A sulfonated reversible thermal gel for the spatiotemporal control of VEGF delivery to promote therapeutic angiogenesis

Despite medical and surgical advancements for the treatment of cardiovascular disease, mortality and morbidity remain high. Therapeutic angiogenesis has been one approach to address the major clinical need for a more effective treatment, but current progress in angiogenic drug delivery is inadequate at providing sufficient bioavailability without causing safety concerns. An injectable sulfonated reversible thermal gel composed of a polyurea conjugated with poly(N-isopropylacrylamide) and sulfonate groups has been developed for the electrostatic binding and delivery of angiogenic factors. The thermal gel allowed for the spatiotemporal control of vascular endothelial growth factor release with a decreased initial burst release and reduced release rate in vitro. A subcutaneous injection mouse model was used to evaluate efficacious vascularization and assess the inflammatory response due to a foreign body. Thermal gel injections showed substantial vascularization properties by inducing vessel formation, recruitment and differentiation of vascular endothelial cells, and vessel stabilization by perivascular cells, while infiltrating macrophages due to the thermal gel injections decreased over time. These results demonstrated effective localization and delivery of angiogenic factors for therapeutic angiogenesis.

尽管在心血管疾病的治疗方面，医疗和外科技术取得了显著进步，但死亡率与发病率仍然居高不下。治疗性血管生成已成为一种应对对更有效治疗方法主要临床需求的方法，但当前血管生成药物递送在提供足够生物利用度的同时，未能充分解决安全性问题。一种由聚氨酯与聚(N-异丙基丙烯酰胺)及磺酸盐基团结合而成的可逆性热凝胶，已被开发用于静电结合和递送血管生成因子。该热凝胶允许对血管内皮生长因子释放进行时空控制，体外表现出降低初始释放量和减少释放速率的特点。通过皮下注射小鼠模型，评估了有效的血管化以及由异物引起的炎症反应。热凝胶注射显示出显著的血管化特性，通过诱导血管形成、血管内皮细胞的募集和分化，以及通过周围细胞实现的血管稳定化，同时由于热凝胶注射导致的浸润性巨噬细胞数量随时间减少。这些结果证明了血管生成因子在治疗性血管生成中的有效定位和递送。