3D printing viscoelastic hydrogel-based scaffolds with a swelling-dependent gate for cartilage injury regeneration.

• The scaffold with dual-pore size bilayer structure is obtained via 3D printing. • A swelling-dependent lower layer hinders blood invasion from the bone marrow. • Sustained inhibitor delivery limits the fatty acid availability to BMSCs. • The scaffold is promising for clinical applications with microfracture surgery. Regeneration of articular cartilage remains a great challenge due to its poor self-healing capacity and weak stability. The microfracture surgery (MF) can provide bone marrow mesenchymal stem cells (BMSCs) and is commonly used in clinical practice, but its therapeutic effect is still limited by the lack of effective adhesion matrix and the uncontrollable tendency to develop fibrosis and even mineralization. In this study, a small molecular drug-loaded viscoelastic hydrogel-based 3D printing bilayer scaffold with a swelling-dependent gate was successfully developed to address these limitations. The scaffold consisted of a lower layer with a smaller pore size and an upper matrix with larger pore size. The former acted as a swelling-dependent gate to switch pore size, which initially was on-state allowing the infiltration of BMSCs, and eventually transformed into off-state serving as a barrier blocking excessive blood support from the bone marrow after swelling-induced closure of pores. This barrier structure cooperated with fatty acid inhibitor-suppressed hypertrophy of neo-cartilage matrix. The latter provided a biocompatible and viscoelastic matrix to guide MSCs toward stable chondrogenic commitment. By integrating structural design with the inhibitor, the bilayer scaffold provides a promising platform for future clinical applications of MF surgery in cartilage regeneration. [ABSTRACT FROM AUTHOR]