Instructive Biomaterials-based Platforms for Tissue Engineering and Regenerative Medicine

工作性质：冠状动脉阻塞等心血管疾病是加拿大的主要死因之一。对于患有严重冠状动脉疾病的患者，有三种治疗选择：（i）冠状动脉旁路移植术，（ii）基于导管的干预，如冠状动脉血管成形术和支架植入术，以及（iii）治疗性血管生成。每一种选择都有其自身的挑战，需要充分实现。外科旁路移植术的成功受到缺乏工程化生物组织替代物的限制，而冠状动脉血管成形术和支架植入术受到最终重新闭塞动脉的平滑肌细胞的不期望的和不受控制的增殖的限制。治疗性血管生成需要将生长因子受控地递送到所需部位，但尚未成功。在接下来的5年里，我的研究计划将专注于开发新的使能技术，以解决与上述（ii）和（iii）相关的挑战：1）Jagged1 Notch配体与支架的功能性缀合，旨在改善血管修复结果，2）设计可生物降解的发光材料用于递送血管生成因子的（无热源的发光聚合物）水凝胶（一种触发小血管形成的物质）和动脉生成因子（一种稳定新形成的血管的物质）。 为什么和谁的研究是重要的：拟议的研究是重要的，因为它汇集了生物材料和分子生物学工具来治疗心脏病。拟议的研究将提供对支架性能中未解决的挑战之一的基本理解。它还提供了一种新的方法来输送血管生长因子，在注射部位对其进行成像，并评估其维持输送的时间。 预期成果：从目标#1开始，我预期开发具有结合锯齿状蛋白1的支架，其将阻止导致再闭塞的不期望的平滑肌细胞增殖。在这个过程中，我还期望获得基本的材料诱导细胞生物学知识。从目标#2开始，我期待开发新型的可生物降解和可注射的固有发光水凝胶，以依次提供两种生物因子，帮助身体在阻塞周围生长侧支血流，而无需手术或支架。这些水凝胶将不仅允许生物分子递送，而且允许注射凝胶的非侵入性成像，以查看其递送的位置和速率。 对研究领域和加拿大的好处：拟议的研究利用一种类型的生物材料（支架）将Jagged1呈现给细胞，另一种新的生物材料用于输送和成像血管生长的生物分子。拟议的研究将导致重大的技术发展，通过基于材料的干预措施应用于人类健康。

The nature of the work to be done: Cardiovascular diseases such as coronary artery occlusion are one of the leading causes of death in Canada. For patients with severe coronary artery disease, there are three treatment options: (i) coronary artery bypass grafting, (ii) catheter-based interventions such as coronary angioplasty and stenting, and (iii) therapeutic angiogenesis. Each of these options has its own challenges to be fully realized. The success of surgical bypass grafting is limited by the lack of engineered biological tissue substitutes whereas coronary angioplasty and stenting are limited by the undesired and uncontrolled proliferation of smooth muscle cells that eventually re-occlude the artery. Therapeutic angiogenesis requires controlled delivery of growth factors into the desired site but has not been successful as yet. Over the next 5 years, my research program will focus on developing novel enabling technologies to address the challenges associated with (ii) and (iii) above by 1) functional conjugation of Jagged1 Notch ligand to stents with the aim of improving vascular reparative outcome, and 2) designing biodegradable luminescent (light emitting polymers without heat source) hydrogels for delivery of an angiogenic factor (a substance that triggers small blood vessel formation) and an arteriogenic factor (a substance that stabilizes the newly formed blood vessel). Why and to whom the research is important: The proposed research is important because it brings together biomaterials and molecular biology tools to treat heart disease. The proposed research will provide fundamental understanding on one of the unsolved challenges in stent performance. It also provides a novel method to deliver blood vessel growth factors, to image them at the site of their injection, and to evaluate how long it sustains delivery. The anticipated outcomes: From Objective #1, I anticipate to develop stents with conjugated Jagged1 that will arrest the undesired smooth muscle cell proliferation that leads to re-occlusion. In the process, I also anticipate gaining fundamental materials-induced cell biology knowledge. From Objective #2, I anticipate developing novel biodegradable and injectable inherently luminescent hydrogels to sequentially deliver two biological factors to help the body grow collateral blood flow around a blockage without the need for surgery or stent. These hydrogels will allow not only for biomolecule delivery but also noninvasive imaging of the injected gels to see its location and rate of delivery. The benefits to the research field and to Canada: The proposed research utilizes one type of biomaterials (stents) to present Jagged1 to cells and another new biomaterial to deliver and image biomolecules for blood vessels growth. The proposed research will result in significant technology development for applications to human health through materials-based interventions.