Fuzzy Controller for Dual Sensors Cardiac Pacemaker System in Patients with Bradycardias at Rest

Cardiovascular disease is defined as a heart rate that is less than 60 bpm. Implantable cardiac devices such as pacemakers are widely used nowadays. In this paper, design and implementation of the heart model can be controlled to be the heart of a patient suffering from a decrease in heart rate (Bradycardia). A system is designed to sense and calculate the heart rate per minute and it is considered as an input to the controller. The design and implementation of Mamdani fuzzy controller to generate electric pulses that mimic the natural pacing system of the heart maintains an adequate heart rate by delivering controlled, rhythmic electrical stimuli to the chambers of the patient heart. The proposed controller is tested by using Matlab/Simulink program

DC electrical stimulation enhances proliferation and differentiation on N2a and MC3T3 cell lines

Background: Electrical stimulation is a novel tool to promote the differentiation and proliferation of precursor cells. In this work we have studied the effects of direct current (DC) electrical stimulation on neuroblastoma (N2a) and osteoblast (MC3T3) cell lines as a model for nervous and bone tissue regeneration, respectively. We have developed the electronics and encapsulation of a proposed stimulation system and designed a setup and protocol to stimulate cell cultures. Methods: Cell cultures were subjected to several assays to assess the effects of electrical stimulation on them. N2a cells were analyzed using microscope images and an inmunofluorescence assay, differentiated cells were counted and neurites were measured. MC3T3 cells were subjected to an AlamarBlue assay for viability, ALP activity was measured, and a real time PCR was carried out. Results: Our results show that electrically stimulated cells had more tendency to differentiate in both cell lines when compared to non-stimulated cultures, paired with a promotion of neurite growth and polarization in N2a cells and an increase in proliferation in MC3T3 cell line. Conclusions: These results prove the effectiveness of electrical stimulation as a tool for tissue engineering and regenerative medicine, both for neural and bone injuries. Bone progenitor cells submitted to electrical stimulation have a higher tendency to differentiate and proliferate, filling the gaps present in injuries. On the other hand, neuronal progenitor cells differentiate, and their neurites can be polarized to follow the electric field applied.Universidad de Sevilla US-1380661Junta de Andalucía P18-FR-2038. 2020–202

Flexible electronic substrates to deliver electromechanical stimuli to regenerative cardiac patches

After myocardial infarction, the stressed environment may cause negative cardiac remodeling. An emerging treatment option, engineered cardiac patches can be mechanically conditioned to increase alignment or electrically stimulated to enable anisotropic conduction. While proper integration with native tissue may require both stimuli, very few studies have applied both simultaneously, and only to extracted tissues. To demonstrate feasibility, a rigid electrode prototype was constructed to incorporate electrical stimulation into a commercially available mechanical conditioning system. Electrodes were assembled to fit the system’s geometry, and parameters were optimized to mimic the human heart rate. Previously, a study used 5-Azacytidine (5-Aza) to differentiate mesenchymal stem cells (MSCs) toward cardiac lineage, which was used here for proof-of-concept testing. Unexpectedly, MSCs treated with 5-Aza and electrically stimulated showed a decrease in cardiac marker troponin and an increase in MSC surface marker gene expression. In this setup, current from rigid electrodes passes through the media; however, under physiologically relevant conditions, electrical signals should propagate directly through cardiomyocytes. Therefore, a method to apply electromechanical stimulation to individual cells was explored in a point source stimulation platform. Electroconductive adhesive (ECA), a composite of silver and polydimethylsiloxane, was used to fabricate flexible elastic microelectrode arrays that provided positive and negative voltage sources to individual cells. Devices were not cytotoxic before applying an electric field; however, applied current caused electrolysis of media and cytotoxicity, even using current stimulation parameters lower than those in published studies. These findings suggest ECA electrochemical properties need more characterization and alternative materials for microelectrodes

A Biohybrid Setup for Coupling Biological and Neuromorphic Neural Networks

Developing technologies for coupling neural activity and artificial neural components, is key for advancing neural interfaces and neuroprosthetics. We present a biohybrid experimental setting, where the activity of a biological neural network is coupled to a biomimetic hardware network. The implementation of the hardware network (denoted NeuroSoC) exhibits complex dynamics with a multiplicity of time-scales, emulating 2880 neurons and 12.7 M synapses, designed on a VLSI chip. This network is coupled to a neural network in vitro, where the activities of both the biological and the hardware networks can be recorded, processed, and integrated bidirectionally in real-time. This experimental setup enables an adjustable and well-monitored coupling, while providing access to key functional features of neural networks. We demonstrate the feasibility to functionally couple the two networks and to implement control circuits to modify the biohybrid activity. Overall, we provide an experimental model for neuromorphic-neural interfaces, hopefully to advance the capability to interface with neural activity, and with its irregularities in pathology

Advanced intelligent control and optimization for cardiac pacemaker systems

Since cardiovascular diseases are major causes of morbidity and mortality in the developed countries and the number one cause of death in the United States, their accurate diagnosis and effective treatment via advanced cardiac pacemaker systems have become very important. Intelligent control and optimization of the pacemakers are significant research subjects. Serious but infrequently occurring arrhythmias are difficult to diagnose. The use of electrocardiogram (ECG) waveform only cannot exactly distinguish between deadly abnormalities and temporary arrhythmias. Thus, this work develops a new method based on frequency entrainment to analyze pole-zero characteristics of the phase error between abnormal ECG and entrained Yanagihara, Noma, and Irisawa (YNI)-response. The thresholds of poles and zeros to diagnose deadly bradycardia and tachycardia are derived, respectively, for the first time. For bradycardia under different states, a fuzzy proportional-integral-derivative (FPID) controller for dual- sensor cardiac pacemaker systems is designed. It can automatically control the heart rate to accurately track a desired preset profile. Through comparing with the conventional algorithm, FPID provides a more suitable control strategy for offering better adaptation of the heart rate, in order to fulfill the patient\u27s physiological needs. This novel control method improves the robustness and performance of a pacemaker system significantly. Higher delivered energy for stimulation may cause higher energy consumption in pacemakers and accelerated battery depletion. Hence, this work designs an optimal single-pulse stimulus to treat sudden cardiac arrest, while minimizing the pulse amplitude and releasing stimulus pain. Moreover, it derives the minimum pulse amplitude for successful entrainment. The simulation results confirm that the optimal single-pulse is effective to induce rapid response of sudden cardiac arrest for heartbeat recovery, while a significant reduction in the delivered energy is achieved. The study will be helpful for not only better diagnosis and treatment of cardiovascular diseases but also improving the performance of pacemaker systems

Intra-Cortical Microelectrode Arrays for Neuro-Interfacing

Neuro-engineering is an emerging multi-disciplinary domain which investigates the electrophysiological activities of the nervous system. It provides procedures and techniques to explore, analyze and characterize the functions of the different components comprising the nervous system. Neuro-engineering is not limited to research applications; it is employed in developing unconventional therapeutic techniques for treating different neurological disorders and restoring lost sensory or motor functions. Microelectrodes are principal elements in functional electric stimulation (FES) systems used in electrophysiological procedures. They are used in establishing an interface with the individual neurons or in clusters to record activities and communications, as well as modulate neuron behaviour through stimulation. Microelectrode technologies progressed through several modifications and innovations to improve their functionality and usability. However, conventional electrode technologies are open to further development, and advancement in microelectrodes technology will progressively meliorate the neuro-interfacing and electrotherapeutic techniques. This research introduced design methodology and fabrication processes for intra-cortical microelectrodes capable of befitting a wide range of design requirements and applications. The design process was employed in developing and implementing an ensemble of intra-cortical microelectrodes customized for different neuro-interfacing applications. The proposed designs presented several innovations and novelties. The research addressed practical considerations including assembly and interconnection to external circuitry. The research was concluded by exhibiting the Waterloo Array which is a high channel count flexible 3-D neuro-interfacing array. Finally, the dissertation was concluded by demonstrating the characterization, in vitro and acute in vivo testing results of the Waterloo Array. The implemented electrodes were tested and benchmarked against commercial equivalents and the results manifested improvement in the electrode performance compared to conventional electrodes. Electrode testing and evaluation were conducted in the Krembil Neuroscience Centre Research Lab (Toronto Western Hospital), and the Neurosciences & Mental Health Research Institute (the Sick Kids hospital). The research results and outcomes are currently being employed in developing chronic intra-cortical and electrocorticography (ECoG) electrode arrays for the epilepsy research and rodents nervous system investigations. The introduced electrode technologies will be used to develop customized designs for the clinical research labs collaborating with CIRFE Lab.1 yea

Alternative Electrode Materials for Prototyping Cell Model-Specific Microelectrode Arrays

Mikroelektrodimatriisi (MEA, microelectrode array) on biologien käyttämä väline solujen sähköisen toiminnan mittaamiseen in vitro olosuhteissa. Pelkkien satunnaisten soluryppäiden ja yksikerroksisten soluviljelmien tutkimisen rinnalla yleistymässä ovat biologiset tutkimuskysymykset, joissa tutkitaan ohjatusti muodostettuja soluverkkoja tai yksittäisiä soluja. Nämä aiheet asettavat sellaisia erityisvaatimuksia elektrodien koolle ja sijainnille MEA-levyllä, sekä ylipäätään MEA-levyn suorituskyvylle, että kaupasta saatavat vakiomalliset MEA-levyt eivät yleensä niitä täytä. Räätälöidyille MEA-levyille onkin tarvetta monella sovellusalueella perussolubiologiasta ja tautimallien kehittämisestä myrkyllisyystutkimuksiin ja lääketestaukseen. Tässä väitöstyössä on valmistettu mikroelektrodeja, joiden materiaalina on käytetty titaania, atomikerroskasvatettua (atomic layer deposition, ALD) iridiumoksidia (IrOx) sekä ionisuihkuavusteiselle elektronisuihkuhöyrystyksellä (ion beam assisten e-beam deposition, IBAD) tuotettua titaaninitridiä (TiN). Elektrodit on karakterisoitu mm. niiden impedanssin, kohinatason ja pinnan morfologian osalta. Lisäksi bioyhteensopivuus ja toimivuus on varmistettu kokeilla, joissa on käytetty ihmisperäisistä kantasoluista johdettuja hermo- ja sydänsoluja. Näiden tutkimusten tarkoituksena on tarjota MEA-valmistukseen lisää vaihtoehtoja, mistä valita eri sovelluksiin parhaiten sopivat ja käytettävissä olevat resurssit parhaiten huomioivat elektrodimateriaalit. Titaanin käyttöä puhtaasti metallimuodossa on mikroelektrodimateriaalina yleisesti vältetty sen johtavuusominaisuuksia häiritsevän hapettumistaipumuksen vuoksi. Valmistukseen kuluva aika ja kustannukset voivat kuitenkin olla räätälöityjen MEA-prototyyppien kehittämisessä olennaisempia tekijöitä kuin prototyypin huippuunsa viritetty suorituskyky, jota usein arvioidaan 1 kHz taajuudella mitatun impedanssin avulla. Kuten odotettua, titaanielektrodien impedanssi oli huomattavan korkea (>1700 kΩ), mutta silti solumittauksissa sekä hermo- että sydänsolujen tuottamat kenttäpotentiaalisignaalit olivat erotettavissa kohinasta. Titaanin etuihin elektrodimateriaalina kuuluvat yleisimpiin vaihtoehtoihin verrattuna vähäisempien ja yksinkertaisempien prosessivaiheiden tarve sekä noin sata kertaa pienemmät raaka-aine kustannukset kultaan ja platinaan verrattuna. IrOx ja TiN ovat yleisesti käytettyjä elektrodien pinnoitusmateriaaleja, joiden tarkoitus on laskea esimerkiksi titaanista tehtyjen elektrodien impedanssia ja kohinatasoa. Tässä työssä tutkittiin mahdollisuutta tehdä pinnoitukset vaihtoehtoisilla, MEA sovelluksissa uusilla menetelmillä, ALD:llä ja IBAD:lla. Vaikka näillä menetelmillä pinnoitettujen 30 μm elektrodien impedanssit (450 kΩ ALD IrOx:lle ja ~90 kΩ IBAD TiN:lle) eivät aivan laskeneetkaan yleisesti käytettyjen sputteroidun TiN:n (30-50 kΩ) ja huokoisen platinan eli Pt black:n (20-30 kΩ) tasolle, niin solumittauksissa etenkään IBAD TiN elektrodien ja sputteroitujen TiN elektrodien välillä ei ollut käytännössä lainkaan havaittavaa eroa kohinatasossa ja signaalipiikkien korkeuksissa. Täten IBAD TiN onkin täysin varteenotettava materiaalivaihtoehto niille, jotka suosivat TiN elektrodeja, mutta joilla ei ole sputteriointiin sopivaa laitetta käytettävissä. ALD:n ja IrOx:n yleiset ominaisuudet sen sijaan puoltavat ALD IrOx:n sopimista erityisesti geometrialtaan haastaviin tapauksiin tai sovelluksiin, joissa elektrodeilta vaaditaan erinomaisia stimulointiominaisuuksia. Lopuksi tässä väitöstyössä kehitettiin esimerkkinä räätälöidyn MEA-levyn vaativasta sovelluksesta yksittäisten sydänsolujen mittaamiseen soveltuva MEA-levy. Tällainen MEA-levy tarjoaa yleisesti käytetylle, mutta työläälle patch-clamp menetelmälle ainutlaatuisen soluja vahingoittamattoman vaihtoehdon yksittäisten solujen tutkimiseksi, sekä mahdollistaa yksittäisen solun ominaisuuksien havainnoinnin paremmin, kuin usein varsin heterogeenisen soluviljelmän tutkiminen vakiomallisella MEA-levyllä. Ratkaisuna tähän oli elektrodien sijoittaminen lähelle solualueen ulkokehää sekä elektrodien halkaisijan kasvattaminen 80 μm:iin tavanomaisesta 30 μm:stä, mikä helpotti solujen asettamista elektrodeille ja mahdollisti solujen sähköisen sykesignaalin mittaamisen. Indiumtinaoksidi (ITO) elektrodien läpinäkyvyys mahdollisti lisäksi mekaanisen sykinnän analysoimisen kuvaan perustuvan mittaamisen avulla.A microelectrode array, MEA, is a tool used by biologists for measuring the electrical activity of cells in vitro. Instead of only studying random cell clusters and monolayers, an increasing number of biological research questions are aimed at studying well- defined cell networks or single cells. This places special demands on the location, size, and overall performance of the MEA electrodes, which the standard, commercially available layouts cannot usually meet. Therefore, custom-designed MEAs are needed for a wide range of applications from basic cell biology and disease model development to toxicity testing and drug screening. This thesis focuses on the fabrication of microelectrodes made of titanium, atomic layer deposited (ALD) iridium oxide (IrOx), and ion beam-assisted e-beam deposited (IBAD) titanium nitride (TiN). These MEAs are characterized, for example, in terms of their impedance, noise level, and surface morphology, and their biocompatibility and functionality are verified by simple experiments with human stem cell-derived neuronal cells and cardiomyocytes. The aim of these studies is to offer more alternatives for MEA fabrication, enabling researchers and practitioners to choose the electrode material that best fits their application from their available resources. Pure titanium is commonly disregarded as an electrode material because of its oxidation tendency, which destabilizes the electrical performance. However, when prototyping customised MEAs, the time and cost of fabricating the subsequent iterations of the prototype can be more decisive factors than the device’s ultimate electrical performance, which is typically evaluated by the impedance value at 1 kHz. As might be expected, although titanium electrodes underperformed in terms of impedance (>1700 kΩ), when used in the cell experiments, the field potentials from both neuronal cells and cardiomyocytes were still easily distinguishable from the noise. There are a number of benefits to using titanium as an electrode material. Besides the fact that it is about hundred times cheaper than other commonly-used materials, such as gold or platinum, it usually requires fewer and often simpler process steps than the most common alternatives. IrOx and TiN are common electrode coatings which, when applied on top of e.g. a titanium electrode, can lower the impedance and the noise level of the electrode. In this study, two alternative deposition methods, ALD and IBAD, were used for IrOx and TiN in MEA applications. Even if the impedance of these 30 μm electrodes (450 kΩ for ALD IrOx and ~90 kΩ for IBAD TiN) did not quite reach the impedance levels of the industry standards, i.e. sputtered TiN (30-50 kΩ) and Pt black (20-30 kΩ), in cell experiments the IBAD TiN electrodes in particular showed no tangible differences in peak amplitudes and noise levels compared with sputtered TiN electrodes. This makes IBAD TiN an attractive alternative material for those who prefer to use TiN electrodes, but do not have access to a sputter coater, for example. ALD IrOx, on the other hand, relies on the potential of the general properties of ALD and IrOx (yet unverified) to provide exceptional performance in designs requiring excellent step coverage or stimulation capability. Finally, as an application example of a custom-designed MEA, a version capable of measuring cardiomyocytes at the single-cell level was developed. The benefit of such an MEA is to offer a unique noninvasive method to study single cells without destroying them with the time-consuming patch clamp method, and without losing cell-specific information, which often occurs if the cell clusters studied with standard MEAs are too heterogenous. This was achieved with a number of innovations. For example, the electrodes were placed near the perimeter of the cell culturing area and had a larger diameter (80 μm) than the usual 30 μm electrodes. This simplified the plating of the cells to the electrodes and enabled the beating of the cells to be electrically recorded. It is also possible to combine that with image-based analysis of mechanical beating through transparent indium tin oxide (ITO) electrodes

Can the Voluntary Drive to a Paretic Muscle be Estimated from the Myoelectric Signal during Stimulation?

Patients with SCI sometimes recover lost function after using FES. This phenomenon, known as the carry-over effect, is not fully understood. One theory used to explain this mechanism is that electrical stimulation of the peripheral nerve causes antidromic action potentials to reach the anterior horn cells in time with the patient’s voluntary effort. This may reinforce the motor pathways and consequently restore voluntary control. However, the theory has never been properly tested and testing requires a method of measuring the voluntary drive. This project aims to find out whether it is possible to estimate the voluntary drive from measured myoelectric signals. The project is based on an FES cycling system with the ability to adjust the stimulation intensity relating to the corresponding voluntary drive. In paretic muscles, the weak voluntary contraction produces an EMG response. The EMG signal cannot be used directly as an indication of the voluntary drive because of the presence of stimulus artefact and reflexes. Two methods were investigated to estimate the voluntary drive. A time domain method was tested using RMS EMG extracted from a range of time windows following the stimulation pulse. This approach was unsatisfactory because the large variations seen in the RMS EMG amplitudes for the same power output as well as the low sensitivity of it to the change of power output. A frequency domain approach was then tested using coherence between co-contracting muscles. It was encouraging to see that the area under the coherence curve in the β band reflected changes in the power output level. However, further tests showed that this area was also greatly influenced by exercise time, becoming unpredictable after 3 minutes. In conclusion, neither of the two methods of using the myoelectric signal from muscles under stimulation is practical for the estimation of voluntary drive