Department of Biomedical Engineering, Amirkabir University of Technology , Tehran, Iran.
Department of Developmental Sciences, Marquette University School of Dentistry , Milwaukee, Wisconsin 53201, United States.
Langmuir. 2016 May 17;32(19):4996-5003. doi: 10.1021/acs.langmuir.5b04645. Epub 2016 May 2.
Alginate is a biopolymer with favorable pH-sensitive properties for oral delivery of peptides and proteins. However, conventional alginate nanogels have limitations such as low encapsulation efficiency because of drug leaching during bead preparation and burst release in high pH values. These shortcomings originate from large pore size of the nanogels. In this work, we proposed an on-chip hydrodynamic flow focusing approach for synthesis of alginate nanogels with adjustable pore size to achieve fine-tunable release profile of the encapsulated bioactive agents. It is demonstrated that the microstructure of nanogels can be controlled through adjusting flow ratio and mixing time directed on microfluidic platforms consisting of cross-junction microchannels. In this study, the average pore size of alginate nanogels (i.e., average molecular weight between cross-links, Mc) was related to synthesis parameters. Mc was calculated from equations based on equilibrium swelling theory and proposed methods to modify the theory for pH-sensitive nanogels. In the equations we derived, size and compactness of nanogels are key factors, which can be adjusted by controlling the flow ratio. It was found that increase in flow ratio increases the size of nanogels and decreases their compactness. The size of on-chip generated nanogels for flow ratio of 0.02-0.2 was measured to be in the range of 68-138 nm. Moreover, a method based on the Mie theory was implemented to estimate the aggregation number (Nagg) of polymer chains inside the nanogels as an indicator of compactness. According to the size and compactness results along with equations of modified swelling theory, Mc obtained to be in the range of 0.5-0.8 kDa. The proposed method could be considered as a promising approach for efficient polypeptides encapsulation and their sustained release.
海藻酸钠是一种具有 pH 敏感性的生物聚合物，适合用于肽类和蛋白质的口服递送。然而，传统的海藻酸钠纳米凝胶由于在珠粒制备过程中药物浸出以及在高 pH 值下的突释，存在包封效率低的局限性。这些缺点源于纳米凝胶的大孔径。在这项工作中，我们提出了一种基于芯片的流体动力学聚焦方法，用于合成具有可调节孔径的海藻酸钠纳米凝胶，以实现对包封生物活性剂的精细可调释放。结果表明，通过在由十字形微通道组成的微流控平台上调节流量比和混合时间，可以控制纳米凝胶的微观结构。在这项研究中，海藻酸钠纳米凝胶的平均孔径（即平均交联分子量，Mc）与合成参数有关。Mc 是根据基于平衡溶胀理论的方程以及为 pH 敏感纳米凝胶修改理论的方法来计算的。在我们推导的方程中，纳米凝胶的大小和紧凑性是关键因素，可以通过控制流量比来调节。结果发现，流量比的增加会增大纳米凝胶的尺寸并降低其紧凑性。对于流量比为 0.02-0.2 的芯片生成的纳米凝胶的尺寸测量结果在 68-138nm 范围内。此外，还实施了一种基于 Mie 理论的方法来估计纳米凝胶中聚合物链的聚集数（Nagg）作为紧凑性的指标。根据尺寸和紧凑性结果以及修改后的溶胀理论方程，得到的 Mc 在 0.5-0.8kDa 的范围内。该方法可以被认为是一种有效的多肽包封和持续释放的有前途的方法。
