Hyaluronan Scaffold for Regenerating Elastin Matrices

用于再生弹性蛋白基质的透明质酸支架

• 批准号: 7196137
• 负责人: ANAND RAMAMURTHI
• 金额: $ 14.48万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-22 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7196137
• 关键词: 3-Dimensional; Address; Adult; Aneurysm; Biochemical; Biocompatible; Biocompatible Materials; Biological Assay; Bioreactors; Blood Vessels; Bolus Infusion; Cardiovascular system; Cells; Collagen; Complex; Condition; Cues; Culture Media; Cultured Cells; Deposition; Desmosine; Devices; Disease; Disruption; Elastic Tissue; Elasticity; Elastin; Elastin Fiber; Exhibits; Extracellular Matrix; Failure; Future; Gene Expression; Glass; Glycosaminoglycans; Growth Factor; Homeostasis; Human; Hyaluronan; Immunofluorescence Immunologic; In Situ; In Vitro; Individual; Inflammation; Inflammatory; Injury; Insulin-Like Growth Factor I; Matrix Metalloproteinases; Mechanics; Mediating; Methods; Modeling; Morphogenesis; Natural regeneration; Northern Blotting; Organ; Outcome; Outcome Study; Output; Phenotype; Play; Protein-Lysine 6-Oxidase; Pulsatile Flow; Rattus; Research Personnel; Role; Signal Pathway; Signal Transduction; Silastic; Smooth Muscle Myocytes; Solutions; Stretching; Structure; Surface; Technology; Testing; Tissue Engineering; Tissues; Tropoelastin; Tube; Tubular formation; Vascular Graft; Week; Work; Wound Healing; base; concept; crosslink; desire; fibrillogenesis; hylan; in vitro Model; in vivo; inhibitor/antagonist; mRNA Expression; malformation; nanofiber; new technology; programs; repaired; response; response to injury; scaffold; size; surface coating; tool; validation studies

DESCRIPTION (provided by applicant): The disruption of vascular elastin matrices due to mechanical injury or acquired diseases (e.g., aneurysms), or their congenital absence or malformation can severely compromise vessel elasticity and elastin-mediated cell signaling important to morphogenesis, injury response, and inflammation. Regeneration of elastin within de-elasticized vessels and within tissue-engineered constructs is limited by the poor elastin output by adult vascular smooth muscle cells (VSMCs). Also, cell scaffold materials that can upregulate elastin synthesis and provide biologic cues necessary to regenerating faithful mimics of native elastin matrices are yet to be identified. Previously we determined that that highly biocompatible, crosslinked scaffolds (hylans) containing hyalruonan (HA), a glycosaminoglycan in the ECM, stimulates cultured VSMCs to synthesize close mimics of native elastin. Evidence suggests that HA fragments, not native long-chain HA elicit these elastogenic responses, although long-chain HA possibly facilitates matrix stabilization. The further fabrication of elastogenic scaffolds containing a mixture of long-chain HA and HA fragments, is however contingent on elucidating (i) the differential effects of surface tethered HA or/ and HA fragments on elastogenesis by adult VSMCs, important to optimizing scaffold composition, (ii) the potential benefits of cell culture within prealigned 3D HA scaffolds than on 2D surfaces, to mimicking vascular elastin ultrastructure, and (iii) the impact of concurrently provided mechanical and biochemical cues on the quality (amount, structure, durability, and mechanics) of the synthesized elastin matrix. AIMS: The objective of this project is to clarify the impact of the above parameters on elastin synthesis in an adult rat VSMC culture model. Aim 1 will optimize the HA-fragment size distribution within surface-tethered mixtures of HA based on their individual effects on elastin synthesis by adult RVSMCs. Aim 2 will investigate the standalone and combined benefits of tubular, electrospun HA nanofiber scaffolds containing the optimized composition determined in Aim 1, cyclic mechanical strain, & growth factor (TGF-b, IGF-1) supplements to matrix quality. SIGNIFICANCE: The study outcomes will create a tool that can be integrated with existing vascular devices to fabricate faithful mimics of native elastin on demand. Such elastin mimics will be useful to augument and repair elastin in degenerated vessels, and also make available an in vitro model to study elastogenesis.

描述（由申请人提供）：由于机械损伤或获得性疾病引起的血管弹性蛋白基质的破坏（例如动脉瘤）或其先天性缺失或畸形会严重损害血管弹性，并严重损害对形态学，损伤，损伤，损伤，和炎症的弹性蛋白介导的细胞信号传导。除弹性血管内和组织工程构建体内弹性蛋白的再生受到成年血管平滑肌细胞（VSMC）的弹性蛋白输出不佳的限制。同样，可以上调弹性蛋白合成并提供生物学提示的细胞支架材料，以再生忠实的模仿天然弹性蛋白基质的模仿。以前，我们确定，高度生物相容性的，交联的支架（Hylans）含有透明质酸（HA），ECM中的糖胺聚糖，刺激了培养的VSMC，以合成亲密的天然弹性蛋白的模拟物。有证据表明，尽管长链HA可能促进了基质稳定，但HA碎片而不是本地长链HA引起这些弹性反应。然而，含有长链HA和HA碎片混合物的弹性脚架的进一步制造是取决于阐明（i）表面束缚的HA或/和HA碎片对成人VSMC的弹性发生的差异作用，对于优化型脚手架成分的弹性生成很重要，（ii）对3D的细胞培养物的潜在培养，（ii）ver can vers curf scaffs的潜在益处，比起了2D的潜在效果。弹性蛋白超微结构以及（iii）同时提供了合成弹性蛋白基质的质量（数量，结构，耐用性和力学）的机械和生化线索。目的：该项目的目的是阐明上述参数对成年大鼠VSMC培养模型中弹性蛋白合成的影响。 AIM 1将根据成人RVSMC对HA表面束缚混合物的HA碎片大小分布进行优化。 AIM 2将研究管状，电纺纳米纤维支架的独立和联合益处，其中包含在AIM 1，环状机械应变和生长因子（TGF-B，IGF-1）补充剂中确定的优化组合物以矩阵质量。意义：研究结果将创建一个工具，可以与现有的血管设备集成，以制造忠实的原生弹性蛋白的模仿。这种弹性蛋白模拟物将对augument和修复退化的血管中的弹性蛋白有用，也可以提供研究弹性发生的体外模型。