UC Berkeley

The global health implications of improper disease screening and diagnosis are tremendous, contributing to unnecessary disease burden and ongoing transmission of infectious diseases. While tools have been developed to help trained physicians and scientists diagnose disease in centralized healthcare facilities, many patients present with symptoms in resource-constrained settings. The limitations in infrastructure and skill present are often incompatible with existing diagnostic tools. The work in this dissertation centers on the engineering design, validation, and deployment of optical diagnostics targeted to these resource constraints. The approaches presented here take advantage of advances in mobile consumer electronics that have put high quality optics, automation, and data transmission capabilities into a compact and widely available package. In Chapter 1, I describe the limitations of current diagnostic tools for two diseases, oral cancer and tuberculosis, and outline the potential for development of novel tools around mobile devices.

In Chapter 2, I present work that is a prerequisite for the rational design of reproducible and quantitative imaging with a mobile phone. Mobile phones and their cameras have seen rapid changes in specifications and performance, but they remain consumer devices with several corresponding limitations for medical use. I characterize the imaging capabilities of mobile phones across time as part of a custom portable microscope, detailing sampling limitations, aberrations, and the consequences of unwanted image processing. I conclude that mobile phones, through appropriate optical design and workflow management, can perform sufficiently for diagnostic imaging applications.

In Chapter 3, I demonstrate a multi-color fluorescence imaging device based on a mobile phone for read-out of a sandwich immunoassay on a microfluidic chip. Microfluidic devices, systems that manipulate small volumes of liquid, have the potential to enable rapid and appropriate diagnostics at the point of care through reducing volume for patient samples and lowering cost. One of the limitations of microfluidic systems is that measuring the output of the device traditionally requires a large conventional microscope and scientific camera for visualization and quantification. Multi-color fluorescence on a mobile phone offers a powerful and portable alternative.

Current diagnostics for tuberculosis, a disease that kills over 1 million people a year globally, have advanced dramatically in the recent decade, but the devices that detect the DNA of tuberculosis have not succeeded in extending testing capabilities to peripheral healthcare settings where they are most needed. New nucleic acid amplification tests are promising for this setting; they eliminate the need for cycling temperature and provide a more rapid time to answer. In Chapter 4, I demonstrate that it is possible to control and measure the amplification of DNA in real-time with this new class of assay using a mobile phone camera. Demonstration of this capability required development of an optical system, custom software, sample handling geometry, and thermal management. I also include initial validation of a primer set contributed by collaborators that is sensitive across a range of strains of tuberculosis. Ongoing work is focused on combining these capabilities into an integrated tuberculosis diagnostic.

In Chapter 5, I present a field deployment of a diagnostic microscope for oral cancer built around a tablet computer. Oral cancer is the single largest cause of cancer mortality for men in India and other high burden countries. Cultural habits that increase the risk of developing oral cancer combine with delays in diagnosis leading to poor prognoses for patients. To improve the diagnostic process, it is important to screen patients early in the disease progression and refer them for a full diagnosis and care. In this work, I adapt both a manual microscope and automated slide-scanning device to the needs of oral cancer screening by brush biopsy. Through collaboration with clinical and corporate partners, these devices have been deployed and data collection has begun. I present initial images generated from patients and classified by pathologists that demonstrate the diagnostic workflow in practice.

Affecting care in a global health setting is a complex challenge, but through work presented in this dissertation I contribute a combination of novel diagnostic method development, detailed device characterization, and field data collection that demonstrate the potential of global health diagnostics based on consumer electronics.