Development and evaluation of point-of-care diagnostic technologies for providers and consumers

Point-of-care (POC) diagnostic technologies aim to expand access to traditional laboratory-based testing to near-patient settings. These settings can range from emergency or intensive care-units (ICUs) in the United States, to remote health posts in sub Saharan Africa. Differences in budget and infrastructure play a role in characterizing the wide array of possible “near patient” settings and must be taken into consideration in the engineering design process. In this dissertation we use translational engineering to develop practical and accessible microfluidic POC immunoassays for diverse settings, that include both provider and consumer facing applications. First, we examined Lyme Disease in the U.S., where existing diagnostic technologies face the challenge of rapid and accurate serodiagnosis in the face of largely non-specific clinical symptoms. We developed a multiplexed rapid test that could replicate enzyme-linked immunosorbent assay (ELISA) performance for Lyme Disease diagnosis. After screening candidate biomarkers, we evaluated performance of the multiplexed microfluidic test against ELISA using clinical serum samples and illustrated the potential to streamline current clinical algorithms requiring two immunoassays (ELISA and Western Blot) into one standalone test suitable for physician’s offices or urgent care clinics in the U.S. We also showed exploratory work towards a similar multiplexed test design for another bacterial spirochete infection, Leptospirosis. Next, we built on previous work towards a POC HIV-syphilis antenatal screening tool, to develop a smartphone-integrated, microfluidic assay for healthcare workers to use in low resource settings. The low-cost ($34), re-usable device (“smartphone dongle”) costs$34 to produce and provides results in 15 minutes. In this work, we focus on assay development efforts undertaken towards development of a fully integrated POC product suitable for deployment in the field, with practical considerations for the use of fingerstick blood, stability, scale-up and transport. We also streamlined the number of manual steps for end-user operation, through the use of lyophilized secondary antibodies, preloaded reagents on cassette, and an automatic result readout. While laboratory demonstration with clinical samples is important for initial characterization of POC devices, field evaluation reveals diagnostic performance under real-world conditions. We tested the device in the hands of minimally trained healthcare workers in Rwanda and saw comparable performance to other immunoassays run under field conditions. We also performed a follow-up pilot field study in Rwanda to evaluate the feasibility of the smartphone dongle platform for self-testing by patients/consumers in a low-resource setting, one of the most challenging use-cases for POC devices. Finally, we sought to integrate intellectual frameworks from behavioral research and user-experience (UX) design in creating a new framework for evaluation of consumer-facing microfluidic devices, specifically towards HIV home-testing in the U.S. While overall rates of HIV are decreasing in the U.S., the population of gay, bisexual and other men who have sex with men (MSM) are disproportionately affected. Self-testing products for sexually transmitted infection (STI) testing could address unmet needs for these target populations in both increasing access and frequency of testing, as well as integrating use with sexual partners for early diagnosis or even prevention. We worked with a cohort of MSMs at high risk for HIV/STI transmission in New York City, and performed for the first time, a structured assessment of completely naïve users interacting with a smartphone interfaced microfluidic diagnostic device (“SMARTtest”). We integrated UX design value model of device usability, credibility, accessibility and acceptability into our evaluation framework, which influence user’s information, knowledge, motivation and behavioral skills towards engaging with a prevention method (“IMB” model). Thus far, such frameworks have rarely been applied to other consumer health monitoring devices, including microfluidic POC devices. As the microfluidic field moves towards more field demonstrations of devices, more untrained and minimally trained users will have access to such tools. It is important to understand how they use devices, what the device failure points are and what the most relevant design features are to spur user adoption and meaningful usage. Underlying our work in creating accessible and practical POC immunoassay tools for infectious disease detection, is the illustration of the translational development roadmap from proof-of-concept assay development to field studies and user-based evaluations for intended end-use settings that range from U.S. based primary care clinics, rural health centers in low-resource settings as well as self-testing environments in both. Incorporating an understanding of the target use-case setting is critical in translating technologies for clinical use, whether in the infrastructure and services that are available, or end-user needs and constraints such as clinical workflow patterns, level of technical expertise and perceptions of usefulness and value. We show how user/use-case focused application of downstream translational engineering and testing informs upstream design choices and accelerates development of POC devices for real-world use. The sum of this work aims to illustrate tenets of translational engineering design and testing to advance insight into building POC products that are poised for greater adoption by target end users, whether they are health providers or consumers

Regulation 61-64 x-rays (title B)

Except as otherwise specifically provided, this regulation applies to all persons who receive, possess, use, transfer, own, or acquire any x-ray producing machine. The provisions of this regulation shall not be interpreted as limiting the intentional exposure of patients to radiation for the purpose of diagnosis, analysis, or therapy by persons licensed to practice one (1) or more of the health professions within the authority granted to them by statute or regulation

Passively-coded embedded microwave sensors for materials characterization and structural health monitoring (SHM)

Monitoring and maintaining civil, space, and aerospace infrastructure is an ongoing critical problem facing our nation. As new complex materials and structures, such as multilayer composites and inflatable habitats, become ubiquitous, performing inspection of their structural integrity becomes even more challenging. Thus, novel nondestructive testing (NDT) methods are needed. Chipless RFID is a relatively new technology that has the potential to address these needs. Chipless RFID tags have the advantage of being wireless and passive, meaning that they do not require a power source or an electronic chip. They can also be used in a variety of sensing applications including monitoring temperature, strain, moisture, and permittivity. However, these tags have yet to be used as embedded sensors. By embedding chipless RFID tags in materials, materials characterization can be performed via multi-bit sensing; that is, looking at how the multi-bit code assigned to the response of the tag changes as a function of material. This thesis develops this method through both simulation and measurement. In doing so, a new coding method and tag design are developed to better support this technique. Furthermore, inkjet-printing is explored as a manufacturing method for these tags and various measurement methods for tags including radar cross-section and microwave thermography are explored --Abstract, page iii

Regulation 61-64 x-rays (title b)

Except as otherwise specifically provided, these regulations apply to all persons who receive, possess, use, transfer, own, or acquire any x-ray producing machine. The provisions of these regulations shall not be interpreted as limiting the intentional exposure of patients to radiation for the purpose of diagnosis, analysis, or therapy by persons licensed to practice one or more of the health professions within the authority granted to them by statute or regulation

Expanding accessibility of diagnostics through miniaturized technologies

There is a disproportionate burden of disease (measured in daily-adjusted life years, or DALYs) in low-income countries. Much of this disparity is due to infectious diseases: 53% of DALYs in Africa are due to infectious diseases, compared with only 3% in the American continents. This disparity is largely due to differences in electrical and transport infrastructure as well as access to skilled personnel and monetary resources. Current diagnostic solutions are primarily designed for high-resource settings and therefore these solutions cannot be easily translated to a lower-resource setting. In order to tackle this health disparity, new solutions must be designed specifically for a lower-resource setting. In this dissertation, we take a translational approach to engineering appropriate diagnostics for resource-limited settings. First, we develop a handheld smartphone accessory to perform an assay similar to enzyme-linked immunosorbent assay (ELISA), traditionally a laboratory-based test. In 15 minutes, it provides an objective diagnostic readout important for minimal training, while using an average of 1.6mW of power and costing only $34. We further develop the device to provide a quantitative hemoglobin measurement simultaneously with an HIV immunoassay, for use in antenatal care screening. The multiplexing two assay types that are clinically relevant has the potential to streamline workflow. While specifications can be demonstrated in the laboratory, the true test of the device must be performed in the field. We brought our smartphone accessory to three health centers in Kigali, Rwanda to be used by healthcare workers with no prior experience in ELISA. After a short 30 minute training, the healthcare workers were able to obtain diagnostic results comparable to other immunoassays run under field conditions. With a simple and user-friendly design, we sought to further expand the usage of our device as a self-testing device, having patients test themselves. Lastly, we explore manufacturable thermoplastics as a material for a microfluidic diagnostic for nucleic acid detection. The sum of this work aims to gain insight into methods of design, testing, and implementation of translational design

Investigating marine particle distributions and processes using in situ optical imaging in the Gulf of Alaska

Thesis (M.S.) University of Alaska Fairbanks, 2015The Gulf of Alaska is a seasonally productive ecosystem surrounded by glaciated coastal mountains with high precipitation. With a combination of high biological production, inputs of suspended sediments from glacial runoff, and contrasting nutrient regimes in offshore and shelf environments, there is a great need to study particle cycling in this region. I measured the concentrations and size distributions of large marine particles (0.06-27 mm) during four cruises in 2014 and 2015 using the Underwater Vision Profiler (UVP). The UVP produces high resolution depth profiles of particle concentrations and size distributions throughout the water column, while generating individual images of objects >500 μm including marine snow particles and mesozooplankton. The objectives of this study were to 1) describe spatial variability in particle concentrations and size distributions, and 2) use that variability to identify driving processes. I hypothesized that UVP particle concentrations and size distributions would follow patterns in chlorophyll a concentrations. Results did not support this hypothesis. Instead, a major contrast between shelf and offshore particle concentrations and sizes was observed. Total concentrations of particles increased with proximity to glacial and fluvial inputs. Over the shelf, particle concentrations on the order of 1000-10,000/L were 1-2 orders of magnitude greater than offshore concentrations on the order of 100/L. Driving processes over the shelf included terrigenous inputs from land, resuspension of bottom sediments, and advective transport of those inputs along and across the shelf. Offshore, biological processes were drivers of spatial variability in particle concentration and size. High quantities of terrigenous sediments could have implications for enhanced particle flux due to ballasting effects and for offshore transport of particulate phase iron to the central iron-limited gyre. The dominance of resuspended material in shelf processes will inform the location of future studies of the biological pump in the coastal Gulf of Alaska. This work highlights the importance of continental margins in global biogeochemical processes

A cost-effective, mobile platform-based, photogrammetric approach for continuous structural deformation monitoring

PhD ThesisWith the evolution of construction techniques and materials technology, the design of modern civil engineering infrastructure has become increasingly advanced and complex. In parallel to this, the development and application of appropriate and efficient monitoring technologies has become essential. Improvement in the performance of structural monitoring systems, reduction of labour and total implementation costs have therefore become important issues that scientists and engineers are committed to solving. In this research, a non-intrusive structural monitoring system was developed based on close-range photogrammetric principles. This research aimed to combine the merits of photogrammetry and latest mobile phone technology to propose a cost-effective, compact (portable) and precise solution for structural monitoring applications. By combining the use of low-cost imaging devices (two or more mobile phone handsets) with in-house control software, a monitoring project can be undertaken within a relatively low budget when compared to conventional methods. The system uses programmable smart phones (Google Android v.2.2 OS) to replace conventional in-situ photogrammetric imaging stations. The developed software suite is able to control multiple handsets to continuously capture high-quality, synchronized image sequences for short or long-term structural monitoring purposes. The operations are fully automatic and the system can be remotely controlled, exempting the operator from having to attend the site, and thus saving considerable labour expense in long-term monitoring tasks. In order to prevent the system from crashing during a long-term monitoring scheme, an automatic system state monitoring program and a system recovery module were developed to enhance the stability. In considering that the image resolution for current mobile phone cameras is relatively low (in comparison to contemporary digital SLR cameras), a target detection algorithm was developed for the mobile platform that, when combined with dedicated target patterns, was found to improve the quality of photogrammetric target measurement. Comparing the photogrammetric results with physical measurements, which were measured using a Zeiss P3 analytical plotter, the returned accuracy achieved was 1/67,000. The feasibility of the system has been proven through the implementation of an indoor simulation test and an outdoor experiment. In terms of using this system for actual structural monitoring applications, the optimal relative accuracy of distance measurement was determined to be approximately 1/28,000 under laboratory conditions, and the outdoor experiment returned a relative accuracy of approximately 1/16,400

Biosensors for Diagnosis and Monitoring

Biosensor technologies have received a great amount of interest in recent decades, and this has especially been the case in recent years due to the health alert caused by the COVID-19 pandemic. The sensor platform market has grown in recent decades, and the COVID-19 outbreak has led to an increase in the demand for home diagnostics and point-of-care systems. With the evolution of biosensor technology towards portable platforms with a lower cost on-site analysis and a rapid selective and sensitive response, a larger market has opened up for this technology. The evolution of biosensor systems has the opportunity to change classic analysis towards real-time and in situ detection systems, with platforms such as point-of-care and wearables as well as implantable sensors to decentralize chemical and biological analysis, thus reducing industrial and medical costs. This book is dedicated to all the research related to biosensor technologies. Reviews, perspective articles, and research articles in different biosensing areas such as wearable sensors, point-of-care platforms, and pathogen detection for biomedical applications as well as environmental monitoring will introduce the reader to these relevant topics. This book is aimed at scientists and professionals working in the field of biosensors and also provides essential knowledge for students who want to enter the field