Porous scaffolds with enzyme-responsive Kartogenin release for recruiting stem cells and promoting cartilage regeneration

• Capillarity of scaffolds could absorb and retain EPSCs immediately post-surgery. • MMP-responsive release of drug promoted recruitment and chondrogenesis of ESPCs. • In vivo cartilage defects were repaired in situ by the enzyme-responsive scaffolds. A capillarity-functional and enzyme-responsive porous scaffold was developed to not only absorb and retain ESPCs from bone marrow blood rapidly via capillarity at the early stage after implantation, but also regulate the chemotactic recruitment and chondrogenic differentiation of ESPCs in response to the local inflammatory microenvironment. We researched the mechanism and effect of capillarity in scaffolds, as well as the enzyme-responsive release of PEGKGN to realize function division. Importantly, a rat cartilage defect model was built to verify the in situ cartilage regeneration through the capillarity-functional and enzyme-responsive porous scaffolds. In situ cartilage regeneration with endogenous stem/progenitor cells (ESPCs) and bioactive scaffolds is attractive in cartilage regeneration. Nevertheless, the optimization of ESPCs recruitment and the establishment of chondrogenic microenvironment are still a huge challenge for better therapeutic outcomes. Herein, a in situ cartilage tissue engineering porous scaffold with enzyme-responsive kartogenin (KGN) release is prepared to not only recruit ESPCs via chemoattractant, but also promote their chondrogenesis. Polyethylene glycol-modified Kartogenin (PEGKGN) and polycaprolactone (PCL) are grafted on poly(L-glutamic acid) (PLGA) to endow the porous scaffolds with good mechanical property, capillarity and enzyme-responsiveness. The scaffolds show a fast absorption of protein solution through capillarity, indicating its capacity of rapid fill with bone marrow blood at the early stage after implantation for the maximum absorption and retention of ESPCs. The release dose of PEGKGN is found to be accelerated by matrix metalloproteinase-2 (MMP-2). And the high-dose PEGKGN can stimulate the migration of bone marrow mesenchyml stem cells (BMSCs) obviously, and the low-dose PEGKGN can promote the chondrogenesis of BMSCs in vitro . The in vivo data demonstrates that the bioactive porous scaffolds enhance in situ cartilage regeneration. The neo-tissues show close structures and components to the healthy cartilages. Thus, the in situ cartilage tissue engineering porous scaffolds with enzyme-responsive KGN release can recruit ESPCs to defects and promote the chondrogenesis effectively, which is a potential treatment for in situ cartilage regeneration.