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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：
10622873
负责人：
Yibing Qyang
金额：
$ 1.1万
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/10622873
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

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（如爆炸伤）或钝性（如骨折）造成血管损伤的患者