Effects of age-related shifts in cellular function and local microenvironment upon the innate immune response to implants

Abstract

The host macrophage response is now well recognized as a predictor of the success or failure of biomaterial implants following placement. More specifically, shifts from an "M1" pro-inflammatory towards a more "M2-like" anti-inflammatory macrophage polarization profile have been shown to result in enhanced material integration and/or tissue regeneration downstream. As a result, a number of biomaterials-based approaches to controlling macrophage polarization have been developed. However, the ability to promote such activity is predicated upon an in-depth, context-dependent understanding of the host response to biomaterials. Recent work has shown the impacts of both tissue location and tissue status (i.e. underlying pathology) upon the host innate immune response to implants, representing a departure from a focus upon implant material composition and form. Thus, the ideas of "biocompatibility," the host macrophage reaction, and ideal material requirements and modification strategies may need to be revisited on a patient, tissue, and disease basis. Immunosenescence, dysregulation of macrophage function, and delayed resolution of immune responses in aged individuals have all been demonstrated, suggesting that the host response to biomaterials in aged individuals should differ from that in younger individuals. However, despite the increasing usage of implantable medical devices in aged patients, few studies examining the effects of aging upon the host response to biomaterials and the implications of this response for long-term integration and function have been performed. The objective of the present manuscript is to review the putative effects of aging upon the host response to implanted materials and to advance the hypothesis that age-related changes in the local microenvrionement, with emphasis on the extracellular matrix, play a previously unrecognized role in determining the host response to implants.

Keywords: Aging; Host response; Implant; Macrophage; Polarization.

Fig. 1

Macrophage polarization exists as a spectrum of phenotypic and functional states. Macrophage polarization states can best be described as a spectrum ranging from antimicrobial, pro-inflammatory M1 macrophages to immunotolerant, anti-inflammatory M2 macrophages. While this review simplifies macrophage polarization states to a basic M1/M2 paradigm for ease of discussion, it is important to note that these extreme polarization states are rare in vivo and macrophage polarization relies on the integration of cytokine signaling in the local microenvironment to polarize macrophages to some intermediate state along the polarization spectrum.

Fig. 2

The early host response to implanted materials in young and aged C57BL/6 mice. (a) Images of H & E-stained tissue cross-sections at 10× and (b) total cell counts (DAPI) surrounding single mesh fibers in 40× images at 3, 7, and 14 days. Scale bars represent 200 mm. Fluorescence microscopy images of (c) Arginase-1 (red) CD68 (green) co-immunolabeling and (e) iNOS (red) CD68 (green) coimmunolabeling at a single mesh fiber at 3, 7, and 14 days. DAPI was used to stain cell nuclei. Scale bars represent 50 mm. Cell count image analysis of (d) Arg- 1+, Arg-1+ CD68+ cells and (f) iNOS+, iNOS+ CD68+ cells at 3, 7, and 14 days. Bars represent the mean ± SEM. Statistical significance as (*) p < 0.05, (**) p < 0.01, (***) p < 0.001, (****) p < 0.0001. All other differences are nonsignificant. N = 7.