Live Monitoring of Microenvironmental pH Based on Extracellular Acidosis around Cancer Cells with Cell-Coupled Gate Ion-Sensitive Field-Effect Transistor

We demonstrated the live monitoring of cellular respiration using an ion-sensitive field-effect transistor (ISFET), focusing on different types of living cells, namely cancer and normal cells. In particular, we realized the label-free, real-time, and noninvasive monitoring of microenvironmental pH behavior based on extracellular acidosis around cancer cells in the long term and in situ. The change in interfacial pH (Delta pH(int)), which was analyzed based on the change in interfacial potential (Delta V-o(ut)) at the cell/gate nanogap interface gradually decreased for every cell-based ISFET. Moreover, the Delta pH(int) for cancer cells shifted by a factor of 5 to 6, which was larger than that for normal cells. This is because cancer cells cause dysbolism and are activated, thereby suppressing oxidative phosphorylation in mitochondria so as not to induce their apoptosis. Therefore, cancer cellular respiration proceeds via the glycolysis pathway, through which lactic acid is eventually released. Additionally, the pH sensitivity of the ISFET device was maintained even when the device was immersed into a cell culture medium for 24 h and 1 w; thus, the effect of nonspecific adsorption of proteins contained in the medium on the pH sensitivity of the ISFET device was negligible in the live monitoring of cellular respiration.