Investigations into optical biosensors in visible-NIR wavelength band for disease detection applications

• Main Author: Pae, Jian Yi
• Other Authors: Murukeshan Vadakke Matham
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2021
• Subjects: Engineering::Nanotechnology; Science::Physics::Optics and light
• Online Access: https://hdl.handle.net/10356/147664
• Institution: Nanyang Technological University

In the latest published results from Global Burden of Disease (GBD) in 2017, the top two contributors to the disease burden which requires the most urgent attention are Alzheimer’s Disease (AD) and female breast cancer. As AD is a neurological disorder with unknown causes, it is almost impossible to adopt any preventive measures. Additionally, current medical tools are unable to reverse the effects of AD. Hence, the best approach is to detect the early onset of AD so that measures can be implemented early to halt or slow down its progress. However, existing techniques for the early detection of AD primarily focus on using neuroimaging which may be too expensive to conduct regularly. Therefore, there is an urgent need for a low-cost method for the early detection of AD. In the case of female breast cancer, despite being the most diagnosed form of cancer, the data also have shown that it has very promising survival rates when the cancer is detected and treated in the early stages. However, the effectiveness of existing breast cancer detection techniques is hugely limited by the low uptake of the screening program. This could be due to the lack of awareness or misconception regarding breast cancer and due to the perceived hassle of having to go for regular screening at periodic intervals. Hence, there is a need to explore alternative breast cancer screening methods that are more hassle-free. A biosensor is a promising candidate in this context, which could provide a low-cost and hassle-free approach for the screening of diseases such as AD and female breast cancer. Electrochemical biosensors are well-established and have already been commercialised such as blood glucose monitors. However, such biosensors typically have low sensitivity which could not be used to accurately diagnose diseases. With the recent improvement in the optics field, optical biosensors are also gaining popularity as they have high sensitivity and a low detection limit. Novel optical biosensors based on the surface plasmon resonance (SPR) effect are even able to achieve label-free sensing by using specially bioengineering bioreceptors with high specificity towards the targeted analytes. One critical limitation is that current fabrication methods are unable to mass produce the nanoscale features which are necessary for the development of compact optical biosensors. Therefore, part of the objectives of this thesis would be the investigations into potential fabrication techniques for the low-cost fabrication of the nanoscale features necessary for forming the optical biosensors. Another research objective is to improve the sensitivity of these optical biosensors so that they will be comparable to conventional laboratory-based detection techniques for high accuracy. Lastly, this thesis would also be investigating the potential of using graphene, which is a 2D material, to develop a novel optical biosensor that can be interrogated electrically and optically. Based on the extensive literature review, interference lithography (IL) was selected as a cost-effective method for producing the nanoscale grating features necessary to form the grating coupled SPR biosensor. IL also has the flexibility of producing different periodic features to suit different biosensor designs. The interference of light waves was first validated using theoretical formulation and further confirmed using theoretical simulations based on the finite-difference time-domain method. Next, two different IL configurations were experimentally validated; the first one was based on a specially fabricated phase grating and the other one was based on a custom fabricated single-input multiple-output (SIMO) optical fibre splitter. The major advantage of optical fibre interference lithography (OFIL) is that there is no need to realign the beams when the angle of incidence was varied. This was successfully demonstrated as nanoscale grating with a range of periodicity from 514 nm to 1,646 nm was easily fabricated by simply adjusting the angle of incidence. The nanoscale grating features were then further developed into a grating coupled SPR biosensor for the sensing of glucose concentration in a sample fluid. The operating range of the biosensor is in the spectral range from around 600 nm to approximately 800 nm which is in the visible – near-infrared (NIR) range. The benefit of this is that the optical sensors in the wavelength are more economical and easier to integrate with conventional optical components. Additionally, nanoparticles were demonstrated as a potential approach to amplify the signal of SPR biosensors. Theoretical simulations showed that the amplification or field enhancement factors of spiky shaped nano-urchins are several orders of magnitude better than in conventional nano-spheres shaped nanoparticles. This was experimentally validated in a gold (Au) nano-urchins based localised surface plasmon resonance (LSPR) biosensors for the sensing of beta-amyloid fibrillation which is an essential biomarker for the early detection of AD. The Au nano-urchins were then added to the surface of a prism coupled SPR biosensor for the sensing of estrogen receptor alpha (ERα) which is a useful biomarker for ERα-positive breast cancer. Lastly, different methods were also investigated for the synthesis of high-quality monolayer graphene. Raman spectroscopy was used to characterise the synthesised graphene which confirms the quality of the synthesised graphene. The transfer of graphene from the growth substrate to the desired substrates was also successfully demonstrated. This allows the development of a graphene-layered heterostructure which was further developed into an electrically controlled SPR biosensor. It is envisioned that the output of this research can contribute to the efforts to improve the current process for disease diagnostics, especially for AD and female breast cancer. The primary advantage is that this method can allow patients to conduct the test at their convenience. This may greatly increase the uptake and screening frequency to ensure the diseases are detected early which would greatly reduce their risks. Additionally, the low-cost fabrication methods for producing the biosensors could also alleviate some of the financial burdens of existing disease screening techniques and improve their effectiveness for the detection of diseases. Lastly, additive manufacturing (AM) methods could also be integrated with the IL system to develop a hybrid manufacturing method where the benefits of both techniques can be exploited. This will form part of the future research work to extend this thesis.