Zwitterionic PEG-PC Hydrogels Modulate the Foreign Body Response in a Modulus-Dependent Manner

Abstract

Reducing the foreign body response (FBR) to implanted biomaterials will enhance their performance in tissue engineering. Poly(ethylene glycol) (PEG) hydrogels are increasingly popular for this application due to their low cost, ease of use, and the ability to tune their compliance via molecular weight and cross-linking densities. PEG hydrogels can elicit chronic inflammation in vivo, but recent evidence has suggested that extremely hydrophilic, zwitterionic materials and particles can evade the immune system. To combine the advantages of PEG-based hydrogels with the hydrophilicity of zwitterions, we synthesized hydrogels with comonomers PEG and the zwitterion phosphorylcholine (PC). Recent evidence suggests that stiff hydrogels elicit increased immune cell adhesion to hydrogels, which we attempted to reduce by increasing hydrogel hydrophilicity. Surprisingly, hydrogels with the highest amount of zwitterionic comonomer elicited the highest FBR. Lowering the hydrogel modulus (165 to 3 kPa), or PC content (20 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. 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.

Dealing with the Foreign‐Body Response to Implanted Biomaterials: Strategies and Applications of New Materials

“…indicated that after implanting PEG based hydrogels with different strengths, lower strength hydrogels caused relatively lower macrophage activation and less severe FBR, [ 162 ] and similar conclusion was also reported by Peyton et al. [ 163 ] In fact, researchers have used this strategy to design and prepare soft and flexible brain electrode materials to replace hard silicon probes, thereby reducing brain inflammatory response and glial cell proliferation, which will cause short recording duration and tissue damage. [ 93,164 ] However, the influence of material stiffness on the FBR is not absolute and could be depend on the type of materials.…”

Nanotechnology in cell replacement therapies for type 1 diabetes

“…It has also been suggested that smooth-contoured implants induce a weaker FBR than those with rough edges [81]. Additionally, material stiffness has also been positively correlated with the magnitude of the FBR by several studies [76,83]. Such findings emphasize that design considerations at length scales ranging from the nanometer to millimeter must be considered in FBR-resistant material design.…”

Controlling Experimental Parameters to Improve Characterization of Biomaterial Fouling

“…On hydrogels that varied in composition and stiffness, total adsorbed protein amounts did not correlate to FBR capsule thickness. LC-MS analysis of adsorbed proteins 30 min after implantation demonstrated that the presence of proteins associated with extracellular matrix construction and cell adhesion were strong predictors of FBR capsule thickness (Jansen et al, 2018).…”

“…Interestingly, unfolded adsorbed fibronectin promoted a proinflammatory state, indicating the need to study protein stability and not only total amounts. The treatment and preparation of materials before cell adhesion assays can impact cell adhesion outcomes; pre-exposing biomaterial surfaces to proteins prior to cell assay impacts cell density and spreading (Jansen et al, 2018). For example, protein choice during pre-exposure impacted the adhesion and spreading of human fibroblasts on polymer coated titanium surfaces; BSA did not significantly influence cell adhesion or spreading unlike fibrinogen, which promoted adhesion and spreading (Pei et al, 2011).…”