Decellularized matrices in tracheal tissue engineering: Expanding horizons in regenerative medicine

Tracheal reconstruction is highly challenging because of the inherent complexity of tracheal anatomy, physiology, and dynamic biomechanics of the tracheal tube. Autografts, allografts, and synthetic prostheses commonly used to reconstruct the trachea are often limited by donor site morbidity, immune rejection, and poor mechanical performance. Preserving native architecture and ECM composition in decellularized extracellular matrix (dECM)-based tracheal grafts provides native-like biocompatibility, degradability, and biomechanical strength, and promotes cellular migration and host–graft integration. This review highlights potential drawbacks of existing tracheal transplantation, including inflammation, immunogenic reactions, mechanical insufficiency, inadequate vascularization, and re-epithelialization. It also provides a roadmap for using dECM as a better scaffold material by integrating optimized decellularization protocols, imaging and artificial intelligence (AI)-guided personalised design, state-of-the-art biofabrication techniques, including 3D and 4D bioprinting, cell sheet technology, and bioreactors, strategies for enhancing graft stability and biofunctionality, along with modern characterization techniques. Furthermore, the translational potential and preclinical and clinical progress are critically assessed, underscoring the need for standardized, scalable, and clinically viable tracheal substitutes.