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

基本信息

批准号：
10636647
负责人：
Yibing Qyang
金额：
$ 66.43万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10636647
关键词：
Acute Address Allogenic Anastomosis - action Animal Model Animals Anticoagulation Arteries Autologous Autologous Transplantation Biomechanics Bioreactors Blast Injuries Blood Blood Vessels Blood coagulation Blunt Trauma Bypass Cardiovascular Physiology Caring Cells Clinical Clothing Coagulation Process Collaborations Collagen Contusions Cryopreservation Deposition Derivation procedure Diabetes Mellitus Diameter Disease Ectopic Expression Elastin Elderly Emergency Situation Emergency treatment Endothelial Cells Endothelium Engineering Ethical Issues Extracellular Matrix Family suidae Fracture Functional disorder Future Generations Glycocalyx Growth HLA Antigens Hemodialysis Histologic Human Immune response Implant In Vitro Injury Intervention Lead Legal patent Letters Life Ligation Limb structure Lower Extremity Mechanics Methods Modeling Monitor Morbidity - disease rate Nature Nude Rats Operative Surgical Procedures Oxygen Patient Care Patients Penetration Performance Periodicity Peripheral Phase II Clinical Trials Polyglycolic Acid Population 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 abdominal aorta advanced disease 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 manufacturing scale-up mechanical properties morphometry mortality patient population porcine model pre-clinical preclinical efficacy prevent scaffold severe injury stem cell derived tissues stem cells thrombogenesis urgent care vascular injury vascular tissue engineering virtual

项目摘要

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.

遭受过穿透性损伤（例如爆炸伤）或钝性损伤（例如骨折）造成的血管损伤的患者和交通事故造成的挫伤）外伤通常会对其小直径外周造成严重损害动脉（2-4毫米，例如胫骨或肱动脉），需要手术干预以绕过或替换受伤的部位血管段。由于血管外伤患者的隐静脉通达性可能较低因爆炸伤或严重交通事故而导致一侧以上下肢严重受伤或丧失，以及合成血管移植物的应用可能会因传染性病毒引起的潜在感染风险而受到阻碍由于这些类型损伤的性质，迫切需要血管移植的替代来源。无细胞组织工程因此，血管移植物（TEVG）可以为以下患者的紧急护理提供一种现成的治疗方法：血管外伤。尽管具有显着机械强度的 TEVG 可以通过培养初级人血管平滑肌细胞（VSMC）脱细胞化，这个平台有几个障碍这阻止了它最终为血管创伤患者提供服务。有限的可扩展性、有限的可访问性、原代 VSMC 之间的供体间功能差异可能会阻碍 TEVG 的生产效率。此外，由于小直径 TEVG 在植入前需要自体内皮细胞 (EC) 涂层，以避免血衣、患者 ECs 由于高龄或疾病而潜在的功能障碍，以及获得和扩展患者自体 EC 所需的大量时间可能会妨碍其在治疗中的适用性急性血管损伤。人类诱导多能干细胞 (hiPSC)，源自体细胞的自我更新细胞细胞通过干细胞因子的异位表达，提供了解决并发症的绝佳替代方案基于原代细胞的 TEVG。由于 hiPSC 几乎可以分化成任何体细胞类型，包括 VSMCs和ECs（hiPSC-VSMCs和hiPSC-ECs），这些细胞提供了无限的细胞来源以获得血管细胞构建质量相当的 TEVG (hiPSC-TEVG)。此外，通过设计表达人类白细胞抗原（HLA）蛋白、非免疫原性或低免疫原性通用 hiPSC 可以被建立，使 hiPSC-TEVG 适合植入任何患者体内。通过利用 hiPSC 平台，TEVG 针对血管创伤患者的治疗可以大规模开发，并且具有可预测性和可重复性机械强度。此外，通过开发和冷冻保存同种异体通用 hiPSC-EC，这些细胞可以立即应用于内皮化 TEVG，以进行小直径血管干预。使用 hiPSC-VSMCs，我们已成功开发出机械强度接近的TEVG 大隐静脉是血管损伤修复中常见的天然移植物。因此，要实现这一未来的应用对于 hiPSC-TEVG，有必要建立有效去细胞化 hiPSC-TEVG 的方法，提供 hiPSC-EC 的管腔层，并评估随后的体内机械特性以了解临床前功效详细说明在本提案中。