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This paper reports the fabrication, testing and obtained performance of a plasmonic sensor employing a gold (Au) nanohole array chip coated with tungsten disulphide (WS2), which is then functionalized for the detection of protein-protein interactions. A key novelty is that the WS2 was deposited as a monoatomic layer using a wafer-scale synthesis method that successfully provided a film of both high quality and uniform thickness. The deposited WS2 film was transferred onto a Au nanohole array chip using a novel method and was subsequently functionalized with biotin. The final sensor was tested and it demonstrated efficient real-time and label-free plasmonic detection of biotin-streptavidin coupling. Specifically, compared to a standard (i.e. uncoated) Au nanohole-based sensor, our WS2-coated Au nanohole array boosted the spectral shift of the resonance wavelength by ∼190%, resulting in a 7.64-fold improvement of the limit of detection (LOD). National Research Foundation (NRF) Submitted/Accepted version This work was supported by the Singapore National Research Foundation (NRF) and French National Research Agency (ANR), grant number (NRF2017–ANR002 2DPS).

Immunomagnetic-based separation has become a viable technique for the separation of cells and biomolecules. Here we report on the design and analysis of a simple and efficient microfluidic device for high throughput and high efficiency capture of cells tagged with magnetic particles. This is made possible by using a microfluidic chip integrated with customized arrays of permanent magnets capable of creating large magnetic field gradients, which determine the effective capturing of the tagged cells. This method is based on manipulating the cells which are under the influence of a combination of magnetic and fluid dynamic forces in a fluid under laminar flow through a microfluidic chip. A finite element analysis (FEA) model is developed to analyze the cell separation process and predict its behavior, which is validated subsequently by the experimental results. The magnetic field gradients created by various arrangements of magnetic arrays have been simulated using FEA and the influence of these field gradients on cell separation has been studied with the design of our microfluidic chip. The proof-of-concept for the proposed technique is demonstrated by capturing white blood cells (WBCs) from whole human blood. CD45-conjugated magnetic particles were added into whole blood samples to label WBCs and the mixture was flown through our microfluidic device to separate the labeled cells. After the separation process, the remaining WBCs in the elute were counted to determine the capture efficiency, and it was found that more than 99.9% WBCs have been successfully separated from whole blood. The proposed design can be used for positive selection as well as for negative enrichment of rare cells.

Low resistance is an important requirement for microcoils which act as a signal receiver to ensure low thermal noise during signal detection. High-aspect ratio (HAR) planar microcoils entrenched in blind silicon trenches have features that make them more attractive than their traditional counterparts employing electroplating through a patterned thick polymer or achieved through silicon vias. However, challenges met in fabrication of such coils have not been discussed in detail until now. This paper reports the realization of such HAR microcoils embedded in Si blind trenches, fabricated with a single lithography step by first etching blind trenches in the silicon substrate with an aspect ratio of almost 3∶1 and then filling them up using copper electroplating. The electroplating was followed by chemical wet etching as a faster way of removing excess copper than traditional chemical mechanical polishing. Electrical resistance was further reduced by annealing the microcoils. The process steps and challenges faced in the realization of such structures are reported here followed by their electrical characterization. The obtained electrical resistances are then compared with those of other similar microcoils embedded in blind vias. MOE (Min. of Education, S’pore) Published version

Our current understanding of clinical significance or the lack thereof of circulating tumor cells (CTCs) is biased by the technology used to isolate these rare cells. Despite the presence of a vast number of academic and commercial technologies, the lack of a standardized and optimized platform has been widely noted. We present a negative enrichment approach, integrating WBC depletion and chemical-free RBC depletion in the same setup without the need for centrifugation, washing or multiple sample handling steps. This approach achieves an average of >90 % recovery of spiked tumor cells and >99 % total WBC depletion in whole blood across multiple cell lines, in a simple and easy-to-use assay. The results presented herein and ongoing improvements aim to fulfill the need for a highly reliable, unbiased, standardized, and optimized CTC isolation platform, using component technologies that are validated for cell isolation. ASTAR (Agency for Sci., Tech. and Research, S’pore) Accepted Version

Size based filtration is one of the common methods employed to isolate circulating tumor cells (CTCs) from whole blood. It is well known that this method suffers from isolation efficiency to purity tradeoff. However, this tradeoff is poorly understood. In this paper, we present the design and manufacturing of a special rectangular slit filter. The filter was designed to retain maximal amounts of nucleated cells, while minimizing the pressure on cells, thereby preserving their morphology. The key parameter, namely, input pressure, was optimized to retain the maximal number of tumor cells, whilst maximizing the depletion of normal blood cells (red and white blood cells and platelets). Our results indicate that for a slit geometry of 5 × 40 μm on a 13 mm circular membrane with a fill factor of 21%, a pressure of 6.9 mBar yields the optimum for maximizing isolation of MCF-7 and depletion of normal blood cells., {"references":["Siyang Zheng, Henry K. Lin, Bo Lu, Anthony Williams, Ram Datar,\nRichard J. Cote and Yu-Chong Tai, \"3D microfilter device for viable\ncirculating tumor cell (CTC) enrichment from blood\", Biomedical\nMicrodevices, vol. 13, no. 1, 2011, pp. 203-213.","Rolle, \" Increase in number of circulating disseminated epithelial cells\nafter surgery for non-small cell lung cancer monitored by\nMAINTRAC(R) is a predictor for relaps: A preliminary report\", World\nJournal of Surgical Oncology, pp. 3-18, 2005.","Zieglschmid, V, Hollmann, C. & Bocher, \"Detection of disseminated\ntumor cells in peripheral blood\", Critical Reviews in Clinical\nLaboratory Sciences, vol. 2, no. 2, 2005, pp. 155-196.","Kahn, H. J, \"Enumeration of circulating tumor cells in the blood of\nbreast cancer patients after filtration enrichment: correlation with disease\nstage\", Breast cancer research and treatment, vol. 86, no. 3, 2004, pp.\n237-247.","Racila, E, \"Detection and characterization of carcinoma cells in the\nblood\", Proceedings of the National Academy of Sciences of the United\nStates of America, vol. 95, no. 8, Apr 1998, pp. 4589-4594.","S. Zheng, H. Lin, J. Q. Liu, M. Balic, R. Datar, R. J. Cote and Y. -C. Tai,\n\"Membrane microfilter device for selective capture, electrolysis and\ngenomic analysis of human circulating tumor cells\", Journal of\nChromatography, vol. 1162, pp. 154-161, Aug 2007.","Siyang Zheng, Henry K Lin, Bo Lu, Anthony Williams, Ram Datar,\nRichard J Cote, Yu-Chong Tai, \"3D microfilter device for viable\ncirculating tumor cell (CTC) enrichment from blood\", Biomedical\nMicrodevices, vol. 13, 2010, pp. 203-213.","B. Lu, S. Zheng, S. Xie and Y. -C. Tai, \"Live capture of circulating\ntumor cells from human blood by a splittable 3D parylene membrane\nfiltration device\", Proc. of ╬╝TAS 2009, 2009, pp. 588-590.","S. J. Tan, L. Yobas, G. Y. H. Lee, C. N. Ong and C. T. Lim,\n\"Microdevice for the isolation and enumeration of cancer cells from\nblood\", Biomedical Microdevices, vol. 11, no.4, pp. 883-892, 2009.\n[10] P. Paterlini-Brechot and N. L. Benali, \"Circulating tumor cells (CTC)\ndetection: Clinical impact and future directions\", Cancer Letters, vol.\n253, pp. 180-204, 2007.\n[11] Bo Lu, Tong Xu, Siyang Zheng, Amir Goldkorn, and Yu-Chong Tai,\n\"Parylene membrane slot filter for the capture analysis and culture of\nviable circulating tumor cells\", Micro Electro Mechanical Systems\n(MEMS), pp. 935-938, Jan 2010\n[12] Tong Xu, Bo Lu, Yu-Chong Tai, and Amir Goldkorn,\"A Cancer\nDetection Platform Which Measures Telomerase Activity from Live\nCirculating Tumor Cells Captured on a Microfilter\", Cancer research,\nAug 2010.\n[13] Zhian Liu, Alberto Fusi1, Eva Klopocki, Alexander Schmittel, Ingeborg\nTinhofer, Anika Nonnenmacher and Ulrich Keilholz, \"Negative\nenrichment by immunomagnetic nanobeads for unbiased characterization\nof circulating tumor cells from peripheral blood of cancer patients\",\nJournal of Translational Medicine, vol. 9, 2011.\n[14] Hong Miao Ji, Victor Samper, Yu Chen, Chew Kiat Heng, Tit Meng Lim\nand Levent Yobas, \"Silicon based microfilters for whole blood cell\nseparation\", Biomed Microdevices, vol. 10, no. 2, 2008, pp. 251-257.\n[15] Liang Zhu, Xue Li Peh, Hong Miao Ji, Cheng Yong Teo, Han Hua\nFeng, Wen-Tso Liu, \"Cell loss in integrated microfluidic device\",\nBiomed Microdevices, vol. 9, no. 5, 2007, pp. 745-750."]}

This chapter intends to provide an introduction to and a very brief summary of the principal categories of color sensors and of their applications, both relatively little known to the general public. First, an introduction describes the background of the topic(s) and the overall context. The main differences between two major but complementary techniques, colorimetry and spectrometry, will be presented here, as well as a quick summary of the scientific, technical, and industrial applications of color sensing. The second section will summarize the basic operational principles and architectures of color sensors realized in silicon. Although stand-alone detectors will also be described and discussed, the main focus will be on solid-state microsensors which can ideally be monolithically integrated together with signal processing circuits onto the same chip as “smart sensors” or intelligent microsystems. First, sensors realized only in monocrystalline silicon are summarized, followed then by those fabricated in other materials, with amorphous silicon and its alloys as the key players in this latter category. Finally, the chapter ends with the sections devoted to Conclusions and References. This chapter presents only a few of the most relevant aspects related to color sensors and examples of their practical applications. It is, in fact, an extensively abbreviated version of a much more detailed and exhaustive review dedicated to both color sensing and microspectrometry, and which is presently in preparation for future submission to Springer Verlag.

Color sensor can be used to verify position of objects, recognize color sequence. Conventional color sensors employ three identical photodiodes with red, green, and blue optical filters deposited on their surface. This approach leads to an increased occupied silicon area. The color sensor with vertically stacked triple-junction structure (investigated in this thesis) can overcome these restrictions. The operation of the color sensor relies on the wavelength dependence of light absorption in silicon. The thorough design of the color sensor included more successive steps. Initially, theoretical calculations were performed to find the depth and depletion region width of each junction required to optimize their spectral responsivity. Once these main features were established, the doping concentrations for each junction were determined and the complete fabrication process was designed. Then TSUPREM-IV was used to simulate the whole process of the device; MEDICI was used to simulate the device optical and electrical characteristics. Afterwards, the mask layout, process run sheets based on two basic models: abrupt junction model and linearly graded junction model, were designed and confirmed. The practical fabrication of the color sensors has been carried out in MFL, using the modified 2?m CMOS process. Finally, the fabricated sensors have been characterized. DOCTOR OF PHILOSOPHY (EEE)

A scheme for magnetic based biomolecular separation, transportation and detection has been proposed, designed, fabricated and successfully demonstrated through a novel micro-fabricated magnetic system. Magnetic separation becomes a popular technique to purify or isolate cells, intracellular and biological active compounds from heterogeneous mixtures. This thesis introduces and demonstrates a fully micro-magnetic system as a magnetic potential concentrator for manipulating micro/nano magnetic particles in bio- molecular separation systems. The functional components of the device are an electrically phased planar electromagnet array and magnetic pillars positioned at specific locations above the surface of the planar electromagnets. The components are located in a microfluidic chamber with a capacity of 5 l. This system presents a new tool of magnetic control for manipulating and sampling biochemical compounds. DOCTOR OF PHILOSOPHY (EEE)

The miniaturization of probes for Magnetic Resonance (MR) analytical methods-Nuclear Magnetic Resonance (NMR), Magnetic Resonance Imaging (MRI), or relaxometry- has been the latest trend which allows portability and analysis of the chemical composition of minute (in the range of nL to L) volumes of sample. MR analyses typically require that such a probe is used in an external setup with a very strong constant magnetic field with no temporal variation and external detector circuits. A critical aspect of the success of such an experiment is to ensure a high signal-to-noise ratio (SNR). However, the resulting value of the SNR delivered by a miniature probe has a complicated dependence on both the external measurement setup, the chemical composition of the sample and the probe design. For probe designers, there are no clear guidelines to suggest how a given the probe will behave under any external measurement setup or chemical composition of the sample under test, or how to approach a probe design so as to optimize design parameters for a good performance in terms of SNR in an MR analysis, e.g. an NMR experiment. Doctor of Philosophy

Much research has been done on biosensors employing microelectrode arrays for biomedical applications. An important application is the detection of circulating tumour cells for cancer diagnostics and treatment. This and many other applications require dealing with a large number of cells, leading to a need for large microelectrode arrays. Fast measurement approaches are required to process these large arrays in the available timeframe. One suitable approach is electrochemical impedance spectroscopy (EIS) if compelling results can be obtained from high frequencies. However, basic design approaches do not scale well with the growing number of electrodes. The increasing need for circuits providing addressing and signal processing leads to mounting parasitic couplings and intensifies the problem of matching between the individual electrodes. While the electrode/electrolyte system is well modelled in the literature, the overall system requires more detailed understanding to improve measurement quality. Moreover, methods need to be developed to improve the specificity of measurement results. Two previously developed active CMOS biosensor chips were studied for this Thesis. The first of these designs was a basic architecture integrating an array of 96x96 microelectrodes and a tree structure for selecting individual electrodes. The second design featured an array of 104x104 microelectrodes, and improved selection scheme and amplifiers close to the electrodes to improve signal integrity. For comparison, passive biosensor chips made from gold electrodes on a glass substrate were studied. Analytical models were developed to improve understanding of the results, and simulations were done to support the findings. Surface treatments with aptamers were explored to improve the selectivity of the biosensor. A new CMOS biosensor incorporating lessons from the previous designs was developed. In this Thesis, the design and manufacturing of the used biosensor chips is described with emphasis on design principles and post-processing. Measurement results are presented and compared. Expanded models are derived to give an improved explanation of the observed results. Simulations results are presented that support the new models and indicate possible improvements of the electrode structure. Improved cell capture utilizing aptamers is described, as well as the effects of the aptamer layer on EIS results. Finally, the new biosensor design featuring source measurement units (SMU) for EIS is presented. Master of Engineering

According World Health Organization (WHO) cancers number among the leading causes of illness and mortality worldwide. The significance of Circulating Tumor Cells (CTCs) for clinical cancer management has been widely recognized. Despite the presence of a vast number of academic and commercial technologies, the lack of a standardized and optimized platform to isolate these rare cells has been widely noted. In this thesis, a thorough study to address the limitations of current CTC isolation platforms is presented. A negative selection approach, which avoids labeling the cells or defining their size, has been recommended as an optimal approach to enrich rare CTCs from whole blood for in vitro diagnostics. Based on this, three different versions of CTC enrichment platforms are successfully developed using techniques such as microfabrication and microfluidics. The proposed CTC isolation platforms have wide contribution in advancing cancer biology research and clinical cancer management. Doctor of Philosophy (EEE)

89 p. Optical detection is one of the most often employed detection mechanisms in medicine and biology. However, the optical methods which have been used so far in DNA detection relied on bulk optical elements and are difficult to miniaturize. Most of the biological research is based on labeling methods that use fluorescence and radioactivity as they allow high throughput evaluation of molecular interaction and the approaches are well established. However, the disadvantages of this very popular method include lack of sensitivity, interference and cross reactivity. Master of Science (Photonics)

In this thesis, PDMS-based AWG microspectrometer for LOC application was demonstrated by foremost developing planar waveguide in PDMS material. The development of planar waveguide focused primarily in design and fabrication of novel PDMS waveguide with single-mode propagation as the basic building block for complex devices. By selecting the appropriate geometrical parameters, single-mode propagation can be generated even in a large cross section PDMS rib waveguide (> 5 μm). The fabrication of PDMS single-mode waveguide involved precise controlled of the slab and rib height to the accuracy of ±0.1 μm as well as the modification of the refractive index from 1.408 to 1.429. The characterization ATTENTION: The Singapore Copyright Act applies to the use of this document. Nanyang Technological University Library VIII of the PDMS waveguide corroborated single-mode propagation at the wavelength of 635 nm with the propagation loss measured to be 0.48 dB/cm for low refractive index contrast waveguides (Δ=0.07%) and 0.2 dB/cm for high refractive index contrast waveguides (Δ=1.18%). DOCTOR OF PHILOSOPHY (EEE)

Optical colour monitoring is essential in many medicine and biology-related applications where absorption/transmission in the visible range is studied. It is thus important to realize and employ good colour detectors which can correctly quantify in measurable units the optical and chromatic changes that appear in the transmission/absorption of the analyzed sample. Other important applications include food or textile dye characterization, high-density information storage and electro-photographic copying of documents. DOCTOR OF PHILOSOPHY (EEE)

126 p. Thin film technology is the current choice of technology in fabrication smart devices and optical systems. As a result of the progress made in the last decades, microelectronic fabrication technology is now being applied in the development of new generations of smart devices such as MEMS, Optical MEMS and BioMEMS. Optics is in fact one of the earliest and most active areas in which MEMS technology has been applied, e.g Lenses, prims, WDM, DWDM, optical filters, tunable optical devices, fiber optics, VCSEL lasers, and currently photonics crystals. Master of Science (Photonics)

Thin film technology is the current technology of choice for the fabrication of most of the optical filters, because of its clear technical advantages, its passive nature that offers simple system integration, and its flexibility and modularity. It has been widely applied to many optical devices and has been field-proven to be reliable. Master of Science (Microelectronics)

The project involved three major areas: emphasizes on the design of the color sensor parameters, translate the designed parameter into an actual structure by performing virtual processing of the device on process simulator: TSUPREM4, extract the characteristic of the virtually fabricated color sensor using a device simulator: MEDICI. Master of Science (Microelectronics)