Rapid Transition Polymer for Temporary Vascular Occlusion During Segmental Liver

项目简介/摘要肝切除术通常用于切除良性或恶性肿瘤。肝脏外科医生面临的一个主要问题是控制肝实质横断时的出血；由于肝脏独特的双血供和广泛的侧支血流，肝脏切面出血可能是有问题的。目前的肝实质横断技术不能充分控制大血管出血。Pringle手法（整个肝门闭塞）使出血最小化，但使整个肝脏暴露于缺血性损伤。为了避免这种情况，外科医生进行“解剖”切除；通往一半肝脏的主要血管被结扎和分开，牺牲了大量的“正常”肝脏，使患者面临肝脏容量不足的风险。“非解剖性”或“节段性”切除可用于靠近周围的肿瘤，但由于无法控制流向目标组织的血流，可能会出现明显出血。恶性肝切除术中出血的有害影响不仅与失血直接相关的发病率和死亡率增加，而且伴随大量围手术期换血而增加复发率、缩短无病间期和降低预期寿命。这一建议描述了一种技术，以实现无血手术，减少出血的风险，同时最大限度地减少器官的热缺血。这项技术将支持微创腹腔镜和机器人技术的采用。Pluromed公司开发了一种水性、生物相容性快速转化聚合物（RTP’s），这种聚合物在低温下以液态存在，但在接近体温时迅速转化为凝胶。这种相变通过冷却是完全可逆的，聚合物一旦溶解就不能再固化。该聚合物在欧洲临床应用于冠状动脉和外周搭桥手术中的暂时性血管闭塞。在猪肾脏的临床前研究已经证明，该技术能够暂时阻断流向待切除肾组织的血流，从而实现无血手术，同时维持肾脏未受损伤部分的正常血流。肝脏循环的复杂性要求研究这种技术用于肝切除术。总体目标是优化技术以达到血管流入控制，提高肝段切除术的便捷性和安全性。这将通过大型动物的体外和体内实验来实现。具体目标是：1。优化聚合物性能和注射技术，实现肝脏暂时闭塞。2. 实现活体猪肝暂时靶向闭塞再灌注。3. 肝段暂时性靶向闭塞再灌注的进一步表征4. 评估暂时靶向闭塞在肝节段性切除术中的疗效。5. 比较肝切除术在慢性生存实验中使用和不使用RTP的情况。一期将展示RTP促进肝节段性切除的能力。第二阶段将把这项技术扩展到肝脏的其余部分，并通过微创技术应用于RTP。重要的是，这项技术与许多应用相关，所提出的工作将作为RTP在其他复杂的、高度血管化的器官（如肺和脾）中使用的范例。公共卫生相关性：肝切除术的数量正在增加，主要是由于肝转移癌患者生存率的提高，然而，尽管在美国每年进行120,000例肝切除术，但这仍然是一项重要且有些风险的手术，出血是主要风险。目前的肝横断技术不能充分控制大血管出血；要么整个肝脏遭受缺血性损伤，要么大面积的“正常”肝脏被牺牲。“节段性”切除可以进行，切除的节段仅限于肿瘤和可接受的边缘，但需要一种技术来实现仅暂时中断目标节段的血流，同时允许正常血流到器官的其余部分。此外，该技术提供无血区域的能力将支持微创腹腔镜和机器人肝脏手术的采用。本应用程序提出了这种技术的优化。

DESCRIPTION (provided by applicant): During Segmental Liver Resection Project Summary/Abstract Liver resection is usually performed for the removal of either benign or malignant tumors. A major issue for the liver surgeon is control of bleeding during parenchymal transection; due to the liver's unique dual blood supply and extensive collateral flow, bleeding from the cut surface of the liver can be problematic. Current techniques for liver parenchymal transection cannot adequately control bleeding from larger vessels. The Pringle maneuver (occlusion of the entire porta-hepatis) minimizes bleeding but exposes the entire liver to ischemic injury. To avoid this, surgeons perform "anatomic" resection; the major vessels to half of the liver are ligated and divided, sacrificing large volumes of "normal" liver and placing the patient at risk for inadequate liver volume. "Non-anatomic" or "segmental" resection can be performed for tumors near the periphery, but significant bleeding can be encountered since blood flow to the targeted tissue cannot be controlled. The deleterious effects of hemorrhage during malignant liver resection are not only increased morbidity and mortality directly related to blood loss, but also increased recurrence rate, shortened disease-free interval and decreased life expectancy accompanying major peri-operative blood replacement. This proposal describes a technique to achieve bloodless surgery and reduce the risk of hemorrhage while minimizing warm ischemia to the organ. This technique will support the adoption of minimally invasive laparoscopic and robotic techniques. Pluromed has developed aqueous, biocompatible Rapid Transition Polymers" (RTP's") that exist in a liquid state at low temperatures but quickly transition to gel near body temperature. This phase change is fully reversible by cooling and the polymer cannot re-solidify once dissolved. The polymer is being used clinically in Europe for temporary vascular occlusion in coronary and peripheral bypass surgery. Pre-clinical work in the porcine kidney has demonstrated the ability to temporarily interrupt flow to only the renal tissue destined for resection, allowing bloodless surgery while maintaining normal flow to the uninvolved portion of the kidney. The complexity of the liver's circulation mandates study of this technique for hepatic resection. The Overall Aim is to optimize the technique to achieve vascular inflow control, improving the ease and safety of segmental liver resection. This will be achieved with in vitro and in vivo experiments in large animals. The Specific Aims are: 1. Optimize the polymer properties and injection techniques to achieve temporary occlusion in the liver. 2. Achieve temporary targeted occlusion and reperfusion in the living porcine liver. 3. Further characterization of temporary targeted occlusion and reperfusion of liver segment 5. 4. Assess the efficacy of temporary targeted occlusion for segmental liver resection. 5. Compare liver resection with and without the use of RTP's in chronic survival experiments. Phase I will demonstrate RTP's ability to facilitate segmental liver resection. Phase II will then expand this technology to the remainder of the liver and to the use of RTP's with minimally invasive techniques. Importantly, this technique is relevant to many applications and the proposed work will serve as a paradigm for the use of RTP's in other complex, highly vascularized organs such as the lungs and spleen. PUBLIC HEALTH RELEVANCE: The number of liver resections is increasing primarily due to the improved survival of cancer patients with liver metastases, yet despite the 120,000 hepatic resections performed each year in the U.S., this remains a significant and somewhat risky operation with hemorrhage as the primary risk. Current techniques for liver transection cannot adequately control bleeding from larger vessels; either the entire liver is subjected to ischemic injury or large areas of "normal" liver are sacrificed. "Segmental" resection can be performed, where the resected segment is limited to the tumor and an acceptable margin, but a technique is needed to achieve temporary interruption of flow to only the targeted segment, while allowing normal flow to the remainder of the organ. Additionally, this technique's ability to provide a bloodless field would support the adoption of minimally invasive laparoscopic and robotic liver surgery. This application proposes optimization of such a technique.