Foreign body response to synthetic polymer biomaterials and the role of adaptive immunity

Abstract

Implanted biomaterials elicit a series of distinct immune and repair-like responses that are collectively known as the foreign body reaction (FBR). These include processes involving innate immune inflammatory cells and wound repair cells that contribute to the encapsulation of biomaterials with a dense collagenous and largely avascular capsule. Numerous studies have shown that the early phase is dominated by macrophages that fuse to form foreign body giant cells that are considered a hallmark of the FBR. With the advent of more precise cell characterization techniques, specific macrophage subsets have been identified and linked to more or less favorable outcomes. Moreover, studies comparing synthetic- and natural-based polymer biomaterials have allowed the identification of macrophage subtypes that distinguish between fibrotic and regenerative responses. More recently, cells associated with adaptive immunity have been shown to participate in the FBR to synthetic polymers. This suggests the existence of cross-talk between innate and adaptive immune cells that depends on the nature of the implants. However, the exact participation of adaptive immune cells, such as T and B cells, remains unclear. In fact, contradictory studies suggest either the independence or dependence of the FBR on these cells. Here, we review the evidence for the involvement of adaptive immunity in the FBR to synthetic polymers with a focus on cellular and molecular components. In addition, we examine the possibility that such biomaterials induce specific antibody responses resulting in the engagement of adaptive immune cells.

Keywords: adaptive immunity; biocompatibility; foreign body; polymers.

Figure 1.

Different cell types in the foreign body reaction to implanted polymeric biomaterials. a) Presence of dendritic cells shown by CD11b (red) staining of tissue samples from humans, approximately 1 year after surgery to repair an abdominal wall hernia using polypropylene mesh. Scale bar = 100 μm. Reprinted from Dievernich et al. Hernia, 2021 under the terms of the Creative Commons CC-BY License [13]. b) Presence of macrophages shown by mac3 (brown) staining of tissue samples from immunocompetent C57BL/6 mice, 4 weeks after a subcutaneous implantation of a poly-ethylene glycol hydrogel. Scale bar = 100 μm. Reprinted with permission from Lynn et al. J Biomed Mater Res A, 2011, 96: 621–631 (John Wiley & Sons) [14]. c) Presence of T cells shown by CD3 (red) staining of tissue samples from Sprague-Dawley rats, 3 weeks after a subcutaneous implantation of a polyurethane-encapsulated biosensor. Reprinted with permission from Ward et al. J Biomater Sci Polym Ed, 2008, 19: 1065–1072 (Taylor & Francis) [15]. d) Presence of B cells shown by B220 (purple) staining of tissue samples from specific pathogen-free female C57BL/6 mice, 4 weeks after a subcutaneous materials injection of nylon mesh. Reprinted with permission from Higgins et al. Am J Pathol, 2009, 175: 161–170 (Elsevier) [16]. e) Presence of natural killer cells shown by CD8a (green) staining of tissue samples from immunocompetent Sprague-Dawley rats, 6 weeks after an intradermal implantation of a polypropylene fumarate coated implant. Scale bar = 20 μm. Reprinted with permission from Bracaglia et al. J Biomed Mater Res A, 2019, 107: 494–504 (John Wiley & Sons) [17]. f) Presence of neutrophils shown by anti- myeloperoxidase antibody (brown) staining of tissue samples from C57BL/6 mice, 14 days after implantation of Dacron protheses in striated muscle tissue. Reprinted with permission from Moussavian et al. J Vasc Surgery, 2016, 64: 1815–1824 (Elsevier) [18].

Figure 2.

The influence of physical and chemical properties of synthetic polymeric biomaterials on the foreign body response. a) Pore size of pHEMA scaffolds affects cellular (red) and collagen (blue) composition of the FBR. Reprinted with permission from Sussman et al. Ann Biomed Eng, 2013, 42: 1508–16 (Springer Nature) [28]. b) H&E stained sections of muscle tissue 14 days after implantation of PVC rods with triangle, pentagon, and circular cross sections. Reprinted with permission from Matlaga et al. J Biomed Mater Res, 1976, 10: 391–7 (John Wiley & Sons) [139]. c) Representative confocal microscopy of foreign body giant cells on flat and electrospun PTFE on day 21. Reprinted with permission from Lamichhane et al. J Biomed Mater Res A, 2017, 105: 244150 (John Wiley & Sons) [33]. d) Representative images revealing fibrous capsule thickness 28 days after PEG hydrogels of low stiffness (left) and high stiffness (right) were implanted subcutaneously in mice. Scale bar = 100um. Reprinted with permission from Jansen et al. Biomacromolecules, 2018, 19: 2880–80 (American Chemical Society) [36]. e) Masson’s trichrome staining of collagen surrounding pHEMA and pCBMA hydrogels after three months implantation. Reprinted with permission from Zhang et al. Nat Biotechnol, 2013, 31: 553–556 (Springer Nature) [140]. Created with BioRender.com.

Figure 3.

Illustration of innate and adaptive immune system cells. Innate immune responses are mediated by macrophages, mast cells, natural killer cells, dendritic cells, monocytes, and granulocytes such as neutrophils, eosinophils and basophils. Adaptive immune responses are mediated by T and B cells. T cells such as CD4⁺ and CD8⁺ T cells recruit macrophages to sites of infection to eliminate microbes while B cells differentiate into antibody-secreting cells, plasma cells, and secrete antibodies, which destroy microbes. Created with BioRender.com.

Figure 4.

Common biomaterial implantation models in rodents. Evaluation of immune responses typically involves implantation of biomaterials into mice or rats and subsequent analyses of cellular and molecular interactions. Biomaterials are most often implanted SC, sometimes enclosed in a metal cage. Other sites include muscle or the vascular system in the case of blood-contacting biomaterials. Intraperitoneal image reprinted and modified from Liappas et al. Biomed Research International 2015 under the terms of the Creative Commons Attribution License [146]. Created with Biorender.com.