5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) has emerged as a hopeful therapy for hypertrophic scar (HS). Yet, the poor permeability of ALA across biological barriers and pro-survival autophagy of fibroblasts have limited the effectiveness of PDT. In the present study, PDT was well-equipped to overcome this therapeutic resistance. Specifically, it developed hyaluronidase (HAase) based dissolving microneedles (MN)with enhanced stiffness and permeability as a spear to deliver ALA into deep lesions by battling the dual barriers of stratum corneum and dense extracellular matrix (ECM). It also applied metformin (Met) MN as a shear to intervene in the respiration and autophagic process for amplified PDT. It observed that HAase significantly enhanced the in vitro and in vivo transdermal delivery efficiency of ALA. At the same time, the combination of HAase and Met successfully boosted the anti-scarring efficacy of PDT by elevating cytotoxicity, promoting permeation, activating signal pathways, and preventing the autophagy process simultaneously. 

This pharmacodynamics study showed that the combination therapy achieves the lowest scar elevation index (SEI), downregulates expression of collagen I and TGF-β1, and decreases LC3 II/I ratio, showing excellent therapeutic efficacy. Hence, such a fully armed PDT integrating a double-prolonged attack on the physiological and pathological barriers suggests a promising topical treatment for deep HS.

Huang Y, Peng T, Hu W, et al. Fully armed photodynamic therapy with spear and shear for topical deep hypertrophic scar treatment. Journal of Controlled Release. 2022;343:408-419. https://doi.org/10.1016/j.jconrel.2022.01.043.