Song Baiyang, Fang Li, Mao Xufeng, Ye Xianwang, Yan Zejun, Ma Qi, Shi Zewen, Hu Yiwei, Zhu Yabin, Cheng Yue
School of Medicine, Ningbo University, Ningbo, China.
Department of Urology, Ningbo First Hospital, Ningbo, China.
Front Bioeng Biotechnol. 2023 Jan 5;10:1092543. doi: 10.3389/fbioe.2022.1092543. eCollection 2022.
The repair of a diseased ureter is an urgent clinical issue that needs to be solved. A tissue-engineered scaffold for ureteral replacement is currently insufficient due to its incompetent bioactivity, especially in long-segment abnormalities. The primary reason is the failure of urothelialization on scaffolds. In this work, we investigated the ability of gelatin-grafted tubular scaffold in ureteral repairment and its related biological mechanism. We designed various porous asymmetric poly (L-lactic acid) (PLLA)/poly (L-lactide-co-e-caprolactone) (PLCL) tubes with a thermally induced phase separation (TIPS) method a change in the ratio of solvents (named PP). To regulate the phenotype of urothelial cells and ureteral reconstruction, gelatin was grafted onto the tubular scaffold using ammonolysis and glutaraldehyde crosslinking (named PP-gel). The and experiments were performed to test the biological function and the mechanism of the scaffolds. The hydrophilicity of the scaffold significantly increased after gelatin grafting, which promoted the adhesion and proliferation of urothelial cells. Through subcutaneous implantation in rats, PP-gel scaffolds demonstrated good biocompatibility. The replacement showed that PP-gel could improve urothelium regeneration and maintain renal function after the ureter was replaced with an ∼4 cm-long PP-gel tube using New Zealand rabbits as the experimental animals. The related biologic mechanism of ureteral reconstruction was detected in detail. The gelatin-grafted scaffold upgraded the integrin α6/β4 on the urothelial cell membrane, which phosphorylates the focal adhesion kinase (FAK) and enhances urothelialization the MAPK/Erk signaling pathway. All these results confirmed that the PP46-gel scaffold is a promising candidate for the constitution of an engineered ureter and to repair long-segment ureteral defects.
患病输尿管的修复是一个亟待解决的临床问题。目前用于输尿管替代的组织工程支架由于其生物活性不足，特别是在长段异常情况下，存在缺陷。主要原因是支架上尿路上皮化失败。在这项工作中，我们研究了明胶接枝管状支架在输尿管修复中的能力及其相关生物学机制。我们采用热致相分离（TIPS）方法，通过改变溶剂比例（命名为PP）设计了各种多孔不对称聚（L-乳酸）（PLLA）/聚（L-丙交酯-共-ε-己内酯）（PLCL）管。为了调节尿路上皮细胞的表型和输尿管重建，使用氨解和戊二醛交联将明胶接枝到管状支架上（命名为PP-gel）。进行了相关实验以测试支架的生物学功能和机制。明胶接枝后支架的亲水性显著增加，这促进了尿路上皮细胞的黏附和增殖。通过在大鼠皮下植入，PP-gel支架表现出良好的生物相容性。以新西兰兔为实验动物，用约4厘米长的PP-gel管替代输尿管的实验表明，PP-gel可以改善尿路上皮再生并维持肾功能。详细检测了输尿管重建的相关生物学机制。明胶接枝支架提升了尿路上皮细胞膜上的整合素α6/β4，使其磷酸化粘着斑激酶（FAK）并通过丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/Erk）信号通路增强尿路上皮化。所有这些结果证实，PP46-gel支架是构建工程化输尿管和修复长段输尿管缺损的有希望的候选材料。
