Zwitterionic hydrogels modulate the foreign body response in a modulus-dependent manner

Reducing the foreign body response (FBR) to implanted biomaterials will enhance their in vivo performance in tissue engineering. Poly(ethylene glycol) (PEG) hydrogels are increasingly popular for this application due to their low cost and ease of use. PEG hydrogels can elicit chronic inflammation upon implantation, but recent evidence has suggested that extremely hydrophilic, zwitterionic hydrogels can reduce the FBR to particles and gels. To expand on this approach, we synthesized hydrogels of co-monomers PEG and the zwitterion phosphorylcholine (PC) to quantify the combinatorial effects of modulus and hydrophilicity on the FBR. Surprisingly, hydrogels with the highest amount of zwitterionic co-monomer elicited the highest FBR we observed. Lowering the hydrogel modulus (165 kPa to 3 kPa), or PC content (20 wt% to 0 wt%), mitigated this effect. A high density of macrophages was found at the surface of implants associated with a high FBR, and mass spectrometry analysis of the proteins adsorbed to these gels implicated extracellular matrix, immune response, and cell adhesion protein categories as drivers of macrophage recruitment to these hydrogels. Overall, we show that modulus regulates macrophage adhesion to zwitterionic-PEG hydrogels, and demonstrate that chemical modifications to hydrogels should be studied in parallel with their physical properties to optimize implant design. Highlights Modulus and zwitterion content independently modulate the foreign body response to soft hydrogels Soft PEG hydrogels synthesized with the zwitterionic PC co-monomer are pro-inflammatory as modulus is increased The chemical and physical properties of hydrogels influence the foreign body response via macrophage recruitment and protein adsorption