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: 9260065
• 负责人: David Alan Vorp
• 金额: $ 22.6万
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260065
• 关键词: Acute; Address; Adipocytes; Adipose tissue; Animal Sources; 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; Mesenchymal Stem Cells; Modeling; Muscle Cells; Outcome; Paired Comparison; Patients; Performance; Pericytes; Population; Preparation; Process; Proteins; Protocols documentation; Rattus; Risk; Rotation; Seeds; Source; Stem cells; Suction Lipectomy; Technology; Testing; Time; Tissue Engineering; Tissues; Translations; Tubular formation; Vacuum; Vascular Graft; Vascular Smooth Muscle; Work; base; cell transformation; clinical translation; cost; design; human stem cells; human subject; implantation; in vivo; innovation; mechanical properties; new technology; novel; pre-clinical; 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.

 产品说明：结合自体细胞的小直径组织工程血管移植物（TEVG）可以为患有心血管疾病的患者提供免疫相容性治疗解决方案。我们和其他人已经表明，间充质干细胞可以促进生物可降解支架重塑成天然样组织，包括重要的血管基质蛋白，如胶原蛋白和弹性蛋白，以及有助于血管稳态的细胞，如血管平滑肌细胞和内皮细胞。最近，我们以这种方式使用来自人类供体的脂肪来源的间充质干细胞创建了TEVG。 该应用程序将解决我们目前的TEVG技术转化为临床的三个关键障碍。首先，在我们目前的TEVG范例中，脂肪来源的干细胞（AD-MSC）在接种到可生物降解的支架中之前进行培养扩增。这引起了对细胞转化或被污染的关注，并且还可能代表关于人员和材料的显著成本。此外，动物源培养基补充剂的存在是任何生物技术的监管障碍。其次，虽然接种移植物的48小时动态培养-也是我们当前TEVG方案的一部分-与替代方法相比是快速的，但它具有与上述细胞培养相同的成本和风险。最后，我们目前的TEVG已被优化为大鼠主动脉间置移植物。创建用于临床翻译的“人类大小的”TEVG构建体将需要至少一个重要过程的“按比例放大”：将细胞接种到支架中。 为了解决这些问题并使我们的TEVG技术更接近临床可行性，我们提出了以下三个具体目的：1）评估在吸脂后立即使用直接从基质血管部分（SVF）收获的细胞的潜力（即，没有培养时间）用于制造我们的TEVG; 2）消除了对我们的接种构建体的体外生物反应器培养的需要，以产生安全和快速制造并准备植入的TEVG;和3）开发新的批量接种装置，其具有以高效率将细胞递送到“人尺寸”支架中的能力。 在完成这项研究后，我们期望已经开发出一种创新的“床边”TEVG制造策略，使用替代的人脂肪来源的细胞来源和用于长管状支架的新型批量接种装置，并且不需要体外培养期。这将通过消除临床转化的重大监管障碍，为血管组织工程提供新的创新范例的基础。