This PDF file contains the front matter associated with SPIE Proceedings Volume 10728, including the Title Page, Copyright information, Table of Contents, Author and Conference Committee lists.

Label-free nano/bio-sensors based on whispering gallery mode (WGM) resonators have been continuously studied over the past decade in virtue of their high sensitivity attained from high quality factor and small mode volume. However, there is still considerable gap between its academic achievements and practical applications which require not only high sensitivity but also low cost and ease of use. In this research, WGM resonator sensors integrated with microfluidic circuits are demonstrated in simple practical form released from strict coupling scheme of tapered fibers, which have long been considered as an essential element but a main hurdle for real applications. By taking advantage of large absorption cross-section of silicon nano-crystals, pump light exposed from the top of silicon-rich nitride (SRN) resonators can efficiently induce light emission spectrum peaks along the resonant modes which are detected by a spectrometer through free space optics. The shift of emission peaks revealing nanoparticles into measurable domain is around 5 times enhanced by nano-slot structure which strongly increases light-matter interaction by tightly confining the mode field in it. The quality factor of the resonators measured in aqueous channels is 7000 corresponding to 0.1 nm of full width at half maximum comparable to the resolution limit of the spectrometer, 0.05 nm. The real-time sensing experiments for the specific binding process of streptavidin to biotin pre-processed on the resonator slot surface showed 60 pM detection limit and 2.14 x 10^14 affinity constant attained from analyzing the binding kinetics by Langmuir model, which corresponds well to the theoretical value.

Electroanalytical methods are increasingly used in the understanding of the complexity of the human brain function in normal and diseased states. The main component of the electroanalytical methods is an electrode and its electrochemical properties are linked to the overall performance of the sensor used in detecting the various electroactive brain chemicals and molecules. In this work, we developed a droplet-based microfluidic platform and characterized a boron-doped ultrananocrystalline diamond (BDUNCD) microelectrode that is modified with multi-walled carbon nanotubes (MWCNTs) thin film and nafion coatings. The coating parameters were systematically altered and studied their effect on dopamine (DA) sensing performance. BDUNCD microelectrodes that were modified with 50 nm thick nafion coating showed a 3-fold increase in DA detection signal, whereas the microelectrodes modified with MWCNT film and nafion coating showed a 10-fold increase in the detection signal. The un-modified and modified BDUNCD microelectrodes were evaluated for their long-term stability (up to 9 h) using a custom droplet-based microfluidics. The MWCNT-nafion modified BDUNCD microelectrode showed the highest sensitivity of 15.01 μA ± 0.2% for 100 μM DA concentration with a limit of detection of 1.78 nM ± 2%.

In the attention focused biomimetic technologies, the snail shell, whose surface is antifouling, is a mimic subject. In this paper, a metamaterial technology to obtain oil repellence and antifouling, not realized on the as fabricated material surfaces, is introduced. Silicon nano-pillars imitating the real snail were evaluated in oil repellence in water. For applying this structure to complex curved surfaces, the soft resin sheet with nano-structure was developed. The fabricated sheet was applied to a tube, and evaluated in oil water mixture flowing. Antifouling and no dirt growing are obtained in the tube inner surface. As an assumed application, the bile duct catheter was fabricated and indwelled in a pig body. After 7 days placement, the catheter inner surface is antifouling, and then the metamaterial catherter indicates the practical capabilities. The demonstrated nano-structures are attractive for a new metamaterial realization.

The ability to conduct diagnostic functions on a single chip has long been of interest to the medical community. Decentralization of laboratories combined with reduced costs, increased speed and a higher throughput of potential assays are all driving forces for lab-on-a-chip technology. The small chip sizes facilitate low sample volumes, which in turn allow better control of the molecular interactions close to the sample surface. The design and quality of transducers, microfluidics and functionalization processes have all improved over recent years. Despite the growing interest for lab-on-a-chip components, several challenges remain. Combining all three disciplines into a high-quality well-functioning chip that is cheap to fabricate while providing reproducible results is challenging. A project attempting to address these challenges is presented. The main goal is to design and fabricate a labon-a-chip silicon photonic biosensor with multiple channels for detection of antigens with improved sensitivity and selectivity compared to state-of-the-art. As a proof-of-concept, the sensor is designed for simultaneous detection of three distinct antigens: C-reactive protein (CRP), lipocalin and tumor necrosis factor (TNF). The main challenge lies within their respective concentrations as well as the specificity for each analyte, where concentrations vary from the mg/ml to pg/ml regime. Multiplexing is achieved by using photonic crystal resonators, which function as drop-filters, allowing for single input/output while simultaneously probing select transducers that are functionalized for different chemistries. The individual resonator designs facilitate different limit-of-detections (LODs) and dynamic ranges for each analyte. Preliminary results from the first single channel prototype are presented, while work on the multiplexed sensor continues.

Carbon nanomaterials have shown promise as biocompatible, conductive scaffolds that direct neural tissue regeneration. The goal is to influence stem cell fate by engineering a controlled micro- and macro- environment that imitates living tissue, while simultaneously monitoring cell metabolites. To approach this goal, we synthesized a highly porous, pyrolitic nanofiber carbon material through a stress-induced graphitization process [1]. The carbon macrostructure was synthesized to have either a random or aligned orientation by controlling nanofiber deposition using an electrospinning technique. The resulting carbon has ideal conductive properties for electrical stimulation, a microstructure allowing for mechanical stimulation, and a controlled, porous 3D geometry mimicking the extracellular matrix (ECM) of mature cells. The unique graphitic structure is abundant in nitrogen heteroatoms and edge planes, which not only improves its electrochemical kinetics (with heterogeneous electron transfer rate of koapp = 0.2 cm/s in dopamine) but also promotes cellular adhesion by increasing nucleation sites for stem cells to attach and form neural networks. The compatibility of the carbon material as a stem cell scaffold was assessed by successfully growing and differentiating mouse neural stem cells (NSCs) on the untreated material without the addition of any ECM proteins or adhesion factors. The influence of fiber alignment on stem cell fate was also studied by growing NSCs on the carbon material with both aligned and randomly oriented nanofibers. Finally, the ability of the material to act as a simultaneous scaffold and sensor was assessed by measuring extremely low concentrations (<1μM) of dopamine in cell media. [1] Ghazinejad, Maziar, et al. "Graphitizing non-graphitizable carbons by stress-induced routes." Scientific reports 7.1 (2017): 16551.

Biosensor based on micro-ring resonator platform has attracted much attention owing to its high sensitivity for identifying various toxins in the environment. Among various bio-toxins, Botulinum neurotoxin (BoNT) are one type of poisonous substances causing the life-threatening neuroparalytic disease and probably used as biological weapon. In our study, a silicon based micro-ring resonator is designed, fabricated and demonstrated to detect BoNT in water sources. First, the capture antibody is labelled on the surface of silicon waveguide for capturing BoNT. The amount of BoNT bound on the surface results in the change of the effective refractive index. As a result, the concentration of toxins can be sensed based on the resonant shift response. Before involving the detection antibody in the assay, the BoNT concentration can be detected in the range from 200 ng/mL to 1 μg/mL. For further improving LOD, a signal enhancement strategy is to use biotin conjugated detection antibody to form a sandwich structure, and then to bind streptavidin-HRP and biotin conjugated anti-HRP antibody. LOD can be improved to 30 ng/mL after linking the detection antibody. After associating with the layer-by-layer structure composed by HRP and anti-HRP antibody on the sandwich assay, LOD can be improved to several pg/mL. Based on this strategy, the process of signal enhancement is flexible to achieve target LOD. And it also can be regenerated and reused after a cycle of detection. Therefore, this platform shows a high potential to apply for robust, realtime and high sensitive detection for various bio-toxins in water sources.

Iodine is an essential micronutrient in modulating critical functions of the body, such as producing thyroid hormones. A deficiency of iodine can cause severe thyroid-related disorders [2], while high doses of iodine can trigger overproduction of thyroid hormones, increasing the risk of developing thyroid dysfunction [1,2]. Therefore, it is critical to assess the iodine concentration in body fluids to monitor and diagnose early signs of diseases. Here we report on a simple, rapid, and highly-sensitive electrochemical detection of urinary iodine (UI) by exploiting the exceptional electrocatalytic capabilities of stress-activated pyrolytic carbon nanofibers (SAPCs). SAPCs are synthesized by stress-induced molecular alignment and subsequent low-temperature pyrolysis of organic carbon precursors. The resulting carbon possesses highly-graphitic structures that are characteristically rich in nitrogen heteroatoms and edge planes [3,4]. The tunable surface of SAPCs can also enhance the sensitivity and specificity of iodide ions in human urine. Furthermore, the high macroporosity of SAPCs increases surface area, creating a large liquid-carbon junction in aqueous solutions, providing efficient ion transport and adsorption capacity. The sensitivity and limit of detection (LoD) of SAPCs were evaluated by obtaining the linearity of molar concentration of iodide ions (I-) vs. current. The sensor specificity of SAPCs electrode for iodide ions was also investigated by adding a series of competitive anions such as F-, Cl-, PO43-, HPO42-, and H2PO4- into the solution and evaluating the effect of interference substances electrochemically. Additionally, the reproducibility of SAPCs for iodide ion detection was assessed by measuring the inter- and intra- coefficients of variability (CV%).

Small form-factor invasive pressure sensors are widely used in minimally invasive surgery, for example to guide decision making in coronary stenting procedures. Current fiber-optic sensors can have high manufacturing complexities and costs, which severely constrains their adoption outside of niche fields. A particular challenge is the ability to rapidly prototype and iterate upon sensor designs to optimize performance for different applications and medical devices. Here, we present a new sensor fabrication method, which involves two-photon polymerization printing and integration of the printed structure onto the end-face of a single-mode optical fiber. The active elements of the sensor were a pressure-sensitive diaphragm and an intermediate temperature-sensitive spacer that was insensitive to changes in external pressure. Deflection of the diaphragm and thermal expansion the spacer relative to the fiber end-face were monitored using phase-resolved low coherence interferometry. A pressure sensitivity of 0.031 rad/mmHg across the range of 760 to 1060 mmHg (absolute pressure), and a temperature sensitivity of 1.2 mrad/°C across the range 20 to 45°C were observed. This method will enable the fabrication of a wide range of fiber-optic sensors with pressure and temperature sensitivities suitable for guiding minimally invasive surgery.

Over twenty years have elapsed since the first report of single molecule surface enhanced Raman spectroscopy (SERS) yet quantitative sensing in the single molecule regime remains elusive. We have recently introduced a new self-assembly method for fabricating sensor surfaces capable of single-molecule SERS with uniform SERS enhancements of 109 over 100s of μm. Yet, the main challenge in quantitative single molecule SERS is the complex, system dependent, hotspot occupancy rate of analyte. In this work, we solve this problem using a new big data method for quantifying analyte concentration in the single molecule regime. Specifically, deep convolutional neural networks are trained with SERS spectra acquired across large sensor surfaces. The universal approximation property of neural networks is used to automatically fit the hotspot occupancy rate of any molecule. We demonstrate quantitative detection of rhodamine 800 as low as 1 femtomolar, where the single molecule regime begins at approximately 100 picomolar concentrations. This method is validated by comparison with traditional, non-quantitative methods of single molecule SERS detection. Further, we use SERS’s rich spectral information and label free detection to demonstrate the simultaneous quantification of multiple analyte molecules. Finally, this new quantification method is used to sense small molecules produced by bacterial biofilms. The proposed method is not system specific and is thus broadly applicable to any SERS sensor capable of large-area, uniform single molecule detection.

Living cells are likely to change their internal temperature during such natural processes as division, gene expression etc. Additionally, they actively react to environmental changes in temperature. Therefore, monitoring of intracell or near cell temperature opens the door for understanding intra-cell chemistry. However, most biological temperature changes expected be relatively small and transient, due to interactions with its environment. Hence, detecting this temperature change is quite challenging. We present the first systematic study of GeV spectra temperature shits on several different samples all demonstrating similar behavior. This temperature shits of zero-phonon line of GeV color center is powerful tool for precise all-optical detection of the temperature. Based on these studies we demonstrate all-optical thermometry with resolution well below 0.1K. Spatial resolution was demonstrated via implementation of the fiber based probe. Besides, we conducted series of proof of principal experiments in pillars and nanodiamonds this way proving possibility to measure temperature with submicron resolution. Achieved resolution together with chemical and physical inertness of nanodiamond passes the way for understanding of thermal function of living organisms and cells.

Molecular beacon (MB) probe is a fluorophore-labeled oligonucleotide and has been widely used in biological analysis and medical diagnostics by detecting DNA or RNA with specific sequences. The MB initially folds into a loop shape that brings the fluorophore close to a quencher for fluorescence quenching. It opens up upon the binding of target DNA that separates the fluorophore from the quencher to allow fluorescence emission. In this paper, we experimentally demonstrate the use of a silver open-ring nanostructure array (ORA) to enhance both fluorescence emission and quenching of MBs for highly sensitive DNA detection. The ORA displays a broadband resonance spectrum to enhance both the excitation and emission of fluorophores. The fluorescence enhancement is highly dependent on the distance between nanostructure and fluorophore. The couplings of the fluorescence emission and the external excitation with the proximate plasmonic nanostructure result in coherent electron oscillations that in turn act as secondary excitation of the fluorophore in a ~10 nm separation distance, leading to fluorescent enhancement. The resonance feature of ORA also improved the Förster resonance energy transfer between the fluorophore and ORA in an even shorter separation distance that promotes the fluorescence quenching. The enhanced fluorescence emission and quenching amplified the on-off ratio of the detection signal. The sensor was integrated into a microfluidic chamber to handle microliter-volume analyte and achieved a ~300 fM detection limit, an equivalent 360 zmol in a 1.2 μL analyte volume, superior to the detection on plane silver surfaces.

We report a parametric study of a long-range plasmon waveguide for the modal profiles, effective index and propagation losses as a function of the metal layer thickness and the variations in the refraction index of the upper cladding. Such device can be used as an optical biosensor. All calculations are performed using COMSOL Multiphysics, and the amplitude- and phase- responses of the device are obtained from the changes in the real and imaginary part of the effective index of the plasmon mode, respectively.

We expanded the capabilities of surface multiplasmonic resonance sensing via a prism-coupled configuration by devising a new scheme to analyze data obtained from simulations and/or experiments. An index-matched substrate with a metal thin film and a chiral sculptured thin film (CSTF) deposited successively on it is affixed to the base of a prism with an isosceles triangle as its cross section. When a fluid is brought in contact with the exposed face of the CSTF, the latter is infiltrated. As a result of infiltration, the traversal of light entering one slanted face of the prism and exiting the other slanted face of the prism is affected. We trained an artificial neural network (ANN) using reflectance data generated from simulations to predict the refractive index of the infiltrant fluid. ANN performance for various incidence conditions was studied. The scheme is quite robust.

Nanomaterials have shown promise for a variety of medical applications due to their unique properties and form factors compared to their bulk counterparts. Several novel medical technologies leveraging these properties are in various stages of development for applications including drug delivery, anti-microbial, diagnostic, or therapy technologies. A subset of these technologies, namely radiation therapy applications, require the nanoparticles to retain their structure and properties in radiation environments. It has been demonstrated that nanoparticle irradiation response can vary greatly from bulk materials response, as damage effects become dominated by sputtering and surface effects. As such, the stability, or rather the resistance of these materials towards radiation-induced degradation needs to be well understood to gauge the efficacy of candidate nanoparticles for these applications. This presentation details ongoing efforts at the In-situ Ion Irradiation Transmission Electron Microscopy (I3TEM) facility at Sandia National Laboratories to study and characterize the structural evolution of nanoparticles utilizing both in-situ and ex-situ ion beam irradiation techniques. Materials systems of interest include CeO2 nanoparticles, used for protecting healthy cells from radiation damage, and Au and HfO2 nanoparticles, used to increase local dose from proton therapies. Observed nanoparticle responses were varied and included stability, coalescence, ablation, cratering, sputtering, and swelling, depending on particle species, morphology, and irradiation condition. This diversity in nanoparticle irradiation response demonstrates the need for additional systematic study to determine the ultimate usefulness of various nanoparticle species for radiation therapy applications.

It has long been known that snail shells have an excellent anti-fouling function, as it is said that there are no dirty snails. The snails encountered during the baiu rainy season in Japan always have clean, shining shells. These shells are known to have convex-concave nanoscale structures on their surface (roughness on the order of approximately 200 nm) that promote the formation of a film of water on the shell surface, creating an ultra-hydrophilic nanoscale structure that repels oils and stains ^[1] . Creating such an ultra-hydrophilic nanoscale structure on a polymer surface should allow us to produce an antifouling polymer sheet. Additionally, producing a tube from a polymer film with this nanoscale structure should make it possible to create a tube with high antifouling properties. The field of technologies based on imitating properties and structures observed in living organisms in nature is called biomimetics ^[2]. This paper reports on the development of antifouling sheets and tubes with antifouling functions fabricated using the above technologies. The first step was creating a mold with an artificial snail shell structure using ZrO₂ nanoparticles [3], whose patterns were then transferred to polymer with nanoimprint technology ^[4-5]. These antifouling sheets and tubes are expected to see wide use for medical applications.

Background: To the date, oral isotretinoin is the most effective treatment for acne scars, and by combining their use with an ablative surgery results in improving the effects of the skin restoration. However, it is highly recommended by dermatologists, to wait for a period of 6 months between the isotretinoin treatment and the laser surgery, and that relative high period of time can lead to negative effects like anxiety or psychological distress in the patients. Our objective is to demonstrate that combining an ablative laser surgery and an isotretinoin treatment at therapeutic doses improves the acne wound healing in a considerably short period of time in comparison with previous studies. Additionally, it is of our interest to evaluate the wound healing due the collagen regeneration by the use of Raman spectroscopy, recently used as a non-invasive medical tool for skin diseases. Method: The study was performed in 9 patients who underwent on an oral isotretinoin treatment due to the presence of acne scars on the face. All patients received one single treatment with a CO₂ Ablative Fractional Laser (AFL) on four zones of the face within a range of four weeks after isotretinoin treatment. Additionally, an untreated measurement in the elbow side of the arm acted as a control. Both treatments, the isotretinoin and the ablative surgery, were performed by the same dermatologist. The patients were evaluated by means of Raman spectroscopy before and after the treatment and for the data processing, two different statistical approaches were applied to the Raman spectra with the objective to assess the presence of a specific collagen type. Results: The patients showed normal wound healing post AFL treatments and it was shown that with a therapeutic dose of oral isotretinoin and with one single laser surgery in a relative short period of time, a collagen regeneration was observed. Conclusion: When combined AFL surgery and isotretinoin treatment at therapeutic doses, a regeneration of a type of collagen is observed, which is quantified non-invasively by Raman spectroscopy.

A bimetallic chip was designed to improve the performance of a surface plasmon resonance (SPR) sensor based on angular interrogation, which demonstrated a relatively low noise level and a high resolution compared with a single gold chip. The calculated refractive index resolution of the bimetallic chip is 5.3 × 10^-7 RIU. In addition, the electric field intensity at the surface of the chip is enhanced. This can guarantee a high sensitivity in a larger sensing region for the measurement of macromolecules, especially in the field of biological sensing. The bimetallic chip SPR sensor was combined with molecularly imprinted polymer (MIP) film as artificial receptor to detect antibiotics. The molecularly imprinted polymer was prepared by photo-polymerization of ciprofloxacin capped with itaconic acid as functional monomer on the bimetallic chip. The thickness of the MIP film was 16 ±2 nm, which was measured with a stylus profiler. The MIP exhibited high selectivity to ciprofloxacin compared with dopamine and penicillin, and the selectivity coefficients of ciprofloxacin，penicillin, and dopamine were 1, 0.22, and 0.19, respectively. The SPR response was proportional to the concentration of ciprofloxacin, the limit of detection (LOD) of which was 0.1 pM or 0.04 ppt，while the LOD for a single gold chip was 0.5 pM. The adsorption of CIP by the MIP bimetallic-coated chip was reversible. Taking the reproducibility of MIP into consideration, a combination of SPR sensing with MIP is a promising method for the detection of ciprofloxacin.

A model of weak phase fluctuations of polycrystalline films of biological fluids is proposed. A correlation approach has been used to describe the polarization manifestations of the linear and circular birefringence of biological planar polycrystalline networks. Algorithms of polarization experimental measurement of the module (orientation map) and phase (phase map) of a set of "two-point" parameters of the Stokes vector are determined. The sets of orientation and phase maps of polycrystalline films of bile and blood are studied experimentally. The diagnostic possibilities of statistical analysis of the module and phase distributions of the "two-point" parameters of the Stokes vector of polarization-inhomogeneous images are considered. The magnitudes and ranges of changes in the set of statistical moments of the 1st and 4th orders that characterize the orientation and phase maps of polycrystalline films of bile and blood are found. The sensitivity, specificity and balanced accuracy of the method of polarization-correlation mapping in the diagnosis of early stage of cholelithiasis, as well as differentiation of the degree of blood losses, were determined.

A multilayered model of the optical anisotropy of the light-scattering layer of biological tissue is considered. The Muller matrix of the depolarizing layer is represented as a superposition of partial matrix operators for linear and circular birefringence-dichroism. For multiple scattering, an algorithm is proposed for the expansion of the Muller matrix in the form of two components. The first is the fully polarized component of the Muller matrix. The second is the completely depolarized component of the Muller matrix. The algorithms for measuring the elements of the fully polarized component of the Muller matrix for distributions of the phase and amplitude anisotropy of the depolarizing biological tissue are found. Maps of the distributions of the completely polarized component of the Muller matrix elements of histological sections of healthy and diabetic rats liver tissue have been studied. Sensitivity, specificity and balanced accuracy of the Muller-matrix reconstruction method of the polycrystalline structure of multiply scattering biological tissues are determined. Within the framework of the statistical analysis of the maps of the elements of the fully polarized component of the Muller matrix, histological sections of the liver tissue, objective criteria for the differentiation of healthy and diabetic rats have been found.

An optical-physical system for extracting information about the fluctuations in the optical anisotropy of strongly scattering biological tissues is considered. A model is proposed for the formation of a depolarized background by birefringent and dichroic structures. An explicit form and symmetry of the completely depolarized component of the Mueller matrix is determined, a second-order differential matrix. An algorithm for the analytic determination of the distributions of elements of a second-order differential matrix is found. Interrelations between the magnitude of the elements of the second-order differential matrix and the fluctuations of the linear and circular birefringence-dichroism are obtained. The technique of diffuse tomography of an optically anisotropic component of strongly scattering biological tissues has been developed and experimentally tested. Maps of the distributions of the elements of the completely depolarized component of the Mueller matrix of the histological sections of the internal organs of the healthy and of the diabetic rats . The sensitivity, specificity and balanced accuracy of the method of diffuse tomography of the polycrystalline structure of tumors of the uterine wall and the degree of hemorrhage of the liver are determined.

The method of azimuthally invariant 3D Muller-matrix mapping of distributions of phase and amplitude anisotropy parameters of partially depolarizing layers of biological tissues of different morphological structures is proposed and substantiated. In the volume of biological samples, the coordinate distributions of the magnitude of the set of Mullermatrix invariants (MMI) histological sections of the myocardium tissue with a spatially structured optical anisotropic fibrillary network, as well as parenchymal tissue of the rat liver with an islet polycrystalline structure, were obtained. The "phase" dependences of the magnitude of the statistical moments of the 1 st - 4 th orders, which characterize the distributions of the MMI values of polarization manifestations of the parameters of linear and circular birefringence and dichroism of the polycrystalline component of different types of biological tissues, are determined. A comparative study was made of the possibilities of differentiation of changes in the parameters of optical anisotropy using traditional 2D and 3D Muller-matrix mapping methods. The optimal conditions for the differentiation of polycrystalline structures of biological tissues - the range of phase sections and the most sensitive parameters - are the statistical moments of the 3rd and 4th orders that characterize the distributions of MMI associated with the polarization manifestations of linear birefringence and dichroism of different types of optically anisotropic structures.

An optical model of the polycrystalline structure of the human blood film is proposed as a superposition of completely polarized and depolarized components. Analytical algorithms for describing the polarization manifestations of such components are found. A new technique for laser sounding of blood films and detection of polarization-inhomogeneous fields by means of variations in the states of polarization of the reference wave is developed. The algorithm of digital holographic reconstruction of distributions of complex amplitudes of the polarization-inhomogeneous object field of polycrystalline films of blood is used. Layered maps of the distribution of azimuth and ellipticity of polarization of the object field of polycrystalline films of blood were obtained and analyzed. 3D distributions of the linear and circular birefringence and dichroism of such films are determined. Sensitivity, specificity and balanced accuracy of the method of digital polarization-holographic 3D reconstruction of the polycrystalline structure of blood films are determined. Statistical analysis of polarization maps of the polycrystalline structure of blood films revealed objective criteria for the diagnosis of breast cancer.