Dual Regulations of Thermosensitive Heparin-Poloxamer Hydrogel Using ε-Polylysine: Bioadhesivity and Controlled KGF Release for Enhancing Wound Healing of Endometrial Injury
Dual Regulations of Thermosensitive Heparin-Poloxamer Hydrogel Using ε-Polylysine: Bioadhesivity and Controlled KGF Release for Enhancing Wound Healing of Endometrial Injury
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DOI：
10.1021/acsami.7b10211
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发表时间：
2017-09-07
影响因子：
9.5
通讯作者：
Zhao, Ying-Zheng
中科院分区：
文献类型：
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作者：
Xu, He-Lin;Xu, Jie;Zhao, Ying-Zheng
水凝胶不仅用作有效的支撑基质来防止子宫内膜损伤后的宫内粘连，而且还可以用作支架来持续释放一些治疗药物，特别是生长因子。然而，由于子宫内膜粘液的快速周转，治疗药物在受损子宫内膜腔内的滞留性差和吸收不良是阻碍其药理作用的两个重要因素。本文中，通过使用肝素修饰的泊洛沙姆（HP）作为基质材料和ε-聚赖氨酸（EPL）作为功能赋形剂描述了粘膜粘附水凝胶。通过流变学评估和粘膜粘附研究筛选各种 EPL-HP 水凝胶配方。研究发现，EPL-HP 水凝胶的流变学和粘膜粘附特性可以通过改变配方中 EPL 的量轻松控制。含有90μg/mL EPL的EPL-HP水凝胶(EPL-HP-90)的储能模量提高至1.9×10(5)Pa，粘附力上升至3.18N(比HP水凝胶高10倍)。此外，与HP水凝胶相比，添加EPL显着加速了模型药物角质形成细胞生长因子（KGF）从EPL-HP水凝胶的体外释放。 EPL-HP-90强大的粘膜粘附能力和加速的药物释放行为使得在子宫腔内给药8小时后，更多的封装的KGF被子宫基底层和子宫内膜腺体吸收。同时，KGF-EPL-HP-90水凝胶治疗3天后，受损子宫内膜形态得到良好修复。与KGF-HP组相比，KGF-EPL-HP-90水凝胶处理后，不仅子宫内膜上皮细胞和腺体的增殖明显增强，再生子宫内膜的血管生成也明显增强。或者，用 KGF-EPL-HP-90 水凝胶处理后，受损子宫内膜中的细胞凋亡受到显着抑制。总体而言，具有合适 KGF 释放曲线的粘膜粘附 EPL-HP 水凝胶可能是比单独 HP 水凝胶更有前景的修复受损子宫内膜的方法。
Hydrogel was not only used as an effective support matrix to prevent intrauterine adhesion after endometrial injury but also served as scaffold to sustain release of some therapeutics, especially growth factor. However, because of the rapid turnover of the endometrial mucus, the poor retention and bad absorption of therapeutic agents in damaged endometrial cavity were two important factors hindering their pharmacologic effect. Herein, a mucoadhesive hydrogel was described by using heparin-modified poloxamer (HP) as the matrix material and epsilon-polylysine (EPL) as functional excipient. Various EPL-HP hydrogels formulations are screened by rheological evaluation and mucoadhesion studies. It was found that the rheological and mucoadhesive properties of EPL-HP hydrogels were easily controlled by changing the amount of EPL in formulation. The storage modulus of EPL-HP hydrogel with 90 mu g/mL of EPL (EPL-HP-90) was elevated to be 1.9 x 10(5) Pa, in accordance with the adhesion force rising to 3.18 N (10-fold higher than HP hydrogels). Moreover, in vitro release of model drug keratinocyte growth factor (KGF) from EPL-HP hydrogel was significantly accelerated by adding EPL in comparison with HP hydrogel. Both strong mucoadhesive ability and the accelerated drug release behavior for EPL-HP-90 made more of the encapsulated KGF absorbed by the uterus basal layer and endometrial glands after 8 h of administration in uterus cavity. Meanwhile, the morphology of endometrium in the injured uterus was repaired well after 3 d of treatment with KGF-EPL-HP-90 hydrogels. Compared with KGF-HP group, not only proliferation of endometrial epithelial cell and glands but also angiogenesis in the regenerated endometrium was obviously enhanced after treatment with KGF-EPL-HP-90 hydrogels. Alternatively, the cellular apoptosis in the damaged endometrium was significantly inhibited after treatment with KGF-EPL-HP-90 hydrogels. Overall, the mucoadhesive EPL-HP hydrogel with a suitable KGF release profile may be a more promising approach than HP hydrogel alone to repair the injured endometrium.