In Host Remodeling of Grafts to Functional Arteries-Translation to Mature Animals

描述（由申请人提供）：血管病变和相关的缺血是美国和其他工业化国家死亡和残疾的主要原因。这种疾病通常通过血管旁路术治疗。然而，只有大约三分之一的患者有适合自体移植的血管。对于这些患者，当血管直径大于6 mm时，合成移植物是一种有效的替代方案。然而，对于更小的动脉开发更有效的替代物存在巨大的治疗需求。为了满足这一需求，许多研究小组致力于在体外构建组织工程血管替代物。不幸的是，那些已经进入临床试验的药物需要3-6个月的时间才能生产，并且依从性很低。最近，已经探索了一种替代方法，其中在体内构建血管。将无细胞的可吸收血管移植物植入动物的循环中，之后身体的自然生长和重塑（G&R）过程产生新的血管代替降解的移植物。移植物的材料特性似乎对该过程至关重要。Wang小组最近在年轻成年大鼠中使用这种方法的工作已经产生了结构合理，直径小的新生动脉。除了动脉胶原蛋白，这些血管还具有神经和正常水平的成熟弹性蛋白，这都是工程动脉置换的新发现。这里的目标以及追求这一目标的下一步是 将我们的成功从年轻的老鼠转化为成熟的成年老鼠。我们的长期目标是通过提供具有现成可用性的血管移植物来改善心血管疾病的治疗，所述血管移植物利用人体自身的再生能力来原位产生替代血管。我们的假设是，年龄较大的动物也会产生新动脉， 当移植物的机械和降解特性被定制以补偿老年动物中改变的胶原蛋白和弹性蛋白产生时，胶原蛋白和弹性蛋白的水平。我们的假设得到了许多研究的支持，这些研究表明胶原蛋白和弹性蛋白的产生受到机械负荷以及我们自己的宿主重塑实验和计算研究的影响。我们计划通过两个具体目标来检验这一假设，从而实现这些目标。在第一个目标中，我们将确定与老年大鼠相比，成年大鼠新动脉形成过程中的差异。这些数据将用于为新动脉形成过程定制生长和重塑计算工具。在第二个目标中，优化算法将与该工具一起用于设计和测试老年大鼠的移植物。拟议研究的预期贡献是开发一种合成移植物，该移植物在成熟动物的宿主新动脉形成中发挥有效作用。这些结果预计将通过为在人体中原位产生小直径新生动脉提供下一个关键步骤而产生重要的积极影响。此外，我们将介绍一种全新的机制驱动的方法来设计组织工程血管。这种方法将对其他组织工程系统具有广泛的价值。

DESCRIPTION (provided by applicant): Vasculopathy and the associated ischemia is the leading cause of mortality and disability in the United States and other industrialized countries. This disease is often treated by vascular bypass. However, only about one-third of patients have blood vessels suitable for autografts. For these patients, synthetic grafts are an effective alternative when the blood vessel diameter is greater than 6 mm. However, there is tremendous therapeutic need to develop more effective replacements for smaller arteries. To meet this need, numerous groups have endeavored to construct tissue engineered vessel replacements in vitro. Unfortunately, those that have reached clinical trials require 3-6 months to produce and have low compliance. More recently, an alternative approach has been explored in which the vessels are constructed in vivo. Acellular, resorbable vascular grafts are implanted in the circulation of animals, after which the body's natural growth and remodeling (G&R) processes create a new vessel in place of the degrading graft. The material properties of the graft appear to be critical for this process. The Wang group's recent work using this approach in young adult rats has yielded structurally sound, small diameter neoarteries. In addition to arterial collagen, these vessels possess nerves and normal levels of mature elastin, both novel findings for engineered arterial replacements. The objective here, and the next step in pursuit of this goal, is to translate our proven success from young to mature adult rats. Our long-term goal is to improve treatment of cardiovascular disease by providing a vascular graft with off- the-shelf availability that utilizes the human body's own regenerative capabilities to create replacement vessel in situ. Our hypothesis is that older animals will also produce neoarteries with appropriate levels of collagen and elastin when the mechanical and degradation properties of the graft are tailored to compensate for altered collagen and elastin production in older animals. Our hypothesis is supported by numerous studies showing production of collagen and elastin is influenced by mechanical load and by our own in-host remodeling experiments and computational studies. We plan to test this hypothesis, and thereby achieve these objectives, through two specific aims. In the first aim, we will identify differences in the neoartery formatio process in mature rats compared with old. These data will be used to tailor a growth and remodeling computational tool for the neoartery formation process. In the second aim, an optimization algorithm will be used with this tool to design and test a graft for older rats. The expected contribution of the proposed research is the development of a synthetic graft which elicits effective in host neoartery formation in mature animals. These results are expected to have an important positive impact by providing the next critical step towards in situ creation of small diameter neoarteries in humans. Further, we will have introduced an entirely new mechanism driven approach for designing tissue engineered blood vessels. Such an approach will have widespread value for other tissue engineered systems.