Fully Autonomous Active Self-Powered Point-of-Care Devices: The Challenges and Opportunities.

Quick and effective point-of-care (POC) devices have the chance to revolutionize healthcare in developed and developing countries since they can operate anywhere the patient is, with the possibility of obtaining and sending the results to the doctor without delay. In recent years, significant efforts have focused on developing new POC systems that can screen for biomarkers continuously and non-invasively in body fluids to prevent, diagnose, and manage diseases. However, one of the critical challenges left to address is how to power them effectively and sufficiently. In developing countries and rural and remote areas, where there are usually no well-established electricity grids or nearby medical facilities, and using batteries is unreliable or not cost-effective, alternative power sources are the most challenging issue for stand-alone and self-sustained POC devices. Here, we provide an overview of the techniques for used self-powering POC devices, where the sample is used to detect and simultaneously generate energy to power the system. Likewise, this paper introduced the state-of-the-art with a review of different research projects, patents, and commercial products for self-powered POCs from the mid-2010s until present day.

Novel Sweat-Based Wearable Device for Advanced Monitoring of Athletic Physiological Biometrics.

Blood testing has traditionally been the gold standard for the physiological analysis and monitoring of professional athletes. In recent years, blood testing has moved out of the laboratory thanks to portable handheld devices, such as lactate meters. However, despite its usefulness and widespread use, blood testing has several drawbacks and limitations, such as the need for the athlete to stop exercising for blood extraction and the inability to have data continuously collected. In this scenario, sweat has become an alternative to blood testing because of its rich content of electrolytes and metabolites, as well as small quantities of sugars, proteins, and ions. Nevertheless, there are few devices capable of analyzing this biofluid and providing useful information to users. In this paper, an electronic system designed for the autonomous analysis of sweat electrolytes and metabolites along with heart rate dynamics is presented. This system is part of a novel wearable device tailored for athletes that offers to the user a real-time assessment of their physiological status and performance.

A single-cell RNA-seq analysis unravels the heterogeneity of primary cultured human corneal endothelial cells.

The cornea is a transparent and avascular tissue located in front of the eye. Its inner surface is lined by a monolayer of corneal endothelial cells (CECs), which maintain the cornea transparency. CECs remain arrested in a non-proliferative state and damage to these cells can compromise their function leading to corneal opacity. The primary culture of donor-derived CECs is a promising cell therapy. It confers the potential to treat multiple patients from a single donor, alleviating the global donor shortage. Nevertheless, this approach has limitations preventing its adoption, particularly culture protocols allow limited expansion of CECs and there is a lack of clear parameters to identify therapy-grade CECs. To address this limitation, a better understanding of the molecular changes arising from the primary culture of CECs is required. Using single-cell RNA sequencing on primary cultured CECs, we identify their variable transcriptomic fingerprint at the single cell level, provide a pseudo-temporal reconstruction of the changes arising from primary culture, and suggest markers to assess the quality of primary CEC cultures. This research depicts a deep transcriptomic understanding of the cellular heterogeneity arising from the primary expansion of CECs and sets the basis for further improvement of culture protocols and therapies.

Elucidating the Corneal Endothelial Cell Proliferation Capacity through an Interspecies Transcriptome Comparison.

The regenerative capacity of corneal endothelial cells (CECs) differs between species; in bigger mammals, CECs are arrested in a non-proliferative state. Damage to these cells can compromise their function causing corneal opacity. Corneal transplantation is the current treatment for the recovery of clear eyesight, but the donor tissue demand is higher than the availability and there is a need to develop novel treatments. Interestingly, rabbit CECs retain a high proliferative profile and can repopulate the endothelium. There is a lack of fundamental knowledge to explain these differences. Gaining information on their transcriptomic variances could allow the identification of CEC proliferation drivers. In this study, human, sheep, and rabbit CECs are analyzed at the transcriptomic level. To understand the differences across each species, a pipeline for the analysis of pathways with different activities is generated. The results reveal that 52 pathways have different activity when comparing species with non-proliferative CECs (human and sheep) to species with proliferative CECs (rabbit). The results show that Notch and TGF-ß pathways have increased activity in species with non-proliferative CECs, which might be associated with their low proliferation. Overall, this study illustrates transcriptomic pathway-level differences that can provide leads to develop novel therapies to regenerate the corneal endothelium.

Non-Invasive Multiparametric Approach To Determine Sweat-Blood Lactate Bioequivalence.

Many sweat-based wearable monitoring systems have been recently proposed, but the data provided by those systems often lack a reliable and meaningful relation to standardized blood values. One clear example is lactate, a relevant biomarker for both sports and health sectors, with a complex sweat-blood bioequivalence. This limitation decreases its individual significance as a sweat-based biomarker. Taking into account the insights of previous studies, a multiparametric methodology has been proposed to predict blood lactate from non-invasive independent sensors: sweat lactate, sweat rate, and heart rate. The bioequivalence study was performed with a large set of volunteers (>30 subjects) in collaboration with sports institutions (Institut Nacional d'Educació Física de Catalunya, INEFC, and Centre d'Alt Rendiment, CAR, located in Spain). A neural network algorithm was used to predict blood lactate values from the sensor data and subject metadata. The developed methodology reliably and accurately predicted blood lactate absolute values, only adding 0.3 mM of accumulated error when compared to portable blood lactate meters, the current gold standard for sports clinicians. The approach proposed in this work, along with an integrated platform for sweat monitoring, will have a strong impact on the sports and health fields as an autonomous, real-time, and continuous monitoring tool.

High-efficient energy harvesting architecture for self-powered thermal-monitoring wireless sensor node based on a single thermoelectric generator.

In recent years, research on transducers and system architectures for self-powered devices has gained attention for their direct impact on the Internet of Things in terms of cost, power consumption, and environmental impact. The concept of a wireless sensor node that uses a single thermoelectric generator as a power source and as a temperature gradient sensor in an efficient and controlled manner is investigated. The purpose of the device is to collect temperature gradient data in data centres to enable the application of thermal-aware server load management algorithms. By using a maximum power point tracking algorithm, the operating point of the thermoelectric generator is kept under control while using its power-temperature transfer function to measure the temperature gradient. In this way, a more accurate measurement of the temperature gradient is achieved while harvesting energy with maximum efficiency. The results show the operation of the system through its different phases as well as demonstrate its ability to efficiently harvest energy from a temperature gradient while measuring it. With this system architecture, temperature gradients can be measured with a maximum error of 0.14 [Formula: see text]C and an efficiency of over 92% for values above 13 [Formula: see text]C and a single transducer.

Approaches for corneal endothelium regenerative medicine.

The state of the art therapy for treating corneal endothelial disease is transplantation. Advances in the reproducibility and accessibility of surgical techniques are increasing the number of corneal transplants, thereby causing a global deficit of donor corneas and leaving 12.7 million patients with addressable visual impairment. Approaches to regenerate the corneal endothelium offer a solution to the current tissue scarcity and a treatment to those in need. Methods for generating corneal endothelial cells into numbers that could address the current tissue shortage and the possible strategies used to deliver them have now become a therapeutic reality with clinical trials taking place in Japan, Singapore and Mexico. Nevertheless, there is still a long way before such therapies are approved by regulatory bodies and become clinical practice. Moreover, acellular corneal endothelial graft equivalents and certain drugs could provide a treatment option for specific disease conditions without the need of donor tissue or cells. Finally, with the emergence of gene modulation therapies to treat corneal endothelial disease, it would be possible to treat presymptomatic patients or those presenting early symptoms, drastically reducing the need for donor tissue. It is necessary to understand the most recent developments in this rapidly evolving field to know which conditions could be treated with which approach. This article provides an overview of the current and developing regenerative medicine therapies to treat corneal endothelial disease and provides the necessary guidance and understanding towards the treatment of corneal endothelial disease.

Single cell transcriptomics reveals the heterogeneity of the human cornea to identify novel markers of the limbus and stroma.

The cornea is the clear window that lets light into the eye. It is composed of five layers: epithelium, Bowman's layer, stroma, Descemet's membrane and endothelium. The maintenance of its structure and transparency are determined by the functions of the different cell types populating each layer. Attempts to regenerate corneal tissue and understand disease conditions requires knowledge of how cell profiles vary across this heterogeneous tissue. We performed a single cell transcriptomic profiling of 19,472 cells isolated from eight healthy donor corneas. Our analysis delineates the heterogeneity of the corneal layers by identifying cell populations and revealing cell states that contribute in preserving corneal homeostasis. We identified expression of CAV1, HOMER3 and CPVL in the corneal epithelial limbal stem cell niche, CKS2, STMN1 and UBE2C were exclusively expressed in highly proliferative transit amplifying cells, CXCL14 was expressed exclusively in the suprabasal/superficial limbus, and NNMT was exclusively expressed by stromal keratocytes. Overall, this research provides a basis to improve current primary cell expansion protocols, for future profiling of corneal disease states, to help guide pluripotent stem cells into different corneal lineages, and to understand how engineered substrates affect corneal cells to improve regenerative therapies.

Self-Powered Point-of-Care Device for Galvanic Cell-Based Sample Concentration Measurement.

A novel self-powered point-of-care low-power electronics approach for galvanic cell-based sample concentration measurement is presented. The electronic system harvests and senses at the same time from the single cell. The system implements a solution that is suitable in those scenarios where extreme low power is generated from the fuel cell. The proposed approach implements a capacitive-based method to perform a non-linear sweep voltammetry to the cell, but without the need to implement a potentiostat amplifier for that purpose. It provides a digital-user readable result without the need for external non-self-powered devices or instruments compared with other solutions. The system conception was validated for a particular case. The scenario consisted of the measurement of a NaCl solution as the electrolyte, which was related to the conductivity of the sample. The electronic reader continuously measured the current with a transfer function gain of 1.012 V mA-1. The overall system exhibited a maximum coefficient of variation of 6.1%, which was an improvement compared with the state-of-the-art. The proof of concept of this electronics system was validated with a maximum power consumption of 5.8 µW using commercial-off-the-self parts.

An Integrated Detection Method for Flow Viscosity Measurements in Microdevices.

Point-of-care devices can analyze or characterize a sample in a short time. New technologies in medical science seek integrations of different measurement techniques for a complete analysis. This study describes the fabrication method, tests, and results of microtechnology as an approach for an integrated rheometer. The portable device measured the average flow velocity to calculate its viscosity. The whole system encompasses a microdevice integrated to a data acquisition system powered by USB and controlled by full custom software. As a result, we obtained an easy-to-handle and fabricate hand-held microrheometer. The device was tested using Newtonian fluids such as Mili-Q water, an aqueous solution of Ethylene-glycol at 40% and 25% and Non-Newtonian blood samples. The whole device can provide the non-linear viscosity of a 0.08 ml blood sample in less than 30 seconds, in a wide range of shear rate with an accuracy of 93%. More importantly, due to its detection method and simplicity, it can be enclosed within almost any fluidic microsystem, including biomedical applications.

Transport and Preservation Comparison of Preloaded and Prestripped-Only DMEK Grafts.

PURPOSE: This study compares the effect of the transport of conventionally prestripped Descemet membrane endothelial keratoplasty (DMEK) tissue with the DMEK revolutionary advanced Preloadable Injection Device (RAPID) preloaded transport system from Geuder AG (Heidelberg, Germany). Endothelial cell loss, tissue integrity, endothelial cell phenotype, and viability were assessed and compared. METHODS: Twelve DMEK grafts were prestripped by the cornea bank and transported using the following 2 conditions: conventional flask (n = 6) or a preloaded transport cartridge (DMEK RAPID, n = 6). After transport, tissues were analyzed for cell density; denuded areas; immunolocalization of corneal endothelial markers, such as ZO-1, CD166, and Na/K ATPase; histology analysis; and cell viability staining with Hoechst, calcein AM, and ethidium homodimer. RESULTS: Endothelial cell loss (10.35% vs. 9.15%) did not differ between transport conditions. Histological analysis confirmed the integrity of the Descemet membrane and endothelial cell layer with both transport conditions. Similarly, the corneal endothelial cell mosaic was conserved in both conditions. The ZO-1 tight junctions confirmed the integrity of the confluent corneal endothelial cell monolayer. CD166 and Na/K ATPase detection with immunofluorescence was also comparable. A similar percentage of dead cells was reported in both conditions (18.1% vs. 16.73%). Moreover, the surface covered with calcein-positive cells (59.02% vs. 61.95%) did not differ between transport conditions. CONCLUSIONS: Our results suggest that DMEK grafts can be prestripped or preloaded into a novel transport cartridge and shipped to the clinic with comparable endothelial cell loss, phenotypical marker expression, and viability to the conventional prestripped donor tissue.

Competitive USB-Powered Hand-Held Potentiostat for POC Applications: An HRP Detection Case.

Considerable efforts are made to develop Point-of-Care (POC) diagnostic tests. POC devices have the potential to match or surpass conventional systems regarding time, accuracy, and cost, and they are significantly easier to operate by or close to the patient. This strongly depends on the availability of miniaturized measurement equipment able to provide a fast and sensitive response. This paper presents a low-cost, portable, miniaturized USB-powered potentiostat for electrochemical analysis, which has been designed, fabricated, characterized, and tested against three forms of high-cost commercial equipment. The portable platform has a final size of 10.5 × 5.8 × 2.5 cm, a weight of 41 g, and an approximate manufacturing cost of $85 USD. It includes three main components: the power module which generates a stable voltage and a negative supply, the front-end module that comprises a dual-supply potentiostat, and the back-end module, composed of a microcontroller unit and a LabVIEW-based graphic user interface, granting plug-and-play and easy-to-use operation on any computer. The performance of this prototype was evaluated by detecting chronoamperometrically horseradish peroxidase (HRP), the enzymatic label most widely used in electrochemical biosensors. As will be shown, the miniaturized platform detected HRP at concentrations ranging from 0.01 ng·mL-1 to 1 µg·mL-1, with results comparable to those obtained with the three commercial electrochemical systems.

Self-Powered Portable Electronic Reader for Point-of-Care Amperometric Measurements.

In this work, we present a self-powered electronic reader (e-reader) for point-of-care diagnostics based on the use of a fuel cell (FC) which works as a power source and as a sensor. The self-powered e-reader extracts the energy from the FC to supply the electronic components concomitantly, while performing the detection of the fuel concentration. The designed electronics rely on straightforward standards for low power consumption, resulting in a robust and low power device without needing an external power source. Besides, the custom electronic instrumentation platform can process and display fuel concentration without requiring any type of laboratory equipment. In this study, we present the electronics system in detail and describe all modules that make up the system. Furthermore, we validate the device's operation with different emulated FCs and sensors presented in the literature. The e-reader can be adjusted to numerous current ranges up to 3 mA, with a 13 nA resolution and an uncertainty of 1.8%. Besides, it only consumes 900 µW in the low power mode of operation, and it can operate with a minimum voltage of 330 mV. This concept can be extended to a wide range of fields, from biomedical to environmental applications.

'Plug-and-Power' Point-of-Care diagnostics: A novel approach for self-powered electronic reader-based portable analytical devices.

This paper presents an innovative approach in the portable Point-of-Care diagnostics field, the Plug-and-Power concept. In this new disposable sensor and plug-and-play reader paradigm, the energy required to perform a measurement is always available within the disposable test component. The reader unit contains all the required electronic modules to run the test, process data and display the result, but does not include any battery or power source. Instead, the disposable part acts as both the sensor and the power source. Additionally, this approach provides environmental benefits related to battery usage and disposal, as the paper-based power source has non-toxic redox chemistry that makes it eco-friendly and safe to follow the same waste stream as disposable test strips. The feasibility of this Plug-and-Power approach is demonstrated in this work with the development of a self-powered portable glucometer consisting of two parts: a test strip including a paper-based power source and a paper-based biofuel cell as a glucose sensor; and an application-specific battery-less electronic reader designed to extract the energy from the test strip, process the signal provided and show the glucose concentration on a display. The device was tested with human serum samples with glucose concentrations between 5 and 30 mM, providing quantitative results in good agreement with commercial measuring instruments. The advantages of the present approach can be extended to any kind of biosensors measuring different analytes and biological matrices, and in this way, strengthen the goals of Point-of-Care diagnostics towards laboratory decentralization, personalized medicine and improving patient compliance.

Efficacy, acceptability and tolerability of Zelesse® for the treatment of non-specific vulvovaginitis in paediatric patients: The NINESSE Study.

Objective To evaluate the efficacy, tolerability and acceptability of Zelesse®, an intimate hygiene wash solution, in the relief of the symptoms and signs of non-specific vulvovaginitis in paediatric patients. Methods The NINESSE Study was a prospective, observational, multicentre study involving females aged 2-8 years who attended paediatric offices with symptoms suggestive of non-specific vulvovaginitis. They were administered Zelesse® as a single treatment for 15 ± 5 days. Pruritus, burning, dysuria, erythema, leucorrhoea and oedema were evaluated before and after treatment. Results A total of 71 paediatric patients were enrolled in the study (mean ± SD age, 4.5 ± 1.9 years). The most significant effects were observed for pruritus and burning, where 98.4% (62 of 63) and 96.9% (63 of 65) of the patients improved after treatment, respectively. Zelesse® demonstrated a beneficial effect on dysuria, erythema, leucorrhoea and oedema. The effects on the symptoms and signs were observed within the first week of treatment; although 44.9% (31 of 69) of patients experienced improvements after 2-3 days. Zelesse® was well accepted and tolerated by most patients. No serious adverse events were reported. Conclusions Zelesse® was very effective for the relief of the symptoms and signs of non-specific vulvovaginitis, in particular pruritus, burning and erythema, in females aged 2-8 years.

Combined Dielectrophoresis and Impedance Systems for Bacteria Analysis in Microfluidic On-Chip Platforms.

Bacteria concentration and detection is time-consuming in regular microbiology procedures aimed to facilitate the detection and analysis of these cells at very low concentrations. Traditional methods are effective but often require several days to complete. This scenario results in low bioanalytical and diagnostic methodologies with associated increased costs and complexity. In recent years, the exploitation of the intrinsic electrical properties of cells has emerged as an appealing alternative approach for concentrating and detecting bacteria. The combination of dielectrophoresis (DEP) and impedance analysis (IA) in microfluidic on-chip platforms could be key to develop rapid, accurate, portable, simple-to-use and cost-effective microfluidic devices with a promising impact in medicine, public health, agricultural, food control and environmental areas. The present document reviews recent DEP and IA combined approaches and the latest relevant improvements focusing on bacteria concentration and detection, including selectivity, sensitivity, detection time, and conductivity variation enhancements. Furthermore, this review analyses future trends and challenges which need to be addressed in order to successfully commercialize these platforms resulting in an adequate social return of public-funded investments.

Cooperative energy harvesting-adaptive MAC protocol for WBANs.

In this paper, we introduce a cooperative medium access control (MAC) protocol, named cooperative energy harvesting (CEH)-MAC, that adapts its operation to the energy harvesting (EH) conditions in wireless body area networks (WBANs). In particular, the proposed protocol exploits the EH information in order to set an idle time that allows the relay nodes to charge their batteries and complete the cooperation phase successfully. Extensive simulations have shown that CEH-MAC significantly improves the network performance in terms of throughput, delay and energy efficiency compared to the cooperative operation of the baseline IEEE 802.15.6 standard.

Combined dielectrophoretic and impedance system for on-chip controlled bacteria concentration: Application to Escherichia coli.

The present paper reports a bacteria autonomous controlled concentrator prototype with a user-friendly interface for bench-top applications. It is based on a microfluidic lab-on-a-chip and its associated custom instrumentation, which consists of a dielectrophoretic actuator, to preconcentrate the sample, and an impedance analyzer, to measure concentrated bacteria levels. The system is composed of a single microfluidic chamber with interdigitated electrodes and an instrumentation with custom electronics. The prototype is supported by a real-time platform connected to a remote computer, which automatically controls the system and displays impedance data used to monitor the status of bacteria accumulation on-chip. The system automates the whole concentrating operation. Performance has been studied for controlled volumes of Escherichia coli samples injected into the microfluidic chip at constant flow rate of 10 µL/min. A media conductivity correcting protocol has been developed, as the preliminary results showed distortion of the impedance analyzer measurement produced by bacterial media conductivity variations through time. With the correcting protocol, the measured impedance values were related to the quantity of bacteria concentrated with a correlation of 0.988 and a coefficient of variation of 3.1%. Feasibility of E. coli on-chip automated concentration, using the miniaturized system, has been demonstrated. Furthermore, the impedance monitoring protocol had been adjusted and optimized, to handle changes in the electrical properties of the bacteria media over time.

An instantaneous low-cost point-of-care anemia detection device.

We present a small, compact and portable device for point-of-care instantaneous early detection of anemia. The method used is based on direct hematocrit measurement from whole blood samples by means of impedance analysis. This device consists of a custom electronic instrumentation and a plug-and-play disposable sensor. The designed electronics rely on straightforward standards for low power consumption, resulting in a robust and low consumption device making it completely mobile with a long battery life. Another approach could be powering the system based on other solutions like indoor solar cells, or applying energy-harvesting solutions in order to remove the batteries. The sensing system is based on a disposable low-cost label-free three gold electrode commercial sensor for 50 µL blood samples. The device capability for anemia detection has been validated through 24 blood samples, obtained from four hospitalized patients at Hospital Clínic. As a result, the response, effectiveness and robustness of the portable point-of-care device to detect anemia has been proved with an accuracy error of 2.83% and a mean coefficient of variation of 2.57% without any particular case above 5%.

Dielectrophoretic concentrator enhancement based on dielectric poles for continuously flowing samples.

We describe a novel continuous-flow cell concentrator microdevice based on dielectrophoresis, and its associated custom-made control unit. The performances of a classical interdigitated metal electrode-based dielectrophoresis microfluidic device and this enhanced version, that includes insulator-based pole structures, were compared using the same setup. Escherichia coli samples were concentrated at several continuous flows and the device's trapping efficiencies were evaluated by exhaustive cell counts. Our results show that pole structures enhance the retention up to 12.6%, obtaining significant differences for flow rates up to 20 µL/min, when compared to an equivalent classical interdigitated electrodes setup. In addition, we performed a subsequent proteomic analysis to evaluate the viability of the biological samples after the long exposure to the actuating electrical field. No Escherichia coli protein alteration in any of the two systems was observed.