Radiation-Induced Salivary Gland Fibrosis: Mechanisms, Emerging Therapies, and Gelatin-Based Bioengineered Models

Radiotherapy is essential for treating head and neck cancer but frequently leads to radiation-induced fibrosis (RIF) in salivary glands (SGs). RIF develops through a cascade of radiation-triggered events, including DNA damage, excessive oxidative stress, and epithelial cell death. Persistent injury can cause cells to become senescent and release inflammatory signals, fueling chronic inflammation. These processes activate pathways, particularly TGF-β/SMAD, resulting in fibroblast activation, myofibroblast differentiation, and extracellular matrix accumulation. Potential treatments include drugs, mesenchymal stem/stromal cell (MSC) therapy, and gene-transfer approaches. In which, MSC therapy is particularly promising as MSCs can migrate to injured tissue and support epithelial regeneration. Yet progress is limited by the difficulty of expanding human acinar cells (ACs) in vitro. To address this gap, tunable alginate-gelatin-hyaluronic acid (AGHA) bioink hydrogels have emerged as a suitable system as gelatin provides adhesion sites for AC attachment and 3D organoid formation, alginate offers tunable mechanical support through ionic crosslinking, and hyaluronic acid contributes essential cues for cell adhesion, migration, and morphogenesis. The aim of this review is to synthesize current understanding of the mechanisms driving RIF, evaluate available therapeutic strategies, and highlight the role of AGHA in generating engineered SG constructs to test MSC therapies for RIF.