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：
10841794
负责人：
Yibing Qyang
金额：
$ 1.14万
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/10841794
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.

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。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Human-Induced Pluripotent Stem-Cell-Derived Smooth Muscle Cells Increase Angiogenesis to Treat Hindlimb Ischemia.

DOI：
10.3390/cells10040792
发表时间：
2021-04-02
期刊：
Cells
影响因子：
6
作者：
Gao X;Gao M;Gorecka J;Langford J;Liu J;Luo J;Taniguchi R;Matsubara Y;Liu H;Guo L;Gu Y;Qyang Y;Dardik A
通讯作者：
Dardik A

Efficient Differentiation of Human Induced Pluripotent Stem Cells into Endothelial Cells under Xenogeneic-free Conditions for Vascular Tissue Engineering.

DOI：
10.1016/j.actbio.2020.11.007
发表时间：
2021-01-01
期刊：
Acta biomaterialia
影响因子：
9.7
作者：
Luo J;Shi X;Lin Y;Yuan Y;Kural MH;Wang J;Ellis MW;Anderson CW;Zhang SM;Riaz M;Niklason LE;Qyang Y
通讯作者：
Qyang Y

Readily Available Tissue-Engineered Vascular Grafts Derived From Human Induced Pluripotent Stem Cells.

DOI：
10.1161/circresaha.121.320315
发表时间：
2022-03-18
期刊：
CIRCULATION RESEARCH
影响因子：
20.1
作者：
Luo, Jiesi;Qin, Lingfeng;Park, Jinkyu;Kural, Mehmet H.;Huang, Yan;Shi, Xiangyu;Riaz, Muhammad;Wang, Juan;Ellis, Matthew W.;Anderson, Christopher W.;Yuan, Yifan;Ren, Yongming;Yoder, Mervin C.;Tellides, George;Niklason, Laura E.;Qyang, Yibing
通讯作者：
Qyang, Yibing

Xenogeneic-free generation of vascular smooth muscle cells from human induced pluripotent stem cells for vascular tissue engineering.

DOI：
10.1016/j.actbio.2020.10.042
发表时间：
2021-01-01
期刊：
Acta biomaterialia
影响因子：
9.7
作者：
Luo J;Lin Y;Shi X;Li G;Kural MH;Anderson CW;Ellis MW;Riaz M;Tellides G;Niklason LE;Qyang Y
通讯作者：
Qyang Y