An effective way to achieve optical clearing in in vitro experiments is to immerse an excised skin sample in an optical clearing agent (OCA) with high refractive index and hyperosmolarity. By immersion, the OCA directly interacts with the dermis, inducing refractive index matching,10,11 dehydration,12–15 collagen fiber dissociation,16–18 or anisotropy factor increase,19 which all contribute to reducing the effective scattering in skin. However, non-invasive optical clearing of skin in vivo is more difficult. The outermost layer of the skin, the stratum corneum, presents a significant barrier to topically applied OCAs and is hence responsible for the poor optical clearing effect. To break the barrier of the stratum corneum, multiple penetration enhancing methods have been introduced, such as chemical enhancers,16,20 ultrasound,21,22 microneedles,23 flashlamp,24,25 laser fractional ablation,26 and photo-irradiation.27 Also, physical massage is commonly known to enhance penetration of topical agents into skin.