(540d) Control of Reversible Covalent Hydrogel Mechanics and Mesh Size Via pH for Protein Delivery

Tuning the mesh size of polymeric hydrogels has long been of interest for the controlled delivery of therapeutics. The microscale structure of a hydrogel polymer backbone plays an important role in the resulting mesh size and hydrogel mechanical properties, and can be controlled using macromer molecular weight, hydrogel swelling ratio, and crosslinking chemistry. pH has been shown in the past to alter hydrogel swelling ratio, which in turn influences the hydrogel mesh size. However, most hydrogel studies that investigate pH effects on mesh size rely on static crosslinks, and the pH responsive effects of dynamic crosslinks on mesh size remains relatively unknown. In this work, we functionalized a multi-arm poly(ethylene-glycol ) (PEG) polymer with a reversible thia-conjugate addition reaction system and measured the kinetic rate constants and mechanical properties of the hydrogel at varying pH values (e.g., pH 5, 7, and 9). Specifically, the two crosslinking polymers were a PEG-thiol and a PEG-benzylcyanoacetamide. The crosslinking kinetics depended strongly on the pH of the aqueous environment, allowing pH changes to be leveraged to alter the hydrogel structure. Low pH values significantly lowered the forward and reverse rate constants, while high pH values led to higher rate constants. The pH-responsiveness of the rate constants also led to a viscoelastic hydrogel with various contributions of the storage and loss moduli to the hydrogel mechanics. Based on rheological frequency sweep data, hydrogels formulated at pH 5 demonstrated over a 100-fold decrease in the crossover point of the shear storage and the shear loss moduli compared to hydrogels formulated at pH 9. Thus, at low pH, the hydrogels more closely approximated an irreversibly crosslinked, elastic hydrogel with a reduced mesh size. To explore the utility of the pH-responsive transition in mesh size, we explored the diffusion and release of a fluorescently labeled BSA model protein from the hydrogel in different pH environments. These results show promise for applications in the oral delivery of protein therapeutics, and the kinetics and mechanical data expands the knowledge of structure-property relationships for reversible covalent hydrogels.