This PDF file contains the front matter associated with SPIE Proceedings Volume 10081, including the Title Page, Copyright information, Table of Contents, Introduction (if any), and Conference Committee listing.

While surface enhanced Raman spectroscopy (SERS) may not compete with the standard central lab approaches for chemical and biological sensing, SERS may have the potential to provide unique capabilities for analytics away from the central lab. Raman spectrometers have evolved from benchtop systems to high-performing handheld instruments that are compatible with analysis of samples in the field. However, for SERS to truly succeed as a “point-of-sample” analytical technique, the SERS sensor must fit the needs of analysis in the field, including little or no sample preparation, minimal peripheral equipment, and ease of use. Traditional plasmonically-active rigid devices do not meet these requirements. Even microfluidic SERS devices generally are not compatible with point-of-sample analysis, as the "world-to-chip" interface presents challenges, and peripheral equipment is generally required.

In this review we will discuss the advances in plasmonic substrates fabricated on porous membranes, leading to SERS sensors that can collect samples via swabbing or dipping, clean up samples through separation, concentrate analytes by lateral flow focusing, and avoid the need for peripheral equipment. In particular, we will focus on inkjet-fabricated devices, which may present the best opportunity for scale-up via roll-to-roll manufacturing. We will also discuss the directions that flexible SERS sensors are moving the field, such as simple fabrication techniques, new support materials, SERS swabs, and SERS-active tapes and films.

Recently the single molecules such as protein and deoxyribonucleic acid (DNA) have been successfully characterized by using a portable solidstate nanopore (MinION) with an electrical detection technique. However, there have been several reports about the high error rates of the fabricated nanopore device, possibly due to an electrical double layer formed inside the pore channel. The current DNA sequencing technology utilized is based on the optical detection method. In order to utilize the current optical detection technique, we will present the formation of the Au nano-pore with Au particle under the various electron beam irradiations. In order to provide the diffusion of Au atoms, a 2 keV electron beam irradiation has been performed During electron beam irradiations by using field emission scanning electron microscopy (FESEM), Au and C atoms would diffuse together and form the binary mixture membrane. Initially, the Au atoms diffused in the membrane are smaller than 1 nm, below the detection limit of the transmission electron microscopy (TEM), so that we are unable to observe the Au atoms in the formed membrane. However, after several months later, the Au atoms became larger and larger with expense of the smaller particles: Ostwald ripening. Furthermore, we also observe the Au crystalline lattice structure on the binary Au-C membrane. The formed Au crystalline lattice structures were constantly changing during electron beam imaging process due to Spinodal decomposition; the unstable thermodynamic system of Au-C binary membrane. The fabricated Au nanopore with an Au nanoparticle can be utilized as a single molecule nanobio sensor.

A need exists for near real-time therapeutic drug monitoring (TDM), in particular for antibiotics and antifungals in patient samples at the point-of-care. To truly fit the point-of-care need, techniques must be rapid and easy to use. Here we report a membrane system utilizing inkjet-fabricated surface enhanced Raman spectroscopy (SERS) sensors that allows sensitive and specific analysis despite the elimination of sophisticated chromatography equipment, expensive analytical instruments, and other systems relegated to the central lab. We utilize inkjet-fabricated paper SERS sensors as substrates for 5FC detection; the use of paper-based SERS substrates leverages the natural wicking ability and filtering properties of microporous membranes. We investigate the use of microporous membranes in the vertical flow assay to allow separation of the flucytosine from whole blood. The passive vertical flow assay serves as a valuable method for physical separation of target analytes from complex biological matrices. This work further establishes a platform for easy, sensitive, and specific TDM of 5FC from whole blood.

Surface-enhanced infrared absorption (SEIRA) is a spectroscopic technique used to identify molecular fingerprints by resonant detection of infrared vibrational modes through coupling with the plasmonic modes of metallic nanostructures. Many reported works have demonstrated its capability to enhance the infrared absorption of solid or liquid samples. However, this technique has not been successfully applied to gas sensing yet due to the short light-matter interaction length and intrinsically weak absorption of gas compared to solid or liquid materials. Usually, IR gas sensing is conducted in a gas cell with a long absorption path. In the paper, we propose an integrated photonic device to expand the application of SEIRA to gas sensing by combining metal-organic framework (MOF) ZIF-8 (zeolitic imidazole framework) with plasmonic nanoantenna array. The device consists of an Au nanopatch array on sapphire substrate and is covered by a thin layer of MOF material. The MOF thin film, which is a new class of highly nanoporous material, serves as a gas absorber to selectively adsorb and concentrate CO2 from ambient environment into the thin layer, which has a high spatial overlap with the high intensity optical field of the plasmonic nanopatch antenna array. Namely, we can effectively increase the gas molecule concentration at the hot-spots for the SEIRA device. The experimentally demonstrated peak IR enhancement factor of the device for carbon dioxide sensing is over 1,100 times.

In this talk I will discuss surface enhanced Raman scattering in silica microsphere resonators based on whispering gallery mode resonance. Recently silica microspheres have attracted attention as a novel substrate for surface enhanced Raman scattering. Whispering gallery mode resonance has been identified as a major enhancement mechanism, along with other effects such as photonic nanojets. In most of the previous experiments, however, free space pumping of the microsphere has been used, which has low efficiency in coupling to the whispering gallery modes. In our approach, we use a tapered fiber coupler for a highly efficient coupling to the whispering gallery modes. Coupling to the microresonator is monitored using a tunable laser. We observe both pump enhancement and Purcell enhancement in the microresonator. Since the linewidth of the whispering gallery modes is much smaller than that of the Raman peaks, sharp peaks corresponding to the whispering gallery modes are overlaid on top of the Raman spectrum of the bulk material. To demonstrate the system’s potential for Raman analysis, I will present the whispering gallery mode surface enhanced Raman spectrum of rhodamine 6G thin film coated on a microsphere resonator.

In combustion, hydrocarbon fuels are burned with oxygen to release energy, carbon dioxide and water vapor. Here, we introduce a photocatalytic reactor for reversing this process, when carbon dioxide and water are combined and using optical and thermal energy from the sun hydrocarbons are produced and oxygen is released. This allows for the sustainable production of hydrocarbon products from non-fossil sources, allowing for the development of “green” hydrocarbon products. Our reactors take the form of modular cells of 10 x 10 x 10 cm scale where light is delivered to nanostructured catalysts through the evanescent field around dielectric slab waveguides. The light distribution is optimized through the use of engineered scattering sites to enhance field uniformity. This is combined with integrated fluidic architecture to deliver a stream rich in water and carbon dioxide (such as exhaust from a natural gas burning plant) to the nanostructured catalyst particles in a narrow channel. Exhaust streams rich in oxygen and hydrocarbon products are collected at the outlet of the reactor cell. The cell is heated using solar thermal energy and temperatures of up to 200°C are achieved, enhancing reaction efficiency. Hydrocarbon products produced include methanol as well as other potentially useful molecules for fuel production or precursors to the manufacture of plastics. These reactors can be coupled to solar collectors to take advantage of the sun as a free source of heat and light, and the modular nature of the cells enables scaling to larger deployments.

Optofluidic biolasers are an emerging tool for bio-sensing and diagnostics. However, in order to facilitate waveguiding, the most common optofluidic distributed feedback (DFB) laser design relies on high-refractive index gain materials which are usually not biocompatible. We report the realization and characterization of evanescently pumped optofluidic DFB lasers with biocompatible aqueous gain fluids. Record low pump thresholds were achieved by optimizing the mode shape in the waveguide structure. Measuring the photonic band dispersion permits to sense the refractive index of the fluidic gain material. Different biological gain materials were studied on our devices.

In this talk, I will discuss the sensitivity enhancement in a whispering-gallery-mode resonator operating at the exceptional points. The exceptional points are obtained by controllably introducing two scatterers within the mode volume of a whispering-gallery-mode resonator. A nanofiber tip is used to mimic a nanoparticle to study the sensitivity enhancement of the resonator operating at the exceptional points. I will present the experimental results demonstrating that the resonator operating at the exceptional points exhibits square-root enhancement in frequency splitting when compared to a single resonator subject to the same amount of perturbation. The dependence of sensitivity enhancement on the angular position and size of the nanofiber tip is also studied. The experimental results agree well with the theoretical predictions and numerical simulations. Our study shows the potential applications of the resonator operating at the exceptional point for ultrasensitive single nanoparticle and biomolecule detection.

The realization of a simple real time biosensor, in which antibodies are immobilized onto surfaces, represents a promising application in the immunoassay development. Among the various sensing approaches, one of the most promising is based on microring resonators, offering a lot of advantages such as mass production, reduced dimensions, label-free and real time detection. The use of the evanescent field as optical transduction principle allows the development of label-free biosensors, in which the antibody is usually immobilized on the sensor surface and the binding of the antigen can be controlled and followed in real-time. The overall performances of immunosensors are strongly related to the optimization of the immobilization process and the integration between the microfluidic parts and the optical detection system. The combination of these two aspects makes the biosensing process very efficient, with a consequent reduction of the response time and improvement of the immobilization process efficiency. In this work we explore the working mechanism of a flow-through microresonator platform. A drilled hole, in the center of the ring, allows the active transport mechanism of the analyte toward the sensing surface with a consequent reduction of the response time. Moreover, we study the effects of oxygen plasma, in terms of duration times and plasma power, on immobilization efficiency of immunoglobulin G (IgG). An improvement of about 20% of the protein adsorption is ascribed to chemico-physical modification of SU-8. The measured sensor response time in flow-through configuration is about five times shorter respect to standard flow-over configuration.

The formation of resonant photonic structures in porous silicon leverages the benefit of high surface area for improved molecular capture that is characteristic of porous materials with the advantage of high detection sensitivity that is a feature of resonant optical devices. This review provides an overview of the biosensing capabilities of a variety of resonant porous silicon photonic structures including microcavities, Bloch surface waves, ring resonators, and annular Bragg resonators. Detection sensitivities > 1000 nm/RIU are achieved for small molecule detection. The challenge of detecting molecules that approach and exceed the pore diameter is also addressed.

Infrared (IR) spectroscopy is widely recognized as a gold standard technique for chemical and biological analysis. Traditional IR spectroscopy relies on fragile bench-top instruments located in dedicated laboratory settings, and is thus not suitable for emerging field-deployed applications such as in-line industrial process control, environmental monitoring, and point-of-care diagnosis. Recent strides in photonic integration technologies provide a promising route towards enabling miniaturized, rugged platforms for IR spectroscopic analysis. It is therefore attempting to simply replace the bulky discrete optical elements used in conventional IR spectroscopy with their on-chip counterparts. This size down-scaling approach, however, cripples the system performance as both the sensitivity of spectroscopic sensors and spectral resolution of spectrometers scale with optical path length. In light of this challenge, we will discuss two novel photonic device designs uniquely capable of reaping performance benefits from microphotonic scaling. We leverage strong optical and thermal confinement in judiciously designed micro-cavities to circumvent the thermal diffusion and optical diffraction limits in conventional photothermal sensors and achieve a record 104 photothermal sensitivity enhancement. In the second example, an on-chip spectrometer design with the Fellgett’s advantage is analyzed. The design enables sub-nm spectral resolution on a millimeter-sized, fully packaged chip without moving parts.

Microring resonators on silicon-on-insulator substrate have been demonstrated to be promising in sensing applications. We study a microring resonator biosensor based on a novel subwavelength grating (SWG) waveguide structure, which consists of periodic silicon pillars in the propagation direction with a subwavelength period. In this structure, effective sensing region includes not only the top and side of the waveguide, but also the space in between the silicon pillars which is on the path of the propagation mode. This leads to greatly increased bulk refractive index sensitivity as well as extended surface sensing region with constantly high surface sensitivity.

Thanks to their low mode volume and high finesse, optical microresonators have emerged as a promising avenue to detect and measure properties of single nanoparticles such as viruses or gold nanoparticles. Thanks to the resulting electromagnetic field enhancement, small nanoparticles, viruses and even single proteins have been trapped in hollow resonators such as photonic crystals or plasmonic tweezers. Such trapping devices with sensing capabilities are on the verge of finding powerful applications in interdisciplinary science. However, the quest for a candidate bringing together in-situ detection, trapping and multiple quantitative measurements of the particle properties supported by a comprehensive understanding still remain elusive. In this work, we show that open-access microcavities fulfil these criteria. Such resonators are made up of two micro-mirrors facing each other separated by a fluid medium in which nanoparticles can diffuse. We have recorded the cavity mode spectra while nanoparticles were optically trapped. Our results demonstrate that these microcavities can be used as optical tweezers with in-situ force calibration and nanoparticle sensing capabilities, including measurement of shape anisotropy. The shift in cavity mode wavelength during a trapping event provides information on both the nanoparticle and trap properties, as well as on the trapping force holding the particle in the trap. We are able to determine in real-time the nanoparticle polarizability, i.e. its optical response to an electromagnetic field, its coefficient of friction and characterize its shape anisotropy. The high level of control in this device makes it a robust analytical tool for real-time nanoparticle characterisation and monitoring.

Laboratory-scale demonstrations of optical biosensing employing structures compatible with CMOS fabrication, including waveguides, Mach-Zehnder interferometers, ring resonators, and photonic crystals, have provided ample validation of the promise of these technologies. However, to date there are relatively few examples of integrated photonic biosensors in the commercial sphere. The lack of successful translation from the laboratory to the marketplace is due in part to a lack of robust manufacturing processes for integrated photonics overall. This talk will describe efforts within the American Institute for Manufacturing Photonics (AIM Photonics), a public-private consortium funded by the Department of Defense, State governments, Universities, and Corporate partners to accelerate manufacturing of integrated photonic sensors.

Urinalysis dipsticks were designed to revolutionize urine-based medical diagnosis. They are cheap, extremely portable, and have multiple assays patterned on a single platform. They were also meant to be incredibly easy to use. Unfortunately, there are many aspects in both the preparation and the analysis of the dipsticks that are plagued by user error. This high error is one reason that dipsticks have failed to flourish in both the at-home market and in low-resource settings. Sources of error include: inaccurate volume deposition, varying lighting conditions, inconsistent timing measurements, and misinterpreted color comparisons. We introduce a novel manifold and companion software for dipstick urinalysis that eliminates the aforementioned error sources. A micro-volume slipping manifold ensures precise sample delivery, an opaque acrylic box guarantees consistent lighting conditions, a simple sticker-based timing mechanism maintains accurate timing, and custom software that processes video data captured by a mobile phone ensures proper color comparisons. We show that the results obtained with the proposed device are as accurate and consistent as a properly executed dip-and-wipe method, the industry gold-standard, suggesting the potential for this strategy to enable confident urinalysis testing. Furthermore, the proposed all-acrylic slipping manifold is reusable and low in cost, making it a potential solution for at-home users and low-resource settings.

X-ray excited luminescent chemical imaging (XELCI) uses a combination of X-ray excitation to provide high resolution and optical detection to provide chemical sensing. A key application is to detect and study implant-associated infection. The implant is coated with a layer of X-ray scintillators which generate visible near infrared light when irradiated with an X-ray beam. This light first passes through a pH indicator dye-loaded film placed over the scintillator film in order to modulate the luminescence spectrum according to pH. The light then passes through tissue is collected and the spectral ratio measured to determine pH. A focused X-ray beam irradiates a point in the scintillator film, and a pH image is formed point-by-point by scanning the beam across the sample. The sensor and scanning system are described along with preliminary results showing images in rabbit models.

An orthopaedic screw was designed with an optical tension-indicator to non-invasively quantify screw tension and monitor the load sharing between the bone and the implant. The screw both applies load to the bone, and measures this load by reporting the strain on the screw. The screw contains a colorimetric optical encoder that converts axial strain into colorimetric changes visible through the head of the screw, or luminescent spectral changes that are detected through tissue. Screws were tested under cyclic mechanical loading to mimic in-vivo conditions to verify the sensitivity, repeatability, and reproducibility of the sensor. In the absence to tissue, color was measured using a digital camera as a function of axial load on a stainless steel cannulated (hollow) orthopedic screw, modified by adding a passive colorimetric strain gauge through the central hole. The sensor was able to quantify clinically-relevant bone healing strains. The sensor exhibited good repeatability and reproducibility but also displayed hysteresis due to the internal mechanics of the screw. The strain indicator was also modified for measurement through tissue by replacing the reflective colorimetric sensor with a low-background X-ray excited optical luminescence signal. Luminescent spectra were acquired through 6 mm of chicken breast tissue. Overall, this research shows feasibility for a unique device which quantifies the strain on an orthopedic screw. Future research will involve reducing hysteresis by changing the mechanism of strain transduction in the screw, miniaturizing the luminescent strain gauge, monitoring bending as well as tension, using alternative luminescent spectral rulers based upon near infrared fluorescence or upconversion luminescence, and application to monitoring changes in pretension and load sharing during bone healing.

The most critical component of a biosensor, the biorecognition element, must exhibit high selectivity and strong affinity for a target of interest in operational sensing. Monoclonal antibodies are the current standard reagents for such devices, but their adaptability, manufacturability, and stability greatly limit their effectiveness in fieldable sensors. Peptides have emerged as potential antibody replacements in such applications due to their similar binding performance, extreme chemical and thermal stabilities, and on-demand scalability. In conjunction with modeling capabilities, work at the Army Research Lab focuses on protein catalyzed capture (PCC) agent technology and bacterial display for the discovery of these novel peptide binding reagents. The synthetic, bottom-up PCC agent technology uses an iterative, in situ "click chemistry" approach to produce high performing peptides against specific epitopes translatable to the protein target. Bacterial display allows rapid reagent discovery due to the combination of fast bacterial growth and effective peptide sequence enrichment through multiple rounds of biopanning. Recent advances in both methods are highlighted in regards to the discovery of reagents against Army high priority protein targets for soldier safety, performance, and diagnostics.

A novel terahertz (THz) otoscope is designed and fabricated to help physicians to diagnose otitis media (OM) with both THz diagnostics and conventional optical diagnostics. The inclusion of indium tin oxide (ITO) glass in the THz otoscope allows physicians to diagnose OM with both THz and conventional optical diagnostics. To determine THz diagnostics for OM, we observed reflection signals from samples behind a thin dielectric film and found that the presence of water behind the membrane could be distinguished based on THz pulse shape. We verified the potential of this tool for diagnosing OM using mouse skin tissue and a human tympanic membrane samples prior to clinical application. The presence of water absorbed by the human membrane was easily distinguished based on differences in pulse shapes and peak-to-peak amplitudes of reflected THz pulses. The potential for early OM diagnosis using the THz otoscope was confirmed by alteration of THz pulse depending on water absorption level.

Flow cytometry (FCM) is based on the detection of scattered light and fluorescence to identify cells with particular characteristics of interest. However most FCM cannot precisely control the flow through its interrogation point and hence the volume and concentration of the sample cannot be immediately obtained. The easiest, most reliable and inexpensive way of obtaining absolute counts with FCM is by using reference beads. We investigated a method of using FCM with reference beads to measure live and dead bacterial concentration over the range of 106 to 108 cells/mL and ratio varying from 0 to 100%. We believe we are the first to use this method for such a large cell concentration range while also establishing the effect of varying the live/dead bacteria ratios.

Escherichia coli solutions with differing ratios of live:dead cells were stained with fluorescent dyes SYTO 9 and propidium iodide (PI), which label live and dead cells, respectively. Samples were measured using a LSR II Flow Cytometer (BD Biosciences); using 488 nm excitation with 20 mW power. Both SYTO 9 and PI fluorescence were collected and threshold was set to side scatter. Traditional culture-based plate count was done in parallel to the FCM analysis. The concentration of live bacteria from FCM was compared to that obtained by plate counts. Preliminary results show that the concentration of live bacteria obtained by FCM and plate counts correlate well with each other and indicates this may be extended to a wider concentration range or for studying other cell characteristics.

In this study, a novel light-based processing method to create an amorphous trehalose matrix for the stabilization of proteins is discussed. Near-IR radiation is used to remove water from samples, leaving behind an amorphous solid with embedded protein. This method has potential applications in the stabilization of protein-based therapeutics and diagnostics that are becoming widely used in the treatment and diagnosis of a variety of diseases. Freeze-drying or freezing are currently the standard for the preservation of proteins, but these methods are expensive and can be challenging in some environments due to a lack of available infrastructure. Light-assisted drying offers a relatively inexpensive method for drying samples. Proteins suspended in a trehalose solution are dehydrated using near-infrared laser light. The laser radiation speeds drying and as water is removed the sugar forms a protective matrix. The goal of this study is to determine processing parameters that result in fast processing times and low end moisture contents (EMC), while maintaining the functionality of embedded proteins. We compare the effect of changing processing wavelength, power and resulting sample temperature, and substrate material on the EMC for two NIR laser sources (1064 nm and 1850 nm). The 1850 nm laser resulted in the lowest EMC (0.1836±0.09 gH2O/gDryWeight) after 10 minutes of processing on borosilicate glass microfiber paper. This suggests a storage temperature of ~3°C.

Based on small-molecule microarrays (SMMs) and oblique-incidence reflectivity difference (OI-RD) scanner, we have developed a novel high-throughput drug preliminary screening platform based on label-free monitoring of direct interactions between target proteins and immobilized small molecules. The screening platform is especially attractive for screening compounds against targets of unknown function and/or structure that are not compatible with functional assay development. In this screening platform, OI-RD scanner serves as a label-free detection instrument which is able to monitor about 15,000 biomolecular interactions in a single experiment without the need to label any biomolecule. Besides, SMMs serves as a novel format for high-throughput screening by immobilization of tens of thousands of different compounds on a single phenyl-isocyanate functionalized glass slide. Based on the high-throughput screening platform, we sequentially screened five target proteins (purified target proteins or cell lysate containing target protein) in high-throughput and label-free mode. We found hits for respective target protein and the inhibition effects for some hits were confirmed by following functional assays. Compared to traditional high-throughput screening assay, the novel high-throughput screening platform has many advantages, including minimal sample consumption, minimal distortion of interactions through label-free detection, multi-target screening analysis, which has a great potential to be a complementary screening platform in the field of drug discovery.