Atrial wall: a 3-D scaffold with formed microvasculature

心房壁：具有已形成的微脉管系统的 3D 支架

基本信息

批准号：
6802221
负责人：
MARGARET D ALLEN
金额：
$ 21.94万
依托单位：
BENAROYA RESEARCH INST AT VIRGINIA MASON
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-03-01 至 2007-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Heart disease remains the number one cause of death in the developed world, in large part because there is no current therapy to replace cardiac myocytes lost to myocardial infarction. The issue of how best to achieve early vascularization in the host is the most important problem limiting the success of all engineered cardiac tissues to date. The atrial appendage is the only expendable autologous cardiac tissue that would be available in virtually every patient. As a new cell source for myocardial infarct repair, autologous atrial tissue is unique in that it has not only autologous cardiomyocytes in a three dimensional scaffold, but also an inherent and extensive capillary microvasculature. Here we will examine whether, like a split thickness skin graft, atrial tissue could be revascularized rapidly by inosculation (anastomoses between formed host and graft vessels), without requiring synthesis of a de novo microvascular network. Although we have shown that atrial myocytes implanted on the ventricle in their natural scaffold survive to at least four weeks, most myocyte loss that occurs is in the first week post implantation. Several complementary strategies designed to improve early revascularization will be explored in a subcutaneous implant model. We will mobilize omentum into the subcutaneous space to examine whether proximity to a larger arterial inflow source would accelerate or augment vascularization. Then, the potential for rotating the re-vascularized tissue to the heart, maintaining its vascular (omental) arterial supply will be explored, a clinically applicable protocol. We will examine the effect on early vascularization of providing local VEGF-165, comparing the efficacy of hydrogel delivery of VEGF-165 to direct AAV gene delivery to the atrial patch. AAV gene therapy will also be used to deliver a heat shock protein directly to the patch, designed to increase myocyte tolerance to ischemia in the period before revascularization. Finally, we will examine whether a synthesis of efficacious strategies would allow us to build a second layer of atrial cardiomyocytes in the subcutaneous bed. We have developed a new AAV vector construct for myocardial gene transfer and also an organ culture system to keep atrial wall alive for up to 2 weeks to facilitate gene delivery. The goal is to produce a living, dynamic three-dimensional cardiac structure that can be engineered in vitro and revascularized rapidly in vivo. Making use of autologous adult atrial myocardium as a living engineered tissue for myocardial infarct repair is a novel bioengineering concept that has potential for imminent clinical applicability.

描述（由申请人提供）：心脏病仍然是发达国家中死亡的第一大原因，这在很大程度上是因为目前没有替代心肌梗塞丢失的心肌细胞的疗法。如何最好地在宿主中实现早期血管化的问题是限制所有工程心脏组织成功的最重要问题。心房附属物是唯一可以在每个患者中可用的消耗性自动心脏组织。作为心肌梗死修复的新细胞来源，自体心房组织是独一无二的，因为它不仅具有三维支架中的自体心肌细胞，而且还具有固有且广泛的毛细血管微胚膜。在这里，我们将检查是否像皮肤移植物分裂一样，可以通过媒介（形成的宿主和移植血管之间的吻合）迅速对心房组织进行血运重建，而无需合成从头微血管网络。尽管我们已经表明，自然脚手架中植入心室的心肌细胞生存至少四个星期，但大多数在植入后第一周发生的肌细胞损失。在皮下植入物模型中将探讨几种旨在改善早期血运重建的互补策略。我们将动员Omentum进入皮下空间，以检查靠近较大的动脉流入来源是否会加速或增强血管化。然后，将探索将重新血管化组织旋转到心脏，维持其血管（胶质）动脉供应的潜力，这是一种临床适用的方案。我们将研究提供局部VEGF-165早期血管化的影响，并比较VEGF-165水凝胶递送到将AAV基因递送到心房斑块的功效。 AAV基因疗法还将用于直接向斑块传递热休克蛋白，旨在在血运重建之前提高肌细胞对缺血的耐受性。最后，我们将研究有效策略的合成是否使我们能够在皮下床中建立第二层心房心肌细胞。我们为心肌基因转移开发了一种新的AAV矢量构建体，也开发了一种器官培养系统，可将房屋壁生存长达2周，以促进基因递送。目的是产生一个活泼的三维心脏结构，可以在体内迅速进行体外和血运重建。利用自体成年心房心肌作为心肌梗塞修复的活的工程组织，是一种新型的生物工程概念，具有可能临近临床适用性的潜力。