Drug Discovery

Enginered Tissue-Based High Content Analysis

Human engineered tissue (EHT)-based high content analysis can be applied to drug discovery projects at their compound screening and lead optimization stage. Mass-produced human engineered tissues will recapitulate physiological functions of native tissues in micro tissues growing in 96-well plates or 384-well plates (coming soon). Patient-derived cells can also be used to fabricate engineered tissues to mimic individual’s disease condition driven by their genetic background.

According to Dr. Francis Collins, Director of NIH:

“The concept of precision medicine — prevention and treatment strategies that take individual variability into account — is not new; blood typing, for instance, has been used to guide blood transfusions for more than a century. But the prospect of applying this concept broadly has been dramatically improved by the recent development of large-scale biologic databases (such as the human genome sequence), powerful methods for characterizing patients (such as proteomics, metabolomics, genomics, diverse cellular assays, and even mobile health technology), and computational tools for analyzing large sets of data. What is needed now is a broad research program to encourage creative approaches to precision medicine, test them rigorously, and ultimately use them to build the evidence base needed to guide clinical practice.”

IVS continues to develop and improve engineered tissues based high content analyzer to improve the efficiency and accuracy of drug discovery. IVS provides services to develop heart failure models driven by genetic mutations. Current projects include phenotyping of patent-specific EHTs for Duchenne muscular dystrophy (supported by NIH) and congenital cardiac defects.

Tissue Mechanics and Diseases

Mechanical foces play pivotal roles in regulatin physiological tissue and organ function and disease development and progression. There are three types of muscle–skeleal, cardiac, and smooth muscle. Contractile force developed by th muscle regulates various physiological function, including breathing, blod pressure, digesting, and locomotion. Many inherited or acquired diseases affect contractility of those muslces.

According to R.G. Wells, mechanical forces also underlie development and progression of tissue fibrosis. The PalpatorTM, a high-throughput soft-tisue mehanical analyzer, measures mechanical properties of human micro-engineered tissues growing in 96-well plates.

Molecular Mechanism

Molecular mechanisms underlying the contractile activities are analyzed in 3D engineered tissues. The bottom of multi-well plates for 3D engineered tissues is sealed with an optically clear plastic (negligible auto fluorescence). They are ideal for high-throughput optical instrument such as automated microscopes and plate readers.

To capture rapid intracellular biochemical events occurring between cardiac beats, high-throughput ultra-rapid optical devices, such as CLARIOstar (BMG labtech) and FDSS/uCell (Hamamatsu), are applied to measure changes in action potential duration and calcium transients. In collaboration with those device providers, we also will support in-house operations of those instruments with IVS 3D engineered tissues at customer sites.

Ready-to-test EHTs in MC-96TM

Drug Discovery with Mixture-Based Chemical Library

Using Positional Scanning and Scaffold Ranking libraries, IVS and Torrey Pines Institutes for Molecular Studies (TPIMS) identified a treatment lead that potentially can treat cardiac fibrosis. Through high content phenotypic analysis of a 42-scaffold scaffold ranking library (each scaffold sample contains mixtures of compounds), one of te scaffolds relieved fibrotic phenotype in a 3D disease tissue model that reconstitutes cardiac fibrosis in vitro.

This Phase I profiling is equivalent to screening >30 million compounds. In Phase II, screening is identifying the most effective individual compounds among the mixture while identifying their molecular targets(s).

The project not only identifies drug candidates and their target for cardiac fibrosis but also demonstrates the power of applying mixture-based chemical libraries in 3D engineered tissue-based high content analysis.

For the TPIMS project,  multi-probe PalpatorTM was used to increase throughputs for mechanical measurements of engineered tissues.