Off-the-shelf, heparinized small diameter vascular graft limits acute thrombogenicity in a porcine model
Off-the-shelf, heparinized small diameter vascular graft limits acute thrombogenicity in a porcine model
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DOI：
10.1016/j.actbio.2022.07.061
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发表时间：
2022-09-29
影响因子：
9.7
通讯作者：
Gerecht, Sharon
中科院分区：
文献类型：
--
作者：
Elliott, Morgan B.;Matsushita, Hiroshi;Gerecht, Sharon
致血栓性对工程化移植物的临床转化提出了挑战。以前，由纤维蛋白水凝胶微纤维管（FMT）和外部聚（ε-己内酯）（PCL）鞘组成的小直径血管移植物（sdVG）支持小鼠的长期通畅性。为了开发具有现成可用性的sdVG，本文报道了FMT的货架稳定性、规模扩大以及抗血栓药物与纤维蛋白支架的成功缀合。FMT在冷冻机、冰箱或室温下储存一年后保持机械稳定性和高保水性。低分子量肝素结合的纤维蛋白支架能够在两周的酶促降解期间局部和持续递送。sdVG的升级制造提供了具有适合人类应用的尺寸和力学的天然可生物降解的移植物。在颈动脉间置猪模型中的植入在4-5周内未显示破裂，所有肝素化sdVG（n = 4）均未发生血栓。在4-5周时，通过管腔表面上的内皮细胞和中间层的初始形成证实了sdVG的重塑。然而，4-5周时的新生内膜增生导致大多数sdVG的狭窄和闭塞，这必须在未来的长期体内评估中解决。现成的，可生物降解的肝素化纤维蛋白sdVG层限制急性血栓形成，同时介导广泛的新组织形成的PCL鞘保持结构的integrity.Statement的重要性要实现临床和商业实用性的小直径血管移植物作为动脉导管，这些设备必须有现成的紧急动脉旁路应用程序的可用性，并缩放到适合人类应用的大小。临床转化的一个严重障碍是血栓形成性。治疗集中在长期的全身药物治疗，这增加了患者出血并发症的风险，或者用抗凝剂涂覆移植物和支架，即使与双重抗血小板治疗相结合，也很少改善患者的预后。我们系统地修改了生物材料特性，以开发抗凝剂包埋的可生物降解移植物，该移植物保持现成的可用性，提供机械稳定性，并通过局部药物输送防止凝块形成。(c)2022 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
Thrombogenicity poses a challenge to the clinical translation of engineered grafts. Previously, small -diameter vascular grafts (sdVG) composed of fibrin hydrogel microfiber tubes (FMT) with an external poly(epsilon-caprolactone) (PCL) sheath supported long-term patency in mice. Towards the development of an sdVG with off-the-shelf availability, the FMT's shelf stability, scale-up, and successful conjugation of an antithrombotic drug to the fibrin scaffold are reported here. FMTs maintain mechanical stability and high-water retention after storage for one year in a freezer, in a refrigerator, or at room temperature. Low molecular weight heparin-conjugated fibrin scaffolds enabled local and sustained delivery during two weeks of enzymatic degradation. Upscaled fabrication of sdVGs provides natural biodegradable grafts with size and mechanics suitable for human application. Implantation in a carotid artery interposition porcine model exhibited no rupture with thrombi prevented in all heparinized sdVGs ( n = 4) over 4-5 weeks. Remodeling of the sdVGs is demonstrated with endothelial cells on the luminal surface and initial formation of the medial layer by 4-5 weeks. However, neointimal hyperplasia at 4-5 weeks led to the stenosis and occlusion of most of the sdVGs, which must be resolved for future long-term in vivo assess-ments. The off-the-shelf, biodegradable heparinized fibrin sdVG layer limits acute thrombogenicity while mediating extensive neotissue formation as the PCL sheath maintains structural integrity.Statement of significanceTo achieve clinical and commercial utility of small-diameter vascular grafts as arterial conduits, these devices must have off-the-shelf availability for emergency arterial bypass applications and be scaled to a size suitable for human applications. A serious impediment to clinical translation is thrombogenicity. Treatments have focused on long-term systemic drug therapy, which increases the patient's risk of bleed-ing complications, or coating grafts and stents with anti-coagulants, which minimally improves patient outcomes even when combined with dual anti-platelet therapy. We systematically modified the biomate-rial properties to develop anticoagulant embedded, biodegradable grafts that maintain off-the-shelf avail-ability, provide mechanical stability, and prevent clot formation through local drug delivery.(c) 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.