Emerging Cytokine Biosensors with Optical Detection Modalities and Nanomaterial-Enabled Signal Enhancement.

Protein biomarkers, especially cytokines, play a pivotal role in the diagnosis and treatment of a wide spectrum of diseases. Therefore, a critical need for advanced cytokine sensors has been rapidly growing and will continue to expand to promote clinical testing, new biomarker development, and disease studies. In particular, sensors employing transduction principles of various optical modalities have emerged as the most common means of detection. In typical cytokine assays which are based on the binding affinities between the analytes of cytokines and their specific antibodies, optical schemes represent the most widely used mechanisms, with some serving as the gold standard against which all existing and new sensors are benchmarked. With recent advancements in nanoscience and nanotechnology, many of the recently emerging technologies for cytokine detection exploit various forms of nanomaterials for improved sensing capabilities. Nanomaterials have been demonstrated to exhibit exceptional optical properties unique to their reduced dimensionality. Novel sensing approaches based on the newly identified properties of nanomaterials have shown drastically improved performances in both the qualitative and quantitative analyses of cytokines. This article brings together the fundamentals in the literature that are central to different optical modalities developed for cytokine detection. Recent advancements in the applications of novel technologies are also discussed in terms of those that enable highly sensitive and multiplexed cytokine quantification spanning a wide dynamic range. For each highlighted optical technique, its current detection capabilities as well as associated challenges are discussed. Lastly, an outlook for nanomaterial-based cytokine sensors is provided from the perspective of optimizing the technologies for sensitivity and multiplexity as well as promoting widespread adaptations of the emerging optical techniques by lowering high thresholds currently present in the new approaches.

Elucidation of Strain-Dependent, Zinc Oxide Nanorod Response for Nanorod-Guided Fluorescence Intensity.

In this work, we examine how strain exerted on individual ZnO nanorods (NRs) can influence the fluorescence signals that are emitted from fluorophore molecules and subsequently coupled into and guided along the NR. We elucidate the relationships between the incremental levels of compressive and tensile strain on the NRs and measured fluorescence intensity of a model fluorophore, rhodamine 6G (R6G), as a function of the position on the NRs. We reveal that compressive strain on the NRs leads to a decrease in the guided fluorescence signal, while tensile strain leads to an increase in the fluorescence intensity. Compared to an unstrained state, approximately 35% decrease (increase) in R6G fluorescence intensity was observed from ZnO NRs when they were under compressive strain of -14% (tensile strain of +10%). Further, our systematic acquisition of the incremental addition of uniaxial strain result in a linear relationship of the coupled fluorescence signal and the amount of applied strain. The degree of fluorescence intensification on nanorod ends (DoF), which is a quantitative indicator for the amount of R6G signals coupled into and waveguided to the NR ends compared to those on the main body, also exhibits a linear relationship with strain. These outcomes, in turn, demonstrate that strain alters the waveguiding capabilities of ZnO NRs in a predictable manner, which can be exploited to modulate and optimize fluorescence and other light signals emitted by a nearby source. Considering the wide utility of ZnO NRs in photonics, optoelectronics, and sensors, insights from our study may be highly valuable to effectively controlling and enhancing optical signals from chemical and biological analytes through strain.

Position- and Polarization-Specific Waveguiding of Multi-Emissions in Single ZnO Nanorods.

We examine multiphoton-produced optical signals waveguided through single ZnO nanorods (NRs) using a newly developed, scanning offset-emission hyperspectral microscopy (SOHM) technique. Specifically, we concurrently analyze waveguiding behaviors of sum-frequency generation (SFG), deep-trap emissions (DTE), and coherent anti-Stokes Raman scattering (CARS) occurring in individual ZnO NRs. SOHM acquires spectrally-indexed and spatially-resolved intensity maps/spectra of waveguided light intensity while excitation/emission collection positions and light polarization are scanned. Hence, the powerful measurement capabilities of SOHM enable quantitative analyses of the different ZnO NR waveguiding behaviors specific to the multiphoton-generated emissions as a function of measurement position, light-matter interaction geometry, and the optical origin of the guided signal. We subsequently reveal the distinct waveguiding behaviors of single ZnO NRs pertaining to the SFG-, DTE-, and CARS-originated signals and discuss particularly attractive ZnO NR properties in CARS waveguiding.

Single nanomaterial level investigation of ZnO nanorod sulfidation reactions via position resolved confocal Raman spectroscopy.

Zinc oxide (ZnO) nanomaterials have been used as desulfurizing sorbents for gaseous streams, zinc sulfide (ZnS)-forming template lattices in nanomaterial synthesis, and agriculturally produced sulfur (S)-removing reagents from the environment. Although various nanoscale forms of ZnO have already been utilized widely for such purposes, there is currently a lack of fundamental insight into the sulfidation of ZnO nanomaterials at the single nanocrystal level. We demonstrate that position-resolved confocal Raman spectroscopy can be successfully used to reveal the sulfidation process of ZnO NRs occurring at the single nanomaterial level. We attained a single crystal level understanding of the facet-dependent sulfidation reactivity of ZnO NRs by tracking the same NRs with Raman spectroscopy before and after the sulfidation reaction and quantitatively analyzing various ZnS-induced phonon scattering intensities from different positions on the NRs. The trend in NR facet-dependent sulfidation reactivity is further substantiated by correlating it with the electron microscopy and fluorescence data measured from the same NRs. The insight obtained from this study may provide the much-needed fundamental knowledge base for designing optimal ZnO nanostructures beneficial to many technological and industrial applications exploiting the ZnO-to-ZnS conversion. Taken together with the well-established methods to synthesize ZnO nanomaterials of specific crystal shapes and structures, our findings from this study may be broadly applicable in formulating and optimizing more advanced, low-dimensional ZnO sorbents and scrubbers for highly effective S removal.

Spatially Correlated, Single Nanomaterial-Level Structural and Optical Profiling of Cu-Doped ZnO Nanorods Synthesized via Multifunctional Silicides.

We demonstrate a straightforward and effective method to synthesize vertically oriented, Cu-doped ZnO nanorods (NRs) using a novel multipurpose platform of copper silicide nanoblocks (Cu3Si NBs) preformed laterally in well-defined directions on Si. The use of the surface-organized Cu3Si NBs for ZnO NR growth successfully results in densely assembled Cu-doped ZnO NRs on each NB platform, whose overall structures resemble thick bristles on a brush head. We show that Cu3Si NBs can uniquely serve as a catalyst for ZnO NRs, a local dopant source of Cu, and a prepatterned guide to aid the local assembly of the NRs on the growth substrate. We also ascertain the crystalline structures, optical properties, and spectroscopic signatures of the Cu-doped ZnO NRs produced on the NBs, both at each module of NRs/NB and at their ensemble level. Subsequently, we determine their augmented properties relative to the pristine form of undoped ZnO NRs and the source material of Cu3Si NBs. We provide spatially correlated structural and optical data for individual modules of Cu-doped ZnO NRs assembled on a Cu3Si NB by resolving them along the different positions on the NB. Ensemble-averaged versus individual behaviors of Cu-doped ZnO NRs on Cu3Si NBs are then compared. We further discuss the potential impact of such ZnO-derived NRs on their relatively unexplored biological and biomedical applications. Our efforts will be particularly useful when exploiting each integrated module of self-aligned, Cu-doped ZnO NRs on a NB as a discretely addressable, active element in solid-state sensors and miniaturized luminescent bioprobes.

Polarization-resolved mechanistic investigation of fluorescence signal intensification on zinc oxide nanorod ends.

The superior optical properties of zinc oxide nanorods (ZnO NRs) have continued to promote their broad use in photonic, photoelectric, light detecting, and biosensing applications. One particularly important property pertinent to biodetection is fluorescence intensification on nanorod ends (FINE), a phenomenon in which a highly spatially localized and strongly intensified fluorescence signal with its extended photostability at the NR ends is seen from the emission profiles of fluorophore-coupled biomolecules on ZnO NRs. Therefore, understanding key parameters affecting the FINE phenomenon and the degree of FINE (DoF) is critical for their applications in biosensors. In this study, we describe in detail the outcomes of polarization-resolved measurements by systematically considering the polarization effects on FINE and DoF as a function of NR tilt angle and position along the NR. Specifically, we elucidate the exact roles of the different states of light polarization in FINE and quantitatively determine the explicit contributions arising from distinctive polarization states to the DoF. We confirm that the presence of the FINE phenomenon is ubiquitous from the fluorophore-coupled ZnO NR systems, regardless of the polarization setting. We subsequently show that DoF is significantly affected by the light-matter interaction geometry. We reveal the specific polarization conditions that contribute dominantly to the FINE effect. The highest DoF from a NR and the greatest NR end intensity can be achieved when both the excitation and collection polarization states are perpendicular to the NR main axis. Insights from this study provide valuable design principles for selecting the polarization state and light-matter interaction geometry to attain maximum FINE as well as DoF on ZnO NRs. The precise understanding of polarization-derived consequences on FINE and DoF manifested differently as a function of the position on individual NRs can also be important for warranting accurate interpretation and quantification of the position-dependent, fluorophore-emitted signals on single ZnO NRs. Hence, our findings from this study can be extremely beneficial in fluorescence-based sensing and detection settings utilizing polarization.

Spatially distinct Raman scattering characteristics of individual ZnO nanorods under controlled polarization: intense end scattering from forbidden modes.

In this study, we characterize incident/scattered polarization-specific and NR position-resolved Raman scattering behaviors of individual zinc oxide nanorods (ZnO NRs). We quantify Raman signals from the five key ZnO phonon modes of E2L, E2H-2L, A1T, E1T, and E2H, and reveal the NR position-dependent Raman scattering characteristics of the phonon modes per given light-matter interaction geometry. We then present Raman intensity maps and elucidate Raman behaviors consistent and incongruous with Raman selection rules. In particular, we identify an intriguing Raman scattering phenomenon from the forbidden modes, distinctively occurring at the two NR ends. Their unexpectedly strong and localized scattering signals at the NR termini are contrasted by the scattering behaviors from the rest of the NR positions agreeing with the selection predictions. By carrying out control measurements on isotropic ZnO microparticles (MPs), we ascertain that the unique NR position-specific Raman responses observed on ZnO NRs originate from their high shape anisotropy. Owing to the superior optical property coupled with reduced dimensionality and high geometric anisotropy, ZnO NRs have gained much attention recently for use in optoelectronic, photonic, and biosensor technologies. Raman scattering has been increasingly exploited as a noninvasive and sensitive analytical tool to investigate NR properties pertinent to these applications. Hence, our endeavors, explicitly providing the spatially distinct, polarized Raman scattering behaviors from individual ZnO NRs, will be central to the correct interpretation of Raman data of both the individual and ensemble NRs as well as to the accurate correlation of the measurement outcomes to their chemical/physical/optical properties. Our efforts may also promote novel applications for polarized Raman scattering whose optical outputs on the various positions along the ZnO NRs can be selectively modulated.