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Rapid detection of toxic and hazardous gases at trace concentrations plays a vital role in industrial, battlefield, and laboratory scenarios. Of interest are both sensitive as well as highly selective sensors. Whispering-gallery mode (WGM) microresonator-based biochemical sensors are among the most sensitive sensors in existence due to their long photon confinement times. One main concern with these devices, however, is their selectivity toward specific classes of target analytes. Here, we employ frequency locked WGM microtoroid optical resonators covalently modified with various polymer coatings to selectively detect the chemical warfare agent surrogate diisopropyl methylphosphonate (DIMP) as well as the toxic industrial chemicals formaldehyde and ammonia at parts-per-trillion concentrations (304, 434, and 117 ppt, respectively). This is 1-2 orders of magnitude better than previously reported, depending on the target, except for pristine graphene and pristine carbon nanotube sensors, which demonstrate similar detection levels but in vacuum and without selectivity. Selective polymer coatings include polyethylene glycol for DIMP sensing, accessed by the modification of commercially available materials, and 3-(triethoxysilyl) propyl-terminated polyvinyl acetate (PVAc) for ammonia sensing. Notably, we developed for the first time an efficient one-pot procedure to access 3-(triethoxysilyl) propyl-terminated PVAc that utilizes cobalt-mediated living radical polymerization and a nitroxyl polymer-terminating agent. Alkaline hydrolysis of PVAc coatings to form polyvinyl alcohol coatings directly bound to the microtoroid proved to be reliable and reproducible, leading to WGM sensors capable of the rapid and selective detection of formaldehyde vapors. The selectivity of these three polymer coatings as sensing media was predicted, in part, based on their functional group content and known reactivity patterns with the target analytes. Furthermore, we demonstrate that microtoroids coated with a mixture of polymers can serve as an all-in-one sensor that can detect multiple agents. We anticipate that our results will facilitate rapid early detection of chemical agents, as well as their surrogates and precursors.

Introduction Current guidelines recommend adding an oral antihyperglycemic agent (AHA) to metformin in patients with type 2 diabetes mellitus (T2DM) uncontrolled on metformin. Recent randomized clinical trials (RCTs) have demonstrated that adding dual AHAs instead of a single AHA provided more effective glycemic control. However, the comparative efficacy of approved single and dual initiation strategies is unknown. Therefore, we conducted a Bayesian network meta-analysis to compare the efficacy of dual and single add-on oral AHAs in patients uncontrolled on metformin. Methods A systematic literature review of RCTs was conducted following Cochrane and ISPOR guidelines. MEDLINE, Embase, and CENTRAL were searched from inception to November 19, 2019. Approved oral doses of sodium–glucose co-transporter-2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists in single or dual initiation therapies were indirectly compared. Outcomes focused on efficacy and included mean change from baseline in hemoglobin A1c (HbA1c), weight, systolic blood pressure (SBP), diastolic blood pressure, and achieving HbA1c target

Three-dimensional structure fabrication using discrete building blocks provides a versatile pathway for the creation of complex nanophotonic devices. The processing of individual components can generally support high-resolution, multiple-material, and variegated structures that are not achievable in a single step using top-down or hybrid methods. In addition, these methods are additive in nature, using minimal reagent quantities and producing little to no material waste. In this article, we review the most promising technologies that build structures using the placement of discrete components, focusing on laser-induced transfer, light-directed assembly, and inkjet printing. We discuss the underlying principles and most recent advances for each technique, as well as existing and future applications. These methods serve as adaptable platforms for the next generation of functional three-dimensional nanophotonic structures.

Rapid biosensing assays to detect SARS-CoV-2 are critical in mitigating the impact of the pandemic. Here, we use a lens-free holographic microscope coupled with deep learning in a rapid and sensitive assay to detect SARS-CoV-2.

The ability to fabricate three-dimensional structures with microscale resolution is critical to many emerging applications. We use an optical tweezers platform with biochemical linking mechanism to assemble 3D structures consisting of hundreds of individual building blocks.

Many air-quality monitoring devices can detect different sizes of particles but cannot quantify individual particle sizes across the range 0.1-10 μm. Here we show such a device that is furthermore cost-effective and portable.

Aims While glycemic control is key in effective type 2 diabetes mellitus management, many patients fail to reach their individualized glycemic goal. This analysis aimed to describe a real-world picture of diabetes management: individualized hemoglobin A1c (HbA1c) goals, rate of goal attainment, HbA1c at each line of therapy, and patient awareness of their glycemic goal. Secondly, we aimed to understand physician satisfaction with HbA1c amongst patients aware vs. those unaware of HbA1c goal. Methods Analysis of physicians and the next ten consulting patients with type 2 diabetes mellitus conducted in Europe and the USA including medical record data abstraction/assessment by physicians, a patient-reported survey and a physician survey. Patients were diagnosed for 3 months or more with a known current and target HbA1c. For the sub-analysis assessment of patient awareness of HbA1c goal, in addition to the above, these patients had to have completed a patient-reported questionnaire and answer the question on awareness of HbA1c goal. Results A total of 730 physicians provided data on 8794 patients with type 2 diabetes mellitus; 5331 patients were eligible for this analysis. Overall, mean (standard deviation, SD) individualized HbA1c goal was 6.8% (0.68%). Of eligible patients, 39.1% met their HbA1c goal; of 60.9% of patients not reaching their HbA1c goal, the mean distance from individualized HbA1c goal was 0.9% (SD 1.0%). Physicians progressed patients’ antihyperglycemic therapy when HbA1c was 8% or higher. Among 2560 patients who were included in the sub-analysis assessing the effect of patient awareness of their HbA1c goal on multiple parameters, 70.5% were aware of their HbA1c goal; mean HbA1c goal was 6.8% (0.7%) and current mean HbA1c value 7.1% (1.2%). A total of 949 patients in the sub-analysis (39.2%) achieved their goal; achieving HbA1c goal was not related to knowledge of goal. Patients aware of their HbA1c goal were slightly more adherent to their antihyperglycemic medication. They also were prescribed more antihyperglycemic agents, more often on a later therapy line receiving a GLP-1 receptor agonist, SGLT2i, or insulin, and more often tested their blood glucose levels than patients who were unaware. Physicians were not satisfied with the current blood glucose level of one third of their patients, believing that more of those who were aware of their HbA1c goal could achieve better glucose control (32.4% of aware vs. 28.2% of unaware patients; p = 0.003). Conclusions Our results showed that the proportion of patients with type 2 diabetes mellitus achieving their goals for glycemic control was suboptimal when compared to current guideline criteria, with only about 40% of patients achieving their individualized HbA1c goal. Treatment intensification was often delayed until HbA1c was 8% and higher. Patients aware of their HbA1c goal were slightly more adherent to their antihyperglycemic medication; however, awareness of HbA1c goal did not enhance goal attainment. This highlights the need for a holistic approach to diabetes management, involving patient education, and patient–physician communication and partnership. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01985-3.

The angular spectrum method (ASM) is commonly used for reconstructing images in digital holography for applications such as lens-free holography and metasurface design. The lack of Fraunhofer or Fresnel approximations and computational speed due to the fast Fourier transform makes ASM a competitive field propagation method. Using a thin-object approximation, ASM can also efficiently compute fields over large areas, enabling faster calculations than those using other methods such as finite difference time domain or Mie theory. However, thin-object approximations are not accurate for nanoscale objects and so ASM is currently unable to accurately recover nanoscale object information. Here we test three ASM transmission models that use a scalar description to model the interaction of a plane wave with a plane of randomly assembled nanoparticles and evaluate the accuracy of each against the discrete dipole method (DDA). Random distributions of nanoparticles are often used in super-resolution, sub-diffraction limit, or specialized sensing applications as they are easy to place. We study the performance of the three transmission models for gold and polystyrene nanospheres of 30 nm, 60 nm, and 100 nm in diameter for different particle densities. The performance of the models is evaluated against simulations using DDA, which is validated against Mie theory calculations, for the same configurations. We show transmission models in ASM that perform within 20% accuracy of the fields calculated using DDA.

Three-dimensional (3D) structures with nanoscale building blocks often benefit from light-matter interaction at the nanometer size scale. The most popular existing technologies for the 3D fabrication of these small structures (e.g. direct laser writing) typically encounter significant restrictions. Here we demonstrate our optical positioning and linking (OPAL) platform for the assembly of multi-material 3D devices consisting of nanoscale components. OPAL integrates an optical trapping setup with a computer-controlled motion platform, microfluidic building block delivery apparatus, and imaging feedback system, overcoming the limitations of many traditional nanofabrication approaches, and establishing a versatile tool for the fabrication of complex 3D nanophotonic structures.

Dipole approximations are commonly used in calculations of light scattering and optical forces acting on nanoparticles. The scattered field strength is proportional to particle volume. For the past...

Metasurfaces are planar nanostructured optical elements for lensing, wave-front shaping, and polarization control. A general but time-consuming metasurface design tool is the finite difference time domain (FDTD) technique. The discrete dipole approximation (DDA) is a rigorous and fast alternative for computing the electromagnetic field scattered by particles, but has not been widely used in metasurface design because of the complicated numerical difficulties imposed by the nanostructure-substrate interaction. Here we present a substrate-compatible DDA formulation using a 1D Green’s function method under cylindrical coordinates, proving that DDA can be a promising alternative method to design and optimize nanophotonic devices.

Lens-free microscopes can utilize holographic reconstruction techniques to recover the image of an object from the digitally recorded superposition of an unperturbed plane wave and a wave scattered by the object. Image reconstruction most commonly relies on the scalar angular spectrum method (ASM). While fast, the scalar ASM can be inaccurate for nanoscale objects, either because of the scalar approximation, or more generally, because it only models field propagation and not light-matter interaction, including inter-particle coupling. Here we evaluate the accuracy of the scalar ASM when combined with three different light-matter interaction models for computing the far-field light scattered by random arrays of gold and polystyrene nanoparticles. Among the three models—a dipole-matched transmission model, an optical path length model, and a binary amplitude model—we find that which model is most accurate depends on the nanoparticle material and packing density. For polystyrene particles at any packing density, there is always at least one model with error below 20%, while for gold nanoparticles with 40% or 50% surface coverage, there are no models that can provide errors better than 30%. The ASM error is determined in comparison to a discrete dipole approximation model, which is more computationally efficient than other full-wave modeling techniques. The knowledge of when and how the ASM fails can serve as a first step toward improved resolution in lens-free reconstruction and can also be applied to other random nanoparticle array applications such as lens-based super-resolution imaging, sub-diffraction beam focusing, and biomolecular sensing.

The optical tweezers platform provides an attractive approach for the fabrication of three-dimensional structures. Existing studies on optical tweezers assembly have mostly focused on the formation of small-scale structures consisting of a single type of dielectric building block. In this work, we demonstrate the potential of our automated optical positioning and linking (OPAL) platform that uses optical trapping for object manipulation and biochemical binding as a linking mechanism. We show a comprehensive analysis of system parameters and fabricate the largest microstructure built to date using this approach. Furthermore, we assemble multicomponent structures consisting of nanoscale building blocks.

Lens-free holographic microscopy (LFHM) is cost-effective and field-portable, making it a promising diagnostic approach for point-of-care applications. However, LFHM has not yet been applied to protein molecule sensing in solution . Here we develop a quantitative large-area binding sensor by combining a high-speed LFHM with a one-step bead-based agglutination assay, where agglutination of >10^4 2-μm beads in solution undergoing Brownian motion are imaged and quantified. We sense NeutrAvidin molecules and interferon-gamma (an immune system biomarker) in solution, achieving a limit of detection of

Accurate, cost-effective, easy-to-use, and point-of-care sensors for protein biomarker levels are important for disease diagnostics. A cost-effective and compact readout approach that has been used for several diagnostic applications is lens-free holographic microscopy, which provides an ultralarge field of view and submicron resolution when it is coupled with pixel super-resolution techniques. Despite its potential as a diagnostic technique, lens-free microscopy has not previously been applied to quantitative protein molecule sensing in solution, which can simplify sensing protocols and ultimately enable measurements of binding kinetics in physiological conditions. Here, we sense interferon-γ (an immune system biomarker) and NeutrAvidin molecules in solution by combining lens-free microscopy with a one-step bead-based agglutination assay, enabled by a custom high-speed light-emitting diode (LED) array and automated image processing routines. We call this a quantitative large-area binding (QLAB) sensor. The high-speed light source provides, for the first time, pixel super-resolved imaging of >104 2 μm beads in solution undergoing Brownian motion, without significant motion blur. The automated image processing routines enable the counting of individual beads and clusters, providing a quantitative sensor readout that depends on both bead and analyte concentrations. Fits to the chemical binding theory are provided. For NeutrAvidin, we find a limit of detection (LOD) of

A portable quantitative large-area binding sensor based on lensfree holographic microscopy, microfluidics, a custom LED array, and computational image processing and feature quantification algorithm has been implemented to sense proteins in solution through microbead agglutination.

Whispering gallery mode resonators such as silica microtoroids can be used as sensitive biochemical sensors. One sensing modality is mode-splitting, where the binding of individual targets to the resonator breaks the degeneracy between clockwise and counter-clockwise resonant modes. Compared to other sensing modalities, mode-splitting is attractive because the signal shift is theoretically insensitive to the polar coordinate where the target binds. However, this theory relies on several assumptions, and previous experimental and numerical results have shown some discrepancies with analytical theory. More accurate numerical modeling techniques could help to elucidate the underlying physics, but efficient 3D electromagnetic finite-element method simulations of large microtoroid (diameter ~90 µm) and their resonance features have previously been intractable. In addition, applications of mode-splitting often involve bacteria or viruses, which are too large to be accurately described by the existing analytical dipole approximation theory. A numerical simulation approach could accurately explain mode splitting induced by these larger particles. Here, we simulate mode-splitting in a large microtoroid using a beam envelope method with periodic boundary conditions in a wedge-shaped domain. We show that particle sizing is accurate to within 11% for radii a<λ/7, where the dipole approximation is valid. Polarizability calculations need only be based on the background media and need not consider the microtoroid material. This modeling approach can be applied to other sizes and shapes of microresonators in the future.

We implemented a lens-free holographic microscope (LFHM) that can image ~105 2-μm microspheres in solution over an ultra-large field-of-view >15 mm2 with sub-micron resolution and enhanced signal-to-noise ratio in less than 1 second. This performance is achieved using a high-speed hardware design for multi-frame pixel super-resolution and a novel sparsity-promoting reconstruction algorithm. We use the microscope as a biomolecular sensor to detect and quantify NeutrAvidin protein molecules. We coat 2-μm microspheres with biotin, which binds strongly to NAv, causing observable bead binding and clustering. This is quantified through an automated image processing algorithm and is used to infer NAv concentrations.

As powerful wave-front shapers, meta-surfaces can be used as planar lenses, polarizers, vortex generators, and other components. A general design approach is the finite difference time domain (FDTD) technique, which is robust but computationally costly. The discrete dipole approximation (DDA) is a rigorous and fast alternative, but has not been widely used in nanophotonic design because of computational complexity resulting from dipole-substrate interactions. Here we present a substrate-compatible DDA formulation using a one-dimensional Green’s function in cylindrical coordinates that accurately handles singularities and high-frequency oscillations. It is significantly faster with similar accuracy compared to several other methods, including FDTD.

For many micro- and nano-photonic applications, current 3D prototyping approaches are unable to provide the necessary resolution or material integration. Optical tweezers (OT) are a potentially attractive solution due to their ability to manipulate various small objects with high precision. Here we show a custom-built automated OT 3D assembly platform that operates with manipulation speeds up to 0.22 mm/s and positioning accuracy better than 50 nm. Furthermore, to the best of our knowledge, we assemble the largest 3D structure to date using an OT platform, consisting of several hundred objects of multiple compositions.

Evidence from clinical trials suggest that newer antihyperglycemic agents (AHAs) have a better clinical profile at a higher dose. However, the utilization of the different doses in the real world is not well known. This study aimed to assess the dose utilization of the 2 newer classes of AHAs using the 2018 Adelphi T2DM Disease Specific Programme, a survey involving 730 physicians and 8794 patients in the U.S. and Europe. The analysis included 1612 patients on sodium glucose cotransporter 2 inhibitors (SGLT2i) and 1073 patients on glucagon like peptide-1 receptor agonist (GLP-1RA), either monotherapy or combined therapy. Dose cut points for SGLT2i drugs were based on doses utilized in cardiovascular outcomes trials (at a compound level, Table 1). There is no standard cut point on dosing in GLP-1RA, therefore a conservative approach was applied (see Table for details). Analyses were performed at class level. SGLT2i drugs were more likely to be prescribed at a high dose (85.7%) to patients who were slightly younger than those receiving a lower dose (57.1 vs. 58.9 years). GLP-1RA were prescribed at high dose in 63.2% of the patients. Mean BMI was higher in patients receiving high dose of a GLP-1 receptor agonist. Disclosure D. Lautsch: Employee; Self; Merck & Co., Inc. E. McLeod: Employee; Self; Pfizer Inc. Stock/Shareholder; Self; Pfizer Inc. T. Wang: Employee; Spouse/Partner; Janssen Pharmaceuticals, Inc. Employee; Self; Merck & Co., Inc. C.D. Gonzalez: Employee; Self; Merck & Co., Inc. S. Rajpathak: Employee; Self; Menarini Group. S. Malkani: None. J. Jackson: None. G. Milligan: None. V. Higgins: None. Funding Merck Sharp & Dohme Corp; Pfizer Inc.

Optical tweezers are a powerful platform for nano- and micro-assembly, as they provide a non-contact and biologically friendly method for the three-dimensional manipulation of objects over a range of sizes and of varying material properties. Three-dimensional micro- and nano-scale structures that are composed of multiple materials often achieve improved performance over single-material designs. In the case of optical devices, the inclusion of both metallic and dielectric media allows for the possibility of achieving functionality which is otherwise inaccessible. Although there are many methods for fabricating small-scale three-dimensional optical devices, the majority of these approaches only deal with a single material or type of material. Thus, in order to create structures that consist of multiple materials, it is typically necessary to use a combination of methods over the course of several steps. Here we show that optical tweezers are a promising technology for the assembly of heterogeneous optical structures in a single process. We demonstrate our approach by fabricating structures using core-shell nanoparticles with metallic shells and dielectric cores as building blocks. To the best of our knowledge, these structures represent the first nanoscale, multi-material devices built using the optical tweezer platform. Furthermore, we discuss several relevant metrics regarding the assembly process such as object translation speeds, placement accuracy, and overall rates of fabrication. Currently, we have achieved lateral speeds up to 0.2 mm/s and placement repeatability down to 50 nm. We suggest future applications of this fabrication method and discuss the next steps in its evolution.

Lens-free on-chip imaging devices provide cost-effective, compact, and wide-field microscopy solutions for fieldwork and global health applications.

Aggregation of > 104 beads due to specific protein molecules is quantified using microfluidic chips, fast lens-free microscopes, and image processing algorithms. The limit of detection, cost, and size are appropriate for COVID-19 point-of-care testing.

Computation of the scattered electromagnetic fields from and optical forces on metallic nanoparticles depend on their dipole moments. We show that an extensively-used volume correction based on skin depth for calculating dipole moments is inaccurate.

Optical tweezers provide a non-contact three-dimensional (3D) method for nanoscale positioning. We assemble a 3D light guiding structure comprising a chain of gold-silica nanoshells and show structures assembled from hundreds of chemically-linked building blocks.

The ability to sense, count, and size microscopic and nanoscopic particles is important in air quality monitoring, biomedical diagnostics, and nanomaterials synthesis. Lensfree holographic microscopy is an attractive sensing platform due to its ultra-large field of view, compact form factor, and cost-effective components. Although submicron resolution has been previously demonstrated using lensfree holographic microscopy, the ability to detect individual microscale and nanoscale objects can pose a challenge due to limited signal to noise ratio (SNR). Previously, we have used vapor-deposited nanoscale polymer lenses to boost the SNR in sensing experiments, however this adds experimental complexity and is not compatible with all types of samples. Here we present a computational approach for boosting SNR in lensfree holographic microscopy. This approach optimizes a sparsity-promoting cost function in conjunction with a pixel superresolution method for synthesizing a high resolution hologram out of multiple low-resolution holograms captured at slightly different angles. The resulting high-resolution hologram can be computationally reconstructed to provide an in-focus image of the sample. We find that a sparsity-promoting cost function yields ~8 dB of improvement over conventional pixel superresolution approaches that involve cardinal neighbor regularization, provided that the surface coverage is below ~4%. The impacts of the sparsity-promoting cost function on image resolution and computational time will be presented, as well as a guide to which regularization parameters work best for given target sizes and coverage densities. These computational approaches can be used to extend the limit of detection of lensfree holographic microscopes in sensing applications.

Three major challenges in biological sensing and imaging systems are to improve sensitivity, resolution, and throughput. In this talk, I present results on using structures seeded or constructed by nanoparticles to provide enhancements in these three areas. We present our work in two parts. First, we have used vapor-deposited liquid nanoscale polyethylene glycol lenses to aid in sensing nanoscale particles that serve as seeds for these nanolenses. This approach is combined with lensfree holographic microscopy to image a transparent sample slide with adsorbed nanoparticles. Lensfree holographic microscopy provides an ultra-large field of view >20 mm^2 together with submicron resolution, however its sensitivity to nanoparticles is limited and particles smaller than ~300 nm cannot be inherently distinguished from background noise. The liquid nanolenses we deposit significantly enhance the sensitivity of this system such that >10^5 particles as small as 40 nm can be individually detected, localized, and sized. The second part of this talk focuses on using optical tweezers to assemble nanophotonic structures out of heterogeneous colloidal nanoparticles. The resulting structures can provide superresolution based on transmission line and metamaterial physical principles. Optically-positioned nanoparticles can also be attached to whispering gallery mode microresonators to enhance their sensitivity and facilitate free-space coupling. Finally, we have investigated the speed with which we can position nanoparticles using optical tweezers, and have measured maximum manipulation rates in excess of 150 um/s, which makes optical tweezers a viable approach for rapid prototyping additive manufacturing of nanophotonic structures.