Enhancing Nanoplasmonic Biosensors Integration With Lab-on-a-Chip Platforms: A Focus on Fabrication and Optical Interrogation Strategies

<p dir="ltr">This Doctoral Thesis explores the integration of nanoplasmonic biosensors within Lab-on-a Chip (LoC) platforms, aiming to build multifunctional systems that will enable multiple analyses on a single sample, streamline workflows and facilitate faster decision-making in disease research and treatment.</p><p dir="ltr">Nanoplasmonic biosensors, which detect changes in the local refractive index using optical structures, offer a promising solution for integration into LoC platforms. These sensors use effectively the interaction between light and free electrons on metal surfaces, creating an evanescent field sensitive to subtle changes in the surrounding medium. This allows for real-time, label-free detection of low-concentration analytes, with their compact size making them ideal for portable devices.</p><p dir="ltr">Despite their potential, integrating nanoplasmonic biosensors into LoC systems presents different obstacles. Research on nanoplasmonic biosensing often concentrates on developing specific components, such as ultra-sensitive nanostructures, rather than focusing on full system integration. Additionally, balancing sensor sensitivity through optical interrogation with integration into compact environments remains a challenge. Finally, current fabrication methods limit the creation of smaller sensor areas, leading to resource waste and obstructing integration, while targeted sensor placement could support multifunctional biosensing and complementary analyses.</p><p dir="ltr">This research focuses on two major nanoplasmonic technologies—Grating-coupled Surface Plasmon Resonance (GC-SPR) and Nanohole Arrays (NHA)—analysing fabrication methods, optical interrogation techniques, and integration strategies to propose ways to improve their scalability and deployment in LoC systems.</p><p dir="ltr">Chapter 1 motivates this research, presenting current biosensor technologies and discussing their benefits, challenges and emerging research areas.</p><p dir="ltr">Chapter 2 introduces the two nanoplasmonic platforms central to this thesis and discusses their suitability for integration into LoC systems.</p><p dir="ltr">Chapter 3 details the design and implementation of two sensing platforms—one using NHA and the other GC-SPR—enabling a comparative analysis. This comprehensive process includes designing, fabricating, and characterising the structures, developing optical interrogation systems, and assessing their performance as refractometric sensors. The chapter also examines current limitations and suggests improvements for their integration into LoC platforms.</p><p dir="ltr">Chapter 4 demonstrates how micro-transfer printing (μTP) can be used for the rapid and accurate assembly of nanoplasmonic structures, transferring them from native substrates to microfluidic settings. A proof-of-concept using NHA demonstrates successful sensor integration, with smooth, homogeneous NHA coupons showing a high sensitivity of 613 nm/RIU, comparable to previous studies.</p><p dir="ltr">In Chapter 5, Fourier optics is used for the angular interrogation of GC-SPR, avoiding the need for complex calibration of moving parts typically required during signal acquisition. A Fourier-transformed beam is generated using a lens, enabling precise angular shifts without adjusting the orientation of the sensor or photodetector, which improves compatibility with LoC platforms and reduces post-adjustment calibration efforts. Experimental validation achieved high sensitivity of 149 deg/RIU, ranking among the top compared to traditional methods.</p><p dir="ltr">Chapter 6 summarises the biosensor setups and integration advancements covered in the thesis. Although both proof-of-concepts were presented independently, the natural progression is to combine these technologies into an optofluidic biosensor, particularly for live-cell or live tissue studies, where smaller sensor areas could enable complementary analyses such as imaging of fluorescence. Another potential direction is enhancing interrogation techniques with adaptive systems that provide programmable light control, simplifying real-time analyte detection and addressing potential sensor imperfections or misalignments in the LoC platform.</p>