Fully Integrated Biochip Platforms for Advanced Healthcare

Recent advances in microelectronics and biosensors are enabling developments of innovative biochips for advanced healthcare by providing fully integrated platforms for continuous monitoring of a large set of human disease biomarkers. Continuous monitoring of several human metabolites can be addressed by using fully integrated and minimally invasive devices located in the sub-cutis, typically in the peritoneal region. This extends the techniques of continuous monitoring of glucose currently being pursued with diabetic patients. However, several issues have to be considered in order to succeed in developing fully integrated and minimally invasive implantable devices. These innovative devices require a high-degree of integration, minimal invasive surgery, long-term biocompatibility, security and privacy in data transmission, high reliability, high reproducibility, high specificity, low detection limit and high sensitivity. Recent advances in the field have already proposed possible solutions for several of these issues. The aim of the present paper is to present a broad spectrum of recent results and to propose future directions of development in order to obtain fully implantable systems for the continuous monitoring of the human metabolism in advanced healthcare applications

A 16 x 16 CMOS amperometric microelectrode array for simultaneous electrochemical measurements

There is a requirement for an electrochemical sensor technology capable of making multivariate measurements in environmental, healthcare, and manufacturing applications. Here, we present a new device that is highly parallelized with an excellent bandwidth. For the first time, electrochemical cross-talk for a chip-based sensor is defined and characterized. The new CMOS electrochemical sensor chip is capable of simultaneously taking multiple, independent electroanalytical measurements. The chip is structured as an electrochemical cell microarray, comprised of a microelectrode array connected to embedded self-contained potentiostats. Speed and sensitivity are essential in dynamic variable electrochemical systems. Owing to the parallel function of the system, rapid data collection is possible while maintaining an appropriately low-scan rate. By performing multiple, simultaneous cyclic voltammetry scans in each of the electrochemical cells on the chip surface, we are able to show (with a cell-to-cell pitch of 456 μm) that the signal cross-talk is only 12% between nearest neighbors in a ferrocene rich solution. The system opens up the possibility to use multiple independently controlled electrochemical sensors on a single chip for applications in DNA sensing, medical diagnostics, environmental sensing, the food industry, neuronal sensing, and drug discovery

Development of an Advanced Zinc Air Flow Battery System (Phase 2)

A zinc-air battery is the promising energy storage technology for large-scale energy storage applications due to its low cost, environmental friendliness, and high energy density. However, the electrically rechargeable zinc−air batteries suffer from poor energy efficiency and cycle life because of critical problems such as passivation, dendrite growth, and hydrogen evolution reaction. The proliferation of zinc−air batteries is limited. The zinc-air flow battery combines the advantages of both a zinc-air battery and a redox flow battery. This combination permits the zinc-air flow battery to compete with the current leading battery technologies in the marketplace. A rechargeable Zn-air flow battery with an automatic control system was designed and prototyped in our previous researches. In this study, the engineering aspects of the Zn-air flow battery system have been investigated. The reactor was re-designed and optimized. The non-reacted dead zinc problems and the deformation of the air cathode were solved in the Gen 2 design. The reactor\u27s electrochemical performance was tripled, which benefited from applying the additive manufacturing processes (3D print) in the mechanical design. The air cathode fabrication process parameters were investigated, including the thickness, the binder content, and the expanded graphite content of the active layer. The 0.2mm was chosen as the desired thickness considering the efficiency of material and the fabrication\u27s easiness. The PTFE content was determined as 5%, and expanded graphite content was 10% in the active layer for the balance of the electronic conductivity and tenacity. The LabVIEW based battery management system build-up and control algorithm was discussed

A REAL-TIME MONITORING IONIC LIQUID CHEMICAL SENSOR FOR HEAVY METALS AND TOXIC POLLUTANTS

Heavy metal and toxic pollutants in water samples cause severe health risks. Current methods used are time consuming; costly, and involve toxic organic solvents: Areal-time, ionic liquid monitoring chemical sensor is needed for instantaneous analysis of samples. Ionic liquids, ion compounds with low melting point, have become popular subject ofstudy because ofthenproperties especially non-toxicity, no vapor pressure and electrochemical properties. Recent studies suggest that ionic liquids can be used as solvents, reaction media or electrolyte, substituting volatile organic solvents, for heavy metals and toxic pollutant electrochemical activity. This research focuses on the use of ionic liquid for the development of a chemical sensor to detect and determine toxic analytes especially lead; Lead was chosen as the metal ion for this study due to its effects on children. [HMIM][TFSI] was chosen for this study due to its electrochemical and environmental properties and anodic stripping voltammetry (ASY* was chosen as analysis method due to its sensitivity range, convenience and cost effectiveness. Due to its simplicity and convenience, carbon paste method was chosen to incorporate the ionic liquid into the electrode design. Results show that the ionic liquid modified carbon paste electrodes measure higher current compared to the simple carbon paste electrodes. It is assumed that the modified electrodes are more sensitive to change in measured current compared to the simple ones. However, since [H3vHM][TFSI] is a hydrophobic ionic liquid, it alone is not capable of interacting with lead ion since metal ions are always hydrated in a solution. Metal ions were not depositing on the electrode surface and there were no peaks registered in the plot. Through research, it was known that ligands and other types of co-solvents can be used to aid metal ion penetration into the hydrophobic ionic liquid phase. Thus, it is hoped that the project can be expanded by incorporating these ligands into the electrode design in the near future. As a conclusion, the ionic liquid modified carbon paste electrodes shows promising signs to be used as chemical sensors for lead detections due their electrochemical and environmental aspects

The Development Of Mems-Based Implantable Oxygen Sensing Systems

Oxygen-based cues are direct assessments for a wide range of in vivo biological effects, ranging from mitochondrial disease to tissue engineering/regenerative medicine. Existing electrochemical oxygen sensors are permanent systems applicable to short-term intraoperative use; devices are extracted before wound closure. Development of biocompatible oxygen sensors for long-term, post-surgery monitoring are therefore, desirable for clinical trials where objective oxygen measures are lacking. A biodegradable oxygen sensor that can break down into non-toxic components after a targeted lifespan, reducing the risk of chronic inflammatory response frequently observed with permanent devices, is another promising approach to advance the postoperative monitoring of oxygen tension and provide an additional means to monitor a number of diseases and injuries that are transient in nature, such as bone fracture, traumatic brain injury and wound healing. In this dissertation, we improved the current oxygen sensing technology to the point that it could be used for long-term applications, and further developed a biodegradable oxygen sensor along with a transient energy source to support the design of completely biodegradable oxygen sensing systems. Specifically, a biocompatible oxygen sensor, integrated with a customized circuit and an off-the-shelf battery were designed, built and tested. Oxygen levels in mouse gluteus muscle and zebrafish trunk muscle were both investigated to examine the sensor’s ability to monitor dynamic oxygen tension in vivo. In addition, a biodegradable battery featuring long shelf life and stable performance in the presence of changing body conditions was designed, fabricated and examined in vitro. Finally, a completely biodegradable oxygen sensor featuring a Mg-Mo galvanic pair was demonstrated. This approach measures physiological oxygen tension in a transient, harmless manner in the body, while simultaneously acting as a potential energy source for additional devices. Additionally, such sensors may have application in transient monitoring of the environment, such as environmental spills and algal tides

Investigation of reagent storage and electrochemical testing on filter paper

Thesis (Ph.D.)--Boston UniversityDiagnosis and detection is one of the most effective means of controlling matters that adversely affect public health and safety. Yet, in the developing world with a high burden of disease, most gold standard diagnostics remain widely inaccessible due to cost and lack of infrastructure. In recent years, one strategy to increase access to health and safety devices has been through the development of point-of-care diagnostics that are low-cost, portable, and easy-to-use for on-site analysis. In particular, paper has recently been in the spotlight as such a point-of-care (POC) platform. Compared to conventional POC tests made of glass or plastic substrates, paper itself is even thinner, light-weight, portable, disposable, and can store biological and chemical molecules for analytical measurement within its fibrous network. Several paper-based tests have demonstrated high sensitivity and specificity to detect proteins, bacteria, and metals for applications in disease diagnosis, health monitoring, and food and water safety. However, several gaps still remain in order to fully develop these paper-based analytical devices for point-of-care use in low-resource settings. First, reagent stability on filter paper is poorly understood, as well as its influence on quantitative, long-term testing. Second, the need for specialized instrumentation to perform the analytical methods on the paper devices can be a logistical and financial burden to end users in resource-limited settings. This dissertation addressed these questions through the development of quantitative paper assays for robust and point-of-care testing in low-resource settings. First, we fabricated micro-paper electrochemical devices, or µPEDs, for the amperometric detection of ethanol. This target analyte has direct applications in the global issue of road safety, which claims thousands of lives due to driving under the influence of alcohol. Also, we demonstrate that ethanol detection can provide the basis for the novel detection of substandard misoprostol, a high impact drug to save mothers from post-partum bleeding that is often the reason for maternal mortality. Second, we developed an independent method to study reagent stability on filter paper under conditions likely encountered in low-resource settings. Methods that enhanced stability were also used in the development of the µPEDs. Finally, we demonstrate that the ethanol measurements on our µPEDs could be performed with a commercial glucose meter, which operate by the same principles required to measure analyte concentrations. This integration of device and reader presents a cheap, reliable, low-power, and portable platform that can be adapted for the detection of other analytes relevant to health and safety

Smartphone-Based pH Sensor for Home Monitoring of Pulmonary Exacerbations in Cystic Fibrosis.

Currently, Cystic Fibrosis (CF) patients lack the ability to track their lung health at home, relying instead on doctor checkups leading to delayed treatment and lung damage. By leveraging the ubiquity of the smartphone to lower costs and increase portability, a smartphone-based peripheral pH measurement device was designed to attach directly to the headphone port to harvest power and communicate with a smartphone application. This platform was tested using prepared pH buffers and sputum samples from CF patients. The system matches within ~0.03 pH of a benchtop pH meter while fully powering itself and communicating with a Samsung Galaxy S3 smartphone paired with either a glass or Iridium Oxide (IrOx) electrode. The IrOx electrodes were found to have 25% higher sensitivity than the glass probes at the expense of larger drift and matrix sensitivity that can be addressed with proper calibration. The smartphone-based platform has been demonstrated as a portable replacement for laboratory pH meters, and supports both highly robust glass probes and the sensitive and miniature IrOx electrodes with calibration. This tool can enable more frequent pH sputum tracking for CF patients to help detect the onset of pulmonary exacerbation to provide timely and appropriate treatment before serious damage occurs

Fabrication of a 3D Printed Porous Junction for Ag|AgCl|gel-KCl Reference Electrode

Fused filament fabrication (FFF) is a 3D printing method that is attracting increased interest in the development of miniaturized electrochemical sensor systems due to its versatility, low cost, reproducibility, and capability for rapid prototyping. A key component of miniaturized electrochemical systems is the reference electrode (RE). However, reports of the fabrication of a true 3D-printed RE that exhibits stability to variations in the sample matrix remain limited. In this work, we report the development and characterization of a 3D-printed Ag|AgCl|gel-KCl reference electrode (3D-RE). The RE was constructed using a Ag|AgCl wire and agar-KCl layer housed in a watertight 3D-printed acrylonitrile butadiene styrene (ABS) casing. The novel feature of our electrode is a 3D-printed porous junction that protects the gel electrolyte layer from chloride ion leakage and test sample contamination while maintaining electrical contact with the sample solution. By tuning the 3D printing filament extrusion ratio (k), the porosity of the junction was adjusted to balance the reference electrode potential stability and impedance. The resulting 3D-RE demonstrated a stable potential, with a potential drift of 4.55 ± 0.46 mV over a 12-h period of continuous immersion in 0.1 M KCl, and a low impedance of 0.50 ± 0.11 kΩ. The 3D-RE was also insensitive to variations in the sample matrix and maintained a stable potential for at least 30 days under proper storage in 3 M KCl. We demonstrate the application of this 3D-RE in cyclic voltammetry and in pH sensing coupled with electrodeposited iridium oxide on a gold electrode. Our method offers a viable strategy for 3D printing a customizable true reference electrode that can be readily fabricated on demand and integrated into 3D-printed miniaturized electrochemical sensor systems

A Wi-Fi cloud-based portable potentiostat for electrochemical biosensors

The measurement of the analyte concentration in electrochemical biosensors traditionally requires costly laboratory equipment to obtain accurate results. Innovative portable solutions have recently been proposed, but usually, they lean on personal computers (PCs) or smartphones for data elaboration and they exhibit poor resolution or portability and proprietary software. This paper presents a low-cost portable system, assembling an ad hoc -designed analog front end (AFE) and a development board equipped with a system on chip integrating a microcontroller and a Wi-Fi network processor. The wireless module enables the transmission of measurements directly to a cloud service for sharing device outcome with users (physicians, caregivers, and so on). In doing so, the system does not require neither the customized software nor other devices involved in data acquisition. Furthermore, when any Internet connection is lost, the data are stored on board for subsequent transmission when a Wi-Fi connection is available. The noise output voltage spectrum has been characterized. Since the designed device is intended to be battery-powered to enhance portability, investigations about battery lifetime were carried out. Finally, data acquired with a conventional benchtop Autolab PGSTAT-204 electrochemical workstation are compared with the outcome of our developed device to validate the effectiveness of our proposal. To this end, we selected ferri/ferrocyanide as redox probe, obtaining the calibration curves for both the platforms. The final outcomes are shown to be feasible, accurate, and repeatable

Towards a commerical microelectrode array based sensor for improved chlorine detection.

The commercial development of a disposable aqueous chlorine sensor based on a novel microelectrode array fabrication process is described. Non-conducting poly(o-phenylenediamine) films are firstly used to passivate conductive surfaces. Ultrasonic ablation of passivated electrode assemblies then results in the formation of a plurality of wells to expose the underlying conductive substrate, thereby forming a microelectrode array. Microelectrode arrays produced in this manner can be exploited within many electrochemical sensing applications; however, portable aqueous chlorine detection has been selected by Microarray Limited (the industrial sponsors of this project) as a primary vehicle for launching its generic production technology. The scale of microelectrode array production has been extended from that of individual gold sputtercoated glass slide electrodes - to the simultaneous production of hundreds of low-cost screen printed carbon-ink based sensors. A focus has been directed at all stages towards permitting the cost-effective large-scale mass production of sensors with a view to challenging existing portable aqueous chlorine measurement technologies both in terms of performance and unit cost. Based on volume batches of 250,000, it has been calculated that Microarray Limited sensors can be manufactured for a unit cost of approximately 2.5 pence, sufficiently low to provide scope for a competitive yet profitable sale price. The Microarray Limited aqueous chlorine detection system has improved the limit of detection from 0.01 ppm to 0.005 ppm total chlorine without sacrificing accuracy. Furthermore, this novel approach to aqueous chlorine detection offers numerous key benefits to the customer including reduced testing time, a more straightforward operation and the elimination of harmful reagents. Product development has been described from an initial concept through to a pre-production phase. The development of an innovative generic sensor packaging technology is also described