Age-related remodeling of the vocal fold extracellular matrix composition, structure, and biomechanics during tissue maturation

Abstract

ABSTRACT Purpose The vocal folds (VFs) are among the most mechanically active connective tissues, vibrating between 80 and 250 hz during speech. Overall VF function is determined by the composition and structure of their extracellular matrix (ECM). During tissue maturation, the VFs remodel from a monolayer of collagen fibers to a tri-layered structure, affecting tissue biomechanics. However, age-related VF ECM remodeling remains poorly understood since few studies have explored the proteins governing collagen fibrillogenesis or the non-collagenous ECM components critical for VF elasticity. Materials and Methods VFs from immature, sexually mature, and skeletally mature rats were evaluated by endoscopy, histology, and electron microscopy for cellular and biochemical composition, ECM organization, and proteoglycan distribution. Nanoindentation modulus was determined by atomic force microscopy. Results Collagen fiber abundance, maturity, and alignment are low in immature rats but show an age-dependent increase during tissue maturation. Lumican and fibromodulin, which regulate early-stage collagen fibril formation, are distributed throughout the VFs, and their abundance decreases with age. Decorin, involved in collagen organization, is concentrated just beneath the epithelium and increases with age. Elastin levels increase during tissue maturation, but hyaluronic acid abundance and distribution remain consistent with age. VF nanoindentation modulus trends toward a decrease with age. Conclusion This work identifies changes in VF ECM composition and organization during tissue maturation, focusing on proteins that regulate collagen fibrillogenesis, fiber assembly, and VF biomechanics. These findings may inform the development of pro-reparative therapies designed to influence collagen network structure and overall ECM dysregulation in a number of laryngeal pathologies.