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.
Highlights
Biomaterials face an inflammatory environment upon implantation, which often leads to medical device failures
Macrophages attempt to degrade the material, fuse into foreign body giant cells, and encapsulate it in fibrous tissue, isolating it from the rest of the body [1]. This foreign body response (FBR) and the formation of the fibrous capsule limit the function of many medical devices, especially diffusion-dependent devices, sensors, and engineered tissues that are intended to integrate with the surrounding tissue
This work does add to the growing body of literature that suggests that both M1 and M2 macrophages contribute to formation of the fibrous capsule in the FBR
Summary
Biomaterials face an inflammatory environment upon implantation, which often leads to medical device failures. Macrophages attempt to degrade the material, fuse into foreign body giant cells, and encapsulate it in fibrous tissue, isolating it from the rest of the body [1]. This foreign body response (FBR) and the formation of the fibrous capsule limit the function of many medical devices, especially diffusion-dependent devices, sensors, and engineered tissues that are intended to integrate with the surrounding tissue. Macrophages can rapidly shift their behavior from pro-inflammatory to anti-inflammatory. The phenotype of the macrophage population is largely M1 at early times after injury, peaking at 1–5 days and decreasing [7, 8]. If the M1-to-M2 transition is disrupted, wounds suffer from chronic inflammation [12, 13]
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