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: 8035751
• 负责人: Peter Stuart McFetridge
• 金额: $ 20.92万
• 依托单位: UNIVERSITY OF FLORIDA
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035751
• 关键词: Adhesions; Adopted; Agonist; Biological; Bioreactors; Blood Platelets; Blood Vessels; Caliber; Cardiac; Cell Proliferation; Cell physiology; Cell surface; Cells; Chemicals; Clinical; Collagen; Complex; Computers; 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; Oxygen measurement, partial pressure, arterial; Performance; Perfusion; Peripheral; Phenotype; Physiologic pulse; Process; Property; Protein C; Pulsatile Flow; Reaction; Seeds; Series; Side; Signal Transduction; Smooth Muscle Myocytes; Sterility; Stimulus; Surface; System; Techniques; Technology; Testing; Thromboplastin; Thrombosis; Time; Tissue Engineering; Tissues; Tubular formation; Umbilical cord structure; Umbilical vein; Vascular Graft; Veins; Work; Wound Healing; conditioning; density; graft failure; immunogenic; implant material; implantation; improved; in vivo; in vivo Model; innovation; migration; reconstruction; regenerative; 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 abluminal 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. 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 Narrative 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 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）：许多因素导致小直径血管移植失败。显然，由于惰性材料不能与周围组织适当地相互作用，因此有效的移植物必须包含细胞成分。机体对植入材料的反应是通过启动一系列复杂的生物反应，大致分为血栓性反应、免疫原性反应和增生性反应。事实上，即使移植物含有细胞成分，这些负面的生物反应也会导致移植物失败。我们的假设是，组织工程血管移植物的细胞成分无法做出适当的反应，导致移植物失败。因此，有必要定义和测量内皮和平滑肌细胞（SMC）功能的特定方面，以提高移植物的性能。在过去的几年里，我们的实验室已经开发了几种创新的方法来开发一个小直径的组织工程血管。我们使用脱细胞人脐静脉（HUV）作为可重构支架。这种支架在机械上与组织分离，形成具有均匀机械性能的长管状支架。我们已经开发了一种水凝胶“收缩包裹”技术，用于快速将高密度的人类SMC播种到血管的腔面。这些初步研究表明，HUV支架具有良好的改造能力。我们这个项目的目标是将HUV完全发展为小直径血管，然后表征和定义导致细胞表型的条件，从而最大限度地减少对血栓形成和炎症信号的不适当反应。我们的具体目标是1)全面评估人类脐静脉支架作为平滑肌细胞早期再生事件的有利环境。2)确定促进人内皮细胞在HUV支架管腔上的附着、生长和功能（体内样）的条件。3)验证流体机械环境的细节是导致内皮细胞采用最小化血栓形成和炎症反应的表型的关键假设。4)验证将平滑肌细胞暴露在缺氧条件下不会严重损害充氧内皮细胞叙事功能的假设