HLS-Self-endothelializing off-the-shelf vascular grafts

HLS-自内皮化现成血管移植物

• 批准号: 9201718
• 负责人: Daniel Swartz
• 金额: $ 22.35万
• 依托单位: ANGIOGRAFT, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9201718
• 关键词: 3 year old; Acute; Address; Adolescent; Affect; Allogenic; Animals; Binding; Biocompatible Materials; Bioreactors; Biotechnology; Blood Circulation; Blood Vessels; Caliber; Cardiovascular Diseases; Carotid Arteries; Cell Culture Techniques; Cells; Childhood; Clinical Trials; Collagen; Comorbidity; Congenital Abnormality; Development; Elastin; Endothelium; Engineering; Ensure; Evaluation; FDA approved; Goals; Growth; Harvest; Heparin; Heparin Binding; Human; Hyperplasia; Implant; In Situ; Infiltration; Injury; Investigation; Longevity; Mechanics; Medial; Medical; Methods; Modeling; Morphology; Operative Surgical Procedures; Patients; Performance; Phase; Property; Proteins; Reporting; Risk; Sheep; Small Intestinal Submucosa; Smooth Muscle; Source; Stenosis; Sterility; Sterilization; Surface; Suture Techniques; Techniques; Technology; Testing; Thrombus; Time; Tissue Engineering; Vascular Endothelial Growth Factors; Vascular Graft; Weight; base; conditioning; cooking; cost; design; implantation; manufacturing process; monolayer; pre-clinical; preconditioning; prevent; protocol development; restoration; scaffold

ABSTRACT HLS16-07 - We propose to develop completely acellular off-the-shelf tissue engineered vascular grafts (TEVG) for the treatment of cardiovascular disease. As base scaffold biomaterial we will use small intestinal submucosa (SIS), FDA approved for other medical indications (Cook Biotech). These acellular tissue engineered grafts will be functionalized to be anti-thrombotic utilizing heparin bound to the SIS and self- endothelializing with vascular endothelial growth factor (VEGF) bound to the heparin-binding domain. The current state-of the-art for TEVG involves pre-cellularization in a lengthy manufacturing process, which is limiting due to long culture times involved in cell expansion and bioreactor pre-conditioning. Further, cell harvest and subsequent culturing from patients with comorbidities adds time and risk to TEVG manufacture. Some existing technologies partially address this problem by utilizing bioreactor culture to develop grafts from allogeneic cell sources, and then decellularizing them before storage and implantation. However, 7-10 weeks of culture time are still required and smaller diameter grafts also require the lumen to be endothelialized with the patients’ own cells prior to implantation, a significant limitation. In contrast, our technology overcomes these major limitations by using heparin/VEGF immobilized in the graft lumen to impart anti-thrombogenic properties as well as to attract the patients’ own cells to populate the graft, thereby eliminating the need for cells. In our preliminary studies, these grafts were tested in an ovine carotid model, where they demonstrated excellent patency and developed a completely confluent endothelial layer in the lumen within 1 month post implantation. In the current proposal, we aim to develop these acellular grafts for pediatric surgical applications by evaluating them in an adolescent ovine growth model for 3 and 6 months to evaluate TEVG growth, patency, remodeling and function. The 6 month time period is equivalent to about 5 human years (sheep lifespan ~ 8 years), during which the size and weight of the animals double and therefore, it is an appropriate time to evaluate graft growth, long-term remodeling and function. Further testing of acellular grafts for specific pediatric applications will be performed in Phase II, as well, storage, stability and sterility which will provide a “off-the-shelf” product for clinical trials.

摘要 HLS 16 -07 -我们建议开发完全脱细胞的现成组织工程血管移植物（TEVG） 用于治疗心血管疾病。作为基础支架生物材料，我们将使用小肠 粘膜下层（SIS），FDA批准用于其他医学适应症（Cook Biotech）。这些非细胞组织 工程化的移植物将利用与SIS结合的肝素和自身的抗血栓功能化。 血管内皮生长因子（VEGF）结合肝素结合域内皮化。的 TEVG的现有技术包括在冗长的制造过程中进行预细胞化， 由于细胞扩增和生物反应器预处理涉及的培养时间长而受到限制。此外，Cell 从患有合并症的患者中收获和随后的培养增加了TEVG制造的时间和风险。 一些现有的技术通过利用生物反应器培养来开发来自 同种异体细胞来源，然后在储存和植入之前使它们脱细胞。然而，7-10周 的培养时间，并且较小直径的移植物也需要管腔内皮化， 植入前患者自身的细胞，这是一个显著的限制。相比之下，我们的技术克服了 这些主要限制是通过使用肝素/VEGF固定在移植物管腔中来赋予抗血栓形成 特性以及吸引患者自己的细胞来填充移植物，从而消除了对 细胞在我们的初步研究中，这些移植物在绵羊颈动脉模型中进行了测试， 术后1个月内，通畅性极佳，管腔内形成完全融合的内皮层 置入在目前的建议中，我们的目标是开发这些无细胞移植物用于儿科手术 通过在青少年绵羊生长模型中评价它们3个月和6个月以评价TEVG生长， 通畅性、重塑和功能。6个月的时间段相当于大约5个人类年（羊 寿命约8年），在此期间，动物的大小和重量增加一倍，因此，这是一个适当的 评估移植物生长、长期重塑和功能的时间。进一步测试脱细胞移植物的特异性 儿科应用将在第二阶段进行，以及储存，稳定性和无菌性，这将提供一个 临床试验的“现成”产品。