Magnetic polymer actuators for microfluidics

The manipulation of fluids on the sub-millimetre scale -microfluidics- finds application in the miniaturisation and integration of biological analysis, chemical synthesis, optics and information technology. In a microfluidic device, fluids need to be transported, mixed, separated and directed in and through a micro-scale system. The effcient mixing of fluids -particularly needed for analysis or synthesis -presents a large challenge in microfluidics. Mixing cannot occur by turbulence because of the low Reynolds number that prevails in micro-channels, and molecular diffusion is rather slow in achieving mixing on the scale of a microfluidic channel. A solution for obtaining mixing on efficient time scales has been to passively or actively manipulate the fluids to induce chaotic advection and increase the interfacial area of two fluids progressively, thereby decreasing the length scale over which diffusion has to take place to mix the fluids. In this thesis we investigate magnetic polymer micro-actuators that can be incorporated on the walls of microfluidic channels and can be actuated with magnetic fields. A magnetic stimulus that addresses micro-actuators is very robust, because of the low interaction between magnetic fields and (bio)chemical fluids. The use of polymeric materials for producing micro-actuators potentially allows for cost-effective micro-devices with integrated fluidic actuation. The aim of the thesis is to provide generic and advanced fluid control inside microfluidic devices, e.g: for the purpose of integrated pumping or for the purpose of mixing. Superparamagnetic and ferromagnetic particles have been dispersed in polymers with a low elastic modulus and the composites have been characterised mechanically and magnetically. A low elastic modulus polymer enables large deflections of micro-actuators with practical magnetic fields. In this thesis, various types of the elastomer polydimethylsiloxane (PDMS) have been used for constructing the polymeric micro-actuators with a low elastic modulus. The efficiency of magnetic actuation on small scales is discussed for two actuator concepts. It is shown that actuation by magnetic torque scales neutrally with miniaturisation, allowing for actuation with externally generated magnetic fields. In contrast, actuation by magnetic gradient force scales inversely proportional to the size of the actuator. Therefore magnetic gradient actuation cannot be induced by an external electromagnet and requires a localised generation of magnetic fields. Because viscous effects dominate over inertial effects at small scales (Reynolds number <1), symmetric and in-phase movements of micro-actuators would induce no net fluid flow. Therefore the generation of asymmetric or out-of-phase movements of microactuators has been investigated for each actuator concept. The interaction of magnetic particles embedded in PDMS has been studied and compared to the interactions in a ferrofluid. The enhancement of magnetic susceptibility due to the particle interactions was found to be limited because of the clustering of magnetic particles in the polymer that induces local demagnetisation. The alignment of clusters of particles in a magnetic field was investigated and the resulting magnetic anisotropy was quantified. Modelling has established that such an intrinsic magnetic anisotropy for an actuator can provide an increase in actuation amplitude up to one order of magnitude, for the same stimulus. The magnetic PDMS composites developed in this thesis have been used to fabricate high aspect ratio micro-actuators that are standing or lying on a substrate. Standing superparamagnetic PDMS micro-actuators were produced by mould replication. The standing micro-actuators have been actuated locally with the high magnetic field gradient generated by an integrated current wire (resulting in actuation by magnetic gradient force). The local stimulus allows for individual addressing of the micro-actuators and potentially enables out-of-phase movements of adjacent actuators. Possible geometries for the actuator device have been explored with models that describe the deffection of the actuators and the heat dissipation in the current wire. The fabricated micro-actuators were found to respond to the magnetic stimulus of the current wire but also to the thermal stimulus associated to the heat dissipation in the current wire, because of temperature dependent swelling of the micro-actuators in a solvent. The different time scales of magnetic and thermal actuation allowed the creation of an asymmetric movement. The standing micro-actuators have also been actuated by a homogeneous magnetic field generated by an external electromagnet (resulting in actuation by magnetic torque). A non-constant phase lag was demonstrated between actuators having different amplitudes of defection, which can potentially provide efficient mixing on small scales. The high frequency actuation of the standing micro-actuators was found to be limited to 5 Hz, which we attribute to the viscous behaviour of the PDMS. Lying ferromagnetic PDMS micro-actuators were produced with lithographic and sacrificial layer techniques. The lying micro-actuators have been actuated by a homogeneous magnetic field generated by an external electromagnet (resulting in actuation by magnetic torque). The permanent magnetisation of the actuators allowed for much larger deflections than for the standing superparamagnetic actuators. For a specific initial magnetisation of the actuators and using a rotating magnetic field, the actuators were shown to exhibit selectively either a symmetric or an asymmetric movement. The actuation at high frequencies of the microactuators was limited by the viscous drag in fluid and, in our experiments, by the high frequency limitations of the electromagnet. The micro-actuators could operate up to a frequency of 50 Hz, which is one order of magnitude higher than for the standing super paramagnetic actuators. The higher actuation frequency indicated that the type of PDMS used to fabricate the lying ferromagnetic micro-actuators exhibits less viscous behaviour. In a microfluidic cavity, the lying ferromagnetic micro-actuators induced local vortices or translational net fluid flows, depending on their initial magnetisation. Two micro-actuators pointing in opposite directions were actuated fully independently with the same external stimulus, depending on the rotation direction of the magnetic field. The different re-magnetisation in each case could explain the possibility for individual actuation. Provided with this independent actuation, two sets of vortices can be controlled individually in a microfluidic device, which is particularly promising to mix fluids with e.g: a blinking vortex protocol. The observed translational net fluid flows can in principle provide integrated pumping in microfluidic device

From Sensors to Silencers: Quinoline- and Benzimidazole-Sulfonamides as Inhibitors for Zinc Proteases

Derived from the extensive work in the area of small molecule zinc(II) ion sensors, chelating fragment libraries of quinoline- and benzimidazole-sulfonamides have been prepared and screened against several different zinc(II)-dependent matrix metalloproteinases (MMPs). The fragments show impressive inhibition of these metalloenzymes and preferences for different MMPs based on the nature of the chelating group. The findings show that focused chelator libraries are a powerful strategy for the discovery of lead fragments for metalloprotein inhibition

A high-pressure hydrogen time projection chamber for the MuCap experiment

The MuCap experiment at the Paul Scherrer Institute performed a high-precision measurement of the rate of the basic electroweak process of nuclear muon capture by the proton, $\mu^- + p \rightarrow n + \nu_\mu$. The experimental approach was based on the use of a time projection chamber (TPC) that operated in pure hydrogen gas at a pressure of 10 bar and functioned as an active muon stopping target. The TPC detected the tracks of individual muon arrivals in three dimensions, while the trajectories of outgoing decay (Michel) electrons were measured by two surrounding wire chambers and a plastic scintillation hodoscope. The muon and electron detectors together enabled a precise measurement of the $\mu p$ atom's lifetime, from which the nuclear muon capture rate was deduced. The TPC was also used to monitor the purity of the hydrogen gas by detecting the nuclear recoils that follow muon capture by elemental impurities. This paper describes the TPC design and performance in detail.Comment: 15 pages, 13 figures, to be submitted to Eur. Phys. J. A; clarified section 3.1.2 and made minor stylistic corrections for Eur. Phys. J. A requirement

High-Affinity Cu(I)-Chelator with Potential Anti-Tumorigenic Action-A Proof-of-Principle Experimental Study of Human H460 Tumors in the CAM Assay

Human lung cancer ranks among the most frequently treated cancers worldwide. As copper appears critical to angiogenesis and tumor growth, selective removal of copper represents a promising strategy to restrict tumor growth. To this end, we explored the activity of the novel high-affinity membrane-permeant Cu(I) chelator PSP-2 featuring a low-zeptomolar dissociation constant. Using H460 human lung cancer cells, we generated small tumors on the chorioallantoic membrane of the chicken embryo (CAM assay) and studied the effects of topical PSP-2 application on their weight and vessel density after one week. We observed a significant angiosuppression along with a marked decrease in tumor weight under PSP-2 application compared to controls. Moreover, PSP-2 exposure resulted in lower ki67+ cell numbers at a low dose but increased cell count under a high dose. Moreover, HIF-1α+ cells were significantly reduced with low-dose PSP-2 exposure compared to high-dose and control. The total copper content was considerably lower in PSP-2 treated tumors, although statistically not significant. Altogether, PSP-2 shows promising potential as an anti-cancer drug. Nevertheless, further animal experiments and application to different tumor types are mandatory to support these initial findings, paving the way toward clinical trials. Keywords: CAM assay; angiogenesis; copper chelation; human lung cance

Technical design of the phase I Mu3e experiment

The Mu3e experiment aims to find or exclude the lepton flavour violating decay at branching fractions above . A first phase of the experiment using an existing beamline at the Paul Scherrer Institute (PSI) is designed to reach a single event sensitivity of . We present an overview of all aspects of the technical design and expected performance of the phase I Mu3e detector. The high rate of up to muon decays per second and the low momenta of the decay electrons and positrons pose a unique set of challenges, which we tackle using an ultra thin tracking detector based on high-voltage monolithic active pixel sensors combined with scintillating fibres and tiles for precise timing measurements

Technical design of the phase I Mu3e experiment

The Mu3e experiment aims to find or exclude the lepton flavour violating decay $\mu \rightarrow eee$ at branching fractions above $10^{-16}$. A first phase of the experiment using an existing beamline at the Paul Scherrer Institute (PSI) is designed to reach a single event sensitivity of $2\cdot 10^{-15}$. We present an overview of all aspects of the technical design and expected performance of the phase~I Mu3e detector. The high rate of up to $10^{8}$ muon decays per second and the low momenta of the decay electrons and positrons pose a unique set of challenges, which we tackle using an ultra thin tracking detector based on high-voltage monolithic active pixel sensors combined with scintillating fibres and tiles for precise timing measurements.Comment: 114 pages, 185 figures. Submitted to Nuclear Instruments and Methods A. Edited by Frank Meier Aeschbacher This version has many enhancements for better readability and more detail

Technical design of the phase I Mu3e experiment

The Mu3e experiment aims to find or exclude the lepton flavour violating decay μ→eee at branching fractions above 10−16. A first phase of the experiment using an existing beamline at the Paul Scherrer Institute (PSI) is designed to reach a single event sensitivity of 2⋅10−15. We present an overview of all aspects of the technical design and expected performance of the phase I Mu3e detector. The high rate of up to 108 muon decays per second and the low momenta of the decay electrons and positrons pose a unique set of challenges, which we tackle using an ultra thin tracking detector based on high-voltage monolithic active pixel sensors combined with scintillating fibres and tiles for precise timing measurements

Seminaphthofluorescein-Based Fluorescent Probes for Imaging Nitric Oxide in Live Cells

Fluorescent turn-on probes for nitric oxide based on seminaphthofluorescein scaffolds were prepared and spectroscopically characterized. The Cu(II) complexes of these fluorescent probes react with NO under anaerobic conditions to yield a 20–45-fold increase in integrated emission. The seminaphthofluorescein-based probes emit at longer wavelengths than the parent FL1 and FL2 fluorescein-based generations of NO probes, maintaining emission maxima between 550 and 625 nm. The emission profiles depend on the excitation wavelength; maximum fluorescence turn-on is achieved at excitations between 535 and 575 nm. The probes are highly selective for NO over other biologically relevant reactive nitrogen and oxygen species including NO3–, NO2–, HNO, ONOO–, NO2, OCl–, and H2O2. The seminaphthofluorescein-based probes can be used to visualize endogenously produced NO in live cells, as demonstrated using Raw 264.7 macrophages.National Science Foundation (U.S.) (CHE-0611944)National Institutes of Health (U.S.) (K99GM092970

Zinc homeostasis and signaling in health and diseases: Zinc signaling

The essential trace element zinc (Zn) is widely required in cellular functions, and abnormal Zn homeostasis causes a variety of health problems that include growth retardation, immunodeficiency, hypogonadism, and neuronal and sensory dysfunctions. Zn homeostasis is regulated through Zn transporters, permeable channels, and metallothioneins. Recent studies highlight Zn’s dynamic activity and its role as a signaling mediator. Zn acts as an intracellular signaling molecule, capable of communicating between cells, converting extracellular stimuli to intracellular signals, and controlling intracellular events. We have proposed that intracellular Zn signaling falls into two classes, early and late Zn signaling. This review addresses recent findings regarding Zn signaling and its role in physiological processes and pathogenesis