A single injection of protein-loaded coacervate-gel significantly improves cardiac function post infarction.
A single injection of protein-loaded coacervate-gel significantly improves cardiac function post infarction.
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DOI：
10.1016/j.biomaterials.2017.02.020
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发表时间：
2017-05
期刊：
影响因子：
14
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Awada HK;Long DW;Wang Z;Hwang MP;Kim K;Wang Y
心肌梗塞（MI）后，心脏发生纤维化病理重塑，而不是修复和再生。由于心肌梗死后出现多种病理，使用多种蛋白质的治疗预计比单药治疗更有效地解决这一系列的病理。实验研究的析因设计指导我们在一次注射中结合三种互补因子：金属蛋白酶组织抑制剂 3 (TIMP-3) 嵌入纤维蛋白凝胶中，用于在治疗的初始阶段发出信号，而碱性成纤维细胞生长因子 (FGF-2) 和基质细胞衍生因子 1-α (SDF-1α) 嵌入肝素凝聚层中 用于持续释放并分布在同一纤维蛋白凝胶中，以在较长时间内发挥其作用。然后在心肌梗塞大鼠模型中测试该凝胶。在第一周后，用蛋白质凝聚层-凝胶复合物处理的大鼠心脏的收缩性稳定并略有改善，而在8周的研究期间用游离蛋白质或盐水处理的大鼠的收缩性继续下降。接受蛋白质凝聚层-凝胶复合治疗的心脏还表现出心室扩张、炎症、纤维化和细胞外基质（ECM）降解减少。血运重建、心肌细胞保存、干细胞归巢和心肌应变增加可能都有助于修复。这项研究证明了心肌梗死多因素治疗方法的潜力，使用三种互补蛋白依次递送以实现全面治愈。该研究还表明，生长因子和细胞因子的控制递送必须成为有效的治疗方法。
After myocardial infarction (MI), the heart undergoes fibrotic pathological remodeling instead of repair and regeneration. With multiple pathologies developing after MI, treatment using several proteins is expected to address this range of pathologies more effectively than a single-agent therapy. A factorial design of experiments study guided us to combine three complementary factors in one injection: tissue inhibitor of metalloproteinases-3 (TIMP-3) was embedded in a fibrin gel for signaling in the initial phase of the treatment, while basic fibroblast growth factor (FGF-2) and stromal cell-derived factor 1-alpha (SDF-1α) were embedded in heparin-based coacervates for sustained release and distributed within the same fibrin gel to exert their effects over a longer period. The gel was then tested in a rat model of myocardial infarction. Contractility of rat hearts treated with the protein coacervate-gel composite stabilized and slightly improved after the first week while contractility continued to decrease in rats treated with free proteins or saline over the 8 week study period. Hearts receiving the protein coacervate-gel composite treatment also exhibited reduced ventricular dilation, inflammation, fibrosis, and extracellular matrix (ECM) degradation. Revascularization, cardiomyocyte preservation, stem cell homing, and increased myocardial strain likely all contributed to the repair. This study demonstrates the potential of a multifactorial therapeutic approach in MI, using three complementary proteins delivered sequentially for comprehensive healing. The study also shows the necessity of controlled delivery for growth factors and cytokines to be an effective treatment.