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: 7834484
• 负责人: Peter Stuart McFetridge
• 金额: $ 3.73万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7834484
• 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; public health relevance; 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 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）：许多因素导致未能成功生产小直径血管移植物。显然，工作移植物必须包含细胞成分，因为惰性材料无法与周围组织适当地相互作用。身体通过引发一系列复杂的生物反应来对植入材料做出反应，这些反应大致分为血栓反应、免疫原性反应和增生反应。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，导致移植失败。因此，有必要定义和测量改善移植物性能所需的内皮细胞和平滑肌细胞（SMC）功能的具体方面。 在过去的几年里，我们的实验室开发了几种创新方法来开发小直径组织工程血管。我们使用脱细胞人脐静脉（HUV）作为可重塑支架。该支架与组织机械隔离，形成具有均匀机械性能的长管状支架。我们开发了一种水凝胶“收缩包裹”技术，可将高密度的人类 SMC 快速接种到血管的腹腔表面上。这些初步研究表明 HUV 支架具有出色的重塑能力。我们这个项目的目标是将 HUV 充分开发为小直径血管，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（包括 SMC 增生）的不当反应。 我们的具体目标是 1) 全面评估人脐静脉 (HUV) 支架作为有利于平滑肌细胞早期再生事件的环境。 2) 确定促进人内皮细胞在 HUV 支架内腔上附着、生长和功能（类似体内）的条​​件。 3) 检验以下假设：流体机械环境的细节对于使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缺氧条件下不会严重损害完全氧合的内皮细胞的功能。 公众健康相关性：我们的目标是开发用于心脏和外周血管重建的功能性血管。采用一种独特的方法，使用源自人类脐静脉的生物支架，该生物支架由脐带加工而成，产生机械均匀、生物相容的材料。本文提出的研究旨在确定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影响。我们相信，这种使用人脐静脉的独特方法与本文描述的技术相结合，可以开发出一种可行的替代方案来缓解这种临床需求。