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Activation of tyrosine kinase receptor B (TrkB), a neurotrophin receptor, has been shown to increase neuronal cell survival and promote regeneration. Stimulation of the TrkB receptor by neurotrophic growth factors has been identified as a possible therapeutic target for the treatment of neurodegenerative disorders. However, growth factor delivery is problematic because of a short half-life in vivo. We have conjugated hNgf-EE, a short peptide mimetic of NGFβ to the surface of polymersome nanoparticles and shown that they are capable of activating the TrkB receptor in vitro in the SHSY-G7 cell line. We propose that polymersomes could act as a scaffold for the delivery of TrkB activating moieties and that the polymersome size and polyethylene glycol surface have been shown to increase in vivo retention time. These multifunctional nanoparticles have potential for the treatment of neurodegenerative disorders by TrkB activation. From the Clinical Editor Tyrosine kinase receptor B activation has been shown to promote regeneration and survival of neurons. However, growth factor delivery to stimulate these receptors remains problematic. The authors demonstrate that a peptide mimetic of NGFβ conjugated to the surface of polymersome nanoparticles is capable of activating the TrkB receptors. These nanoparticles may offer a novel treatment strategy for a variety of neurodegenerative disorders.

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease are increasing in prevalence as our aging population increases in size. Despite this, currently there are no disease-modifying drugs available for the treatment of these conditions. Drosophila melanogaster is a highly tractable model organism that has been successfully used to emulate various aspects of these diseases in vivo. These Drosophila models have not been fully exploited in drug discovery and design strategies.This review explores how Drosophila models can be used to facilitate drug discovery. Specifically, we review their uses as a physiologically-relevant medium to high-throughput screening tool for the identification of therapeutic compounds and discuss how they can aid drug discovery by highlighting disease mechanisms that may serve as druggable targets in the future. The reader will appreciate how the various attributes of Drosophila make it an unsurpassed model organism and how Drosophila models of neurodegeneration can contribute to drug discovery in a variety of ways.Drosophila models of human neurodegenerative diseases can make a significant contribution to the unmet need of disease-modifying therapeutic intervention for the treatment of these increasingly common neurodegenerative conditions.

Cell specific targeting is an emerging field in nanomedicine. Homing of the multifunctional nanoparticles (MFNPs) is achieved by the conjugation of targeting moieties on the nanoparticle surface. The inner ear is an attractive target for new drug delivery strategies as it is hard to access and hearing loss is a significant worldwide problem. In this work we investigated the utility of a Nerve Growth Factor-derived peptide (hNgf_EE) functionalized nanoparticles (NPs) to target cells of the inner ear. These functionalized NPs were introduced to organotypic explant cultures of the mouse inner ear and to PC-12 rat pheochromocytoma cells. The NPs did not show any signs of toxicity. Specific targeting and higher binding affinity to spiral ganglion neurons, Schwann cells and nerve fibers of the explant cultures were achieved through ligand mediated multivalent binding to tyrosine kinase receptors and to p75 neurotrophin receptors. Unspecific uptake of NPs was investigated using NPs conjugated with scrambled hNgf_EE peptide. Our results indicate a selective cochlear cell targeting by MFNPs, which may be a potential tool for cell specific drug and gene delivery to the inner ear.

The delivery of drugs or genes to the inner ear in a controlled and biocompatible manner could lead to new treatments for conditions such as Meniere’s disease, tinnitus, schwannomas of the ear, and for improving hearing. The concept of multifunctional nanoparticles, which are targetable, biodegradable, and traceable, has led to new approaches to controlled drug release and localized delivery to specific cell populations. Tissue-specific delivery can be achieved by functionally “addressed” nanostructures loaded with a therapeutic molecule. In the present study, we investigated the incorporation, distribution, and toxicology of amphiphilic block copolymer nanoparticles (NPs) in spiral ganglion (SG) cell cultures. Adult human and guinea pig SG neurons and glia/Schwann dissociated cell cultures were expanded, grown for several weeks, and then studied live using time-lapse video microscopy and high-resolution light microscopy. The cells were further characterized using immunocytochemistry for the neural marker TuJ1 and the glia cell markers S-100 and GFAP, and their morphology was studied in more detail using scanning electron microscopy (SEM). These cell cultures were exposed to fluorescently (Dil)-loaded NPs for different time periods and at different concentrations, and the uptake was studied using fluorescence microscopy. The study demonstrates that DiI-loaded NPs can be internalized into guinea pig SG neurons as well as into human and guinea pig SG glia/Schwann cells without indication of toxicity or reduced viability. After 4 hours, almost 100% of both the neurons and the glia cells had incorporated the NPs into the cytoplasm. No uptake could be detected in the nucleus and no evidence of internalization could be seen in axons or in the growth cone area of the neuron. Especially in the glia cells, the NPs were detected in small vesicles surrounding the nucleus and occasionally in the periphery of the cytoplasm. This information could lead to the development of more specialized NPs, targeting only SG neurons or Schwann cells.

Heavy-ion-induced soft and hard breakdown are investigated in thin gate oxides as a function of linear energy transfer, fluence, and voltage applied during irradiation. It is found that postirradiation oxide conduction is well described by the Sune quantum point contact model.

Proton damage is investigated for several types of modern light-emitting diodes (LEDs), examining the damage from the standpoint of older models based on lifetime degradation as well as the simpler method of normalized degradation. An empirical model is developed to describe injection-enhanced annealing in amphoterically doped LEDs. Experimental results on "aged" devices show that wearout degradation does not decrease the sensitivity of devices to radiation damage.

Fundamental differences in design influence the way that linear and digital optocouplers are degraded by radiation. Linear optocouplers are more affected by current drive conditions because the detector operates in a high-injection region when the LED produces normal light output, and do not have the extra operating margin that is inherent in digital optocouplers. Although LED degradation is often the dominant degradation mechanism in space environments, degradation of optocouplers with improved LEDs is limited by photoresponse degradation. Phototransistor gain has a relatively minor effect except at very high radiation levels.

Proton tests of linear integrated circuits have identified devices where significantly more damage occurs at equivalent total dose levels with protons than with gamma rays. The difference is attributed to displacement damage, and it can be important for hardened devices as well as for unhardened technologies. Proton testing may be required for applications of circuits that use substrate and lateral pnp transistors in critical circuit functions where protons comprise a significant fraction of the space environment.

Single-event upset is investigated for optocouplers using heavy ions. The threshold LET for optocouplers with internal high-gain amplifiers is very low, causing output transients to occur even when the optocouplers are irradiated with short-range alpha particles. Although previous work with high-energy protons showed that transients were caused by charge collected in the large-area photodetector, transients generated in the high-gain amplifier make a significant contribution to the total cross section when optocouplers are irradiated with heavy ions. The transient pulse width increases with LET, exceeding 400 ns for long-range particles above 7 MeV-cm/sup 2//mg. This is about an order of magnitude greater than the pulse width that occurs when they are irradiated with protons. The ion range must exceed 50 /spl mu/m to characterize the cross section and pulse width in these devices.

Spacecraft performance requirements drive the utilization of commercial-off-the-shelf (COTS) components and emerging technologies in systems. The response of these technologies to radiation is often complex. This engenders a set of emerging radiation hardness assurance (RHA) issues which include displacement damage in optocouplers, high-precision and hybrid devices, enhanced low dose rate (ELDR) and proton damage enhancement (PDE) in linear circuits, linear transients, and catastrophic single event effects (SEEs) phenomena. NASA has developed an approach to designing reliable space systems which address these emerging RHA issues. This programmatic methodology includes hazard definition, hazard evaluation, requirements definition, evaluation of device usage, and application of radiation engineering techniques with the active involvement of designers. Risk assessment is an integral constituent in the approach as is an established program to assess future technology needs for programs.

A hardness assurance test approach has been developed for bipolar linear circuits and devices in space. It consists of an initial test for dose rate sensitivity and a characterization test method to develop the conditions for a lot acceptance test at high dose rate. For parts with adequate design margin and/or well behaved parts a generic elevated temperature irradiation test is proposed.

Hearing loss is a very significant health problem. The methods currently available for inner ear drug delivery are limited and a noninvasive cell-specific drug delivery strategy needs to be found. Aim: In this study we investigated the ability of polymersomes, lipid core nanocapsules and hyperbranched poly-L-lysine to cross the round window membrane. Materials & Methods: Nanoparticles (NPs) used in this study have different size and chemical compositions. Freshly frozen human temporal bones were used for this investigation. Intact human round window membrane within the freshly frozen human temporal bone served as an excellent model to test the membrane permeation and distribution within the tissues. Results: In this investigation we were able to visualize the NPs across the round window membrane. The NPs were subsequently found to be distributed in the sensory hair cells, nerve fibers and to other cells of the cochlea. Conclusion: This finding raises hope in terms of future multifunctional NP-based drug delivery strategy to the human inner ear.

Dose-rate effects are studied in shallow trench isolation regions. Increased damage is observed at low dose rate, with a different dose dependence compared to tests done at high dose rate. A three-dimensional modeling program was used to show that charge trapping occurs much deeper in the trench region when sufficient charge is present to reduce the field in the trench.

The authors examine laser simulation of single-particle effects in some detail, investigating the effects of doping density and charge collection depth on funneling and charge collection, and accounting for the spreading of the focused laser beam within the silicon material. Calculations using the device simulation code PISCES are compared for heavy ions and lasers to investigate the accuracy of laser simulation of single-particle effects. Experimental charge collection measurements with heavy ions are used to establish the accuracy of the PISCES simulations. >

The ion-induced gate edge effect and excess charge collection effect present in GaAs MESFETs are not present in InP and GaAs HFETs. An SEU (single event upset) characterization study shows that these devices can provide an SEU rate which is lower than that of unhardened CMOS. >

There are numerous concepts of nanoparticle mediated drug delivery. The major advantage will be the option of targeted drug delivery to specific target cells thus avoiding high systemic loads of potentially toxic chemicals. Any kind of drug delivery by nanoparticles relies on delivery of the drug into the cell. In most cases that means drug delivery into the cytoplasm, and in some instances delivery of the drug to extracellular domains of transmembrane signalling molecules. Whenever viable cells are confronted with nanoparticles these are ingested by endocytosis rather then passage through the cell plasma membrane. Once inside endosomal vesicles the nanoparticles or at least their drug payload requires release into the cytoplasm in order to exert it’s biological effect. In order to monitor whether a drug delivered by nanoparticles is biologically active a toxic model drug, disulfiram, was chosen as a payload with micelle and liposome nanoparticles. L929 mouse fibroblasts were incubated with these disulfiram loaded naoparticles and cell viability was determined by quantification of celluar reductase activity. Applied nanoparticles are toxic to the cells. However, with respect to the disulfiram payload a 100-fold higher disulfiram concentration is required in comparison to free disulfiram for a biological effect. Hence, the toxic effect is most likely not due to the disulfiram delivered by the nanoparticles but rather to the amount of free disulfiram that is present in the nanoparticle preparation. Therefore it is advised to carefully characterize the nanoparticle suspension for the amount of free payload molecules.

An ion induced charge collection study, using an array of GaAs enhancement-mode MESFET geometries, has identified two primary excess charge collection effects, a fringe field effect and a gated channel effect. The introduction of a buried p-layer was found to suppress the fringe field effect, which resulted in a reduction in the maximum excess charge collected. The LET threshold for SEU was similar for both processes. For the devices used in this study, the results suggest that the gated channel effect is primarily responsible for the low SEU LET threshold. >

Special test structures fabricated with three different CMOS processes were used to investigate the effect of elevated temperature on single-particle latchup. The latchup threshold was strongly affected by contact geometry, and its temperature dependence is consistent with a model based on triggering of the vertical parasitic transistor. Threshold LET values decreased by about a factor of 2.5 at 125 degrees C relative to room temperature values for all three processes. Saturation cross sections exceeded the isolation well area for the two bulk processes because of diffused charge. Laser studies showed that latchup could be triggered by strikes outside the isolation well, consistent with the diffused charge mechanism. These same mechanisms were consistent with measurements of the latchup cross section of a static CMOS RAM. >

Single-particle latchup in bulk CMOS was examined using heavy ions, a californium fission source, and a pulsed laser. Experiments with the laser demonstrated that latchup triggering was caused by secondary photocurrent in either the vertical or lateral parasitic transistor. Charge diffusion is shown to be important for bipolar transistor responses in latchup, which in turn makes it important to have uniform charge deposition for depths of 10 mu m or more. Californium sources have insufficient range, which causes cross sections measured with californium to be much lower than cross sections from heavy ion experiments. >

The single-event upset (SEU) characterization of GaAs enhancement/depletion (E/D) MESFET logic circuits was experimentally performed for five different logic families. The results indicate a large charge collection volume, independent of the logic family. These results can be attributed to a gate edge effect and an enhanced source-drain charge collection mechanism. The consequence of these effects is to increase the upset rate in space by more than two orders of magnitude. Soft-error rates were estimated for each logic family and spanned the range from 2.3*10/sup -3/ to 4.7*10/sup -4/ errors/bit-day. >

Low- and high-dose-rate testing results are compared for CMOS technologies. The long-term experiments extend over time periods of more than one year so that comparisons could be made over time frames more nearly like those in the space environment. High-temperature annealing is evaluated as a means of accelerating the annealing time and predicting low-dose-rate results. The data on hardened CMOS and CMOS/SOS devices show that for these particular processes, annealing at 100 degrees C did not accelerate trapped hole annealing. Differences between expected and actual results are identified, and recommendations are made for improving test procedures. >

Total dose test results are presented for two high-voltage transistors and three bipolar integrated circuits. Circuit tests were done at a dose rate of 0.005 rad(Si)/s because the devices are sensitive to enhanced damage at low dose rate (ELDRS). An unusual response was observed for one operational amplifier where the sign of the input bias current reversed after it was exposed to approximately 10 krad(Si) at low dose rate.

The effect of various commercial power devices are presented. The devices have proved to be very fragile to single event effects, with some of the devices actually succumbing to catastrophic SEE with protons.

Analog-to-digital (A/D) converters are critical components in many space and military systems, and there have been numerous advances in A/D converter technology that have increased the resolution and conversion time. The increased performance is due to two factors: (1) advances in circuit design and complexity, which have increased the number of components and the integration density; and (2) new process technologies, such as BiCMOS, which provide better performance, cost, and smaller size in mixed-signal circuits. High-speed A/D converters, with conversion rates above 1 MHz, present a challenge to circuit designers and test engineers. Their complex architectures and high-performance specifications result in numerous possible failure modes when they are subjected to ionizing radiation. The dominant failure mode may depend on the specific application because the fundamental effects on MOS and bipolar transistors are strongly affected by bias conditions.

The energy dependence of proton displacement damage effects is investigated for light-emitting diodes (LEDs) and laser diodes. Injection-enhanced annealing occurs more rapidly when devices are irradiated with protons below 50 MeV compared with annealing from 200-MeV protons. A different interpretation of damage in amphoterically doped LEDs is used to show that the dependence of damage on energy is relatively flat for energies above 50 MeV, in contrast to older results in the literature that show a continued decrease in damage at higher energies.

We studied the effects of heavy ion and /spl gamma/-ray irradiation on radiation-induced leakage current (RILC) and time-dependent dielectric breakdown (TDDB) life distributions of ultra-thin oxides (

Micropower op-amps; bipolar and CMOS, from Burr-Brown and Maxim are compared and critical parameters are characterized for total dose response with a 2.7 V power supply voltage. The Burr-Brown bipolar device showed much more degradation than the CMOS device at high dose rate. The results are also compared with a NSC CMOS device. The Maxim bipolar device showed enhanced low dose rate effects.

The pace of device scaling has increased rapidly in recent years. Experimental CMOS devices have been produced with feature sizes below 0.1 /spl mu/m, demonstrating that devices with feature sizes between 0.1 and 0.25 /spl mu/m will likely be available in mainstream technologies after the year 2000. This paper discusses how the anticipated changes in device dimensions and design are likely to affect their radiation response in space environments. Traditional problems, such as total dose effects, SEU and latchup are discussed, along with new phenomena. The latter include hard errors from heavy ions (microdose and gate-rupture errors), and complex failure modes related to advanced circuit architecture. The main focus of the paper is on commercial devices, which are displacing hardened device technologies in many space applications. However, the impact of device scaling on hardened devices is also discussed.

Dose rate and dose enhancement (DE) factors were measured at fifteen gamma sources at eight different laboratories using thermoluminescent dosimeters (TLDs) from two independent sources and pMOS RADFETs, respectively. Dose enhancement factors were determined by comparing the responses of RADFETs with ceramic and gold-flashed kovar lids. Dose enhancement factors measured within Pb/Al test enclosures varied from essentially 1.0 (no enhancement) very close to a Co-60 room or tunnel source up to 1.24 within an enclosed Gammacell 220. DE factors between 1.5 and 1.8 were measured within a Pb/Al box behind a 2-inch Pb brick attenuator in a Co-60 room source. Two Cs-137 sources evaluated were characterized by DE factors extending from 1.17 up to 1.3-1.4 inside the Pb/Al box. Gamma cell dose rates determined from TLDs from the Naval Surface Warfare Center (NSWC)-Crane and Sandia National Laboratories (SNL) were generally close to expected levels. Dose rates were measured in an ARACOR 4100 X-ray source using both SNL dual-dielectric RADFETs and Radiation Experiments and Monitors (REM) thick thermal oxide RADFETs.

The 1996 total dose data compendium on ELDRS in bipolar linear circuits is updated. The new data include 37 data sets at high and low dose rate on 29 part types from nine manufacturers. A new table on elevated temperature irradiation has been added. References for each data set are provided.

Total dose tests of six different low dropout voltage regulators show sensitivity to both dose rate and bias during exposure. All devices tested exhibited Enhanced Low Dose Rate Sensitivity (ELDRS) and performed worse for the unbiased irradiation condition. Behavior of critical parameters in different dose rate and bias conditions is compared and the impact on hardness assurance methodology is discussed.

The Electronics Radiation Characterization (ERC) project of the NASA Electronic Parts and Packaging (NEPP) Program is responsible for the radiation effects research on microelectronics and photonics for NASA. In this presentation, we present our roadmap for providing aid to NASA flight projects, technology developers, and the aerospace community.

Permanent and transient effects are discussed that are induced in linear integrated circuits by space radiation. Recent developments include enhanced damage at low dose rate, increased damage from protons due to displacement effects, and transients in digital comparators that can cause circuit malfunctions. Methods of selecting and testing devices for space applications are discussed, along with examples of radiation effects in fielded space systems.

We present a compendium of optocoupler radiation test data including data on neutron, proton and heavy ion displacement damage (DD), single event transients (SET) and degradation due to total ionizing dose (TID). Proton data includes ionizing and non-ionizing damage mechanisms.

Hot-carrier-induced degradation due to AC stress on short-channel MOSFETs is discussed. It is observed that pulsed gate voltage stressing with a short falltime (0.7 ns) can cause additional lifetime degradation in the form of drain-current reduction. The AC-enhanced degradation is more pronounced at higher frequencies. >

Microelectromechanical sensors, ADXL50 and XMMAS40G accelerometers which are fabricated with surface micromachining techniques are characterized for their total dose radiation response. Different failure mechanisms were observed when the sensor element or the whole device was irradiated.

Topological factors that affect latchup were investigated using test structures fabricated in two different CMOS foundries. The geometry of isolation well contacts was found to have a large effect on photocurrent responses because of the effect of the lateral resistance of the well. Experiments that delayed the application of bias until time periods long after the radiation pulse subsided showed that latchup would still occur, with relatively small increases in the radiation intensity required to induce latchup until the delays exceeded several microseconds. This shows that the fast transition of the radiation pulse is not required to trigger latchup, and it also shows how latchup can occur at high intensities after internal voltages collapse to near zero at short times. Latchup tests of a 64K SRAM (static random-access memory) revealed a latchup window that was caused by the presence of two different internal latchup paths with different radiation triggering levels and holding voltages. Data on this device and several MSI devices show how the power-supply current-surge characteristics can be used to select radiation test levels to minimize interference from latchup windows. >

A simple model for interpreting and extrapolating time-dependent effects in the irradiation of microelectronic devices is tested by fitting its predictions to published and previously unpublished experimental data. The goal is to evaluate the applicability of such a model to hardness assurance testing in cases where defect growth and annealing processes (time-dependent effects) are significant. Data are presented indicating hole annealing times varying by more than six orders of magnitude. The implications of the large variation in hole annealing times for hardness assurance testing are explored. >

Radiation effects testing, part selection, and hardness assurance for application to electronic components in the natural space environment are discussed. The emphasis is on semiconductor devices, primarily silicon microcircuits, which are used in the greatest quantity and which, in most cases, are the most sensitive. After a summary of the natural space radiation environment and the effects of radiation on semiconductor devices, laboratory simulation of space radiation and extrapolation to space are covered. Radiation testing is performed to understand failure mechanisms, to characterize the radiation response of specific devices, and to provide data for lot acceptance. Part selection and hardness assurance are discussed by contrasting the traditional approach with the unique aspects of space systems. Some recommendations are made for treating the more complex aspects of space system microcircuit hardness assurance. >

A lumped-model approach is used to determine three-dimensional effects that often dominate latchup behavior in complex integrated circuits. A preprocessor is used that automatically generates a SPICE-compatible file of up to several thousand elements from a basic description of the topology and physics of local structures. The results show that internal potential drops in the substrate and isolation wells are much larger than the metallization resistance contribution for devices with asymmetrical topology. The work also shows that alterations in the back contact, such as partial removal of the central portion for backside laser simulation, increase lateral voltage drops in the substrate by more than one order of magnitude, substantially changing the latchup characteristics. The model can be used to calculate distributed potentials that are important for latchup and the latchup window effect and to determine the effect of metal shadowing or nonuniform carrier generation when laser simulation is used. >

The goal of the NASA HPCC Remote Exploration and Experimentation (REE) Project is to transfer commercial supercomputing technology into space. The project will use state of the art, low-power, non-radiation-hardened, COTS hardware chips and COTS software to the maximum extent possible, and will rely on software-implemented fault tolerance to provide the required levels of availability and reliability. We outline the methodology used to develop a detailed radiation fault model for the REE Testbed architecture. The model addresses the effects of energetic protons and heavy ions which cause single event upset and single event multiple upset events in digital logic devices and which are expected to be the primary fault generation mechanism. Unlike previous modeling efforts, this model will address fault rates and types in computer subsystems at a sufficiently fine level of granularity (i.e., the register level) that specific software and operational errors can be derived. We present the current state of the model, model verification activities and results to date, and plans for the future. Finally, we explain the methodology by which this model will be used to derive application-level error effects sets. These error effects sets will be used in conjunction with our Testbed fault injection capabilities and our applications' mission scenarios to replicate the predicted fault environment on our suite of onboard applications.