title: Temporal and spatial distribution of macrophage phenotype markers in the foreign body response to glutaraldehyde-crosslinked gelatin hydrogels.
abstract: Currently, it is not well understood how changes in biomaterial properties affect the foreign body response (FBR) or macrophage behavior. Because failed attempts at biomaterial degradation by macrophages have been linked to frustrated phagocytosis, a defining feature of the FBR, we hypothesized that increased hydrogel crosslinking density (and decreased degradability) would exacerbate the FBR. Gelatin hydrogels were crosslinked with glutaraldehyde (0.05, 0.1, and 0.3%) and implanted subcutaneously in C57BL/6 mice over the course of 3 weeks. Interestingly, changes in hydrogel crosslinking did not affect the thickness of the fibrous capsule surrounding the hydrogels, expression of the pan-macrophage marker F480, expression of three macrophage phenotype markers (iNOS, Arg1, CD163), or expression of the myofibroblast marker aSMA, determined using semi-quantitative immunohistochemical analysis. With respect to temporal changes, the level of expression of the M1 marker (iNOS) remained relatively constant throughout the study, while the M2 markers Arg1 and CD163 increased over time. Expression of these M2 markers was highly correlated with fibrous capsule thickness. Differences in spatial distribution of staining also were noted, with the strongest staining for iNOS at the hydrogel surface and increasing expression of the myofibroblast marker aSMA toward the outer edge of the fibrous capsule. These results confirm previous reports that macrophages in the FBR exhibit characteristics of both M1 and M2 phenotypes. Understanding the effects (or lack of effects) of biomaterial properties on the FBR and macrophage phenotype may aid in the rational design of biomaterials to integrate with surrounding tissue.
authors.affiliation: a School of Biomedical Engineering, Science, and Health Systems , Drexel University , Philadelphia , PA , USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Yu
authors.affiliation: b Shanghai Key Tissue Engineering Laboratory , Shanghai Jiao Tong University , Shanghai , China.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Wang
authors.affiliation: a School of Biomedical Engineering, Science, and Health Systems , Drexel University , Philadelphia , PA , USA.
authors.forename: Sina
authors.initials: S
authors.lastname: Nassiri
authors.affiliation: c Institute of Science and Technology in Medicine , Keele University , Stoke-on-Trent , UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kwan
authors.affiliation: a School of Biomedical Engineering, Science, and Health Systems , Drexel University , Philadelphia , PA , USA.
authors.forename: Chau
authors.initials: C
authors.lastname: Dang
authors.affiliation: b Shanghai Key Tissue Engineering Laboratory , Shanghai Jiao Tong University , Shanghai , China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: a School of Biomedical Engineering, Science, and Health Systems , Drexel University , Philadelphia , PA , USA.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Spiller
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D005549:Foreign-Body Reaction / Q000139:chemically induced / Q000378:metabolism*; D005780:Gelatin / Q000737:chemistry*; D005976:Glutaral / Q000737:chemistry*; D020100:Hydrogels / Q000737:chemistry / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D058628:Myofibroblasts / Q000187:drug effects; D010641:Phenotype; D062211:Spatio-Temporal Analysis; D013997:Time Factors
chemical_list: D015415:Biomarkers; D020100:Hydrogels; D005780:Gelatin; D005976:Glutaral
keywords: Foreign body response; gelatin hydrogel; glutaraldehyde crosslinking; macrophage phenotype