefore, computer simulations are a helpful tool to overcome these limitations since they can reproduce with fidelity experimental observations, permit to split the problem to treat into more simple substudies, and allow the possibility of performing preliminary investigations impossible to carry out in the clinical practice. This PhD thesis is focused on the analysis for accuracy of the multielectrode mapping systems through computational models and simulations. For this purpose, we developed realistic multiscale models in order to simulate atrial electrical reentrant activity, first in a sheet of atrial tissue and, then, in the whole atria. Then, we analysed the effects of the multi-electrode geometrical configurations on the accuracy of localizing rotors, by using multi-electrode arrays with equidistant inter-electrode distances, as well as multi-electrode basket catheters with non-equidistant inter-electrode distances. After computing the intracavitary unipolar electrograms, we performed phase maps, phase singularity detections to track rotors, and dominant frequency maps. We finally found out that the accuracy of multi-electrode mapping systems depends on their position inside the atrial cavity, the electrode-to-tissue distance, the inter-electrode distance, and the contribution of far field sources. Furthermore, as a consequence of these factors, false rotors might appear and could contribute to failure of atrial fibrillation ablation procedures.La fibril·lació auricular és una de les arítmies cardíaques més comuns observades en la pràctica clínica. Per tant, és de vital importància desenvolupar noves tecnologies destinades a diagnosticar i acabar amb aquest tipus d'arítmia, per tal de millorar la qualitat de vida dels pacients i reduir els costos dels sistemes nacionals de salut. En els últims anys, ha augmentat l'ús de les noves tècniques de mapeig auricular, basades en sistemes multielèctrode per a mapejar l'activitat elèctrica auricular en humans. Aquestes tècniques permeten localitzar i ablacionar els impulsors de la fibril·lació auricular, com són les fonts focals o els rotors. No obstant això, encara hi ha incertesa sobre la seua precisió i els procediments experimentals per al seu anàlisi estan limitats a causa del seu caràcter invasiu. Per tant, les simulacions computacionals són una eina molt útil per a superar aquestes limitacions, en permetre reproduir amb fidelitat les observacions experimentals, dividir el problema sota estudi en subestudis més simples, i realitzar investigacions preliminars impossibles de dur a terme en el pràctica clínica. Aquesta tesi doctoral es centra en l'anàlisi de la precisió del sistemes de mapeig multielèctrode mitjançant els models i les simulacions computacionals. Per a això, desenvolupàrem models realistes multiescala per tal de simular activitat elèctrica auricular reentrant, en primer lloc en una làmina de teixit auricular, i en segon lloc a les aurícules completes. Posteriorment, analitzàrem els efectes de les configuracions geomètriques multielèctrode en la precisió de la localització dels rotors, mitjançant l'ús d'agrupacions multielèctrode amb distàncies interelèctrode equidistants, així com catèters de tipus basket amb distàncies interelèctrode no equidistants. Després de calcular els electrogrames unipolars intracavitaris, vam realitzar mapes de fase, deteccions de singularitat de fase per a rastrejar els rotors, i mapes de freqüència dominants. Finalment, vam descobrir que la precisió dels sistemes de mapeig multielèctrode depèn de la seua posició dins de la cavitat auricular, de la distància entre els elèctrodes i el teixit, de la distància interelèctrode, i de la contribució de les fonts de camp llunyà. A més, com a conseqüència d'aquests factors, es va observar l'aparició de rotors falsos que podrien contribuir al fracàs de l'ablació de la fibril·lació auricular.Martínez Mateu, L. (2018). Mapping of the electrical activity of human atria. Multiscale modelling and simulations [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/104604TESI

    Numerical modelling of electrical stimulation for cartilage tissue engineering

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    In this thesis, the design and validity of numerical models of electrical stimulation for cartilage tissue engineering are critically assessed at different scales. In sum, the results of this thesis pave the way for experimentally validated numerical models of electrical stimulation devices for cartilage tissue engineering. Furthermore, models of tissue samples can be developed down to the cellular scale and will contribute to the development of patient-specific stimulation approaches
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