Human-Organoid Models: Accomplishments to Salvage Test-Animals

It takes multi million dollars to develop a new drug as an estimated 1 out of 10,000 chemicals that enter the discovery cycle (Figure 1) ever reaches the market. The rising percentage of late-stage clinical failures (50% in phase 3) is also alarming. The imperative reason for such low success is our inability to represent human tissue in laboratory. Test models like flat surface cell-culture, virtual computational methods and small animals cannot replicate human system; as a consequence the outcome has not been clinically valuable most of the time. Cells accustomed to spatially dynamicmicroenvironment are conventionally studied in isolation; mostly as homogeneous cultures must not be expected to display bona-fide behavior. Engagement of cells with immediate extracellular matrix (ECM) and neighboring cells has been overlooked while evaluating their response to peripheral stimulus; be it in the form of drug or toxin or intrinsic physiological entities like enzymes and hormones. Nevertheless, lack of appropriate ECM milieu has impacted least on in vitro studies related to intracellular molecular-machinery saving us from getting fundamentally wrong.

Non-availability of a flexible 3D system is attributed to be the major obstacle in establishing new standards through organotypic cell culture [3]. Nevertheless, commercial availability of scaffolds like Ultra-Web®, Extracell®, ECM-analog®, BD-Matrigel®, Corning-Matrigel®, Alvetex®, BioVaSc®, Algimatrix® and spheroids of 3D-Biotek® that allow organotypic culture and especially the ones available in conventional plate formats are expected to change the scene.

A dynamic and reciprocal exchange of information between cells and ECM contributes significantly in tissue specific gene expression regulating its morphology and physiology. The hierarchy of ECMmediated signaling in tissue differentiation and physiology is elegantly demonstrated by Bissell et althrough ex vivo modeling of milk secreting mammary glands using Matrigel a tumor derived ECM. We need an efficient cell-interactive scaffold of benign origin, having good shelf-life and stability, for studying cell-ECM dynamics in an experimental micro-environment. Adapting organotype culture could reveal true behavior of cells in real tissue like layout and also elaborate on contextual cell-cell and cell-ECM dynamic relation. Cell- ECM dynamics being at the helm of fundamental understanding of normal vs. abnormal-cell response could thus provide an altogether new meaning to our approach towards therapeutics. Improved comprehension of bi-directional relation of cell with its surrounding milieu has a potential to create a new line of drug design focused on empowering and restoring the natural microenvironment to revert the unhealthy or diseased condition.

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