PDF(Pubmed)
Abstract：
Tissue-engineered vascular grafts (TEVGs) poised for regenerative applications are central to effective vascular repair, with their efficacy being significantly influenced by scaffold architecture and the strategic distribution of bioactive molecules either embedded within the scaffold or elicited from responsive tissues. Despite substantial advancements over recent decades, a thorough understanding of the critical cellular dynamics for clinical success remains to be fully elucidated. Graft failure, often ascribed to thrombogenesis, intimal hyperplasia, or calcification, is predominantly linked to improperly modulated inflammatory reactions. The orchestrated behavior of repopulating cells is crucial for both initial endothelialization and the subsequent differentiation of vascular wall stem cells into functional phenotypes. This necessitates the TEVG to provide an optimal milieu wherein immune cells can promote early angiogenesis and cell recruitment, all while averting persistent inflammation. In this study, we present an innovative TEVG designed to enhance cellular responses by integrating a physicochemical gradient through a multilayered structure utilizing synthetic (poly (ester urethane urea), PEUU) and natural polymers (Gelatin B), thereby modulating inflammatory reactions. The luminal surface is functionalized with a four-arm polyethylene glycol (P4A) to mitigate thrombogenesis, while the incorporation of adhesive peptides (RGD/SV) fosters the adhesion and maturation of functional endothelial cells. The resultant multilayered TEVG, with a diameter of 3.0 cm and a length of 11 cm, exhibits differential porosity along its layers and mechanical properties commensurate with those of native porcine carotid arteries. Analyses indicate high biocompatibility and low thrombogenicity while enabling luminal endothelialization and functional phenotypic behavior, thus limiting inflammation in in-vitro models. The vascular wall demonstrated low immunogenicity with an initial acute inflammatory phase, transitioning towards a pro-regenerative M2 macrophage-predominant phase. These findings underscore the potential of the designed TEVG in inducing favorable immunomodulatory and pro-regenerative environments, thus holding promise for future clinical applications in vascular tissue engineering.
摘要：
为再生应用做好准备的组织工程血管移植物（TEVGs）是有效血管修复的核心，它们的功效受到支架结构和嵌入支架内或从响应组织中引出的生物活性分子的战略分布的显着影响。尽管近几十年来取得了实质性进展，对临床成功的关键细胞动力学的透彻理解仍有待完全阐明。移植物失败,通常归因于血栓形成，内膜增生,或者钙化,主要与不当调节的炎症反应有关。重新增殖细胞的协调行为对于最初的内皮化和随后的血管壁干细胞分化为功能性表型至关重要。这需要TEVG提供一个最佳环境，其中免疫细胞可以促进早期血管生成和细胞募集，同时避免持续性炎症。在这项研究中,我们提出了一种创新的TEVG，旨在通过利用合成的多层结构整合物理化学梯度来增强细胞反应（聚（酯氨基甲酸酯脲），PEUU）和天然聚合物（明胶B），从而调节炎症反应。管腔表面用四臂聚乙二醇（P4A）功能化，以减轻血栓形成。而粘附肽（RGD/SV）的掺入促进了功能性内皮细胞的粘附和成熟。由此产生的多层TEVG，直径3.0厘米，长度11厘米，沿其各层表现出不同的孔隙率和与天然猪颈动脉相当的机械性能。分析表明高生物相容性和低血栓形成性，同时使腔内皮化和功能性表型行为，从而限制了体外模型中的炎症。血管壁在急性炎症初期表现出低免疫原性，向促再生M2巨噬细胞占优势的阶段过渡。这些发现强调了设计的TEVG在诱导有利的免疫调节和促再生环境中的潜力，因此有望在血管组织工程的未来临床应用。
