Animal physiology is about more than just isolated cells—biological systems work as multicellular units of tissues and organs that sense their mechanical microenvironment. Cells allowed to grow on soft, three-dimensional scaffolds will mimic the tissue better than those growing on a hard, two-dimensional tissue culture plates, postulated biophysicist Tetsuro Wakatsuki, co-founder and CSO of InvivoSciences.
InvivoSciences grows isolated primary cells or differentiated stem cells in specialized 8- or 96-chamber systems that can be read on a microplate reader. It uses mainly a collagen base, “but we mix in a lot of other factors and matrix,” Wakatsuki said. For cardiac assays, because the natural cardiac tissue is composed of more than just muscle cells, “we use different cell types to be able to mimic the cardiac tissue.” Such cultures have the added benefit of being viable for months rather than the weeks a 2-D culture will typically last.
The system is used to measure the effect of compounds on contractility and metabolic activity. Yet some drugs function through idiopathic pathways—through unknown mechanisms. “So, in order to detect the adverse effect of the drugs, you need to have a functional tissue” with, for example, a representative biomechanical structure. “That’s what we provide.”
“You would like to incorporate not only basic screens of a cell that’s in contact with a potentially toxic compound, but also be in a position to mimic what the body does,” pointed out Jonathan Dordick, director of the Center for Biotechnology & Interdisciplinary Studies at Rensselaer Polytechnic Institute and co-founder of Solidus Biosciences. When a drug goes into the body it is metabolized by the liver, “so you’ve got to take into account metabolism as well.”
The cornerstone of Solidus’ platform is the data analysis toxicity assay chip (DataChip), a microarray slide capable of supporting 1,080 3-D cell cultures embedded in alginate. Test compounds are added to a second slide, the metabolizing enzyme toxicity assay chip (MetaChip), which contains spots of enzymes such as liver P450 isoforms that catalyze reactions. When the two chips are sandwiched together, the parent compounds and their metabolites can “then transfer down to the DataChip and enter into the alginate spot, enter into the cells, and do what they do,” Dordick explained.
The chips are separated after a period of time—up to 24 hours—and the DataChip is then allowed to incubate in cell culture medium for another couple of days. The DataChip is washed, stained, and read on a typical microarray scanner. “The number of cells correlates to a dose-response as a function of concentration of drug that you added.”
Solidus is currently developing a second-generation platform. Here, the DataChip will physically snap on to a microwell containing the MetaChip, making it easier for customers to work with in-house, Dordick noted.