Although ischemic heart disease is the leading cause of death worldwide, mainstay treatments ultimately fail because they do not adequately address disease pathophysiology. Restoring the microvascular perfusion deficit remains a significant unmet need and may be addressed via delivery of pro-angiogenic cytokines. The therapeutic effect of cytokines can be enhanced by encapsulation within hydrogels, but current hydrogels do not offer sufficient clinical translatability due to unfavorable viscoelastic mechanical behavior which directly impacts the ability for minimally-invasive catheter delivery. In this report, we examine the therapeutic implications of dual-stage cytokine release from a novel, highly shear-thinning biocompatible catheter-deliverable hydrogel. We chose to encapsulate two protein-engineered cytokines, namely dimeric fragment of hepatocyte growth factor (HGFdf) and engineered stromal cell-derived factor 1α (ESA), which target distinct disease pathways. The controlled release of HGFdf and ESA from separate phases of the hyaluronic acid-based hydrogel allows extended and pronounced beneficial effects due to the precise timing of release. We evaluated the therapeutic efficacy of this treatment strategy in a small animal model of myocardial ischemia and observed a significant benefit in biological and functional parameters. Given the encouraging results from the small animal experiment, we translated this treatment to a large animal preclinical model and observed a reduction in scar size, indicating this strategy could serve as a potential adjunct therapy for the millions of people suffering from ischemic heart disease.

中文翻译：

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多相导管注射水凝胶可实现双阶段蛋白质工程细胞因子释放，以减轻小动物模型和大动物模型心肌梗塞后不良的左心室重构

尽管缺血性心脏病是世界范围内的主要死亡原因，但主要治疗方法最终失败，因为它们没有充分解决疾病的病理生理学问题。恢复微血管灌注不足仍然是一个重要的未满足需求，可以通过递送促血管生成细胞因子来解决。细胞因子的治疗效果可以通过封装在水凝胶中来增强，但由于不利的粘弹性力学行为直接影响微创导管输送的能力，目前的水凝胶不能提供足够的临床可转化性。在本报告中，我们研究了一种新型的、高度剪切稀化的生物相容性导管可输送水凝胶的双阶段细胞因子释放的治疗意义。我们选择封装两种蛋白质工程细胞因子，即肝细胞生长因子 (HGFdf) 的二聚体片段和工程基质细胞衍生因子 1α (ESA)，它们针对不同的疾病途径。由于释放的精确时间，HGFdf 和 ESA 从透明质酸基水凝胶的不同相的受控释放允许延长和显着的有益效果。我们在心肌缺血的小动物模型中评估了这种治疗策略的治疗效果，并观察到生物学和功能参数的显着益处。鉴于小动物实验的令人鼓舞的结果，我们将这种治疗转化为大型动物临床前模型并观察到疤痕大小的减少，表明这种策略可以作为数百万患有缺血性心脏病的人的潜在辅助治疗。