Autogeneration of an Artery: A Biomimetric Strategy

动脉的自动生成：生物模拟策略

• 批准号: 6829831
• 负责人: Elliot Chaikof
• 金额: $ 34.43万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-10 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6829831
• 关键词: angiogenesis; angiogenesis factor; antithrombogenic surface; artery; artificial membranes; baboons; bioengineering /biomedical engineering; biomaterial development /preparation; biomimetics; biotechnology; blood vessel prosthesis; cardiovascular prosthesis; cell adhesion; cell migration; cell proliferation; chemical synthesis; fibroblast growth factor; heparan sulfate; human tissue; medical implant science; medical rehabilitation related tag; nanotechnology; polymers; recombinant proteins; sphingosine; tissue engineering; tissue support frame; vascular endothelium; vascular smooth muscle

DESCRIPTION (provided by applicant): In this proposal, we hypothesize that the induction of a functional endothelial lining on the surface of a small diameter vascular prosthesis can be achieved after graft implantation by controlled local delivery of proangiogenic growth factors. Specifically, we postulate that recombinant heparan sulfate-mimetic compounds, when formulated as nanoparticles that are incorporated into a fibrin gel, provide a useful strategy for the efficient delivery of Fibroblast Growth Factor-2 (FGF-2) and sphingosine-1-phosphate (S1P), as synergistic angiogenic factors. Moreover, in association with a membrane-mimetic blood-contacting surface, we postulate that the risk of thrombosis can be minimized during the period prior to complete endothelialization. Specifically, we intend to: (1) Define the features of heparan sulfate proteoglycan-mimics that dictate effective sequestration and local cell mediated delivery of pro-angiogenic growth factors. Recombinant proteoglycan mimics and other self-assembling protein-based copolymers will be formulated as nanoparticles that are incorporated into fibrin gels and examined as delivery vehicles for Fibroblast Growth Factor-2 (FGF-2) and sphingosine-1-phosphate (S1P). Protein particle degradation and compound release rates will be modulated by the presence of proteolytically sensitive sites. The interactive effects of combined FGF-2 and S1P delivery on the kinetics and magnitude of the angiogenic response will be investigated using in vitro and in vivo models. (2) Synthesize and characterize a membrane-mimetic glycocalyx for selective endothelial growth in a thromboresistant microenvironment. Membrane-mimetic thin films presenting both protein and carbohydrate ligands that promote endothelial cell growth will be synthesized on fibrin gels. Endothelial cell adhesive, migratory and proliferative behavior will be defined and selective EC-dependant anti-thrombogenic properties will be measured, including the capacity to activate protein C, dephosphorylate ADP, and produce nitric oxide. (3) Characterize the biomimetic material properties, which influences spontaneous endothelialization and resistance to neointimal hyperplasia in vivo. A small diameter vascular prosthesis will be functionalized with membrane- and proteoglycan-mimetic components and surgical implant studies performed to test the hypothesis that combined local delivery of FGF-2 and S1P potentiates the endothelialization of a thromboresistant interface while minimizing neointimal hyperplasia. In addition to morphometric measurements of graft healing, the functional properties of the induced endothelial lining will be characterized using immunohistochemical and other techniques.

描述（由申请人提供）： 在此提案中，我们假设通过控制促进血管生成生长因子的局部递送，可以在移植物植入后诱导较小的直径血管假体表面的功能性内皮衬里。具体而言，我们假设重组肝硫酸盐模拟化合物作为纳米颗粒的配制，这些纳米颗粒被掺入纤维蛋白凝胶中时，为有效地递送成纤维细胞生长因子2（FGF-2）（FGFF-2）和鞘氨氨酸-1-磷酸盐（S1P）提供了有用的策略，作为协同的血管生成因子。此外，与膜模拟的血液接触表面相关，我们假设在完成内皮化之前的期间可以最大程度地减少血栓形成的风险。具体而言，我们打算：（1）定义硫酸乙酰肝素蛋白聚糖模仿的特征，该特征决定了有效的隔离和局部细胞介导的促血管生长生长因子的传递。重组蛋白聚糖模拟物和其他基于蛋白质的共聚物共聚物将被配制为纳米颗粒，这些纳米颗粒被掺入纤维蛋白凝胶中，并作为成纤维细胞生长因子2（FGFF-2）（FGF-2）和鞘氨氨酸-1-磷酸盐（S1P）的递送车进行检查。蛋白质颗粒降解和复合释放速率将通过蛋白水解敏感位点的存在调节。联合FGF-2和S1P递送对血管生成反应的动力学的相互作用将使用体外和体内模型研究。 （2）合成并表征膜模拟糖囊泡在血栓抗体微环境中的选择性内皮生长。在纤维蛋白凝胶上合成了促进内皮细胞生长的蛋白质和碳水化合物配体的膜模拟薄膜。将定义内皮细胞粘合剂，迁移和增殖行为，并测量选择性EC依赖性抗THRONTOMIC特性，包括激活蛋白质C，去磷酸化ADP的能力并产生一氧化氮。 （3）表征了仿生物质的特性，从而影响自发的内皮化和对体内新内膜增生的抗性。小直径的血管假体将用膜和蛋白聚糖的模拟成分和手术植入物研究进行功能化，以检验以下假设，该假说结合了FGF-2和S1P的局部递送，可增强脑力耐药界面的内皮化，同时最小化植物膜膜过度超质量。除了对移植物愈合的形态测量值外，还将使用免疫组织化学和其他技术来表征诱导的内皮内衬的功能特性。