Department of Bioengineering, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado 80045, United States.
Department of Medicine, Division of Cardiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado 80045, United States.
ACS Biomater Sci Eng. 2022 Sep 12;8(9):3883-3898. doi: 10.1021/acsbiomaterials.2c00616. Epub 2022 Aug 11.
Myocardial infarction causes cardiomyocyte death and persistent inflammatory responses, which generate adverse pathological remodeling. Delivering therapeutic proteins from injectable materials in a controlled-release manner may present an effective biomedical approach for treating this disease. A thermoresponsive injectable gel composed of chitosan, conjugated with poly(-isopropylacrylamide) and sulfonate groups, was developed for spatiotemporal protein delivery to protect cardiac function after myocardial infarction. The thermoresponsive gel delivered vascular endothelial growth factor (VEGF), interleukin-10 (IL-10), and platelet-derived growth factor (PDGF) in a sequential and sustained manner . An acute myocardial infarction mouse model was used to evaluate polymer biocompatibility and to determine therapeutic effects from the delivery system on cardiac function. Immunohistochemistry showed biocompatibility of the hydrogel, while the controlled delivery of the proteins reduced macrophage infiltration and increased vascularization. Echocardiography showed an improvement in ejection fraction and fractional shortening after injecting the thermal gel and proteins. A factorial design of experimental study was implemented to optimize the delivery system for the best combination and doses of proteins for further increasing stable vascularization and reducing inflammation using a subcutaneous injection mouse model. The results showed that VEGF, IL-10, and FGF-2 demonstrated significant contributions toward promoting long-term vascularization, while PDGF's effect was minimal.
心肌梗死导致心肌细胞死亡和持续的炎症反应，从而产生不良的病理性重构。从可注射材料中以控制释放的方式递送治疗性蛋白质可能是治疗这种疾病的一种有效生物医学方法。开发了一种由壳聚糖组成的温敏型可注射凝胶，其与聚（异丙基丙烯酰胺）和磺酸基团相共轭，用于时空蛋白质递送来保护心肌梗死后的心脏功能。该温敏凝胶以顺序和持续的方式递送电切素（VEGF）、白细胞介素-10（IL-10）和血小板衍生生长因子（PDGF）。使用急性心肌梗死小鼠模型评估聚合物的生物相容性，并确定递药系统对心脏功能的治疗效果。免疫组织化学显示水凝胶具有生物相容性，而蛋白质的控制释放减少了巨噬细胞浸润并增加了血管生成。超声心动图显示注射热凝胶和蛋白质后射血分数和短轴缩短率均有所改善。通过皮下注射小鼠模型实施实验研究的析因设计，以优化递药系统，以最佳组合和剂量的蛋白质进一步增加稳定的血管生成并减少炎症。结果表明，VEGF、IL-10 和 FGF-2 显著促进长期血管生成，而 PDGF 的作用最小。
