Hydration‐Induced Void‐Containing Hydrogels for Encapsulation and Sustained Release of Small Hydrophilic Molecules

Abstract Efficient encapsulation and sustained release of small hydrophilic molecules from traditional hydrogel systems are challenging due to the large mesh size of 3D networks and high water content. Furthermore, the encapsulated molecules are prone to early release from the hydrogel prior to use, resulting in a short shelf life of the formulation. Here, a hydration‐induced void‐containing hydrogel (HVH) based on hyperbranched polyglycerol‐poly(propylene oxide)‐hyperbranched polyglycerol (HPG‐PPG‐HPG) as a robust and efficient delivery system is presented for small hydrophilic molecules. Specifically, after the HPG‐PPG‐HPG is incubated overnight at 4 °C in the drug solution, it is hydrated into a hydrogel containing micron‐sized voids, which can encapsulate hydrophilic drugs and achieve 100% drug encapsulation efficiency. In addition, the voids are surrounded by a densely packed polymer matrix, which restricts drug transport to achieve sustained drug release. The hydrogel/drug formulation can be stored for several months without changing the drug encapsulation and release properties. HVH hydrogels are injectable due to shear thinning properties. In rats, a single injection of the HPG‐PPG‐HPG hydrogel containing 8 µg of tetrodotoxin (TTX) produces sciatic nerve block lasting up to 10 h without any TTX‐related systemic toxicity nor local toxicity to nerves and muscles.