Human voice production is dependent on the flexible vocal fold lamina propria that can vibrate when brought together while being driven by the airstream from the trachea. Voice overuse or abuse can lead to scarring that disrupts the natural pliability of the lamina propria and results in hoarseness and other symptoms of vocal dysfunction. The reduction of vocal fold scarring remains a significant therapeutic challenge. We propose to develop two parallel tissue engineering approaches that will lead to the regeneration of vocal fold lamina propria. The first method will apply injectable hydrogels to prevent scar formation, improve the pliability of damaged tissue, initiate active tissue remodeling, and ultimately, afford in vivo regeneration of functional vocal fold lamina propria. The second approach relies on in vitro functional tissue formation by the appropriate combination of cells, artificial extracellular matrices (ECM), biological cues and mechanical stimuli. We are developing artificial ECM based on crosslinked particle networks (XPN) that consist of hyaluronic acid (HA) hydrogel particles (HGP) and water soluble functional polymers. The hydrogel particles are designed to exhbit controlled sizes, defined surface functionality, improved enzymatic stability, and spatial/temporal display of biologically active molecules including antifibrotic drugs, growth factor morphogens and cell adhesion peptides. The XPN, on the other hand, will have tunable viscoelasticty and controlled degradation that capture the mechanical and biological characteristics of the native lamina propria. The existence of two levels of crosslinking (within and between individual HGP) offers potential for rapid recovery from mechanical stress. The crosslinking chemistry is designed to allow for in situ encapsulation of vocal fold fibroblasts (VFF). To mimic the mechanical environment experienced by the vocal fold tissue, we propose to construct a bioreactor that is capable of delivering well-defined vibrational and tensile stresses to the cell-encapsulated scaffolds. The combination of vocal fold fibroblasts, elastic and bioactive artificial ECM, and a dynamtic bioreactor offers exciting opportunity for in vitro tissue engineering of vocal fold lamina propria.
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