High-content screening (HCS) approaches have become increasingly common in drug discovery with HCS technologies integrated across the drug discovery pipeline, from target identification/validation to high-throughput phenotypic screening to lead candidate drug characterisation including SAR, MOA and toxicity profiling.
Recent years have seen an increasing demand for these drug discovery and development processes to use more predictive, higher complexity, physiologically relevant three-dimensional (3D) cell models that better mimic in vivo environments than simpler two-dimensional (2D) models. By reproducing important parameters of the in vivo environment, 3D models can enable improved assessment of drug toxicity and target validation. Such 3D cellular models may include spheroids, organoids or induced pluripotent stem cell (iPSC)-derived cell models. Another important and expanding field for 3D cell culture-based models is that of ‘organ-on-a-chip’, whereby living human cells are assembled onto microchips using microfluidic technologies. This technology has the potential to revolutionise drug development, disease modelling and personalised medicine. These microchips offer an alternative to traditional animal testing and can potentially offer a quicker path to clinical trials.
While the development of quantitative assays using 3D cell models has emerged as an attractive investigative tool, challenging 3D high-content image acquisition and analysis workflows have hindered wider adoption by the screening and automated imaging communities. Next-generation high-content, high-throughput tools for microscopy offer innovative and automated techniques for evaluating this complex biology. One company that is helping to pioneer this technology is Molecular Devices. With technology such as the ImageXpress Micro Confocal High-Content Imaging System and MetaXpress 3D Analysis Module with 3D Viewer, screening 3D cell models within a single, integrated interface can dramatically reduce the time to discovery. Implementation of these more complex 3D assays also requires high resolution to capture publication-quality images and data. Enhanced assay sensitivity can be achieved by taking advantage of the optical properties of confocal imaging, capturing images with a high signal-to-noise ratio while reducing out-of-focus light for crisper images and accurate cellular detail.
Molecular Devices is partnering with companies that specialise in physiologically relevant cell models such as Mimetas, which offers the OrganoPlate, a 3D organ-on-a-chip platform. This is a fully compatible microfluidic culture plate, enabling testing of compounds in any throughput on miniaturised organ models.
Molecular Devices also works closely with HCS Pharma, which creates innovative 3D cellular models that enable researchers to perform phenotypic screening on more relevant 3D cellular assays that also consider the extracellular matrix (ECM). To reach this goal, it has acquired Biomimesys technology, which is a natural hyaluronic acid-based hydroscaffold, biofunctionalised with other ECM components to better mimic the microenvironment of every organ. All of these technologies are being imaged and analysed with the ImageXpress Micro Confocal High-Content Imaging System.
There is also a trend towards simplicity in high-content screening approaches. Researchers create the greatest value for their organisation when they focus their efforts and time on their research and not on learning how to use the suite of complex instrumentation within their laboratory. With this in mind, the ImageXpress Pico Automated Cell Imager was recently launched as an easy-to-use imaging system with over 25 pre-configured analysis protocols available. In addition, it features a browser-based, icon-driven software that enables untrained scientists to easily access their data anytime and anywhere.
One of the challenges with the increasing complexity of HCS approaches, particularly with the movement towards complex 3D models, and the resurgence of multi-parametric phenotypic screening, is the increased volumes of both image data and metadata, which needs to be stored and archived safely, resulting in greater reliance on a high-quality, redundant IT infrastructure. This challenge is further compounded by the necessity to conserve data for the long term. Finally, while cloud-based data management has been discussed as a possible solution, at this point such infrastructure is unlikely to adequately address the demands of these higher-complexity assays, or to overcome the reluctance of users to store their data on third-party servers. That said, Molecular Devices’ HCS solutions do offer some capabilities that may help reduce the overall ‘data burden’ that comes with adoption of these more complex screening approaches. For example, it has developed targeted imaging workflows to pre-scan samples at low magnification to identify hits, and then capture more detailed data for only those hits at higher magnification – ultimately streamlining hit evaluation and saving disk space.