Hyaluronan Hydrogels for the Local Delivery of Mesenchymal Stromal Cells to the Injured Vocal Fold.

ABSTRACT

Mesenchymal stromal cells (MSCs) promote wound healing by expediting the inflammatory phase. Local injection of MSCs into injured vocal folds (VFs) is effective in animal models, suggesting suitability for clinical translation. Despite their therapeutic potential, MSCs do not persist within the VF. This study evaluates whether hyaluronan (HA) hydrogels offer a safe delivery vehicle for local injection of MSCs into VFs, and increase longevity of the cells within the injured tissue. MSCs ± HA hydrogel were exposed to interleukin (IL)1ß, IL8, and chemokine (C-C motif) ligand 4, and evaluated for mRNA expression of matrix remodeling genes and secretion of immunomodulatory/prohealing factors. Chemotaxis/invasion in response to inflammation was evaluated. A lapin model of VF injury evaluated in vivo effects of MSCs ± HA hydrogel on enhancing VF healing. Histological evaluation of inflammation, type I collagen expression, HA hydrogel resorption, and MSC persistence was evaluated at 3 and 25 days after injury. MSCs within HA hydrogel were responsive to their extracellular environment, upregulating immunomodulatory factors when exposed to inflammation. Despite delayed migration out of the gel in vitro, the MSCs did not persist longer within the injured tissue in vivo. MSCs ± HA hydrogel exerted equivalent dampening of inflammation in vivo. The gel was resorbed within 25 days and no edema was evident. HA hydrogels can be safely used in the delivery of MSCs to injured VFs, minimizing leakage of administered cells. MSCs within the HA hydrogel did not persist longer than those in suspension, but did exert comparable therapeutic effects.