Zhao Fuli, Wu Di, Yao Dan, Guo Ruiwei, Wang Weiwei, Dong Anjie, Kong Deling, Zhang Jianhua
Department of Polymer Science and Technology and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China; Tianjin Key Laboratory of Membrane Science and Desalination Technology, Tianjin University, Tianjin 300072, China.
Department of Polymer Science and Technology and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.
Acta Biomater. 2017 Dec;64:334-345. doi: 10.1016/j.actbio.2017.09.044. Epub 2017 Sep 30.
Long-term and daily subcutaneous injections of insulin for the treatment of insulin-dependent diabetic patients often lead to poor patient compliance and undesired complications. Phenylboronic acid (PBA)-based polymeric hydrogels have been widely considered as one of the most promising insulin delivery system to replace the frequent insulin injections. However, their applications are limited by clinically irrelevant glucose-responsive range, slow response rate, low tissue-adhesiveness and poor biodegradability, undesirable leakage at normoglycemic state. Herein, we report a novel implantable insulin hydrogel for glucose-regulated delivery of insulin based on a unique particle-hydrogel hybrid platform featuring fast glucose responsiveness at physiological pH, shear-thinning behavior for injection, tissue-adhesive function for long-lasting adherence, and full biodegradability for safe use. The system was thoroughly characterized both in vitro and in vivo and was demonstrated to hold these unique functions. Using streptozotocin-induced diabetic mice as a model, it was shown that a single subcutaneous injection of the insulin-loaded particle-hydrogel formulation led to quasi-steady-state blood glucose levels within the normal range for about two weeks. In addition, the preparation of the formulation only involved simple mixing and self-assembling processes, and thus it had great scalability and reproducibility for practical use. The highly feasible preparation, excellent performance, inherent biocompatibility and biodegradability make this novel composite hydrogel promising platform for diabetes therapy.
Phenylboronic acid (PBA)-based polymeric hydrogels have been widely considered as one of the most promising insulin delivery system to replace the frequent insulin injections. However, these hydrogels, mostly based on a variety of PBA-containing acrylamide monomers, are still far from clinical reality. Building upon a unique particle-hydrogel hybrid platform, herein we report a novel implantable insulin storage and delivery system with multifunctionalities including fast glucose-sensitiveness at physiological pH, shear-thinning behavior for injection, tissue-adhesive function for long-lasting adherence, biodegradable materials for safe use and well-controlled insulin release. These unique functions were demonstrated through research both in vitro and in vivo. In addition, the preparation of the formulation was simple, and thus it had great scalability and reproducibility for practical use.
长期每日皮下注射胰岛素治疗胰岛素依赖型糖尿病患者常常导致患者依从性差和出现不良并发症。基于苯硼酸（PBA）的聚合物水凝胶已被广泛认为是最有前景的胰岛素递送系统之一，以取代频繁的胰岛素注射。然而，它们的应用受到临床无关的葡萄糖响应范围、响应速率慢、组织粘附性低、生物降解性差以及在正常血糖状态下不期望的泄漏的限制。在此，我们报道了一种新型的可植入胰岛素水凝胶，用于基于独特的颗粒-水凝胶混合平台进行葡萄糖调节的胰岛素递送，该平台在生理pH下具有快速葡萄糖响应性、用于注射的剪切变稀行为、用于持久粘附的组织粘附功能以及用于安全使用的完全生物降解性。该系统在体外和体内都进行了全面表征，并被证明具有这些独特功能。以链脲佐菌素诱导的糖尿病小鼠为模型，结果表明单次皮下注射负载胰岛素的颗粒-水凝胶制剂可使血糖水平在正常范围内维持约两周的准稳态。此外，该制剂的制备仅涉及简单的混合和自组装过程，因此在实际应用中具有很大的可扩展性和可重复性。这种高度可行的制备方法、优异的性能、固有的生物相容性和生物降解性使这种新型复合水凝胶成为糖尿病治疗的有前景的平台。
基于苯硼酸（PBA）的聚合物水凝胶已被广泛认为是最有前景的胰岛素递送系统之一，以取代频繁的胰岛素注射
