Towards single molecule detection using photoacoustic microscopy

Recently, a number of optical imaging modalities have achieved single molecule sensitivity, including photothermal imaging, stimulated emission microscopy, ground state depletion microscopy, and transmission microscopy. These optical techniques are based on optical absorption contrast, extending single-molecule detection to non-fluorescent chromophores. Photoacoustics is a hybrid technique that utilizes optical excitation and ultrasonic detection, allowing it to scale both the optical and acoustic regimes with 100% sensitivity to optical absorption. However, the sensitivity of photoacoustics is limited by thermal noise, inherent in the medium itself in the form of acoustic black body radiation. In this paper, we investigate the molecular sensitivity of photoacoustics in the context of the thermal noise limit. We show that single molecule sensitivity is achievable theoretically at room temperature for molecules with sufficiently fast relaxation times. Hurdles to achieve single molecule sensitivity in practice include development of detection schemes that work at short working distance, <100 microns, high frequency, <100 MHz, and low loss,