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.

Tissue engineering-based therapeutic strategies for vocal fold repair and regeneration

“…[1,10] The epithelium is composed of stratified squamous cells and has a primary role of protecting the deeper layers of tissue, and as a result this layer undergoes repeated turnover. [21] The lamina propria (LP) is a collagen and elastin-rich, pliable vibratory layer of connective tissue positioned between epithelium and muscle tissue,[22] sub-categorized into three distinct layers: superficial lamina propria (SLP), intermediate lamina propria (ILP), and deep lamina propria (DLP).…”

“…[10] This approach, from a clinical perspective, offers attractive advantages over traditional materials implantation, as it has the potential to solidify injecting materials into any desired shape at the site of injury with enhanced interfacial interlocking with surrounding normal tissues. This strategy also minimizes the invasiveness and potential trauma to patients, limits the risk of infection and secondary scar formation, and reduces treatment costs with easy practice and increased patient accessibility.…”

“…This strategy also minimizes the invasiveness and potential trauma to patients, limits the risk of infection and secondary scar formation, and reduces treatment costs with easy practice and increased patient accessibility. [10,65] To date, injectable hydrogels investigated for vocal fold tissue regeneration have largely focused on hyaluraonic acid (HA) and its derivatives due to the significant relevance of HA’s biological and biomechanical functionalities in vivo . [65,66]…”

“…A few small, thin walled vessels are present which represents angiogenesis (A). [10] Reprinted with permission from Graupp, M.; Bachna-Rotter, S.; Gerstenberger, C.; et al Eur. Arch.…”

“…[6] While surgical techniques and behavioral treatments are currently employed to treat voice disorders, surgical interventions can cause scarring and yield inconsistent results. [5,8] Thus, tissue regeneration methods combining the use of bioactive factors, injectable scaffolds, and stem cell therapy have remained of significant research interest in the development of methods to treat vocal fold scarring and vocal fold replacement,[9,10] although challenges in integrated treatment of the mechanical and biological properties of materials has limited the success of these approaches. In this article, we review recent advances and progress in vocal fold repair and regeneration from a tissue engineering-based therapeutic perspective, focusing on (1) biomaterials intended to mimic the mechanical properties of native VF tissues; (2) bioreactor designs that capture dynamic vocal biomechanical properties, and (3) both in vitro and in vivo applications of these biomaterials, informed by results from bioreactor studies, in vocal fold tissue engineering.…”