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物有相当大的局限性，尽管几十年的完善。小动脉替代物的两个关键挑战是高顺应性和无血栓性。我们的长期目标是创造机械性能好、无血栓形成和血管反应性的小动脉替代物。这项提案的目的是设计机械能力的小动脉。本申请的中心假设是仿生培养环境将促进具有代表天然血管的结构和性质的小动脉的形成。我们将通过在动态机械条件下合理设计的弹性支架中培养血管祖细胞来创造模拟血管生成和血管发生的培养条件。这种创新的方法可能会导致在不久的将来生理顺应性，并最终无血栓形成和血管反应性。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。根据目标1，我们将用弹性和刚性生物材料制造管状支架，用于目标2和3，以检查支架特性对所得人工动脉结构和特性的影响。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下，我们将培养循环内皮祖细胞和平滑肌细胞，以设计具有匹配天然动脉顺应性的紧密相互作用的内膜/中膜复合物。目标3将侧重于通过增加外膜层来增加结构的强度和稳定性，同时保持内膜/中膜层的高顺应性。目标1至3的综合工作预计将创造出具有机械能力的小动脉，为未来的抗血栓形成和血管反应性研究提供坚实的基础。这个多学科的建议结合了生物材料和再生医学的主要研究者的互补专业知识，以及血管细胞生物学，生物力学和血液材料界面现象的合作者。当成功完成时，拟议的研究预计将代表血管替代品领域的重大进展，并加速组织工程动脉从实验室承诺到床边效益的转变。

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.