尽管有儿茶酚毒性，如何设计用于细胞封装的含儿茶酚水凝胶,ACS Applied Bio Materials

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尽管有儿茶酚毒性，如何设计用于细胞封装的含儿茶酚水凝胶
ACS Applied Bio Materials ( IF 4.6 ) Pub Date : 2023-06-20 , DOI: 10.1021/acsabm.3c00306
Capucine Guyot _{1,

2} , Tommy Malaret _{1,

2} , Francesco Touani Kameni ₂ , Marta Cerruti ₃ , Sophie Lerouge _{1,

2}

Affiliation

儿茶酚 (cat) 是一种高粘性二酚，可以通过化学方式接枝到壳聚糖 (CH) 等聚合物上，使其也具有粘性。然而，含儿茶酚材料在实验上显示出很大的毒性变异性，尤其是在体外。虽然尚不清楚这种毒性是如何出现的，但大多数关注点是儿茶酚氧化成醌，释放出活性氧（ROS），进而通过氧化应激导致细胞凋亡。为了更好地了解其作用机制，我们检查了几种用不同氧化水平和交联制备的猫-壳聚糖 (cat-CH) 水凝胶的浸出曲线、过氧化氢 ( H ₂ O ₂ ) 产生和体外细胞毒性。方法。为了产生具有不同氧化倾向的cat-CH，我们将氢咖啡酸（HCA，更容易氧化）或二氢苯甲酸（DHBA，不太容易氧化）接枝到CH的主链上。水凝胶可以使用高碘酸钠（NaIO ₄）引发氧化交联进行共价交联，也可以使用碳酸氢钠（SHC）进行物理交联。使用NaIO ₄作为交联剂提高了水凝胶的氧化水平的同时，还显着降低了体外细胞毒性、H ₂ O ₂的产生以及介质中儿茶酚和醌的浸出。对于所有测试的凝胶，细胞毒性可能与醌的释放直接相关，而不是与 H ₂ O ₂的产生或儿茶酚的释放相关，这表明氧化应激可能不是儿茶酚细胞毒性的主要原因，因为醌毒性的其他途径也发挥了作用。结果还表明，如果（i）儿茶酚基团化学键合到聚合物主链上以防止浸出，或者（ii）所选的含猫分子对氧化。结合使用其他交联化学或更有效的纯化方法，这些策略可用于合成各种类型的细胞相容性含猫支架。

"点击查看英文标题和摘要"

How to Design Catechol-Containing Hydrogels for Cell Encapsulation Despite Catechol Toxicity

Catechol (cat) is a highly adhesive diphenol that can be chemically grafted to polymers such as chitosan (CH) to make them adhesive as well. However, catechol-containing materials experimentally show a large variability of toxicity, especially in vitro. While it is unclear how this toxicity emerges, most concerns are directed toward the oxidation of catechol into quinone that releases reactive oxygen species (ROS) which can, in turn, cause cell apoptosis through oxidative stress. To better understand the mechanisms at play, we examined the leaching profiles, hydrogen peroxide (H₂O₂) production, and in vitro cytotoxicity of several cat-chitosan (cat-CH) hydrogels that were prepared with different oxidation levels and cross-linking methods. To create cat-CH with different propensities toward oxidation, we grafted either hydrocaffeic acid (HCA, more prone to oxidation) or dihydrobenzoic acid (DHBA, less prone to oxidation) to the backbone of CH. Hydrogels were cross-linked either covalently, using sodium periodate (NaIO₄) to trigger oxidative cross-linking, or physically, using sodium bicarbonate (SHC). While using NaIO₄ as a cross-linker increased the oxidation levels of the hydrogels, it also significantly reduced in vitro cytotoxicity, H₂O₂ production, and catechol and quinone leaching in the media. For all gels tested, cytotoxicity could be directly related to the release of quinones rather than H₂O₂ production or catechol release, showing that oxidative stress may not be the main reason for catechol cytotoxicity, as other pathways of quinone toxicity come into play. Results also suggest that the indirect cytotoxicity of cat-CH hydrogels fabricated through carbodiimide chemistry can be reduced if (i) catechol groups are chemically bound to the polymer backbone to prevent leaching or (ii) the chosen cat-bearing molecule has a high resistance to oxidation. Coupled with the use of other cross-linking chemistries or more efficient purification methods, these strategies can be adopted to synthesize various types of cytocompatible cat-containing scaffolds.

更新日期：2023-06-20

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