Pulmonary inflammatory responses and retention dynamics of cellulose nanofibrils

Cellulose nanofibrils (CNFs) are advanced biomaterials valued for their strength, lightweight nature, and low thermal expansion, making them suitable for diverse industrial applications. However, their potential inhalation risks necessitate thorough safety evaluations. This study investigates the pulmonary inflammatory effects and retention of CNFs following intratracheal instillation in rats. TEMPO-oxidized CNF (CNF1; 11.5 nm × 1.8 μm), mechanically fibrillated CNF (CNF2; 23.9 nm × 2.4 μm), and shorter-fibrillated CNF (CNF3; 21.6 nm × 1.2 μm) were administered at 2.0 mg/kg body weight. Endotoxin contamination was assessed using lipopolysaccharide (LPS) controls. Pulmonary inflammation was evaluated 28 days post-instillation, and lung retention of chemically stained CNFs was tracked for 90 days. Results indicated: (1) CNFs were taken up by alveolar macrophages, but no significant acute inflammation was observed; (2) CNF characteristics, particularly fiber diameter and length, play a key role in influencing lung inflammation responses and determining inflammation sites; (3) endotoxin levels in the CNF dispersions may have limited effects on inflammatory responses; and (4) CNFs persist in lung tissue for extended periods, indicating slow clearance. While immediate inflammatory responses were minimal, the prolonged retention of CNFs in the lungs could contribute to chronic low-grade inflammation. Given the variability in CNF properties influenced by raw materials and manufacturing processes, it is essential to test each CNF type individually, including toxicological endpoints beyond inflammation, to accurately assess their potential health risks.