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      The Effect of Biomaterials Used for Tissue Regeneration Purposes on Polarization of Macrophages

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          Abstract

          Activation of macrophages is critical in the acute phase of wound healing after implantation of surgical biomaterials. To understand the response of macrophages, they are often cultured in vitro on biomaterials. Since a wide range of biomaterials is currently used in the clinics, we undertook a systematic review of the macrophage polarization in response to these different surgical biomaterials in vitro. Beside the chemistry, material characteristics such as dimension, pore size, and surface topography are of great influence on the response of macrophages. The macrophage response also appears to depend on the differences in sterilization techniques that induce lasting biochemical changes or residues of chemicals and their byproducts used for sterilization. Regarding tissue-based biomaterials, macrophages on human or porcine dermis, strongly cross-linked by chemicals elicit in general a proinflammatory response with higher amounts of proinflammatory cytokines. Synthetic biomaterials such as polyethylene, polyethylene terephthalate (PET) + polyacrylamide (PAAm), PET + sodium salt of poly(acrylic acid) (PAANa), perfluoropolyether (PFPE) with large posts, PEG-g-PA, and polydioxanone (PDO) always appear to elicit an anti-inflammatory response in macrophages, irrespective of origin of the macrophages, for example, buffy coats or full blood. In conclusion, in general in vitro models contribute to evaluate the foreign body reaction on surgical biomaterials. Although it is difficult to simulate complexity of host response elicited by biomaterials, after their surgical implantation, an in vitro model gives indications of the initial foreign body response and allows the comparison of this response between biomaterials.

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

          Macrophages have been classified as having plastic phenotypes which exist along a spectrum between M1 (classically activated; pro-inflammatory) and M2 (alternatively activated; regulatory, homeostatic). To date, the effects of polarization towards an 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 (r(2)=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 vs. M2 response. Both M2 and M0 macrophage conditioned media 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. Copyright © 2011 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
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            Macrophage phenotype as a determinant of biologic scaffold remodeling.

            Macrophage phenotype can be characterized as proinflammatory (M1) or immunomodulatory and tissue remodeling (M2). The present study used a rat model to determine the macrophage phenotype at the site of implantation of two biologic scaffolds that were derived from porcine small intestinal submucosa (SIS) and that differed mainly according to their method of processing: the Restore device (SIS) and the CuffPatch device (carbodiimide crosslinked form of porcine-derived SIS (CDI-SIS)). An autologous tissue graft was used as a control implant. Immunohistologic methods were used to identify macrophage surface markers CD68 (pan macrophages), CD80 and CCR7 (M1 profile), and CD163 (M2 profile) during the remodeling process. All graft sites were characterized by the dense population of CD68+ mononuclear cells present during the first 4 weeks. The SIS device elicited a predominantly CD163+ response (M2 profile, p < 0.001) and showed constructive remodeling at 16 weeks. The CDI-SIS device showed a predominately CD80+ and CCR7+ response (M1 profile, p < 0.03), and at 16 weeks was characterized by chronic inflammation. The autologous tissue graft showed a predominately CD163+ response (M2) at 1 week, with a dual M1/M2 population (CD80+, CCR7+, and CD163+) by 2 and 4 weeks and moderately well organized connective tissue by 16 weeks. The processing methods used during the manufacturing of a biologic scaffold can have a profound influence upon the macrophage phenotype profile and downstream remodeling events. Routine histologic examination alone is inadequate to determine the phenotype of mononuclear cells that participate in the host response to the scaffold.
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              Macrophage functional polarization (M1/M2) in response to varying fiber and pore dimensions of electrospun scaffolds.

              In this study, we investigated the effect of fiber and pore size of an electrospun scaffold on the polarization of mouse bone marrow-derived macrophages (BMMΦs) towards regenerative (M2) or inflammatory (M1) phenotypes. BMMΦs were seeded on Polydioxanone (PDO) scaffolds electrospun from varying polymer concentrations (60, 100, and 140 mg/ml). Higher polymer concentrations yielded larger diameter fibers with larger pore sizes and porosity. BMMΦ cultured on these scaffolds showed a correlation between increasing fiber/pore size and increased expression of the M2 marker Arginase 1 (Arg1), along with decreased expression of the M1 marker inducible nitric oxide synthase (iNOS). Secretion of the angiogenic cytokines VEGF, TGF-β1 and bFGF was higher among cultures employing larger fiber/pore size scaffolds (140 mg/ml). Using a 3D in vitro angiogenesis bead assay, we have demonstrated that the M2-like profile of BMMΦ induced by the 140 mg/ml is functional. Furthermore, our results show that the pore size of a scaffold is a more critical regulator of the BMMΦ polarization compared to the fiber diameter. The study also shows a potential role for MyD88 in regulating M1 BMMΦ signaling on the large vs. small fiber/pore size PDO scaffold. These data are instructive for the rationale design of implantable prosthetics designed to promote in situ regeneration. Copyright © 2013 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Biores Open Access
                Biores Open Access
                biores
                BioResearch Open Access
                Mary Ann Liebert, Inc. (140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA )
                2164-7844
                2164-7860
                01 January 2016
                2016
                01 January 2016
                : 5
                : 1
                : 6-14
                Affiliations
                [ 1 ]Department of Surgery, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands.
                [ 2 ]Department of Orthopedics, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands.
                [ 3 ]Department of Otorhinolaryngology, Head and Neck Surgery, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands.
                [ 4 ]Metronix-Sofradim Production , Trévoux, France.
                Author notes
                [*] [ * ]Address correspondence to: Yvonne M. Bastiaansen-Jenniskens, PhD, Department of Orthopedics, Erasmus MC, University Medical Center , Wytemaweg 80, Ee1651b, Rotterdam 3015 GE, The Netherlands, E-mail: y.bastiaansen@ 123456erasmusmc.nl
                Article
                10.1089/biores.2015.0041
                10.1089/biores.2015.0041
                4744891
                26862468
                390ef43e-08c0-4170-9a44-b939cf7761cc
                © Geesien S.A. Boersema et al. 2016; Published by Mary Ann Liebert, Inc.

                This Open Access article is distributed under the terms of the Creative Commons License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

                History
                Page count
                Figures: 1, Tables: 2, References: 52, Pages: 9
                Categories
                Comprehensive Review

                biomaterials,in vitro models,macrophage response,review
                biomaterials, in vitro models, macrophage response, review

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