Wendy Uyen Dittmer

Rapid integrated biosensor for multiplexed immunoassays based on actuated magnetic nanoparticles

The realization of biomolecular detection assays for diagnostic purposes is technologically very challenging because such tests demand full integration for ease of use and need to deliver a high analytical performance with cost-effective use of materials. In this article an optomagnetic immunoassay technology is described based on nanoparticles that are magnetically actuated and optically detected in a stationary sample fluid. The dynamic control of nanoparticles by magnetic fields impacts the key immunoassay process steps, giving unprecedented speed, assay control and seamless integration of the total test. The optical detection yields sensitive and multiplexed assays in a low-cost disposable cartridge. We demonstrate that the optomagnetic technology enables high-sensitivity one-step assays in blood serum/plasma and whole saliva. Drugs of abuse are detected at sub-nanogram per millilitre levels in a total assay time of 1 min, and the cardiac marker troponin I is detected at sub-picomole per litre concentrations in a few minutes. The optomagnetic technology is fundamentally suited for high-performance integrated testing and is expected to open a new paradigm in biosensing.

Rapid, high sensitivity, point-of-care test for cardiac troponin based on optomagnetic biosensor

BACKGROUND We present a prototype handheld device based on a newly developed optomagnetic technology for the sensitive detection of cardiac troponin I (cTnI) in a finger-prick blood sample with a turnaround time of 5 min. METHODS The test was completed in a compact plastic disposable with on-board dry reagents and superparamagnetic nanoparticles. In our one-step assay, all reaction processes were precisely controlled using electromagnets positioned above and below the disposable. Nanoparticle labels (500 nm) bound to the sensor surface via a sandwich immunoassay were detected using the optical technique of frustrated total internal reflection. RESULTS A calibration function measured in plasma demonstrates a limit of detection (mean of blank plus 3-fold the standard deviation) of 0.03 ng/mL cTnI. A linear regression analysis of the region 0.03-6.5 ng/mL yields a slope of 37+/-4, and a linear correlation coefficient of R2=0.98. The measuring range could be extended substantially to 100 ng/mL by simultaneously imaging a second spot with a lower antibody concentration. CONCLUSIONS The combination of magnetic particles and their fine actuation with electromagnets permits the rapid and sensitive detection of cTnI. Because of the potential high analytical performance and ease-of-use of the test, it is well suited for demanding point-of-care diagnostic applications.

Sensitive and rapid immunoassay for parathyroid hormone using magnetic particle labels and magnetic actuation.

A rapid method for the sensitive detection of proteins using actuated magnetic particle labels, which are measured with a giant magneto-resistive (GMR) biosensor, is described. The technique involves a 1-step sandwich immunoassay with no fluid replacement steps. The various assay binding reactions as well as the bound/free separation are entirely controlled by magnetic forces induced by electromagnets above and below the sensor chip. During the assay, particles conjugated with tracer antibodies are actuated through the sample for target capture, and rapidly brought to the sensor surface where they bind to immobilized capture antibodies. Weakly or unbound labels are removed with a magnetic force oriented away from the GMR sensor surface. For the measurement of parathyroid hormone (PTH), a detection limit in the 10 pM range is obtained with a total assay time of 15 min when 300 nm particles are used. The same sensitivity can be achieved in 5 min when 500 nm particles are used. If 500 nm particles are employed in a 15-minute assay, then 0.8 pM of PTH is detectable. The low sample volume, high analytical performance and high speed of the test coupled with the compact GMR biosensor make the system especially suitable for sensitive testing outside of laboratory environments.

Packaging of silicon sensors for microfluidic bio-analytical applications

A new industrial concept is presented for packaging biosensor chips in disposable microfluidic cartridges to enable medical diagnostic applications. The inorganic electronic substrates, such as silicon or glass, are integrated in a polymer package which provides the electrical and fluidic interconnections to the world and provides mechanical strength and protection for out-of-lab use. The demonstrated prototype consists of a molded interconnection device (MID), a silicon-based giant magneto-resistive (GMR) biosensor chip, a flex and a polymer fluidic part with integrated tubing. The various processes are compatible with mass manufacturing and run at a high yield. The devices show a reliable electrical interconnection between the sensor chip and readout electronics during extended wet operation. Sandwich immunoassays were carried out in the cartridges with surface functionalized sensor chips. Biological response curves were determined for different concentrations of parathyroid hormone (PTH) on the packaged biosensor, which demonstrates the functionality and biocompatibility of the devices. The new packaging concept provides a platform for easy further integration of electrical and fluidic functions, as for instance required for integrated molecular diagnostic devices in cost-effective mass manufacturing.

Frequency Tuning of Collapse-Mode Capacitive Micromachined Ultrasonic Transducer

HighlightsFrequency tuning of CMUT operated in (deep‐)collapse mode is experimentally quantified.The CMUT is operated at bias voltages up to three times higher than the collapse voltage.Fabricated CMUT operates reliably for single‐use imaging catheter application.Images are constructed based on combinations of driving frequency and bias voltage.Reciprocity measurements indicate the same bias voltage can be used for transmit and receive. &NA; The information in an ultrasound image depends on the frequency that is used. In a clinical examination it may therefore be beneficial to generate ultrasound images acquired at multiple frequencies, which is difficult to achieve with conventional transducers. Capacitive micromachined ultrasonic transducers (CMUTs) offer a frequency response that is tunable by the bias voltage. In this study we investigate this frequency tunability for ultrasonic imaging. We characterized a CMUT array operated at bias voltages up to three times higher than the collapse‐voltage. All elements of the array were connected to a single transmit and receive channel through a bias circuit. We quantified the transmit‐receive and transmit sensitivity as a function of frequency for a range of bias voltages. Impulse response measurements show that the center frequency is modifiable between 8.7 MHz and 15.3 MHz with an applied bias voltage of −50 V to −170 V. The maximum transmit sensitivity is 52 kPa/V at a center frequency of 9.0 MHz with an applied bias voltage of −105 V. The −3 dB transmit range in center frequency accessible with the variable bias voltage is 6.7–15.5 MHz. This study shows that a collapse‐mode CMUT can operate efficiently at multiple center frequencies when the driving pulse and the bias voltage are optimized. We demonstrate the usefulness of frequency tuning by comparing images at different optimal combinations of driving frequency and bias voltage, acquired by linearly moving the transducer across a tissue mimicking phantom.