Optimizing Bioactive Hydrogels to Control Angiogenesis and Inflammation in Functi

描述(申请人提供)：促进与周围组织和/或循环系统的交流/相互作用的生物医学植入物由于纤维包膜带来的巨大扩散障碍和增加的电阻而变得无效。这些装置的例子包括生物材料植入物、生物传感器、植入式药物输送装置和组织工程支架。异物反应的特点是炎性细胞的募集增强。对于成功的植入物，理想的做法是让高度血管化的组织包围和穿透设备。血管生成是指从现有的血管系统中形成新的血管。血管生成和炎症在体内对所有生物材料植入的反应都是不可避免的。大多数生物材料植入物的设计要么是为了减少炎症，要么是为了改善血管形成。尽管已经取得了进展，但许多研究忽略了炎症与血管生成之间的重要相互联系，只关注简单的体外结果。事实上，生物材料的最终临床成功将需要处理复杂的体内环境的相互联系。越来越多的证据表明，炎症细胞调节与血管生成相关的内皮细胞的功能。然而，炎症中启动血管生成的信号是复杂的，很难定义。这项拟议的研究解决了这样的假设：生物材料诱导的炎症反应可能是控制血管生成的关键。阐明生物材料诱导炎症中血管生成的生理机制将为下一代生物材料的设计和制造提供新的范式。为了验证这一假说，我们合成了一类新型生物材料--聚乙二醇型酪氨酸衍生聚碳酸酯水凝胶，并进行了表征。通过在聚合物上引入功能肽，水凝胶支架将变得更具生物活性，以控制炎症和血管生成。将进行一系列研究，以探讨炎症在水凝胶支架上血管生成中的作用(S)。这项研究将对植入靶向生物材料的研究产生很大的影响，因为阐明启动宿主炎症反应和随后的生物材料血管化的机制是高风险的，但非常重要。明确的机制的确定将为生物材料植入物的功能生存提供一个有效和现实的范式，说明炎症与血管生成的相互联系。这项研究将涉及复杂的基于生物工程的技术挑战，例如开发一种新型的生物材料支架，制造具有生物活性的支架材料，以及使用多光子显微镜测量多种细胞功能的定量成像方法。这项工作的高风险性质需要几种不同的方法来生成支架并对其进行修改，以测试炎症在血管生成中的作用，以及血管生成在植入功能和存活中的作用。与公共健康相关：该项目将优化所有生物材料植入物应用中存在的炎症过程的固有能力，以1)通过利用植入物支架中的生物活性分子促进血管生成，以及2)改进植入物的设计，以释放引导血管生成的降解产物。为了克服研究生物材料的炎症和血管生成反应的困难，将使用几种高风险的体外和体内方法。

DESCRIPTION (provided by applicant): Biomedical implants that facilitate communication/interaction with the surrounding tissue and/or circulatory system are rendered ineffective by the huge diffusion barrier and increased electrical resistance presented by the fibrous capsule. Examples of these devices include biomaterial implants, biosensors, implantable drug-delivery devices and tissue-engineering scaffolds. The foreign body response is characterized by enhanced recruitment of inflammatory cells. For successful implants, it is ideal to have the device surrounded and penetrated by highly vascularized tissue. Angiogenesis is the formation of new blood vessels from the existing vascular system. Both angiogenesis and inflammation are inescapable in vivo responses to all biomaterial implants. Most biomaterial implants are designed either to reduce inflammation or to improve vascularization. Although progress has been made, many studies overlook the important interconnectivity of inflammation with angiogenesis and focus on only simple in vitro outcomes. Indeed, eventual clinical success of biomaterials will require coping with the interconnectivity of the complex in vivo environment. There is emerging evidence that inflammatory cells regulate the functions of endothelial cells related to angiogenesis. However, the signals initiating angiogenesis in inflammation are complex and difficult to define. The proposed research addresses the hypothesis: the biomaterial-induced inflammatory response may be critical to control angiogenesis. Elucidating a clear physiological mechanism for angiogenesis in biomaterial-induced inflammation will provide new paradigms of biomaterial design and fabrication for the next generation of biomaterials. In order to test this hypothesis, a new class of biomaterials, hydrogels-fabricated from Polyethylene glycol (PEG)-cross-linked tyrosine-derived polycarbonate, has been synthesized and characterized. The hydrogel scaffolds will be made more bioactive to control inflammation and angiogenesis by introducing functional peptides on the polymers. A series of studies will be performed to investigate the role(s) of inflammation in angiogenesis on the hydrogel scaffolds. This study will have high impact on implantation-targeted biomaterial research, because elucidating a mechanism that initiates host inflammatory responses and the subsequent vascularization of biomaterial implants is high risk but very important. The identification of a clear mechanism will provide an efficient and realistic paradigm of the interconnectivity of inflammation with angiogenesis for the functional survival of biomaterial implants. This study will involve sophisticated bioengineering-based technical challenges, such as development of a new class of biomaterial scaffolds, fabrication of scaffold materials to be bioactive, and a quantitative imaging approach using multiphoton microscopy to measure multiple cell functions. The high risk nature of this work has necessitated several different approaches to generate the scaffolds and modify them for testing of the role of inflammation in angiogenesis and of angiogenesis in implant function and survival. PUBLIC HEALTH RELEVANCE: This project will optimize the inherent ability of the inflammatory process present in all biomaterial implant applications to 1) promote angiogenesis by utilizing bioactive molecules in the implant scaffold and 2) enhance design of the implant to release degradation products that direct angiogenesis. To overcome the difficulties in studying inflammatory and angiogenic responses to biomaterials, several high risk in vitro and in vivo methods will be utilized.