Abstract
The extracellular ionic microenvironment has a close relationship to biological activities such as by cellular respiration, cancer development, and immune response. A system composed of ion-sensitive field-effect transistors (ISFET), cells, and program-controlled fluidics has enabled the acquisition of real-time information about the integrity of the cell membrane via pH measurement. Here we aimed to extend this system toward floating cells such as T lymphocytes for investigating complement activation and pharmacokinetics through alternations in the plasma membrane integrity. We functionalized the surface of tantalum oxide gate insulator of ISFET with oleyl-tethered phosphonic acid for interacting with the plasma membranes of floating cells without affecting the cell signaling. The surface modification was characterized by X-ray photoelectron spectroscopy and water contact angle measurements. The Nernst response of −37.8 mV/pH was obtained for the surface-modified ISFET at 37 °C. The oleyl group-functionalized gate insulator successfully captured Jurkat T cells in a fluidic condition without acute cytotoxicity. The system was able to record the time course of pH changes at the cells/ISFET interface during the process of instant addition and withdrawal of ammonium chloride. Further, the plasma membrane injury of floating cells after exposure by detergent Triton™ X-100 was successfully determined using the modified ISFET with enhanced sensitivity as compared with conventional hemolysis assays.
Highlights
Biological pH is heterogeneously distributed in vivo
A system composed of ion-sensitive field-effect transistors (ISFET), cells, and program-controlled fluidics has enabled the acquisition of real-time information about the integrity of the cell membrane via pH measurement
oleylacetamide triethylenglycol hexylphosphonic acid (OEP) is consisted of hydrophobic oleyl group, hydrophilic triethylene glycol (TEG) linker, and metal oxide-reactive phosphonic acid (Figure 1(A))
Summary
Gastric mucosa generates a pH gradient for preventing gastric epithelial cell damage by gastric acid (pH 1.0–1.5).[1] Cell metabolism alters extracellular pH. Cancer or tumor cells induce tissue acidification (pH 6.5–6.9), which is attributed to the secretion of lactic acid because of an enhanced glycolysis in anaerobic conditions.[2] Tissue acidification activates phagocytosis of leukocytes in the innate immune system.[3] The complement system is enhanced in acidic microenvironments.[4] Extracellular pH is closely related to intracellular activities such as by enzymes, ion channels, and organelles.[5] Fluorescence imaging by molecular probes or quantum dots is the standard method for pH sensing in vitro and in vivo.[6,7] Optical methods can be applied to individual cells due to a high spatiotemporal resolution. These are label-free, but have limitation in positioning and miniaturization
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