Biomedical point-of-care microanalyzer for potentiometric determination of ammonium ion in plasma and whole blood.

Some inborn errors of metabolism and other diseases can result in increasing blood ammonium (hyperammonemia episodes), which can cause serious neurological complications in patients or even death. Early diagnosis, follow up and treatment are essential to minimize irreversible damages in brain. Currently, adequate analytical instrumentation for the necessary ammonium bedside determination is not available in all health centers but only in clinical laboratories of reference hospitals. We therefore have developed a low cost and portable potentiometric Point-of-Care microanalyzer (POC) to address this problem. It consists of a cyclic olefin copolymer-based microanalyzer, the size of a credit card and working in continuous flow, which integrates microfluidics, a gas-diffusion module and a potentiometric detection system. The analytical features achieved are a linear range from 30 to 1000 µmol L-1 NH4+, a detection limit of 18 µmol L-1 NH4+ and a required sample volume of 100 µL, which comply with the medical requirements. Plasma and blood samples are analyzed with no significant differences observed between ammonium concentrations obtained with both the proposed microanalyzer and the reference method. This demonstrates the value of the developed POC for bedside clinical applications.

Electrophysiological and histological characterization of atrial scarring in a model of isolated atrial myocardial infarction.

Background: Characterization of atrial myocardial infarction is hampered by the frequent concurrence of ventricular infarction. Theoretically, atrial infarct scarring could be recognized by multifrequency tissue impedance, like in ventricular infarction, but this remains to be proven. Objective: This study aimed at developing a model of atrial infarction to assess the potential of multifrequency impedance to recognize areas of atrial infarct scar. Methods: Seven anesthetized pigs were submitted to transcatheter occlusion of atrial coronary branches arising from the left coronary circumflex artery. Six weeks later the animals were anesthetized and underwent atrial voltage mapping and multifrequency impedance recordings. The hearts were thereafter extracted for anatomopathological study. Two additional pigs not submitted to atrial branch occlusion were used as controls. Results: Selective occlusion of the atrial branches induced areas of healed infarction in the left atrium in 6 of the 7 cases. Endocardial mapping of the left atrium showed reduced multi-frequency impedance (Phase angle at 307 kHz: from -17.1° ± 5.0° to -8.9° ± 2.6°, p < .01) and low-voltage of bipolar electrograms (.2 ± 0.1 mV vs. 1.9 ± 1.5 mV vs., p < .01) in areas affected by the infarction. Data variability of the impedance phase angle was lower than that of bipolar voltage (coefficient of variability of phase angle at307 kHz vs. bipolar voltage: .30 vs. .77). Histological analysis excluded the presence of ventricular infarction. Conclusion: Selective occlusion of atrial coronary branches permits to set up a model of selective atrial infarction. Atrial multifrequency impedance mapping allowed recognition of atrial infarct scarring with lesser data variability than local bipolar voltage mapping. Our model may have potential applicability on the study of atrial arrhythmia mechanisms.

Phase angle by electrical bioimpedance is a predictive factor of hospitalisation, falls and mortality in patients with cirrhosis.

The phase angle is a versatile measurement to assess body composition, frailty and prognosis in patients with chronic diseases. In cirrhosis, patients often present alterations in body composition that are related to adverse outcomes. The phase angle could be useful to evaluate prognosis in these patients, but data are scarce. The aim was to analyse the prognostic value of the phase angle to predict clinically relevant events such as hospitalisation, falls, and mortality in patients with cirrhosis. Outpatients with cirrhosis were consecutively included and the phase angle was determined by electrical bioimpedance. Patients were prospectively followed to determine the incidence of hospitalisations, falls, and mortality. One hundred patients were included. Patients with phase angle ≤ 4.6° (n = 31) showed a higher probability of hospitalisation (35% vs 11%, p = 0.003), falls (41% vs 11%, p = 0.001) and mortality (26% vs 3%, p = 0.001) at 2-year follow-up than patients with PA > 4.6° (n = 69). In the multivariable analysis, the phase angle and MELD-Na were independent predictive factors of hospitalisation and mortality. Phase angle was the only predictive factor for falls. In conclusion, the phase angle showed to be a predictive marker for hospitalisation, falls, and mortality in outpatients with cirrhosis.

Endocardial infarct scar recognition by myocardial electrical impedance is not influenced by changes in cardiac activation sequence.

BACKGROUND: Measurement of myocardial electrical impedance can allow recognition of infarct scar and is theoretically not influenced by changes in cardiac activation sequence, but this is not known. OBJECTIVES: The objectives of this study were to evaluate the ability of endocardial electrical impedance measurements to recognize areas of infarct scar and to assess the stability of the impedance data under changes in cardiac activation sequence. METHODS: One-month-old myocardial infarction confirmed by cardiac magnetic resonance imaging was induced in 5 pigs submitted to coronary artery catheter balloon occlusion. Electroanatomic data and local electrical impedance (magnitude, phase angle, and amplitude of the systolic-diastolic impedance curve) were recorded at multiple endocardial sites in sinus rhythm and during right ventricular pacing. By merging the cardiac magnetic resonance and electroanatomic data, we classified each impedance measurement site either as healthy (bipolar amplitude ≥1.5 mV and maximum pixel intensity <40%) or scar (bipolar amplitude <1.5 mV and maximum pixel intensity ≥40%). RESULTS: A total of 137 endocardial sites were studied. Compared to healthy tissue, areas of infarct scar showed 37.4% reduction in impedance magnitude (P < .001) and 21.5% decrease in phase angle (P < .001). The best predictive ability to detect infarct scar was achieved by the combination of the 4 impedance parameters (area under the receiver operating characteristic curve 0.96; 95% confidence interval 0.92-1.00). In contrast to voltage mapping, right ventricular pacing did not significantly modify the impedance data. CONCLUSION: Endocardial catheter measurement of electrical impedance can identify infarct scar regions, and in contrast to voltage mapping, the impedance data are not affected by changes in cardiac activation sequence.

In-bed vital signs monitoring system based on unobtrusive magnetic induction method with a concentric planar gradiometer.

SIGNIFICANCE: Unobtrusive vital signs monitoring is of major importance for various medical areas such as detection and treatment of sleep disorders, monitoring neonates and burned victims, home health care and smart home applications and wearables among others. Such applications call for monitoring methods in which the patient's natural state is less interfered with. An ideal device would be non-invasive, minimally restrictive, robust enough to compensate movements of the patients, and would operate without relying on the patient's full cooperation. OBJECTIVE: This paper focuses on the design and development of an unobtrusive vital signs monitoring system particularly suited for long-term monitoring placed under the mattresses. APPROACH: The system is based on the magnetic induction sensing method, designed to infer presence on the bed, breathing and cardiac activity, and consists of two coils for excitation and detection. The new detection coil is based on a concentric planar gradiometer for canceling the primary field. The signal acquisition system has been designed using simple electronics to avoid ending up with a complex and expensive system. The experimental results were compared with reference signals coming from other known sensors with different technical bases for benchmarking and identifying the advantages and/or drawbacks of the new system regarding other techniques. The designed system was also studied in regards to safety standards and limitations for the exposure to the magnetic fields. MAIN RESULTS: Experimental results confirm the suitability and safety of the sensor for long-term cardiac and respiratory monitoring. The system is able to detect respiration and cardiac activity as well as the presence on the bed and changes in position.

Recognition of Fibrotic Infarct Density by the Pattern of Local Systolic-Diastolic Myocardial Electrical Impedance.

Myocardial electrical impedance is a biophysical property of the heart that is influenced by the intrinsic structural characteristics of the tissue. Therefore, the structural derangements elicited in a chronic myocardial infarction should cause specific changes in the local systolic-diastolic myocardial impedance, but this is not known. This study aimed to characterize the local changes of systolic-diastolic myocardial impedance in a healed myocardial infarction model. Six pigs were successfully submitted to 150 min of left anterior descending (LAD) coronary artery occlusion followed by reperfusion. 4 weeks later, myocardial impedance spectroscopy (1-1000 kHz) was measured at different infarction sites. The electrocardiogram, left ventricular (LV) pressure, LV dP/dt, and aortic blood flow (ABF) were also recorded. A total of 59 LV tissue samples were obtained and histopathological studies were performed to quantify the percentage of fibrosis. Samples were categorized as normal myocardium (<10% fibrosis), heterogeneous scar (10-50%) and dense scar (>50%). Resistivity of normal myocardium depicted phasic changes during the cardiac cycle and its amplitude markedly decreased in dense scar (18 ± 2 Ω·cm vs. 10 ± 1 Ω·cm, at 41 kHz; P < 0.001, respectively). The mean phasic resistivity decreased progressively from normal to heterogeneous and dense scar regions (285 ± 10 Ω·cm, 225 ± 25 Ω·cm, and 162 ± 6 Ω·cm, at 41 kHz; P < 0.001 respectively). Moreover, myocardial resistivity and phase angle correlated significantly with the degree of local fibrosis (resistivity: r = 0.86 at 1 kHz, P < 0.001; phase angle: r = 0.84 at 41 kHz, P < 0.001). Myocardial infarcted regions with greater fibrotic content show lower mean impedance values and more depressed systolic-diastolic dynamic impedance changes. In conclusion, this study reveals that differences in the degree of myocardial fibrosis can be detected in vivo by local measurement of phasic systolic-diastolic bioimpedance spectrum. Once this new bioimpedance method could be used via a catheter-based device, it would be of potential clinical applicability for the recognition of fibrotic tissue to guide the ablation of atrial or ventricular arrhythmias.

Early detection of acute transmural myocardial ischemia by the phasic systolic-diastolic changes of local tissue electrical impedance.

Myocardial electrical impedance is influenced by the mechanical activity of the heart. Therefore, the ischemia-induced mechanical dysfunction may cause specific changes in the systolic-diastolic pattern of myocardial impedance, but this is not known. This study aimed to analyze the phasic changes of myocardial resistivity in normal and ischemic conditions. Myocardial resistivity was measured continuously during the cardiac cycle using 26 different simultaneous excitation frequencies (1 kHz-1 MHz) in 7 anesthetized open-chest pigs. Animals were submitted to 30 min regional ischemia by acute left anterior descending coronary artery occlusion. The electrocardiogram, left ventricular (LV) pressure, LV dP/dt, and aortic blood flow were recorded simultaneously. Baseline myocardial resistivity depicted a phasic pattern during the cardiac cycle with higher values at the preejection period (4.19 ± 1.09% increase above the mean, P < 0.001) and lower values during relaxation phase (5.01 ± 0.85% below the mean, P < 0.001). Acute coronary occlusion induced two effects on the phasic resistivity curve: 1) a prompt (5 min ischemia) holosystolic resistivity rise leading to a bell-shaped waveform and to a reduction of the area under the LV pressure-impedance curve (1,427 ± 335 vs. 757 ± 266 Ω·cm·mmHg, P < 0.01, 41 kHz) and 2) a subsequent (5-10 min ischemia) progressive mean resistivity rise (325 ± 23 vs. 438 ± 37 Ω·cm at 30 min, P < 0.01, 1 kHz). The structural and mechanical myocardial dysfunction induced by acute coronary occlusion can be recognized by specific changes in the systolic-diastolic myocardial resistivity curve. Therefore these changes may become a new indicator (surrogate) of evolving acute myocardial ischemia.

Interpulse multifrequency electrical impedance measurements during electroporation of adherent differentiated myotubes.

In this study, electrical impedance spectroscopy measurements are performed during electroporation of monolayers of differentiated myotubes. The time resolution of the system (1 spectrum/ms) enable 860 full spectra (21 frequencies from 5 kHz to 1.3 MHz) to be acquired during the time gap between consecutive pulses (interpulse) of a classical electroporation treatment (8 pulses, 100 µs, 1 Hz). Additionally, the characteristics of the custom microelectrode assembly used allow the experiments to be performed directly in situ in standard 24 multi-well plates. The impedance response dynamics are studied for three different electric field intensities (400, 800 and 1200 V/cm). The multifrequency information, analysed with the Cole model, reveals a short-term impedance recovery after each pulse in accordance with the fast resealing of the cell membrane, and a long-term impedance decay over the complete treatment in accordance with an accumulated effect pulse after pulse. The analysis shows differences between the lowest electric field condition and the other two, suggesting that different mechanisms that may be related with the reversibility of the process are activated. As a result of the multifrequency information, the system is able to measure simultaneously the conductivity variations due to ion diffusion during electroporation. Finally, in order to reinforce the physical interpretation of the results, a complementary electrical equivalent model is used.

Myocardial contractility assessed by dynamic electrical impedance measurements during dobutamine stress.

In this study, the electrical impedance of myocardial tissue is measured dynamically during the cardial cycle. The multisine-based approach used to perform electrical impedance spectroscopy (EIS) measurements allows acquiring complete spectral impedance information of the tissue dynamics during contraction. Measurements are performed in situ in the left ventricule of swines during contractility stress tests induced by dobutamine infusion. Additionally, the ECG and the left ventricular (LV) pressure are also acquired synchronously to the impedance signals. The calculated impedance magnitude exhibits a periodic behavior during tissue contraction. The amplitude (peak-to-peak) of this signal is quantified and the compared to the maximum first derivative of the LV pressure (dP/dtmax) that is used as an indicator of contractility variations. The results show a linear correlation between impedance amplitude and dP/dtmax during dobutamine-increased contractility. The present work demonstrates how fast EIS measurements during heart contraction can represent a feasible method to assess changes in myocardial contractility.

Physiological conditioning by electric field stimulation promotes cardiomyogenic gene expression in human cardiomyocyte progenitor cells.

The optimal cell lineage for cardiac-regeneration approaches remains mysterious. Additionally, electrical stimulation promotes cardiomyogenic differentiation of stimulated cells. Therefore, we hypothesized that electrical conditioning of cardiomyocyte progenitor cells (CMPCs) might enrich their cardiovascular potential. CMPCs were isolated from human adult atrial appendages, characterized, and electrically stimulated for 7 and 14 days. Electrical stimulation modulated CMPCs gene and protein expression, increasing all cardiac markers. GATA-binding protein 4 (GATA4) early transcription factor was significantly overexpressed (P = 0.008), but also its coactivator myocyte enhancer factor 2A (MEF2A) was upregulated (P = 0.073) under electrical stimulation. Moreover, important structural proteins and calcium handling-related genes were enhanced. The cardioregeneration capability of CMPCs is improved by electrical field stimulation. Consequently, short-term electrical stimulation should be a valid biophysical approach to modify cardiac progenitor cells toward a cardiogenic phenotype, and can be incorporated into transdifferentiation protocols. Electrostimulated CMPCs may be best-equipped cells for myocardial integration after implantation.

A new spiral microelectrode assembly for electroporation and impedance measurements of adherent cell monolayers.

In this study, a new microelectrode assembly based on spiral geometry applicable to in situ electroporation of adherent cell monolayers on standard multiwell plates is presented. Furthermore, the structure is specially conceived to perform electrical impedance spectroscopy (EIS) measurements during electroporation. Its performance for cell membrane permeabilization is tested with a fluorescent probe. Gene electrotransfer is also assayed using a plasmid DNA encoding GFP in four different cell lines (CHO, HEK293, 3T3-L1 and FTO2B). Additionally, siRNA α-GFP electrotransfection is tested in GFP gene-expressing CHO cells. Our data show considerable differences between permeabilization and gene transfer results and cell line dependence on gene expression rates. Successful siRNA electro-mediated delivery is also achieved. We demonstrate the applicability of our device for electroporation-mediated gene transfer of adherent cells in standard laboratory conditions. Finally, electrical impedance measurements during electroporation of CHO and 3T3-L1 cells are also given.

An implantable bioimpedance monitor using 2.45 GHz band for telemetry.

This paper describes a multi-frequency single-channel electrical implantable bioimpedance monitor (35 mm × 35 mm × 10 mm, weight 52 g) powered by a NiMH battery. By using the tetrapolar method and injecting 10 µA(peak), the monitor is capable of measuring at 14 different frequencies, from 100 Hz to 200 kHz. It contains a ZigBee transceiver to monitor the measurements performed, and has an embedded memory for backing up the data. RC networks and in-situ heart excised tissues were used to test the system. When measuring a full spectrum every 5 min, 35 days of autonomy are possible due to the low power consumption of the monitor. Temperature drift was estimated by short-term and long-term measurements. Temperature cycling was used to measure modulus and phase angle stability. The result was a very low effect on a modulus decrease of 2.34 Ω, with respect to an impedance of 322 Ω, at 100 Hz and a phase angle increase of 1.1°, at 200 kHz. In addition, measurement errors were bigger at low frequencies because of the high impedance of the electrodes used, which was higher than 10 kΩ at frequencies below 1 kHz.

In-cycle myocardium tissue electrical impedance monitoring using broadband impedance spectroscopy.

Measurements of myocardium tissue impedance during the cardiac cycle have information about the morphology of myocardium cells as well as cell membranes and intra/extra cellular spaces. Although the variation with time of the impedance cardiac signal has information about the myocardium tissue activity during the cardiac cycle, this information has been usually underestimated in the studies based on frequency-sweep Electrical Impedance Spectroscopy (EIS) technique. In these cases, the dynamic behavior was removed from the impedance by means of averaging. The originality of this research is to show the time evolution of in-vivo healthy myocardium tissue impedance during the cardiac cycle, being measured with a multisine excitation at 26 frequencies (1 kHz-1 MHz). The obtained parameters from fitting data to a Cole model are valid indicators to explain the time relation of the systolic and diastolic function with respect to the myocardium impedance time variation. This paper presents a successful application of broadband Impedance Spectroscopy for time-varying impedance monitoring. Furthermore, it can be extended to understand various unsolved problems in a wide range of biomedical and electrochemical applications, where the system dynamics are intended to be studied.

Changes in myocardial electrical impedance in human heart graft rejection.

BACKGROUND: Monitoring of post-transplant heart rejection is currently based on endomyocardial biopsy analysis. This study aimed to assess the effects of heart graft rejection on myocardial electrical impedance. METHODS AND RESULTS: Twenty-nine cardiac transplant patients and 9 controls underwent measurement of myocardial electrical impedance using a specifically designed amplifying system. The module and phase angle of myocardial impedance were measured. Histopathological rejection grading was performed according to ISHLT classification. Fifty impedance tests were performed in transplanted patients. Myocardial impedance (Z) was higher in controls than in transplanted patients (p<0.001) and followed a progressive decline at increasing current frequencies (p<0.001). Likewise, the phase angle of impedance in controls ranged from positive values at low frequencies to negative values at higher frequencies (from 2.5+/-0.9 degrees at 10 kHz to -3.8+/-2.1 degrees at 300 kHz, p<0.001). Rejection was associated with a significant decrease in myocardial impedance (Z) (15+/-6.6 Omega in grade 0, 13+/-6.0 Omega in grade 1A, and 3.3+/-0.9 Omega in grade 3A at 10 kHz, p<0.003). CONCLUSIONS: Mild degrees of cardiac graft rejection are associated with significant changes in myocardial electrical impedance in transplant patients. Further clinical investigation is warranted to assess the potential of cardiac impedance to detect heart graft rejection.

Single-step 3-d image reconstruction in magnetic induction tomography: theoretical limits of spatial resolution and contrast to noise ratio.

Magnetic induction tomography (MIT) is a low-resolution imaging modality for reconstructing the changes of the complex conductivity in an object. MIT is based on determining the perturbation of an alternating magnetic field, which is coupled from several excitation coils to the object. The conductivity distribution is reconstructed from the corresponding voltage changes induced in several receiver coils. Potential medical applications comprise the continuous, non-invasive monitoring of tissue alterations which are reflected in the change of the conductivity, e.g. edema, ventilation disorders, wound healing and ischemic processes. MIT requires the solution of an ill-posed inverse eddy current problem. A linearized version of this problem was solved for 16 excitation coils and 32 receiver coils with a model of two spherical perturbations within a cylindrical phantom. The method was tested with simulated measurement data. Images were reconstructed with a regularized single-step Gauss-Newton approach. Theoretical limits for spatial resolution and contrast/noise ratio were calculated and compared with the empirical results from a Monte-Carlo study. The conductivity perturbations inside a homogeneous cylinder were localized for a SNR between 44 and 64 dB. The results prove the feasibility of difference imaging with MIT and give some quantitative data on the limitations of the method.

Effect of electrode locations and respiration in the characterization of myocardial tissue using a transcatheter impedance method.

Our objective is to evaluate whether it is possible to characterize the passive electrical properties of myocardial tissue in contact with the electrocatheters used in arrhythmia diagnosis or radio frequency ablation techniques. To characterize the tissue, we propose the use of electrical impedance spectroscopy to measure the impedance between the catheter tip and an external electrode, assuming a three-electrode method. We constructed a 3D finite-element model of the thorax to estimate the impedance as measured in different situations. We defined an area on the anterior wall of the left ventricle in which we simulated three tissue states: healthy, acute ischaemic and scar. We studied the effect of the following parameters on the measured impedance spectrum: the position of the external electrode, the position and orientation of the catheter tip and the overall effect of the subject's respiration. Results show that the highest frequency phase (around 300 kHz) yields the best differentiation of tissue states and that it is less sensitive to respiration than the impedance magnitude. The phase is also less influenced by the catheter tip position (either touching the wall or floating) and the orientation of the catheter inside the left ventricle. The best position for the external electrode is on the chest; this position is less affected by breathing and is more sensitive to tissue changes. One can still distinguish between tissue states if the external electrode is placed on the back, but the effect of respiration is higher.