Hyaluronic acid hydrogels for vocal fold wound healing

Abstract

The unique vibrational properties inherent to the human vocal fold have a significant detrimental impact on wound healing and scar formation. Hydrogels have taken prominence as a tissue engineered strategy to restore normal vocal structure and function as cellularity is low. The frequent vibrational and shear forces applied to, and present in this connective tissue make mechanical properties of such hydrogels a priority in this active area of research. Hyaluronic acid has been chemically modified in a variety of ways to address cell function while maintaining desirable tissue mechanical properties. These various modifications have had mixed results when injected in vivo typically resulting in better biomechanical function but not necessarily with a concomitant decrease in tissue fibrosis. Recent work has focused on seeding mesenchymal progenitor cells within 3D architecture of crosslinked hydrogels. The data from these studies demonstrate that this approach has a positive effect on cells in both early and late wound healing, but little work has been done regarding the biomechanical effects of these treatments. This paper provides an overview of the various hyaluronic acid derivatives, their crosslinking agents, and their effect when implanted into the vocal folds of various animal models.

Keywords: hyaluronic acid hydrogel; progenitor cell; tissue engineering; vocal fold.

Figure 1. Hyaluronic acid chain showing repeating structure of D-glucuronic acid (GlcA) and N-acetyl-D-glucuronic acid (GlcNAc). The β linkages between residues are marked as well.

Figure 2. Hyaluronic acid backbone with attached DTP crosslinker. The 2-carboxylic acid group on D-glucuronic acid (GlcA) serves as the site for covalent attachment of the DTP crosslinker.

Figure 3. Representative 40x coronal sections of the vocal fold treated with a trichrome stain. Statistical significance established by blinded pathologist qualitatively categorizing the fibrosis level for each section. (A) CMHA-S treated vocal folds showing mild fibrosis. Visual inspection indicates a significant decrease in fibrosis between the CMHA-S treatment group and saline-treated controls (p = 0.0158). (B) HA-DTPH-PEGDA treated vocal folds showing moderate fibrosis. No statistical difference between fibrosis levels seen in saline-treated controls (p = 0.1645). (C) Saline treated controls showing moderate fibrosis.