Readily Available Stem Cell-Based Vascular Grafts for Emergent Surgical Care

用于紧急手术护理的现成干细胞血管移植物

• 批准号: 10189694
• 负责人: Yibing Qyang
• 金额: $ 66.43万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189694
• 关键词: Abdomen; Acute; Address; Allogenic; Anastomosis - action; Animal Model; Animals; Arteries; Autologous; Autologous Transplantation; Biomechanics; Bioreactors; Blast Injuries; Blood; Blood Vessels; Blood coagulation; Blunt Trauma; Bypass; Caliber; Cardiovascular Physiology; Caring; Cells; Clinical; Clothing; Coagulation Process; Collagen; Contusions; Cryopreservation; Deposition; Derivation procedure; Diabetes Mellitus; Disease; Ectopic Expression; Elastin; Elderly; Emergency Situation; Emergency treatment; Endothelial Cells; Endothelium; Engineering; Ethical Issues; Extracellular Matrix; Family suidae; Fracture; Functional disorder; Future; Generations; Growth; HLA Antigens; Hemodialysis; Histologic; Human; Immune response; Implant; In Vitro; Injury; Intervention; Lead; Letters; Life; Ligation; Limb structure; Lower Extremity; Mechanics; Modeling; Monitor; Morbidity - disease rate; Nature; Nude Rats; Operative Surgical Procedures; Oxygen; Patient Care; Patients; Performance; Periodicity; Peripheral; Phase II Clinical Trials; Polyglycolic Acid; Pre-Clinical Model; Production; Property; Proteins; Rattus; Reproducibility; Residual state; Saphenous Vein; Smooth Muscle Myocytes; Somatic Cell; Source; Stem Cell Factor; Stretching; Supplementation; Surface; Tensile Strength; Tibial Arteries; Time; Traffic accidents; Transplantation; Trauma; Treatment Efficacy; Variant; Vascular Endothelial Cell; Vascular Graft; Vascular Smooth Muscle; Vascular remodeling; Wait Time; advanced disease; base; brachial artery; cell type; endothelial stem cell; experience; immunogenic; immunosuppressed; implantation; in vivo; in vivo Model; induced pluripotent stem cell; infection risk; injured; injury and repair; limb loss; mechanical properties; morphometry; mortality; patient population; porcine model; pre-clinical; preclinical efficacy; prevent; scaffold; scale up; severe injury; stem cell derived tissues; stem cells; thrombogenesis; tissue stem cells; urgent care; vascular injury; vascular tissue engineering; virtual

Patients who have undergone vascular trauma resulting from penetrating (e.g. blast injury) or blunt (e.g. fracture and contusion from a traffic accident) trauma often experience severe damage to their small-diameter peripheral arteries (2-4mm, e.g. tibial or brachial arteries) and require surgical intervention to bypass or replace the injured vessel segments. As the accessibility of saphenous veins may be low in patients of vascular trauma due to severe injuries or loss of more than one lower extremity as a result of blast injury or severe traffic accident, and the application of synthetic vascular grafts can be hindered by the potential risk of infection due to the contagious nature of these types of injuries, an alternative source of vascular graft is in dire need. Acellular tissue engineered vascular grafts (TEVGs) therefore may offer a readily available treatment for emergency care for patients of vascular trauma. Although TEVGs of significant mechanical strength can be developed from culturing primary human vascular smooth muscle cells (VSMCs) followed by decellularization, this platform has several obstacles which prevent it from ultimately serving victims of vascular trauma. The finite expandability, limited accessibility, and donor-to-donor functional variations among primary VSMCs may hinder the efficiency of TEVG production. Further, as small-diameter TEVGs require autologous endothelial cell (EC) coating prior to implantation to avoid blood clothing, potential dysfunction of patient ECs due to either advanced age or disease, as well as the significant time required to derive and expand the patient's autologous ECs, could prevent applicability in treating acute vascular injury. Human induced pluripotent stem cells (hiPSCs), self-renewable cells derived from somatic cells by the ectopic expression of stem cell factors, provide an excellent alternative to address the complications of primary cell based TEVGs. As hiPSCs can be differentiated into virtually any somatic cell type, including VSMCs and ECs (hiPSC-VSMCs and hiPSC-ECs), these cells provide an unlimited cell source to obtain vascular cells to construct TEVGs of comparable quality (hiPSC-TEVGs). Further, by engineering the expression of human leukocyte antigen (HLA) proteins, non- or low-immunogenic universal hiPSCs could be established, making the hiPSC-TEVGs suitable for implantation into any patient. Through utilizing the hiPSC platform, TEVGs for patients of vascular trauma can be developed on a massive scale, and of predictable and reproducible mechanical strength. Additionally, through developing and cryopreserving allogeneic universal hiPSC-ECs, these cells could be immediately applied to endothelialize TEVGs for small-diameter vascular intervention. Using hiPSC-VSMCs, we have successfully developed TEVGs with mechanical strength approaching that of saphenous veins, the common native grafts in vascular injury repair. Therefore, to achieve this future application of hiPSC-TEVGs, it is essential to establish the approach to efficiently decellularize the hiPSC-TEVGs, provide a luminal layer of hiPSC-ECs, and assess subsequent mechanical properties in vivo for preclinical efficacy as detailed in this proposal.

因穿透性（例如爆炸损伤）或钝器而导致的血管创伤的患者（例如骨折 创伤经常对其小直径的外围造成严重损害 动脉（2-4mm，例如胫骨或肱动脉），需要手术干预才能绕过或替换受伤 船只段。由于大隐静脉的可及性在血管创伤患者中可能很低 由于爆炸损伤或严重的交通事故，严重伤害或丧失了一个以上的下肢， 合成血管移植物的应用可能会因传染性引起的潜在感染风险而阻碍 这些类型的伤害的性质，是急需的血管移植的另一种来源。细胞组织工程 因此 血管创伤。尽管可以通过培养主要的机械强度来发展具有重要机械强度的TeVG 人血管平滑肌细胞（VSMC）随后进行脱细胞，该平台有几个障碍 这阻止了它最终为血管创伤的受害者服务。有限的可扩展性，有限的可访问性， 主要VSMC之间的供体对供体功能变化可能会阻碍TEVG生产的效率。 此外，由于小直径TEVG需要自体内皮细胞（EC）涂层，以避免 血液衣服，患者EC的潜在功能障碍是由于年龄或疾病引起的 得出和扩展患者的自体EC所需的大量时间，可以防止适用于治疗 急性血管损伤。人类诱导的多能干细胞（HIPSC），可自我再生细胞，源自躯体 通过异位表达干细胞因子的细胞，为解决并发症提供了一种绝佳的选择 基于原代细胞的TEVG。由于HIPSC几乎可以分为任何体细胞类型，包括 VSMC和ECS（HIPSC-VSMC和HIPSC-EC），这些细胞提供了无限的细胞来源以获得血管 细胞构建具有可比质量的TEVG（HIPSC-TEVGS）。此外，通过工程 可以建立人类白细胞抗原（HLA）蛋白，非免疫原性HIPSC，可以建立 使HIPSC-TEVG适合植入任何患者。通过利用HIPSC平台TEVGS 对于血管创伤的患者，可以大规模发展，并且可预测且可重复性 机械强度。此外，通过开发和冷冻层次的同种异体通用HIPSC-EC， 这些细胞可以立即用于内皮化TEVGs进行小直径的血管干预。使用 HIPSC-VSMC，我们成功地开发了具有机械强度的TEVG，接近 大隐静脉，是血管损伤修复中常见的天然移植物。因此，要实现这一未来应用 在HIPSC-TEVG中，必须建立有效脱毛的方法，提供HIPSC-TEVG，提供 HIPSC-EC的腔层，并评估体内的随后的机械性能作为临床前疗效 在此提案中详细介绍。