Application of feedback system control (FSC) to identify the optimized osteogenic drug cocktails

Abstract

We established a novel expeditious drug screening approach, Feedback system control (FSC) with differential evolution (DE), to search for optimal drug cocktails that induced robust osteoblastogenesis of mesenchymal stem cells. The prototype drug cocktails composed of 7 independent factors including BMP-2 at 10 different concentrations were prepared to investigate the efficiency of FSC. As a trial, two osteogenic biomarkers were utilized as fitness indices in the FSC processes: alkaline phosphatase (ALP) expression as an early osteogenic marker and in vitro calcium precipitation as a later marker. Notably, drug cocktails that FSC identified using the ALP assay lacked to induce in vitro mineralization. The next FSC trial with mineralization assays identified a different set of drug cocktails that generated more specific osteogenic differentiation. The required doses of BMP-2 varied significantly in these drug cocktails. The results demonstrated the FSC to be a useful tool in optimizing the combinatory drug cocktails. Furthermore, the identified multiple factors may provide a novel clue to elucidate the complex biological system, such as osteogenic differentiation.