Instructive Biomaterials-based Platforms for Tissue Engineering and Regenerative Medicine

待开展工作的性质：冠状动脉闭塞等心血管疾病是加拿大的主要死亡原因之一。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）基于导管的干预措施，如冠状动脉成形术和支架置入术，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生物组织替代品的限制，而冠状动脉成形术和支架植入术则受到平滑肌细胞不希望和不受控制的增殖的限制，平滑肌细胞最终会再次阻塞动脉。治疗性血管生成需要有控制地将生长因子输送到所需部位，但迄今尚未成功。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配体与支架的功能偶联，旨在改善血管修复效果；2)设计可生物降解的发光（无热源发光聚合物）水凝胶，用于输送血管生成因子（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）。为什么以及对谁来说这项研究很重要：这项拟议中的研究很重要，因为它将生物材料和分子生物学工具结合起来治疗心脏病。拟议的研究将为支架性能尚未解决的挑战之一提供基本的理解。它还提供了一种新的方法来输送血管生长因子，在注射部位对它们进行成像，并评估它维持输送的时间。预期结果：从目标1来看，我期望开发具有共轭Jagged1的支架，该支架将阻止导致再闭塞的不希望的平滑肌细胞增殖。在这个过程中，我也期望获得基本的材料诱导细胞生物学知识。从目标2来看，我期望开发一种新型的可生物降解和可注射的固有发光水凝胶，以连续传递两种生物因子，以帮助身体在堵塞周围生长侧支血液，而无需手术或支架。这些水凝胶不仅可以用于生物分子的递送，还可以对注射的凝胶进行无创成像，以查看其位置和递送速度。对研究领域和加拿大的好处：拟议的研究利用一种生物材料（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.