Biomimetic Trachea Engineering via a Modular Ring Strategy Based on Bone-Marrow Stem Cells and Atelocollagen for Use in Extensive Tracheal Reconstruction

The fabrication of biomimetic tracheas with a architecture of cartilaginous rings alternately interspersed between vascularized fibrous tissue (CRVFT) has the potential to perfectly recapitulate the normal tracheal structure and function. Herein, the development of a customized chondroitin-sulfate-incorporating type-II atelocollagen (COL II/CS) scaffold with excellent chondrogenic capacity and a type-I atelocollagen (COL I) scaffold to facilitate the formation of vascularized fibrous tissue is described. An efficient modular ring strategy is then adopted to develop a CRVFT-based biomimetic trachea. The in vitro engineering of cartilaginous rings is achieved via the recellularization of ring-shaped COL II/CS scaffolds using bone marrow stem cells as a mimetic for native cartilaginous ring tissue. A CRVFT-based trachea with biomimetic mechanical properties, composed of bionic biochemical components, is additionally successfully generated in vivo via the alternating stacking of cartilaginous rings and ring-shaped COL I scaffolds on a silicone pipe. The resultant biomimetic trachea with pedicled muscular flaps is used for extensive tracheal reconstruction and exhibits satisfactory therapeutic outcomes with structural and functional properties similar to those of native trachea. This is the first study to utilize stem cells for long-segmental tracheal cartilaginous regeneration and this represents a promising method for extensive tracheal reconstruction.