Publicaciones del IMSE

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Autor: Juan A. Serrano Viseas
Año: Desde 2002

Artículos de revistas


A computer-aided design tool for biomedical OBT sensor tuning in cell-culture assays
P. Pérez, J.A. Serrano, M.E. Martín, P. Daza, G. Huertas and A. Yúfera
Journal Paper · Computer Methods and Programs in Biomedicine, vol. 200, article 105840, 2020
resumen      doi      

It is proposed a computer program for system design of biosensors applied to monitoring cell culture dynamics. The program allows obtaining confident system information by electrical stimulation. All system components (electrodes, cell culture and test circuits) are properly modelled. The employed procedure can be applied to any other 2D electrode layout or alternative circuit technique for ECIS test. Finally, deep insight information on cell size, number, and time-division can be extracted from the comparison with real cell culture assays in the future.

Alternative General Fitting Methods for Real-Time Cell-Count Experimental Data Processing
J.A. Serrano, P. Perez, G. Huertas and A. Yufera
Journal Paper · IEEE Sensors Journal, vol. 20, no. 24, pp 15177-15184, 2020
resumen      doi      

This paper reports two general methods for extraction of cell-electrode electrical model parameters in cell culture (CC) assays. The presented approaches can be applied to CC assays based on electrical cell-substrate impedance spectroscopy (ECIS) technique for real-time supervision, providing the cell number per square centimeter, i.e., the cell density, as main result. Both of the proposed methods - minimization of system equations and data predictive model - search, during the experiment, the optimum values of the electrical model parameters employed for the electrode-cell model. The results of this search enable a fast and efficient calculation of the involved cell-electrode model parameters and supply real-time information on the cell number. For the sake of experimental validation, we applied the proposed methods to practical CCs in cell growth assays with a cell line of AA8 Chinese hamster ovarian fibroblasts and the Oscillation Based Test technique for bioimpedance measurements. These methods can be easily extrapolated to any general cell lines and/or other bioimpedance test methodologies.

3D-printed sensors and actuators in cell culture and tissue engineering: Framework and research challenges
P. Pérez, J.A. Serrano and A. Olmo
Journal Paper · Sensors, vol. 20, no. 19, article 5617, 2020
resumen      doi      pdf

Three-dimensional printing technologies have been recently proposed to monitor cell cultures and implement cell bioreactors for different biological applications. In tissue engineering, the control of tissue formation is crucial to form tissue constructs of clinical relevance, and 3D printing technologies can also play an important role for this purpose. In this work, we study 3D-printed sensors that have been recently used in cell culture and tissue engineering applications in biological laboratories, with a special focus on the technique of electrical impedance spectroscopy. Furthermore, we study new 3D-printed actuators used for the stimulation of stem cells cultures, which is of high importance in the process of tissue formation and regenerative medicine. Key challenges and open issues, such as the use of 3D printing techniques in implantable devices for regenerative medicine, are also discussed.

Electrical modeling of the growth and differentiation of skeletal myoblasts cell cultures for tissue engineering
A. Olmo, Y. Yuste, J.A. Serrano, A. Maldonado-Jacobi, P. Pérez, G. Huertas, S, Pereira, A. Yufera and F. de la Portilla
Journal Paper · Sensors, vol. 20, no. 11, article 3152, 2020
resumen      doi      pdf

In tissue engineering, of utmost importance is the control of tissue formation, in order to form tissue constructs of clinical relevance. In this work, we present the use of an impedance spectroscopy technique for the real-time measurement of the dielectric properties of skeletal myoblast cell cultures. The processes involved in the growth and differentiation of these cell cultures in skeletal muscle are studied. A circuit based on the oscillation-based test technique was used, avoiding the use of high-performance circuitry or external input signals. The effect of electrical pulse stimulation applied to cell cultures was also studied. The technique proved useful for monitoring in real-time the processes of cell growth and estimating the fill factor of muscular stem cells. Impedance spectroscopy was also useful to study the real-time monitoring of cell differentiation, obtaining different oscillation amplitude levels for differentiated and undifferentiated cell cultures. Finally, an electrical model was implemented to better understand the physical properties of the cell culture and control the tissue formation process.

Remote Cell Growth Sensing using Self-Sustained Bio-Oscillations
P. Pérez, G. Huertas, A. Olmo, A. Maldonado-Jacobi, J. Serrano, M. Martín, P. Daza and A. Yúfera
Journal Paper · Sensors, vol. 18, no. 8, art. 2550, 2018
resumen      doi      pdf

A smart sensor system for cell culture real-time supervision is proposed, allowing for a significant reduction in human effort applied to this type of assay. The approach converts the cell culture under test into a suitable "biological" oscillator. The system enables the remote acquisition and management of the "biological" oscillation signals through a secure web interface. The indirectly observed biological properties are cell growth and cell number, which are straightforwardly related to the measured bio-oscillation signal parameters, i.e., frequency and amplitude. The sensor extracts the information without complex circuitry for acquisition and measurement, taking advantage of the microcontroller features. A discrete prototype for sensing and remote monitoring is presented along with the experimental results obtained from the performed measurements, achieving the expected performance and outcomes.

An empirical-mathematical approach for calibration and fitting cell-electrode electrical models in bioimpedance tests
J.A. Serrano, G. Huertas, A. Maldonado-Jacobi, A. Olmo, P. Pérez, M.E. Martín, P. Daza and A. Yúfera
Journal Paper · Sensors, vol. 18, no. 7, article 2354, 2018
resumen      doi      pdf

This paper proposes a new yet efficient method allowing a significant improvement in the on-line analysis of biological cell growing and evolution. The procedure is based on an empirical-mathematical approach for calibration and fitting of any cell-electrode electrical model. It is valid and can be extrapolated for any type of cellular line used in electrical cell-substrate impedance spectroscopy (ECIS) tests. Parameters of the bioimpedance model, acquired from ECIS experiments, vary for each cell line, which makes obtaining results difficult and -to some extent-renders them inaccurate. We propose a fitting method based on the cell line initial characterization, and carry out subsequent experiments with the same line to approach the percentage of well filling and the cell density (or cell number in the well). To perform our calibration technique, the so-called oscillation-based test (OBT) approach is employed for each cell density. Calibration results are validated by performing other experiments with different concentrations on the same cell line with the same measurement technique. Accordingly, a bioimpedance electrical model of each cell line is determined, which is valid for any further experiment and leading to a more precise electrical model of the electrode-cell system. Furthermore, the model parameters calculated can be also used by any other measurement techniques. Promising experimental outcomes for three different cell-lines have been achieved, supporting the usefulness of this technique.

Sensing Cell-Culture Assays with Low-Cost Circuitry
P. Pérez, G. Huertas, A. Maldonado-Jacobi, M. Martín, J.A. Serrano, A. Olmo, P. Daza and A. Yúfera
Journal Paper · Scientific Reports, vol. 8, no. 1, article 8841, 2018
resumen      doi      pdf

An alternative approach for cell-culture end-point protocols is proposed herein. This new technique is suitable for real-time remote sensing. It is based on Electrical Cell-substrate Impedance Spectroscopy (ECIS) and employs the Oscillation-Based Test (OBT) method. Simple and straightforward circuit blocks form the basis of the proposed measurement system. Oscillation parameters - frequency and amplitude - constitute the outcome, directly correlated with the culture status. A user can remotely track the evolution of cell cultures in real time over the complete experiment through a web tool continuously displaying the acquired data. Experiments carried out with commercial electrodes and a well-established cell line (AA8) are described, obtaining the cell number in real time from growth assays. The electrodes have been electrically characterized along the design flow in order to predict the system performance and the sensitivity curves. Curves for 1-week cell growth are reported. The obtained experimental results validate the proposed OBT for cell-culture characterization. Furthermore, the proposed electrode model provides a good approximation for the cell number and the time evolution of the studied cultures.

Congresos


Effects of Electrical Fields on Neuroblastoma (N2A) Cell Differentiation: Preliminary Results
D. Martin-Fernández, P. Pérez-García, M.E. Martín, P. Daza, J.A. Serrano-Viseas, G. Huertas and A. Yúfera
Conference · International Conference on Biomedical Electronics and Devices BIODEVICES 2021
resumen     

This work describes Electrical Stimulations (ES) assays on stem cells. The neuroblastoma (N2A) cell linage was submitted to several electrical fields to enable and enhance its differentiation toward neurons. Both Direct Current (DC) and Alternated Current (AC) time dependent electric field protocols were applied to N2A cell culture under differentiation conditions, obtaining different responses. Control and electrically excited samples’ number of differentiated cells and neurite lengths were measure after differentiation. Results showed that DC fields have a strong influence on N2A differentiation since the percentage of differentiated cells and the neurites lengths were the highest. In addition, a significant alignment of neurites measured with the applied electrical field has been detected, which demonstrates the high sensitivity of differentiation processes to electrical field polarity.

Fast Simulation of Non-Linear Circuits using Semi-Analytical Solutions based on the Matrix Exponential
J.A. Serrano, A.J. Gines and E. Peralías
Conference · IEEE International Symposium on Circuits and Systems ISCAS 2020
resumen     

This paper presents a new simulation method for fast evaluation of non-linear circuits. The proposed approach solves the non-linear ordinary differential equation (ODE) set of the system using a semi-analytical solution based on the matrix exponential. The method is fully general and suitable for different circuits, including switched-capacitor (SC) architectures, analog to digital converters (Pipeline, SAR, Sigma-Delta ADCs) or digital to analog converters. For illustration purpose in this paper, an analog signal processing front-end for discrete-time data acquisition system is considered as case study. The circuit comprises a Flip-Around Sample&Hold followed by a Programmable Gain Amplifier (PGA), based on a Correlated Double-Sampling amplifier, and a back-end ADC. The model includes non-linearity associated to switches, capacitive parasitics, finite nonlinear DC-gain and non-linear settling behavior including slew-rate. Comparison with traditional ODE numerical solvers shows a reduction of the computation time in almost two orders of magnitude with negligible difference in terms of accuracy.

Designing bioimpedance based sensors for cell cultures test
P. Perez, A. Yúfera, J.A. Serrano and G. Huertas
Conference · Conference on Design of Circuits and Integrated Systems DCIS 2020
resumen     

This work presents a procedure to improve biomedical sensor design flow by including information taken from sensor technical specifications and data from its biomedical dynamics, in our case, the system described is sensing cell culture assays. The main structural components of a biosensor for cell culture with real-time monitoring are analyzed, modelled and incorporated into the system design flow in such a way that the resulting sensor designed by the procedure will engender analysis of the circuits' constraints and cell sensitivity, together with the dynamics imposed by the living cells. The time evolution for general cell cultures is reproduced, and an image processing approach is applied to transduce the cell increments to the cell-electrode parameters as previously defined. The proposed tool is applied to the Electrical Cell-Substrate Sensing (ECIS) technique for cell culture test using herein the Oscillation Based Test (OBT) as a bioimpedance testing method. Other bioimpedance test techniques could be directly implemented into the proposed tool to profit similar results. The aforementioned tool, that fully models a cell-culture assay, was experimentally tested using the AA8 cell line, and the results presented in this paper validating the tool predictions.

Fast Simulation of Non-linear Circuits using Semi-Analytical Solutions based on the Matrix Exponential
J.A. Serrano, A.J. Ginés, E. Peralias and A. Rueda
Conference · Conference on Design of Circuits and Integrated Systems DCIS 2019
resumen     

This paper presents a new simulation method for fast evaluation of non-linear circuits. The proposed approach solves the non-linear ordinary differential equation (ODE) set of the system using a semi-analytical solution based on the matrix exponential. The method is fully general and suitable for different circuits, including switched-capacitor (SC) architectures, analog to digital converters (Pipeline, SAR, Sigma-Delta ADCs) or digital to analog converters (SC, Current-steering DACs). For illustration purpose in this paper, an analog signal processing front-end for discrete-time data acquisition system is considered as case study. The circuit comprises a Flip-Around Sample&Hold followed by a programmable gain amplifier (PGA) based on a Correlated Double-Sampling amplifier. The model includes non-linearity associated to switches, capacitive parasitics, finite non-linear Dcgain and non-linear settling behavior including slew-rate. Comparison with traditional ODE numerical solvers shows a reduction of the computation time in more than two orders of magnitude with negligible difference in terms of accuracy.

Characterization of Implanted Stents through Neointimal Tissue Bioimpedance Simulations
J.M. Portillo-Anaya, P. Pérez, G. Huertas, A. Olmo, J.A. Serrano, A. Maldonado-Jacobi and A. Yúfera
Conference · International Conference of the IEEE Engineering in Medicine and Biology Society EMBC2019
resumen     

This work describes how is possible the definition of the light hole or lumen in implanted stents affected by restenosis processes using the BioImpedance (BI) as biomarker. The main approach is based on the fact that neointimal tissues implied in restenosis can be detected and measured thanks to their respective conductivity and dielectric properties. For this goal, it is proposed a four-electrode setup for bioimpedance measurement. The influence of the several involved tissues in restenosis: fat, muscle, fiber, endothelium and blood, have been studied at several frequencies, validating the setup and illustrating the sensitivity of each one. Finally, a real example using a standard stent, has been analyzed for stable and vulnerable plaques in restenosis test cases, demonstrating that the proposed method is useful for the stent obstruction test. Bioimpedance simulation test has been performed using the electric physics module in COMSOL Multiphysics®.

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