Nanoscale photoacoustic tomography for label-free super-resolution imaging: simulation study.

Resolutions higher than the optical diffraction limit are often desired in the context of cellular imaging and the study of disease progression at the cellular level. However, three-dimensional super-resolution imaging without reliance on exogenous contrast agents has so far not been achieved. We present nanoscale photoacoustic tomography (nPAT), an imaging modality based on the photoacoustic effect. nPAT can achieve a dramatic improvement in the axial resolution of the photoacoustic imaging. We derive the theoretical resolution and sensitivity of nPAT and demonstrate that nPAT can achieve a maximum axial resolution of 9.2 nm. We also demonstrate that nPAT can theoretically detect smaller numbers of molecules (∼273) than conventional photoacoustic microscopy due to its ability to detect acoustic signals very close to the photoacoustic source. We simulate nPAT imaging of malaria-infected red blood cells (RBCs) using digital phantoms generated from real biological samples, showing nPAT imaging of the RBC at different stages of infection. These simulations show the potential of nPAT to nondestructively image RBCs at the nanometer resolutions for in vivo samples without the use of exogenous contrast agents. Simulations of nPAT-enabled functional imaging show that nPAT can yield insight into malarial metabolism and biocrystallization processes. We believe that the experimental realization of nPAT has important applications in biomedicine.