Advanced interrogation methods for integrated photonic biosensors

Improved point-of-care diagnostics would revolutionise the way healthcare is delivered, increasing efficacy and safety, and cutting costs as our population ages, as well as significantly fostering the implementation of telehealth. Integrated photonic biosensors have the potential to enable this significant advancement. Integrated photonic biosensors measure biochemical substances with the use of photonic technology. They can achieve remarkable limits of detection and have excellent multiplexing potential and low fabrication costs when fabricated in high volume, which makes them ideal candidates for point-of-care applications. Interferometric photonic biosensors are amongst the most sensitive biosensors. However, their high sensitivity comes at the cost of more complicated interrogation systems, to accommodate for characteristics such as non-linearity and bias dependency. In order to achieve reliable biomedical measurements in point-of-care applications, there is a need for advanced interrogation methods for photonic biosensors. This thesis investigates current integrated photonic biosensor measurement concepts with the example of cardiac troponin measurements and provides insight into the limitations of this technology. Based on these findings, it investigates how concepts from optical data communication can be applied to the field of integrated photonic biosensors to create advanced interrogation methods for biomedical point-of-care applications. Chapter 1 motivates this work, as well as introduces current biosensor technology, and discusses their advantages, challenges and current research interests. Chapter 2 introduces different types of biosensors. It introduces the three major transducer types, the difference between label-based and label-free optical biosensors and discusses the suitability of different types of photonic biosensors for point-of-care applications. Chapter 3 explains the design and implementation of an interferometric integrated photonic biosensor system. It investigates the current limitations of this biosensor technology with a real-world application. The insight gained in this chapter is used to identify possible improvements of photonic biosensors and in particular their interrogation system. Chapter 4 demonstrates how an optical frequency comb can be used to enhance the functionality of an integrated photonic biosensor platform by sampling the spectral response of a Mach-Zehnder interferometer at 120° intervals. The phase is extracted by a vector sum of three comb-line measurements. This phase measurement approach significantly improves accuracy, reduces the dependency on the bias of the interferometer, and it is robust against intensity fluctuations that are common to each of the comb-lines. A limit of detection of 3.7 * 10^-7 RIU is demonstrated using a simple silicon photonic interferometric refractive index sensor, without requiring any modifications of the photonic chip. Chapter 5 demonstrates how a measurement concept known from dual-comb spectroscopy can be applied to interrogate photonic biosensors. This measurement approach increases the symmetry of the optical path, employs heterodyne detection techniques and has potential for future multiplexing applications. A limit of detection of 1.5 * 10^-6 RIU is demonstrated using a simple silicon photonic interferometric refractive index sensor. The presented implementation is less stable than the single comb system, which is likely due to polarisation drift and the components used. These instabilities prevent this demonstrated implementation from reaching its huge noise reduction potential. Future work is required and needs to address the instability of this system. Chapter 6 summarises the different biosensor setups and phase extraction methods presented in this thesis. The comb phase extraction systems significantly improve the stability and usability of the biosensor, however opportunities to further improve each of these systems have been identified. Additional avenues such as multiplexing and interfacing with resonant structures such as rings are also discussed as future work.