Marko Baller

Multiple label-free biodetection and quantitative DNA-binding assays on a nanomechanical cantilever array

We report a microarray of cantilevers to detect multiple unlabeled biomolecules simultaneously at nanomolar concentrations within minutes. Ligand-receptor binding interactions such as DNA hybridization or protein recognition occurring on microfabricated silicon cantilevers generate nanomechanical bending, which is detected optically in situ. Differential measurements including reference cantilevers on an array of eight sensors can sequence-specifically detect unlabeled DNA targets in 80-fold excess of nonmatching DNA as a background and discriminate 3′ and 5′ overhangs. Our experiments suggest that the nanomechanical motion originates from predominantly steric hindrance effects and depends on the concentration of DNA molecules in solution. We show that cantilever arrays can be used to investigate the thermodynamics of biomolecular interactions mechanically, and we have found that the specificity of the reaction on a cantilever is consistent with solution data. Hence cantilever arrays permit multiple binding assays in parallel and can detect femtomoles of DNA on the cantilever at a DNA concentration in solution of 75 nM.

A chemical sensor based on a microfabricated cantilever array with simultaneous resonance-frequency and bending readout

Abstract We present a chemical sensor based on a microfabricated array of eight silicon cantilevers actuated at their resonance-frequency and functionalized by polymer coatings. The operating principle relies on transduction of chemical or physical processes into a mechanical response. After exposure to analyte vapor, analyte molecules diffuse into the cantilever coating, which begins to swell. Jointly with the mass increase, a change of interfacial stress between coating and cantilever occurs, resulting in a bending of the cantilevers. Our setup allows the simultaneous detection of cantilever oscillation and bending of eight cantilevers by time-multiplexed optical beam deflection readout. The ac component of the cantilever response is demodulated, and the cantilever resonance-frequency is tracked by a custom-built phase-locked loop. By filtering out the ac component (oscillation), the dc signal (bending) is extracted, yielding information on mass as well as surface stress changes simultaneously. Detection results of water, primary alcohols, alkanes and perfumes are presented.

A cantilever array-based artificial nose

We present quantitative and qualitative detection of analyte vapors using a microfabricated silicon cantilever array. To observe transduction of physical and chemical processes into nanomechanical motion of the cantilever, swelling of a polymer layer on the cantilever is monitored during exposure to the analyte. This motion is tracked by a beam-deflection technique using a time multiplexing scheme. The response pattern of eight cantilevers is analyzed via principal component analysis (PCA) and artificial neural network (ANN) techniques, which facilitates the application of the device as an artificial chemical nose. Analytes tested comprise chemical solvents, a homologous series of primary alcohols, and natural flavors. First differential measurements of surface stress change due to protein adsorption on a cantilever array are shown using a liquid cell.

An artificial nose based on a micromechanical cantilever array

A novel chemical sensor based on a micromechanical array of silicon cantilevers is presented. Chemical reactions are transduced by sensitization of cantilevers with coatings such as metals, self-assembled monolayers, or polymers into a mechanical response. This is read out using an optical beam-deflection technique by a sequential readout scheme. Reference cantilever sensors permit subtraction of background signals (differential measurement). Coating of each cantilever sensor with a different sensitive layer allows operation of the array-device as a new form of chemical nose. Detection of hydrogen, primary alcohols, natural flavors, and water vapor is demonstrated. We show that the magnitude of sensor response is proportional to the amount of analyte present.

A nanomechanical device based on linear molecular motors

An array of microcantilever beams, coated with a self-assembled monolayer of bistable, redox-controllable [3]rotaxane molecules, undergoes controllable and reversible bending when it is exposed to chemical oxidants and reductants. Conversely, beams that are coated with a redox-active but mechanically inert control compound do not display the same bending. A series of control experiments and rational assessments preclude the influence of heat, photothermal effects, and pH variation as potential mechanisms of beam bending. Along with a simple calculation from a force balance diagram, these observations support the hypothesis that the cumulative nanoscale movements within surface-bound “molecular muscles” can be harnessed to perform larger-scale mechanical work.

The nanomechanical NOSE

We present a novel chemical sensor based on a microfabricated array of silicon cantilevers. Individual cantilevers are sensitized for the detection of analytes using metal coatings. Analyte molecules chemisorbing or physisorbing on the cantilever coating and chemical reactions produce a change in interfacial stress between analyte molecules and cantilever. This leads to a nanomechanical response of the cantilever, i.e. bending. The bending is read out using a time-multiplexed optical beam-deflection technique. From magnitude and temporal evolution of the bending, quantitative information on analyte species and concentration is derived. Here, we demonstrate the detection of ethene and water vapor with such a nanomechanical nose.

Microfluidic reactor geometries for radiolysis reduction in radiopharmaceuticals

Autoradiolysis describes the degradation of radioactively labeled compounds due to the activity of the labeled compounds themselves. It scales with activity concentration and is of importance for high activity and microfluidic PET tracer synthesis. This study shows that microfluidic devices can be shaped to reduce autoradiolysis by geometric exclusion of positron interaction. A model is developed and confirmed by demonstrating in-capillary storage of non-stabilized [(18)F]FDG (2-[(18)F]Fluoro-2-deoxy-d-glucose) at max. 23 GBq/ml while maintaining >90% radiochemical purity over 14 h.

A solvent resistant lab-on-chip platform for radiochemistry applications

The application of microfluidics to the synthesis of Positron Emission Tomography (PET) tracers has been explored for more than a decade. Microfluidic benefits such as superior temperature control have been successfully applied to PET tracer synthesis. However, the design of a compact microfluidic platform capable of executing a complete PET tracer synthesis workflow while maintaining prospects for commercialization remains a significant challenge. This study uses an integral system design approach to tackle commercialization challenges such as the material to process compatibility with a path towards cost effective lab-on-chip mass manufacturing from the start. It integrates all functional elements required for a simple PET tracer synthesis into one compact radiochemistry platform. For the lab-on-chip this includes the integration of on-chip valves, on-chip solid phase extraction (SPE), on-chip reactors and a reversible fluid interface while maintaining compatibility with all process chemicals, temperatures and chip mass manufacturing techniques. For the radiochemistry device it includes an automated chip-machine interface enabling one-move connection of all valve actuators and fluid connectors. A vial-based reagent supply as well as methods to transfer reagents efficiently from the vials to the chip has been integrated. After validation of all those functional elements, the microfluidic platform was exemplarily employed for the automated synthesis of a Gastrin-releasing peptide receptor (GRP-R) binding the PEGylated Bombesin BN(7-14)-derivative ([(18)F]PESIN) based PET tracer.

Photonic bandgap fiber enabled Raman detection of nitrogen gas

Raman detection of nitrogen gas is very difficult without a multi-pass arrangement and high laser power. Hollow-core photonic bandgap fibers (HC-PBF) provide an excellent means of concentrating light energy in a very small volume and long interaction path between gas and laser. One particular commercial fiber with a core diameter of 4.9 microns offers losses of about 1dB/m for wavelengths between 510 and 610 nm. If 514nm laser is used for excitation, the entire Raman spectrum up to above 3000 cm-1 will be contained within the transmission band of the fiber. A standard Raman microscope launches mW level 514nm laser light into the PBF and collects backscattered Raman signal exiting the fiber. The resulting spectra of nitrogen gas in air at ambient temperature and pressure exhibit a signal enhancement of about several thousand over what is attainable with the objective in air and no fiber. The design and fabrication of a flow-through cell to hold and align the fiber end allowed the instrument calibration for varying concentrations of nitrogen. The enhancement was also found to be a function of fiber length. Due to the high achieved Raman signal, rotational spectral of nitrogen and oxygen were observed in the PBF for the first time to the best of our knowledge.

An Electronic Nose Based on A Micromechanical Cantilever Array

We present a novel chemical sensor based on a micromechanical array of silicon cantilevers sensitized for the detection of analytes using cantilever coatings such as metals, self-assembled monolayers, or polymers. Chemical reactions are transduced into a mechanical response and read out using an optical beam-deflection technique. Detection of primary alcohols, natural flavors, and water vapor is demonstrated.