Trends in Injectable Biomaterials for Vocal Fold Regeneration and Long-Term Augmentation

Human vocal folds (VFs), a pair of small, soft tissues in the larynx, have a layered mucosal structure with unique mechanical strength to support high-level tissue deformation by phonation. Severe pathological changes to VF have causes including surgery, trauma, age-related atrophy, and radiation, and lead to partial or complete communication loss and difficulty in breathing and swallowing. VF glottal insufficiency requires injectable VF biomaterials such as hyaluronan, calcium hydroxyapatite, and autologous fat to augment VF functions. Although these biomaterials provide an effective short-term solution, significant variations in patient response and requirements of repeat reinjection remain notable challenges in clinical practice. Tissue engineering strategies have been actively explored in the search of an injectable biomaterial that possesses the capacity to match native tissue's material properties while promoting permanent tissue regeneration. This review aims to assess the current status of biomaterial development in VF tissue engineering. The focus will be on examining state-of-the-art techniques including modification with bioactive molecules, cell encapsulation, composite materials, and in situ crosslinking with click chemistry. We will discuss potential opportunities that can further leverage these engineering techniques in the advancement of VF injectable biomaterials. Impact Statement Injectable vocal fold (VF) biomaterials augment tissue function through minimally invasive procedures, yet there remains a need for long-term VF reparation. This article reviews cutting-edge research in VF biomaterial development to propose safe and effective tissue engineering strategies for improving regenerative outcomes. Special focus is paid to methods to enhance bioactivity and achieve tissue-mimicking mechanical properties, longer in situ stability, and inherent biomaterial bioactivity.