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An injectable, click-crosslinked, cytomodulin-modified hyaluronic acid hydrogel for cartilage tissue engineering
NPG Asia Materials ( IF 8.6 ) Pub Date : 2019-06-21 , DOI: 10.1038/s41427-019-0130-1
Seung Hun Park , Ji Young Seo , Joon Yeong Park , Yun Bae Ji , Kyungsook Kim , Hak Soo Choi , Sangdun Choi , Jae Ho Kim , Byoung Hyun Min , Moon Suk Kim

This is the first report, to our knowledge, of the preparation of an injectable in situ–forming click-crosslinked hyaluronic acid (Cx-HA) hydrogel (Cx-HA-CM) containing chemical immobilized cytomodulin-2 (CM), a chondrogenic differentiation factor, and on the utility of human periodontal ligament stem cells (hPLSCs) as a cell source for cartilage tissue engineering. hPLSCs served here as a stem cell source tolerant to ex vivo manipulation. CM induced in vitro chondrogenic differentiation of hPLSCs comparable to induction with traditional TGF-β. Cx-HA was prepared via a click-reaction between tetrazine-modified HA and transcyclooctene-modified HA. Cx-HA displayed significantly more features of a stiff hydrogel than HA. Cx-HA had a three-dimensional porous interconnected structure, absorbed a large volume of biological medium, and showed excellent biocompatibility. In contrast to HA, the Cx-HA hydrogel persisted in vitro and in vivo for an extended period, as evidenced by in vivo near-infrared fluorescence imaging. CM covalently linked to Cx-HA (Cx-HA-CM) remained inside Cx-HA for a prolonged period compared with CM physically loaded onto Cx-HA [Cx-HA (+CM)]. Cx-HA-CM also caused better chondrogenic differentiation of hPLSCs, as evidenced by Alcian blue and Safranin O staining, and greater increases in the expression of type II collagen, glycosaminoglycan content and SOX9, aggrecan, and type 2α1 collagen mRNA levels. Thus, compared to Cx-HA (+CM), the hPLSC-loaded Cx-HA-CM hydrogel induced greater chondrogenic differentiation of hPLSCs via CM that was retained in the hydrogel for a much longer period of time.



中文翻译:

可注射的,点击交联的,细胞调节素修饰的透明质酸水凝胶,用于软骨组织工程

据我们所知,这是首次制备含有化学固定的细胞调节素2(CM)的可注射原位形成的点击交联的透明质酸(Cx-HA)水凝胶(Cx-HA-CM),这是一种成软骨细胞分化因子,以及人类牙周膜干细胞(hPLSCs)作为软骨组织工程的细胞来源的实用性。hPLSCs在这里用作耐受离体操作的干细胞来源。CM诱导的hPLSC的软骨形成分化与传统TGF-β的诱导相当。Cx-HA是通过四嗪修饰的HA和反式环辛烯修饰的HA之间的点击反应制备的。与HA相比,Cx-HA显示出更多的硬质水凝胶特征。Cx-HA具有三维多孔互连结构,吸收了大量生物介质,并显示出极好的生物相容性。与HA相比,Cx-HA水凝胶在体外和体内均能持续较长时间,这在体内近红外荧光成像中得到了证明。与物理装载到Cx-HA上的CM [Cx-HA(+ CM)]相比,与Cx-HA共价连接的CM(Cx-HA-CM)在Cx-HA内保留的时间更长。Cx-HA-CM还可引起hPLSCs更好的软骨分化,如阿尔辛蓝和番红O染色所证明的,并且II型胶原蛋白的表达,糖胺聚糖含量和SOX9,聚集蛋白聚糖和2α1型胶原蛋白mRNA水平的增加更大。因此,与Cx-HA(+ CM)相比,负载hPLSC的Cx-HA-CM水凝胶通过在水凝胶中保留更长时间的CM诱导了hPLSC的更大软骨分化。Cx-HA水凝胶可在体内和体外持续较长时间,这在体内近红外荧光成像中得到了证明。与物理装载到Cx-HA上的CM [Cx-HA(+ CM)]相比,与Cx-HA共价连接的CM(Cx-HA-CM)在Cx-HA内保留的时间更长。Cx-HA-CM还可引起hPLSCs更好的软骨分化,如阿尔辛蓝和番红O染色所证明的,并且II型胶原蛋白的表达,糖胺聚糖含量和SOX9,聚集蛋白聚糖和2α1型胶原蛋白mRNA水平的增加更大。因此,与Cx-HA(+ CM)相比,负载hPLSC的Cx-HA-CM水凝胶通过在水凝胶中保留更长时间的CM诱导了hPLSC的更大软骨分化。Cx-HA水凝胶可在体内和体外持续较长时间,这在体内近红外荧光成像中得到了证明。与物理装载到Cx-HA上的CM [Cx-HA(+ CM)]相比,与Cx-HA共价连接的CM(Cx-HA-CM)在Cx-HA内保留的时间更长。Cx-HA-CM还可引起hPLSCs更好的软骨分化,如阿尔辛蓝和番红O染色所证明的,并且II型胶原蛋白的表达,糖胺聚糖含量和SOX9,聚集蛋白聚糖和2α1型胶原蛋白mRNA水平的增加更大。因此,与Cx-HA(+ CM)相比,负载hPLSC的Cx-HA-CM水凝胶通过在水凝胶中保留更长时间的CM诱导了hPLSC的更大软骨分化。与物理装载到Cx-HA上的CM [Cx-HA(+ CM)]相比,与Cx-HA共价连接的CM(Cx-HA-CM)在Cx-HA内保留的时间更长。Cx-HA-CM还可引起hPLSCs更好的软骨分化,如阿尔辛蓝和番红O染色所证明的,并且II型胶原蛋白的表达,糖胺聚糖含量和SOX9,聚集蛋白聚糖和2α1型胶原蛋白mRNA水平的增加更大。因此,与Cx-HA(+ CM)相比,负载hPLSC的Cx-HA-CM水凝胶通过在水凝胶中保留更长时间的CM诱导了hPLSC的更大软骨分化。与物理装载到Cx-HA上的CM [Cx-HA(+ CM)]相比,与Cx-HA共价连接的CM(Cx-HA-CM)在Cx-HA内保留的时间更长。Cx-HA-CM还可引起hPLSCs更好的软骨分化,如阿尔辛蓝和番红O染色所证明的,并且II型胶原蛋白的表达,糖胺聚糖含量和SOX9,聚集蛋白聚糖和2α1型胶原蛋白mRNA水平的增加更大。因此,与Cx-HA(+ CM)相比,负载hPLSC的Cx-HA-CM水凝胶通过在水凝胶中保留更长时间的CM诱导了hPLSC的更大软骨分化。II型胶原蛋白的表达,糖胺聚糖含量和SOX9,聚集蛋白聚糖和2α1型胶原蛋白mRNA水平的增加更大。因此,与Cx-HA(+ CM)相比,负载hPLSC的Cx-HA-CM水凝胶通过在水凝胶中保留更长时间的CM诱导了hPLSC的更大软骨分化。II型胶原蛋白的表达,糖胺聚糖含量和SOX9,聚集蛋白聚糖和2α1型胶原蛋白mRNA水平的增加更大。因此,与Cx-HA(+ CM)相比,负载hPLSC的Cx-HA-CM水凝胶通过在水凝胶中保留更长时间的CM诱导了hPLSC的更大软骨分化。

更新日期:2019-11-18
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