Development and assessment of a natural bio scafold for vascular reconstruction

用于血管重建的天然生物支架的开发和评估

• 批准号: 7475394
• 负责人: Peter Stuart McFetridge
• 金额: $ 35.21万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475394
• 关键词: Adhesions; Adopted; Agonist; Biological; Bioreactors; Blood Platelets; Blood Vessels; Caliber; Cardiac; Cell Proliferation; Cell physiology; Cell surface; Cells; Chemicals; Clinical; Collagen; Compatible; Complex; Computers; Condition; Contracts; Coronary artery; Development; E-Selectin; Endothelial Cells; Endothelium; Ensure; Environment; Event; Failure; Frequencies; Goals; Growth; Human; Hydrogels; Hyperplasia; Hypoxia; Implant; Industry; Inflammatory; Inflammatory Response; Investigation; Laboratories; Lead; Legal patent; Leukocytes; Liquid substance; Measures; Mechanical Stimulation; Mechanics; Modeling; Natural regeneration; Numbers; Oxygen measurement, partial pressure, arterial; Performance; Perfusion; Peripheral; Phenotype; Physiologic pulse; Process; Property; Protein C; Public Health; Pulsatile Flow; Pulse taking; Rate; Reaction; Seeds; Series; Side; Signal Transduction; Smooth Muscle Myocytes; Standards of Weights and Measures; Stimulus; Surface; System; Techniques; Technology; Testing; Thromboplastin; Thrombosis; Time; Tissue Engineering; Tissues; Tubular formation; Umbilical cord structure; Umbilical vein; Vascular Graft; Veins; Week; Work; Wound Healing; density; graft failure; immunogenic; implant material; implantation; improved; in vivo; innovation; migration; reconstruction; response; scaffold; tissue regeneration

DESCRIPTION (provided by applicant): Numerous factors have contributed to the failure to produce a successful small diameter vascular graft. It is clear that a working graft must include a cellular component since inert materials are unable to interact appropriately with the surrounding tissue. The body responds to implanted materials by initiating a complex series of biological reactions, broadly grouped as thrombotic, immunogenic and hyperplastic responses. In fact, even with grafts that include a cellular component, these negative biological responses occur leading to graft failure. It is our hypothesis that it is the inability of the cellular component of a tissue engineered vascular graft to respond appropriately that leads to graft failure. Therefore it is essential to define and measure specific aspects of endothelial and smooth muscle cell (SMC) function that are required to improve graft performance. Over the last several years, our laboratory has developed several innovative approaches for the development of a small diameter tissue engineered blood vessel. We use a decellurized human umbilical vein (HUV) as a remodelable scaffold. This scaffold is mechanically isolated from the tissue resulting in a long, tubular scaffold with uniform mechanical properties. We have developed a hydrogel 'shrink-wrapping' technique for rapidly seeding high densities of human SMC onto the ablumenal surface of the vessel. These preliminary investigations have shown the HUV scaffold to have an excellent capacity to remodel. Our goal with this project is to fully develop the HUV as a small diameter blood vessel, then characterize and define conditions leading to a cell phenotype that minimizes inappropriate responses to thrombogenic and inflammatory signals, including SMC hyperplasia. Our specific aims are 1) Comprehensively assess the human umbilical vein (HUV) scaffold as an environment favorable for early regenerative events of smooth muscle cells. 2) Identify conditions promoting attachment, growth, and function (in vivo-like) of human endothelial cells on the lumen of the HUV scaffold. 3) Test the hypothesis that details of the fluid mechanical environment are critical in causing endothelial cells to adopt a phenotype that minimizes thrombosis and an inflammatory response. 4) Test the hypothesis that exposing the smooth muscle cells to hypoxic conditions does not severely impair the function of the fully oxygenated endothelial cells. PUBLIC HEALTH RELEVANCE: Our aim to develop functional blood vessels for cardiac and peripheral vascular reconstruction. A unique approach is taken using a bioscaffold derived from the human umbilical veins that have been machined from umbilical cords to yield a mechanically uniform, biologically compatible material. The investigations proposed herein aim to defined conditions that promote regeneration of the vascular wall to confer biological functionality. Further, we will investigate parameters that modulate undesirable cell function, such as negative aspects of wound healing. We believe, this unique approach using the human umbilical vein in concert with technologies described herein, a viable alternative can be developed to alleviate this clinical demand.

描述（由申请人提供）：许多因素导致未能产生成功的小直径血管移植物。显然，由于惰性材料无法与周围的组织相互作用，因此工作移植物必须包括细胞成分。人体通过启动一系列复杂的生物反应来应对植入的材料，该反应被广泛分组为血小板，免疫原性和增生反应。实际上，即使有包括细胞成分的移植物，这些阴性生物学反应也会导致移植物衰竭。我们的假设是，组织工程血管移植的细胞成分无法适当响应，从而导致移植物衰竭。因此，必须定义和测量内皮和平滑肌细胞（SMC）功能的特定方面，以改善移植性能。 在过去的几年中，我们的实验室开发了几种创新方法来开发小型组织工程血管。我们使用脱身的人脐静脉（HUV）作为可重塑的支架。该支架是从组织中机械分离的，导致长管支架具有均匀的机械性能。我们已经开发了一种水凝胶“收缩包裹”技术，用于将高密度的人SMC迅速播种到容器的空白表面上。这些初步研究表明，HUV支架具有出色的重塑能力。该项目我们的目标是将HUV充分发展为小直径血管，然后将其表征和定义导致细胞表型的疾病，从而最大程度地减少对血栓形成和炎症信号的不适当反应，包括SMC增生。 我们的具体目的是1）全面评估人类脐静脉（HUV）支架，这是一种有利于平滑肌细胞再生事件的环境。 2）确定人类内皮细胞在HUV支架的腔内促进人内皮细胞的依恋，生长和功能（体内样）的条件。 3）检验以下假设：流体机械环境的细节对于导致内皮细胞采用最小化血栓形成和炎症反应的表型至关重要。 4）检验以下假设：将平滑肌细胞暴露于低氧条件下不会严重损害全氧化内皮细胞的功能。 公共卫生相关性：我们的目标是开发用于心脏和周围血管重建的功能性血管。使用源自脐带加工的人脐静脉的生物遵循的生物遵循，采取了一种独特的方法，以产生机械均匀的生物学兼容材料。本文提出的研究旨在定义促进血管壁再生以赋予生物功能的条件。此外，我们将研究调节不良细胞功能的参数，例如伤口愈合的负面方面。我们认为，这种独特的方法使用人类脐静脉与本文所述的技术协同使用，可以开发出可行的替代方法来减轻这种临床需求。