Lysine-mediated optical clearing for enhanced in vivo skin microvascular imaging

Skin optical clearing reduces light scattering to enable high-resolution deep-tissue imaging, yet most agents still trade optical performance against practical usability for in vivo applications. Here we identify lysine, an endogenous small molecule, as an effective optical clearing agent selected on the basis of the hydrogen-bonding capacity and refractive-index matching. Standardized ex vivo and in vivo protocols were established and evaluated with resolution targets, optical transmittance, three-dimensional fluorescence imaging, and histology in mouse skin. At 35% (w/v), lysine produced rapid clearing, substantial gains in transdermal spatial resolution, transmittance increases exceeding 200% at 532 nm, and effective imaging depths greater than 220 µm. Relative to glycerol, sucrose, and hyaluronic acid, lysine achieved robust clearing while inducing minimal tissue shrinkage. In vivo , lysine markedly improved dermal microvascular contrast and visibility; intermittent reapplication sustained the effect against circulatory dilution. Histological examination confirmed tissue compatibility. These results establish lysine-mediated optical clearing as a practical approach for enhancing biomedical optical imaging of skin and supporting applications such as microvascular visualization and light delivery for photodynamic therapy.