Photovoltaic, wireless wide-field epiretinal prosthesis to treat retinitis pigmentosa.

PURPOSE: To develop and evaluate a photovoltaic, wireless wide-field epiretinal prosthesis for the treatment of retinitis pigmentosa. METHODS: A mosaic array of thinned silicon-based photodiodes with integrated thin-film stimulation electrodes was fabricated with a flexible polyimide substrate film to form a film-based miniaturized electronic system with wireless optical power and signal transmission and integrated electrostimulation. Manufactured implants were characterized with respect to their optoelectronic performance and biocompatibility following DIN EN ISO 10993. RESULTS: A 14 mm diameter prosthesis containing 1276 pixels with a maximum sensitivity at a near infrared wavelength of 905 nm and maximized stimulation current density 30-50 µm below the electrodes was developed for direct activation of retinal ganglion cells during epiretinal stimulation. Fabricated prostheses demonstrated mucosal tolerance and the preservation of both metabolic activity, proliferation and membrane integrity of human fibroblasts as well as the retinal functions of bovine retinas. Illumination of the prosthesis, which was placed epiretinally on an isolated perfused bovine retina, with infrared light resulted in electrophysiological recordings reminiscent of an a-wave (hyperpolarization) and b-wave (depolarization). CONCLUSIONS: A photovoltaic, wireless wide-field epiretinal prosthesis for the treatment of retinitis pigmentosa using near infrared light for signal transmission was designed, manufactured and its biocompatibility and functionality demonstrated in vitro and ex vivo.

Bio-potential noise of dry printed electrodes: physiology versus the skin-electrode impedance.

Objective. To explore noise characteristics and the effect physiological activity has on the link between impedance and noise.Approach. Dry-printed electrodes are emerging as a new and exciting technology for skin electro-physiology. Such electrode arrays offer many advantages including user convenience, quick placement, and high resolution. Here we analyze extensive electro-physiological data recorded from the arm and the face to study and quantify the noise of dry electrodes, and to characterize the link between noise and impedance. In particular, we studied the effect of the physiological state of the subject (e.g. rapid eye movement sleep) on noise.Main results. We show that baseline noise values extracted from dry electrodes in the arm are in agreement with the Nyquist equation. In the face, on the other hand, the measured noise values were higher than the values predicted by the Nyquist equation. In addition, we studied how different electrode properties affect performances, including electrode size, shape, and material properties.Significance. Altogether, the results presented here provide a basis for understanding dry electrode performances and substantiate their great potential in electro-physiological investigations.

Monitoring of wearing and occlusion times with smart shutter glasses-A proof of concept.

PURPOSE: To develop and evaluate an electronic glasses frame for smart liquid crystal shutter glasses that monitors wearing and occlusion times to potentially improve therapy adherence in amblyopia therapy of children. METHODS: The first generation of an electronic glasses frame for adults was further developed, miniaturized and functionally tested in a proof of concept study on a small group of healthy children. Seven healthy children (4 females, 3 males, 2-9 years) were enrolled in the study. The subjects were instructed to wear the smart shutter glasses and to record their activities in daily life. Averaged and individual results were calculated for the precision of wearing position detection and activity recognition. Also, the proper execution of the configured occlusion pattern was observed. RESULTS: The first generation of an electronic glasses frame for smart liquid crystal shutter glasses in a miniaturized form factor for children. A key element is the implementation of the adaptive shutter operation and of smart algorithms for real-time therapy monitoring. In the proof of concept study, these algorithms monitored the state of wearing position, the wearer's activity and the configured occlusion pattern. The average agreement of the detected states of wearing position was 72.6%. The average activity recognition match was 77.3%. The removal of the glasses was 100% correctly detected and the occlusion was 100% halted when active motion was recognized. CONCLUSION: The assembled smart shutter glasses for children are suitable for demonstrating the feasibility of continuous therapy monitoring by calculating wearing and occlusion times due to smart algorithms for wearing position detection, activity recognition, and occlusion monitoring. However, further research and studies are necessary to optimize the individual fit and performance of this wearable therapeutic device.

Virtual Biopsy by Electrical Impedance Spectroscopy in Barrett's Carcinoma.

PURPOSE: Early detection of adenocarcinomas in the esophagus is crucial for achieving curative endoscopic therapy. Targeted biopsies of suspicious lesions, as well as four-quadrant biopsies, represent the current diagnostic standard. However, this procedure is time-consuming, cost-intensive, and examiner-dependent. The aim of this study was to test whether impedance spectroscopy is capable of distinguishing between healthy, premalignant, and malignant lesions. An ex vivo measurement method was developed to examine esophageal lesions using impedance spectroscopy immediately after endoscopic resection. METHODS: After endoscopic resection of suspicious lesions in the esophagus, impedance measurements were performed on resected cork-covered tissue using a measuring head that was developed, with eight gold electrodes, over 10 different measurement settings and with frequencies from 100 Hz to 1 MHz. RESULTS: A total of 105 measurements were performed in 60 patients. A dataset of 400 per investigation and a total of more than 42,000 impedance measurements were therefore collected. Electrical impedance spectroscopy (EIS) was able to detect dysplastic esophageal mucosa with a sensitivity of 81% in Barrett's esophagus. CONCLUSION: In summary, EIS was able to distinguish different tissue characteristics in the different esophageal tissues. EIS thus holds potential for further development of targeted biopsies during surveillance endoscopy. Trial Registration NCT04046601.

Novel Cost-Efficient Graphene-Based Impedance Biosensor for the Analysis of Viral Cytopathogenicity and the Effect of Antiviral Drugs.

Biosensors become increasingly relevant for medical diagnostics, pharmaceutical industry, and environmental technology, for example, to test new drugs easily and reliably or to detect cell growth in changing environmental conditions. Novel materials like graphene are promising candidates to produce biosensors on an industrial scale by means of printing processes. To reach this aim, methods for the reliable and automated production of electrode structures and their coating are required. We present an impedance biosensor in the format of a microtiter plate, fabricated by highly efficient roll-to-roll printing of graphene-based microstructures on large-area polymer foils. Proof-of-principle experiments show the evidence of the suitability of the printed graphene biosensors for impedance-based monitoring of viral cytopathogenicity and its inhibition in the presence of antiviral drugs. The developed system is a promising approach toward cost-efficient impedimetric biosensors for high-throughput screening in vaccine research and antiviral drug development.

Context-sensitive smart glasses monitoring wear position and activity for therapy compliance-A proof of concept.

PURPOSE: To improve the acceptance and compliance of treatment of amblyopia, the aim of this study was to show that it is feasible to design an electronic frame for context-sensitive liquid crystal glasses, which can measure the state of wear position in a robust manner and detect distinct motion patterns for activity recognition. METHODS: Different temple designs with integrated temperature and capacitive sensors were developed to realize the detection of the state of wear position to distinguish three states (correct position/wrong position/glasses taken off). The electronic glasses frame was further designed as a tool for accelerometer data acquisition, which was used for algorithm development for activity classification. For this purpose, training data of 20 voluntary healthy adult subjects (5 females, 15 males) were recorded and a 10-fold cross-validation was computed for classifier selection. In order to perform functional testing of the electronic glasses frame, a proof of concept study was performed in a small group of healthy adults. Four healthy adult subjects (2 females, 2 males) were included to wear the electronic glasses frame and to protocol their activities in their everyday life according to a defined test protocol. Individual and averaged results for the precision of the state of wear position detection and of the activity recognition were calculated. RESULTS: Context-sensitive control algorithms were developed which detected the state of wear position and activity in a proof of concept. The pilot study revealed an average of 91.4% agreement of the detected states of wear position. The activity recognition match was 82.2% when applying an additional filter criterion. Removing the glasses was always detected 100% correctly. CONCLUSION: The principles investigated are suitable for detecting the glasses' state of wear position and for recognizing the wearer´s activity in a smart glasses concept.

Microfluidic In Vitro Platform for (Nano)Safety and (Nano)Drug Efficiency Screening.

Microfluidic technology is a valuable tool for realizing more in vitro models capturing cellular and organ level responses for rapid and animal-free risk assessment of new chemicals and drugs. Microfluidic cell-based devices allow high-throughput screening and flexible automation while lowering costs and reagent consumption due to their miniaturization. There is a growing need for faster and animal-free approaches for drug development and safety assessment of chemicals (Registration, Evaluation, Authorisation and Restriction of Chemical Substances, REACH). The work presented describes a microfluidic platform for in vivo-like in vitro cell cultivation. It is equipped with a wafer-based silicon chip including integrated electrodes and a microcavity. A proof-of-concept using different relevant cell models shows its suitability for label-free assessment of cytotoxic effects. A miniaturized microscope within each module monitors cell morphology and proliferation. Electrodes integrated in the microfluidic channels allow the noninvasive monitoring of barrier integrity followed by a label-free assessment of cytotoxic effects. Each microfluidic cell cultivation module can be operated individually or be interconnected in a flexible way. The interconnection of the different modules aims at simulation of the whole-body exposure and response and can contribute to the replacement of animal testing in risk assessment studies in compliance with the 3Rs to replace, reduce, and refine animal experiments.

Toward Alginate-Based Membrane Technology for High Performance Recovery of Heavy Metals in Cells.

One of the major environmental problems is a global metal contamination. Heavy metals are nonbiodegradable and tend to accumulate in living organisms. Therefore, searching for biocompatible materials with enhanced sorption capabilities for selective removal of toxic elements from complex environments, low cost, ease of operation, and large available quantities that meet all requirements of the Green Chemistry concept is a current engineering and analytical task. We present a comprehensive study toward construction of an advanced biomembrane-based technology for recovery of several heavy metals and ruthenium by microdimensional alginate scaffolds. The chosen design of alginate scaffolds and their operational conditions were monitored during removal of Cd(II), Co(II), Pb(II), As(III), and Ru(III) in modeled aqueous solutions, cell culture medium, and in the presence of A549 lung cells by a tandem of biological (live/dead cell test), physical nanoanalytical (TEM/EDX, SEM/EDX), and chemical (FT-IR, HR-ICP-MS) assays. More precisely, the impact of certain experimental conditions, viz., medium acidity and matrix effects on sorption capacity of the above-mentioned elements, was investigated in detail. Remarkably, a different attachment behavior during adsorption of chosen elements by alginate scaffolds was observed. In addition, we revealed an essential concentration dependent effect of loaded heavy metals and ruthenium on cultivated cells. The obtained data allow us to gain a deeper insight into the interactions occurring in the studied biomaterial-inorganic system. Moreover, the obtained dependencies can be widely used for the development of alginate-based membrane technology employed for the protection of environmental and biological samples from the toxic pollutants.

Diagnosing early Barrett's neoplasia and oesophageal squamous cell neoplasia by bioimpedance spectroscopy in human tissue.

BACKGROUND: Detection of early oesophageal cancer in surrounding normal tissue can be challenging, but detection is essential to determine the subsequent treatment. Dysplastic tissue can be detected by using electrical impedance spectroscopy (EIS). OBJECTIVE: The aim of the present study was to evaluate the feasibility and value of EIS in the diagnosis of oesophageal neoplasia. METHODS: This prospective ex-vivo study included 23 patients with early oesophageal cancer (17 with Barrett's cancer and six with early squamous cell cancer). Immediately after endoscopic resection, the electrical properties of the resected specimens were investigated using a pencil probe (5 mm in diameter, frequency range from 100 Hz to 1 MHz). Punch biopsies were taken from the measured site in order to compare the results of EIS with histology. RESULTS: EIS was able to detect dysplastic oesophageal mucosa with a high rate of accuracy (82% in Barrett's oesophagus and 100% in squamous oesophagus) A total of 54 different sites in 26 tumours were evaluated. CONCLUSIONS: EIS was able to differentiate reliably between non-neoplastic and neoplastic oesophageal mucosa. Using EIS, it might be possible to use it for targeted biopsies and to avoid unnecessary biopsies during cancer surveillance in future.

Towards a cellular multi-parameter analysis platform: fluorescence in situ hybridization (FISH) on microhole-array chips.

Highly-sensitive analysis systems based on cellular multi-parameter are needed in the diagnostics. Therefore we improved our previously developed chip platform for another additional analysis method, the fluorescence in situ hybridization. Fluorescence in situ hybridization (FISH) is a technique used in the diagnostics to determine the localization and the presence or absence of specific DNA sequence. To improve this labor- and cost-intensive method, we reduced the assay consumption by a factor of 5 compared to the standard protocol. Microhole chips were used for making the cells well addressable. The chips were fabricated by semiconductor technology on the basis of a Silicon wafer with a thin deposited silicon nitride layer (Si(3)N(4)). Human retina pigment epithelia (ARPE-19) cells were arrayed on 5-µm holes of a 35 × 35 microhole-array by a gently negative differential pressure of around 5 mbar. After 3 hours of incubation the cells were attached to the chip and the FISH protocol was applied to the positioned cells. A LabView software was developed to simplify the analysis. The software automatically counts the number of dots (positive labeled chromosome regions) as well as the distance between adjacent dots. Our developed platform reduces the assay consumption and the labor time. Furthermore, during the 3 hours of incubation non-invasive or minimal-invasive methods like Raman- and impedance-spectroscopy can be applied.

Fully integrated monolithic optoelectronic transducer for real-time protein and DNA detection: the NEMOSLAB approach.

The development and testing of a portable bioanalytical device which was capable for real-time monitoring of binding assays was demonstrated. The device was based on arrays of nine optoelectronic transducers monolithically integrated on silicon chips. The optocouplers consisted of nine silicon avalanche diodes self-aligned to nine silicon nitride waveguides all converging to a single silicon detector. The waveguides were biofunctionalized by appropriate recognition molecules. Integrated thick polymer microchannels provided the necessary fluidic functions to the chip. A single sided direct contact scheme through a board-to-board receptacle was developed and combined with a portable customized readout and control instrument. Real-time detection of deleterious mutations in BRCA1 gene related to predisposition to hereditary breast/ovarian cancer was performed with the instrument developed using PCR products. Detection was based on waveguided photons elimination through interaction with fluorescently labeled PCR products. Detection of single biomolecular binding events was also demonstrated using nanoparticles as labels. In addition, label-free monitoring of bioreactions in real time was achieved by exploiting wavelength filtering on photonic crystal engineered waveguides. The proposed miniaturized sensing device with proper packaging and accompanied by a portable instrument can find wide application as a platform for reliable and cost effective point-of-care diagnosis.

Drug delivery from the oral cavity: focus on a novel mechatronic delivery device.

Dental drug delivery systems have been used for a long time, in particular for the local therapy of diseases affecting the oral cavity. Research today concentrates on the design of formulations to increase their retention time. Even today, however, prosthetic devices incorporating drug delivery are rarely used. Mainly, they are focused on prophylaxis and the release of antibacterial agents. However, as buccal delivery, because of its undeniable advantages, has become popular for systemic drug delivery, and prolonged well-controlled release has been identified as beneficial, especially for chronic diseases, a new class of delivery systems is evolving: highly miniaturized computerized delivery systems, integrated into a dental appliance. Dental delivery systems today are used in two ways: the main application is the local treatment of diseases affecting the oral cavity itself like periodontitis or fungal infections. The second is for systemic drug delivery.