Linking the foreign body response and protein adsorption to PEG-based hydrogels using proteomics

Abstract

Poly(ethylene glycol) (PEG) hydrogels with their highly tunable properties are promising implantable materials, but as with all non-biological materials, they elicit a foreign body response (FBR). Recent studies, however, have shown that incorporating the oligopeptide RGD into PEG hydrogels reduces the FBR. To better understand the mechanisms involved and the role of RGD in mediating the FBR, PEG, PEG-RGD and PEG-RDG hydrogels were investigated. After a 28-day subcutaneous implantation in mice, a thinner and less dense fibrous capsule formed around PEG-RGD hydrogels, while PEG and PEG-RDG hydrogels exhibited stronger, but similar FBRs. Protein adsorption to the hydrogels, which is considered the first step in the FBR, was also characterized. In vitro experiments confirmed that serum proteins adsorbed to PEG-based hydrogels and were necessary to promote macrophage adhesion to PEG and PEG-RDG, but not PEG-RGD hydrogels. Proteins adsorbed to the hydrogels in vivo were identified using liquid chromatography-tandem mass spectrometry. The majority (245) of the total proteins (≥300) that were identified was present on all hydrogels with many proteins being associated with wounding and acute inflammation. These findings suggest that the FBR to PEG hydrogels may be mediated by the presence of inflammatory-related proteins adsorbed to the surface, but that macrophages appear to sense the underlying chemistry, which for RGD improves the FBR.

Unbiased Analysis of the Impact of Micropatterned Biomaterials on Macrophage Behavior Provides Insights beyond Predefined Polarization States

“…Only a few studies have looked specifically at the response of macrophages to hydrogels 23 . Gelatin methacryloyl (GelMA) hydrogels are becoming increasingly popular as they combine the bioactivity of gelatin with the tunability of a photo-crosslinkable hydrogel 19,24 .…”

The effect of surface modification of mesoporous silica micro-rod scaffold on immune cell activation and infiltration

“…More recently, a series of studies show that implantation of PEG hydrogels in vivo resulted in a more robust inflammatory response, characterized by a thicker fibrous capsule around the hydrogel, compared to PEG-RGD hydrogels [28]. Murine macrophages seeded on PEG hydrogels showed higher expression of IL-1β and TNF-α [28, 29] and PEG hydrogels adsorbed more serum proteins related to acute inflammation than PEG-RGD hydrogels [31]. …”

“…It has been shown that PEG hydrogels can activate serum complement proteins, leading to subsequent immune cell recognition [31]. Monodispersed and highly concentrated PEG polymers ranging from 2K to 11K [33], PEG 5000 stabilized carbon-nanotubes [34] and lipid-PLGA-PEG nanoparticles [35] were shown to generate complement activation when incubated with human serum.…”

Adding Functions to Biomaterial Surfaces through Protein Incorporation

“…[277] Amongst peptides of interest the cell adhesion properties of the RGD peptide have been particularly exploited in material functionalization. RGD is the smallest fibronectin-derived sequence that retains its cell-binding ability and is recognized by multiple cell-bound integrins, [278] leading to enhanced cellular adhesion on functionalized surfaces, [279] a reduced foreign body response [280] and, in some cases, increased cellular migration. RGD has been utilized to seed a poly(methylpentene) membrane with lung endothelial cells to create a bioartificial lung [281] and to promote short-term adhesion, proliferation and differentiation of neural stem cells on polyester materials, albeit less effectively than (laminin-derived) IKVAV in the latter case.…”