Compliant and strong small arteries engineered in vitro

描述(申请人提供)：在美国，冠状动脉疾病是导致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。小动脉替代物的两个关键挑战是高顺应性和非血栓形成。我们的长期目标是创造机械能力强、无血栓形成和血管反应性的小动脉替代品。这项提议的目标是设计机械能力强的小动脉。这一应用的中心假设是，仿生培养环境将促进具有代表本地血管的结构和特性的小动脉的形成。我们将通过在动态机械条件下在合理设计的弹性支架中培养血管前体细胞来创造模拟血管生成和血管生成的培养条件。这一创新的方法可能在不久的将来导致生理顺应性，并最终导致非血栓形成和血管反应性。在强劲的初步数据的指导下，这一假说将通过追求三个具体目标来检验。在目标1中，我们将使用弹性和刚性生物材料制作管状支架，用于目标2和3，以检测支架性能对合成的人工动脉结构和性能的影响。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下，我们将循环内皮祖细胞与平滑肌细胞一起培养，以设计出与顺应性匹配的天然动脉紧密相互作用的内膜/中膜复合材料。目标3将专注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/中层的高顺应性。AIMS 1至3的联合工作预计将创造机械性能良好的小动脉，为未来抗血栓形成和血管反应性的研究提供坚实的基础。这一多学科的建议结合了生物材料和再生医学的首席研究员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的互补专业知识。当成功完成后，这项拟议的研究有望代表着血管替代品领域的重大进步，并加快组织工程动脉从长期承诺到床边益处的转变。

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.