Graphene oxide nanoscaffold functionalized with adipose-derived mesenchymal stem cells and sildenafil promotes urethral stricture repair and tissue regeneration

IF 2.5 4区生物学 Q1 ANATOMY & MORPHOLOGY

Tissue & cell Pub Date : 2025-10-02 DOI:10.1016/j.tice.2025.103171

Marcela Durán , Gabriela Cardoso de Arruda Camargo , Gabriela Oliveira , João Carlos Cardoso Alonso , Paulo César Martins Alves , Bruno Bosh Volpe , José Ronaldo de Castro Roston , Sergio San Juan Dertkigil , Angela Cristina Malheiros Luzo , Nelson Durán , Wagner José Fávaro

{"title":"Graphene oxide nanoscaffold functionalized with adipose-derived mesenchymal stem cells and sildenafil promotes urethral stricture repair and tissue regeneration","authors":"Marcela Durán , Gabriela Cardoso de Arruda Camargo , Gabriela Oliveira , João Carlos Cardoso Alonso , Paulo César Martins Alves , Bruno Bosh Volpe , José Ronaldo de Castro Roston , Sergio San Juan Dertkigil , Angela Cristina Malheiros Luzo , Nelson Durán , Wagner José Fávaro","doi":"10.1016/j.tice.2025.103171","DOIUrl":null,"url":null,"abstract":"<div><div>Urethral stricture is a common and challenging urological disorder marked by fibrotic narrowing of the urethral lumen, which leads to urinary obstruction and diminished quality of life. Current surgical options are associated with high recurrence rates and limited tissue regeneration. To address these limitations, we developed a multifunctional therapeutic platform integrating a nanostructured graphene oxide scaffold functionalized with polyethylene glycol and poly(ε-caprolactone) (GO/PEG-NH₂/PCL), seeded with human adipose-derived mesenchymal stem cells (ADMSCs) and combined with oral sildenafil. In vitro analyses confirmed scaffold biocompatibility and sustained ADMSC viability, as assessed by fluorescence microscopy, with preservation of spindle-shaped morphology at low GO concentrations. In vivo, we employed a rabbit model of surgically induced urethral stricture and compared four groups: Control, Stricture, Scaffold+ADMSCs, and Scaffold+ADMSCs+Sildenafil. Ten weeks post-treatment, histological and immunohistochemical evaluations revealed that the combinatorial approach significantly restored urethral architecture and lumen patency. This was accompanied by reduced collagen deposition, enhanced smooth muscle organization, and upregulated expression of epithelial differentiation markers (Uroplakin, Desmocollin) and progenitor markers (CD117), alongside downregulation of the fibrotic mediator MMP2. Quantitative scoring indicated that fibrosis and inflammation levels in the treated group approached those of normal tissue. The GO/PEG-NH₂/PCL nanoscaffold supported ADMSC adhesion and differentiation, while sildenafil provided complementary antifibrotic and angiogenic modulation. Together, these findings support this composite system as a promising regenerative strategy for functional urethral repair, offering translational relevance for the management of complex urethral strictures.</div></div>","PeriodicalId":23201,"journal":{"name":"Tissue & cell","volume":"98 ","pages":"Article 103171"},"PeriodicalIF":2.5000,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Tissue & cell","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0040816625004537","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ANATOMY & MORPHOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Urethral stricture is a common and challenging urological disorder marked by fibrotic narrowing of the urethral lumen, which leads to urinary obstruction and diminished quality of life. Current surgical options are associated with high recurrence rates and limited tissue regeneration. To address these limitations, we developed a multifunctional therapeutic platform integrating a nanostructured graphene oxide scaffold functionalized with polyethylene glycol and poly(ε-caprolactone) (GO/PEG-NH₂/PCL), seeded with human adipose-derived mesenchymal stem cells (ADMSCs) and combined with oral sildenafil. In vitro analyses confirmed scaffold biocompatibility and sustained ADMSC viability, as assessed by fluorescence microscopy, with preservation of spindle-shaped morphology at low GO concentrations. In vivo, we employed a rabbit model of surgically induced urethral stricture and compared four groups: Control, Stricture, Scaffold+ADMSCs, and Scaffold+ADMSCs+Sildenafil. Ten weeks post-treatment, histological and immunohistochemical evaluations revealed that the combinatorial approach significantly restored urethral architecture and lumen patency. This was accompanied by reduced collagen deposition, enhanced smooth muscle organization, and upregulated expression of epithelial differentiation markers (Uroplakin, Desmocollin) and progenitor markers (CD117), alongside downregulation of the fibrotic mediator MMP2. Quantitative scoring indicated that fibrosis and inflammation levels in the treated group approached those of normal tissue. The GO/PEG-NH₂/PCL nanoscaffold supported ADMSC adhesion and differentiation, while sildenafil provided complementary antifibrotic and angiogenic modulation. Together, these findings support this composite system as a promising regenerative strategy for functional urethral repair, offering translational relevance for the management of complex urethral strictures.

查看原文本刊更多论文

脂肪源间充质干细胞和西地那非功能化氧化石墨烯纳米支架促进尿道狭窄修复和组织再生。

尿道狭窄是一种常见且具有挑战性的泌尿系统疾病，其特征是尿道管腔纤维化变窄，导致尿路梗阻和生活质量下降。目前的手术选择与高复发率和有限的组织再生有关。为了解决这些局限性，我们开发了一种多功能治疗平台，该平台集成了用聚乙二醇和聚（α -己内酯）（GO/PEG-NH₂/PCL）功能化的纳米结构氧化石墨烯支架，植入人脂肪来源的间充质干细胞（ADMSCs），并与口服西地那非联合使用。体外分析证实了支架的生物相容性和持续的ADMSC活力，通过荧光显微镜评估，在低氧化石墨烯浓度下保持纺锤形形态。在体内，我们采用兔手术致尿道狭窄模型，并比较四组：对照组、狭窄组、支架+ADMSCs组和支架+ADMSCs+西地那非组。治疗10周后，组织学和免疫组织化学评价显示，联合入路明显恢复尿道结构和管腔通畅。这伴随着胶原沉积减少，平滑肌组织增强，上皮分化标志物（Uroplakin, Desmocollin）和祖细胞标志物（CD117）的表达上调，以及纤维化介质MMP2的下调。定量评分显示，治疗组的纤维化和炎症水平接近正常组织。氧化石墨烯/PEG-NH 2 /PCL纳米支架支持ADMSC粘附和分化，而西地那非提供互补的抗纤维化和血管生成调节。总之，这些发现支持这种复合系统作为功能性尿道修复的一种有希望的再生策略，为复杂尿道狭窄的治疗提供了翻译相关性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Tissue & cell 医学-解剖学与形态学

CiteScore

3.90

自引率

0.00%

发文量

234

期刊介绍： Tissue and Cell is devoted to original research on the organization of cells, subcellular and extracellular components at all levels, including the grouping and interrelations of cells in tissues and organs. The journal encourages submission of ultrastructural studies that provide novel insights into structure, function and physiology of cells and tissues, in health and disease. Bioengineering and stem cells studies focused on the description of morphological and/or histological data are also welcomed. Studies investigating the effect of compounds and/or substances on structure of cells and tissues are generally outside the scope of this journal. For consideration, studies should contain a clear rationale on the use of (a) given substance(s), have a compelling morphological and structural focus and present novel incremental findings from previous literature.