Somarathna Maheshika, Hwang Patrick Tj, Millican Reid C, Alexander Grant C, Isayeva-Waldrop Tatyana, Sherwood Jennifer A, Brott Brigitta C, Falzon Isabelle, Northrup Hannah, Shiu Yan-Ting, Stubben Chris J, Totenhagen John, Jun Ho-Wook, Lee Timmy
Department of Medicine and Division of Nephrology, University of Alabama at Birmingham, AL, 35294, USA.
Department of Biomedical Engineering, University of Alabama at Birmingham, AL, 35294, USA; Endomimetics, LLC, Birmingham, AL, 35242, USA.
Biomaterials. 2022 Jan;280:121254. doi: 10.1016/j.biomaterials.2021.121254. Epub 2021 Nov 18.
Vascular access is the lifeline for hemodialysis patients and the single most important component of the hemodialysis procedure. Arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis patients, but nearly 60% of AVFs created fail to successfully mature due to early intimal hyperplasia development and poor outward remodeling. There are currently no therapies available to prevent AVF maturation failure. First, we showed the important regulatory role of nitric oxide (NO) on AVF development by demonstrating that intimal hyperplasia development was reduced in an overexpressed endothelial nitric oxide synthase (NOS3) mouse AVF model. This supported the rationale for the potential application of NO to the AVF. Thus, we developed a self-assembled NO releasing nanomatrix gel and applied it perivascularly at the arteriovenous anastomosis immediately following rat AVF creation to investigate its therapeutic effect on AVF development. We demonstrated that the NO releasing nanomatrix gel inhibited intimal hyperplasia formation (more than 70% reduction), as well as improved vascular outward remodeling (increased vein diameter) and hemodynamic adaptation (lower wall shear stress approaching the preoperative level and less vorticity). Therefore, direct application of the NO releasing nanomatrix gel to the AVF anastomosis immediately following AVF creation may enhance AVF development, thereby providing long-term and durable vascular access for hemodialysis.
血管通路是血液透析患者的生命线，也是血液透析过程中最重要的单一组成部分。动静脉内瘘（AVF）是血液透析患者首选的血管通路，但由于早期内膜增生和向外重塑不良，近60%建立的AVF未能成功成熟。目前尚无预防AVF成熟失败的治疗方法。首先，我们通过证明在内皮型一氧化氮合酶（NOS3）过表达的小鼠AVF模型中内膜增生减少，展示了一氧化氮（NO）对AVF发育的重要调节作用。这支持了将NO应用于AVF的潜在原理。因此，我们开发了一种自组装的NO释放纳米基质凝胶，并在大鼠AVF创建后立即在动静脉吻合处血管周围应用，以研究其对AVF发育的治疗效果。我们证明，NO释放纳米基质凝胶抑制内膜增生形成（减少超过70%），改善血管向外重塑（静脉直径增加）和血流动力学适应（壁面剪应力降低至接近术前水平且涡度减小）。因此，在AVF创建后立即将NO释放纳米基质凝胶直接应用于AVF吻合处可能会促进AVF发育，从而为血液透析提供长期且持久的血管通路。
