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

一种经历生长和适应、保持通畅并具有终身功能的活血管假体 功能性，从而用健康的替代品完全取代患病的血管，是 血管外科手术;然而，目前还不能获得特别是用于小直径血管的这种假体。 因此，该原理证明提案是建立一种简单有效的方法，用于再生 体内小直径动脉。我们的核心假设是转录调节酶的抑制剂 CDK 8（细胞周期蛋白依赖性激酶8）可以将脱细胞的血管支架转化为成熟的动脉;即，的 再生小直径动脉在体内。使用半粘性的， 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初步研究，表明：1）靶向血管 通过CDK 8抑制剂Senexin的血管周围递送驻留在脱细胞血管支架中的干细胞（VSCs） 移植后立即A处理3天有利于血管移植物的动脉转化。2)一 Senexin A涂覆的合成可降解聚合物可以将Senexin A的有效浓度维持在最高达 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： 目标1。为了表征Senexin A的血管周围递送对脱细胞的细胞转化的影响， 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 使用良好表征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个简单而有效的再生方法 的小直径动脉，提供了一个新的概念，即，脱细胞血管支架， 整合用于控制VSCs归巢和分化的再生信号可以导致完全的 成熟血管的体内再生，开创了生物工程血管植入物的新领域， 血管再生

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.