A Biodegradable Vascular Coupling Device for End-to-End Anastomosis

项目摘要 本提案中的显微外科创新(MSI)的目标是开发一种可生物降解的血管偶联装置 (VCD)，它将取代目前用于连接微血管和静脉的手缝合技术和 大血管端到端血管修复手术。我们的设备对动脉和静脉都有效，可以快速连接 这两个管子的末端密封性很好，管腔内不会留下任何异物接触。 血流成河。我们已经使用可生物降解的聚(乳酸-己内酯)(PLACL)制造了原型设备 (95%聚乳酸和5%己内酯))没有多种尺寸的活动部件，以适应不同尺寸的血管 血管修复场景)。该设备与已有的Synovis静脉连接设备(现在是 Baxter)，因为它将由生物兼容材料制成，但与Synovis设备显著不同，因为它不 具有任何金属部件，是完全可生物降解的，可方便地用于动静脉和吻合口 可以更快地执行。这种方法将减少手术套间所需的时间，降低成本 与手术相关，并通过最大限度地减少人为错误和支架置入术来降低吻合口失败的可能性 打开吻合口。这种可生物降解的装置将在长期需要增加血液流量的情况下有用 例如缺氧或成长中的孩子。我们的产品将包含一个尺寸工具，内圈在1.0 mm到4.00 mm之间，在0.5 mm之间 内环和外环之间的间距分别为0.1 mm、0.2 mm和0.3 mm，以及安装工具。 这项提案的核心技术是由犹他大学开发的，并已授权给MSI， 最近从大学剥离出来的一家公司。我们已经生产了一系列尺寸在1-7毫米之间的原型 适用于显微外科手术，并已在多个动物身上成功测试了我们的设备，进行了1至3个月的研究。 在过去的几年里，我们团队发表了多篇论文。 为了成功地将这种设备商业化，我们需要(I)开发和表征用于小口径容器的设备 (通过采访70多名外科医生确定客户需求)，(Ii)长期研究(设备退化，内膜到内膜 (3)在GMP认证设施中制造的模具和工具的开发；(4)生物兼容性测试； 和(V)510K应用。具体目标是通过产品商业化管道将MSI的VCD 正如我们的研究战略所反映的那样。作为国家和大学资助的精益帆布队列的一部分，我们进行了超过 100次采访(75名外科医生，其中包括19名参加2017年3月西部山区整形外科学会会议的医生，由 杰伊·阿加瓦尔)。我们了解到，设备的市场接受度要求VCD的总尺寸 减少约50%，需要演示1.5至2.00 mm的设备，并将数据与Gold进行比较 标准是可取的。我们第二阶段的目标除了进行必要的工作以获得监管外，还反映了这种学习 批准。 假设1.可生物降解的血管偶联装置可以在生理环境中提供必要的偶联强度 条件为1.0 mm至3.00 mm的血管。 具体目的1.评估直径1.5 mm至3.00 mm的血管偶联装置的体外功能 假设2.可生物降解的血管偶联装置可以在体内对小血管进行血管吻合 管径1.5 mm至3.00 mm的血管。植入不会影响血管通畅，也不会有严重的异物 就会产生身体反应。 具体目的2.评价小直径生物可降解偶联装置的体内应用效果和性能。 假设3.使用可生物降解血管偶联装置的血管吻合时间将低于黄金标准 方法：研究方法。 具体目的3.评价生物可降解偶联装置的有效性并比较其在体内的性能 大直径动脉和静脉(3.0至4.5毫米)的黄金标准。 假设4.A.基于聚乳酸的血管偶联装置可以使用GMP认证的设施来制造。B.PLACL 血管偶联装置具有良好的生物相容性。 具体目标4.制造血管联轴器模具及零件。B.进行全面的 与第三方(Nelson实验室)对MSI的血管偶联装置进行生物兼容性测试。

Project Summary The objective of Microsurgical Innovations (MSI) in this proposal is to develop a biodegradable vascular coupling device (VCD), which would replace the hand suturing technique currently used to connect arteries and veins in microvascular and macrovascular end-to-end vascular repair surgeries. Our device works for both arteries and veins and can rapidly connect the two vessel ends together in a watertight seal without leaving any foreign material in the lumen to come in contact with flowing blood. We have manufactured prototype devices using biodegradable poly(lactic acid-co-caprolactone) (PLACL (95% PLA and 5% caprolactone)) with no moving parts in multiple sizes to accommodate varying vessel size in a range of vascular repair scenarios). This device has similarities to the already available Synovis vein coupling device (now part of Baxter) in that it will be made of biocompatible materials, but significantly differs from the Synovis device in that it does not have any metallic parts, is completely biodegradable, can be used easily for both arteries and veins and the anastomosis can be performed much more rapidly. This approach would reduce the time required in the surgery suite, reduce costs associated with surgery, and reduce the likelihood of failure of the anastomosis, by minimizing human error and stenting open the anastomosis. The biodegradable device will be useful in cases of chronic need of increased blood flow requirement e.g. hypoxia or growing child. Our product will contain a sizing tool, inner ring between 1.0 mm to 4.00 mm at 0.5 mm intervals and a gap between the inner ring and outer ring ranging from 0.1 mm, 0.2 mm and 0.3 mm, and installation tools. The technology at the center of this proposal has been developed at the University of Utah and has been licensed to MSI, a recent spin-out company from the University. We have produced a series of prototypes between 1-7 mm size range that are applicable to microsurgery and have tested our device successfully in multiple animals for 1 to 3 month long studies. Multiple papers by our team have been published in the last few years. For successful commercialization of this device we need to (i) develop and characterize devices for small caliber vessels (customer need identified by interviewing over 70 surgeons), (ii) long term study (device degradation, intima to intima healing, patency), (iii) mold and tool development with manufacturing in GMP certified facilities, (iV) biocompatibility testing, and (V) 510 K application. Specific aims are geared towards moving MSI’s VCD through product commercialization pipeline as reflected by our research strategy. As part of state and university funded lean canvas cohorts, we conducted more than 100 interviews (>75 surgeons including 19 at the Mountain West Plastic Surgery Society meeting in March 2017 hosted by Jay Agarwal). We learned that the readiness of the device for market acceptance required that the overall size of the VCD be reduced by about 50%, that demonstration of 1.5 to 2.00 mm devices was needed, and comparison data with gold standards was desired. Our Aims for Phase II reflect this learning in addition to doing work necessary to obtain regulatory approval. Hypothesis 1.The biodegradable vascular coupling device can provide the necessary coupling strength in physiological conditions for 1.0 mm to 3.00 mm blood vessels. Specific Aim 1. To evaluate the functionality of vascular coupling devices 1.5 mm to 3.00 mm diameter ex vivo Hypothesis 2. Vascular anastomosis can be performed with the biodegradable vascular coupling device in vivo for small caliber vessels (1.5 mm to 3.00 mm diameter). The implantation will not affect blood vessel patency and no severe foreign body response will occur. Specific Aim 2. To evaluate the effectiveness and performance of small diameter biodegradable coupling devices in vivo. Hypothesis 3. Vascular anastomosis time with the biodegradable vascular coupling device will be lower than gold standard methods. Specific Aim 3. To evaluate the effectiveness and compare performance of the biodegradable coupling device in vivo with gold standards for larger diameter artery and vein (3.0 to 4.5 mm). Hypothesis 4. A. The PLA-based vascular coupling device can be manufactured using GMP certified facilities. B. The PLACL based vascular coupling device is biocompatible. Specific Aim 4. A. To manufacture vascular coupling device molds and parts. B. To conduct comprehensive biocompatibility testing with a third party (Nelson laboratories) for MSI’s vascular coupling device.