Rapid Transition Polymer for Temporary Vascular Occlusion During Segmental Liver

用于肝段暂时血管闭塞的快速转变聚合物

• 批准号: 8143055
• 负责人: Peter Nathan Madras
• 金额: $ 11.24万
• 依托单位: PLUROMED, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8143055
• 关键词: Adoption; Anatomy; Angiography; Animal Experiments; Animals; Applications Grants; Area; Autopsy; Benign; Biocompatible; Biopsy; Blood; Blood Circulation; Blood Vessels; Blood flow; Body Temperature; Brain; Bypass; Caliber; Cancer Patient; Cardiovascular system; Catheterization; Chronic; Clinic; Clinical; Clinical Research; Complex; Contrast Media; Coronary; Coronary Artery Bypass; Data; Development; Disease; Drug Formulations; Elasticity; Ensure; Europe; European Union; Evaluation; Excision; Failure; Family suidae; Fluoroscopy; Gel; Gonadal structure; Government; Hemorrhage; Hemostatic Agents; Hemostatic function; Hepatic; Hepatic artery; Hepatobiliary; Imagery; In Vitro; Individual; Infusion procedures; Injection of therapeutic agent; Injury; Interruption; Kidney; Left; Life; Life Expectancy; Liquid substance; Liver; Liver Circulation; Liver Function Tests; Lung; Malignant - descriptor; Malignant Neoplasms; Measurement; Measures; Medical center; Metastatic Neoplasm to the Liver; Modeling; Monitor; Morbidity - disease rate; Nephrectomy; Operative Surgical Procedures; Organ; Pathology; Patients; Perfusion; Peripheral; Persons; Phase; Photography; Play; Polymers; Portal vein structure; Property; Radio; Recurrence; Renal Tissue; Reperfusion Therapy; Research; Research Design; Resected; Risk; Robotics; Role; Safety; Saline; Series; Site; Small Business Innovation Research Grant; Specific qualifier value; Spleen; Surface; Surgeon; Surgical incisions; System; Techniques; Technology; Therapeutic Embolization; Tissues; United States National Institutes of Health; Vascular blood supply; Veins; Venous; Visual; Warm Ischemia; Water; Weight; Work; Writing; abstracting; aqueous; base; cold temperature; commercialization; data modeling; experience; improved; in vivo; minimally invasive; mortality; novel; operation; phase change; pre-clinical; pressure; public health relevance; renal artery; research study; tumor

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.

描述（由申请人提供）：在节段性肝切除术期间项目摘要/摘要肝切除术通常用于切除良性或恶性肿瘤。肝脏外科医生的一个主要问题是在实质横切期间控制出血;由于肝脏独特的双重血液供应和广泛的侧支循环，肝脏切割表面的出血可能是有问题的。目前的肝实质横切技术不能充分控制较大血管的出血。普林格尔操作（整个肝门的闭塞）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;结扎并分割一半肝脏的主要血管，牺牲大量“正常”肝脏，并将患者置于肝脏体积不足的风险中。"非解剖"或"节段性"切除可用于周边附近的肿瘤，但由于无法控制流向靶组织的血流，可能会遇到严重出血。恶性肿瘤肝切除术中出血的有害影响不仅增加了与失血直接相关的发病率和死亡率，而且增加了复发率，缩短了无病间隔，降低了围手术期主要血液置换的预期寿命。该提案描述了一种实现无血手术并降低出血风险的技术，同时最大限度地减少器官的热缺血。该技术将支持采用微创腹腔镜和机器人技术。Pluromed开发了水性、生物相容性快速转变聚合物（RTP），这种聚合物在低温下以液态存在，但在接近体温时迅速转变为凝胶。这种相变通过冷却是完全可逆的，并且聚合物一旦溶解就不能再固化。该聚合物在欧洲临床上用于冠状动脉和外周旁路手术中的暂时血管闭塞。猪肾的临床前工作已经证明了暂时中断仅流向预定切除的肾组织的血流的能力，允许无血手术，同时保持流向肾脏未受累部分的正常血流。肝脏循环的复杂性要求研究这种肝切除技术。总体目标是优化技术以实现血管流入控制，提高节段性肝切除术的易用性和安全性。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。优化聚合物特性和注射技术，以实现肝脏中的暂时闭塞。2.在活体猪肝中实现临时靶向闭塞和再灌注。3.肝段5的临时靶向闭塞和再灌注的进一步表征。4.评估临时靶向阻断用于肝段切除术的有效性。5.在慢性生存实验中比较肝切除术中使用和不使用RTP的情况。第一阶段将证明RTP的能力，以促进节段性肝切除。第二阶段将把这项技术扩展到肝脏的其余部分，并使用RTP的微创技术。重要的是，这种技术与许多应用相关，并且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的生存率提高，然而，尽管美国每年进行120，000例肝切除术，这仍然是一个重要的和有些危险的手术，出血是主要的危险。目前的肝横切技术不能充分控制较大血管的出血;整个肝脏受到缺血性损伤或大面积的"正常"肝脏被牺牲。可以进行"节段性"切除，其中切除的节段限于肿瘤和可接受的边缘，但是需要一种技术来实现仅对靶向节段的流动的暂时中断，同时允许对器官的其余部分的正常流动。此外，该技术提供无血视野的能力将支持微创腹腔镜和机器人肝脏手术的采用。本申请提出了这种技术的优化。

项目成果

Feasibility of bloodless liver resection using Lumagel, a reverse thermoplastic polymer, to produce temporary, targeted hepatic blood flow interruption.

使用 Lumagel（一种反向热塑性聚合物）进行无血肝脏切除术的可行性，以产生暂时的、有针对性的肝血流中断。

• DOI: 10.1111/j.1477-2574.2011.00412.x
• 发表时间: 2012
• 期刊: HPB : the official journal of the International Hepato Pancreato Biliary Association
• 作者: Pomposelli,JamesJ;Akoad,Mohamed;Flacke,Sebastian;Benn,JamesJ;Solano,Mauricio;Kalra,Aarti;Madras,PeterN
• 通讯作者: Madras,PeterN