Carthew J, Frith J E, Forsythe J S, Truong V X
Department of Materials Science and Engineering, Monash Institute of Medical Engineering, Monash University, Clayton, 3800 VIC, Australia.
J Mater Chem B. 2018 Mar 7;6(9):1394-1401. doi: 10.1039/c7tb02764h. Epub 2018 Feb 19.
Tetrazine-norbornene ligation has previously been applied in bioorthognal polymer crosslinking to form hydrogels suitable for 3D cell culture. However, the tetrazine group is prone to reduction by the free thiol in a biological environment, reducing the crosslinking efficiency and shortening the storage of tetrazine containing linkers. Here, we introduce a method to form a tetrazine group in situ by catalytic oxidation of the dihydrogen tetrazine using horse radish peroxidase (HRP). Enzymatic oxidation is highly efficient at a low HRP concentration and does not require hydrogen peroxide, allowing for rapid gelation when HRP was added to an aqueous solution of 4-arm PEG dihydrogentetrazine and gelatin norbornene. The storage modulus of the resultant gels can be varied by changing the concentration of the crosslinker, which is in the range of 1.2-3.8 kPa. Human mesenchymal stem cells encapsulated within these gels, with varying stiffness, display varied interactions and morphologies and can be maintained with prolonged culture periods of at least 32 days of 3D culture. The enzymatic activation of tetrazine-norbornene is therefore an attractive addition to the tetrazine ligation that is highly suitable for cell related studies in tissue engineering.
四嗪-降冰片烯连接反应此前已应用于生物正交聚合物交联,以形成适用于3D细胞培养的水凝胶。然而,在生物环境中,四嗪基团容易被游离硫醇还原,从而降低交联效率并缩短含四嗪连接体的储存时间。在此,我们介绍一种通过使用辣根过氧化物酶(HRP)催化氧化二氢四嗪原位形成四嗪基团的方法。酶促氧化在低HRP浓度下效率很高,且不需要过氧化氢,当将HRP添加到四臂聚乙二醇二氢四嗪和明胶降冰片烯的水溶液中时可实现快速凝胶化。通过改变交联剂的浓度可以改变所得凝胶的储能模量,其范围为1.2-3.8 kPa。封装在这些具有不同硬度的凝胶中的人间充质干细胞表现出不同的相互作用和形态,并且可以在至少32天的3D培养延长培养期内维持。因此,四嗪-降冰片烯的酶促活化是对四嗪连接反应有吸引力的补充,非常适合组织工程中与细胞相关的研究。
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