Thomas Velten

MICRON: Small Autonomous Robot for Cell Manipulation Applications

Manipulating in the micro- or even nano world still poses a great challenge to robotics. Conventional (stationary) systems suffer from drawbacks regarding integration into process supervision and multi-robot approaches, which become highly relevant to fight scaling effects. This paper describes work currently being carried out which aims to make automated manipulation of micrometer-scaled objects possible by robots with nanometer precision. The goal is to establish a small cluster of (up to five) micro robots equipped with on-board electronics, sensors and wireless power supply. Power autonomy has been reached using inductive energy transmission from an external wireless power supply system or a battery based system. Electronics requirements are fulfilled in the electronic module with the full custom integrated circuit design for the robot locomotion control and the closed loop force control for AFM tool in cell manipulation applications. The maximum velocity obtained is about 0.4 mm/s with a saw tooth voltage signals of 20Vpp and 2500 Hz. In order to keep a AFM tool on micro-robot a specific tip with integrated piezoresistance, instead of the classical laser beam methodology, is validated for force measurement.

Fully integrated monolithic optoelectronic transducer for real-time protein and DNA detection: The NEMOSLAB approach

The development and testing of a portable bioanalytical device which was capable for real-time monitoring of binding assays was demonstrated. The device was based on arrays of nine optoelectronic transducers monolithically integrated on silicon chips. The optocouplers consisted of nine silicon avalanche diodes self-aligned to nine silicon nitride waveguides all converging to a single silicon detector. The waveguides were biofunctionalized by appropriate recognition molecules. Integrated thick polymer microchannels provided the necessary fluidic functions to the chip. A single sided direct contact scheme through a board-to-board receptacle was developed and combined with a portable customized readout and control instrument. Real-time detection of deleterious mutations in BRCA1 gene related to predisposition to hereditary breast/ovarian cancer was performed with the instrument developed using PCR products. Detection was based on waveguided photons elimination through interaction with fluorescently labeled PCR products. Detection of single biomolecular binding events was also demonstrated using nanoparticles as labels. In addition, label-free monitoring of bioreactions in real time was achieved by exploiting wavelength filtering on photonic crystal engineered waveguides. The proposed miniaturized sensing device with proper packaging and accompanied by a portable instrument can find wide application as a platform for reliable and cost effective point-of-care diagnosis.

Manipulating biological cells with a micro-robot cluster

Micromanipulation is an appreciated and powerful method to modify biological material. By injecting DNA or specific liquids into a biological cell, designated reactions or behaviors can be provoked. The aim of this paper is to describe three components of a fully automated opticonsisting of a micro-robot cluster with an integrated micro-fluidic SyringeChip. The electronic system, microfluidic Syringe-Chip, and infrared communication are the components that have been built and are ready for integration into a MiCRoN robot. The concept of a biological cell manipulation with the aid of the integrated sub-systems is being presented here. The first injection experiment is done after completion of the MiCRoN robot-cluster.

Towards a cellular multi-parameter analysis platform: Fluorescence in situ hybridization (FISH) on microhole-array chips

Highly-sensitive analysis systems based on cellular multi-parameter are needed in the diagnostics. Therefore we improved our previously developed chip platform for another additional analysis method, the fluorescence in situ hybridization. Fluorescence in situ hybridization (FISH) is a technique used in the diagnostics to determine the localization and the presence or absence of specific DNA sequence. To improve this labor- and cost-intensive method, we reduced the assay consumption by a factor of 5 compared to the standard protocol. Microhole chips were used for making the cells well addressable. The chips were fabricated by semiconductor technology on the basis of a Silicon wafer with a thin deposited silicon nitride layer (Si3N4). Human retina pigment epithelia (ARPE-19) cells were arrayed on 5-μm holes of a 35×35 microhole-array by a gently negative differential pressure of around 5 mbar. After 3 hours of incubation the cells were attached to the chip and the FISH protocol was applied to the positioned cells. A LabView software was developed to simplify the analysis. The software automatically counts the number of dots (positive labeled chromosome regions) as well as the distance between adjacent dots. Our developed platform reduces the assay consumption and the labor time. Furthermore, during the 3 hours of incubation non-invasive or minimal-invasive methods like Raman- and impedance-spectroscopy can be applied.

A hybrid microfluidic system for cancer diagnosis based on MEMS biosensors

A microfluidic system for cancer diagnosis based around a core MEMS biosensor technology is presented in this paper. The principle of the MEMS biosensor is introduced and the functionalisation strategy for cancer marker recognition is described. In addition, the successful packaging and integration of functional MEMS biosensor devices are reported herein. This ongoing work represents one of the first hybrid systems to integrate a PCB packaged silicon MEMS device into a disposable microfluidic cartridge.

Diagnosing early Barrett’s neoplasia and oesophageal squamous cell neoplasia by bioimpedance spectroscopy in human tissue

Background Detection of early oesophageal cancer in surrounding normal tissue can be challenging, but detection is essential to determine the subsequent treatment. Dysplastic tissue can be detected by using electrical impedance spectroscopy (EIS). Objective The aim of the present study was to evaluate the feasibility and value of EIS in the diagnosis of oesophageal neoplasia. Methods This prospective ex-vivo study included 23 patients with early oesophageal cancer (17 with Barrett’s cancer and six with early squamous cell cancer). Immediately after endoscopic resection, the electrical properties of the resected specimens were investigated using a pencil probe (5 mm in diameter, frequency range from 100 Hz to 1 MHz). Punch biopsies were taken from the measured site in order to compare the results of EIS with histology. Results EIS was able to detect dysplastic oesophageal mucosa with a high rate of accuracy (82% in Barrett’s oesophagus and 100% in squamous oesophagus) A total of 54 different sites in 26 tumours were evaluated. Conclusions EIS was able to differentiate reliably between non-neoplastic and neoplastic oesophageal mucosa. Using EIS, it might be possible to use it for targeted biopsies and to avoid unnecessary biopsies during cancer surveillance in future.

Packaging of a silicon-based Biochip

We present a sophisticated method for the packaging of a micro-electro-mechanical biochip, which leaves the sensitive surface area of the chip uncovered to allow for direct contact to aqueous environment. Together with adequate integration in a fluidic cartridge, the packaging method allows for the realization of a lab-on-chip (LOC). A fluidic interface to the cartridge is provided as well as electrical interfaces to the biochip electronics located in a readout instrument. The biochip features a central membrane and electrodes, both located in the central chip area, and bond pads distributed along the rim of the chip. The packaging method ensures a hermetic separation between the membrane sensing area interfaced to liquids and the bond pad area. Challenging was the fact that both, the freely moving membrane and the bond pads for electrical interconnection are positioned very close to each other on the same chip surface area. We mounted the biochip into a recess of a rigid printed circuit board and electrically connected it to the latter with a proprietary MicroFlex Interconnection (MFI) technology. A customized coating method using a specially shaped silicone casting-mold ensured a very thin, hermetic encapsulation, which left the membrane safe and freely accessible.

Integration of a bioMEMS device into a disposable microfluidic cartridge for medical diagnostics

A microfluidic system for cancer diagnostics based around a core MEMS biosensor technology is presented in this paper. The principle of the MEMS biosensor is introduced and the functionalisation strategy for cancer marker recognition is described. In addition, the successful packaging and integration of functional MEMS biosensor devices are reported herein. This ongoing work represents one of the first hybrid systems to integrate a PCB packaged silicon MEMS device into a disposable microfluidic cartridge.

A hybrid MEMS-based microfluidic system for cancer diagnosis

A microfluidic system for cancer diagnosis based around a core MEMS biosensor technology is presented in this paper. The principle of the MEMS biosensor is introduced and the functionalisation strategy for cancer marker recognition is described. In addition, the successful packaging and integration of functional MEMS biosensor devices are reported herein. This ongoing work represents one of the first hybrid systems to integrate a PCB packaged silicon MEMS device into a disposable microfluidic cartridge.

Biocompatible Flow Sensor with Integrated Solvent Concentration Measurement

We report on the concept and development of two micro sensors for application in an intraoral drug delivery system (DDS) that has the size of two molar teeth. The micro sensors add intelligence to the DDS: a flow sensor measuring the mass flow of the drug solution and a concentration sensor detecting when the drug pill inside the DDS is going to be exhausted. Both sensors are monolithically integrated on one sensor chip having dimensions of 5times3times1 mm3. The flow sensor is optimized for a measuring range of 50 mul/h. The concentration sensor is able to measure concentrations which are around the solubility limit of the used drug substance. The sensor we report here provides the opportunity to dynamically measure the concentration in the close vicinity of the location where the mass flow is measured. Thus, the combined sensor is not only able to measure the flux of the drug solution but is also able to determine the flux of a dissolved substance at any time.