\r\n\tThe book Automation and Control aims to publish original, previously unpublished, case studies, research, survey and tutorial works as chapters, on both applied and theoretical aspects, which are covered by book’s topics and keywords. Consequently, the authors may send chapters covering applications in manufacturing and industrial automation, advanced and intelligent control systems, robotics, computer controlled systems and other domains.
",isbn:"978-1-83962-714-9",printIsbn:"978-1-83962-713-2",pdfIsbn:"978-1-83962-715-6",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"09ba24f6ac88af7f0aaff3029714ae48",bookSignature:"Prof. Constantin Volosencu",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9893.jpg",keywords:"Process control, Real-time control, Adaptive control, Robust control, Biologically inspired systems, Fuzzy systems, Power grid, Renewable energy and sustainability, Swarm robotics, Virtual reality, Computing and communications, Aerospace control",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 15th 2019",dateEndSecondStepPublish:"November 5th 2019",dateEndThirdStepPublish:"January 4th 2020",dateEndFourthStepPublish:"March 24th 2020",dateEndFifthStepPublish:"May 23rd 2020",remainingDaysToSecondStep:"a month",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,editors:[{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.jpeg",biography:"Costantin Volosencu is a professor at Politehnica University of Timisoara, Department of Automation. He is an author of 10 books and 4 book chapters as well as an editor of 6 books. He has over 153 scientific papers published in journals and conference proceedings, holds 27 patents and is a manager of research grants. He is a member of editorial boards of international journals, former plenary speaker, member in scientific committees and chair at international conferences. He has researches in the field of control systems, electrical drives, power ultrasounds, fuzzy logic, neural networks, fault detection and diagnosis, sensor networks and distributed parameter systems. He developed electrical equipments for machine tools, spooling machines, high power ultrasound processes and other, with homologation of 18 prototypes and 12 zero manufacturing series.",institutionString:"Politehnica University of Timisoara",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"6",institution:{name:"Polytechnic University of Timişoara",institutionURL:null,country:{name:"Romania"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"22",title:"Robotics",slug:"physical-sciences-engineering-and-technology-robotics"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"280415",firstName:"Josip",lastName:"Knapic",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/280415/images/8050_n.jpg",email:"josip@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copy-editing and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"2020",title:"New Technologies",subtitle:"Trends, Innovations and Research",isOpenForSubmission:!1,hash:"170d84903f390df23023d0623d8577d3",slug:"new-technologies-trends-innovations-and-research",bookSignature:"Constantin Volosencu",coverURL:"https://cdn.intechopen.com/books/images_new/2020.jpg",editedByType:"Edited by",editors:[{id:"1063",title:"Prof.",name:"Constantin",surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2021",title:"Cutting Edge Research in New 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by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"63693",title:"The Modeling, Design, Fabrication, and Application of Biosensor Based on Electric Cell-Substrate Impedance Sensing (ECIS) Technique in Environmental Monitoring",doi:"10.5772/intechopen.81178",slug:"the-modeling-design-fabrication-and-application-of-biosensor-based-on-electric-cell-substrate-impeda",body:'A large number of the world’s population live in areas with high risks of environment. Industrialization and usage of nonbiodegradable and non-eco-friendly material are harmful to the environment. Rapid urbanization, increasing population, and extensive agriculture all are threats to the Earth’s supply of fresh water. Clean and reliable drinking water can be guaranteed by periodic and extensive testing. Effectively and efficiently environmental monitoring approaches are necessary. ECIS sensing is one of the techniques among them. The ECIS is becoming an increasingly popular technique, which is able to analyze cell behaviors by measuring the impedance profile spectroscopy [1, 2]. The measured cell impedance provides information about cell morphology and electric properties, including intercellular junction conditions, numbers and densities, attachment, migration, proliferation, invasion, barrier function, membrane capacitance, and cytoplasm conductivity [1, 2, 3, 4, 5, 6]. A common ECIS sensor is composed of a working electrode and a counter electrode. Some types of ECIS sensors have a third electrode, the reference electrode, which is used to provide the reference voltage for electrochemical measurements. The traditional ECIS sensors are fabricated on rigid substrate that limits the application in some of dynamically moving environments. Zhang et al. [7, 8] have fabricated the ECIS sensors on stretchable polymer. Such sensors are able to simulate in vitro the dynamic environment of organisms, such as pulsation, bending, and stretching, which enables investigations on cell behavior that undergoes mechanical stimuli in biological tissue [9, 10, 11, 12].
The cells, attaching and spreading on the ECIS sensors, behave like an insulating medium after seeding. The insulating medium restricts the ion movement between the electrodes [13, 14]. As a result, the measured impedance increases gradually as more cells attach onto the surface. When the cells form a monolayer on the electrodes, the impedance becomes stabilized. The impedance may fluctuate slightly due to cell attachment migration, deformation, and detachment [9, 15, 16, 17, 18]. Some chemical, biological, or physical stimuli on measured cells will influence the impedance response due to the changes in cell monolayer caused by cell-cell interactions, cell-substrate interactions, or changing cell electrical properties [2, 9]. Recently, the application of ECIS sensors has been extended to cell-based assays and toxicity study [18].
The ECIS sensors have different configurations including working electrode dimensions, counter electrode dimensions, and distance between electrodes. However, the relationship between the electrode configuration and detection sensitivity has not been further studied. A study on detection sensitivity of ECIS sensors is meaningful for sensor design, fabrication, and applications.
Detection sensitivity is critical in the applications of ECIS sensors, which depends on sensor configuration, such as electrode dimension and the distance between the electrodes [19]. Wang et al. studied the detection sensitivity of ECIS sensors only with interdigital electrodes [20]. Several mathematical models have been introduced to analyze the relationship between measured cell impedance and cell morphology and behaviors [1, 2, 10, 21, 22, 23, 24, 25, 26, 27, 28]. In those models, cell membrane and cell cytoplasm were assumed to be capacitors and resistors, respectively, and cell impedance was calculated as a combination of the capacitors and resistors [24, 25, 26, 27, 28]. However, the current may switch from one path to another or creating a hybrid path in reality, which was considered by some models [1, 2, 10, 14]. Nevertheless, these models assumed that the current flows radially between the substratum and the ventral surface of the cell, and the electric potential is constant inside the cell. However, the electric potential cannot be assumed to be constant inside the cell if the current flows through the entirety of the cell. This assumption is invalidated by Ohm’s law.
In this study, the influence of ECIS sensor configuration on detection sensitivity and the analysis of paths of current flow of ECIS have been carried out for improving the detection sensitivity, design, and application of ECIS sensors. The ECIS sensors are optimized for water toxicity testing. Several ECIS sensors are used to perform the toxicity testing in detecting the toxic effects from phenol, ammonia, nicotine, and aldicarb, and the impedance response successfully indicate the toxic effect. The gradient of measured impedance qualitatively is related to the concentration of toxicants.
In order to monitor the environments effectively, systematically analyzing the relationship between the electric properties of measured subjects and output of ECIS sensors are needed. In this section, a model related to electric field distribution of ECIS sensing, which can be used in quantifying the ECIS sensor measurements, is created with a partial differential equation. The model of ECIS is established in cylindrical coordinates (r, θ, z) as shown in Figure 1 and simplified into polar coordinates (r, z) due to its axisymmetric property.
Illustration of cell impedance sensing on a working electrode. The electric potential at the coordinate (r, z) is V(r, z). ρ and ρ1 are the resistivity of the cell culture medium and cytoplasm respectively. Zm1, Zm2 and Zn are the specific impedance of the basal, apical cell membrane, and electrode-electrolyte interface respectively (in Ωm). h1 is the average distance between the ventral surface of cell and electrode-electrolyte interface. h2 is the average thickness of the cell. d is the average horizontal distance between adhesive cells. Vc is the electrical potential on the working electrode.
The governing equation of electric field distribution of ECIS sensing (as shown in Eq. (1)) can be obtained from the differential form of Ohm’s law between electric potential and current (as shown in Eq. (2)), Kirchhoff’s circuit law at a point of interest (r, z) (as shown in Eq. (3)), and the gradient of electric potential (as shown in Eq. (4)). The solution of the governing equation is shown in Eq. (5), which is the same as the solution in Giaever et al. ECIS model when the variable z is held as constant [1, 2, 23, 29]. The detailed information about the mode can be referred to in [19]. These three coefficients A, D, and c are calculated as A = −2.3, D = 3.3, and c = 4749.83 by using the parameters listed in [19, 30, 31, 32, 33, 34, 35, 36].
where ρ is the resistivity of the cell culture medium (electrolyte); I1 and I2 are the current flowing through the point (r,z) in r and z directions, respectively; er and ez are the unit vectors of the r and z directions; E is the electric field at any point (r,z); V is the electric potential at the point (r, z); and dI1 and dI2 are the infinitesimally small currents of I1 and I2. dI1 and dI2 have the same sign;
In this model, the impedance of a single cell (Zsingle cell) is able to be calculated by dividing the electric potential difference between the apical V(rc, h1) and ventral surfaces of a single cell V(rc, h1 + h2)0 by the total current flowing through and around the cell, as shown in Eq. (6).
where I2 is the current flowing through a single cell, Ij is the current flowing through the intercellular junction gap; h1 is the average distance between the ventral surface of cell and electrode-electrolyte interface; h2 is the average thickness of the cell layer; rc is the average radius of a single cell; f is the measurement frequency; ρ1 is the resistivity of cell cytoplasm; ε is the relative permittivity of the cell membrane; ε0 is the vacuum permittivity, which is 8.85 × 10−12 F/m; and t and σ are the thickness and conductivity of the cell membrane, respectively.
The impedance of a cell monolayer (Z) is calculated as the sum of the impedance on current path, including the impedance from working electrode Zworking, counter electrode Zcounter, and cell culture medium Rs, as shown in Eq. (7).
where Zn is the specific impedance of the electrode-medium interface (unit Ωm2), which can be calculated according to the parameters referred to [19, 37, 38, 39, 40, 41]; S1 and S2 are the surface areas of the working and counter electrodes, respectively; S is the total surface area of the ECIS sensor, which contains the working electrode, counter electrode, and nonelectrode area; n is the number of cells seeded on the ECIS sensor; Rs is the impedance of the culture medium, which can be calculated according to the parameters referred to [19, 42, 43, 44, 45, 46, 47]; Zcell-sub is the impedance of the culture medium between the electrode-electrolyte interface and ventral surface of cell, which can be calculated by dividing the electric potential difference between the edge and center of a single cell by the total current flowing through and around the cell [19].
The design of ECIS sensors includes the dimensions of working electrodes and counter electrodes, and the distance between them is critical in environmental monitoring because those designing parameters will influence the detection sensitivity of ECIS sensors.
The radius of working electrode (Ri) and the distance between the edges of the sensing electrodes (dio) can be optimized by using the mathematical model with the parameters related to cell morphology and electric properties and surrounding culture medium.
During impedance measurements, ions move through the cell monolayer between the working and counter electrodes which follow many paths. The counter electrodes must have adequate sensing area in order to provide adequate circuit connection. The larger Ri working electrode provides more current paths, which decreases the corresponding impedance. Higher impedance values can improve the data quality of the measured impedance by increasing signal-to-noise ratio, which is useful particularly for sensing small changes in cell behavior. However, the working electrode should not be too small in order to measure adequate number of cells and to guarantee sufficient cell-to-cell contact area.
In this study, the ECIS sensors with Ri from 100 to 400 μm were fabricated to analyze the relationship between Ri and measured cell impedance. Figure 2 illustrates the cell morphology on those sensors. The simulated cell impedance by using Ri within the same range was also obtained from the mathematical model. The experimental and simulated impedance of cell were shown in Figure 3. The simulated impedance curve matches the experimental data closely with maximum difference 13.29%, which is acceptable when considering the fluctuation of measured impedance. The consistency of the simulated impedance with the experimental impedance validates this model’s ability to optimize the Ri according to the range of measured cell number and expected output impedance level during sensor designing.
BAEC monolayer on ECIS sensors with different Ri (dio = 3.5 mm).
Relationships between Ri and experimental impedance, and between Ri and simulated impedance at 8000 Hz (n = 4 ∼ 6, dio = 3.5 mm).
The distance between the edges of the sensing electrodes (dio) is another factor that should be considered in designing ECIS sensors. Figure 4 shows the experimental impedance and the simulated impedance with different dio. The average experimental impedance slightly changed from 12.50 to 12.52 KΩ, when dio changed from 1000 to 3500 μm. The simulated impedance was calculated by using Eq. (7). dio only slightly influences the simulated impedance because the natural logarithm of the quotient of
Relationships between dio and experimental impedance, and between dio and simulated impedance, measured at 8000 Hz (n = 6 ∼ 7, Ri = 100 μm). The three images show the cell morphology of BAECs on the ECIS sensors with dio of 1 mm, 2 mm, and 3.5 mm, respectively.
Detection sensitivity reflects the fineness of impedance response to the changes of cell behavior in cell-based assay environmental monitoring. The detection sensitivity of ECIS sensors is influenced by Ri. According to the previous experimental results, ECIS sensors with Ri larger than 200 μm do not respond sensitively and quickly on cell morphology changes. So, ECIS sensors with Ri of 100 and 150 μm were fabricated to study the influence of Ri on the detection sensitivity. Cell densities, 90,000, 100,000, and 110,000 cells/cm2, were used to study the relationship between cell density and impedance. Figure 5 shows the impedance shifts versus the cell density changes with Ri of 100 and 150 μm. Figure 6 shows the corresponding cell morphology on different ECIS sensors. When the cell density changes are 10,000 cells/cm2 (from 90,000 to 100,000 cells/cm2), the impedance increased 597 and 350 Ω for the sensors with Ri of 100 and 150 μm, respectively. When the cell density changes are 20,000 cells/cm2 (from 90,000 to 110,000 cells/cm2), the impedance increased 1336 and 880 Ω for the sensors with Ri of 100 and 150 μm, respectively. The experimental results indicate that the sensors with larger Ri illustrate less impedance changes with the same amount of cell density changes. Therefore, the sensors with smaller Ri are able to detect more sensitive changes in cell density. Therefore, ECIS sensors with smaller dimension working electrodes illustrate better detection sensitivity on changes in cell density. Another benefit is that smaller Ri requires fewer cells in cell-based assays.
Impedance shifts to cell density changes with sensors’ Ri of 100 μm and 150 μm (n = 3). The cell density change from 90,000 cells/cm2 to 100,000 or 110,000 cells/cm2.
Cell morphology with 90,000, 100,000, and 110,000 cells/cm2 cell densities on ECIS sensors (Ri = 100 μm and Ri = 150 μm).
Based on the analysis above, the ECIS sensors with Ri of 100–125 μm and dio of 3.5 mm are preferred in environmental monitoring because Ri of 100–125 μm will allow the ECIS sensors to be sensitive to sense the cell morphology changes due to environment influence and own good anti-interference ability. The area of counter electrodes should be as large as possible to guarantee sufficient contact area between electrode and cells. dio of 3.5 mm is enough to avoid the current bypassing the cell layer in ECIS measurements.
The fabrication of ECIS sensors can follow different photolithography techniques. The substrates are usually nonconductive materials, includes glass, printed circuit board (PCB) [1, 2, 3, 4, 19, 23], and polymer including polydimethylsiloxane (PDMS) [9] and polycarbonate [1, 2, 3, 18, 19]. The ECIS arrays were fabricated on glass by thin film deposition and lift-off photolithography technique, as shown in Figure 7. Initially, the photoresist AZ5214E (MicroChemicals, Somerville, NJ) was coated on glass slides with spinning coater at 2000 rpm. After baking on hotplate at 110°C for 50 seconds, the coated photoresist was exposure to ultraviolet (UV) light. Then, a reversal bake is carried out at 120°C for 2 minutes. Finally, UV light with intensity larger than 200 mJ/cm2 was exposure on the photoresist pattern. The electrode pattern was created after immersing the slides with photoresist in the AZ 100 Remover (MicroChemicals, Somerville, NJ). The remover is able to dissolve the photoresist without the first exposure (image reverse). A 20-nm-thick chromium (Cr) followed by a 150-nm-thick gold (Au) was coated on the substrate to form the sensor’s electrodes by thermal evaporation. The sensing electrodes were formed after the lift-off process. Then, the photoresist SU-8 (MicroChem, Westborough, MA) was used to cover the substrate except the sensing areas. The sensor arrays were treated with 95% sulfuric acid at 60°C for 15 seconds [48] followed by washing with deionized water (DI) and then treated with 8% (3-aminopropyl)triethoxysilane (APTES) at 50°C for 2 hours to improve the surface biofunctionality. Finally, cell culture wells (Lab-Tek 8-well culture wares) were glued onto the sensor array. Figure 8 shows the fabricated ECIS sensor array and its configuration. Ri is the radius of the working electrode, Rco is the outer radius of the counter electrode, dio is the distance between the edges of the electrodes, and S1 and S2 are the areas of the working and counter electrodes, respectively.
Illustration of ECIS sensor fabrication.
The array of eight ECIS sensors.
The inherent impedance of the Au/Cr electrodes of fabricated ECIS sensors is measured by microwave probe station (Cascade Microtech Inc., Beaverton, OR) and impedance analyzer (Agilent 4294) as shown in Figure 9. The maximum inherent impedance was 19 Ω at 8000 Hz, which is much lower than the measured cellular impedance of thousands of ohms. Thus, the inherent impedance of the sensor can be neglected.
Distribution of equipotential lines in the space between the ventral cell surface and electrode-electrolyte interface layer. The axisymmetric axis of the cell locates at x = 0 (red dashed line).
Bovine aortic endothelial cells (BAECs, VEC Technologies, Rensselaer, NY) were used in this study. The BAECs were cultured in minimum essential medium (MEM, GIBCO, Grand Island, NY) with 10% fetal bovine serum (FBS, GIBCO, Grand Island NY) under standard mammalian cell culturing conditions (37°C and 5% CO2). Confluent BAEC were trypsinized to detach the cells from the cell culture flasks to prepare the cell suspension. Then, the cell suspension was centrifuged on the bottom of centrifuge tube followed by aspirating off the upper supernatant. Finally, certain amount of cell culture medium was added into centrifuge tube to prepare specific concentration of the cell suspension.
This study investigated the toxicant detection by using the ECIS sensors. The toxicants used in this study are phenol (RICCA, Arlington, TX), ammonia (Acros Organics, Fair Lawn, NJ), nicotine (Fisher Scientific, Hanover Park, IL), and aldicarb (SPEX CertiPrep, Metuchen, NJ). All the toxicants were diluted with Dulbecco’s phosphate-buffered saline (DPBS, Mediatech, Inc., Manassas, VA). The osmolarity of diluted toxicant solution was considered to be in the suitable range for cell culture because the small volume of toxicants added into DPBS will not change the concentration of essential ingredients of DPBS dramatically.
Impedance analyzer Agilent 4294 and ECIS measurement system (Applied Biophysics, Troy, NY) was used to measure the cell impedance. The AC signal applied to the cells was monitored by using Tektronix oscilloscope DPO2014B. Two MAXIM DG408 Multiplexers, controlled by an NI USB-6008 multifunction data acquisition card, were used as a 16-channel multiplexer between the impedance analyzer and the sensor arrays. The NI USB-6008 and Agilent 4294 were controlled by LabVIEW programs to perform the data acquisition shown as Figure 10. The ECIS sensor arrays, covered with BAECs on the sensing electrodes, were kept in an incubator with 37°C and 5% CO2 during the impedance measurement.
Experimental setup of cell impedance measurement.
The cell seeding density and measurement frequency are need to be optimized to obtain reasonable measurement results. BAECs were seeded with different cell densities of 150,000, 125,000, and 100,000 cells/cm2 on ECIS sensor. The impedance values were recorded and normalized in the initial 46 hours after seeding onto the ECIS sensor array, as shown in Figure 11. The morphology of cells with seeding density 125,000 cells/cm2 at different time points was also shown in Figure 11. The cells gradually spread on the surface of ECIS sensors after seeding and eventually form a monolayer with stable impedance. The cell impedance gradually increased in the initial 8–20 hours, which indicates the initial formation of a loose monolayer and stable up to the end of the impedance measurements. The cell morphology was checked under microscope frequently. The corresponding impedance readings were used to represent the impedance of the cell monolayer for cell-based assays. In Figure 11, the impedance of cell monolayer with higher seeding densities increases more rapidly than cells with lower seeding densities because higher seeding densities allow the cells to have tighter and stronger intercellular junctions and the corresponding ion insulating abilities are better. The impedance of cells with the highest seeding density, 150,000 cells/cm2, decreased after initial formation (around 8 hours) of cell monolayer due to the cell movement on the surface of ECIS sensors. Also, the impedance of cells with 150,000 cells/cm2 seeding density is not stable as those with 125,000 and 100,000 cells/cm2 seeding densities. The cells with a seeding density of 100,000 cells/cm2 need 20 hours to be confluent and have low impedance compared with those with higher seeding densities. Hence, the cell seeding density, 125,000 cells/cm2, was chosen as the preferred seeding density in the toxicity testing.
Impedance response of BAECs measured by an ECIS sensor array at 8000 Hz and the image of cell morphology.
The optimal measurement frequency allows the sensors to obtain the largest difference in measured impedance between a sample with and without cells [19]. In this study, the impedance of cell monolayer was measured with different frequencies from 500 Hz to 64 kHz. The optimal measurement frequency was optimized to be 8000 Hz in experimental measurements.
The ECIS sensors need to be prepared before the toxicity testing. ECIS sensors were cleaned by oxygen plasma to provide a sterilized surface for cell seeding. Then phosphate-buffered saline (PBS, GIBCO, Grand Island, NY) was used to clean the sensor surface again. Before cell seeding, 30 μg/ml fibronectin (GIBCO, Grand Island, NY) was coated on the surface of the sensors to improve cell attachment. BAECs were seeded onto each sensor with a seeding density of 125,000 cells/cm2. The cell morphology was checked under microscope. The selected toxicants were introduced to each well to perform toxicity testing after monolayer formation. Figure 12 shows normalized impedance response after introducing 0.1 and 0.2 mM aldicarb and the cell morphology after introducing 0.2 mM aldicarb. Some of the cells detached from the substrate. The normalized impedance decreases to 0.84 and 0.76 times its original impedance value within 3 hours when treated with 0.1 and 0.2 mM aldicarb, respectively. The cell morphology changed and even detached from the sensors. Figure 13 shows the normalized impedance response after introducing 0.1 and 0.2 mM phenol as toxicant. The BAEC detached from substrate after introducing 0.2 mM phenol. The decreasing impedance curves indicate the toxic effect on BAECs. The normalized impedance values rapidly decreased to 0.80 and 0.74 times its original impedance value within 2 hours when treated with 0.1 and 0.2 mM phenol, respectively. The image shows the cells obviously detached from the sensor. Figure 14 shows the normalized impedance response after introducing 2 and 5 mM ammonia as toxicant. Those lines shows that the normalized impedance values rapidly decreased to 0.78 and 0.68 times its original impedance value within 1 hour when treated with 2 and 5 mM ammonia, respectively. The image shows the cell morphology after 1 hour after introducing ammonia. The cells morphology changed and very easily detached from the sensor substrate. Figure 15 shows the normalized impedance of BAEC after exposing to 0.8 and 1.3 mM nicotine as toxicant. The normalized impedance rapidly decreased to 0.92 and 0.75 times its original value within 2 hours when treated with 1.3 and 0.8 mM nicotine, respectively. The image shows the BAEC morphology after exposed to 1.3 mM nicotine. Most of the cell detached from the sensor due to the toxic effect of nicotine.
The normalized impedance of BAEC exposed to aldicarb.
The normalized impedance of BAEC exposed to phenol.
The normalized impedance of BAEC exposed to 2 mM and 5 mM ammonia, and the image shows the BAEC morphology after exposure to 5 mM of ammonia.
The normalized impedance of BAEC exposed to 0.8 mM and 1.3 mM nicotine. The image shows the cell morphology after exposure to 1.3 mM nicotine.
The cell morphology and decreasing impedance curves indicate the toxic effect and the effectiveness of ECIS sensing on environmental monitoring within short period of time. Different concentrations of toxicants are qualified according to the gradients of normalized impedance. ECIS sensing technique is able to perform environmental monitoring effectively and efficiently compared with other approaches.
In this study, the biosensors based on ECIS sensing technique were used to monitor and measure the environmental toxicants, including the phenol, ammonia, nicotine, and aldicarb. A model, validated by experimental results, was created to analyze the electric potential distribution of ECIS sensing and guide the designing, especially the sensing area of sensor electrodes. The detection sensitivity of ECIS sensors was optimized. The experimental results show that ECIS sensors are capable to detect and qualify the environmental toxicants rapidly. The concentration of toxicants can be indicated from the gradients of normalized cell impedance.
We appreciate Dr. Ioana Voiculescu’s and Andres Rivera’s support in this study.
The subcutaneous implantable cardioverter defibrillator (S-ICD) offers an alternative rescue device for sudden cardiac death in the form of an implantable device that can offer defibrillation therapy without the need for a transvenous lead. Lead failure is the most frequent source of complication requiring surgical revision. Approximately 20% of transvenous leads fail within 10 years and extraction may lead to devastating complications, including death [1, 2, 3, 4, 5]. The S-ICD differs from conventional transvenous ICD systems in other important ways: an S-ICD requires no transvenous leads (the most frequent source of device complications) but S-ICDs do not offer bradycardia pacing, antitachycardia pacing, cardiac resynchronization, plus they have limited programmability. Approved in Europe in 2009, the S-ICD system (SQ-RX 1010, Boston Scientific, Natick, Massachusetts, USA) consists of a pulse generator and a tripolar defibrillation lead, both of which are implanted subcutaneously. In terms of size, weight, and footprint, the S-ICD device is larger and heavier than a conventional transvenous ICD (approximately 130 vs. 60 g, respectively).
S-ICDs are indicated for primary and secondary prevention but are seen as particularly useful for primary-prevention patients with a long life expectancy. The selection of an S-ICD system over a transvenous ICD may be based on a variety of factors. Transvenous ICD patients who experience device-related complications, such as lead problems, may be revised to an S-ICD device. In a German multicenter study, 25% of S-ICD patients had a previous transvenous system explanted because of device complications [6].
The S-ICD system is composed of a tripolar parasternal lead, positioned to the left (about 1–2 cm) and parallel to the sternal midline; this lead plugs into the pulse generator, which is implanted over the fifth to sixth rib and positioned submuscularly between the midaxillarly and anterior axillary lines. The lead has three electrodes, two of which sense only. The defibrillation electrode is positioned between the two sensing electrodes. The sensing vector is created from the sensing electrode to the can, with the device automatically selecting the better electrode for the vector to assure optimal sensing. Device implantation may require minimal (to verify final position) to no fluoroscopy, as much of the technique relies on anatomical landmarks [7]. See Figure 1.
The S-ICD device is implanted over the fifth to sixth rib and to the side; the parasternal lead senses the subcutaneous ECG and automatically determines which of two sensing vectors to use (top or bottom electrode to can). (Artwork by Todd Cooper, courtesy of Jo Ann LeQuang).
A three-incision technique (plus pocket formation) was originally pioneered for S-ICD implantation, and a newer two-incision approach has been described in the literature [8]. The two-incision approach creates an intermuscular pocket for the pulse generator rather than a subcutaneous pocket by incising the inframammary crease at the anterior border of the latissimus dorsi, allowing the generator to fit between the two muscles. Then a small incision at the xiphoid process (in the same direction as pocket incision) allows an electrode insertion device to tunnel the lead in place [8, 9]. In a study of 36 patients, the two-incision approach was found to be safe and effective and it may produce superior cosmetic results compared to the three-incision approach [9]. See Figure 2.
Lateral view of a patient with an implanted S-ICD. (Courtesy of Dr. Peter Magnusson with permission of patient.).
The time required for device implantation has been recently reported as an average of 68 ± 20 minutes which includes intraoperative defibrillation threshold (DT) testing [10]. DT testing is of decreasing importance with transvenous ICDs but remains a much-discussed topic for S-ICD systems. Guidelines still recommend DT testing during S-ICD implantation, even though it is often used without intraoperative testing based on generalized findings from transvenous systems [11, 12, 13]. In a study of 98 S-ICD patients, 25% of patients failed to convert their induced arrhythmia with the first intraoperative 65 joule shock, necessitating further therapy delivery and/or external defibrillation. In this study, 24/25 patients could be successfully defibrillated following either reversal of shocking polarity or lead reposition although the desired 10 joules safety margin could not be achieved in 4/24 of these patients [14]. This suggests the importance of perioperative DT testing. However, 100% of patients could be converted from defibrillation with an internal 80 joule shock [14]. In a subsequent study of 110 consecutive S-ICD patients, 50% (n = 55) did not undergo defibrillation testing at implant for any of several reasons (including patient condition, age, and physician preference). In this group, 11% had episodes of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) necessitating therapy delivery and all of them were effectively converted with the first 80 joule shock [15]. Ventricular tachycardia is a rhythm disorder originating in the heart’s lower chambers that has a rate of at least 100 beats per minute; ventricular fibrillation is a much faster, chaotic heart rhythm that causes the heart to quiver rather than pump effectively. Thus, the notion that DT testing at implant is necessary for S-ICD patients has been challenged.
S-ICD implantation may be carried out under local anesthesia [16], conscious sedation, or general anesthesia (64.1% of U.S. implants of S-ICD systems [17]. The rate of complications at implant is low and the most commonly reported complication is infection (1.8%) [18]. By dispensing with the transvenous leads, the S-ICD system avoids periprocedural and complications associated with conventional transvenous defibrillation leads, i.e. pericardial effusion, pneumothorax, accidental arterial puncture, nerve plexus injury, and tricuspid valve damage [19].
S-ICDs appear to have similar rates of infection and other complications as transvenous systems and to be similarly effective in rescuing patients from sudden cardiac death, but there are important distinctions between the two systems.
In a retrospective study of 1160 patients who received an implantable defibrillator (either transvenous system or S-ICD) at two centers in the Netherlands, patients were analyzed using propensity matching to yield 140 matched patient pairs. The rates of complications, infection, and inappropriate therapy were statistically similar between groups, but S-ICD patients had significantly fewer lead-related complications than the transvenous group (0.8 vs. 11.5%, p = 0.030) and more non-lead-related complications (9.9 vs. 2.2%, p = 0.047) [20]. The most frequently reported S-ICD complication involved device sensing.(20) Pooled data from the Investigational Device Exemption (IDE) and postmarket registry EFFORTLESS (n = 882) found S-ICD-related complications occurred at a rate of 11.1% at 3 years, but with no lead failures, S-ICD-related endocarditis, or bacteremia [21]. An IDE allows a device that is the subject of a clinical study to be used to collect data about safety and effectiveness that may be later used to submit to the U.S. Food and Drug Administration (FDA). Device-related complications were more frequent with transvenous systems when compared to S-ICD devices in a propensity-matched case–control study of 69 S-ICD and 69 transvenous ICD patients followed for a mean of 31 ± 19 or 32 ± 21 months, respectively. About 29% of transvenous ICD patients experienced a device-related complication compared to 6% of S-ICD patients, reducing the risk of complications for S-ICD patients by 70%; transvenous lead problems were the most frequently reported complication in the former group [22].
In the largest study of S-ICD patients (n = 3717) to date, complications were low at 1.2% overall. The most frequently reported complications were cardiac arrest (0.4%), hematoma (0.3%), death (0.3%), lead dislodgement (0.1%), myocardial infarction (0.1%), and hemothorax (<0.1%) [23]. Device revision during index hospitalization was infrequent (0.1%) [23]. Infections occur at roughly similar rates with S-ICD and transvenous systems but with the important distinction that S-ICD infections may sometimes be resolved with conservative therapy (course of antibiotics with device left in place), whereas most transvenous ICD infections necessitate the extraction of the device and the transvenous leads. In a survey from the U.K. reporting on data from 111 S-ICD patients, 11/111 (10%) of patients experienced infection, of whom 6 could be successfully treated conservatively without device extraction [24]. The EFFORTLESS registry (n = 472) reported a 4% rate of documented or suspected infections and complication-free rates at 30 and 360 days were 97 and 94%, respectively [25].
Once implanted, the S-ICD device delivers a nonprogrammable, high-energy rescue shock (80 joules) to the thorax compared to shocks of 45 joules to the heart administered by conventional transvenous systems. Notably the S-ICD delivers a 65 joule shock during implant testing. Therapy delivery differs markedly between S-ICD and transvenous systems in terms of the amount of energy delivered, location of shocking vectors, and potential for damage to surrounding tissue or the heart. In a porcine study, the mean time to therapy delivery was significantly longer with an S-ICD than a transvenous system (19 vs. 9 seconds, p = 0.001) but the S-ICD shocks were associated with less elevation of cardiac biomarkers. The longer time to therapy may be advantageous in that device patients often experience short runs of nonsustained VT. On the other hand, S-ICD shocks were associated with more skeletal muscle injuries than transvenous device shocks owing to the energy patterns resulting from the device placement but the clinical relevance of this is likely negligible [26].
Effective shock therapy is often defined as conversion of an episode of VT/VF within five shocks, differing from effective first-shock therapy which occurs when the initial shock converts the arrhythmia. In a study of 79 S-ICD patients at a tertiary center, 7.6% of patients experienced at least one appropriate shock for a ventricular tachyarrhythmia during the follow-up period (mean 12.8 ± 13.7 months) [27]. In a multicenter study from Germany (n = 40), shock efficacy was 96.4% [95% confidence interval (CI), 12.8–100%] and first-shock efficacy was 57.9% (95% CI, 35.6–77.4%) [6]. In an effort to analyze S-ICD efficacy in a large group of diverse patients, data from the Investigation Device Exemption (IDE) clinical study and the EFFORTLESS post-market registry were pooled to provide information about 882 patients followed for 651 ± 345 days. About 59 patients experienced therapy delivery for 111 spontaneous VT/VF episodes with first-shock efficacy in 90.1% of events and shock efficacy (termination with five or fewer shocks) in 98.2% of patients [21]. In the EFFORTLESS registry (n = 472), first-shock efficacy in discrete episodes of VT/VF was 88% and shock efficacy within five shocks was 100% [25].
Inappropriate shock describes therapy delivery to treat an episode which the device inappropriately detects as a ventricular tachyarrhythmia. Inappropriate shocks have been recognized as a significant clinical challenge with transvenous systems as well as S-ICDs. In a tertiary care center study of 79 S-ICD patients, inappropriate shock occurred in 8.9% (n = 7) of patients, attributable to T-wave oversensing, atrial tachyarrhythmia with rapid atrioventricular conduction, external interference and/or baseline oversensing due to lead movement [27]. T-wave oversensing occurs when the device inappropriately senses ventricular repolarizations (the T-waves on the electrocardiograph) counting them as ventricular events, leading to double counting of the intrinsic ventricular rate. In a multicenter German study (n = 40) with a median follow-up of 229 days, four patients (10%) experienced 21 arrhythmic episodes resulting in 28 therapy deliveries. Four of these episodes were inappropriately identified by the device as ventricular tachyarrhythmias, with the result that two patients received inappropriate shocks. This results in a rate of 10% inappropriately detected ventricular tachycardia and 5% delivery of inappropriate therapy [6]. In a study using pooled data from the IDE and EFFORTLESS post-market registry (n = 882), the three-year rate for inappropriate therapy delivery was 13.1% [21].
It does not appear there are statistically more cases of inappropriate therapy in S-ICD patients compared to transvenous ICD patients. A propensity-matched study (69 patients with a transvenous ICD and 69 with an S-ICD) found the rate of inappropriate shocks was 9% in the transvenous and 3% in the S-ICD groups but this was not statistically significant (p = 0.49) [22]. In a study of 54 S-ICD patients in a real-world prospective registry, the one-year rate for inappropriate therapy delivery was 17%, most of whom had single-zone programming [10].
Inappropriate shocks with S-ICDs may be minimized. Most of them are caused by T-wave oversensing. In a survey from the U.K. (n = 111 implanted patients covered), 24 appropriate shocks were delivered in 12% of the patients (n = 13) and 51 inappropriate shocks were delivered in 15% of the patients (n = 17), of which 80% could be traced to T-wave oversensing [24]. In the EFFORTLESS registry (n = 472), there was a 7% rate of inappropriate therapy delivery in 360 days, mainly due to oversensing [25]. The main causes of inappropriate therapy delivery have been reported to be supraventricular tachycardia (SVT) at a rate above the discrimination zone, T-wave oversensing, other types of oversensing (e.g. interference), SVT discrimination errors, and low-amplitude signals [21]. Inappropriate therapy delivery due to T-wave oversensing can often be remedied by adjusting the sensing vector or adding another discrimination zone (dual-zone programming) [10].
Certain patients may be at elevated risk for inappropriate shock. A single-center study of 18 hypertrophic cardiomyopathy (HCM) patients implanted with an S-ICD system and followed for a mean 31.7 ± 15.4 months concluded that HCM patients may be at elevated risk for T-wave oversensing which could lead to inappropriate therapy delivery. In this study, 39% of these HCM patients had T-wave oversensing and 22% of the study population (n = 4) experienced inappropriate therapy delivery [28]. An evaluation of 581 S-ICD patients found that inappropriate shocks caused by oversensing occurred in 8.3% of S-ICD patients and patients with HCM and/or a history of atrial fibrillation were at elevated risk for inappropriate therapy [29]. There is a paucity of data on the use of S-ICD devices in HCM patients, but a small study of 27 HCM patients screened for possible S-ICD therapy found 85% (n = 23) were deemed appropriate candidates and 15 had the device implanted [30]. At implant testing, all patients were successfully defibrillated with a 65 joules shock and most induced arrhythmias were terminated with a 50 joules shock (12/15). After the median follow-up period of 17.5 months (range 3–35 months), there were no appropriate shocks and one inappropriate shock, attributed to oversensing caused when the QRS amplitude was reduced while the patient bent forward. In this particular high-risk patient group of HCM patients without a pacing indication, the S-ICD was effective at detecting and terminating tachyarrhythmias [30].
The mortality risk with S-ICD implantation is low, but merits scrutiny. On the one hand, S-ICD implantation is generally associated with fewer risks than transvenous ICD implantation in that no transvenous leads are required. On the other hand, patient selection for S-ICD may favor more high-risk patients (such as those with a prior infection, renal failure, comorbid conditions such as diabetes) but also includes many younger and generally fitter patients. Overall, mortality data from S-ICD studies appears favorable. In a pooled analysis combining IDE data and EFFORTLESS registry information, the one-year and two-year mortality rates were 1.6 and 3.2%, respectively [21]. In a study of real-world use of S-ICDs in 54 primary- and secondary-prevention patients, mortality at the mean follow-up duration of 2.6 ± 1.9 years was 11% but no patient died of sudden cardiac arrest [10]. In a six-month study comparing 91 S-ICD and 182 single-chamber transvenous ICD patients, mortality rates were similar although the S-ICD patients had more severe pre-existing illness at implant [31]. It may be that the similar mortality rates between transvenous and S-ICD populations reflects the patient populations rather than the implantation procedure or device characteristics [23].
The S-ICD device was designed to be a streamlined system with fewer than 10 programmable features (transvenous ICDs have over 100 programmable features) and to perform in a largely automated fashion in terms of device function. The recent introduction of dual-zone programming to S-ICDs added a degree of programmability and reduced inappropriate shock [32]. Arrhythmia detection in the S-ICD relies on a system of template matching, based on waveform morphology of the subcutaneous ECG obtained at implant [33]. Oversensing and sensing-related problems are the most frequently reported problems but are being addressed in terms of device design and programmability. T-wave oversensing occurs when the device incorrectly identifies a T-wave as a QRS complex and counts it as a native ventricular beat, which leads to double-counting the rate. The use of dual-zone device programming has reduced the incidence of inappropriate therapy as a result of double-counting caused by T-wave oversensing [34]. T-wave inversions and QRS complexes that are overly large or very small may be particularly vulnerable to sensing anomalies. Reprogramming the sensing vector or therapy zones may be helpful in such instances [35, 36]. In a propensity-matched study comparing transvenous ICDs to S-ICDs, there were three inappropriate shocks in the S-ICD group, all of which were due to T-wave oversensing in sinus rhythm and all of which could be eliminated with adjustment of the sensing vector [22]. Furthermore, it has been observed with increasing operator experience and better programming techniques, sensing problems have been reduced [21]. In a study using pooled data from the IDE and EFFORTLESS registry, the rate of inappropriate therapy associated with oversensing was <1% [21]. When inappropriate shock occurs, the stored electrograms will likely help identify the cause. If lead malposition is suspected, a chest X-ray may be appropriate. In case of oversensing, the sensing vector may be optimized, device programming may be revised to add a second detection zone, or pharmacological therapy may be added [32].
SVT discrimination likewise relies on template-matching (which is similar to transvenous systems) but the S-ICD may be able to accomplish this with a higher degree of resolution than transvenous ICDs [33]. The use of dual-zone programming appears advantageous.
Primary- and secondary-prevention patients represent two distinct patient populations who may be treated with S-ICD therapy, although S-ICDs seem particularly well suited for primary-prevention patients. Secondary-prevention patients have a lower rate of comorbid conditions and significantly higher left-ventricular ejection fractions (LVEF) than primary-prevention patients (48 vs. 36%, p < 0.0001), while primary-prevention patients had a higher incidence of heart failure and were more likely to have had a transvenous ICD implanted before the S-ICD. Primary-prevention patients also have a higher rate of ischemic cardiomyopathy (41 vs. 33%) and nonischemic cardiomyopathy (28 vs. 12%) [18]. S-ICDs have been shown to be effective for both primary- and secondary-prevention patients. In a study of 856 S-ICD patients (mean follow-up 644 days), there were no significant differences between primary- and secondary-prevention populations in the rates of effective arrhythmia conversions, inappropriate therapy, mortality or complications although appropriate therapy delivery was delivered to significantly more secondary-prevention than primary prevention patients (11.9 vs. 5.0%, p = 0.0004) [18].
The freedom from any appropriate therapy delivery was 88.4% among primary-prevention patients with an LVEF ≤35 and 96.2% among primary-prevention patients with an LVEF >35%. The freedom from any appropriate therapy delivery among secondary-prevention patients was 92.1% [18]. Spontaneous conversion to sinus rhythm was more frequent among primary-prevention patients (about 48% of all ventricular tachyarrhythmias) compared to secondary-prevention patients (31%) [18]. However, the rates of inappropriate therapy delivery and complications were similar for both primary- and secondary-prevention patients [18].
S-ICD systems are indicated for patients who require rescue defibrillation but do not need bradycardia pacing support and would not benefit from antitachycardia pacing or cardiac resynchronization therapy. This includes primary- and secondary-prevention patients. By avoiding transvenous leads, the S-ICD is particularly appropriate for patients with occluded veins or limited venous access (who are not suitable candidates for transvenous systems) and the S-ICD may be beneficial for younger, fitter, and active patients. The generator position of the S-ICD patient may make it easier and safer for strong, fit patients to resume active lifestyles without jeopardizing lead position.
Despite the fact that S-ICD devices are larger than transvenous systems, their lateral placement may result in more pleasing esthetic results than a conventional transvenous ICD. Young device patients likely will have a lifetime of device therapy, resulting over time in much hardware in their vasculature; the S-ICD thus presents an advantage in that regard. It appears that S-ICDs are implanted in a younger patient population; a survey of multiple U.K. hospitals (n = 111 patients) found the median patient age was 33 (range 10–87 years) [24]. The mean age of patients in the EFFORTLESS registry was 49 ± 18 years (range 9–88 years) [25]. Younger patients with cardiomyopathy or channelopathy often have a high rate of complications with conventional transvenous ICDs [37] and it has been thought they may be better served with an S-ICD device [9].
In a multicenter case–control study, it was found that 59.4% of S-ICD patients were primary-prevention and the main underlying cardiac conditions were dilated cardiomyopathy (36.2%), ischemic cardiomyopathy (15.9%), and HCM (14.5%) [38]. In particular, these patients have been considered challenging to treat with a conventional transvenous ICD in that they may have an erratic electrical substrate in the heart and increased left-ventricular mass, which could contribute to an elevated DT. First-shock efficacy rates of up to 88% are promising in light of these challenges [25]. In a study of 50 hypertrophic cardiomyopathy patients implanted with S-ICDs, 96% of patients could be induced to an arrhythmia at implant and of the 73 episodes of VF induced, 98% were successfully converted with 65 joules from the S-ICD during DT testing. One patient in this study (2%) required rescue external defibrillation [39]. The patient who failed internal defibrillation had a body mass index of 36 and was successfully converted by an 80 joules shock with reversed polarity from the S-ICD [39].
The most recent guidelines to address S-ICD were published by the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society in 2017 [40]. The An S-ICD is indicated (Class of Recommendation 1, level of evidence B) for patients who meet indication criteria for a transvenous ICD but who have inadequate vascular access or are at high risk of infection and for whom there is no anticipated need for bradycardia or antitachycardia pacing. Further, implantation of an S-ICD is deemed reasonable for patients with an ICD indication for whom there is no anticipated need for bradycardia or antitachycardia pacing (Class of Recommendation IIa, level of evidence B). An S-ICD is contraindicated in a patient who is indicated for bradycardia pacing, antitachycardia pacing for termination of ventricular tachyarrhythmias, and/or cardiac resynchronization therapy (Class of Recommendation III, level of evidence B) [40].
The European Society of Cardiology guidelines from 2015 report that S-ICDs are effective in preventing sudden cardiac death and the device is recommended as an alternative to transvenous ICDs in patients who are indicated for defibrillation but not pacing support, cardiac resynchronization therapy, or antitachycardia pacing (Class IIa, Level C). Moreover, the S-ICD was considered to be a useful alternative for patients in whom venous access was difficult or for patients who had a transvenous system explanted because of an infection or for young patients expected to need long-term ICD therapy [41].
Those considered for S-ICD therapy should be screened with a modified version of the three-channel surface electrocardiogram (ECG) set up to represent the sensing vectors of the S-ICD. With the patient both standing and supine, the ratio of R-wave to T-wave should be established and signal quality evaluated. If any of the three vectors does not result in satisfactory sensing, the S-ICD should not be implanted. Once the actual device is implanted in the patient, the system automatically selects the optimal sensing vector [11].
The S-ICD may be programmed to detect arrhythmias using a single- or dual-zone configuration. In the dual-zone configuration, a lower cutoff rate defines what might be called a “conditional shock zone” to which a discrimination algorithm is applied so that therapy is withheld if the rhythm might be deemed supraventricular in origin or non-arrhythmic oversensing. This discrimination zone relies on a form of template matching. Above that rate, a cutoff establishes the “shock zone” which delivers a shock based on the rate criterion alone. When the capacitors charge in anticipation of shock delivery, a confirmation algorithm assures the persistence of the arrhythmia prior to sending the shock. Shocks are delivered at the nonprogrammable 80 joules of energy [11].
The evolution of the S-ICD adds an important new device into the armamentarium for rescuing patients from sudden cardiac death. To further improve S-ICD technology, size reduction, increased battery longevity, and improved T-wave rejection will be needed. In the near future, improvement in sensing function might eliminate the need for a separate screening ECG prior to implant, which could optimize clinical workflow.
Improved battery technology is particularly important as the S-ICD is often used in patients with a relatively long life expectancy. Leadless pacemaker systems that might work together with an S-ICD are in development which would allow for bradycardia pacing support, antitachycardia pacing and a subcutaneous defibrillator without transvenous leads [32]. The development of a leadless epicardial pacemaker might allow for left-atrial and left-ventricular pacing function to be integrated to the S-ICD. Taken altogether, these improvements could make the S-ICD the preferred device in the vast majority of cases for rescue from sudden cardiac death.
The subcutaneous implantable cardioverter defibrillator (S-ICD) offers an alternative to transvenous ICDs but the two systems should not be considered interchangeable. The S-ICD is appropriate for patients who require only rescue defibrillation (primary or secondary prevention) but does not offer bradycardia pacing, antitachycardia pacing, overdrive pacing, or cardiac resynchronization therapy. S-ICD devices may be appropriate in patients who have occluded vasculature or device infection with a transvenous system. Effectiveness, rate of infections, and survival rates are similar for both devices although, in general, S-ICDs may be implanted in patients with more serious underlying conditions such as end-stage renal disease or advanced diabetes. Infections with S-ICDs are more likely to be effectively treated with a conservative course of antibiotic therapy and no device extraction. Inappropriate shocks occur at similar rates with both systems but are more likely caused by oversensing in the S-ICD. A main advantage of S-ICDs over transvenous systems is the elimination of the transvenous defibrillation lead which may be considered the Achilles heel of the transvenous system, having a 10-year complication rate of 25%. It is likely that considerable advances in ICD therapy will occur in the next decade as the S-ICD systems are further refined.
The authors have no conflicts of interest to declare.
Yuri Gagarin was the first human to travel into space in 1961, and subsequently, more than 500 people have followed. We have learned so much since then, however, there are many questions that remain unanswered. The Humans in Space program seeks to facilitate the creation of new knowledge that will help find solutions to these questions through the development of a first-of-its-kind and more complete library of open access space life sciences and related areas knowledge.
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\n\nThe mission of the Humans in Space Program is to create a unique, open-access reservoir of knowledge in the area of space life science, based on an interdisciplinary and comprehensive approach that will promote interaction between world-leading experts, academics and researchers. With education and the global dissemination of research at its core, the program will be an ambitious collection of experts, high-quality literature and lectures.
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