Department of Biomedical Engineering, National University of Singapore, 4 Engineering Drive 3, 04-08, 117583, Singapore.
Lab Chip. 2020 Aug 7;20(15):2756-2764. doi: 10.1039/d0lc00296h. Epub 2020 Jul 1.
Cardiovascular disease is a chronic disease that leads to impaired cardiac function and requires long-term management to control its progression. Despite the importance of hydrogels for therapeutic applications, a contradiction between the size of a hydrogel and the amount of loaded drug has been encountered when using conventional fabrication methods. In this study, biocompatible reservoir microcapsules (diameter ∼100 μm) with a large liquid core and polymeric shell were fabricated via a one-step phase separation of poly(ethylene glycol)diacrylate (PEGDA) and dextran within pre-gel droplets through microfluidics. By controlling the process of phase separation, high drug-loading efficiency (∼80%) for long-term release (30 days) of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) was achieved. Drug molecules were dispersed within the liquid core at a concentration above saturation solubility for sustained delivery via regulation of the shells. Effective therapeutic enhancement of human umbilical vein endothelial cell (HUVEC) and umbilical artery smooth muscle cell (SMC) proliferation and tube formation in vitro promoted rapid cell proliferation and increased the number of migrated cells by ∼1.7 times. Moreover, in vivo blood vessel regeneration for cardiovascular control induced by sustained dual-drug (VEGF and PDGF) delivery to the rat heart was achieved, showing the effectiveness of long-term protein delivery in improving cardiac function and significantly reducing ventricular wall thickness and fibrosis of the infarct region. The ratio of heart tissue scarring was reduced to 11.2% after microcapsule treatment compared with 21.4% after saline treatment in the rat model. By using these reservoir microcapsules, similar sustained delivery of proteins, mRNAs and biologic drugs could be developed for the treatment of a range of long-term chronic diseases and regenerative medicine.
心血管疾病是一种慢性疾病，会导致心脏功能受损，需要长期管理来控制其进展。尽管水凝胶在治疗应用中非常重要，但在使用传统制造方法时，遇到了水凝胶的尺寸与加载药物的量之间的矛盾。在这项研究中，通过微流控技术，在预凝胶液滴内一步进行聚乙二醇二丙烯酸酯（PEGDA）和葡聚糖的相分离，制备了具有大液芯和聚合物壳的生物相容性储库微胶囊（直径约 100 μm）。通过控制相分离过程，实现了血管内皮生长因子（VEGF）和血小板衍生生长因子（PDGF）的高载药效率（约 80%）和长达 30 天的持续释放。通过调节壳层，药物分子在高于饱和溶解度的浓度下分散在液芯内，实现了药物的持续传递。体外有效促进人脐静脉内皮细胞（HUVEC）和脐动脉平滑肌细胞（SMC）增殖和管腔形成，促进了细胞的快速增殖，使迁移细胞的数量增加了约 1.7 倍。此外，通过向大鼠心脏持续递送双药物（VEGF 和 PDGF），实现了心血管控制的体内血管再生，表明长期蛋白质递送在改善心脏功能和显著减少梗死区域心室壁厚度和纤维化方面的有效性。与盐水治疗相比，微胶囊治疗后大鼠心脏组织瘢痕的比例从 21.4%降低到 11.2%。通过使用这些储库微胶囊，可以开发出类似的蛋白质、mRNA 和生物药物的持续递送，用于治疗一系列慢性疾病和再生医学。
