Macrophage phenotype as a predictor of constructive remodeling following the implantation of biologically derived surgical mesh materials

Abstract

Macrophages have been classified as having plastic phenotypes which exist within a spectrum between M1 (classically activated; pro-inflammatory) and M2 (alternatively activated; regulatory, homeostatic). To date, the effects of polarization towards a predominantly M1 or M2 phenotype have been studied largely in the context of response to pathogen or cancer. Recently, M1 and M2 macrophages have been shown to play distinct roles in tissue remodeling following injury. In the present study, the M1/M2 paradigm was utilized to examine the role of macrophages in the remodeling process following implantation of 14 biologically derived surgical mesh materials in the rat abdominal wall. In situ polarization of macrophages responding to the materials was examined and correlated to a quantitative measure of the observed tissue remodeling response to determine whether macrophage polarization is an accurate predictor of the ability of a biologic scaffold to promote constructive tissue remodeling. Additionally the ability of M1 and M2 macrophages to differentially recruit progenitor-like cells in vitro, which are commonly observed to participate in the remodeling of those ECM scaffolds which have a positive clinical outcome, was examined as a possible mechanism underlying the differences in the observed remodeling responses. The results of the present study show that there is a strong correlation between the early macrophage response to implanted materials and the outcome of tissue remodeling. Increased numbers of M2 macrophages and higher ratios of M2:M1 macrophages within the site of remodeling at 14 days were associated with more positive remodeling outcomes (r2=0.525–0.686, p<0.05). Further, the results of the present study suggest that the constructive remodeling outcome may be due to the recruitment and survival of different cell populations to the sites of remodeling associated with materials that elicit an M1 versus M2 response. Both M2 and M0 macrophage conditioned medias were shown to have higher chemotactic activities than media conditioned by M1 macrophages (p<0.05). A more thorough understanding of these issues will logically influence the design of next generation biomaterials and the development of regenerative medicine strategies for the formation of functional host tissues.

Polymer-Based Reconstruction of the Inferior Vena Cava in Rat: Stem Cells or RGD Peptide?

“…From this standpoint, PDO and PHVBB outperformed PU with regard to the predominance of infiltrating regulatory ED2 macrophages, a phenotype associated with less inflammatory tissue scarring and improved remodelling. 35,36 The enhanced ED2 response to PDO and PHBVV is consistent with our concurrent findings of higher expressions of the anti-inflammatory IL-10 cytokine and MCP-1 chemokine. In contrast, PU was associated with a much greater inflammatory response, with a persisting insulation of the patches and, occasionally, granulomas, which have also been reported in other applications.…”

Pro‐Regenerative Hydrogel Restores Scarless Skin during Cutaneous Wound Healing

“…Brown et al revealed that increased numbers of M2 macrophages and higher ratios of M2:M1 macrophages could lead to more positive remodeling outcomes. [34] Given the potential of immune modulating scaffolds for wound healing, we then nail down those hydrogels that can support M2 macrophages. Unlike typical methods of validating scaffolds in vivo followed by characterizing the macrophage phenotype via histology, [41] we proactively examined the impact of macromers on macrophage phenotype in vitro, thus determining the pro-regenerative scaffolds.…”

“…Transition to an M2 phenotype occurs concurrently with resolution of the inflammatory process and the initiation of the remodeling phase of wound healing. [34] Once monocytes are differentiated into macrophages, polymers are added to examine how they affect the macrophage proliferation (n = 6) ( Figure 2Bi). Matristem powder (collagen extraction from pig bladder) showed significantly lower impacts on both day 2 and day 4, indicating it may not induce macrophage-related inflammation.…”

“…[33] Additionally, macrophages also mediate extracellular matrix (ECM) synthesis at the remodeling stage, thus impacting wound healing in all stages. Recent studies indicate that there is a strong correlation between the macrophage responses to implanted scaffolds, [34] and a favorable M2 phenotype could encourage a constructive tissue remodeling. Chen et al recently showed that a thermosensitive hydrogel that modulates the inflammatory phenotype promoted rapid wound healing in diabetic mice.…”

Restoring Mucosal Barrier Function and Modifying Macrophage Phenotype with an Extracellular Matrix Hydrogel: Potential Therapy for Ulcerative Colitis

“…Specifically, ECM materials derived via decellularization of a variety of allogeneic or xenogeneic source tissues have been shown to induce a phenotypic transition from the proinflammatory macrophage and lymphocyte phenotype toward a regulatory, "anti-inflammatory" and healing phenotype [9,31,32,33], and to promote endogenous stem/progenitor cell activation and recruitment [11,29,34,35].…”