This PDF file contains the front matter associated with SPIE Proceedings Volume 10510, including the Title Page, Copyright information, Table of Contents, and Conference Committee listing.

We demonstrate enhanced detection sensitivity of a slow light Mach-Zehnder interferometer (MZI) sensor by incorporating multi-hole defects (MHDs). Slow light MZI biosensors with a one-dimensional photonic crystal in one arm have been previously shown to improve the performance of traditional MZI sensors based on the increased lightmatter interaction that takes place in the photonic crystal region of the structure. Introducing MHDs in the photonic crystal region increases the available surface area for molecular attachment and further increases the enhanced lightmatter interaction capability of slow light MZIs. The MHDs allow analyte to interact with a greater fraction of the guided wave in the MZI. For a slow light MHD MZI sensor with a 16 μm long sensing arm, a bulk sensitivity of 151,000 rad/RIU-cm is demonstrated experimentally, which is approximately two-fold higher than our previously reported slow light MZI sensors and thirteen-fold higher than traditional MZI biosensors with millimeter length sensing regions. For the label-free detection of nucleic acids, the slow light MZI with MHDs also exhibits a two-fold sensitivity improvement in experiment compared to the slow light MZI without MHDs. Because the detection sensitivity of slow light MHD MZIs scales with the length of the sensing arm, the tradeoff between detection limit and device size can be appropriately mitigated for different applications. All experimental results presented in this work are in good agreement with finite difference-time domain-calculations. Overall, the slow light MZI biosensors with MHDs are a promising platform for highly sensitive and multiplexed lab-on-chip systems.

Efficient methods for the accurate analysis of drug toxicities are in urgent demand as failures of newly discovered drug candidates due to toxic side effects have resulted in about 30% of clinical attrition. The high failure rate is partly due to current inadequate models to study drug side effects, i.e., common animal models may fail due to its misrepresentation of human physiology. Therefore, much effort has been allocated in the development of organ-on-a-chip models which offer a variety of human organ models mimicking a multitude of human physiological conditions. However, it is extremely challenging to analyze the transient and long-term response of the organ models to drug treatments during drug toxicity tests, as the proteins secreted from the organ-on-a-chip model are minute due to its volumetric size, and current methods for detecting said biomolecules are not suitable for real-time monitoring. As protein biomolecules are being continuously secreted from the human organ model, fluorescence techniques are practically impossible to achieve real-time fluorescence labeling in the dynamically changing environment, thus making a label-free approach highly desirable for the organ-on-achip applications. In this paper, we report the use of a photonic-crystal biosensor integrated with a microfluidic system for sensitive label-free bioassays of secreted protein biomolecules from a heart-on-the-chip model created with cardiomyocytes derived from human induced pluripotent stem cells.

Surface-enhanced Raman scattering (SERS) spectroscopy has attracted considerable attention recently as a powerful detection platform in biosensing because of the wealth of inherent information ascertained about the chemical and molecular composition of a sample. However, real-world samples are often composed of many components, which renders the detection of constitutes of mixed samples very challenging for SERS sensing. Accordingly, separation techniques are needed before SERS measurements. Thin layer chromatography (TLC) is a simple, fast and costeffective technique for analyte separation and can a play pivotal role for on-site sensing. However, combining TLC with SERS is only successful to detect a limited number of analytes that have large Raman scattering cross sections. As a kind of biogenic amine, histamine (2-(4-imidazolyl)-ethylamine) has a relationship with many health problems resulting from seafood consumption occurring worldwide. Diatomaceous earth consists of fossilized remains of diatoms, a type of hard-shelled algae. As a kind of natural photonic biosilica from geological deposits, it has a variety of unique properties including highly porous structure, excellent adsorption capacity, and low cost. In addition, the two dimensional periodic pores on diatomite earth with hierarchical nanoscale photonic crystal features can enhance the localized optical field. Herein, we fabricate TLC plates from diatomite as the stationary phase combining with SERS to separate and detect histamine from seafood samples. We have proved that the diatomite on the TLC plate not only functions as stationary phase, but also provides additional Raman enhancement, in which the detection limit of 2 ppm was achieved for pyrene in mixture.

Silicon photonics is becoming a consolidated technology, mainly in the telecom/datacom sector, but with a great potential in the chemical and biomedical sensor market too, mainly due to its CMOS compatibility, which allows massfabrication of huge numbers of miniaturized devices at a very low cost per chip. Integrated photonic sensors, typically based on resonators, interferometers, or periodic structures, are easy to multiplex as the light is confined in optical waveguides.

In this work, we present a silicon-photonic sensor capable of measuring refractive index and chemical binding of biomolecules on the surface, using a low-cost phase interrogation scheme. The sensor consists of a pair of balanced Mach-Zehnder interferometers with interaction lengths of 2.5 mm and 22 mm, wound to a sensing area of only 500 μm x500 μm. The phase interrogation is performed with a fixed laser and an active phase demodulation approach based on a phase generated carrier (PGC) technique using a phase demodulator integrated within the chip. No laser tuning is required, and the technique can extract the univocal phase value with no sensitivity fading. The detection only requires a photo-receiver per interferometer, analog-to-digital conversion, and simple processing performed in real-time. We present repeatable and linear refractive index measurements, with a detection limit down to 4.7·10^-7 RIU. We also present sensing results on a chemically-functionalized sample, where anti-BSA to BSA (bovine serum albumin) binding curves are clearly visible for concentrations down to 5 ppm. Considering the advantages of silicon photonics, this device has great potential over several applications in the chemical/biochemical sensing industry.

Whispering-gallery-mode optical resonators have shown their potentials for sensing applications in recent years owing to significantly enhanced light-matter interactions in a strongly confined volume. Boosting the sensitivity of the sensor and miniaturing the sensing system are two of the most important directions of whispering-galley-mode sensors. In this talk, I will present our recent work on novel sensing mechanism to enhance the sensitivity of a whispering-gallery-mode sensor, and a portable, wireless sensing system which can be fully controlled by smart devices. By tuning two nanoscale scatterers within the mode volume, a whispering-gallery-mode resonator can be steered to non-Hermitian degeneracies, also known as exceptional points. Due to the complex-square-root topology at the vicinity of exceptional points, the frequency splitting induced by a target object (with sufficiently small perturbation) is proportional to the square-root of its perturbation strength, and is thus larger than the frequency splitting obtained in conventional sensing schemes which is proportional to the perturbation strength of the target object. We also demonstrated that, by integrating a packaged sensor, a microcontroller, a wireless transceiver and power supply, we could build a miniature whispering-gallery-mode sensing system with a wireless interface. A customized iOS app has been developed to monitor and adjust the system parameters, and collect and analyze the sensing signals. This wireless sensing system could be employed to measure temperature distribution in a selected area. Our studies help broaden the applications of the whispering-gallery-mode resonators as an innovative sensor platform.

One of the major goals of medicine is the development of portable diagnostic tools. Recent advances in nano-magnetism, reviewed in this talk, might allow the development of efficient lab-on-a-chip portable devices. - Regarding on-chip manipulation of biological matter, we proposed and used a special type of domain walls in magnetic-nanostructures as moveable “magnetic-nanotweezers” [1, 2]. We have demonstrated precise and robust manipulation of magnetic nanoparticles [3,4] and bio-entities (proteins and cells) [1,5] labeled with magnetic nanoparticles in solution with nm-scale precision by means of an externally applied magnetic field, which allowed for remote on-chip operation. - Regarding biosensing, plasmonic nanostructures are currently attracting great attention due to their intrinsically small size and localized sensing volume/area. Typical plasmonic sensing utilizes the localized surface-plasmon (LSP) resonance shift due to the local refractive index change upon molecular adsorption. We have shown that the use of ferromagnetic nanostructures allows for a phase sensitive detection of LSPs shift, enabled by their magneto-optical activity [6], with vastly improved performances and sensitivity down to the single molecule level [7]. We are developing further this approach and its integration into practically applicable biomedical sensing devices [8]. More specifically, we are exploring the use of specially designed “janus” particles made of 100-nm-diamter silica nanospheres half covered with multilayers of Fe/Au or Co/Au. They display simultaneous and large anisotropic magnetic and plasmonic properties to be conveniently used in our recently proposed opto-magnetic approach [8] that is being already exploited in commercialized portable device (BluSense Diagnostics, http://www.blusense-diagnostics.com/). [1] M. Donolato et al., Adv. Mater. 22, 2706 (2010) [2] M. Donolato et al., Adv. Mater. 25, 623 (2013) [3] Torti et al., Appl. Phys. Lett. 101, 142405 (2013) [4] A. Sarella et al., Adv. Mater. 26, 2384 (2014) [5] M. Donolato et al., Lab Chip 11, 2976 (2011) [6]N. Maccaferri et al., Phys. Rev. Lett. 111, 167401 (2013) [7] N. Maccaferri et al., Nat. Commun. 6, 6150 (2015); R. Verre et al., Nanoscale 8, 10576 (2016) [8] M. Donolato et al., Anal. Chem. 87, 1622 (2015); J. Yang et al., Biosensors and Bioelectronics 75, 396 (2016)

Luminex 200 is a flow cytometer that is widely used to detect very small concentrations of biomarkers. For biomarkers detection, fluorescently labeled probes and magnetic beads are attached to target molecules. After several washing and separation steps to remove unbound fluorescent molecules, single magnetic beads pass one by one through a narrow channel and their fluorescent signal is measured. Previously, we presented a novel magnetic modulation biosensing (MMB) system, which provides very high sensitivity in biomarkers detection. Unlike the particle by particle approach of flow cytometry, the MMB system is based on aggregating the magnetic beads and manipulating them in and out of the excitation laser beam. The modulation separates the signal from the background noise without washing steps. Using the MMB platform, we were able to detect Interleukin-8 with a limit of detection of 0.04 ng/L. Here, we provide a head-to-head comparison of the MMB platform and the Luminex 200 instrument. Comparisons were performed by processing identical bead-based tests in both systems. Using Luminex Triple Dye Beads, we showed that the MMB has at least 2x better sensitivity than the Luminex 200. In addition, we used a cardiac Troponin I assay and showed that the MMB has 10x better sensitivity than the Luminex 200. While the Luminex 200 has multiplexing capabilities, the MMB system provides higher sensitivity and a washless protocol that facilitates the use of the platform in point of care applications.

Zika virus is a flavivirus, which was introduced into Brazil from the Pacific Islands and spread rapidly throughout the Americas. It became the first major infectious disease linked to human birth defects and created a global alarm that the World Health Organization (WHO) declared a Public Health Emergency of International Concern. Due to high cross-reactivity between the different flaviviruses, current commercial serological assays have limited specificity. Recently developed non-structural 1 (NS1) protein-based ELISA assay significantly improved the specificity, but reduced the sensitivity. Here, utilizing our magnetic modulation biosensing (MMB) system, we present a highly sensitive and specific Zika IgM & IgG serological tests. Twenty Zika positive (reverse transcription-PCR) serum specimens from days 2–60 were tested and compared to a prior study done with commercial Euroimmun Anti-ZIKV ELISA IgM and IgG. Dose response of recombinant human IgG and human IgM antibodies showed that the MMB has a limit of detection that is an order of magnitude better than the commercial Euroimmun kit. The MMB sensitivity of the IgM and IgG assays was 100%. In comparison, the sensitivity of the Euroimmun kit was 30-60%.

In many applications such as fractional ablative laser treatments, pain control, and fat removal, it is crucial to determine the temperature distribution across different layers of the tissue. We present a hybrid model consisting of point-wise temperature measurements and mathematical modeling of the simultaneous conduction and phase-change heat transfer to determine the coupling between the surface temperature and the isotherm planes across the tissue. The high accuracy and reliability, low sensitivity to variations in tissue texture and structure, simple design and implementation, as well as non-invasive nature of the method employed make the new system a robust tool in monitoring the temperature distribution and controlling the cooling or heating rate. The new system significantly increases the efficacy, safety, and reliability of the tissue thermal management treatments and reduces the risk of damage to non-target tissues especially for aggressive treatments.

We have developed GaInAsP semiconductor photonic crystal nanolaser biosensor and demonstrated the detection of ultralow-concentration (fM to aM) proteins and deoxyribonucleic acids (DNAs) adsorbed on the device surface. In general, this type of photonic sensors exploiting optical resonance has been considered to detect the refractive index of biomolecules via the wavelength shift. However, this principle cannot explain the detection of such ultralowconcentration. Therefore, we investigated another candidate principle, i.e., ion sensitivity. We consider such a process that 1) the electric charge of biomolecules changes the nanolaser’s surface charge, 2) the Schottky barrier near the semiconductor surface is increased or decreased, 3) the distribution of photopumped carriers is modified by the barrier, 4) the refractive index of the semiconductor is changed by the carrier effects, and 5) the laser wavelength shifts. To confirm this process, we electrochemically measured the zeta and flatband potentials when charged electrolyte polymers were adsorbed in water. We clearly observed that these potentials temporally behaved consistently with that of the laser wavelength, which suggests that polymers significantly acted on the Schottky barrier. The same behaviors were also observed for the adsorption of 1 fM DNA. We consider that a limited number of charged DNA changed the surface functional group of the entire device surface. Such charge effects will be the key that achieves the ultrahigh sensitivity in the nanolaser biosensor.

We demonstrate a scalable multi-layer integrated photonics platform that operates over a multi-octave wavelength range, from the near-ultraviolet (NUV) to the near-infrared (NIR). The platform is CMOS compatible and consists of silicon nitride (Si₃N₄) and alumina (Al₂O₃) optical waveguides cladded with silicon dioxide (SiO₂). We demonstrate low-loss waveguides and passive components including diffractive vertical grating couplers for input/output (I/O). The multilayer nature of the platform enables complex routing of multiple wavelengths, making it useful for a variety of applications including integrated atomic-molecular-optical (AMO) and biophotonic systems.

The guided-mode resonance (GMR) sensor operates with quasi-guided modes induced in periodic films. The resonance is enabled by 1D or 2D nanopatterns that are expeditiously fabricated. Optical sensors are needed in many fields including medical diagnostics, chemical analyses, and environmental monitoring. Inducing resonance in multiple modes enables extraction of complete bioreaction information including the biolayer thickness, biolayer refractive index, and any change in the refractive index in the background buffer solution. Thus, we refer to this version of the GMR sensor as the complete biosensor. We address the fundamentals, state of technological development, and implementation of this basic sensor modality.

We describe the detection of trace concentrations of chemical agents using waveguide-enhanced Raman spectroscopy in a photonic integrated circuit fabricated by AIM Photonics. The photonic integrated circuit is based on a five-centimeter long silicon nitride waveguide with a trench etched in the top cladding to allow access to the evanescent field of the propagating mode by analyte molecules. This waveguide transducer is coated with a sorbent polymer to enhance detection sensitivity and placed between low-loss edge couplers. The photonic integrated circuit is laid-out using the AIM Photonics Process Design Kit and fabricated on a Multi-Project Wafer. We detect chemical warfare agent simulants at sub parts-per-million levels in times of less than a minute. We also discuss anticipated improvements in the level of integration for photonic chemical sensors, as well as existing challenges.

Wide-field interferometric microscopy is a common-path interferometry technique that allows for label-free and high-throughput detection of weakly scattering sub-diffraction-limited biological nanoparticles. Such nanoparticles appear as diffraction-limited-spots in the image and optically resolving them beyond their ‘digital’ detection still remains a challenge owing to the diffraction barrier as well as the typical signal levels that fall below the noise floor. In this study, we demonstrate the utility of computational optics in the interference enhanced nanoparticle imaging to improve its resolving power to obtain structural information on clinically relevant and often complexed-shaped biological nanoparticles such as viruses and exosomes. We consider a spatially incoherent structured illumination based image reconstruction strategy in wide-field interferometric microscopy to achieve high contrast nanoparticle imaging with super-resolution. Our reconstruction technique makes use of the optical transfer function of the system derived via an analytical model based on angular spectrum representation. We provide experimental demonstrations using an artificial sample to quantify the resolution enhancement as well as a biological sample for concept demonstration. We also benchmark the results against gold standard images obtained using an electron microscope. Our highly-sensitive super-resolution imaging system constitutes a noncomplex optical design, which can be realized with simple modifications to a conventional epi-illumination microscope, offering a cost-effective alternative to the laborious and expensive standard high-resolution microscopy techniques. It has a broad spectrum of applications ranging from clinical diagnostics to biotechnological research.

The cytology of the cerebrospinal fluid is traditionally performed by an operator (physician, biologist) by means of a conventional light microscope. The operator visually counts the leukocytes (white blood cells) present in a sample of cerebrospinal fluid (10 μl). It is a tedious job and the result is operator-dependent. Here in order to circumvent the limitations of manual counting, we approach the question of numeration of erythrocytes and leukocytes for the cytological diagnosis of meningitis by means of lens-free microscopy. In a first step, a prospective counts of leukocytes was performed by five different operators using conventional optical microscopy. The visual counting yielded an overall 16.7% misclassification of 72 cerebrospinal fluid specimens in meningitis/non-meningitis categories using a 10 leukocyte/μL cut-off. In a second step, the lens-free microscopy algorithm was adapted step-by-step for counting cerebrospinal fluid cells and discriminating leukocytes from erythrocytes. The optimization of the automatic lens-free counting was based on the prospective analysis of 215 cerebrospinal fluid specimens. The optimized algorithm yielded a 100% sensitivity and a 86% specificity compared to confirmed diagnostics. In a third step, a blind lens-free microscopic analysis of 116 cerebrospinal fluid specimens, including six cases of microbiology confirmed infectious meningitis, yielded a 100% sensitivity and a 79% specificity. Adapted lens-free microscopy is thus emerging as an operator-independent technique for the rapid numeration of leukocytes and erythrocytes in cerebrospinal fluid. In particular, this technique is well suited to the rapid diagnosis of meningitis at point-of-care laboratories.

Physical properties of a cell are often valuable information about the status of the cell, and developing technologies to measure such properties is important to enhance the progress in, for example, diagnosis of diseases. In this paper, we present a photonically driven DNA nanomachine with hybrid functions: providing a physical operation to a cell and reporting the cell's response. The DNA nanomachine can be controlled according to optical signals, and therefore the measurement is achieved locally at designated positions and at desired times. Black hole quenchers (BHQs) are introduced to drive the DNA nanomachine using light. When the DNA nanomachine is irradiated with the light at the excitation wavelength of the BHQs, the thermal energy is produced from the BHQs to drive the DNA nanomachine. To demonstrate a basic functionality, we constructed a DNA nanomachine that transformed between a linear conformation and a hairpin-like conformation depending on the presence or absence of a controlling DNA. This conformation change will be able to provide a force to deform cells as a physical operation. The response of the cell is reported as fluorescence resonance energy transfer (FRET) signals. An experimental result demonstrated that the FRET signal changed according to the presence or absence of the controlling DNA. The method is expected to be useful in measuring the stiffness of a cell.

Chemical sensing based on Localized Surface Plasmonic Resonances (LSPR) and the ultra-sharp optical features of surface lattice resonances (SLR) of arrays of metallic nanoantennas have attracted much attention. Recently we studied biosensing based on the transition between LSPR and SLR (hybridization phase), demonstrating significantly higher refractive index sensitivity than each of these resonances individually. In this contribution we study the impact of size and shape of the metallic nanoantennas on the hybridization process and the way they influence application of this process for biosensing, wherein miniscule variation of the refractive index of the environment leads to dramatic changes in the spectral properties of the arrays.

Portable high-sensitivity biosensors exhibit a growing demand in healthcare, food industry and environmental monitoring sectors. Optical biosensors based on photonic integration platforms are attractive candidates due to their high sensitivity, compactness and multiplexing capabilities. However, they need a low-cost and reliable integration with the microfluidic system. Laser-micropatterned double-sided biocompatible adhesive tapes are promising bonding layers for hybrid integration of an optofluidic biochip. As a part of the EU-PHOCNOSIS project, double-sided adhesive tapes have been proposed to integrate the polymer microfluidic system with the optical integrated waveguide sensor chip. Here the adhesive tape should be patterned in a micrometer scale in order to create an interaction between the sample that flows through the polymer microchannel and the photonic sensing microstructure. Three laser-assisted structuring methods are investigated to transfer microchannel patterns to the adhesive tape. The test structure design consists of a single channel with 400 μm wide, 30 mm length and two circular receivers with 3 mm radius. The best structuring results are found by using the picosecond UV laser where smooth and straight channel cross-sections are obtained. Such patterned tapes are used to bond blank polymer substrates to blank silicon substrates. As a proof of concept, the hybrid integration is tested using colored DI-water. Structuring tests related to the reduction of channel widths are also considered in this work. The use of this technique enables a simple and rapid manufacturing of narrow channels (50-60 μm in width) in adhesive tapes, achieving a cheap and stable integration of the optofluidic biochip.

Organic distributed feedback (DFB) lasers have been attractive for optical chemosensors since the amplified light-matter interaction leads to high sensitivity and detectability of the sensor. However, quenching quantum efficiency of the probe dye under multiple optical pumping marks the limit on the life time of the organic DFB laser based chemosensor. Here, we report the usefulness of the short lived organic DFB laser fabricated by spin-coated natural silk protein and sodium fluorescein dye solution on the permanently useable quartz grating as a physically transient, cost-effective and eco-friendly laser chemosensor. The physically transient and eco-friendly DFB laser showed high sensitivity to hydrochloric acid (HCl) acid vapor. The HCl vapor exposure to the fabricated physically transient DFB laser attenuates the lasing by degrading the optical response of the dye-doped silk film. The response of the physically transient DFB laser chemosensor to HCl is 30 times faster than that in fluorescence. We show the elapsed time to cease lasing depends on the concentration of HCl vapor and the thickness of the active silk/dye layer. Moreover, a new laser sample can be simply fabricated by washing-out and recoating silk/dye solution on the quartz grating. Additionally, the use of silk protein promises eco- and bio-friendly chemosensing due to favorable material traits like no creation of pollution and biocompatibility. Our approach would expand to detection of other important analytes by choosing proper probe dyes.

The graphene market continues to expand across a range of applications including consumer electronics, sensors, flexible wearables, supercapacitors, conductive inks and coatings. Thanks to graphene’s extraordinary electrical and mechanical properties a new generation of rapid, sensitive, low-cost bio/chemical sensors can be envisaged with impact upon healthcare, drug discovery, and bio/chemical detection applications. Here we present the graphene-related R&D work at RISE Acreo with focus upon three objectives: graphene materials including wafer scale graphene-on-SiC, chemically synthesized graphene oxide (GO), reduced graphene oxide (RGO) and graphene quantum dots (or carbon nano particles); design and fabrication of the graphene devices, especially on their multiplexed sensing capability for enabling detection of multiple targets on a miniature integrated chip; and analysis of sensing mechanisms. A few sensor examples will be described in this work, one is a graphene sensor to monitor glucose for diabetes. Another is a dopamine (DA) sensor utilizing graphene/ZnO-tetrapod hybrids for early diagnosis of Parkinson diseases (PD). DA is an important biomarker in the serum of patients with PD. The third one is a proton transmission detector utilizing 3D graphene onto SiC, which can initiate a new application for the detection of ionizing particle irradiation onto living cells. Finally, graphene sensors for forensic applications will be addressed; for instance, detection of amphetamine and TNT has been explored, aiming at rapid onsite crime scene analysis. In addition, a comprehensive analysis of the market and commercial opportunities of these devices will be presented.