Perivascular graft heparin delivery using biodegradable polymer wraps
Perivascular graft heparin delivery using biodegradable polymer wraps
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DOI：
10.1016/s0142-9612(00)00154-x
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发表时间：
2000-11-01
期刊：
影响因子：
14
通讯作者：
Karnovsky, MJ
中科院分区：
文献类型：
--
作者：
Edelman, ER;Nathan, A;Karnovsky, MJ
肝素仍然是参与血管损伤反应过程的金标准抑制剂。虽然该化合物在培养和动物模型中对血管细胞具有深远而广泛的影响，但其临床应用充其量是值得怀疑的。很明显，肝素的给药方式对其潜力至关重要，鉴于肝素的半衰期短和复杂的药代动力学，常规给药方式可能不足以观察到益处。口服肝素时，肝素被降解为无活性的低聚物碎片，而全身给药由于需要持续输注和潜在的不受控制的出血而变得复杂。因此，备选肝素输送系统已提出，以最大限度地发挥局部作用，同时限制全身毒性。然而，由于肝素是如此有效的抗血栓化合物，并且由于现有的局部递送系统缺乏精确调节释放动力学的能力，即使是部位特异性治疗也容易出血。我们现在描述了一种新的可生物降解系统的设计和开发，用于血管周围肝素到血管壁的输送，具有明确的释放动力学。该系统由肝素包封聚乳酸-羟基乙酸酯（pLGA）微球隔离在海藻酸盐凝胶。肝素在体外可在25天内获得控制释放。研究了影响这些基质中肝素释放的实验变量。凝胶渗透色谱（GPC）和扫描电镜（SEM）监测了降解过程，发现其与释放动力学具有良好的相关性。肝素释放凝胶以剂量依赖的方式抑制组织培养中牛血管平滑肌细胞的生长。此外，在剥脱和介入血管移植疾病动物模型中，即使标准基质型释放明显不受控制的出血，凝胶释放也能控制血管损伤。因此，该系统可以提供一种有效的方法来检查各种化合物在加速动脉病变中控制平滑肌细胞增殖的作用，并揭示这些过程的生物学性质。(C) 2000 Elsevier Science Ltd.版权所有。
Heparin remains the gold-standard inhibitor of the processes involved in the vascular response to injury. Though this compound has profound and wide-reaching effects on vascular cells in culture and animal models, its clinical utility has been questionable at best. It is clear that the mode of heparin delivery is critical to its potential and it may well be that routine forms of administration are insufficient to observe benefit given the heparin's short half-life and complex pharmacokinetics. When ingested orally, heparin is degraded to inactive oligomer fragments while systemic administration is complicated by the need for continuous infusion and the potential for uncontrolled hemorrhage. Thus alternative heparin delivery systems have been proposed to maximize regional effects while limiting systemic toxicity. Yet, as heparin is such a potent antithrombotic compound and since existing local delivery systems lack the ability to precisely regulate release kinetics, even site-specific therapy is prone to bleeding. We now describe the design and development of a novel biodegradable system for the perivascular delivery of heparin to the blood vessel wall with well-defined release kinetics. This system consists of heparin-encapsulated poly(DL lactide-co-glycolide) (pLGA) microspheres sequestered in an alginate gel. Controlled release of heparin from this heterogeneous system could be obtained over a period of 25 days in vitro. The experimental variables affecting heparin release from these matrices were investigated. Gel permeation chromatography (GPC) and scanning electron microscopy (SEM) were used to monitor the degradation process and found to correlate well with the release kinetics. Heparin-releasing gels inhibited growth of bovine vascular smooth muscle cells in tissue culture in a dose-dependent manner. Moreover, gel release controlled vascular injury in denuding and interposition vascular graft animal models of disease even when uncontrolled bleeding was evident with standard matrix-type release. This system may therefore provide an effective means of examining the effects of various compounds in the control of smooth muscle cell proliferation in accelerated arteriopathies and also shed light on the biologic nature of these processes. (C) 2000 Elsevier Science Ltd. All rights reserved.