Hong Yuping, Liu Ning, Zhou Rong, Zhao Xinxin, Han Yaguang, Xia Fangfang, Cheng Jin, Duan Meng, Qian Qirong, Wang Xiuying, Cai Weidong, Zreiqat Hala, Feng Dagan, Xu Jianrong, Cui Daxiang
Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China.
Department of Joint Surgery and Sports Medicine, Changzheng Hospital, Second Naval Military University, 415 Fengyang Road, Shanghai 200003, P. R. China.
ACS Biomater Sci Eng. 2020 Nov 9;6(11):6276-6284. doi: 10.1021/acsbiomaterials.0c00724. Epub 2020 Oct 13.
Articular cartilage has a highly organized structure, responsible for supporting tremendous mechanical loads. How to repair defected articular cartilage has become a great challenge as the avascular nature of cartilage limits its regenerative ability. Aiming to facilitate chondrogenic differentiation and cartilage regeneration, we recently explored a novel combination therapy using soluble poly-l-lysine/Kartogenin (L-K) nanoparticles and a poly(lactic--glycolic acid) PLGA/methacrylated hyaluronic acid (PLHA) complex scaffold. The potential use for joint cartilage reconstruction was investigated through L-K nanoparticles stimulating adipose-derived stem cells (ADSCs) on PLHA scaffolding, which ultimately differentiated into cartilage . In this study, on one hand, an effective method was established for obtaining uniform L-K nanoparticles by self-assembly. They were further proved to be biocompatible to ADSCs cytotoxicity assays and to accelerate ADSCs secreting type 2 collagen in a dose-dependent manner by immunofluorescence. On the other hand, the porous PLHA scaffold was manufactured by the combination of coprecipitation and ultraviolet (UV) cross-linking. Nanoindentation technology-verified PLHA had an appropriate stiffness close to actual cartilage tissue. Additional microscopic observation confirmed that the PLHA platform supported proliferation and chondrogenesis for ADSCs . In the presence of ADSCs, a 12-week osteochondral defect regeneration by the combination therapy showed that smooth and intact cartilage tissue successfully regenerated. Furthermore, the results of combination therapy were superior to those of phosphate-buffered saline (PBS) only, KGN, or KGN/PLHA treatment. The results of magnetic resonance imaging (MRI) and histological assessment indicated that the renascent tissue gradually regenerated while the PLHA scaffold degraded. In conclusion, we have developed a novel multidimensional combination therapy of cartilage defect repair that facilitated cartilage regeneration. This strategy has a great clinical translational potential for articular cartilage repair in the near future.
关节软骨具有高度有序的结构，负责承受巨大的机械负荷。由于软骨的无血管特性限制了其再生能力，如何修复受损的关节软骨已成为一项巨大挑战。为了促进软骨生成分化和软骨再生，我们最近探索了一种新型联合疗法，即使用可溶性聚-L-赖氨酸/卡托金（L-K）纳米颗粒和聚（乳酸-乙醇酸）PLGA/甲基丙烯酸化透明质酸（PLHA）复合支架。通过在PLHA支架上用L-K纳米颗粒刺激脂肪来源干细胞（ADSCs），研究了其在关节软骨重建中的潜在用途，这些干细胞最终分化为软骨。在本研究中，一方面，建立了一种通过自组装获得均匀L-K纳米颗粒的有效方法。通过细胞毒性试验进一步证明它们对ADSCs具有生物相容性，并通过免疫荧光以剂量依赖方式加速ADSCs分泌Ⅱ型胶原蛋白。另一方面，通过共沉淀和紫外线（UV）交联相结合制备了多孔PLHA支架。纳米压痕技术验证PLHA具有接近实际软骨组织的合适硬度。额外的显微镜观察证实PLHA平台支持ADSCs的增殖和软骨生成。在ADSCs存在的情况下，联合疗法进行12周的骨软骨缺损再生显示成功再生出光滑完整的软骨组织。此外，联合疗法的结果优于仅使用磷酸盐缓冲盐水（PBS）、KGN或KGN/PLHA治疗的结果。磁共振成像（MRI）和组织学评估结果表明，新生组织在PLHA支架降解的同时逐渐再生。总之，我们开发了一种促进软骨再生的新型软骨缺损修复多维联合疗法。该策略在不久的将来对关节软骨修复具有巨大的临床转化潜力。
