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Aug 1, 2013 (Vol. 33, No. 14)

Molecular Imaging Driving Development

  • Pharmacoimaging combines traditional pharmacology with broad imaging capabilities, enabling better decision making, improved clinical trial design, and more confident lead candidate selection.

    Imaging technologies are also being used for drug safety assessment, both to screen drugs in the discovery stage and to provide supporting data later on.

    Increasingly, imaging will be incorporated into preclinical and clinical studies to interrogate and quantify both drug efficacy and safety in the same animals or patients, according to presentations given at World Pharma Congress’ recent “Molecular Imaging Conference in Drug Discovery and Development.”

    “The uniqueness of our approach is to focus more on the drug target and disease biology up front, as we develop a picture of whether and how in vivo imaging can enhance intended decision making,” says Patrick McConville, Ph.D., CSO and COO at Molecular Imaging.

    “Our approach drives successful pharmacoimaging by ensuring inherent relevance of the data output to the intended biological or molecular question, and how this relates to the clinical path and related decision making,” Dr. McConville explained.

    In vivo imaging facilitates access to information that is more directly relevant to drug mechanism or that cannot be obtained through other means. Further, imaging biomarkers are being used to provide readout of a broad range of relevant physiological and functional parameters, including metabolism, cellularity, proliferation, hypoxia, and inflammation. Such data enables measurement of disease progression and response to targeted therapies, at a mechanistic level.

    Imaging has become a standard tool for characterizing biologic molecule targeting and biodistribution using isotopes for PET, SPECT, and fluorophores. Labeling of antibodies, antibody-drug conjugates, proteins and peptides, and nanoparticles for image-based detection, is a powerful approach to drug discovery and development.

    New imaging modalities including photoacoustic technology and clinical fluorescence will provide powerful approaches to translational medicine.

  • High-Throughput Toxicity Screening

    Click Image To Enlarge +
    Scanning electron micrograph of a cardiac cell grown on the IMEC CMOS multi-electrode array. The chip is able to record intracellular action potentials from individual cells in a noninvasive manner, opening the door to novel drug screening platforms based on silicon technology.

    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.

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