3D printing, also known as ”additive manufacturing”, indicates a set of fabrication techniques that build objects by adding material, typically layer by layer. The main advantages of 3D printing are unlimited shapes and geometry, fast prototyping, and cost-effective small scale production. Two-photon lithography (TPL) is a laserbased 3D printing technique with submicron resolution, that can be used to create miniaturized structures. One of the most compelling applications of TPL is the 3D printing of miniaturized optical elements with unprecedented complexity, small-scale and precision. This could be potentially beneficial in biophotonics, a multidisciplinary research field in which light-based techniques are used to study biological processes. My research has been aimed at demonstrating novel applications of 3D printing based on TPL to different biophotonic applications. In particular, here we show 3D printed micro-optical structures that enhance and/or enable novel functions in advanced biophotonics methods as two-photon microendoscopy, optical trapping and Stimulated Raman Scattering microscopy. Remarkably, the micro-optical structures presented in this thesis enable the implementation of advanced techniques in existing or simpler microscopy setups with little to no modification to the original setup. This possibility is essentially allowed by the unique miniaturization and in-situ 3D printing capabilities offered by TPL.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第21106号 / 工博第4470号 / 新制||工||1695(附属図書館) / 京都大学大学院工学研究科材料工学専攻 / (主査)教授 杉村 博之, 教授 邑瀬 邦明, 教授 山田 啓文 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

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Using silicon based microfabrication and materials, a photonic platform, capable of single bioparticle analysis, has been developed. This platform combines liquid and hollow core waveguides on the micron-scale (5 µm x 12 µm) to isolate femtoliter sized sample volumes. Fluorescence excitation and signals in the visible range are directed into and out of the sample volume at an orthogonal angle to maximize signal-to-noise. In order to guide light in a low-index material antiresonant reflecting optical waveguides (ARROWs) were incorporated into the platform. This thesis reveals the development path of these structures over several device generations including innovations in material, geometries, and fabrication techniques to increase detection sensitivity. As a result of these developments, this photonic platform has shown to successfully detect virus samples and other particles. This thesis also presents a new idea for increasing the signal to noise ratio (SNR) by incorporating Y-splitter devices into the design. Specifically, the 1 x 2 and 1 x 4 splitter structures can be used as orthogonal excitation points to the liquid core waveguide. When fluorescently tagged particles are introduced into the hollow core, these points create an optical signal that is correlated in time and space. The data collected by a photodetector can then be processed by an algorithm to increase SNR. Such advancements have shown to increase the SNR by 175 times.

Electrostatically actuated silicon membranes were designed, modeled, fabricated, and characterized. The intended application was for use in a microspeaker. Fabrication issues necessitated the use of thick diaphragms with a large gap between the electrodes. The devices did not function as speakers but did show actuation with a high DC voltage. Device dimensions were chosen by examining membrane mechanics, testing the processing steps required for device fabrication, and modeling with COMSOL. Several adhesives were researched to fabricate the device sidewalls, including BCB, PMMA, and TRA-Bond F112. A method for patterning PMMA through photolithography was found using a scanning electron microscope. Masks were designed in AutoCAD to create the electrostatically actuated devices and a microfabrication process was developed to produce diaphragms that could be characterized. Twenty micron thick diaphragms were fabricated by etching an SOI wafer in 25% TMAH and the etch depth was measured with a profilometer. Glass slides were coated with gold and patterned with positive photoresist to create counter-electrodes. The diaphragms were bonded to the glass slides using a forty micron thick layer of patterned SU-8 as sidewalls. Bonding was successful in the initial fabrication testing but not successful for the final devices. The final fabrication run resulted in eight devices that were partially bonded. Three devices were chosen to test the membrane actuation and the data analyzed for statistical significance. A DC voltage was applied to the electrodes with a MEMS driver and the change in force measured with a micro-force displacement system. Data analysis showed device actuation at high voltages (300V) for the medium and large devices.

Preterm infants are at risk for respiratory distress syndrome (RDS) due to immature lungs, leading to notable neonatal mortality. About 10% of US births are premature. While mechanical ventilation is a common RDS treatment, it can cause complications. If it fails, extracorporeal membrane oxygenation (ECMO) is employed, but standard ECMO devices are not suited for preterm babies. The limitations of hollow fiber membrane oxygenators used in ECMO have spurred interest in an artificial placenta that connects to the umbilical cord and supports lung growth. Microfluidic blood oxygenators, with their biomimetic designs, have being explored for this purpose. This thesis advances microfabrication techniques for Lung Assist Devices (LADs), focusing on two main objectives: I. Improving Throughput for Elevated Blood Flow Rates: This section delves into refining Microfluidic Blood Oxygenators (MBOs) to accommodate greater blood flow rates. By combining parallel units, we increased throughput and optimized LAD designs. Newly designed MBOs, with an expanded gas exchange surface area, can manage blood flow rates up to 60 mL/min. Using these enhanced MBOs, we constructed a novel LAD achieving superior oxygenation compared to predecessors. Our in vitro tests confirmed that this LAD can sustain blood flow rates of up to 150 ml/min, elevating oxygen saturation by approximately 20%—equivalent to an oxygen transfer of 7.48 mL/min, a leading figure for AP-type devices. II. Hierarchically Designed Microchannels: The second objective revolves around developing microchannels with a hierarchical layout to mitigate stagnation and high shear stress regions. Traditional photolithography poses challenges at channel intersections, inducing clotting risks. We pioneered alternative microfabrication methods, yielding diverse microchannels and intricate hierarchical designs that emulate natural vascular networks devoid of dead zones. These advancements have propelled the microfabrication domain for artificial placenta-like LADs. Utilizing our method, we produced channels varying from hundreds to a few microns in height with a single exposure and an opal diffuser. Thin membranes (~60 µm top and ~45 µm bottom) were amalgamated, culminating in a total depth of about 200 µm. Such oxygenators excel in oxygenating blood even at intense flow rates of up to 15 mL/min per unit. Leveraging these hierarchically designed MBOs, we crafted a LAD supporting a flow rate of 100 mL/min, offering an oxygen transfer of 5.21 mL/min. Both LADs developed in this research proficiently support premature neonates weighing up to 2 kg. Notably, the priming volume of the LAD using the enhanced MBOs has been substantially minimized, underscoring its advancements over earlier models. Realizing these objectives can transform neonatal care, addressing respiratory challenges in premature neonates and bolstering their chances for a healthier life. / Thesis / Master of Science (MSc)

Silicon Nanowire-based biosensors owe their sensitivity to the large surface area to volume ratio of the nanowires. However, presently they have only been shown to detect specific bio-markers in low-salt buffer environments. The first part of this thesis presents a pertinent next step in the evolution of these sensors by presenting the specific detection of a target analyte (NT-ProBNP) in a physiologically relevant solution such as serum. By fabrication of the nanowires down to widths of 60 nm, choosing appropriate design parameters, optimization of the silicon surface functionalization recipe and using a reduced gate oxide thickness of 5 nm; these sensors are shown to detect the NT-ProBNP bio-marker down to 2ng/ml in serum. The observed high background noise in the measured response of the sensor is discussed and removed experimentally by the addition of an extra microfabrication step to employ a differential measurement scheme. It is also shown how the modulation of the local charge density via external static electric fields (applied by on-chip patterned electrodes) pushes the sensitivity threshold by more than an order of magnitude. These demonstrations bring the silicon nanowire-based biosensor platform one step closer to being realized for point-of-care (POC) applications. In the second half of the thesis, it is demonstrated how silicon micromechanical piezoelectric resonators could be tasked to provide wireless power to such POC bio-systems. At present most sensing and actuation platforms, especially in the implantable format, are powered either via onboard battery packs which are large and need periodic replacement or are powered wirelessly through magnetic induction, which requires a proximately located external charging coil. Using energy harnessed from electric fields at distances over a meter; comprehensive distance, orientation, and power dependence for these first-generation devices is presented. The distance response is non-monotonic and anomalous due to multi-path interferences, reflections and low directivity of the power receiver. This issue is studied and evaluated using COMSOL Multiphysics simulations. It is shown that the efficiency of these devices initially evaluated at 3% may be enhanced up to 15% by accessing higher frequency modes.

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