Controlled release of neurotrophin-3 from fibrin gels for spinal cord injury
Controlled release of neurotrophin-3 from fibrin gels for spinal cord injury
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DOI：
10.1016/j.jconrel.2004.05.003
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发表时间：
2004-08-11
影响因子：
10.8
通讯作者：
Sakiyama-Elbert, SE
中科院分区：
文献类型：
--
作者：
Taylor, SJ;McDonald, JW;Sakiyama-Elbert, SE
这项工作的目的是评估使用基于亲和力的递送系统以受控方式从纤维蛋白凝胶释放神经营养素-3（NT-3）作为脊髓损伤治疗的可行性。使用基于肝素的递送系统（HBDS）通过非共价相互作用将NT-3包裹在纤维蛋白凝胶内以减缓NT-3的基于扩散的释放，从而允许纤维蛋白的细胞活化降解介导释放。HBDS由三种组分组成：固定化连接肽、肝素和NT-3。接头肽含有因子XIIIa底物，并在聚合过程中与纤维蛋白共价交联。这种固定的连接肽将肝素隔离在纤维蛋白凝胶内，隔离的肝素结合NT-3，阻止其扩散。进行数学建模以检查肝素浓度对NT-3最初与纤维蛋白结合的分数的影响。体外释放研究证实，肝素浓度调节NT-3的基于扩散的释放。与未修饰的纤维蛋白相比，含有HBDS和NT-3的纤维蛋白凝胶刺激鸡背根神经节的神经生长高达54%，表明释放的NT-3具有生物活性。在初步的体内研究中，含有HBDS和NT-3的纤维蛋白凝胶在9天时显示脊髓损伤中的神经纤维密度相对于未修饰的纤维蛋白增加。(C)2004 Elsevier B. V.保留所有权利。
The goal of this work was to assess the feasibility of using affinity-based delivery systems to release neurotrophin-3 (NT-3) in a controlled manner from fibrin gels as a therapy for spinal cord injury. A heparin-based delivery system (HBDS) was used to immobilize NT-3 within fibrin gels via non-covalent interactions to slow diffusion-based release of NT-3, thus allowing cell-activated degradation of fibrin to mediate release. The HBDS consists of three components: immobilized linker peptide, heparin and NT-3. The linker peptide contained a Factor XIIIa substrate and was covalently cross-linked to fibrin during polymerization. This immobilized linker peptide sequesters heparin within fibrin gels, and sequestered heparin binds NT-3, preventing its diffusion. Mathematical modeling was performed to examine the effect of heparin concentration on the fraction of NT-3 initially bound to fibrin. In vitro release studies confirmed that heparin concentration modulates diffusion-based release of NT-3. Fibrin gels containing the HBDS and NT-3 stimulated neural outgrowth from chick dorsal root ganglia by up to 54% versus unmodified fibrin, demonstrating that the NT-3 released is biologically active. In a preliminary in vivo study, fibrin gels containing the HBDS and NT-3 showed increased neural fiber density in spinal cord lesions versus unmodified fibrin at 9 days. (C) 2004 Elsevier B.V. All rights reserved.