剪切应力响应性微胶囊的制备及性能研究

Many blood cells possess shear-stress responsive property.For example, red blood cells can be greatly deformed by the shear force during passing through narrow capillary vessel, and platelets can be activated by the high shear stress in the thrombosed region of vessel and rapidly adhere to the near surface.One can imagine that the performance of synthetic carriers will be greatly enhanced if they can mimic the shear-stress responsive property of blood cells.In this study,shear-stress responsive microcapsules will be designed and fabricated using layer-by-layer assembly technique, which have the features of tunable assembly blocks and driving force as well as highly tailored structures and properties . The micro-fluidic channel and micro-capillary devices will be emploied to study the relationship between the structures and shear-stress responsive properties of microcapsules. After carefull optimization of the fabrication conditions, the microcapsules whose modulus can be reduced under higher shear stress thus can be easily deformed to passing through narrow capillary will be obtained. Further more, the microcapsules which can release the drugs under the activation of higher shear stress in the stenotic and thrombosed regions of model blood vessels will also be fabricated.The shear-stress responsive microcapsules not only have potential applications as drug carriers, but also are good candidates as micro-reactors and micro-sensors used in vivo.

多种血液细胞具有剪切应力响应性，例如红细胞在通过狭窄毛细血管时细胞膜可在剪切应力作用下大幅拉伸变形，从而易于通过；血小板可以感知形成血栓血管部位的高剪切应力，从而被激活而快速粘附在血栓部位。赋予人工合成的微载体优异的剪切应力响应性，有望极大提高载体的综合性能。本项目利用基于模板的层层组装（LBL）微胶囊组装单元和驱动力灵活多变、微结构和性能高度可调控的特点，设计和制备剪切应力响应性微胶囊。以可原位实时观测的微流道和毛细管器件为主要研究手段，重点阐明微胶囊结构对其剪切应力响应行为的影响。优化制备条件，获得能在增强的剪切应力作用下囊壁模量降低，易于拉伸变形通过毛细管的聚电解质微胶囊和能对狭窄的病变血管部位升高的剪切应力响应而释放药物的微胶囊。具有这种性能的微胶囊并不局限于作为药物微载体，也可为设计和制备各种用于体内的微反应器和微传感器提供有益启示。

本项目利用LBL模板组装微胶囊结构和性能高度可调控、组装单元和驱动力灵活多变的特点，设计和制备剪切应力响应性微胶囊。我们首先合成了结构和性能可调控的主客体分子修饰的聚电解质和纳米粒子。以这类聚电解质为组装单元制备了中空微胶囊；以环糊精修饰的纳米粒子为组装单元制备了胶体微胶囊，发现其有客体分子和pH双重响应行为。采用多孔CaCO3为模板制备得到弹性的聚氨酯微胶囊。胶囊内部有填充，且存在疏水微区，可有效包埋疏水性物质。通过改变实验条件调控胶囊的弹性。PU微胶囊通过自制的微流道后，当形变比例为32%时，胶囊的形状恢复比例高达82.4%，说明聚氨酯微胶囊在剪切作用下具有良好的形变恢复性能。制备了两面凸圆饼状仿血小板形状的碳酸钙微粒，以其为模板尺寸类似的两面凸血小板形和球形微胶囊，在胶囊表面修饰促粘分子。制备了模拟血管的微流道并在其表面修饰纤连蛋白后接种内皮细胞来模仿血管内壁，用于研究在流动条件下两种形状微胶囊在流道内壁的内皮细胞上的粘附状况。结果表明，在流体剪切作用下，两面凸血小板形微胶囊比球形微胶囊更多地粘附在内皮细胞。制备了不同性质的纳米粒子/红细胞复合载体，详细研究了不同表面性质的纳米粒子与红细胞的结合能力以及复合载体在模拟病变血管狭窄部位受增高的剪切力作用纳米粒子的脱落情况。胶囊形状除了影响其在流体剪切作用力下的流动和粘附行为以外，也强烈影响胶囊与细胞的相互作用。我们通过渗透压法制备得到了碗状聚电解质微胶囊，发现在相同条件下，碗状微胶囊能够更多更快地被细胞吞噬。其次制备了球形和盘状的聚氨酯微胶囊，发现细胞对盘状胶囊的摄取量和摄取速率均大于球形胶囊。此外发现了重氮树脂组装得到微粒，通过透明质酸（HA）表面修饰后可被肿瘤细胞中的选择性胞吞。重氮粒子被胞吞后进入溶酶体，在紫外光照下分解释放N2，破坏了溶酶体的膜完整性，从而实现了对肿瘤细胞的杀伤。