Tuning biomaterial stiffness augments innate and adaptive immune responses in the skin

We created microporous annealed particle (MAP) hydrogels as a tunable, injectable biomaterial that can form a porous scaffold in injured tissue. We found that simply by incorporating an antigen into the MAP hydrogel, that we can stimulate hair follicle and sebaceous gland regeneration in healing wounds. In this study, we investigated how the stiffness of the hydrogel affects immune responses to the hydrogel. We found by tuning the concentration of polyethylene glycol (PEG) building blocks in the hydrogel, we can change the stiffness of the hydrogel. These stiffer MAP hydrogels recruited more neutrophils into wounds than MAP hydrogels of the original stiffness. Using a subcutaneous implant model, we found that stiffer MAP hydrogels resulted in enhanced recruitment of neutrophils and monocytes at Day 7 and enhanced recruitment of CD206+ macrophages in wounds at Day 14. Incorporating antigen into stiffer MAP hydrogels resulted in increased high affinity and low affinity antibody production to the antigen at Day 14 and Day 28. Interestingly, antibody responses were independent of Toll-like receptor signaling as MyD88-/-TRIF-/-mice displayed similar immune cell recruitment and antibody responses to antigen containing MAP scaffolds. Our work offers valuable insights into how biomaterial cues, including stiffness, represent a novel method to rapidly tune innate and adaptive immune responses independent of traditional pattern recognition pathways to biomaterials.