Biointegrating Dialysis Access Graft with Self Stabilizing Flow

 描述(由申请人提供)：目的：本第二阶段SBIR方案的目标是评估一种新型血液透析通路移植物设计(ePTFE由纹理微孔硅胶外层处理)的长期通畅性和安全性，并完成必要的开发步骤，以准备用于临床评估的设备。第一阶段的可行性研究显示，在绵羊模型中，与未经治疗的ePTFE对照组相比，12周的通畅率和新生内膜增生的减少明显更好。意义：需要频繁的治疗(每周至少3次)使得维持血液透析患者可靠的血管通路具有极大的挑战性。由于自体动静脉(AV)瘘高度成熟失败(首选血管通路选择)，以及出于长期通畅性考虑而不愿使用AV移植物(最安全的替代方案)，超过一半的第一年血液透析患者和超过20%的长期血液透析患者通过不安全的、易感染的“最后手段”导管进行治疗。静脉移植物失去通畅性的主要原因是静脉吻合口新生内膜增生，导致管腔进行性狭窄，导致不稳定的低血流继而导致血栓形成。成功地在临床上引入克服增生问题的房室移植物将增加进入途径的选择，尤其是能够显著减少高危导管的使用。创新：许多因素，包括植入时的手术创伤，移植物-静脉顺应性不匹配，以及不利的血流动力学剪应力模式，都被认为是导致新生内膜增生的原因。但导致人造动静脉动静脉移植物失败的根本原因是自我强化的“死亡螺旋”反馈环路(增生导致低流量，从而上调增生的进展)。通过使用外部生物界面来处理ePTFE移植物，以防止形成纤维状的移植物周围组织囊，消除了通常的机械收缩效应。保留的移植物周围组织的自然动态顺应性允许移植物壁弹性和振动运动的更大自由。这减少了顺应性失配，并在ePTFE-新生内膜界面提供了更有利的应力条件。它还改变了通常的增生症的流动效应。狭窄阻力的增加 通过加宽上游水力直径的机构进行补偿。这似乎用更有利的自我稳定反馈环取代了病理反馈环。前景看好的I期结果表明，这种方法可以导致房室移植物临床性能和可靠性的重大飞跃。方法：具体目标是：1)评估长期通畅性，2)证明插管的安全性，3)完成必要的功能和可靠性测试。拟议的研发步骤将支持后续的IDE应用程序，用于这种II类设备的第一次人类早期可行性研究。项目的成功将为大部分透析患者提供更安全、更可靠的治疗选择。

 DESCRIPTION (provided by applicant): Objective: The goals of this Phase II SBIR proposal are to evaluate longer-term patency and safety of a novel hemodialysis access graft design (ePTFE treated with textured microporous silicone exterior layer) and complete the necessary development steps to prepare the device for clinical evaluation. The Phase I feasibility study demonstrated markedly superior patency and reduction of neointimal hyperplasia compared to untreated ePTFE controls through 12 weeks in a sheep model. Significance: The need for frequent treatments (at least 3x per week) makes maintenance of reliable vascular access for hemodialysis patients extremely challenging. As a result of high maturation failure in autogenous arteriovenous (AV) fistulas (the preferred vascular access option) and a reluctance to use AV grafts (the safest alternative) due to longer-term patency concerns, more than half of all first-year hemodialysis patients, and more than 20% longer term, are treated via unsafe "last-resort" infection-prone catheters. Loss of patency by AV grafts is primarily due to development of neointimal hyperplasia at the venous anastomosis, which causes progressive narrowing of the lumen, leading to unstable low flow followed by thrombosis failure. Successful clinical introduction of an AV graft overcoming the hyperplasia problem would increase access options, and especially, enable a significant reduction in the use of high-risk catheters. Innovation: A number of factors, including surgical trauma at time of implant, graft-vein compliance mismatch, and unfavorable hemodynamic shear stress patterns are known to contribute to neointimal hyperplasia. But the underlying root cause of the problem that causes synthetic AV grafts to fail is the self-reinforcing "death spiral" feedback loop (hyperplasia causes low flow, which upregulates the advance of hyperplasia). By treating ePTFE grafts with an exterior biointerface that prevents the formation of a fibrous perigraft tissue capsule, the usual mechanical constriction effects are eliminated. The retained natural dynamic compliance of the perigraft tissue permits greater freedom for elastic and vibratory motion of the graft wall. This reduces compliance mismatch and provides more favorable stress conditions at the ePTFE-neointima interface. It also changes the usual flow effect of hyperplasia. An increase in stenotic resistance is compensated via a mechanism that widens the upstream hydraulic diameter. This appears to replace the pathologic feedback loop with a more favorable self-stabilizing feedback loop. The promising Phase I results suggest that this approach can lead to a major leap in AV graft clinical performance and reliability. Approach: Specific aims are 1) evaluating long-term patency, 2) demonstrating cannulation safety, and 3) completing requisite function and reliability testing. The proposed R&D steps will support a subsequent IDE application for a First-In-Human Early Feasibility Study for this Class II device. Project success would offer a safer and more reliable treatment option for a large fraction of the dialysis patient population.