High-Throughput Toxicity Screening
The CMOS-based microelectrode array (MEA) system combines the advantages of both MEA systems and patch clamp systems, enabling noninvasive recording from complete cellular monolayers. It can record intracellular action potentials. With more than 16,000 sensor sites that can be addressed individually, the chip increases data output at single-cell resolution.
The new silicon microelectrode array platform developed by Dries Braeken, Ph.D., R&D team leader, and his colleagues at the Interuniversitair Micro-Electronica Centrum (IMEC) in Belgium, is equipped with thousands of sensors on a single silicon chip, to target single cells growing on the surface. The standard silicon technology integrating all amplifiers, filters, stimulation and impedance circuitry into the chip, facilitates massive parallelization and increasingly efficient and cheaper systems. Additional ultra-small electrodes enable recording and stimulation of single cells.
As Dr. Braeken explained, “We developed a new assay to record signals that are much larger in amplitude than extracellular signals—up to 20 mV versus one to two mV.”
These signals closely resemble intracellular signals recorded with patch clamp techniques. The assay makes use of the integrated stimulation circuitry to create transient nanopores by electroporation of the membrane patch. This creates a low-resistance path to the intracellular milieu, enabling observation of the full shape of the action potential. The intracellular signals are available from a single cell over five consecutive days.
For example, cardiac cellular signals recorded by this chip allowed for the accurate measurement of cardiac action potential duration, upstroke velocity, and different phases of the downstroke.
The CMOS MEA system is poised for a multiwell format, allowing ultra-high throughput without compromising signal quality. Software design and automation should enable extraction of specific ion channel parameters for drug screening. The technology can be integrated in organ-on-a-chip systems for more advanced predictive toxicology screening of cardiac or neuronal cells.
Dr. Braeken also presented a lens-free imaging method that is cheaper than conventional microscopy, while providing detailed information and a large field of view.
“Lens-free imaging makes it possible to perform bright-field microscopy of cells with high resolution—to 1.4 µm—and a large field of view—up to 20 mm,” he elaborates.
With this approach, the sample under investigation is illuminated by a coherent light source, and diffraction patterns are captured on a CMOS imager chip positioned underneath the sample. Images from cell cultures are obtained using dedicated image reconstruction algorithms.
“The lens-free imaging system is an optical component-free, compact, and cheap imaging system with high resolution and a large field of view,” Dr. Braeken claimed.
The resulting images are comparable to those taken with a conventional phase contrast microscope. The technique also enables reconstruction of a holographic image of cells. It is portable inside a cell incubator for direct time-lapse imaging.
Integrating the lens-free imaging system into cell bioreactors helps to monitor the kinetics of cell growth and differentiation, for example, in human stem cell cultures.