Synthesis and Characterization of in Situ Cross-Linkable Hyaluronic Acid-Based Hydrogels with Potential Application for Vocal Fold Regeneration

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Abstract

Despite a well-recognized clinical need for a material to replace missing or damaged vibratory connective tissue of the vocal fold, materials have yet to be engineered specifically for this purpose. Injectable hydrogels are particularly attractive because they would require a minimally invasive surgical procedure, could fill irregular defects, and could be designed to have viscoelastic properties similar to the normal tissue. We therefore synthesized a series of photo-cross-linkable hydrogels using hyaluronic acid (HA) as the starting material. The hydrogel precursors studied included HA modified with glycidyl methacrylate (HA/GMA), HA partially oxidized by sodium periodate (HAox) followed by GMA conjugation (HAox/GMA), and HA grafted with a synthetic polymer before introduction of GMA. The synthetic polymer employed was oligomeric poly(2-hydroxyethyl methacrylate) (P(HEMA)) with 31 mol % poly(N,N-dimethylacrylamide) (P(DMAM)), and the resulting hydrogel precursors were referred to as (HAox-g-Py)/GMA (y%: grafting percent). The macromonomers were characterized by GPC and 1H NMR. Hydrogels were obtained by subjecting the aqueous macromonomer solutions to UV irradiation in the presence of a photoinitiator. Under physiological conditions HAox/GMA hydrogel exhibited the highest swelling ratio and degraded most readily, whereas (HAox-g-P1.9)/GMA hydrogel swelled to a lesser extent and was most resistant to enzymatic degradation. Mechanical tests using an acoustic shaker yielded viscoelastic properties from 20 to 180 Hz. HAox/GMA hydrogel showed the lowest viscoelastic modulus and viscosity while (HAox-g-P1.9)/GMA hydrogel exhibited the highest values. The interior structures of the fully swollen hydrogels examined by scanning electron microscopy (SEM) showed the presence of fibrous or porous morphology. The cell cytotoxicity study indicated that HAox/GMA macromonomer was cytocompatible at concentrations less than 0.2 mg/mL, and there was no loss of cells when encapsulated in (HAox-g-P1.9)/GMA photo-cross-linked network. These new hydrogels have potential as injectable formulations for regeneration of the vocal fold's mucosal layered microstructure.

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