An injectable collagen-genipin-carbon dot hydrogel combined with photodynamic therapy to enhance chondrogenesis
An injectable collagen-genipin-carbon dot hydrogel combined with photodynamic therapy to enhance chondrogenesis
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可注射胶原-京尼平-碳点水凝胶结合光动力疗法增强软骨形成
DOI：
10.1016/j.biomaterials.2019.05.001
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发表时间：
2019-10-01
期刊：
影响因子：
14
通讯作者：
Zheng, Li
中科院分区：
文献类型：
--
作者：
Lu, Zhenhui;Liu, Sijia;Zheng, Li
胶原蛋白已被广泛用于软骨修复，但其低刚度和快速降解不利于软骨形成。在这里，我们通过天然产物交联剂（京尼平）将生物相容性碳点纳米颗粒（CD NPs）缀合到胶原上以制备可注射水凝胶（称为胶原-京尼平-CD纳米颗粒，CGN）。CGN水凝胶由于京尼平的交联作用和CD NPs的存在而显示出增加的刚度，并且可以通过光动力疗法（PDT）产生适量的活性氧（ROS）。刚度增强和ROS生成均导致骨髓源性干细胞（BMSC）的软骨分化改善以及随后用于软骨缺损修复的软骨再生增强。具体而言，CGN水凝胶呈现出比纯胶原蛋白水凝胶高21倍的压缩模量和低39.3%的降解速率。PDT和CGN水凝胶的组合使BMSC的增殖增加了50.3%，使其软骨特异性基因的表达成倍上调，并使第21天的GAG分泌增加了205.1%。这种组合也在短短8周内加速了软骨再生。刚度增强和ROS产生分别通过调节TGF-β/SMAD和mTOR信号通路协同促进软骨形成分化。CD修饰的水凝胶注射和PDT治疗的组合代表了软骨缺损微创修复的新策略。
Collagen has been widely used for cartilage repair, but its low stiffness and rapid degradation disfavor chondrogenesis. Here we conjugated biocompatible carbon dot nanoparticles (CD NPs) onto collagen through a natural product crosslinker (genipin) to prepare an injectable hydrogel (termed collagen-genipin-CD nanoparticles, CGN). The CGN hydrogel showed increased stiffness due to the cross-linking effect of genipin and the presence of CD NPs, and could produce a moderate amount of reactive oxygen species (ROS) by photodynamic therapy (PDT). Both the stiffness enhancement and ROS generation resulted in improved chondrogenic differentiation of bone marrow-derived stem cells (BMSCs) and the subsequent enhanced cartilage regeneration for cartilage defect repair. Specifically, the CGN hydrogel presented a 21-fold higher compression modulus and a 39.3% lower degradation rate than the pure collagen hydrogel. A combination of both PDT and CGN hydrogel increased the BMSCs proliferation by 50.3%, upregulated their expression of cartilage-specific genes by multiple folds, and enhanced GAG secretion by 205.1% on day 21. This combination also accelerated the cartilage regeneration within as short as 8 weeks. The stiffness enhancement and ROS generation synergistically contributed to chondrogenic differentiation by regulating the TGF-beta/SMAD and mTOR signaling pathway, respectively. The combination of CD-modified hydrogel injection and PDT treatment represents a new strategy for minimally invasive repair of cartilage defects.