Compliant and strong small arteries engineered in vitro

描述（由申请人提供）：冠状动脉疾病是美国死亡和残疾的主要原因。目前的治疗方法包括自体动脉和静脉移植，尽管经过了几十年的改进，但仍有相当大的局限性。小动脉替代品的两个关键挑战是高顺应性和非血栓性。我们的长期目标是创造机械能力强、无血栓形成性和血管反应性的小动脉替代品。这项建议的目的是设计机械上有能力的小动脉。该应用的中心假设是，仿生培养环境将促进小动脉的形成，其结构和特性代表了天然血管。我们将在动态力学条件下，通过在合理设计的弹性支架中培养血管祖细胞，创造一个模拟血管生成和血管生成的培养条件。这种创新的方法可能在不久的将来导致生理顺应性，并最终导致非血栓性和血管反应性。在强有力的初步数据的指导下，这一假设将通过追求三个具体目标来检验。在目标1中，我们将使用弹性体和硬质生物材料制造管状支架，这些材料将用于目标2和目标3中，以检查支架性能对合成人工动脉的结构和性能的影响。目标2和目标3的反馈将指导支架的选择和优化。在目标2中，我们将用平滑肌细胞培养循环内皮祖细胞，以设计密切相互作用的内膜/介质复合材料，使其与天然动脉的顺应性相匹配。目的3将侧重于通过增加外膜层来增加构建物的强度和稳定性，同时保持内膜/中膜层的高度顺应性。目标1至目标3的联合工作有望创造机械能力强的小动脉，为未来抗血栓性和血管反应性的研究提供坚实的基础。这个多学科的提案结合了生物材料和再生医学的首席研究员和血管细胞生物学、生物力学和血液材料界面现象的合作者的互补专业知识。一旦成功完成，拟议的研究预计将代表血管替代品领域的重大进步，并加速组织工程动脉从临床应用到临床应用的转化。

DESCRIPTION (provided by applicant): Coronary artery disease is the leading cause of mortality and disability in the US. Current treatment methods including autologous artery and vein grafts have considerable limitations despite decades of refinement. Two critical challenges in small artery substitutes are high compliance and nonthrombogenicity. Our long-term goal is to create mechanically competent, nonthrombogenic and vasoresponsive small artery substitutes. The objective of this proposal is to engineer mechanically competent small arteries. The central hypothesis of this application is that a biomimetic culture environment will facilitate the formation of small arteries with structure and properties representative of the native vessels. We will create a culture condition that mimics angiogenesis and vasculogenesis by cultivating vascular progenitor cells in rationally-designed elastomeric scaffolds under dynamic mechanical conditions. This innovative approach may lead to physiological compliance in the near future, and nonthrombogenicity and vasoresponsiveness ultimately. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims. Under aim 1, we will fabricate tubular scaffolds from elastomeric and stiff biomaterials that will be used in aims 2 and 3 to examine the effects of scaffold properties on the structure and properties of the resultant artificial arteries. The feedbacks from aims 2 and 3 will guide the selection and optimization of the scaffolds. Under aim 2, we will culture circulating endothelial progenitor cells with smooth muscle cells to engineer closely interacting intima/media composites with compliance matching native arteries. Aim 3 will focus on increasing the strength and stability of the constructs by adding an adventitia layer while maintaining the high compliance of the intima/media layer. The combined work in aims 1 to 3 is expected to create mechanically competent small arteries that provides a solid foundation for future investigations in antithrombogenicity and vasoresponsiveness. This multidisciplinary proposal combines the complementary expertise of the Principal Investigator in biomaterial and regenerative medicine, and the Collaborators in vascular cell biology, biomechanics, and blood-material interfacial phenomenon. When successfully completed, the proposed research is expected to represent a significant advance in the field of blood vessel substitutes and accelerate the translation of tissue-engineered arteries from benchside promise to bedside benefit.