Disulfide cross-linked hyaluronan hydrogels
Disulfide cross-linked hyaluronan hydrogels
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DOI：
10.1021/bm025603c
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发表时间：
2002-11-01
影响因子：
6.2
通讯作者：
Prestwich, GD
中科院分区：
文献类型：
--
作者：
Shu, XZ;Liu, YC;Prestwich, GD
开发了一种新的二硫键交联策略，用于从硫醇修饰的 HA 制备透明质酸 (HA) 水凝胶。首先，合成二硫双（丙二酰肼）（DTP）和二硫双（丁酸二酰肼）（DTB），然后通过碳二亚胺化学与HA偶联。接下来，使用二硫苏糖醇(DTT)还原最初形成的凝胶的二硫键，在彻底透析后得到相应的硫醇修饰的大分子衍生物HA-DTPH和HA-DTBH。 HA-DTPH和HA-DTBH的取代度可控制在可用葡萄糖醛酸羧酸基团的20%至70%之间。 HA-硫醇衍生物的 pK(a) 值通过分光光度法测定为 pK(a) = 8.87 (HADTPH) 和 pK(a) = 9.01 (HA-DTBH)。硫醇基团可以在空气中被氧化以重新形成二硫键，从而形成HA-DTPH和HA-DTBH水凝胶膜。用稀 H(2)O(2) 进一步氧化这些水凝胶会产生额外的交联，并产生溶胀性较差的薄膜。二硫键交联是可逆的，并且薄膜可以用DTT再次还原成溶胶。蓝色葡聚糖从交联膜中的释放被用作药物释放的模型。 HA-DTPH溶液在生理条件下也实现了快速凝胶化，这证明了原位细胞封装的能力。因此，L-929鼠成纤维细胞被封装在HA-DTPH水凝胶中；这些细胞在体外培养 3 天期间保持活力并增殖。
A new disulfide cross-linking strategy was developed to prepare hyaluronic acid (HA) hydrogel from thiolmodified HA. First, dithiobis(propanoic dihydrazide) (DTP) and dithiobis(butyric dihydrazide) (DTB) were synthesized and then coupled to HA with carbodiimide chemistry. Next, disulfide bonds of the initially formed gel were reduced using dithiothreitol (DTT) to give, after exhaustive dialysis, the corresponding thiol-modified macromolecular derivatives HA-DTPH and HA-DTBH. The degree of substitution of HA-DTPH and HA-DTBH could be controlled from 20% to 70% of available glucuronate carboxylic acid groups. The pK(a) values of the HA-thiol derivatives were determined spectrophotometrically to be pK(a) = 8.87 (HADTPH) and pK(a) = 9.01 (HA-DTBH). The thiol groups could be oxidized in air to reform disulfide linkages, which resulted in HA-DTPH and HA-DTBH hydrogel films. Further oxidation of these hydrogels with dilute H(2)O(2) created additional cross-links and afforded poorly swellable films. The disulfide cross-linking was reversible, and films could be again reduced to sols with DTT. Release of blue dextran from crosslinked films was used as a model for drug release. The rapid gelation of the HA-DTPH solution under physiological conditions was also achieved, which demonstrated the capacity for in situ cell encapsulation. Thus, L-929 murine fibroblasts were encapsulated in HA-DTPH hydrogel; these cells remained viable and proliferated during 3 days of culture in vitro.