MULTILAYER VASCULAR GRAFTS BASED ON COLLAGEN-MIMETIC HYDROGELS

基于仿胶原水凝胶的多层血管移植物

• 批准号: 8604392
• 负责人: Elizabeth Marie Cosgriff-Hernandez
• 金额: $ 30.39万
• 依托单位: TEXAS ENGINEERING EXPERIMENT STATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8604392
• 关键词: Address; Adhesions; Adult; Affect; Affinity; American; Animals; Arteries; Autologous; Behavior; Binding; Biopolymers; Blood Vessels; Caliber; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Cell Adhesion; Cell Communication; Cell Proliferation; Cells; Characteristics; Clinical; Collagen; Collagen Type IV; Coronary Arteriosclerosis; Coronary artery; Coupled; Development; Devices; Drug Formulations; Endothelial Cells; Environment; Enzymes; Ethylene Glycols; Experimental Designs; Failure; Family; Family suidae; Gel; Goals; Hybrids; Hydrogels; Hyperplasia; Individual; Integrin Binding; Integrins; Mechanics; Mediating; Modeling; Nature; Outcome; Parents; Peripheral arterial disease; Phenotype; Platelet aggregation; Polymer Chemistry; Polyurethanes; Process; Property; Proteins; Resistance; Risk; Role; Signal Transduction; Site; Smooth Muscle Myocytes; Stem cells; Sterilization; Structure; Surgical sutures; Thrombosis; United States; Vascular Graft; Work; base; biomaterial compatibility; cell behavior; cell growth; cell type; clinically relevant; cytokine; density; design; ethylene glycol; implantation; improved; in vivo; migration; mimetics; mortality; novel; pre-clinical; pressure; repaired; response; scaffold; success; tool

DESCRIPTION (provided by applicant): A major roadblock in the development of off-the-shelf, small-caliber vascular grafts is achieving rapid endothelialization of the scaffold while minimizin the risk of thrombosis, intimal hyperplasia, and mechanical failure. Given that platelet aggregation and smooth muscle cell proliferation may be mediated by controlling endothelial cell (EC) growth and phenotype, the development of materials that direct appropriate EC behavior would have a significant impact on small vessel repair and replacement. However, matrix properties which promote graft endothelialization may not be consistent with those appropriate to sustain the loads associated with adult vasculature. To address this limitation, we propose to fabricate multilayered hydrogel-electrospun mesh scaffolds in which a hydrogel layer provides a local environment inductive of rapid endothelialization and an electrospun mesh sleeve provides bulk strength, compliance matching, and suture retention. Thus, each component can be individually tuned to achieve improved outcomes without detriment to other design goals. We propose to circumvent the limitations associated with native biopolymer gels by generating novel bioactive hydrogels using the collagen-mimetic protein Scl2.28 (Scl2). Scl2 is a recently discovered protein which has the triple helical structure characteristic of native collagen but lacks collagen's array of cell adhesion, cytokine binding, and enzyme-cleavage sites. For the present work, we have introduced ¿1¿1 and ¿2¿1 adhesion sites into the "parent" Scl2 to provide a mechanism for EC interactions while maintaining the low platelet aggregation associated with Scl2. Scl2-based hydrogel formulations that induce desired cell behaviors will be utilized in the fabrication of the multilayer vascular graft reinforced with non-degradable electrospun mesh "sleeves" designed to have mechanical properties similar to native coronary arteries. Aim 1. Identify PEGDA-Scl2 compositions that promote rapid endothelialization of the vascular graft (adhesion, migration, quiescent phenotype) while maintaining the non-thrombogenic nature of Scl2 proteins. Aim 2. Fabricate a multilayer vascular graft with clinically-relevant mechanical properties (burst pressure, suture retention strength, compliance) by reinforcing hydrogels with electrospun polyurethane sleeves. Aim 3. Assess biocompatibility and biostability of each component of the composite graft. Aim 4. Evaluate multilayer grafts in vivo after implantation as carotid grafts in a Yucatan miniature pig model. At the end of the 5 year period, we will have evaluated these new conduits in preclinical animal studies and demonstrated their potential utility as off-the-shelf, small-caliber vascular grafts. From a fundamental perspective, this family of hybrid materials will provide the tools to elucidate endothelialization processes critical to the clinical success of numerous cardiovascular devices. Furthermore, the control over both bioactivity and modulus afforded by PEGDA-Scl2 gels, combined with the ability to target a range of different cell types by incorporating different integrin binding motifs into Scl2, will form a powerful platform in the creation of new bioactive materials for a wide range of biomedical applications.

描述（由适用提供）：在现成的，小口径的血管移植物开发中的主要障碍正在实现脚手架的快速内皮化，而最小化的人血栓形成，直发育和机械故障的风险。鉴于血小板聚集和平滑肌细胞增殖可以通过控制内皮细胞（EC）生长和表型来介导，因此指导适当的EC行为的材料的发展将对小血管修复和替​​换产生重大影响。但是，促进移植内皮化的基质特性可能与适合维持与成人脉管系统相关的负载的基质特性不一致。为了解决这一限制，我们建议制造多层水凝胶 - 电源网状网状支架，其中水凝胶层提供了局部环境，可通过快速内皮化和电纺网套管提供散装强度，合规性匹配和缝合力。这就是可以单独调整每个组件以实现改进的结果，而不会损害其他设计目标。我们建议通过使用胶原蛋白模拟蛋白SCL2.28（SCL2）产生新型的生物活性水凝胶来规避与天然生物聚合物凝胶相关的局限性。 SCL2是一种最近发现的蛋白质，具有天然胶原蛋白的三重螺旋结构特征，但缺乏胶原蛋白的细胞粘附阵列，细胞因子结合和酶 - 裂解位点。对于目前的工作，我们将€1“ 1和„ 2€1的粘附位点引入了“父” SCL2，以提供EC相互作用的机制，同时保持与SCL2相关的低血小板聚集。基于SCL2的水凝胶配方会影响所需的细胞行为，用于制造多层血管移植物，该多层血管移植物用不可降解的电纺网“袖子”加固，其设计具有类似于天然冠状动脉的机械性能。目标1。确定促进血管颗粒快速内皮化的PEGDA-SCL2组合物（粘附，迁移，静态表型），同时保持SCL2蛋白的非表现性质。 AIM 2。通过用电纺聚氨酯袖子增强水凝胶，制造具有临床上相关的机械性能，爆发压力，缝合力保留强度，合规性）的多层血管颗粒。 AIM 3。评估复合晶粒每个组成部分的生物相容性和可生物兼容性。 AIM 4。在Yucatan微型猪模型中植入后作为颈动脉图形在体内评估多层图形。在5年结束时，我们将评估临床前动物研究中的这些新导管，并证明了它们作为现成的小口径血管图形的潜在效用。从基本的角度来看，这种混合材料家族将提供工具，以阐明内皮化过程对众多心血管设备的临床成功至关重要。此外，PEGDA-SCL2凝胶对生物活性和模量的控制，结合通过将不同的整合素结合基序纳入SCL2，可以靶向一系列不同的细胞类型的能力，将在创建新的生物活性材料的新生物活性材料中为广泛的生物医学应用形成强大的平台。