Therapeutic potential of gel-based injectables for vocal fold regeneration

Abstract

Vocal folds are anatomically and biomechanically unique, thus complicating the design and implementation of tissue engineering strategies for repair and regeneration. Integration of an enhanced understanding of tissue biomechanics, wound healing dynamics and innovative gel-based therapeutics has generated enthusiasm for the notion that an efficacious treatment for vocal fold scarring could be clinically attainable within several years. Fibroblast phenotype and gene expression are mediated by the three-dimensional mechanical and chemical microenvironment at an injury site. Thus, therapeutic approaches need to coordinate spatial and temporal aspects of the wound healing response in an injured vocal tissue to achieve an optimal clinical outcome. Successful gel-based injectables for vocal fold scarring will require a keen understanding of how the native inflammatory response sets into motion the later extracellular matrix remodeling, which in turn will determine the ultimate biomechanical properties of the tissue. We present an overview of the challenges associated with this translation as well as the proposed gel-based injectable solutions.

Figure 1. Normal rat vocal fold

Coronal histological image of the mid-membranous rat vocal fold stained with hematoxylin and eosin. Superficial to deep, the layers of the vocal fold include the stratified squamous epithelium (E), the lamina propria (LP) and thyroarytenoid muscle (M).

Figure 2. Scarred rat vocal fold

Coronal histological image of the midmembranous rat vocal fold three days following a scarification injury (hematoxylin and eosin stain). The specimen demonstrates the early inflammatory response associated with injury. There is some evidence of granulation, but significant fibrosis has not yet occurred. The epithelium is thick and irregular and the basal cells are disorganized. The lamina propria is more cellular than found in Figure 1, and contains increased fibroblasts (F) and inflammatory cells including neutrophils (N) and macrophages (M). The extracellular matrix (ECM) also appears to be altered as compared to Figure 1. A few small, thin walled vessels are present which represents angiogenesis (A).

Figure 3. Chemistry of HyStem®-C formation

The crosslinking of thiol-modified gelatin (Gelin-S®) and CMHA-S (Glycosil®) occurs within 10–30 minutes at pH 7.4 and does not alter the viability of cells nor affect peripheral tissues.

Figure 4. Rheological characterization of various vocal fold injectables

Reprinted with permission from The Laryngoscope, 117(3):516–521 ([47]). Viscoelasticity of hyaluronan and nonhyaluronan based vocal fold injectables: implications for mucosal versus muscle use. Shear stress applied by a parallel plate rheometer evaluated the viscoelastic properties of four vocal fold injectables prior to injection. Cadaveric vocal fold mucosa data is present for comparison. Data includes mean elastic shear moduli (A), mean viscous shear moduli (B), and mean dynamic viscosities (C).