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（由申请人提供）：鉴于血小板聚集，开发现成的小口径血管移植物的一个主要障碍是实现支架的快速内皮化，同时最大限度地降低血栓形成、内膜增生和机械故障的风险。平滑肌细胞增殖可能是通过控制内皮细胞 (EC) 生长和表型来介导的，开发指导适当 EC 行为的材料将对小血管产生重大影响然而，促进移植物内皮化的基质特性可能与维持成人脉管系统相关负荷的特性不一致，为了解决这一限制，我们建议制造多层水凝胶电纺网状支架，其中水凝胶层提供了局部环境诱导快速内皮化，静电纺丝网套提供整体强度、顺应性匹配和缝线保留，因此，每个组件都可以单独调整以实现更好的结果，而不损害其他设计目标。建议通过使用胶原模拟蛋白 Scl2.28 (Scl2) 生成新型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螺旋结构特征，但缺乏胶原蛋白的细胞阵列。对于目前的工作，我们介绍了 ¿ 1¿1 和 ¿1 2¿1 粘附位点进入“母体”Scl2，以提供 EC 相互作用的机制，同时维持与 Scl2 相关的低血小板聚集，诱导所需的细胞行为，将用于制造多层血管移植物增强。具有不可降解的静电纺丝网“套筒”，其设计具有与天然冠状动脉相似的机械特性。 目标 1. 鉴定促进快速收缩的 PEGDA-Scl2 成分。血管移植物的内皮化（粘附、迁移、静止表型），同时保持 Scl2 蛋白的非血栓形成性质。 目标 2. 通过强化制造具有临床相关机械性能（爆破压力、缝线保留强度、顺应性）的多层血管移植物。目标 3. 评估复合移植物各成分的生物相容性和生物稳定性。在尤卡坦小型猪模型中作为颈动脉移植物植入后体内评估多层移植物。在 5 年期结束时，我们将在临床前动物研究中评估这些新导管，并证明它们作为现成的小型导管的潜在用途。从基本角度来看，该混合材料系列将提供阐明对众多心血管装置的临床成功至关重要的内皮化过程的工具，此外，还可以控制这两种生物活性。 PEGDA-Scl2 凝胶提供的性能和模量，再加上通过将不同的整联蛋白结合基序整合到 Scl2 中来靶向一系列不同细胞类型的能力，将形成一个强大的平台，为广泛的生物医学应用创建新的生物活性材料。