Sparse feature selection methods identify unexpected global cellular response to strontium-containing materials

Significance Although new-generation biomaterials are increasingly complex and sophisticated, their development remains largely empirical, and functional outcomes are difficult to predict. Extending the biological evaluation of biomaterials beyond the assessment of preassumed effects would allow a better understanding of the material-driven cell responses. Here we illustrate how applying an objective, nondiscriminative approach to explore the global cell responses to a series of bone substitutes with various compositions can uncover unexpected, important changes at the gene and cellular levels and can provide in-depth knowledge of the effects of specific material properties on cell behavior. Despite the increasing sophistication of biomaterials design and functional characterization studies, little is known regarding cells’ global response to biomaterials. Here, we combined nontargeted holistic biological and physical science techniques to evaluate how simple strontium ion incorporation within the well-described biomaterial 45S5 bioactive glass (BG) influences the global response of human mesenchymal stem cells. Our objective analyses of whole gene-expression profiles, confirmed by standard molecular biology techniques, revealed that strontium-substituted BG up-regulated the isoprenoid pathway, suggesting an influence on both sterol metabolite synthesis and protein prenylation processes. This up-regulation was accompanied by increases in cellular and membrane cholesterol and lipid raft contents as determined by Raman spectroscopy mapping and total internal reflection fluorescence microscopy analyses and by an increase in cellular content of phosphorylated myosin II light chain. Our unexpected findings of this strong metabolic pathway regulation as a response to biomaterial composition highlight the benefits of discovery-driven nonreductionist approaches to gain a deeper understanding of global cell–material interactions and suggest alternative research routes for evaluating biomaterials to improve their design.