(367d) Investigating the Impact of Bond Exchange Kinetics on the Injectability of Dynamic Covalent Hydrogels

Emerging strategies to treat disease increasingly involve the use of cell therapies. Among the methods used to deliver cell therapies, injection is advantageous due to its minimally invasive and direct nature. However, extensional forces experienced during injection can result in low post-injection cell viabilities, and poor cell retention in vivo can necessitate use of large cell numbers. To address these challenges, injectable hydrogels have been proposed as vehicles for cell encapsulation. Studies have demonstrated that injectable hydrogels with reversible crosslinks can enhance post-injection encapsulated cell viability. However, there is typically a mismatch between the hydrogel properties required for flow during injection and the robust mechanics required for stable scaffolds post-injection. To address this mismatch, we have developed poly(ethylene glycol) (PEG)-based hydrogels crosslinked via a reversible thia-conjugate addition reaction with a benzalcyanoacetamide. Compared to macromers with an unsubstituted benzalcyanoacetamide (PEG-BCA), those with a cyano-substituted benzalcyanoacetamide (PEG-CBCA) preferentially increased the rate of crosslink formation. We demonstrated that increasing the forward bond exchange kinetics increased the hydrogel plateau storage modulus without significantly affecting the relaxation time. Next, we measured the impact of these bond exchange kinetics on hydrogel injection force using a syringe pump fitted with a force sensor. In addition to bond exchange kinetics, parameters including the injection flow rate and the needle geometry affect the injection force. Thus, we performed measurements with a fixed, clinically relevant flow rate and needle geometry, and we assessed the impact of material properties on injection force. Increasing hydrogel modulus with polymer concentration, while holding bond exchange kinetics constant, led to an increase in the required injection force. When the plateau storage moduli of the PEG-BCA and PEG-CBCA hydrogels were matched, we found that accelerated bond exchange kinetics resulted in lower injection forces. Ongoing work investigates the rheological properties of these hydrogels under continuous shear to simulate injection and quantify the yield stress. In addition, we are assessing the effect of bond exchange kinetics on post-injection encapsulated cell viability. Taken together, we anticipate that these studies will yield insight that will inform the selection and design of injectable hydrogels with increased moduli for use in the delivery of cell therapies.