The presence and concentration of oxygen in biological systems has a large impact on the behavior and viability of many types of cells, including the differentiation of stem cells or the growth of tumor cells. As a result, the integration of oxygen sensors within cell culture environments presents a powerful tool for quantifying the effects of oxygen concentrations on cell behavior, cell viability, and drug effectiveness. Because microfluidic cell culture environments are a promising alternative to traditional cell culture platforms, there is recent interest in integrating oxygen-sensing mechanisms with microfluidics for cell culture applications. Optical, luminescence-based oxygen sensors, in particular, show great promise in their ability to be integrated with microfluidics and cell culture systems. These sensors can be highly sensitive and do not consume oxygen or generate toxic byproducts in their sensing process. This paper presents a review of previously proposed optical oxygen sensor types, materials and formats most applicable to microfluidic cell culture, and analyzes their suitability for this and other in vitro applications.

We demonstrate the design, fabrication and measurement of integrated Bragg gratings in a compact single-mode silicon-on-insulator ridge waveguide. The gratings are realized by corrugating the sidewalls of the waveguide, either on the ridge or on the slab. The coupling coefficient is varied by changing the corrugation width which allows precise control of the bandwidth and has a high fabrication tolerance. The grating devices are fabricated using a CMOS-compatible process with 193 nm deep ultraviolet lithography. Spectral measurements show bandwidths as narrow as 0.4 nm, which are promising for on-chip applications that require narrow bandwidths such as WDM channel filters. We also present the die-to-die nonuniformity for the grating devices on the wafer, and our analysis shows that the Bragg wavelength deviation is mainly caused by the wafer thickness variation.

Standard silicon photonic strip waveguides offer a high intrinsic refractive index contrast; this permits strong light confinement, leading to compact bends, which in turn facilitates the fabrication of devices with small footprints. Sub-wavelength grating (SWG) based waveguides can allow the fabrication of low loss devices with specific, engineered optical properties. The combination of SWG waveguides with optical micro-resonators can offer the possibility of achieving resonators with properties different from the traditional SOI rings. One important property that SWG rings can offer is decreased light confinement in the waveguide core; this improves the resonator's sensitivity to changes in the cladding refractive index, making the rings ideal for refractive index sensing applications. In this paper, we present the design and experimental characterization of SWG based rings realized on SOI chips without upper cladding (permitting their use as sensors). The fabricated rings offer quality factors in the range of ~1k-6k, depending on SWG parameters. Based on the comparison of experimental and simulated data we expect sensitivities exceeding 383 nm/RIU in water and 270 nm/RIU in air, showing excellent potential for use in sensing applications.

Silicon photonic biosensors are highly attractive for multiplexed Lab-on-Chip systems. Here, we characterize the sensing performance of 3 µm TE-mode and 10 µm dual TE/TM-mode silicon photonic micro-disk resonators and demonstrate their ability to detect the specific capture of biomolecules. Our experimental results show sensitivities of 26 nm/RIU and 142 nm/RIU, and quality factors of 3.3x10(4) and 1.6x10(4) for the TE and TM modes, respectively. Additionally, we show that the large disks contain both TE and TM modes with differing sensing characteristics. Finally, by serializing multiple disks on a single waveguide bus in a CMOS compatible process, we demonstrate a biosensor capable of multiplexed interrogation of biological samples.

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We demonstrate the application of a microfluidic platform combining spatiotemporal oxygen control and long-term microscopy monitoring to observe tumour spheroid response to hypoxia. The platform is capable of recreating physiologically-relevant low and cycling oxygen levels not attainable in traditional cell culture environments, while image-based monitoring visualizes cell response to these physiologically-relevant conditions. Monitoring spheroid cultures during hypoxic exposure allows us to observe, for the first time, that spheroids swell and shrink in response to time-varying oxygen profiles switching between 0% and 10% O2; this swelling-shrinkage behaviour appears to be driven by swelling of individual cells within the spheroids. We also apply the system to monitoring tumour models during anticancer treatment under varying oxygen conditions. We observe higher uptake of the anticancer agent doxorubicin under a cycling hypoxia profile than under either chronic hypoxia or in vitro normoxia, and the two-photon microscopy monitoring facilitated by our system also allows us to observe heterogeneity in doxorubicin uptake within spheroids at the single-cell level. Combining optical sectioning microscopy with precise spatiotemporal oxygen control and 3D culture opens the door for a wide range of future studies on microenvironmental mechanisms driving cancer progression and resistance to anticancer therapy. These types of studies could facilitate future improvements in cancer diagnostics and treatment.

We demonstrate that when using cell-laden core-shell hydrogel beads to support the generation of tumor spheroids, the shell structure reduces the out-of-bead and monolayer cell proliferation that occurs during long-term culture of tumor cells within core-only alginate beads. We fabricate core-shell beads in a two-step process using simple, one-layer microfluidic devices. Tumor cells encapsulated within the bead core will proliferate to form multicellular aggregates which can serve as three-dimensional (3-D) models of tumors in drug screening. Encapsulation in an alginate shell increased the time that cells could be maintained in three-dimensional culture for MCF-7 breast cancer cells prior to out-of-bead proliferation, permitting formation of spheroids over a period of 14 days without the need move the cell-laden beads to clean culture flasks to separate beads from underlying monolayers. Tamoxifen and docetaxel dose response shows decreased toxicity for multicellular aggregates in three-dimensional core-shell bead culture compared to monolayer. Using simple core-only beads gives mixed monolayer and 3-D culture during drug screening, and alters the treatment result compared to the 3-D core-shell or the 2-D monolayer groups, as measured by standard proliferation assay. By preventing the out-of-bead proliferation and subsequent monolayer formation that is observed with core-only beads, the core-shell structure can obviate the requirement to transfer the beads to a new culture flask during drug screening, an important consideration for cell-based drug screening and drugs which have high multicellular resistance index.

Silicon photonic resonators, implemented using silicon-on-insulator substrates, are promising for numerous applications. The most commonly studied resonators are ring/racetrack resonators. We have fabricated these and other resonators including disk resonators, waveguide-grating resonators, ring resonator reflectors, contra-directional grating-coupler ring resonators, and racetrack-based multiplexer/demultiplexers. While numerous resonators have been demonstrated for sensing purposes, it remains unclear as to which structures provide the highest sensitivity and best limit of detection; for example, disc resonators and slot-waveguide-based ring resonators have been conjectured to provide an improved limit of detection. Here, we compare various resonators in terms of sensor metrics for label-free bio-sensing in a micro-fluidic environment. We have integrated resonator arrays with PDMS micro-fluidics for real-time detection of biomolecules in experiments such as antigen-antibody binding reaction experiments using Human Factor IX proteins. Numerous resonators are fabricated on the same wafer and experimentally compared. We identify that, while evanescent-field sensors all operate on the principle that the analyte's refractive index shifts the resonant frequency, there are important differences between implementations that lie in the relationship between the optical field overlap with the analyte and the relative contributions of the various loss mechanisms. The chips were fabricated in the context of the CMC-UBC Silicon Nanophotonics Fabrication course and workshop. This yearlong, design-based, graduate training program is offered to students from across Canada and, over the last four years, has attracted participants from nearly every Canadian university involved in photonics research. The course takes students through a full design cycle of a photonic circuit, including theory, modelling, design, and experimentation.