High throughput screening

High throughput screening (HTS) is a technique utilised in scientific experimentation in fields of biology, materials science and chemistry. It has become the method of choice in drug discovery processes. HTS utilises advanced robotics, data processing software, liquid handling devices and sensitivity detectors, to carry out a wide array of chemical, genetic or pharmacological tests in a short period of time. It enables researchers to identify active compounds, antibodies or genes associated with a bio-molecular pathway.

The data gathered from HTS, often provide the initial information necessary for drug design and toxicology assays. 3D In-vitro cultures for drug discovery Drug development consists of many stages that begins with lead discovery and optimisations, preclinical validation, through to clinical trials. HTS is an important contributor at the beginning stage by providing small compound libraries that can then be used in target identification. Presently most cell based assays used in HTS are performed on 2D cultured cells, cultivated on plastic surfaces. However much of the data provided by 2D cultured cells are not representative of cells in-vivo.

Cell in-vivo grow in 3D plane, comprising of a complex microenvironment that determines the structure and functions of tissues. This limitation is attributed to the high failure rate in drug discovery, in which only small fraction of the drugs make it to the market for clinical use. 3D cell cultures have thus gained significant ground in overcoming the limitations posed by traditional 2D cultures. 3D cultures closely mimic the in-vivo cellular environments with predictable cellular structure and function and thus able provide better accuracy for drug discovery processes.

3D cell culture models representative of in-vivo cell state A representative 3D cell culture model would contain a physiologically or pathophysiologically relevant microenvironment, in which the cells are able to divide, aggregate and differentiate. Furthermore it would contain cell-cell interactions and cell-extra cellular matrix (ECM) interactions (ECM) with in-vivo like, tissue specific stiffness, oxygen, nutrient and waste gradients and other scaffolding cells. The current 3D cell culture models available do not provide all these criteria but comes with their own strengths and limitations.

These models can be categorised as scaffold, or non scaffolding, or other hybrid 3D cultures. For instance, traditional 3D cultures produced using spinner flasks or rotatory devices provide 3D spheroids in large scale, but they cannot be miniaturised and hence not compatible for HTS. Scaffold based 3D models contain more in-vivo like cell to cell and cell to ECM environment, where as scaffold free models has more physiologically relevant cellular gradients. The choice of model is thus determined by the type of data required, and its applications. However more modern advances in 3D cultures have provided small scale cultures that are compatible with automated HTS allowing for discovery of new candidates for drug development in more physiologically relevant cultures.

These developments are being made in all categories of 3D cell culture models. Additionally, 3D cell culture models using human cells overcomes the many limitations of mouse models such as the high cost and ethical considerations, and being non-representative of human disease progression or predict side effects of drugs such as drug induced liver toxicity. With increasing advances being made in 3D cell culture models, researchers are better able to create a more physiologically relevant cellular events that yield in-vivo like drug response, moving the drug discovery processes towards an art of precision and patient specific medicine.