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：
6845741
负责人：
MARGARET D ALLEN
金额：
$ 15.36万
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 2005-08-31
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的第一大死亡原因，很大程度上是因为目前没有治疗方法可以替代因心肌梗塞而损失的心肌细胞。如何最好地在宿主体内实现早期血管化的问题是迄今为止限制所有工程化心脏组织成功的最重要问题。心耳是几乎每个患者都可以获得的唯一消耗性自体心脏组织。作为心肌梗死修复的新细胞来源，自体心房组织的独特之处在于它不仅具有三维支架中的自体心肌细胞，而且还具有固有的广泛的毛细血管微血管系统。在这里，我们将检查心房组织是否可以像分层皮肤移植物一样通过接种（形成的宿主血管和移植血管之间的吻合）快速实现血运重建，而不需要从头合成微血管网络。尽管我们已经证明，植入心室的自然支架中的心房肌细胞可以存活至少四个星期，但大多数肌细胞损失发生在植入后的第一周。将在皮下植入模型中探索旨在改善早期血运重建的几种补充策略。我们将动员大网膜进入皮下空间，以检查靠近较大的动脉流入源是否会加速或增强血管化。然后，将探索将血管再造组织旋转至心脏、维持其血管（网膜）动脉供应的潜力，这是一种临床适用的方案。我们将检查提供局部 VEGF-165 对早期血管形成的影响，比较水凝胶递送 VEGF-165 与直接将 AAV 基因递送至心房补片的功效。 AAV 基因疗法还将用于将热休克蛋白直接递送至贴片，旨在提高血运重建前心肌细胞对缺血的耐受性。最后，我们将检查有效策略的综合是否允许我们在皮下床中构建第二层心房心肌细胞。我们开发了一种用于心肌基因转移的新型 AAV 载体构建体，以及一种器官培养系统，可保持心房壁存活长达 2 周，以促进基因传递。目标是产生一种活的、动态的三维心脏结构，可以在体外进行工程设计并在体内快速进行血运重建。利用成人自体心房心肌作为活体工程组织进行心肌梗塞修复是一种新颖的生物工程概念，具有迫在眉睫的临床应用潜力。