For intervention of cardiovascular diseases, biodegradable and biocompatible, poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP) are emerging as agents of choice for controlled and targeted drug delivery. Therefore development of PLGA-NP with optimal physico-chemical properties will allow efficient binding and thus delivery of drug to targeted cells under various patho-physiological conditions. The force kinetics and its dependence on size of the NPs will be crucial for designing the NPs. Since optical tweezers allow non-contact, highly sensitive force measurement with high spatial and temporal resolution, we utilized it for studying interaction forces between magnetic PLGA nanoparticles with smooth muscle cells (SMC). In order to investigate effect of size, interaction force for 200 to 1100nm PLGA NP was measured. For similar interaction duration, the force was found to be higher with increase in size. The rupture force was found to depend on time of interaction of SMC with NPs.

Wearable monitoring systems have caught considerable attention recently due to their potential in many domains including smart health and well-being. These new biomedical monitoring systems aim to provide continuous patient monitoring and proactive care options. Realization of this vision requires research that addresses a number of challenges, in particular, regarding limited resources that the wearable sensor networks offer. This paper presents an overview of different strategies for prolonging system lifetimes through power optimization in such systems. Particular emphasis is given to enhancing processing and communication architectures with respect to the signal processing requirements of the system.

It represents a viable solution for the realization of a portable biosensor platform that could screen/diagnose acute myocardial infarction by measuring cardiac marker concentrations such as cardiac troponin I (cTnI), creatine kinase MB (CK-MB), and myoglobin (MYO) for application to u-health monitoring system. The portable biosensor platform introduced in this presentation has a more compact structure and a much higher measuring resolution than a conventional spectrometer system. Portable guided-mode resonance (GMR) biosensor platform was composed of a biosensor chip stage, an optical pick-up module, and a data display panel. Disposable plastic GMR biosensor chips with nano-grating patterns were fabricated by injection–molding. Whole blood filtration and label-free immunoassay were performed on these single chips, automatically. Optical pick-up module was fabricated by using the miniaturized bulk optics and the interconnecting optical fibers and a tunable VCSEL (vertical cavity surface emitting laser). The reflectance spectrum from the GMR biosensor was measured by the optical pick-up module. Cardiac markers in human serum with concentrations less than 0.1ng/mL were analyzed using a GMR biosensor. Analysis time was 30min, which is short enough to meet clinical requirements. Our results show that the GMR biosensor will be very useful in developing lowcost portable biosensors that can screen for cardiac diseases.

There is an increasing need and challenge for early rapid and accurate detection, identification, and quantification of chemical, biological, and energetic hazards in many fields of interest (e.g., medical, environmental, industrial, and defense applications). Increasingly to meet these challenges, researchers are turning to interdisciplinary approaches combining spectroscopy with nanoscale platforms to create technologies that offer viable and novel solutions for today’s sensing needs. One technology that has gained increasing popularity to meet these needs is surface enhanced Raman scattering (SERS). SERS is particularly advantageous as it does not suffer from interferences from water, requires little to no sample preparation, is robust and can be used in numerous environments, is relatively insensitive to the wavelength of excitation employed and produces a narrow-band spectral signature unique to the molecular vibrations of the analyte. SERS enhancements (chemical and electromagnetic) are typically observed on metalized nanoscale roughened surfaces. For ideal SERS sensing, a commercially available uniform and reproducible nanoscale surface demonstrating high sensitivity are desirable. Additionally, if these surfaces can be modified for the selective sensing of hazard materials, an ideal sensor platform for dynamic in field measurements can be imagined. In this proceedings paper, preliminary efforts towards the characterization and application of commercially available next generation Klarite substrates will be demonstrated. Additionally, efforts toward chemical modification of these substrates, through peptide recognition elements, can be used for the targeted sensing of hazardous materials.

Biological membranes represent a critical hindrance for administering active molecules which are often unable to reach their designated intracellular target sites. In order to overcome this barrier-like behavior not easily circumvented by many pharmacologically-active molecules, synthetic transporters have been exploited to promote cellular uptake. Linking or complexing therapeutic molecules to peptides that can translocate through the cellular membranes could enhance their internal delivery, and consequently, a higher amount of active compound would reach the site of action. Use of cell penetrating peptides (CPPs) is one of the most promising strategy to efficiently translocate macromolecules through the plasma membrane, and have attracted a lot of attention. New translocating peptides are continuously described and in the present review, we will focus on viral derived peptides, and in particular a peptide (gH625) derived from the herpes simplex virus type 1 (HSV-1) glycoprotein H (gH) that has proved to be a useful delivery vehicle due to its intrinsic properties of inducing membrane perturbation.

The reduction of electrode size down to nanometers could dramatically enhance detection sensitivity and temporal resolution. Nanoelectrode arrays (NEAs) are of particular interest for ultrasensitive biosensors. Here we report the study of two types of biosensors for measuring enzyme activities using NEAs fabricated with vertically aligned carbon nanofibers (VACNFs). VACNFs of ~100 nm in average diameter and 3-5 μm in length were grown on conductive substrates as uniform vertical arrays which were then encapsulated in SiO2 matrix leaving only the tips exposed. We demonstrate that such VACNF NEAs can be used in profiling enzyme activities through monitoring the change in electrochemical signals induced by enzymatic reactions to the peptides attached to the VACNF tip. The cleavage of the tetrapeptide with a ferrocene tag by a cancerrelated protease (legumain) was monitored with AC voltammetry. Real-time electrochemical impedance spectroscopy (REIS) was used for fast label-free detection of two reversible processes, i.e. phosphorylation by c-Src tyrosine kinase and dephosphorylation by protein tyrosine phosphatase 1B (PTP1B). The REIS data of phosphorylation were slow and unreliable, but those of dephosphorylation showed large and fast exponential decay due to much higher activity of phosphatase PTP1B. The kinetic data were analyzed with a heterogeneous Michaelis-Menten model to derive the “specificity constant” k_cat/K_m, which is 8.2x10³ M^-1s^-1 for legumain and (2.1 ± 0.1) x 10⁷ M^-1s^-1 for phosphatase (PTP1B), well consistent with literature. It is promising to develop VACNF NEA based electrochemical enzymatic biosensors as portable multiplex electronic techniques for rapid cancer diagnosis and treatment monitoring.

In this paper, we fabricated gold particle array substrate by thermal dewetting technique. The fabrication process is simple, reliable, cost efficient with comparing to other techniques. From optical characteristic it shows light trapping ability to reduce reflectance around 75%. Combining light trapping and its localized plasmonic properties, this substrate has significant advantages on plasmonic based sensing methods such as surface enhanced Raman scattering (SERS). SERS measurement has been performed and the enhancement factor is 2.58×10⁵. Further more, after silver thin film deposition the enhancement can be increased up to 2 orders and the enhancement factor is 3.66×10⁷.

This work presents a novel photothermal nanoblade that utilizes metallic nanostructures to light energy from short laser pulses to generate highly localized and shaped explosive cavitation bubbles which enables rapid cut of a lightly contacting cell membrane of a mammalian cell. Photothermal nanoblade can generate micrometer-sized membrane access ports for delivering large size cargo with high efficiency and high cell viability. Biologic and inanimate cargo over 3-orders of magnitude in size including DNA, RNA, 200 nm polystyrene beads, to 2 μm bacteria have also been successfully delivered into multiple mammalian cell types.

Detection of circulating tumor cells (CTCs) from patient blood samples offers a desirable alternative to invasive tissue biopsies for screening of malignant carcinomas. A rigorous CTC detection method must identify CTCs from millions of other formed elements in blood and distinguish them from healthy tissue cells also present in the blood. CTCs are known to overexpress surface receptors, many of which aid them in invading other tissue, and these provide an avenue for their detection. We have developed carbon nanotube (CNT) thin film devices to specifically detect these receptors in intact cells. The CNT sidewalls are functionalized with antibodies specific to Epithelial Cell Adhesion Molecule (EpCAM), a marker overexpressed by breast and other carcinomas. Specific binding of EpCAM to anti-EpCAM antibodies causes a change in the local charge environment of the CNT surface which produces a characteristic electrical signal. Two cell lines were tested in the device: MCF7, a mammary adenocarcinoma line which overexpresses EpCAM, and MCF10A, a non-tumorigenic mammary epithelial line which does not. Introduction of MCF7s caused significant changes in the electrical conductance of the devices due to specific binding and associated charge environment change near the CNT sidewalls. Introduction of MCF10A displays a different profile due to purely nonspecific interactions. The profile of specific vs. nonspecific interaction signatures using carbon based devices will guide development of this diagnostic tool towards clinical sample volumes with wide variety of markers.

SERS biotags are made from polymer-encapsulated silver nanoparticle dimers infused with unique Raman reporter molecules, and carry peptides as cell recognition moieties. We demonstrate their potential use for early and rapid identification of malignant cells, a central goal in cancer research. SERS biotags (SBTs) can be routinely synthesized and simultaneously excited with a single, low intensity laser source, making the determination of the relative contribution of the individual SBTs to the overall spectrum tractable. Importantly for biomedical applications, SERS employs tissuepenetrating lasers in the red to near-infrared range resulting in low autofluorescence. We have previously described a multiplexed, ratiometric method that can confidently distinguish between cancerous and noncancerous epithelial prostate cells in vitro based on receptor overexpression. Here we present the progress towards the application of this quantitative methodology for the identification of cancer cells in a microfluidic flow-focusing device. Beads are used as cell mimics to characterize the devices. Cells (and beads) are simultaneously incubated with two sets of SBTs while in suspension (simulating cells’ capture from blood), then injected into the device for laser interrogation under flow. Each cell event is characterized by a composite Raman spectrum, deconvoluted into its single components to ultimately determine their relative contribution. We show that using SBTs ratiometrically can provide cell identification insensitive to normal causes of uncertainty in optical measurements such as variations in focal plane, cell concentration, autofluorescence, and turbidity.

Low-density lipoproteins (LDL), a natural in vivo carrier of cholesterol in the vascular system, play a key role in the delivery of hydrophobic photosensitizers (pts) to tumor cells in photodynamic therapy (PDT) of cancer. To make this delivery system even more efficient, we have constructed a nano-delivery system by coating of LDL surface by polyethylene glycol (PEG) and dextran. Fluorescence spectroscopy and confocal fluorescence imaging were used to characterize redistribution of hypericin (Hyp), a natural potent pts, loaded in LDL/PEG and LDL/dextran complexes to free LDL molecules as well as to monitor cellular uptake of Hyp by U87-MG cells. It was shown than the redistribution process of Hyp between LDL molecules is significantly suppressed by dextran coating of LDL surface. On the other hand, PEG does not significantly influence this process. The modification of LDL molecules by the polymers does not inhibit their recognition by cellular LDL receptors. U-87 MG cellular uptake of Hyp loaded in LDL/PEG and LDL/dextran complexes appears to be similar to that one observed for Hyp transported by unmodified LDL particles. It is proposed that by polymers modified LDL molecules could be used as a basis for construction of a drug transport system for targeted delivery of hydrophobic drugs to cancer cells expressing high level of LDL receptors.

Here we report work done toward detection and characterization of micro-and nano-structures in bitumen, including mineral particles-clay and sand as well as metal-organic micro-and nano-structures containing porphyrines. X-ray micro-tomograph with monochromatic radiation has been used for detection of the structures. In order to detect and characterize nano-and micro-structures tomograph’s operational wavelength has been tuned to absorption wavelength of “chemical element of interest” X-ray spectrum: whatever it is Si or porphyrine-forming metals like V, Ni, Co. Contrast between X-ray absorption of micro-structures containing specific element and average bitumen’s environment absorption provides a tool for measurement of element mass concentration as well as size and mass density distributions of micro-and nano structures not only on surface but in bitumen volume. Specifically the most interest is in measurement of vanadyl porphyrines and other metal containing chemicals in asphaltene micro-structures changing per asphalten concentration due to bitumen processing.

Förster resonance energy transfer (FRET) between CdSe/ZnS core/shell quantum dots (QDs) and the photochromic protein bacteriorhodopsin (bR) in its natural purple membrane (PM) has been modulated by independent tuning of the Förster radius, overlap integral of the donor emission spectrum and acceptor absorption spectrum, and the distance between the donor (QD) and acceptor (bR retinal). The results have shown that the observed energy transfer from QDs to bR corresponds to that predicted by a multiple-acceptors geometric model describing the FRET phenomenon for QDs quasi-epitaxied on a crystalline lattice of bR trimers. Linking of QDs and bR via streptavidin–biotin linkers of different lengths caused FRET with an efficiency reaching 82%, strongly exceeding the values predicted by the classical FRET theory. The data not only demonstrate the possibility of nano-bioengineering of efficient hybrid materials with controlled energy-transfer properties, but also emphasize the necessity to develop an advanced theory of nano–bio energy transfer that would explain experimental effects contradicting the existing theoretical models.

In the past decades, increasing attention has been paid to the preparation of “smart” functionalized polymer particles reversibly responding to slight environmental changes, such as variations in temperature, pH, and ionic strength. The composite polymer particles consisting of a solid poly(acrolein-co-styrene) core and a poly(N-vinylcaprolactam) (PVCL) polymer shell doped with CdSe/ZnS semiconductor quantum dots (QDs) were prepared. The thermosensitive response of the composite particles was observed as a decrease in their hydrodynamic diameter upon heating above the lower critical solution temperature of the thermosensitive PVCL polymer used as a shell. Embedding QDs in the PVCL shell makes it possible to obtain particles whose fluorescence is sensitive to temperature changes. The temperature-dependent fluorescence of particles was determined by reversible variation of the distances between QDs in the PVCL shell as a result of temperature-driven conformational changes in this polymer. In addition, these particles can be used as carriers of biomolecule (e.g., bovine serum albumin, BSA) characterized by reversibly temperature-dependent fluorescence, which can serve as the basis for optical detection methods in bioassays, such as the measurement of local temperature in nanovolumes, biosensing, etc.

In this paper we demonstrate the possibility of modifying porous silicon (PSi) particles with surface chemistry and immobilizing a biopolymer, gelatin for the detection of protease enzymes in solution. A rugate filter, a one-dimensional photonic crystal, is fabricated that exhibits a high-reflectivity optical resonance that is sensitive to small changes in the refractive index. To immobilize gelatin in the pores of the particles, the hydrogen-terminated silicon surface was first modified with an alkyne, 1,8-nonadiyne via hydrosilylation to protect the silicon surfaces from oxidation. This modification allows for further functionality to be added such as the coupling of gelatin. Exposure of the gelatin modified particles to the protease subtilisin in solution causes a change in the refractive index, resulting in a shift of the resonance to shorter wavelengths, indicating cleavage of organic material within the pores. The ability to monitor the spectroscopic properties of microparticles, and shifts in the optical signature due to changes in the refractive index of the material within the pore space, is demonstrated.

This paper outlines our recent efforts in using solid-state nanopores as a biosensing platform. Traditionally biosensors concentrate mainly on the detection platform and not on signal processing. This decoupling can lead to inferior sensors and is exacerbated in nanoscale devices, where device noise is large and large dynamic range is required. This paper outlines a novel platform that integrates the nano, micro and macroscales in a closely coupled manner that mitigates many of these problems. We discuss our initial results of DNA translocation through the nanopore. We also briefly discuss the use of molecular recognition properties of aptamers with the versatility of the nanopore detector to design a new class of biosensors in a CMOS compatible platform.

The high performance GaN light emitting diode (LED) from sapphire wafer has been transferred on a plastic substrate with 308nm XeCl laser lift-off (LLO) for next generation flexible lighting applications. SU-8 passivation with thermal release tape (TRT) adhesive enables structure coverage and adhesion so that it can be an excellent candidate for a carrier substrate for non-wetting transfer process using laser liftoff technology. The dimensions of the laser beam are also investigated in two types (3μm x 5cm and 1.2mm x 1.2mm) to reduce stress when decomposition of GaN occurs. With careful optimization of carrier substrate and laser beam conditions, we can fabricate flexible GaN LED on polyimide substrates which shows similar electrical properties to the GaN LED on bulk sapphire substrate.

Three-dimensional (3D) imaging with Short wavelength infrared (SWIR) Laser Detection and Range (LADAR) systems have been successfully demonstrated on various platforms. It has been quickly adopted in many military and civilian applications. In order to minimize the LADAR system size, weight, and power (SWAP), it is highly desirable to maximize the camera sensitivity. Recently Spectrolab has demonstrated a compact 32x32 LADAR camera with single photo-level sensitivity at 1064. This camera has many special features such as non-uniform bias correction, variable range gate width from 2 microseconds to 6 microseconds, windowing for smaller arrays, and short pixel protection. Boeing integrated this camera with a 1.06 μm pulse laser on various platforms and demonstrated 3D imaging. The features and recent test results of the 32x128 camera under development will be introduced.

A crossed-strip detector initially developed at UC Berkeley’s Space Sciences Laboratory has been demonstrated as a laboratory benchtop instrument and is now in the process of being integrated by Los Alamos National Laboratory into a portable, real-time, single-photon-counting camera system. The crossed-strip detector consists of 32 anode strips along each of two axes sealed inside a vacuum tube behind a photocathode and a microchannelplate stack. A photon incident on the photocathode produces a cloud of charge from the microchannel plates that falls onto a portion of the 64 anode strips, producing a signal on a subset of channels along each axis and requiring that all anode channels continually be analyzed simultaneously. To maximize the photon flux that can be accepted by the sensor with minimal deadtime, the crossed-strip sensor has been combined with shortershaping- time amplifiers and higher-rate digitizers than previously used. With the ultimate goal of reaching 100 million events per second, FPGA-implementable algorithms have been developed for the identification of pulses on each anode channel and the determination of the pulses’ time and amplitude. From the pulse times and amplitudes, a charge cloud can be reconstructed and the centroid determined to produce the time and position of each incident photon. The data-analysis procedure will be discussed, measurements detailing the performance of the camera system as it exists at this point will be presented, and the planned layout of the embedded camera system hardware will be detailed.

We report a study of the performance of an avalanche photodiode (APD) as a function of temperature from 564 K to 74 K. The dark current at avalanche onset decreases from 564 K to 74 K by approximately a factor of 125 and from 300 K to 74K the dark current at avalanche offset is reduced by a factor of about 10. The drop would have been considerably larger if the activation energy at avalanche onset (Ea) did not also decrease with decreasing temperature. These data give us insights into how to improve the single-photon counting performance of a GaN based ADP.

Abstract—We demonstrate a sinusoidally-gated InGaAs/InP photodiode pair operated at wavelength of 1310 nm with high photon detection efficiency (PDE) and low dark count rate (DCR). The photodiode pair is biased in a balanced scenario so that the common component of the output signal is cancelled. The concept of balanced photodiodes helps improve detection efficiency while canceling the common mode signal, which, in this case, is the capacitive response of the photodiodes. In conventional sinusoidal gating, an extra component, – an RF filter (or several) at the gating frequency, is utilized to filter out the gating signal and leave the avalanche signal for detection. For this configuration, sinusoidally-gated counting systems are restricted to a single frequency. With the balanced single photon diodes (SPAD), sinusoidal gating within a continuous frequency range is feasible. A printed circuit with symmetric layout of two bias tees was fabricated on a duroid board to enable the application of AC and DC signals for the dual SPADs. At a laser repletion rate of 1 MHz and temperature of 240 K the DCR and PDE were 58 kHz and 43%, respectively. Afterpulsing probability was lower compared with a sinusoidually-gated single SPAD. Jitter of 240 ps was achieved with 1 photon per pulse for an excess bias of 1.6%.

Active depth imaging approaches are being used in a number of emerging applications, for example in environmental sensing, manufacturing and defense. The high sensitivity and picosecond timing resolution of the time-correlated single-photon counting technique can provide distinct advantages in the trade-offs between required illumination power, range, depth resolution and data acquisition durations. These considerations must also address requirements for eye-safety, especially in applications requiring outdoor, kilometer range sensing. We present a scanning time-of-flight imager based on MHz repetition-rate pulsed illumination operating with sub-milliwatt average power. The use of a scanning mechanism permits operation with an individual, high-performance single-photon detector. The system has been used with a number of non-cooperative targets, in different weather conditions and various ambient light conditions. We consider a number of system issues, including the range ambiguity issue and scattering from multiple surfaces. The initial work was performed at wavelengths around 850 nm for convenient use with Si-based single photon avalanche diode detectors, however we will also discuss the performance at a wavelength of 1560 nm, made using superconducting nanowire single photon detectors. The use of the latter wavelength band allows access to a low-loss atmospheric window, as well as greatly reduced solar background contribution and less stringent eye safety considerations. We consider a range of optical design configurations and discuss the performance trade-offs and future directions in more detail.

Near-infrared light can be used to determine the optical properties (absorption and scattering) of human tissue. Optical tomography uses this principle to image the internal structure of parts of the body by measuring the light that is scattered in the tissue. An imager for optical tomography was designed based on a detector with 128x128 single photon pixels that included a bank of 32 time-to-digital converters. Due to the high spatial resolution and the possibility of performing time resolved measurements, a new contactless setup has been conceived. The setup has a resolution of 97ps and operates with a laser source with an average power of 3mW. This new setup generated an high amount of data that could not be processed by established methods, therefore new concepts and algorithms were developed to take advantage of it. Simulations show that the potential resolution of the new setup would be much higher than previous designs. Measurements have been performed showing its potential. Images derived from the measurements showed that it is possible to reach a resolution of at least 5mm.

Requirements like device miniaturization, insensitivity to magnetic field and cost aspects in the field of low level light detection will lead to a replacement of the conventional photomultiplier tube by Silicon Photomultiplier (SiPM) for several applications in case the photon detection efficiency will be comparably higher at the same price level. This novel solid-state sensor consists of an array of parallel connected avalanche photodiodes operated in limited Geiger-mode. The triggered cells are recovered by an upstream connected quenching resistor. The main characteristics are gain, noise, photon detection efficiency (PDE), dynamic range and time resolution. To meet the requirements of various potential applications, SiPMs need to be available with several micro pixel sizes and total active areas. For this reason KETEK produces devices with microcell pitches from 15μm up to 100μm and total active sensor areas from 1.0 x 1.0 mm² up to 6.0 mm x 6.0 mm². The effects of this scaling on the SiPM device parameters are discussed.

The Silicon Photomultiplier (SiPM) is a novel device for low level light detection in various applications, for example scintillator- and fiber readout.^1;2 The SiPM is insensitive to magnetic fields and has a high photon detection effciency. Current devices have a high optical crosstalk probability, which causes a significant increase of the excess noise factor.³ It may replace traditional Photo Multiplier Tubes (PMT) when the optical crosstalk is reduced to a lower level of below 10%. Depending on the quantity of hot electrons in the Geiger discharge approximately three to fifty secondary photons (in average three photons per 10⁵ avalanche electrons⁴) with a wavelength range from 450nm to 1600nm are emitted from the excited cell in all directions.⁵ Some of those secondary photons cause the discharge of the neighboring cell.^6;7 The different mechanism of optical crosstalk are categorized as direct and indirect crosstalk. To reduce direct crosstalk an optical barrier has to be implemented between the single micro cells.⁸ Thus, we have investigated different technological concepts with regard to the trench shape, the trench etching process as well as the trench fill material.

A sophisticated technique to study ultra-high-energy cosmic rays is to measure the extensive air showers they cause in the atmosphere. Upon impact on the atmosphere, the cosmic rays generate a cascade of secondary particles, forming the air shower. The shower particles excite the atmospheric nitrogen molecules, which emit fluorescence light in the near ultraviolet regime when de-exciting. Observation of the fluorescence light with suitable optical telescopes allows a reconstruction of the energy and arrival direction of the initial particle. Due to their high photon detection efficiency, silicon photomultipliers (SiPMs) promise to improve current photomultipliertube- based fluorescence telescopes. We present the design and a full detector simulation of an SiPM-based fluorescence telescope prototype, together with the expected telescope performance, and our first construction steps. The simulation includes the air showers, the propagation of the fluorescence light through the atmosphere and its detection by our refracting telescope. We have also developed a phenomenological SiPM model based on measurements in our laboratories, simulating the electrical response. This model contains the photon detection efficiency, its dependence on the incidence angle of light and the effects of thermal and correlated noise. We have made a full performance analysis for the detection of air showers including the environmental background light. Moreover, we will present the RandD in compact modular electronics using photon counting techniques for the telescope readout.