Aptamer-Directed Bidirectional Modulation of Vascular Niches for Promoted Regeneration of Segmental Trachea Defect

The simultaneous regeneration of avascular cartilage ring and vascular connective tissue in one biomimetic tracheal substitute has remained a remarkable challenge in the clinical breakthrough of tissue-engineered trachea for repairing segmental trachea defect. Herein, an unprecedented strategy based on bidirectional modulation of vascular niches is developed through tailoring the tissue-specific scaffolds with programmable functional nucleic acids. Namely, the antiangiogenic characteristic of cartilage-specific scaffold enables development of an avascular niche, and thereby facilitating the regeneration of biomimetic cartilage. Conversely, the angiogenic capability of connective tissue-specific scaffold fosters the creation of a vascular niche, and thus enhancing the regeneration of biomimetic connective tissue. Importantly, the steadily immobilized nucleic acids in specific scaffolds enable the seamless integration of angiogenic and antiangiogenic functions without mutual interference. As such, biomimetic tracheas are successfully engineered with the vascular connective tissue scattering between avascular cartilage rings using the assembly of tissue-specific scaffolds. The results from in vivo trachea regeneration and the in situ trachea reconstruction demonstrate the satisfactory tissue-specific regeneration of (a)vascular niches along with optimal structural, mechanical, and physiological features. This study represents the first demonstration of trachea regeneration promoted by modulation of tissue-specific vascular niches, which adds an additional dimension for the clinical trachea reconstruction.