Rapid, efficient, and economical synthesis of PET tracers in a droplet microreactor: application to O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET).

BackgroundConventional scale production of small batches of PET tracers (e.g. for preclinical imaging) is an inefficient use of resources. Using O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET), we demonstrate that simple microvolume radiosynthesis techniques can improve the efficiency of production by consuming tiny amounts of precursor, and maintaining high molar activity of the tracers even with low starting activity.ProceduresThe synthesis was carried out in microvolume droplets manipulated on a disposable patterned silicon "chip" affixed to a heater. A droplet of [18F]fluoride containing TBAHCO3 was first deposited onto a chip and dried at 100 °C. Subsequently, a droplet containing 60 nmol of precursor was added to the chip and the fluorination reaction was performed at 90 °C for 5 min. Removal of protecting groups was accomplished with a droplet of HCl heated at 90 °C for 3 min. Finally, the crude product was collected in a methanol-water mixture, purified via analytical-scale radio-HPLC and formulated in saline. As a demonstration, using [18F]FET produced on the chip, we prepared aliquots with different molar activities to explore the impact on preclinical PET imaging of tumor-bearing mice.ResultsThe microdroplet synthesis exhibited an overall decay-corrected radiochemical yield of 55 ± 7% (n = 4) after purification and formulation. When automated, the synthesis could be completed in 35 min. Starting with < 370 MBq of activity, ~ 150 MBq of [18F]FET could be produced, sufficient for multiple in vivo experiments, with high molar activities (48-119 GBq/μmol). The demonstration imaging study revealed the uptake of [18F]FET in subcutaneous tumors, but no significant differences in tumor uptake as a result of molar activity differences (ranging 0.37-48 GBq/μmol) were observed.ConclusionsA microdroplet synthesis of [18F]FET was developed demonstrating low reagent consumption, high yield, and high molar activity. The approach can be expanded to tracers other than [18F]FET, and adapted to produce higher quantities of the tracer sufficient for clinical PET imaging

Strategic Optimization Techniques For FRTU Deployment and Chip Physical Design

Combinatorial optimization is a complex engineering subject. Although formulation often depends on the nature of problems that differs from their setup, design, constraints, and implications, establishing a unifying framework is essential. This dissertation investigates the unique features of three important optimization problems that can span from small-scale design automation to large-scale power system planning: (1) Feeder remote terminal unit (FRTU) planning strategy by considering the cybersecurity of secondary distribution network in electrical distribution grid, (2) physical-level synthesis for microfluidic lab-on-a-chip, and (3) discrete gate sizing in very-large-scale integration (VLSI) circuit. First, an optimization technique by cross entropy is proposed to handle FRTU deployment in primary network considering cybersecurity of secondary distribution network. While it is constrained by monetary budget on the number of deployed FRTUs, the proposed algorithm identi?es pivotal locations of a distribution feeder to install the FRTUs in different time horizons. Then, multi-scale optimization techniques are proposed for digital micro?uidic lab-on-a-chip physical level synthesis. The proposed techniques handle the variation-aware lab-on-a-chip placement and routing co-design while satisfying all constraints, and considering contamination and defect. Last, the first fully polynomial time approximation scheme (FPTAS) is proposed for the delay driven discrete gate sizing problem, which explores the theoretical view since the existing works are heuristics with no performance guarantee. The intellectual contribution of the proposed methods establishes a novel paradigm bridging the gaps between professional communities

Molecular approaches for low-cost point-of-care pathogen detection in agriculture and forestry

Early detection of plant diseases is a crucial factor to prevent or limit the spread of a rising infection that could cause significant economic loss. Detection test on plant diseases in laboratory can be laborious, time consuming, expensive and normally requires specific technical expertise. Moreover in the developing Countries it is often difficult to find laboratories equipped for this kind of analysis. Therefore, in the last years a high effort has been made for the development of fast, specific, sensitive and cost-effective tests that can be successfully used in plant pathology directly in the field, by low-specialized personnel using minimal equipment. Nucleic acid-based methods have proven to be a good choice for the development of detection tools in several fields, such as human/animal health, food safety and water analysis and their application in plant pathogen detection is becoming more and more common. In the present review, the more recent nucleic acid-based protocols for point-of care plant pathogen detection and identification are described and analyzed. All these methods have a high potential for early detection of destructive diseases in agriculture and forestry; they should help making molecular detection for plant pathogens accessible to anyone, anywhere and at anytime. We do not suggest that on site methods should replace completely lab-testing, which remains crucial for more complex researches, such as identification and classification of new pathogens or the study of plant defence mechanisms. Instead, POC analysis can provide a useful, fast and efficient preliminary in field screening that is crucial in the struggle against plant pathogens

Microextrusion 3D Printing of Optical Waveguides and Microheaters

The drive for smaller and more compact devices presents several challenges in materials and fabrication strategies. Although photolithography is a well-developed method for creating microdevices, the disparate requirements in fabrication strategies, material choices, equipment and process complexities have limited its applications. Microextrusion printing (μEP) provides a promising alternative for microfabrication. Compared to the traditional techniques, the attractions lie in the wide range of printable material choice, greater design freedom, fewer processing steps, lower cost for customized production, and the plurality of compatible substrates. However, while extrusion-based 3D printing processes have been successfully applied at the macroscale, this seeming simplicity belies the dynamic complexities needed for consistent, repeatable, and cost-effective printing at the microscale. The fundamental understanding of the microextrusion printing process is still lacking. One primary goal of this dissertation, therefore, is to develop the fundamental understanding of μEP. This study elucidates the underlying principles of this printing technique, offering an overall roadmap - stepwise guide for successful printing based on both results in the literature and our experimental tests. The primary motivation is to provide users at both the research and industrial platforms with the requisite knowledge base needed for adapting μEP for microfabrication. Ultimately, this understanding, optimization of materials properties, and process parameters dictate the resolution and quality of the printed features. Following the improved understanding of microextrusion printing, two complementary goals were set. First, in order to test and validate the applicability the framework, a high-resolution microextrusion 3D printer was designed and implemented to enable high precision printing of microdevices and microstructures. Second, taking advantage of the guiding framework and printing platform, printing of novel materials and devices including flexible optics and a high-temperature microheater were explored and demonstrated. One common thread is observed throughout this work, that is, the development of the fundamental understanding of microextrusion 3D printing and its application for creating functional microdevices and structures. This work opens new possibilities and versatile approach for low-cost patterning of materials and functional devices

NASA Tech Briefs, May 2010

Topics covered include: Instrument for Analysis of Greenland's Glacier Mills Cryogenic Moisture Apparatus; A Transportable Gravity Gradiometer Based on Atom Interferometry; Three Methods of Detection of Hydrazines; Crossed, Small-Deflection Energy Analyzer for Wind/Temperature Spectrometer; Wavefront Correction for Large, Flexible Antenna Reflector; Novel Micro Strip-to-Waveguide Feed Employing a Double-Y Junction; Thin-Film Ferro Electric-Coupled Microstripline Phase Shifters With Reduced Device Hysteresis; Two-Stage, 90-GHz, Low-Noise Amplifier; A 311-GHz Fundamental Oscillator Using InP HBT Technology; FPGA Coprocessor Design for an Onboard Multi-Angle Spectro-Polarimetric Imager; Serrating Nozzle Surfaces for Complete Transfer of Droplets; Turbomolecular Pumps for Holding Gases in Open Containers; Triaxial Swirl Injector Element for Liquid-Fueled Engines; Integrated Budget Office Toolbox; PLOT3D Export Tool for Tecplot; Math Description Engine Software Development Kit; Astronaut Office Scheduling System Software; ISS Solar Array Management; Probabilistic Structural Analysis Program; SPOT Program; Integrated Hybrid System Architecture for Risk Analysis; System for Packaging Planetary Samples for Return to Earth; Offset Compound Gear Drive; Low-Dead-Volume Inlet for Vacuum Chamber; Simple Check Valves for Microfluidic Devices; A Capillary-Based Static Phase Separator for Highly Variable Wetting Conditions; Gimballing Spacecraft Thruster; Finned Carbon-Carbon Heat Pipe with Potassium Working Fluid; Lightweight Heat Pipes Made from Magnesium; Ceramic Rail-Race Ball Bearings; Improved OTEC System for a Submarine Robot; Reflector Surface Error Compensation in Dual-Reflector Antennas; Enriched Storable Oxidizers for Rocket Engines; Planar Submillimeter-Wave Mixer Technology with Integrated Antenna; Widely Tunable Mode-Hop-Free External-Cavity Quantum Cascade Laser; Non-Geiger-Mode Single-Photon Avalanche Detector with Low Excess Noise; Using Whispering-Gallery-Mode Resonators for Refractometry; RF Device for Acquiring Images of the Human Body; Reactive Collision Avoidance Algorithm; Fast Solution in Sparse LDA for Binary Classification; Modeling Common-Sense Decisions in Artificial Intelligence; Graph-Based Path-Planning for Titan Balloons; Nanolaminate Membranes as Cylindrical Telescope Reflectors; Air-Sea Spray Airborne Radar Profiler Characterizes Energy Fluxes in Hurricanes; Large Telescope Segmented Primary Mirror Alignment; and Simplified Night Sky Display System

Design and Optimization Methods for Pin-Limited and Cyberphysical Digital Microfluidic Biochips

<p>Microfluidic biochips have now come of age, with applications to biomolecular recognition for high-throughput DNA sequencing, immunoassays, and point-of-care clinical diagnostics. In particular, digital microfluidic biochips, which use electrowetting-on-dielectric to manipulate discrete droplets (or "packets of biochemical payload") of picoliter volumes under clock control, are especially promising. The potential applications of biochips include real-time analysis for biochemical reagents, clinical diagnostics, flash chemistry, and on-chip DNA sequencing. The ease of reconfigurability and software-based control in digital microfluidics has motivated research on various aspects of automated chip design and optimization.</p><p>This thesis research is focused on facilitating advances in on-chip bioassays, enhancing the automated use of digital microfluidic biochips, and developing an "intelligent" microfluidic system that has the capability of making on-line re-synthesis while a bioassay is being executed. This thesis includes the concept of a "cyberphysical microfluidic biochip" based on the digital microfluidics hardware platform and on-chip sensing technique. In such a biochip, the control software, on-chip sensing, and the microfluidic operations are tightly coupled. The status of the droplets is dynamically monitored by on-chip sensors. If an error is detected, the control software performs dynamic re-synthesis procedure and error recovery.</p><p>In order to minimize the size and cost of the system, a hardware-assisted error-recovery method, which relies on an error dictionary for rapid error recovery, is also presented. The error-recovery procedure is controlled by a finite-state-machine implemented on a field-programmable gate array (FPGA) instead of a software running on a separate computer. Each state of the FSM represents a possible error that may occur on the biochip; for each of these errors, the corresponding sequence of error-recovery signals is stored inside the memory of the FPGA before the bioassay is conducted. When an error occurs, the FSM transitions from one state to another, and the corresponding control signals are updated. Therefore, by using inexpensive FPGA, a portable cyberphysical system can be implemented.</p><p>In addition to errors in fluid-handling operations, bioassay outcomes can also be erroneous due the uncertainty in the completion time for fluidic operations. Due to the inherent randomness of biochemical reactions, the time required to complete each step of the bioassay is a random variable. To address this issue, a new "operation-interdependence-aware" synthesis algorithm is proposed in this thesis. The start and stop time of each operation are dynamically determined based on feedback from the on-chip sensors. Unlike previous synthesis algorithms that execute bioassays based on pre-determined start and end times of each operation, the proposed method facilitates "self-adaptive" bioassays on cyberphysical microfluidic biochips.</p><p>Another design problem addressed in this thesis is the development of a layout-design algorithm that can minimize the interference between devices on a biochip. A probabilistic model for the polymerase chain reaction (PCR) has been developed; based on the model, the control software can make on-line decisions regarding the number of thermal cycles that must be performed during PCR. Therefore, PCR can be controlled more precisely using cyberphysical integration.</p><p>To reduce the fabrication cost of biochips, yet maintain application flexibility, the concept of a "general-purpose pin-limited biochip" is proposed. Using a graph model for pin-assignment, we develop the theoretical basis and a heuristic algorithm to generate optimized pin-assignment configurations. The associated scheduling algorithm for on-chip biochemistry synthesis has also been developed. Based on the theoretical framework, a complete design flow for pin-limited cyberphysical microfluidic biochips is presented.</p><p>In summary, this thesis research has led to an algorithmic infrastructure and optimization tools for cyberphysical system design and technology demonstrations. The results of this thesis research are expected to enable the hardware/software co-design of a new class of digital microfluidic biochips with tight coupling between microfluidics, sensors, and control software.</p>Dissertatio

Novel Network Paradigms: Microfluidic and M2M Communications

The present thesis focuses on two appealing paradigms that are expected to characterize the next generation of communication systems: microfluidic networking and Machine to Machine (M2M) Communications. Concerning the former topic, we show how it is possible to introduce switching and routing mechanism in microfluidic systems. We define some simple mathematical models that capture the macroscopic behavior of droplets in microfluidic networks. Then, we use them to implement a simulator that is able to reproduce the motion and predict the path of droplets in a generic microfluidic system. We validate the simulator and apply it to design a network with bus topology. Finally, we prove the feasibility of attaining molecular communication in this domain by describing a simple protocol that exploits droplets length/interdistance modulation to send information. The research activity on M2M, instead, is aimed at the investigation of two critical issues that are expected to affect Machine-Type Communication (MTC), i.e. energy efficiency and massive access. Regarding energy efficiency, we address the problem of delivering a fixed data payload over a Rayleigh fading wireless channel with the purpose of minimizing the average total energy cost, given by the sum of the transmit energy and an overhead circuit energy, to complete it. This scenario is well suited for uplink cellular MTC in future 5G Internet of Things (IoT) use cases, where the focus is more on device energy efficiency than on throughput. We describe the optimal transmission policies to be used under various coordinated access scenarios with different levels of channel state information and transmitter/receiver capabilities, and show the corresponding theoretical bounds. In the last part of the work, we study the asymptotic performance of uncoordinated access schemes with Multi Packet Reception (MPR) and Successive Interference Cancellation (SIC) techniques for contention resolution at the receiver. The corresponding results in terms of throughput in a massive access M2M scenario are finally evaluated and discussed