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An all-electronic, droplet-based batch microfluidic device, operated using the electrowetting on dielectric (EWOD) mechanism was developed for on-demand synthesis of N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB), the most commonly used 18F-prosthetic group for biomolecule labeling. In order to facilitate the development of peptides, and proteins as new diagnostic and therapeutic agents, we have diversified the compact EWOD microfluidic platform to perform the three-step radiosynthesis of [18F]SFB starting from the no carrier added [18F]fluoride ion. In this report, we established an optimal microliter droplet reaction condition to obtain reliable yields and synthesized [18F]SFB with sufficient radioactivity for subsequent conjugation to the anti-PSCA cys-diabody (A2cDb) and for small animal imaging. The three-step, one-pot radiosynthesis of [18F]SFB radiochemistry was adapted to a batch microfluidic platform with a reaction droplet sandwiched between two parallel plates of an EWOD chip, and optimized. Specifically, the ratio of precursor to base, droplet volume, reagent concentration, reaction time, and evaporation time were found be to be critical parameters. [18F]SFB was successfully synthesized on the EWOD chip in 39 ± 7% (n = 4) radiochemical yield in a total synthesis time of ∼120 min ([18F]fluoride activation, [18F]fluorination, hydrolysis, and coupling reaction, HPLC purification, drying and reformulation). The reformulation and stabilization step for [18F]SFB was important to obtain a high protein labeling efficiency of 33.1 ± 12.5% (n = 3). A small-animal immunoPET pilot study demonstrated that the [18F]SFB-PSCA diabody conjugate showed specific uptake in the PSCA-positive human prostate cancer xenograft. The successful development of a compact footprint of the EWOD radiosynthesizer has the potential to empower biologists to produce PET probes of interest themselves in a standard laboratory.

Boron neutron capture therapy (BNCT) targets invasive, radioresistant cancers but requires a selective and high B-10 loading boron drug. This manuscript investigates boron-rich poly(ethylene glycol)- block -(poly(4-vinylphenyl boronate ester)) polymer micelles synthesized via atom transfer radical polymerization for their potential application in BNCT. Transmission electron microscopy (TEM) revealed spherical micelles with a uniform size of 43 ± 10 nm, ideal for drug delivery. Additionally, probe sonication proved effective in maintaining the micelles' size and morphology postlyophilization and reconstitution. In vitro studies with B16-F10 melanoma cells demonstrated a 38-fold increase in boron accumulation compared to the borophenylalanine drug for BNCT. In vivo studies in a B16-F10 tumor-bearing mouse model confirmed enhanced tumor selectivity and accumulation, with a tumor-to-blood (T/B) ratio of 2.5, surpassing BPA's T/B ratio of 1.8. As a result, mice treated with these micelles experienced a significant delay in tumor growth, highlighting their potential for BNCT and warranting further research.

Malignant cancers, known for their pronounced heterogeneity, pose substantial challenges to monotherapeutic strategies and contribute to the risk of metastasis. Addressing this, our study explores the synergistic potential of combining boron neutron capture therapy (BNCT) with immune checkpoint blockade to enhance cancer treatment efficacy. We synthesized boron-rich block copolymer micelles as a novel boron drug for BNCT. Characterization was conducted using nuclear magnetic resonance, gel-permeation chromatography, transmission electron microscopy, and dynamic light scattering. These micelles, with an optimal size of 91.3 nm and a polydispersity index of 0.18, are suitable for drug delivery applications. In vitro assessments on B16-F10 melanoma cells showed a 13-fold increase in boron uptake with the micelles compared to borophenyl alanine (BPA), the conventional boron drug for BNCT. This resulted in a substantial increase in BNCT efficacy, reducing cell viability to 77% post-irradiation in micelle-treated cells, in contrast to 90% in BPA-treated cells. In vivo, melanoma-bearing mice treated with these micelles exhibited an 8-fold increase in boron accumulation in tumor tissues versus those treated with BPA, leading to prolonged tumor growth delay (5.4 days with micelles versus 3.3 days with BPA). Moreover, combining BNCT with anti-PD-L1 immunotherapy further extended the tumor growth delay to 6.6 days, and enhanced T-cell infiltration and activation at tumor sites, thereby indicating a boosted immune response. This combination demonstrates a promising approach by enhancing cytotoxic T-cell priming and mitigating the immunosuppressive effects of melanoma tumors., Competing Interests: Competing interes ts: The authors declare that they have no competing interests., (Copyright © 2024 Yi-Lin Chiu et al.)

Triple-negative breast cancer (TNBC) is characterized by highly proliferative cancer cells and is the only subtype of breast cancer that lacks a targeted therapy. Boron neutron capture therapy (BNCT) is an approach that combines chemotherapy with radiotherapy and can potentially offer beneficial targeted treatment for TNBC patients owing to its unique ability to eradicate cancer cells selectively while minimizing damage to the surrounding healthy cells. Since BNCT relies on specific delivery of a high loading of B10 to the tumor site, there is growing research interest to develop more potent boron-based drugs for BNCT that can overcome the limitations of small-molecule boron compounds. In this study, polyethylene-glycol-coated boron carbon oxynitride nanoparticles (PEG@BCNO) of size 134.2±23.6nm were prepared as a promising drug for BNCT owing to their high boron content and enhanced biocompatibility. The therapeutic efficiency of PEG@BCNO was compared with a state-of-the-art 10 BPA boron drug in mice bearing MDA-MB-231 tumor. In the orthotopic mouse model, PEG@BCNO showed higher B10 accumulation in the tumor tissues (6 μg 10 B/g tissue compared to 3 μg 10 B/g tissue in mice administered B10-enriched 10 BPA drug) despite using the naturally occurring 11 B/ 10 B boron precursor in the preparation of the BCNO nanoparticles. The in vivo biodistribution of PEG@BCNO in mice bearing MDA-MB-231 showed a tumor/blood ratio of ~3.5, which is comparable to that of the state-of-the-art 10 BPA-fructose drug. We further demonstrated that upon neutron irradiation, the mice bearing MDA-MB-231 tumor cells treated with PEG@BCNO and 10 BPA showed tumor growth delay times of 9 days and 1 day, respectively, compared to mice in the control group after BNCT. The doubling times (DTs) for mice treated with PEG@BCNO and 10 BPA as well as mice in the control group were calculated to be 31.5, 19.8, and 17.7 days, respectively. Immunohistochemical staining for the p53 and caspase-3 antibodies revealed that mice treated with PEG@BCNO showed lower probability of cancer recurrence and greater level of cellular apoptosis than mice treated with 10 BPA and mice in the control group. Our study thus demonstrates the potential of pegylated BCNO nanoparticles in effectively inhibiting the growth of TNBC tumors compared to the state-of-the-art boron drug 10 BPA., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pei Yuin Keng reports financial support was provided by National Science and Technology Council., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This study presents the utilization of MoS 2 as a diffusion barrier for metal interconnects, in situ transmission electron microscopy (TEM) observations are employed for comprehensive understanding. The diffusion-blocking ability of MoS 2 is discussed by the diffusion and phase transformation between Ru and Si via TEM diffraction and imaging. When the sample is heated to a high temperature such that MoS 2 loses the ability to block the diffusion, Si diffuses through the MoS 2 into the Ru layer, leading to the formation of Ru 2 Si 3 . Both multilayer and monolayer (1L) MoS 2 exhibit exceptional diffusion-blocking ability up to 800 °C. Furthermore, plasma-treated 1L-MoS 2 shows a slightly low diffusion-blocking temperature of 750 °C, while the dangling bonds in MoS 2 improve the interfacial adhesion. These findings suggest that MoS 2 holds great potential as a diffusion barrier for metal interconnects.

In this study, we investigated the thermal stabilities of butylphosphonic acid (BPA) and aminopropyltriethoxysilane (APTES) self-assembled monolayers (SAM) on a Si substrate. The thermal desorption and the thermal cleavage of the BPA and APTES SAM film on the Si substrate were studied by X-ray photoelectron spectroscopy (XPS) upon thermal treatment from 50 to 550 °C. XPS analyses show that the onset of the thermal desorption of the APTES monolayer occurs at 250 °C and the APTES SAM completely decomposed at 400 °C. Conversely, BPA SAM on Si shows that the onset of thermal desorption occurs at 350 °C, and the BPA SAM completely desorbed at approximately 500 °C. Our study revealed that the organophosphonate SAM is a more stable SAM in modifying the dielectric sidewalls of a Cu interconnect when compared to organosilane SAM. To overcome the spontaneous reaction of the organophosphonate film on the metal substrate, a simple orthogonal functionalization method using thiolate SAM as a sacrificial layer was also demonstrated in this study., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Boron-based nanomaterials are emerging as non-toxic, earth-abundant (photo)electrocatalyst materials in solar energy conversion for the production of solar hydrogen fuel and environmental remediation. Boron carbon oxynitride (BCNO) is a quaternary semiconductor with electronic, optical, and physicochemical properties that can be tuned by varying the composition of boron, nitrogen, carbon, and oxygen. However, the relationship between BCNO's structure and -photocatalytic activity relationship has yet to be explored. We performed an in-depth spectroscopic analysis to elucidate the effect of using two different nitrogen precursors and the effect of annealing temperatures in the preparation of BCNO. BCNO nanodisks (D = 6.7 ± 1.1 nm) with turbostratic boron nitride diffraction patterns were prepared using guanidine hydrochloride as the nitrogen source precursor upon thermal annealing at 800°C. The X-ray photoelectron spectroscopy (XPS) surface elemental analysis of the BCNO nanodisks revealed the B, C, N, and O compositions to be 40.6%, 7.95%, 37.7%, and 13.8%, respectively. According to the solid-state 11 B NMR analyses, the guanidine hydrochloride-derived BCNO nanodisks showed the formation of various tricoordinate BN x (OH) 3-x species, which also served as one of the photocatalytic active sites. The XRD and in-depth spectroscopic analyses corroborated the preparation of BCNO-doped hexagonal boron nitride nanodisks. In contrast, the BCNO annealed at 600 °C using melamine as the nitrogen precursor consisted of layered nanosheets composed of B, C, N, and O atoms covalently bonded in a honeycomb lattice as evidence by the XRD, XPS, and solid-state NMR analysis ( 11 B and 13 C) analyses. The XPS surface elemental composition of the melamine-derived BCNO layered structures consisted of a high carbon composition (75.1%) with a relatively low boron (5.24%) and nitrogen (7.27%) composition, which indicated the formation of BCNO-doped graphene oxides layered sheet structures. This series of melamine-derived BCNO-doped graphene oxide layered structures were found to exhibit the highest photocatalytic activity, exceeding the photocatalytic activity of graphitic carbon nitride. In this layered structure, the formation of the tetracoordinate BN x (OH) 3-x (CO) species and the rich graphitic domains were proposed to play an important role in the photocatalytic activity of the BCNO-doped graphene oxides layered structures. The optical band gap energies were measured to be 5.7 eV and 4.2 eV for BCNO-doped hexagonal boron nitride nanodisks and BCNO-doped graphene oxides layered structures, respectively. Finally, BCNO exhibited an ultralong photoluminescence with an average decay lifetime of 1.58, 2.10, 5.18, and 8.14 µs for BGH01, BGH03, BMH01, BMH03, respectively. This study provides a novel metal-free photocatalytic system and provides the first structural analysis regarding the origin of BCNO-based photocatalyst., (© 2021. The Author(s).)

Boron neutron capture therapy (BNCT) is a powerful and selective anti-cancer therapy utilizing 10 B-enriched boron drugs. However, clinical advancement of BCNT is hampered by the insufficient loading of B-10 drugs throughout the solid tumor. Furthermore, the preparation of boron drugs for BNCT relies on the use of the costly B-10 enriched precursor. To overcome these challenges, polymer-coated boron carbon oxynitride (BCNO) nanoparticles, with ~30% of boron, were developed with enhanced biocompatibility, cell uptake, and tumoricidal effect via BNCT. Using the ALTS1C1 cancer cell line, the IC 50 of the PEG@BCNO, bare, PEI@BCNO were determined to be 0.3 mg/mL, 0.1 mg/mL, and 0.05 mg/mL, respectively. As a proof-of-concept, the engineered non- 10 B enriched polymer-coated BCNO exhibited excellent anti-tumor effect via BNCT due to their high boron content per nanoparticle and due to the enhanced cellular internalization and retention compared to small molecular 10 B-BPA drug. The astrocytoma ALTS1C1 cells treated with bare, polyethyleneimine-, and polyethylene glycol-coated BCNO exhibited an acute cell death of 24, 37, and 43%, respectively, upon 30 min of neutron irradiation compared to the negligible cell death in PBS-treated and non-irradiated cells. The radical approach proposed in this study addresses the expensive and complex issues of B-10 isotope enrichment process; thus, enabling the preparation of boron drugs at a significantly lower cost, which will facilitate the development of boron drugs for BNCT.

The development of a heterogeneous catalyst for use in environmental remediation remains a challenging and attractive research endeavor. Specifically, for Fenton reactions, most research approaches have focused on the preparation of iron-containing heterostructures as photo-Fenton catalysts that utilize visible light for enhancing the degradation efficiency. Herein, the synthesis and novel application of C,N-doped iron borates are demonstrated as single-component heterogeneous photo-Fenton catalysts with high Fenton activity under visible light. Under the optimal conditions, 10 mg of the catalyst is shown to achieve effective degradation of 10 ppm methylene blue (MB) dye, Rhodamine B (RhB) dye, and tetracycline (TC) under simulated solar irradiation with a first-order rate constant of k = 0.218 min -1 , 0.177 min -1 , and 0.116 min -1 , respectively. Using MB as a model system, the C,N-doped iron borate exhibits 10- and 26-fold increases in catalytic activity relative to that of the 50 nm hematite nanoparticles and that of the non-doped iron borate, respectively, in the presence of H 2 O 2 under the simulated solar irradiation. Furthermore, the optimum reaction conditions used only 320 equivalents of H 2 O 2 with respect to the concentration of dye, rather than the several thousand equivalents of H 2 O 2 used in conventional heterogeneous Fenton catalysts. In addition, the as-prepared C,N-doped iron borate achieves 75% MB degradation after 20 min in the dark, thus enabling the continuous degradation of pollutants at night and in areas with poor light exposure. The stability and recyclability of C,N-doped iron borate for the oxidation of MB was demonstrated over three cycles with insignificant loss in photo-Fenton activity. The high Fenton activity of the C,N-doped iron borate is considered to be due to the synergistic action between the negatively-charged borate ligands and the metal center in promoting the Fenton reaction. Moreover, carbon and nitrogen doping are shown to be critical in modifying the electronic structure and increasing the conductivity of the catalyst. In view of its synthetic simplicity, high efficiency, low cost of reagents, and minimal cost of operation (driven by natural sunlight), the as-prepared heterogeneous single-component metal borate catalyst has potential application in the industrial treatment of wastewater.

An all-electronic, droplet-based batch microfluidic device, operated using the electrowetting on dielectric (EWOD) mechanism was developed for on-demand synthesis of N -succinimidyl-4-[ 18 F]fluorobenzoate ([ 18 F]SFB), the most commonly used 18 F-prosthetic group for biomolecule labeling. In order to facilitate the development of peptides, and proteins as new diagnostic and therapeutic agents, we have diversified the compact EWOD microfluidic platform to perform the three-step radiosynthesis of [ 18 F]SFB starting from the no carrier added [ 18 F]fluoride ion. In this report, we established an optimal microliter droplet reaction condition to obtain reliable yields and synthesized [ 18 F]SFB with sufficient radioactivity for subsequent conjugation to the anti-PSCA cys-diabody (A2cDb) and for small animal imaging. The three-step, one-pot radiosynthesis of [ 18 F]SFB radiochemistry was adapted to a batch microfluidic platform with a reaction droplet sandwiched between two parallel plates of an EWOD chip, and optimized. Specifically, the ratio of precursor to base, droplet volume, reagent concentration, reaction time, and evaporation time were found be to be critical parameters. [ 18 F]SFB was successfully synthesized on the EWOD chip in 39 ± 7% ( n = 4) radiochemical yield in a total synthesis time of ∼120 min ([ 18 F]fluoride activation, [ 18 F]fluorination, hydrolysis, and coupling reaction, HPLC purification, drying and reformulation). The reformulation and stabilization step for [ 18 F]SFB was important to obtain a high protein labeling efficiency of 33.1 ± 12.5% ( n = 3). A small-animal immunoPET pilot study demonstrated that the [ 18 F]SFB-PSCA diabody conjugate showed specific uptake in the PSCA-positive human prostate cancer xenograft. The successful development of a compact footprint of the EWOD radiosynthesizer has the potential to empower biologists to produce PET probes of interest themselves in a standard laboratory., Competing Interests: Drs van Dam and Keng are consultants to Sofie Biosciences. The Regents of the University of California have licensed technology to Sofie Biosciences that was invented by Drs van Dam, and Keng, and have taken equity in Sofie Biosciences as part of the licensing transaction., (This journal is © The Royal Society of Chemistry.)

Positron emission tomography (PET) is a molecular diagnostic imaging technology to quantitatively visualize biological processes in vivo . For many applications, including imaging of low tissue density targets (e.g. neuroreceptors), imaging in small animals, and evaluation of novel tracers, the injected PET tracer must be produced with high molar activity to ensure low occupancy of biological targets and avoid pharmacologic effects. Additionally, high molar activity is essential for tracers with lengthy syntheses or tracers transported to distant imaging sites. We show that radiosynthesis of PET tracers in microliter volumes instead of conventional milliliter volumes results in substantially increased molar activity, and we identify the most relevant variables affecting this parameter. Furthermore, using the PET tracer [ 18 F]fallypride, we illustrate that molar activity can have a significant impact on biodistribution. With full automation, microdroplet platforms could provide a means for radiochemists to routinely, conveniently, and safely produce PET tracers with high molar activity., Competing Interests: Competing Interests Drs. van Dam and Phelps are founders of Sofie Biosciences, Inc., Dr. Phelps is a board member of Sofie Biosciences, and Drs. van Dam and Keng are consultants to Sofie Biosciences. The Regents of the University of California have licensed technology to Sofie Biosciences that was invented by Drs. van Dam, Keng, and Lazari, and have taken equity in Sofie Biosciences as part of the licensing transaction.

The emerging technology of digital microfluidics is opening up the possibility of performing radiochemistry at the microliter scale to produce tracers for positron emission tomography (PET) labeled with fluorine-18 or other isotopes. Working at this volume scale not only reduces reagent costs but also improves specific activity (SA) by reducing contamination by the stable isotope. This technology could provide a practical means to routinely prepare high-SA tracers for applications such as neuroimaging and could make it possible to routinely achieve high SA using synthesis strategies such as isotopic exchange. Reagent droplets are controlled electronically, providing high reliability, a compact control system, and flexibility for diverse syntheses with a single-chip design. The compact size may enable the development of a self-shielded synthesizer that does not require a hot cell. This article reviews the progress of this technology and its application to the synthesis of PET tracers.

CE coupled with UV detection was assessed as a possible platform for the chemical identity and purity analysis of positron emission tomography (PET) tracers using [(18)F]FAC and [(18)F]FLT as examples. Representative samples containing mixtures of the tracers plus well-known impurities, as well as real radioactive samples (formulated for injection), were analyzed. Using MEKC with SDS in a neutral phosphate buffer, the separation of all compounds in the samples was achieved with baseline resolutions in less than 4.5min and 3min for FLT and FAC samples, respectively. In comparison to the gold-standard for chemical analysis (i.e. HPLC/UV), we have demonstrated improvements in analysis times, and comparable LOD. Although the reproducibility in migration time is slightly lower than that of the HPLC, identification of the compounds was still possible due to good peak separation. In addition, we show that CE can be used to identify and quantify Krytofix2.2.2 (a toxic and commonly used phase transfer catalyst) in less than 2min and with a LOD of 45μg/mL (non-optimized). These results demonstrate adequate performance for chemical identity and purity analysis. Combined with the potential for miniaturization into a microchip format, these results suggest the potential of CE as an integral part of a miniaturized quality control system for PET tracers., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Radiotracer synthesis is an ideal application for microfluidics because only nanogram quantities are needed for positron emission tomography (PET) imaging. Thousands of radiotracers have been developed in research settings but only a few are readily available, severely limiting the biological problems that can be studied in vivo via PET. We report the development of an electrowetting-on-dielectric (EWOD) digital microfluidic chip that can synthesize a variety of (18)F-labeled tracers targeting a range of biological processes by confirming complete syntheses of four radiotracers: a sugar, a DNA nucleoside, a protein labelling compound, and a neurotransmitter. The chip employs concentric multifunctional electrodes that are used for heating, temperature sensing, and EWOD actuation. All of the key synthesis steps for each of the four (18)F-labeled tracers are demonstrated and characterized with the chip: concentration of fluoride ion, solvent exchange, and chemical reactions. The obtained fluorination efficiencies of 90-95% are comparable to, or greater than, those achieved by conventional approaches.

[(18)F]fallypride was synthesized in a batch microfluidic chip with a radiochemical yield of 65 ± 6% (n = 7) and an average specific activity of 730 GBq μmol(-1) (20 Ci μmol(-1)) (n = 4). Specific activity was ~2-fold higher than [(18)F]fallypride synthesized in a macroscale radiosynthesizer, despite starting with significantly less radioactivity, and thus safer conditions, in the microchip.

Unlabelled: Access to diverse PET tracers for preclinical and clinical research remains a major obstacle to research in cancer and other disease research. The prohibitive cost and limited availability of tracers could be alleviated by microfluidic radiosynthesis technologies combined with a high-yield microscale radiosynthetic method. In this report, we demonstrate the multistep synthesis of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) with high yield on an electrowetting-on-dielectric (EWOD) microfluidic radiosynthesizer, previously developed in our group. We have identified and established several parameters that are most critical in the microscale radiosynthesis, such as the reaction time, reagent concentration, and molar ratios, to successfully synthesize (18)F-FLT in this compact platform., Methods: (18)F-FLT was synthesized from the 3-N-Boc-1-[5-O-(4,4'-dimethoxytrityl)-3-O-nosyl-2-deoxy-β-D-lyxofuranosyl] thymine precursor on the EWOD chip starting from the first solvent exchange and (18)F-fluoride ion activation step to the final deprotection step. The fluorination reaction was performed in a mixture of thexyl alcohol and dimethyl sulfoxide. The crude product after deprotection was collected from the chip and purified on a custom-made solid-phase extraction cartridge and subjected to quality control testing. The purified (18)F-FLT was suitable for small-animal PET studies in multiple nude mice xenografted with the A431 carcinoma cell line., Results: (18)F-FLT was successfully synthesized on the EWOD microdevice coupled with an off-chip solid-phase extraction purification with a decayed-corrected radiochemical yield of 63% ± 5% (n = 5) and passed all of the quality control tests required by the U.S. Pharmacopeia for radiotracers to be injected into humans. We have successfully demonstrated the synthesis of several batches of (18)F-FLT on EWOD, starting with approximately 333 MBq of radioactivity and obtained up to 52 MBq (non-decay-corrected) of (18)F-FLT on cartridge purification. The specific activity of 2 representative preparations of (18)F-FLT synthesized on the EWOD chip were measured to be 1,800 and 2,400 GBq/μmol., Conclusion: The EWOD microchip and optimized synthesis method in combination represent an effective platform for synthesizing (18)F-FLT with high yield and of good quality for imaging. This compact platform, with configurable synthesis steps, could potentially form the basis of a stand-alone system that decouples PET probe production from the cyclotron and specialized radiochemistry facilities and increases diversity and flexibility in probe production.

We present a simple microreactor with dimethyl sulfoxide (DMSO) phase-change valves suitable for performing batch organic chemistry under high temperature and pressure conditions. As a proof of principle, we demonstrate a radiofluorination reaction important in the synthesis of [(18)F]FAC, a new positron emission tomography biomarker for immune system monitoring and prediction of chemotherapy response. We achieved high radioactivity recovery (97 ± 1%, n = 3) and conversion efficiency (83 ± 1%, n = 3), comparable to that achieved with macroscale systems, but with a volume 30× smaller. This platform overcomes the limitations of previously reported phase-change valves in terms of compatibility with organic chemistry, and extends the range of reaction conditions for carrying out harsh batch chemistry at the microscale.

Microfluidic technologies provide an attractive platform for the synthesis of radiolabeled compounds. Visualization of radioisotopes on chip is critical for synthesis optimization and technological development. With Cerenkov imaging, beta particle emitting isotopes can be localized with a sensitive CCD camera. In order for Cerenkov imaging to also serve as a quantitative tool, it is necessary to understand how material properties relevant to Cerenkov emission, namely, index of refraction and beta particle stopping power, affect Cerenkov light output. In this report, we investigate the fundamental physical characteristics of Cerenkov photon yield at different stages of [(18)F]FDG synthesis on the electrowetting on dielectric (EWOD) microfluidic platform. We also demonstrate how Cerenkov imaging has enabled synthesis optimization. Geant4, a Monte Carlo program applied extensively in high energy physics, is used to simulate Cerenkov photon yield from (18)F beta particles traversing materials of interest during [(18)F]FDG synthesis on chip. Our simulations show that the majority (approximately two-thirds) of the (18)F beta particle energy available to produce Cerenkov photons is deposited on the glass plates of the EWOD chip. This result suggests the possibility of using a single calibration factor to convert Cerenkov signal to radioactivity, independent of droplet composition. We validate our simulations with a controlled measurement examining varying ratios of [(18)O]H2O, dimethyl sulfoxide (DMSO), and acetonitrile (MeCN), and find a consistent calibration independent of solvent composition. However, the calibration factor may underestimate the radioactivity in actual synthesis due to discoloration of the droplet during certain steps of probe synthesis. In addition to the attractive quantitative potential of Cerenkov imaging, this imaging strategy provides indispensable qualitative data to guide synthesis optimization. We are able to use this imaging technique to optimize the mixing protocol as well as identify and correct for loss of radioactivity due to the migration of radioactive vapor outside of the EWOD heater, enabling an overall increase in the crude radiochemical yield from 50 ± 3% (n = 3) to 72 ± 13% (n = 5).

Digital microfluidic chips provide a new platform for manipulating chemicals for multi-step chemical synthesis or assays at the microscale. The organic solvents and reagents needed for these applications are often volatile, sensitive to contamination, and wetting, i.e. have contact angles of <90° even on the highly hydrophobic surfaces (e.g., Teflon® or Cytop®) typically used on digital microfluidic chips. Furthermore, often the applications dictate that the processes are performed in a gas environment, not allowing the use of a filler liquid (e.g., oil). These properties pose challenges for delivering controlled volumes of liquid to the chip. An automated, simple, accurate and reliable method of delivering reagents from sealed, off-chip reservoirs is presented here. This platform overcomes the issues of evaporative losses of volatile solvents, cross-contamination, and flooding of the chip by combining a syringe pump, a simple on-chip liquid detector and a robust interface design. The impedance-based liquid detection requires only minimal added hardware to provide a feedback signal to ensure accurate volumes of volatile solvents are introduced to the chip, independent of time delays between dispensing operations. On-demand dispensing of multiple droplets of acetonitrile, a frequently used but difficult to handle solvent due to its wetting properties and volatility, was demonstrated and used to synthesize the positron emission tomography (PET) probe [(18)F]FDG reliably.

We demonstrate a new approach to impedance measurement on digital microfluidics chips for the purpose of simple, sensitive, and accurate volume and liquid composition measurement. Adding only a single series resistor to existing AC droplet actuation circuits, the platform is simple to implement and has negligible effect on actuation voltage. To accurately measure the complex voltage across the resistor (and hence current through the device and droplet), the designed system is based on software-implemented lock-in amplification detection of the voltage drop across the resistor which filters out noise, enabling high-resolution and low-limit signal recovery. We observe picoliter sensitivity with linear correlation of voltage to volume extending to the microliter volumes that can be handled by digital microfluidic devices. Due to the minimal hardware, the system is robust and measurements are highly repeatable. The detection technique provides both phase and magnitude information of the real-time current flowing through the droplet for a full impedance measurement. The sensitivity and resolution of this platform enables it to distinguish between various liquids which, as demonstrated in this paper, could potentially be extended to quantify solute concentrations, liquid mixtures, and presence of analytes.

We have developed an all-electronic digital microfluidic device for microscale chemical synthesis in organic solvents, operated by electrowetting-on-dielectric (EWOD). As an example of the principles, we demonstrate the multistep synthesis of [(18)F]FDG, the most common radiotracer for positron emission tomography (PET), with high and reliable radio-fluorination efficiency of [(18)F]FTAG (88 ± 7%, n = 11) and quantitative hydrolysis to [(18)F]FDG (> 95%, n = 11). We furthermore show that batches of purified [(18)F]FDG can successfully be used for PET imaging in mice and that they pass typical quality control requirements for human use (including radiochemical purity, residual solvents, Kryptofix, chemical purity, and pH). We report statistical repeatability of the radiosynthesis rather than best-case results, demonstrating the robustness of the EWOD microfluidic platform. Exhibiting high compatibility with organic solvents and the ability to carry out sophisticated actuation and sensing of reaction droplets, EWOD is a unique platform for performing diverse microscale chemical syntheses in small volumes, including multistep processes with intermediate solvent-exchange steps.

The preparation of polystyrene-coated cobalt oxide nanowires is reported via the colloidal polymerization of polymer-coated ferromagnetic cobalt nanoparticles (PS-CoNPs). Using a combination of dipolar nanoparticle assembly and a solution oxidation of preorganized metallic colloids, interconnected nanoparticles of cobalt oxide spanning micrometers in length were prepared. The colloidal polymerization of PS-CoNPs into cobalt oxide (CoO and Co(3)O(4)) nanowires was achieved by bubbling O(2) into PS-CoNP dispersions in 1,2-dichlorobenzene at 175 degrees C. Calcination of thin films of PS-coated cobalt oxide nanowires afforded Co(3)O(4) metal oxide materials. Transmission electron microscopy (TEM) revealed the formation of interconnected nanoparticles of cobalt oxide with hollow inclusions, arising from a combination of dipolar assembly of PS-CoNPs and the nanoscale Kirkendall effect in the oxidation reaction. Using a wide range of spectroscopic and electrochemical characterization techniques, we demonstrate that cobalt oxide nanowires prepared via this novel methodology were electroactive with potential applications as nanostructured electrodes for energy storage.

We describe the synthesis and characterization of polymer-coated ferromagnetic cobalt nanoparticles (CoNPs). The synthesis of end-functionalized polystyrene surfactants possessing amine, carboxylic acid, or phosphine oxide end-groups was accomplished using atom-transfer radical polymerization. This versatile synthetic method enabled the production of multigram quantities of these polymeric surfactants that stabilized ferromagnetic CoNPs when dispersed in organic media. An in-depth investigation into the synthesis of polystyrene-coated ferromagnetic CoNPs was also conducted using various combinations of these polymeric surfactants in the thermolysis of dicobaltoctacarbonyl (Co(2)(CO)(8)). Moreover, the application of a dual-stage thermolysis with Co(2)(CO)(8) allowed for the preparation of large samples (200-820 mg) per batch of well-defined and dispersable ferromagnetic nanoparticles. Characterization of these functionalized nanoparticle materials was then done using transmission electron microscopy, X-ray diffraction, vibrating sample magnetometry, and thermogravimetric analysis. Self-assembly of these dipolar nanoparticles was investigated in solutions cast onto supporting substrates, where local nematic-like ordering of nanoparticle chains was observed along with a tendency of adjacent chains to form "zippering" configurations, both phenomena having been predicted by recent simulations of dipolar fluids in conjunction with van der Waals interactions.