Instructive Biomaterials-based Platforms for Tissue Engineering and Regenerative Medicine

要做的工作的性质：在加拿大，冠状动脉闭塞等心血管疾病是主要的死亡原因之一。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，如冠状动脉成形术和支架植入，以及(Iii)治疗性血管生成。这些选择中的每一个都有自己的挑战需要充分实现。外科搭桥术的成功受制于缺乏工程化的生物组织替代品，而冠状动脉成形术和支架植入术则受制于不受欢迎和不受控制的平滑肌细胞增殖，最终导致动脉重新闭塞。治疗性血管生成需要将生长因子控制地输送到所需部位，但到目前为止还没有成功。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，通过1)Jagged1 Notch配体与支架的功能结合以改善血管修复结果，以及2)设计可生物降解的发光(无热源发光聚合物)水凝胶来传递血管生成因子(一种触发小血管形成的物质)和一种动脉生成因子(一种稳定新形成的血管的物质)，以应对与上述(Ii)和(Iii)相关的挑战。 为什么以及对谁来说这项研究很重要：这项拟议的研究之所以重要，是因为它将生物材料和分子生物学工具结合在一起，用于治疗心脏病。这项拟议的研究将提供对支架性能中尚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，在注射部位对它们进行成像，并评估其持续输送的时间。 预期结果：从目标1开始，我期望开发具有结合Jagged1的支架，它将阻止导致再闭塞的不受欢迎的平滑肌细胞增殖。在这个过程中，我还期待获得基础材料诱导的细胞生物学知识。从目标2开始，我期望开发新型的可生物降解和可注射的固有发光水凝胶，以顺序提供两种生物因子，帮助身体在不需要手术或支架的情况下，在阻塞周围形成侧支循环。这些水凝胶不仅允许生物分子输送，而且还可以对注射的凝胶进行非侵入性成像，以了解其位置和输送速度。 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传递和成像用于血管生长的生物分子。拟议的研究将通过以材料为基础的干预措施，为应用于人类健康带来重大技术开发。

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.