Vibrant reflective sensors with percolation film Fabry-Pérot nanocavities.

Dynamically reconfigurable structural colors are promising materials for new smart optical systems. However, improved reflected color quality (e.g., saturation, optical contrast, angular invariance) and larger tuning range/sensitivity are needed. Here, we demonstrate a vibrant, actively tunable system which meets these needs via coupling broadband plasmonic resonators to a responsive polymer film. Our structure consists of near-percolation gold nanoislands deposited on a poly[methyl methacrylate] (PMMA) spacer above a gold mirror, forming a Fabry-Pérot nanocavity. Broadband absorption in this system creates vivid reflected colors, while the polymer spacer enables continuous tuning over a wide color space. By exploiting swelling effects in PMMA, we show fast, reversible color switching in response to organic vapors. Our sensitive optical structure amplifies small vapor-induced changes in the spacer thickness, enabling naked-eye detection of changes as small as 10 nm. Additionally, optical absorption >99% yields modulation contrasts up to 80:1, opening the door to ultra-sensitive on-chip signal measurements, complementing the visual colorimetric readout. This structure has immediate implications for colorimetric bio/chemical sensing and may also find application to reflective displays and flexible/adaptive optical coatings.

Fabrication of monodisperse magnetic nanorods for improving hyperthermia efficacy.

BACKGROUND: Hyperthermia is one of the promising cancer treatment strategies enabled by local heating with the use of tumor-targeting magnetic nanoparticles (MNP) under a non-invasive magnetic field. However, one of the remaining challenges is how to achieve therapeutic levels of heat (without causing damages to regular tissues) in tumors that cannot be effectively treated with anti-tumor drug delivery. RESULTS: In this work, we report a facile method to fabricate magnetic nanorods for hyperthermia by one-step wet chemistry synthesis using 3-Aminopropyltrimethoxysilane (APTMS) as the shape-controlling agent and ferric and ferrous ions as precursors. By adjusting the concentration of APTMS, hydrothermal reaction time, ratios of ferric to ferrous ions, magnetic nanorods with aspect ratios ranging from 4.4 to 7.6 have been produced. At the clinically recommended field strength of 300 Oe (or less) and the frequency of 184 kHz, the specific absorption rate (SAR) of these nanorods is approximately 50 % higher than that of commercial Bionized NanoFerrite particles. CONCLUSIONS: This increase in SAR, especially at low field strengths, is crucial for treating deep tumors, such as pancreatic and rectal cancers, by avoiding the generation of harmful eddy current heating in normal tissues.

Flexible Electrostatic Transducer Array with Displacement Control for Haptic Sensing and Actuation.

We developed flexible electrostatic transducers with both a single element and a 2×2 array format to actuate at a precise displacement across a range of loads with a control circuitry and algorithm. The transducer, composed of a moving buckled film with an integrated electrode and a rigid electrode, can be used to simultaneously generate and sense displacements. A circuit and computer program were designed to demonstrate displacement control and quantify the sensing precision of the transducer. Specifically, we applied a range of voltage and load conditions to the transducer and array and measured the displacement while under loading through capacitive sensing. The change in capacitance was linear with respect to the area of the electrode in contact and matched theoretical predictions when described as a function of the displacement. The transducer was loaded with weights in the range of 5-27 mN and capacitance-driving voltage graphs were obtained. An 8Hz driving frequency was used to move the transducer, while a 10.8kHz signal was used to sense the capacitance. These were used to build a predictive model to correct for sensed load to maintain a average displacement. It was found that a transducer of dimensions 10mm × 40mm was able to maintain displacement under loads of 5-27mN, while a matrix composed of 10mm × 20mm transducers was able to maintain displacement under loads of 2.5-11mN. In general, the detection thresholds of human skin can range between 5-20mN of force and 2-20um of displacement for frequencies between 1Hz and 250Hz, so these values are in line with what is needed to build a functional haptic wearable device. The present work provides a method to quantitatively measure and control a new type of flexible transducer for a variety of haptic applications.

Method for Inkjet-printing PEDOT:PSS polymer electrode arrays on piezoelectric PVDF-TrFE fibers.

We present a method for printing conductive polymers onto P(VDF-TrFE) nanofibers to create all-polymer piezoelectric devices. Inkjet printing is an attractive fabrication approach for rapid prototyping of flexible electronics, but until now with limited applications in developing P(VDF-TrFE) nanofiber-based devices. We have demonstrated an approach to infill the void space within a piezoelectric nanofibrous matrix to allow for the inkjet printing of aqueous inks while avoiding leakage that typically leads to electrical shorting and without significant loss of voltage output. This was done using a diluted PDMS solution and a commercially available conductive ink. The 1 cm2 devices showed a 254 mV/N sensitivity to impact as well as a sensitivity to bending. The device was shown to be able to detect breathing and pulse rate when placed superficially to the carotid and radial arteries. Using these techniques, flexible piezoelectric sensing can be done in an array format, shown with applications in foot movement sensing.

Flexible Piezoelectric Nanogenerators Using Metal-doped ZnO-PVDF Films.

Piezoelectric nanomaterial-polymer composites represent a unique paradigm for making flexible energy harvesting and sensing devices with enhanced devices' performance. In this work, we studied various metal doped ZnO nanostructures, fabricated and characterized ZnO nanoparticle-PVDF composite thin film, and demonstrated both enhanced energy generation and motion sensing capabilities. Specifically, a series of flexible piezoelectric nanogenerators (PENGs) were designed based on these piezoelectric composite thin films. The voltage output from cobalt (Co), sodium (Na), silver (Ag), and lithium (Li) doped ZnO-PVDF composite as well as pure ZnO-PVDF samples were individually studied and compared. Under the same experimental conditions, the Li-ZnO based device produces the largest peak-to-peak voltage (3.43 Vpp) which is about 9 times of that of the pure ZnO based device, where Co-ZnO, Na-ZnO and Ag-ZnO are 1.2, 4.9 and 5.4 times, respectively. In addition, the effect of doping ratio of Li-ZnO is studied, and we found that 5% is the best doping ratio in terms of output voltage. Finally, we demonstrated that the energy harvested by the device from finger tapping at ~2 Hz can charge a capacitor with a large output power density of 0.45 W/cm3 and light up an ultraviolet (UV) light-emitting diode (LED). We also showed the device as a flexible wearable motion sensor, where different hand gestures were detected by the device with distinctive output voltage amplitudes and patterns.

Metallic photonic crystal-based sensor for cryogenic environments.

We investigate the design, characterization, and application of metallic photonic crystal (MPC) structures, consisting of plasmonic gold nanogratings on top of a photonic waveguide, as transducers for lab-on-chip biosensing in cryogenic environments. The compact design offers a promising approach to sensitive, in situ biosensing platforms for astrobiology applications (e.g., on the "icy moons" of the outer solar system). We fabricated and experimentally characterized three MPC sensor geometries, with variable nanograting width, at temperatures ranging from 300 K to 180 K. Sensors with wider nanogratings were more sensitive to changes in the local dielectric environment. Temperature-dependent experiments revealed an increase in plasmonic resonance intensity of around 13% at 180 K (compared with 300 K), while the coupled plasmonic-photonic resonance was less sensitive to temperature, varying by less than 5%. Simulation results confirm the relative temperature stability of the plasmonic-photonic mode and, combined with its high sensitivity, suggest a novel application of this mode as the sensing transduction mechanism over wide temperature ranges. To our knowledge, this is among the first reports of the design and characterization of a nanoplasmonic sensor specifically for low-temperature sensing operation.

Microfluidics-enabled rational design of ZnO micro-/nanoparticles with enhanced photocatalysis, cytotoxicity, and piezoelectric properties.

Microfluidics-based reactors enables the controllable synthesis of micro-/nanostructures for a broad spectrum of applications from materials science, bioengineering to medicine. In this study, we first develop a facile and straightforward flow synthesis strategy to control zinc oxide (ZnO) of different shapes (sphere, ellipsoid, short rod, long rod, cube, urchin, and platelet) on a few seconds time scale, based on the 1.5-run spiral-shaped microfluidic reactor with a relative short microchannel length of ca. 92 mm. The formation of ZnO is realized simply by mixing reactants through two inlet flows, one containing zinc nitrate and the other sodium hydroxide. The structures of ZnO are tuned by choosing appropriate flow rates and reactant concentrations of two inlet fluids. The formation mechanism behind microfluidics is proposed. The photocatalysis, cytotoxicity, and piezoelectric capabilities of as-synthesized ZnO from microreactors are further examined, and the structure-dependent efficacy is observed, where higher surface area ZnO structures generally behave better performance. These results bring new insights not only in the rational design of functional micro-/nanoparticles from microfluidics, but also for deeper understanding of the structure-efficacy relationship when translating micro-/nanomaterials into practical applications.

Advances in liquid biopsy on-chip for cancer management: Technologies, biomarkers, and clinical analysis.

Liquid biopsy, as a minimally invasive method of gleaning insight into the dynamics of diseases through a patient fluid sample, has been growing in popularity for cancer diagnosis, prognosis, and monitoring. While many technologies have been developed and validated in research laboratories, there has also been a push to expand these technologies into other clinical settings and as point of care devices. In this article, we discuss and evaluate microchip-based technologies for circulating tumor cell (CTC), exosome, and circulating tumor nucleic acid (ctNA) capture, detection, and analysis. Such integrated systems streamline otherwise multiple-step, manual operations to get a sample-to-answer quantitation. In addition, analysis of disease biomarkers is suited to point of care settings because of ease of use, low consumption of sample and reagents, and high throughput. We also cover the basics of biomarkers and their detection in biological fluid samples suitable for liquid biopsy on-chip. We focus on emerging technologies that process a small patient sample with high spatial-temporal resolution and derive clinically meaningful results through on-chip biomarker sensing and downstream molecular analysis in a simple workflow. This critical review is meant as a resource for those interested in developing technologies for capture, detection, and analysis platforms for liquid biopsy in a variety of settings.

Combined immunomagnetic capture coupled with ultrasensitive plasmonic detection of circulating tumor cells in blood.

We demonstrate enhanced on-chip circulating tumor cell (CTC) detection through the incorporation of plasmonic-enhanced near-infrared (NIR) fluorescence screening. Specifically, the performance of plasmonic gold coated chips was evaluated on our previously reported immunomagnetic CTC capture system and compared to the performance of a regular chip. Three main performance metrics were evaluated: capture efficiency, capture reproducibility, and clinical efficacy. Use of the plasmonic chip to capture SK-BR-3 cells in PBS, resulted in a capture efficiency of 82%, compared to 76% with a regular chip. Both chips showed excellent capture reproducibility for all three cells lines evaluated (MCF-7, SK-BR-3, Colo 205) in both PBS and peripheral blood, with R2 values ranging from 0.983 to 0.996. Finally, performance of the plasmonic chip was evaluated on thirteen peripheral blood samples in patients with both breast and prostate cancer. The regular chip detected 2-8 cells per 5 mL of blood, while the plasmonic chip detected 8-85 cells per 5 mL of blood in parallel samples. In summary, we successfully demonstrate improved CTC capture and detection capabilities through use of plasmonic-enhanced near-infrared (NIR) fluorescence screening in both in vitro and ex vivo experiments. This work not only has the potential to improve clinical outcomes though improved CTC analysis, but also demonstrates successful interface design between plasmonic materials and cell capture for bioanalytical applications.

Biomimetic hierarchical walnut kernel-like and erythrocyte-like mesoporous silica nanomaterials: controllable synthesis and versatile applications.

We developed a facile and controllable strategy to fabricate biomimic walnut kernel-like mesoporous silica nanomaterial (WMSN) and erythrocyte-like mesoporous silica nanomaterial (EMSN). The former possesses unique multi-shell hollow structure and surface wrinkles while the latter has special multi-stack structure and bowl-shaped depression. These hierarchical materials with distinct structures can be finely tuned by changing the molar ratios of two surfactants, cetyltrimethylammonium bromide and 11-mercaptoundecanoic acid. The mechanism of structural formation through intermolecular interactions was revealed and validated experimentally. The promising potential applications of WMSN and EMSN in adsorption, cellular imaging, drug delivery, and cancer theranostics were further identified.

Patterned Plasmonic Surfaces-Theory, Fabrication, and Applications in Biosensing.

Low-profile patterned plasmonic surfaces are synergized with a broad class of silicon microstructures to greatly enhance near-field nanoscale imaging, sensing, and energy harvesting coupled with far-field free-space detection. This concept has a clear impact on several key areas of interest for the MEMS community, including but not limited to ultra-compact microsystems for sensitive detection of small number of target molecules, and "surface" devices for optical data storage, micro-imaging and displaying. In this paper, we review the current state-of-the-art in plasmonic theory as well as derive design guidance for plasmonic integration with microsystems, fabrication techniques, and selected applications in biosensing, including refractive-index based label-free biosensing, plasmonic integrated lab-on-chip systems, plasmonic near-field scanning optical microscopy and plasmonics on-chip systems for cellular imaging. This paradigm enables low-profile conformal surfaces on microdevices, rather than bulk material or coatings, which provide clear advantages for physical, chemical and biological-related sensing, imaging, and light harvesting, in addition to easier realization, enhanced flexibility, and tunability.

Multifunctional Magnetic Particles for Combined Circulating Tumor Cells Isolation and Cellular Metabolism Detection.

We for the first time demonstrate multi-functional magnetic particles based rare cell isolation combined with the downstream laser desorption/ionization mass spectrometry (LDI-MS) to measure the metabolism of enriched circulating tumor cells (CTCs). The characterization of CTCs metabolism plays a significant role in understanding the tumor microenvironment, through exploring the diverse cellular process. However, characterizing cell metabolism is still challenging due to the low detection sensitivity, high sample complexity, and tedious preparation procedures, particularly for rare cells analysis in clinical study. Here we conjugate ferric oxide magnetic particles with anti-EpCAM on the surface for specific, efficient enrichment of CTCs from PBS and whole blood with cells concentration of 6-100 cells per mL. Moreover, these hydrophilic particles as matrix enable sensitive and selective LDI-MS detection of small metabolites (MW<500 Da) in complex bio-mixtures and can be further coupled with isotopic quantification to monitor selected molecules metabolism of ~50 CTCs. Our unique approach couples the immunomagnetic separation of CTCs and LDI-MS based metabolic analysis, which represents a key step forward for downstream metabolites analysis of rare cells to investigate the biological features of CTCs and their cellular responses in both pathological and physiological phenomena.

Plasmonic nanograting enhanced quantum dots excitation for cellular imaging on-chip.

We present the design and integration of a two-dimensional (2D) plasmonic nanogratings structure on the electrode of colloidal quantum dot-based light-emitting diodes (QDLEDs) as a compact light source towards arrayed on-chip imaging of tumor cells. Colloidal quantum dots (QDs) were used as the emission layer due to their unique capabilities, including multicolor emission, narrow bandwidth, tunable emission wavelengths, and compatibility with silicon fabrication. The nanograting, based on a metal-dielectric-metal plasmonic waveguide, aims to enhance the light intensity through the resonant reflection of surface plasmon (SP) waves. The key parameters of plasmonic nanogratings, including periodicity, slit width, and thicknesses of the metal and dielectric layers, were designed to tailor the frequency bandgap such that it matches the wavelength of operation. We fabricated QDLEDs with the integrated nanogratings and demonstrated an increase in electroluminescence intensity, measured along the direction perpendicular to the metal electrode. We found an increase of 34.72% in QDLED electroluminescence intensity from the area of the pattern and an increase of 32.63% from the photoluminescence of QDs deposited on a metal surface. We performed ex vivo transmission-mode microscopy to evaluate the nucleus-cytoplasm ratios of MDA-MB 231 cultured breast cancer cells using QDLEDs as the light source. We showed wavelength dependent imaging of different cell components and imaging of cells at higher magnification using enhanced emission from QDLEDs with integrated plasmonic nanogratings.

Laser-Patterning of Micromagnets for Immuno-Magnetophoretic Exosome Capture.

Efficient isolation and patterning of biomolecules is a vital step within sample preparation for biomolecular analysis, with numerous diagnostic and therapeutic applications. For exosomes, nanoscale lipid-bound biomolecules, efficient isolation is challenging due to their minute size and resultant behavior within biofluids. This study presents a method for the rapid isolation and patterning of magnetically tagged exosomes via rationally designed micromagnets. Micromagnet fabrication utilizes a novel, scalable, and high-throughput laser-based fabrication approach that enables patterning at microscale lateral resolution (<50 µm) without lithographic processing and is agnostic to micromagnet geometry. Laser-based processing allows for flexible and tunable device configurations, and herein magnetophoretic capture within both an open-air microwell and an enclosed microfluidic system is demonstrated. Patterned micromagnets enhance localized gradient fields throughout the fluid medium, resulting in rapid and high efficiency magnetophoretic separation, with capture efficiencies nearing 70% after just 1s within open-air microwells, and throughputs upward of 3 mL h-1 within enclosed microfluidic systems. Using this microchip architecture, immunomagnetic exosome isolation and patterning directly from undiluted plasma samples is further achieved. Lastly, a FEA-based modeling workflow is introduced to characterize and optimize micromagnet unit cells, simulating magnetophoretic capture zones for a given micromagnet geometry.

Generative Adversarial Network Model to Classify Human Induced Pluripotent Stem Cell-Cardiomyocytes based on Maturation Level.

Objective: Our study develops a generative adversarial network (GAN)-based method that generates faithful synthetic image data of human cardiomyocytes at varying stages in their maturation process, as a tool to significantly enhance the classification accuracy of cells and ultimately assist the throughput of computational analysis of cellular structure and functions. Methods: Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) were cultured on micropatterned collagen coated hydrogels of physiological stiffnesses to facilitate maturation and optical measurements were performed for their structural and functional analyses. Control groups were cultured on collagen coated glass well plates. These image recordings were used as the real data to train the GAN model. Results: The results show the GAN approach is able to replicate true features from the real data, and inclusion of such synthetic data significantly improves the classification accuracy compared to usage of only real experimental data that is often limited in scale and diversity. Conclusion: The proposed model outperformed four conventional machine learning algorithms with respect to improved data generalization ability and data classification accuracy by incorporating synthetic data. Significance: This work demonstrates the importance of integrating synthetic data in situations where there are limited sample sizes and thus, effectively addresses the challenges imposed by data availability.

Immunomagnetic nanoscreening of circulating tumor cells with a motion controlled microfluidic system.

Combining the power of immunomagnetic assay and microfluidic microchip operations, we successfully detected rare CTCs from clinical blood samples. The microfluidic system is operated in a flip-flop mode, where a computer-controlled rotational holder with an array of microfluidic chips inverts the microchannels. We have demonstrated both theoretically and experimentally that the direction of red blood cell (RBC) sedimentation with regards to the magnetic force required for cell separation is important for capture efficiency, throughput, and purity. The flip-flop operation reduces the stagnation of RBCs and non-specific binding on the capture surface by alternating the direction of the magnetic field with respect to gravity. The developed immunomagnetic microchip-based screening system exhibits high capture rates (more than 90%) for SkBr3, PC3, and Colo205 cell lines in spiked screening experiments and successfully isolates CTCs from patient blood samples. The proposed motion controlled microchip-based immunomagnetic system shows great promise as a clinical tool for cancer diagnosis and prognosis.

Dual fluorescent hollow silica nanofibers for in situ pH monitoring using an optical fiber.

This study reports a sensitive and robust pH sensor based on dual fluorescent doped hollow silica nanofibers (hSNFs) for in situ and real-time pH monitoring. Fluorescein isothiocyanate (FITC) and tris(2,2'-bipyridyl)dichlororuthenium(ii) hexahydrate (Ru(BPY)3) were chosen as a pH sensitive dye and reference dye, respectively. hSNFs were synthesized using a two-step method in a reverse micelle system and were shown to have an average length of 6.20 µm and average diameter of 410 nm. The peak intensity ratio of FITC/Ru(BPY)3 was used to calibrate to solution pH changes. An optical-fiber-based fluorescence detection system was developed that enabled feasible and highly efficient near-field fluorescence detection. The developed system enables fully automated fluorescence detection, where components including the light source, detector, and data acquisition unit are all controlled by a computer. The results show that the developed pH sensor works in a linear range of pH 4.0-9.0 with a fast response time of less than 10 s and minimal sample volume of 50 µL, and can be stored under dark conditions for one month without failure. In addition, the as-prepared hSNF-based pH sensors also have excellent long-term durability. Experimental results from ratiometric sensing confirm the high feasibility, accuracy, stability and simplicity of the dual fluorescent hSNF sensors for the detection of pH in real samples.

Engineering Biomimetic Extracellular Matrix with Silica Nanofibers: From 1D Material to 3D Network.

Biomaterials at nanoscale is a fast-expanding research field with which extensive studies have been conducted on understanding the interactions between cells and their surrounding microenvironments as well as intracellular communications. Among many kinds of nanoscale biomaterials, mesoporous fibrous structures are especially attractive as a promising approach to mimic the natural extracellular matrix (ECM) for cell and tissue research. Silica is a well-studied biocompatible, natural inorganic material that can be synthesized as morpho-genetically active scaffolds by various methods. This review compares silica nanofibers (SNFs) to other ECM materials such as hydrogel, polymers, and decellularized natural ECM, summarizes fabrication techniques for SNFs, and discusses different strategies of constructing ECM using SNFs. In addition, the latest progress on SNFs synthesis and biomimetic ECM substrates fabrication is summarized and highlighted. Lastly, we look at the wide use of SNF-based ECM scaffolds in biological applications, including stem cell regulation, tissue engineering, drug release, and environmental applications.

Heart-on-Chip for Combined Cellular Dynamics Measurements and Computational Modeling Towards Clinical Applications.

Organ-on-chip or micro-engineered three-dimensional cellular or tissue models are increasingly implemented in the study of cardiovascular pathophysiology as alternatives to traditional in vitro cell culture. Drug induced cardiotoxicity is a key issue in drug development pipelines, but the current in vitro and in vivo studies suffer from inter-species differences, high costs, and lack of reliability and accuracy in predicting cardiotoxicity. Microfluidic heart-on-chip devices can impose a paradigm shift to the current tools. They can not only recapitulate cardiac tissue level functionality and the communication between cells and extracellular matrices but also allow higher throughput studies conducive to drug screening especially with their added functionalities or sensors that extract disease-specific phenotypic, genotypic, and electrophysiological information in real-time. Such electrical and mechanical components can tailor the electrophysiology and mechanobiology of the experiment to better mimic the in vivo condition as well. Recent advancements and challenges are reviewed in the fabrication, functionalization and sensor assisted mechanical and electrophysiological measurements, numerical and computational modeling of cardiomyocytes' behavior, and the clinical applications in drug screening and disease modeling. This review concludes with the current challenges and perspectives on the future of such organ-on-chip platforms.

Plasmonic nanosensors for point-of-care biomarker detection.

Advancement of materials along with their fascinating properties play increasingly important role in facilitating the rapid progress in medicine. An excellent example is the recent development of biosensors based on nanomaterials that induce surface plasmon effect for screening biomarkers of various diseases ranging from cancer to Covid-19. The recent global pandemic re-confirmed the trend of real-time diagnosis in public health to be in point-of-care (POC) settings that can screen interested biomarkers at home, or literally anywhere else, at any time. Plasmonic biosensors, thanks to its versatile designs and extraordinary sensitivities, can be scaled into small and portable devices for POC diagnostic tools. In the meantime, efforts are being made to speed up, simplify and lower the cost of the signal readout process including converting the conventional heavy laboratory instruments into lightweight handheld devices. This article reviews the recent progress on the design of plasmonic nanomaterial-based biosensors for biomarker detection with a perspective of POC applications. After briefly introducing the plasmonic detection working mechanisms and devices, the selected highlights in the field focusing on the technology's design including nanomaterials development, structure assembly, and target applications are presented and analyzed. In parallel, discussions on the sensor's current or potential applicability in POC diagnosis are provided. Finally, challenges and opportunities in plasmonic biosensor for biomarker detection, such as the current Covid-19 pandemic and its testing using plasmonic biosensor and incorporation of machine learning algorithms are discussed.