Biomechanically matched and multistage hybrid porous scaffolds for stem cell-based osteochondral regeneration

Osteochondral tissue has limited self-repair ability owing to its ischemic microenvironment and mechanically challenging conditions. Cell-based tissue engineering, a promising strategy for osteochondral regeneration, is influenced by the osteochondral-inducing scaffolds, such as bioactive agents and bionic microstructures, and mechanical properties. The current platforms are unsatisfactory because they fail to match the mechanical strength of natural osteochondral tissue while retaining high porosity and bioactivity. Hence, we developed growth factor-free multistage porous hybrid scaffolds composed of poly(lactic-co-glycolic acid) (PLGA) backbones with milli-micrometer two-stage pores and bioactive poly(γ-ethyl-l-glutamate) (PELG) thermo-responsive hydrogel. Highly porous pure PLGA backbones with controllable pore structures and tunable mechanical strength were prepared using low-temperature deposition modeling 3D printing and salt-leaching method with sodium chloride (NaCl) as a porogen. The arginine-glycine-aspartic acid (RGD) peptide and the chondrogenic molecule kartogenin (KGN) were conjugated to the terminals of poly(ethylene glycol) and PELG to enhance cell proliferation and induce cartilage differentiation, respectively. Moreover, the multistage PLGA/^RGDPELG_KGN porous hybrid scaffolds provided conducive environments for the proliferation and chondrogenesis of peripheral blood-derived mesenchymal stem cells (PBMSCs) and successfully repaired critical-sized osteochondral defects in the rabbit femoral trochlea, indicating its clinical potential for osteochondral repair.