Atomic force microscopy (AFM) is an effective platform for in vitro manipulation and analysis of living cells in medical and biological sciences. To introduce additional new features and functionalities into a conventional AFM system, we investigated the photocatalytic nanofabrication and intracellular Raman imaging of living cells by employing functionalized AFM probes. Herein, we investigated the effect of indentation speed on the cell membrane perforation of living HeLa cells based on highly localized photochemical oxidation with a catalytic titanium dioxide (TiO2)-functionalized AFM probe. On the basis of force-distance curves obtained during the indentation process, the probability of cell membrane perforation, penetration force, and cell viability was determined quantitatively. Moreover, we explored the possibility of intracellular tip-enhanced Raman spectroscopy (TERS) imaging of molecular dynamics in living cells via an AFM probe functionalized with silver nanoparticles in a homemade Raman system integrated with an inverted microscope. We successfully demonstrated that the intracellular TERS imaging has the potential to visualize distinctly different features in Raman spectra between the nucleus and the cytoplasm of a single living cell and to analyze the dynamic behavior of biomolecules inside a living cell.
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