A modular, plasmin-sensitive, clickable poly(ethylene glycol)-heparin-laminin microsphere system for establishing growth factor gradients in nerve guidance conduits.
A modular, plasmin-sensitive, clickable poly(ethylene glycol)-heparin-laminin microsphere system for establishing growth factor gradients in nerve guidance conduits.
复制标题
一个模块化的，纤溶酶敏感的，可单击的聚乙二醇） - 肝素 - 氯胺微球系统，用于在神经引导导管中建立生长因子梯度。
DOI：
10.1016/j.biomaterials.2015.08.054
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发表时间：
2015-12
期刊：
影响因子：
14
通讯作者：
Elbert DL
中科院分区：
文献类型：
--
作者：
Roam JL;Yan Y;Nguyen PK;Kinstlinger IS;Leuchter MK;Hunter DA;Wood MD;Elbert DL
周围神经再生是一个复杂的问题，尽管有许多进步和创新，仍然有次优的结果。与生物衍生的脱细胞神经移植物和自体移植物相比，完全合成的神经引导导管（NGC）允许对其性质进行精确的工程设计，是有希望的，但仍远不是最佳的。我们已经开发了一种几乎完全合成的NGC，其允许控制可溶性生长因子递送动力学、细胞引发的降解性和细胞附着。我们集中在空间图案的胶质细胞源性的人神经营养因子（GDNF），促进运动轴突的延伸。基础支架由含肝素的聚（乙二醇）（PEG）微球组成。模块化微球形式大大简化了可逆结合GDNF的浓度梯度的形成。为了促进轴突延伸，我们设计了具有可调纤溶酶降解性的微球。还添加“点击”交联化学以允许支架形成，而没有将生长因子共价偶联至支架的风险。共价结合层粘连蛋白促进细胞粘附。证实从这些微球释放的GDNF保持其活性。使用3D打印支架在硅胶导管内形成分级支架。完全形成的NGC含有纤溶酶可降解的PEG/肝素支架，其在可逆结合的GDNF中形成线性梯度。将NGC植入具有切断的坐骨神经的大鼠中以确认体内降解性和缺乏主要异物反应。NGC还促进了轴突再生进入管道。
Peripheral nerve regeneration is a complex problem that, despite many advancements and innovations, still has sub-optimal outcomes. Compared to biologically derived acelluar nerve grafts and autografts, completely synthetic nerve guidance conduits (NGC), which allow for precise engineering of their properties, are promising but still far from optimal. We have developed an almost entirely synthetic NGC that allows control of soluble growth factor delivery kinetics, cell-initiated degradability and cell attachment. We have focused on the spatial patterning of glial-cell derived human neurotrophic factor (GDNF), which promotes motor axon extension. The base scaffolds consisted of heparin-containing poly(ethylene glycol) (PEG) microspheres. The modular microsphere format greatly simplifies the formation of concentration gradients of reversibly bound GDNF. To facilitate axon extension, we engineered the microspheres with tunable plasmin degradability. ‘Click’ cross-linking chemistries were also added to allow scaffold formation without risk of covalently coupling the growth factor to the scaffold. Cell adhesion was promoted by covalently bound laminin. GDNF that was released from these microspheres was confirmed to retain its activity. Graded scaffolds were formed inside silicone conduits using 3D-printed holders. The fully formed NGC’s contained plasmin-degradable PEG/heparin scaffolds that developed linear gradients in reversibly bound GDNF. The NGC’s were implanted into rats with severed sciatic nerves to confirm in vivo degradability and lack of a major foreign body response. The NGC’s also promoted robust axonal regeneration into the conduit.