HCS and HCA systems, which involve automated microscopy and image analysis, were first introduced over twenty years ago. Although the equipment has since evolved, the screening process typically remains universal amongst the scientific community.
Traditional screening and imaging methods limit quantitative results to clusters of thousands of cells. HCS allows a combination of morphological and functional information to be recorded for individual cells. HCS uses automation, fluorescence imaging and detection, and specialized algorithms to provide visualization and quantification for large-scale applications.
These visualizations make it useful in a variety of fields that require live cell imaging, such as drug discovery, cell behavior/mechanisms, and in vitro toxicology studies. HCS systems are also ideal for studying 3D cell culture models.
Like high-throughput screening (HTS), high-content imaging enables a more efficient workflow by automating the imaging process and removing possible investigator bias by providing highly quantitative rather than subjective results.
However, the two techniques have their differences. While HTS binds its targets in larger dimensions, HCS focuses on cell-based target responses, including the change in phenotype of the whole cell. In other words, HCS sacrifices some throughput capabilities for more comprehensive data.
Since its introduction, high-content screening systems have continually evolved. This evolution includes developments to the automated microscope hardware—cameras and confocal optics, for instance—as well as substantial software enhancements, improving image acquisition, analysis, evaluation, and data storage.
HCS improvements have supported the growing high-content screening requirements for higher-throughput, phenotypic screening and assays involving complex disease models, such as live cells, primary cells, stem cells and 3D spheroids.
HCS is a multi-step methodology that assists with the image capture and analysis of various biological processes. This imaging technique is highly favored and frequently used in drug screening for its precision.
Although it remains similar in methodology, there are a number of methods and applications to distinguish between. We cover some of those below.
HCS follows a three-step process including automated image capture via fluorescence labeling, image processing, and cellular analysis. First, the sampled cells are exposed to a stimulus and are labeled with fluorescent molecules.
The molecules of these antibodies or probes are then recognized by the cells and activate a quantitative effect, marking the targeted stimulus of interest and capturing the images.
For example, an antibody may be used to interact with cellular histones and identify the damaged DNA. Once this process is complete, specialized algorithms are used to quantify the probe signals.
Retrieved images can be used with transcriptomics that can further analyze the mechanisms of the cell morphology and phenotypic characteristics.
Recent developments of HCS technology have shifted its use from secondary to primary drug compound screening. The pharmaceutical field primarily uses this analytical software to monitor cytotoxicity, solubility, permeability, and general stability of drugs.
These factors are identified and analyzed at single cellular levels, allowing researchers to remove factors that could potentially conflict with an assay.
me other applications of high content imaging include:
HCS technology generally combines fluorescence microscopy, cellular image analysis software (such as flow cytometry), and IT-systems to analyze and store data at the single-cell level. Together, these handle the steps in taking fluorescent images of cells and providing rapid, automated and unbiased experiment assessments.
HCS instruments are categorized by various specifications, all of which influence the instrument’s versatility and overall cost. These can include image acquisition speed, a built in pipette or injector for fast kinetic assays, a live cell chamber with temperature, humidity, and CO2 controls, and even additional imaging modes such as confocal, bright field, phase contrast and fluorescence resonance energy transfer (FRET).
An important difference in the HCS system’s imaging capabilities is whether the instrument can perform confocal imaging or not, as confocal microscopy enables higher image signal to noise and higher resolution than fluorescence and epi-fluorescence microscopy.
If the instrument is confocal, it operates using either a laser light source, a single spinning disk with pinholes or slits, virtual slit, or a dual spinning disk. There are trade offs to using confocal microscopy, however. This includes affects on sensitivity, resolution, speed, phototoxicity, and photo-bleaching. Furthermore, the instrument can be more complex, creating an increase in costs.
Dr. Lans Taylor created HCS in 1996 to improve the process of screening cells and provide a subcellular individual analysis level.
HCS integrates historical developments in both genomics and cytology. Since its discovery, HCS has rapidly expanded to different fields including systems cell biology and pharmaceuticals.
In the near future, this technology is expected to be integrated with individualized medicine. Physicians aim to use HCS for identifying biological markers for patients, leading to genetic and medical treatment results personalized for each individual.
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