A novel approach for transforming decelluarized vessel grafts into small-diameter arteries

将脱细胞血管移植物转化为小直径动脉的新方法

基本信息

批准号：
9317769
负责人：
Taixing Cui
金额：
$ 16.69万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9317769
关键词：
Affect Alginates Antigens Arteries Attenuated Biocompatible Materials Biological Assay Biology Biomedical Engineering Bioreactors Blood Vessel Prosthesis Blood Vessels Caliber Cell physiology Cells Clinic Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinases Disease Drug Delivery Systems Endothelial Cells Environment Enzymes FDA approved Genetic Transcription Glycolates Growth Growth Factor Homing Human Hydrophobicity Hyperplasia Implant In Situ In Vitro Infiltration Inflammatory Lead Legal patent Life Mechanics Microspheres Molecular Profiling Mus Muscle Cells Natural regeneration Operative Surgical Procedures Pharmaceutical Preparations Pilot Projects Process Prosthesis Recruitment Activity Signal Transduction Stem cells System Testing Time Tissues Transcriptional Regulation Transplantation Vascular Smooth Muscle Vascular remodeling Vein graft Veins Work base biodegradable polymer biomaterial compatibility cytokine experience in vivo inhibitor/antagonist innovation mechanical properties novel novel strategies regenerative repaired scaffold stem cell differentiation success

项目摘要

A living vascular prosthesis that experiences growth and adaptation, remains patent, and has life-long functionality, thereby completely replacing the diseased vessel with a healthy alternative, is the Holy Grail for vascular surgery; however, such prosthesis particularly for small-diameter vessels are currently unavailable. Hence, this proof of principle proposal is to establish a simple and efficient approach for the regeneration of small diameter arteries in vivo. Our central hypothesis is that an inhibitor of a transcription-regulating enzyme CDK8 (cyclin-dependent kinase 8) could transform decellularized vessel scaffolds into mature arteries; i.e., the regeneration of small-diameter arteries in vivo. Delivery of the drug is achieved using a semi-viscous, bioengineered, biocompatible, and biodegradable Alginate/PLGA system applied perivascularly during the grafting process. The underlying rationale comes from our pilot studies indicating that: 1) Targeting vascular stem cells (VSCs) residing in decellularized vessel scaffolds by perivascular delivery of CDK8 inhibitor Senexin A for 3 days immediately after transplantation facilitates arterial transformation of the vessel grafts. 2) A Senexin A-coated synthetic degradable polymer could maintain the effective concentration of Senexin A up to 2 weeks in a hydrophobic environment. Accordingly, our hypothesis will be tested by 2 specific aims as follows: Aim 1. To characterize the effect of perivascular delivery of Senexin A on the transformation of decellularized vessel scaffolds into arteries. Aim 2. To establish the efficacy of optimized Senexin A perivascular delivery using well-characterized, degradable, biomaterials for the transformation of decellularized vessel scaffolds into arteries. This proposed work will establish for the first time a simple and efficient approach for the regeneration of small-diameter arteries in vivo, providing a novel concept, i.e., a decellularized vessel scaffold with proper integration of regenerative signals for controlling VSCs homing and differentiation could lead to a complete regeneration of mature vessels in vivo and initiating a new venue of bioengineering vascular implants for vessel regeneration.

一种活的血管假体，可以经历生长和适应，保持专利，并具有终生功能，从而用健康的替代品完全取代患病的血管，是圣杯血管外科；然而，目前还没有这种特别适用于小直径血管的假体。因此，这个原理证明提案旨在建立一种简单有效的方法来再生体内小直径动脉。我们的中心假设是转录调节酶的抑制剂 CDK8（细胞周期蛋白依赖性激酶8）可以将脱细胞血管支架转化为成熟动脉；即体内小直径动脉的再生。使用半粘性、生物工程、生物相容性和可生物降解的藻酸盐/PLGA 系统在血管周围应用嫁接过程。基本原理来自我们的试点研究，表明：1）针对血管通过血管周围递送 CDK8 抑制剂 Senexin，使干细胞 (VSC) 驻留在脱细胞血管支架中移植后立即进行 3 天的 A 促进血管移植物的动脉转化。 2）A Senexin A 包被的合成可降解聚合物可以维持 Senexin A 的有效浓度高达在疏水环境中2周。因此，我们的假设将通过以下两个具体目标进行检验：目的 1. 表征 Senexin A 的血管周围递送对脱细胞细胞转化的影响血管支架进入动脉。目标 2. 确定优化的 Senexin A 血管周围递送的功效使用特征良好的可降解生物材料将脱细胞血管支架转化为动脉。这项拟议的工作将首次建立一种简单有效的再生方法体内小直径动脉的研究，提供了一个新的概念，即具有适当的脱细胞血管支架整合再生信号来控制 VSC 归巢和分化可能会导致完整的体内成熟血管的再生，开创了生物工程血管植入的新领域血管再生。