The inappropriate regenerated fibrous cartilage and subchondral bone of the injured chondral defect ultimately cause degeneration of the regenerated cartilage, which eventually leads to the failure of cartilage repair. In this study, we developed a macrophage-modulated and injectable ‘building block’ drug delivery system comprised of porous chitosan (CS) microspheres and hydroxypropyl chitin (HPCH) hydrogel, where the dimethyloxallyl glycine (DMOG) was encapsulated in the thermosensitive HPCH hydrogel (HD) while kartogenin (KGN) was conjugated on the porous CS microspheres (CSK-PMS). The developed HD/CSK-PMS composite scaffold effectively modulated the microenvironment at the defect site, achieved local macrophage M2 polarization and promoted cartilage regeneration. The fast-degradable HD favored hyaline cartilage regeneration, while the highly stable CSK-PMS supported the endochondral ossification and regenerated the subchondral bone. In vitro and in vivo evaluations revealed that the newly developed HD/CSK-PMS as a controlled drug delivery system could effectively create M2 macrophage microenvironment and orchestrate osteochondral (OC) regeneration. These findings indicate the importance of the immune microenvironment and subchondral bone for high-quality cartilage repair, and thus the immunomodulation-based hydrogel/PMS composite system could be a promising candidate for OC regeneration.

损伤软骨缺损的再生纤维软骨和软骨下骨不合适，最终导致再生软骨退化，最终导致软骨修复失败。在这项研究中，我们开发了一种由多孔壳聚糖（CS）微球和羟丙基甲壳素（HPCH）水凝胶组成的巨噬细胞调节和可注射“构件”药物递送系统，其中二甲基乙二烯丙基甘氨酸（DMOG）被封装在热敏性HPCH水凝胶中。 HD）而kartogenin（KGN）缀合在多孔CS微球（CSK-PMS）上。开发的HD/CSK-PMS复合支架有效地调节了缺损部位的微环境，实现局部巨噬细胞M2极化，促进软骨再生。可快速降解的 HD 有利于透明软骨再生，而高度稳定的 CSK-PMS 支持软骨内骨化并再生软骨下骨。体外和体内评估表明，新开发的 HD/CSK-PMS 作为受控药物递送系统可以有效地创造 M2 巨噬细胞微环境并协调骨软骨 (OC) 再生。这些发现表明免疫微环境和软骨下骨对高质量软骨修复的重要性，因此基于免疫调节的水凝胶/PMS复合系统可能是OC再生的有希望的候选者。