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 NaYF4:Yb, Tm@NaYF4:Nd (approximate to 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.