Sutureless Laparoscopic Partial Nephrectomy Using Laser Tissue Welding: Preclinic

使用激光组织焊接进行无缝腹腔镜肾部分切除术：临床前

• 批准号: 8312097
• 负责人: GILAD E AMIEL
• 金额: $ 40.9万
• 依托单位: LASER TISSUE WELDING, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-10 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8312097
• 关键词: Abdomen; Abdominal Abscess; Ablation; Accounting; Address; Adverse event; Aftercare; Albumins; Animals; Anticoagulation; Area; Benign; Bile fluid; Biocompatible Materials; Biological Preservation; Blood; Blood Coagulation Disorders; Burn injury; Caliber; Cerebrospinal Fluid; Clinical; Clinical Research; Clinical Trials; Coagulation Process; Complex; Control Groups; Creatinine clearance measurement; Defect; Device Safety; Devices; Diagnosis; Domestic Pig; Drug resistance; Environment; Esophageal; Evaluation; Excision; Extravasation; Family suidae; Fiber Optics; Fistula; Frequencies; Goals; Government; Grant; Guidelines; Healed; Hematoma; Hemorrhage; Hemostatic Agents; Hemostatic function; Histologic; Hospital Costs; Hospitals; Human; Hypospadias; Image; In Vitro; Incidence; Institutional Review Boards; Kidney; Kidney Neoplasms; Lasers; Length; Length of Stay; Lesion; Life; Liquid substance; Liver; Liver neoplasms; Lymph; Malignant - descriptor; Marketing; Mediating; Medical; Medicine; Methods; Morbidity - disease rate; Necrosis; Neoplasms; Nephrectomy; Nephrons; Newly Diagnosed; Normal tissue morphology; Nuclear; Operative Surgical Procedures; Optics; Organ; Organ Donor; Outcome; Pancreas; Patients; Perforation; Persons; Phase; Postoperative Hemorrhage; Postoperative Period; Prevalence; Procedures; Pseudomonas aeruginosa; Randomized; Renal Cell Carcinoma; Renal Mass; Renal carcinoma; Renal function; Renal pelvis; Resected; Robotics; Safety; Scanning; Septicemia; Small Business Innovation Research Grant; Solid; Spinal Cord; Spinal nerve structure; Spleen; Staging; Sterility; Sterilization; Streptococcus pyogenes; Study Subject; Surface; Surgeon; Surgical sutures; Technology; Testing; Therapeutic Effect; Time; Tissues; Toxic effect; Toxicology; Transfusion; Trauma; United States; Urethra; Urethral Diverticulum; Urethral Stricture; Urine; Vascular blood supply; Visceral; Warm Ischemia; Welding; base; biomaterial compatibility; blood product; cancer transplantation; college; commercial application; gastrointestinal; healing; improved; in vivo; innovation; liver repair; liver transplantation; methicillin resistant Staphylococcus aureus; migration; minimally invasive; mortality; novel; pre-clinical; preclinical efficacy; preclinical safety; pressure; prevent; prospective; prototype; radiofrequency; reconstruction; renal artery; repaired; response; scaffold; seal; secondary infection; success; tissue repair; tissue support frame; tissue trauma; tissue welding; tumor; urinary

DESCRIPTION (provided by applicant): Preservation of functioning renal parenchyma is important and nephron-sparing surgery substitutes for radical nephrectomy in appropriately selected patients with renal cell carcinoma. Laparoscopic partial nephrectomy (LPN) has demonstrated excellent outcomes in terms of oncologic control, but is under-used due to major technical challenges of parenchymal hemostasis, pelvi-caliceal reconstruction, parenchymal renorrhaphy, bleeding and prolonged warm ischemia. Laser Tissue Welding, Inc. (LTW) uses a non-compressive, non-ablative technology to join and seal tissues for controlling the leakage of blood, gastrointestinal fluids, urine, bile, lymph, and cerebrospinal fluid. It is life saving when used on the surfaces of solid visceral organs, such as the liver spleen, pancreas and kidney, involved in trauma, cancer and transplantation in presence of coagulopathies or anticoagulation. Preclinical in vivo chronic4, 6 animal studies and with a phase I SBIR prototype manufacturing of characterized and validated biomaterials was completed. Under a phase II SBIR our company has commenced human clinical trials for the liver resections under a FDA IDE approval. Fast Track Phase I: Specific Aims* (Time: 6 months) 1. Laparoscopic partial nephrectomy using laser tissue welding combination device: Eight week preclinical safety and efficacy studies in 12 pigs. The purpose of this study is to evaluate biocompatibility and toxicity for performing the laser tissue welding procedure applied to the kidney of domestic pigs after laparoscopic partial nephrectomy. Twelve pigs will be randomly assigned to two groups of 6 pigs each (control and treatment). Both the control group and the treatment group will have temporary occlusion of the organ's blood supply for ten minutes and will undergo a partial nephrectomy. The study group will undergo tissue welding and the control group partial nephrectomy without additional treatment. All animals will be terminated at 8 weeks. 2. Investigational device exemption submission and approval. 3. IRB approval Fast Track Phase II Specific Aims* (Time: 24 months) Laparoscopic partial nephrectomy using laser tissue welding device: Safety and Efficacy Clinical Trial. 1. Pilot human feasibility clinical study in 10 patient. 2. Pivotal one center prospective randomized clinical study randomized to 20 test subjects and 20 controls. These are actual patients undergoing robotically assisted laparoscopic resection of T1A (<4cm) renal tumors. All subjects will undergo occlusion of the renal artery and resection of the tumor. The study group will undergo tissue welding and the control group conventional suturing of the defect. Safety will be assessed by tabulating the frequency of adverse events, such as 30 day postoperative morbidity due to a) secondary infection, intra-abdominal abscess formation and septicemia, b) late bleeding or secondary hemorrhage or hematoma; c) urine leak; d) damage to the kidney parenchyma evident by compromised renal function or long term renal function via creatinine clearance and MAG3 nuclear renal scan and e) mortality. Efficacy will be determined by comparing treatment and controls with respect to the objective response rate based on the number of patients who achieve a) complete hemostasis; b) Renal artery clamp time required to achieve hemostasis; c) intraoperative and postoperative blood loss; d) blood product transfusions; e) operative time; f) ICU stay; g) hospital stay and f) total hospital costs. Technology innovation: LTW using our propriety biomaterials is an enhanced surgical ability that enables hemostatic sealing of tissues accurately and instantly without compression, ablation or thermal damage, thus enabling surgical interventions not deemed possible before. These unmet clinical needs are sealing of solid visceral organs (liver, kidney, pancreas and spleen) involved in polytrauma, and neoplasms; spinal cord and nerve reattachment; sterilization of contaminated wounds, sealing of dural, esophageal and duodenal perforations; and providing a scaffold for tissue ingrowth. Anticipated Outcomes: Submission of a single pre-market market approval (PMA) application with separate IDE applications for each anatomical region. Potential commercial applications: LTW may be used to sealing and joining all tissues. Applications include liver trauma repair and after resection for primary and metastatic liver tumors; split liver transplants doubling donor organ pool; partial nephrectomy for benign and malignant lesions; urethral repair: for hypospadias, urethral stricture, urethral diverticulum, and urethral fistulae and all surgical procedures that currently use sutures. PUBLIC HEALTH RELEVANCE: The current proposal aims at Nephron Sparing surgery of small renal lesions. In 2008 there were approximately 46,410 newly diagnosed cases of kidney cancer in the United States, the majority of which represent renal cell carcinoma (RCC). The prevalence of cancer of the kidney and renal pelvis is 296,074, with 61.3% localized or 181493 patients. Although the overall incidence of RCC has been steadily increasing for the past two decades, in large part due to the increased application of abdominal imaging, there has been a concurrent downward stage migration, with small renal masses, defined as lesions with a maximum diameter of 4 cm or less, now accounting for the largest proportion of newly diagnosed renal tumors. Most of these lesions can be safely resected without the need to remove the whole kidney. However, this requires clamping of the renal artery for the length of the procedure and complex reconstructive suturing of the kidney resulting in loss of kidney function. With LTW technology we hope to eliminate the need for suturing the kidney, significantly reduce renal artery clamp time and improve hemostasis, which will improve renal preservation and function. Laser tissue welding (LTW) is an enhanced non-compressive and non-ablative surgical capability that can seal low pressure fluid leaks instantly and accurately, including blood, gastrointestinal fluids, urine, bile, lymph, and cerebrospinal fluid. LTW is specifically useful when dealing with solid visceral organs with a soft friable parenchyma, such as the liver and kidney. It enables the surgeon to undertake resections in non-anatomical planes join and seal the parenchyma with minimal thermal damage. Relevance Laser Tissue Welding is an enhanced surgical capability, a new paradigm that can address important unmet medical needs. Saves lives: Quickly repairs and controls of hemorrhage in patients who cannot clot. Blood conservation: Reduced transfusion requirements. Salvages organs and tissues: Joins and seals without burning. Enabling curative surgical resection: Does not ablate tumors or normal parenchyma. Provides intraoperative tissue diagnosis of tumor free margins. Shorting operating time: Quick and accurate. Faster Healing and Shorter hospital stay: Due to decreased tissue trauma. Can be used in a contaminated environment : Sterilizes contaminated wounds of drug- resistant super bugs like Methicillin-Resistant Staphylococcus aureus (MRSA), Streptococcus pyogenes and Pseudomonas aeruginosa. Fibro-optic capable: Minimally invasive laparoscopic & robotic applications.

描述（由申请人提供）：保留功能性肾实质很重要，在适当选择的肾细胞癌患者中，保留肾单位的手术可以替代根治性肾切除术。腹腔镜肾部分切除术（LPN）在肿瘤控制方面表现出良好的效果，但由于实质止血、盆肾重建、肾实质缝合、出血和长时间热缺血等主要技术挑战而未得到充分利用。 Laser Tissue Welding, Inc. (LTW) 使用非压缩、非烧蚀技术来连接和密封组织，以控制血液、胃肠液、尿液、胆汁、淋巴液和脑脊液的渗漏。这是拯救生命的时候 用于实体内脏器官的表面，例如肝、脾、胰腺和肾，涉及创伤、癌症和存在凝血病或抗凝的移植。临床前体内慢性 4、6 项动物研究以及经过表征和验证的生物材料的 I 期 SBIR 原型制造已经完成。根据 II 期 SBIR，我们公司已在 FDA IDE 批准下开始肝脏切除的人体临床试验。快速通道第一阶段：具体目标*（时间：6 个月） 1. 使用激光组织焊接组合装置进行腹腔镜部分肾切除术：在 12 头猪中进行为期八周的临床前安全性和有效性研究。本研究的目的是评估生物相容性和毒性 用于在腹腔镜肾部分切除术后对家猪的肾脏进行激光组织焊接手术。将 12 头猪随机分配到两组，每组 6 头猪（对照组和治疗组）。对照组和治疗组都会暂时阻断器官的血液供应十分钟，并进行部分肾切除术。研究组将进行组织焊接，对照组将进行肾部分切除术，无需额外治疗。所有动物将在第 8 周时处决。 2. 研究器械豁免提交和批准。 3. IRB 批准快速通道 II 期具体目标*（时间：24 个月）使用激光组织焊接装置进行腹腔镜肾部分切除术：安全性和有效性临床试验。 1. 在10名患者中进行人体可行性临床试验研究。 2. 关键一中心前瞻性随机临床研究，随机分配给 20 名测试受试者和 20 名对照者。这些是接受机器人辅助腹腔镜 T1A（<4cm）肾肿瘤切除术的真实患者。所有受试者都将接受肾动脉闭塞和肿瘤切除。研究组将进行组织焊接，对照组将进行缺损的常规缝合。将通过列出不良事件的频率来评估安全性，例如由于 a) 继发感染、腹内脓肿形成和败血症，b) 晚期出血或继发性出血或血肿而导致的术后 30 天发病率； c) 漏尿； d) 通过肌酐清除率和 MAG3 核肾扫描显示肾功能受损或长期肾功能明显损害肾实质，以及 e) 死亡率。疗效将通过比较治疗和对照的客观缓解率来确定，该缓解率基于实现 a) 完全止血的患者数量； b) 钳夹肾动脉达到止血所需的时间； c) 术中和术后失血量； d) 血液制品输注； e) 手术时间； f) 入住 ICU； g) 住院时间和 f) 住院总费用。技术创新：使用我们专有生物材料的 LTW 增强了手术能力，能够准确、即时地止血密封组织，而不会产生压缩、消融或热损伤，从而实现以前认为不可能的手术干预。这些未满足的临床需求是封闭涉及多发伤和肿瘤的实体内脏器官（肝、肾、胰腺和脾）；脊髓和神经重新附着；消毒受污染的伤口，密封硬脑膜、食道和十二指肠穿孔；并为组织向内生长提供支架。预期结果：提交一份单一的上市前市场批准 (PMA) 申请，并为每个解剖区域提供单独的 IDE 申请。潜在的商业应用：LTW 可用于密封和连接所有组织。应用包括肝脏创伤修复以及原发性和转移性肝脏肿瘤切除后；分割肝移植使供体器官库增加一倍；肾部分切除术治疗良性和恶性病变；尿道修复术：用于尿道下裂、尿道狭窄、尿道憩室等 尿道瘘和目前使用缝合的所有外科手术。 公共健康相关性：当前提案旨在对小型肾脏病变进行肾单位保留手术。 2008年，美国大约有46,410例新诊断的肾癌病例，其中大部分为肾细胞癌（RCC）。肾癌和肾盂癌的患病率为 296,074 例，其中 61.3% 为局限性癌症，即 181493 例。尽管肾细胞癌的总体发病率在过去二十年中一直在稳步上升，这在很大程度上是由于腹部影像学应用的增加，但同时出现了向下阶段的迁移，肾脏肿块较小，定义为最大直径为4厘米以下，目前占新诊断肾肿瘤的比例最大。大多数病变可以安全切除，无需切除整个肾脏。然而，这需要在手术过程中夹紧肾动脉，并对肾脏进行复杂的重建缝合，从而导致肾功能丧失。通过LTW技术，我们希望消除缝合肾脏的需要，显着减少肾动脉钳夹时间并改善止血，这将改善肾脏的保存和功能。激光组织焊接（LTW）是一种增强的非压缩和非烧蚀手术能力，可以立即准确地密封低压流体泄漏，包括血液、胃肠液、尿液、胆汁、淋巴液和脑脊液。 LTW 在处理具有柔软易碎实质的实心内脏器官（例如肝脏和肾脏）时特别有用。它使外科医生能够在非解剖平面上进行切除，以最小的热损伤连接和密封实质组织。相关性激光组织焊接是一种增强的手术能力，是一种可以解决重要的未满足的医疗需求的新范例。挽救生命：快速修复和控制无法凝血的患者的出血。节约血液：减少输血需求。抢救器官和组织：连接和密封而不燃烧。 实现治愈性手术切除：不会消融肿瘤或正常实质。提供无肿瘤边缘的术中组织诊断。缩短操作时间：快速、准确。更快的愈合和更短的住院时间：由于组织创伤减少。可在污染环境中使用：对耐甲氧西林金黄色葡萄球菌（MRSA）、化脓性链球菌和铜绿假单胞菌等耐药超级细菌污染的伤口进行消毒。 光纤功能：微创腹腔镜和机器人应用。