Upconversion Nanoparticles Embedded Photonic Contact Lens for Transepithelial Corneal Crosslinking Using Hyaluronate – Riboflavin Conjugate

Abstract Corneal cross‐linking (CXL) has shown an effect on halting or slowing the disease progression of keratoconus. However, the standard Dresden protocol necessitates painful epithelial removal and prolonged ultraviolet (UV) exposure. Here, a minimally invasive, transepithelial CXL (TE‐CXL) approach is presented using upconversion nanoparticles (UCNPs)‐loaded contact lenses (UCLs) with 88.7% visible light transparency, after topical delivery of hyaluronate–riboflavin (HA–RF) conjugates. The core‐shell structured UCNPs of NaYF 4 :Yb, Tm@NaYF 4 :Nd (≈32 nm) are synthesized and embedded into medical‐grade polydimethylsiloxane (PDMS) contact lenses. HA–RF conjugates are synthesized by 1‐ethyl‐3‐(3‐dimethylaminopropyl) carbodiimide (EDC)/imidazole chemistry, enabling a 3.7‐fold increase in transepithelial riboflavin (RF) delivery compared to the conventional riboflavin solution. Collagen cross‐linking, fibrillogenesis, and singlet oxygen generation assays confirmed the effective near infrared (NIR)‐to‐UV/blue upconversion. Following the topical administration of HA‐RF conjugates, UCLs are applied to rabbit eyes and irradiated with NIR light, eliminating the need for epithelial debridement. The treated corneas exhibited biomechanical strength comparable to that of the conventional epithelial‐removal protocols, with remarkable biocompatibility and no adverse effect for up to four weeks post‐treatment. This innovative UCL‐based CXL treatment, leveraging HA–RF conjugates and NIR activation, would offer a promising and patient compliant alternative for keratoconus therapy.