Nitric oxide releasing nanomatrix wrap to enhance dialysis fistula maturation

 描述(由申请人提供)：超过500,000名美国患者患有终末期肾脏疾病，超过80%的患者选择血液透析作为肾脏替代治疗方案。护理透析患者的跟腱是发展一种功能正常和耐用的血管通路，最好是动静脉瘘。每年治疗血管通路功能障碍的费用总计超过10亿美元。这在很大程度上是由于动静脉瘘(AVF)未成熟的比例很高。动静脉瘘产生后，60%的动静脉动静脉瘘由于早期静脉新生内膜发育和血管扩张不足而未能成功成熟用于透析。目前，尚无有效的治疗方法来促进血管通路成熟。内仿生技术已经开发出一种纳米基质涂层，它模仿天然内皮的特征属性。这种纳米基质可以被涂覆在生物兼容的电纺聚己内酯(EPCL)薄片上，然后在创建时包裹在透析AVF周围。该涂层在2个月内持续释放一氧化氮(NO)，从而招募和保留内皮细胞和内皮祖细胞。它还结合了一种内皮细胞黏附配体，促进内皮细胞的保留和迁移。NO的持续释放也促进了健康的AVF成熟所需的适当的血管扩张。这种涂层还限制了平滑肌(SMC)的增殖，这是一个额外的好处，因为SMC的增殖在AVF的未成熟中起着重要作用。纳米骨架涂层是一种生物相容的多肽基材料，通过简单的水蒸发将其覆盖在ePCL片材上。这种包衣方法将炎症反应的风险降至最低。在第一阶段SBIR中，我们建议评估和优化ePCL片材的涂层。这将包括评估物理特征和评估对内皮细胞和平滑肌细胞生长的影响。与伯明翰阿拉巴马大学的Lee博士合作，这种涂层的有效性将在已建立的啮齿动物AVF模型中进行评估，并与未涂层的ePCL片材进行比较。开发一种促进AVF成熟的涂层可能会对需要透析的患者的治疗产生重大影响。随着第一阶段的成功完成，我们计划在第二阶段进入大型动物研究。

 DESCRIPTION (provided by applicant): More than 500,000 U.S. patients have end stage renal disease and over 80% utilize hemodialysis as their renal replacement modality of choice. The Achilles Heel in the care of dialysis patients is the development of a functioning and durable vascular access, preferably an arteriovenous fistula. The annual cost of treating vascular access dysfunction totals over one billion US dollars. This is largely due to the high proportion of arteriovenous fistulas (AVFs) that fail to mature. After creation, sixty percent of AVFs fail to mature successfully for dialysis use, due to early venous neointimal development and inadequate vasodilation. At present, there are no effective therapies to promote vascular access maturation. Endomimetics has developed a nanomatrix coating that mimics the characteristic properties of native endothelium. This nanomatrix can be coated on biocompatible electrospun polycaprolactone (ePCL) sheets that are then wrapped around the dialysis AVF at the time of creation. The coating provides sustained release of nitric oxide (NO) over 2 months, thus recruiting and retaining endothelial cells and endothelial progenitor cells. It also incorporates a endothelial cell adhesive ligand that promotes endothelial cell retention and migration. The sustained release of NO also promotes appropriate vasodilation necessary for healthy AVF maturation. This coating also limits smooth muscle (SMC) proliferation, an additional benefit since SMC proliferation plays a significant role in AVF non-maturation. The nanomatrix coating is a biocompatible peptide based material and is coated on ePCL sheets by simple water evaporation. This coating method minimizes the risk of inflammatory responses. In this Phase I SBIR, we propose to evaluate and optimize the coating for ePCL sheets. This will include evaluation of physical characteristics and assessing effects on endothelial and smooth muscle cell growth. In collaboration with Dr. Lee at the University of Alabama at Birmingham, the efficacy of this coating will be evaluated in an established rodent AVF model, and compared with non-coated ePCL sheets. Development of a coating that promotes AVF maturation may have significant impact in the treatment of patients requiring dialysis. With successful completion of Phase I, we plan to move forward in Phase II to large animal studies.