An Autologous, Culture-Free, Adipose Cell-Based Tissue Engineered Vascular Graft

一种自体、无培养、基于脂肪细胞的组织工程血管移植物

• 批准号: 9015874
• 负责人: David Alan Vorp
• 金额: $ 19.18万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9015874
• 关键词: Acute; Address; Adipocytes; Adipose tissue; Animals; Autologous; Biological; Bioreactors; Blood Vessels; Bypass; Caliber; Cardiovascular Diseases; Cardiovascular system; Cell Culture Techniques; Cell Fraction; Cells; Clinic; Clinical; Collagen; Culture Media; Data; Devices; Elastin; Endothelial Cells; Evaluation; Fatty acid glycerol esters; Gold; Harvest; Homeostasis; Hour; Human; Human Resources; Implant; In Vitro; Lead; Length; Length of Stay; Mechanics; Mesenchymal Stem Cells; Modeling; Outcome; Paired Comparison; Patients; Performance; Pericytes; Population; Preparation; Process; Property; Proteins; Protocols documentation; Rattus; Risk; Seeds; Smooth Muscle Myocytes; Source; Stem cells; Suction Lipectomy; Technology; Testing; Time; Tissue Engineering; Tissues; Translations; Tubular formation; Vacuum; Vascular Graft; Vascular Smooth Muscle; Work; base; cell transformation; cost; design; human subject; implantation; in vivo; innovation; new technology; novel; public health relevance; research clinical testing; scaffold; scale up; vascular tissue engineering

 DESCRIPTION: Small-diameter tissue engineered vascular grafts (TEVGs) that incorporate autologous cells may provide an immuno-compatible treatment solution for patients with cardiovascular disease. We and others have shown that mesenchymal stem cells can promote remodeling of a biodegradable scaffold into native-like tissue that includes important vascular matrix proteins, such as collagen and elastin, and cells which contribute to vascular homeostasis, such as vascular smooth muscle cells and endothelial cells. Most recently, we have created TEVGs in this manner using adipose-derived mesenchymal stem cells from human donors. This application will address three critical barriers to translation of our current TEVG technology to the clinic. First, in our current TEVG paradigm, adipose-derived stem cells (AD-MSCs) are culture-expanded before seeding into biodegradable scaffolds. This presents a concern for the cells transforming or becoming contaminated, and also could represent significant costs with respect to personnel and materials. In addition, the presence of animal-sourced culture media supplements is a regulatory hurdle for any biological technology. Second, while the dynamic culture of a seeded graft for 48 hours - also part of our current TEVG protocol - is rapid compared to alternate approaches, it carries the same costs and risks as stated above for cell culture. Finally, our current TEVG has been optimized as an aortic interposition graft in the rat. Creating "human-sized" TEVG constructs for clinical translation wil require "scale-up" of at least one important process: seeding of cells into the scaffold. To address these concerns and advance our TEVG technology closer toward clinical feasibility, we propose the following three Specific Aims: 1) Evaluate the potential of using cells directly harvested from the stromal vascular fraction (SVF) immediately following liposuction (i.e., without time in culture) for fabricating our TEVG; 2) Eliminate the need for in-vitro bioreactor culture of our seeded construct to yield a TEVG that is safely and rapidly fabricated and ready to implant; and 3) Develop a new bulk-seeding device with the ability to deliver cells at high efficiency into "human-sized" scaffolds. Upon completion of this study, we expect to have developed an innovative "bedside" TEVG fabrication strategy using an alternative human adipose-derived cell source and a novel bulk-seeding device for long tubular scaffolds, and requiring no in vitro culture period. This will provide the basis of a new, innovative paradigm in vascular tissue engineering by eliminating significant regulatory barriers to clinical translation.

 描述：掺入自体细胞的小直径组织工程血管移植物（TEVG）可能为心血管疾病患者提供免疫兼容治疗溶液。我们和其他人表明，间充质干细胞可以促进可生物降解的支架重塑为天然样组织，其中包括重要的血管基质蛋白，例如胶原蛋白和弹性蛋白，以及有助于血管稳态的细胞，例如血管平滑肌细胞和内皮细胞。最近，我们使用人类供体的脂肪衍生的间充质干细胞以这种方式创建了TEVG。该应用程序将解决我们当前TEVG技术向诊所翻译的三个关键障碍。首先，在我们当前的TEVG范式中，脂肪来源的干细胞（AD-MSC）在播种成可生物降解的支架之前是培养的。这对转化或被污染的细胞引起了人们的关注，并且在人和材料方面也可能代表大量成本。此外，动物来源的培养基补充剂的存在是任何生物技术的调节障碍。其次，虽然种子等级的动态培养持续48小时（也是我们当前TEVG方案的一部分）与替代方法相比，它的成本和风险与上述细胞培养相同。最后，我们当前的TEVG已被优化为大鼠的主动脉介入移植物。创建用于临床翻译的“人尺寸” TEVG构造将需要至少一个重要的过程：将细胞播种到脚手架中。为了解决这些问题并促进我们的TEVG技术更接近临床可行性，我们提出以下三个具体目的：1）评估在吸脂后立即使用从基质血管分数（SVF）收获的细胞（即文化中没有时间）来制造我们的TEVG的潜力； 2）消除了我们种子构建体的体外生物反应器培养物的需求，以产生安全，快速制造并准备植入的Tevg； 3）开发一种新的散装装置，能够将高效的细胞输送到“人尺寸”脚手架中。这项研究完成后，我们希望使用替代人类脂肪衍生的细胞来源和一种新型的长管支架的新型散装式植物来制定创新的“床头” TEVG制造策略，并且不需要体外培养时期。这将提供血管组织工程中新的创新范式的基础，方法是消除临床翻译的重大调节障碍。