Characterization of a new class of surface micromachined pumps.

This is the latest in a series of LDRD's that we have been conducting with Florida State University/Florida A&M University (FSU/FAMU) under the campus executive program. This research builds on the earlier projects; ''Development of Highly Integrated Magnetically and Electrostatically Actuated Micropumps'' (SAND2003-4674) and ''Development of Magnetically and Electrostatically Driven Surface Micromachined Pumps'' (SAND2002-0704P). In this year's LDRD we designed 2nd generation of surface micromachined (SMM) gear and viscous pumps. Two SUMMiT{trademark} modules full of design variations of these pumps were fabricated and one SwIFT{trademark} module is still in fabrication. The SwIFT{trademark} fabrication process results in a transparent pump housing cover that will enable visualization inside the pumps. Since the SwIFT{trademark} pumps have not been tested as they are still in fabrication, this report will focus on the 2nd generation SUMMiT{trademark} designs. Pump testing (pressure vs. flow) was conducted on several of the SUMMiT{trademark} designs resulting in the first pump curve for this class of SMM pumps. A pump curve was generated for the higher torque 2nd generation gear pump designed by Jason Hendrix of FSU. The pump maximum flow rate at zero head was 6.5 nl/s for a 30V, 30 Hz square wave signal. This level of flow rate would be more than adequate for our typical SMM SUMMiT{trademark} or SwIFT{trademark} channels which have typical volumes on the order of 50 pl

Safety analysis of high pressure 3He-filled micro-channels for thermal neutron detection.

This document is a safety analysis of a novel neutron detection technology developed by Sandia National Laboratories. This technology is comprised of devices with tiny channels containing high pressure {sup 3}He. These devices are further integrated into large scale neutron sensors. Modeling and preliminary device testing indicates that the time required to detect the presence of special nuclear materials may be reduced under optimal conditions by several orders of magnitude using this approach. Also, these devices make efficient use of our {sup 3}He supply by making individual devices more efficient and/or extending the our limited {sup 3}He supply. The safety of these high pressure devices has been a primary concern. We address these safety concerns for a flat panel configuration intended for thermal neutron detection. Ballistic impact tests using 3 g projectiles were performed on devices made from FR4, Silicon, and Parmax materials. In addition to impact testing, operational limits were determined by pressurizing the devices either to failure or until they unacceptably leaked. We found that (1) sympathetic or parasitic failure does not occur in pressurized FR4 devices (2) the Si devices exhibited benign brittle failure (sympathetic failure under pressure was not tested) and (3) the Parmax devices failed unacceptably. FR4 devices were filled to pressures up to 4000 + 100 psig, and the impacts were captured using a high speed camera. The brittle Si devices shattered, but were completely contained when wrapped in thin tape, while the ductile FR4 devices deformed only. Even at 4000 psi the energy density of the compressed gas appears to be insignificant compared to the impact caused by the incoming projectile. In conclusion, the current FR4 device design pressurized up to 4000 psi does not show evidence of sympathetic failure, and these devices are intrinsically safe

Meso-scale controlled motion for a microfluidic drop ejector.

The objective of this LDRD was to develop a uniquely capable, novel droplet solution based manufacturing system built around a new MEMS drop ejector. The development all the working subsystems required was completed, leaving the integration of these subsystems into a working prototype still left to accomplish. This LDRD report will focus on the three main subsystems: (1) MEMS drop ejector--the MEMS ''sideshooter'' effectively ejected 0.25 pl drops at 10 m/s, (2) packaging--a compact ejector package based on a modified EMDIP (Electro-Microfluidic Dual In-line Package--SAND2002-1941) was fabricated, and (3) a vision/stage system allowing precise ejector package positioning in 3 dimensions above a target was developed

Magnetophoretic bead trapping in a high-flowrate biological detection system.

This report contains the summary of the 'Magnetophoretic Bead Trapping in a High-Flowrate Biological Detection System' LDRD project 74795. The objective of this project is to develop a novel biodetection system for high-throughput sample analysis. The chief application of this system is in detection of very low concentrations of target molecules from a complex liquid solution containing many different constituents--some of which may interfere with identification of the target molecule. The system is also designed to handle air sampling by using an aerosol system (for instance a WESP - Wet Electro-Static Precipitator, or an impact spray system) to get air sample constituents into the liquid volume. The system described herein automatically takes the raw liquid sample, whether air converted or initially liquid matrix, and mixes in magnetic detector beads that capture the targets of interest and then performs the sample cleanup function, allowing increased sensitivity and eliminating most false positives and false negatives at a downstream detector. The surfaces of the beads can be functionalized in a variety of ways in order to maximize the number of targets to be captured and concentrated. Bacteria and viruses are captured using antibodies to surface proteins on bacterial cell walls or viral particle coats. In combination with a cell lysis or PCR (Polymerase Chain Reaction), the beads can be used as a DNA or RNA probe to capture nucleic acid patterns of interest. The sample cleanup capability of this system would allow different raw biological samples, such as blood or saliva to be analyzed for the presence of different infectious agents (e.g. smallpox or SARS). For future studies, we envision functionalizing bead surfaces to bind to chemical weapons agents, radio-isotopes, and explosives. The two main objectives of this project were to explore methods for enhancing the mixing of the capture microspheres in the sample, and to develop a novel high-throughput magnetic microsphere trap. We have developed a novel technique using the magnetic capture microspheres as 'stirrer bars' in a fluid sample to enhance target binding to the microsphere surfaces. We have also made progress in developing a polymer-MEMS electromagnet for trapping magnetic spheres in a high-flowrate fluid format

Viral RNA testing and automation on the bead-based CBNE detection microsystem.

We developed prototype chemistry for nucleic acid hybridization on our bead-based diagnostics platform and we established an automatable bead handling protocol capable of 50 part-per-billion (ppb) sensitivity. We are working towards a platform capable of parallel, rapid (10 minute), raw sample testing for orthogonal (in this case nucleic acid and immunoassays) identification of biological (and other) threats in a single sensor microsystem. In this LDRD we developed the nucleic acid chemistry required for nucleic acid hybridization. Our goal is to place a non-cell associated RNA virus (Bovine Viral Diarrhea, BVD) on the beads for raw sample testing. This key pre-requisite to showing orthogonality (nucleic acid measurements can be performed in parallel with immunoassay measurements). Orthogonal detection dramatically reduces false positives. We chose BVD because our collaborators (UC-Davis) can supply samples from persistently infected animals; and because proof-of-concept field testing can be performed with modification of the current technology platform at the UC Davis research station. Since BVD is a cattle-prone disease this research dovetails with earlier immunoassay work on Botulinum toxin simulant testing in raw milk samples. Demonstration of BVD RNA detection expands the repertoire of biological macromolecules that can be adapted to our bead-based detection. The resources of this late start LDRD were adequate to partially demonstrate the conjugation of the beads to the nucleic acids. It was never expected to be adequate for a full live virus test but to motivate that additional investment. In addition, we were able to reduce the LOD (Limit of Detection) for the botulinum toxin stimulant to 50 ppb from the earlier LOD of 1 ppm. A low LOD combined with orthogonal detection provides both low false negatives and low false positives. The logical follow-on steps to this LDRD research are to perform live virus identification as well as concurrent nucleic acid and immunoassay detection

Development of highly integrated magetically and electrostatically actuated micropumps : LDRD 64709 final report.

The pump and actuator systems designed and built in the SUMMiT{trademark} process, Sandia's surface micromachining polysilicon MEMS (Micro-Electro-Mechanical Systems) fabrication technology, on the previous campus executive program LDRD (SAND2002-0704P) with FSU/FAMU (Florida State University/Florida Agricultural and Mechanical University) were characterized in this LDRD. These results demonstrated that the device would pump liquid against the flow resistance of a microfabricated channel, but the devices were determined to be underpowered for reliable pumping. As a result a new set of SUMMiT{trademark} pumps with actuators that generate greater torque will be designed and submitted for fabrication. In this document we will report details of dry actuator/pump assembly testing, wet actuator/pump testing, channel resistance characterization, and new pump/actuator design recommendations

Open‐label, clinical trial extension:Two‐year safety and efficacy results of seladelpar in patients with primary biliary cholangitis

SummaryBackgroundSeladelpar is a potent and selective peroxisome proliferator‐activated receptor‐δ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti‐cholestatic, anti‐inflammatory and anti‐pruritic effects.AimsTo evaluate the long‐term safety and efficacy of seladelpar in patients with PBC.MethodsIn an open‐label, international, long‐term extension study, patients with PBC completing seladelpar lead‐in studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10 mg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non‐alcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2 years.ResultsThere were no serious treatment‐related adverse events observed among 106 patients treated with seladelpar for up to 2 years. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2 years of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] &lt;1.67 × ULN, ≥15% decrease in ALP, and total bilirubin ≤ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2.ConclusionsSeladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year. Clinicaltrials.gov: NCT03301506; Clinicaltrialsregister.eu: 2017‐003910‐16.</jats:sec

Open-label, clinical trial extension: Two-year safety and efficacy results of seladelpar in patients with primary biliary cholangitis

BACKGROUND: Seladelpar is a potent and selective peroxisome proliferator-activated receptor-δ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti-cholestatic, anti-inflammatory and anti-pruritic effects. AIMS: To evaluate the long-term safety and efficacy of seladelpar in patients with PBC. METHODS: In an open-label, international, long-term extension study, patients with PBC completing seladelpar lead-in studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10 mg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non-alcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2 years. RESULTS: There were no serious treatment-related adverse events observed among 106 patients treated with seladelpar for up to 2 years. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2 years of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] <1.67 × ULN, ≥15% decrease in ALP, and total bilirubin ≤ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2. CONCLUSIONS: Seladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year

An Interdisciplinary Consensus Approach to Pulmonary Hypertension in Developmental Lung Disease

It is increasingly recognised that diverse genetic respiratory disorders present as severe pulmonary hypertension (PH) in the neonate and young infant, but many controversies and uncertainties persist regarding optimal strategies for diagnosis and management to maximise long-term outcomes. To better define the nature of PH in the setting of developmental lung disease (DEVLD), in addition to the common diagnoses of bronchopulmonary dysplasia and congenital diaphragmatic hernia, we established a multidisciplinary group of expert clinicians from stakeholder paediatric specialties to highlight current challenges and recommendations for clinical approaches, as well as counselling and support of families. In this review, we characterise clinical features of infants with DEVLD/DEVLD-PH and identify decision-making challenges including genetic evaluations, the role of lung biopsies, the use of imaging modalities and treatment approaches. The importance of working with team members from multiple disciplines, enhancing communication and providing sufficient counselling services for families is emphasised to create an interdisciplinary consensus

Microsystem strategies for sample preparation in biological detection.

The objective of this LDRD was to develop microdevice strategies for dealing with samples to be examined in biological detection systems. This includes three sub-components: namely, microdevice fabrication, sample delivery to the microdevice, and sample processing within the microdevice. The first component of this work focused on utilizing Sandia's surface micromachining technology to fabricate small volume (nanoliter) fluidic systems for processing small quantities of biological samples. The next component was to develop interfaces for the surface-micromachined silicon devices. We partnered with Micronics, a commercial company, to produce fluidic manifolds for sample delivery to our silicon devices. Pressure testing was completed to examine the strength of the bond between the pressure-sensitive adhesive layer and the silicon chip. We are also pursuing several other methods, both in house and external, to develop polymer-based fluidic manifolds for packaging silicon-based microfluidic devices. The second component, sample processing, is divided into two sub-tasks: cell collection and cell lysis. Cell collection was achieved using dielectrophoresis, which employs AC fields to collect cells at energized microelectrodes, while rejecting non-cellular particles. Both live and dead Staph. aureus bacteria have been collected using RF frequency dielectrophoresis. Bacteria have been separated from polystyrene microspheres using frequency-shifting dielectrophoresis. Computational modeling was performed to optimize device separation performance, and to predict particle response to the dielectrophoretic traps. Cell lysis is continuing to be pursued using microactuators to mechanically disrupt cell membranes. Novel thermal actuators, which can generate larger forces than previously tested electrostatic actuators, have been incorporated with and tested with cell lysis devices. Significant cell membrane distortion has been observed, but more experiments need to be conducted to determine the effects of the observed distortion on membrane integrity and cell viability. Finally, we are using a commercial PCR DNA amplification system to determine the limits of detectable sample size, and to examine the amplification of DNA bound to microspheres. Our objective is to use microspheres as capture-and-carry chaperones for small molecules such as DNA and proteins, enabling the capture and concentration of the small molecules using dielectrophoresis. Current tests demonstrated amplification of DNA bound to micron-sized polystyrene microspheres using 20-50 microliter volume size reactions