Acta Biomaterialia ( IF 9.4 ) Pub Date : 2020-08-18 , DOI: 10.1016/j.actbio.2020.08.011 Yuichi Matsuzaki 1 , Ryuma Iwaki 1 , James W Reinhardt 1 , Yu-Chun Chang 2 , Shinka Miyamoto 1 , John Kelly 1 , Jacob Zbinden 3 , Kevin Blum 3 , Gabriel Mirhaidari 2 , Anudari Ulziibayar 1 , Toshihiro Shoji 1 , Christopher K Breuer 4 , Toshiharu Shinoka 5
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To date, there has been little investigation of biodegradable tissue engineered arterial grafts (TEAG) using clinically relevant large animal models. The purpose of this study is to explore how pore size of electrospun scaffolds can be used to balance neoarterial tissue formation with graft structural integrity under arterial environmental conditions throughout the remodeling process. TEAGs were created with an outer poly-ε-caprolactone (PCL) electrospun layer and an inner sponge layer composed of heparin conjugated 50:50 poly (l-lactide-co-ε-caprolactone) copolymer (PLCL). Outer electrospun layers were created with four different pore diameters (4, 7, 10, and 15 µm). Fourteen adult female sheep underwent bilateral carotid artery interposition grafting (n = 3–4 /group). Our heparin-eluting TEAG was implanted on one side (n = 14) and ePTFE graft (n = 3) or non-heparin-eluting TEAG (n = 5) on the other side. Twelve of the fourteen animals survived to the designated endpoint at 8 weeks, and one animal with 4 µm pore diameter graft was followed to 1 year. All heparin-eluting TEAGs were patent, but those with pore diameters larger than 4 µm began to dilate at week 4. Only scaffolds with a pore diameter of 4 µm resisted dilation and could do so for up to 1 year. At 8 weeks, the 10 µm pore graft had the highest density of cells in the electrospun layer and macrophages were the primary cell type present. This study highlights challenges in designing bioabsorbable TEAGs for the arterial environment in a large animal model. While larger pore diameter TEAGs promoted cell infiltration, neotissue could not regenerate rapidly enough to provide sufficient mechanical strength required to resist dilation. Future studies will be focused on evaluating a smaller pore design to better understand long-term remodeling and determine feasibility for clinical use.
Statement of Significance
In situ vascular tissue engineering relies on a biodegradable scaffold that encourages tissue regeneration and maintains mechanical integrity until the neotissue can bear the load. Species-specific differences in tissue regeneration and larger mechanical forces often result in graft failure when scaling up from small to large animal models. This study utilizes a slow-degrading electrospun PCL sheath to reinforce a tissue engineered arterials graft. Pore size, a property critical to tissue regeneration, was controlled by changing PCL fiber diameter and the resulting effects of these properties on neotissue formation and graft durability was evaluated. This study is among few to report the effect of pore size on vascular neotissue formation in a large animal arterial model and also demonstrate robust neotissue formation.
中文翻译：
在大型动物模型中，电纺可生物降解的组织工程动脉移植物中孔径对新组织形成的影响。
迄今为止，很少使用临床相关的大型动物模型对可生物降解的组织工程动脉移植物（TEAG）进行研究。这项研究的目的是探讨在整个重构过程中，在动脉环境条件下如何使用电纺支架的孔径来平衡新动脉组织的形成与移植物结构的完整性。用外部聚-ε-己内酯（PCL）电纺丝层和内部海绵层（由肝素共轭50:50聚（1-丙交酯-ε-己内酯）共聚物（PLCL））制成的TEAGs。产生具有四个不同孔径（4、7、10和15 µm）的外电纺丝层。14只成年雌性羊接受了双侧颈动脉介入移植（n = 3-4 /组）。我们的肝素洗脱TEAG植入一侧（n = 14）和ePTFE移植物（n = 3）或非肝素洗脱TEAG（n = 5）。14只动物中有12只在第8周存活到指定的终点，然后将一只移植有4 µm孔径的动物随访1年。所有肝素洗脱的TEAG均已获专利，但那些孔径大于4 µm的支架在第4周就开始扩张。只有孔径为4 µm的支架才可以扩张，并且可以长达1年。在8周时，10 µm孔移植物在电纺层中具有最高的细胞密度，巨噬细胞是存在的主要细胞类型。这项研究突出了在大型动物模型中为动脉环境设计可生物吸收的TEAG的挑战。虽然较大孔径的TEAG促进细胞浸润，但新组织不能足够迅速地再生以提供足以抵抗扩张所需的机械强度。
重要声明
原位血管组织工程依赖于可生物降解的支架，该支架可促进组织再生并保持机械完整性，直到新组织可以承受负荷为止。当从小型动物模型放大到大型动物模型时，组织再生和较大的机械力的特定物种差异通常会导致移植失败。这项研究利用缓慢降解的电纺PCL护套来增强组织工程动脉移植物。通过改变PCL纤维的直径来控制对组织再生至关重要的孔径，并评估这些特性对新组织形成和移植物耐久性的影响。这项研究是少数在大型动物动脉模型中报告孔径对血管新组织形成的影响的研究，并且还证明了稳健的新组织形成。
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