Mechanisms of Foreign Body Giant Cell Formation in Response to Implantable Biomaterials

Abstract

Long term function of implantable biomaterials are determined by their integration with the host's body. Immune reactions against these implants could impair the function and integration of the implants. Some biomaterial-based implants lead to macrophage fusion and the formation of multinucleated giant cells, also known as foreign body giant cells (FBGCs). FBGCs may compromise the biomaterial performance and may lead to implant rejection and adverse events in some cases. Despite their critical role in response to implants, there is a limited understanding of cellular and molecular mechanisms involved in forming FBGCs. Here, we focused on better understanding the steps and mechanisms triggering macrophage fusion and FBGCs formation, specifically in response to biomaterials. These steps included macrophage adhesion to the biomaterial surface, fusion competency, mechanosensing and mechanotransduction-mediated migration, and the final fusion. We also described some of the key biomarkers and biomolecules involved in these steps. Understanding these steps on a molecular level would lead to enhance biomaterials design and improve their function in the context of cell transplantation, tissue engineering, and drug delivery.

Keywords: actin cytoskeleton; biomaterials; foreign body giant cells (FBGCs); immune response; macrophages fusion; mechanotransduction.

Figure 1

Schematic representation of the histopathological features of multinucleated giant cell subtypes. Examples of histological giant cells micrographs are provided, representing the cellular response within the subcutaneous implantation sites of biomaterials. (a) Foreign body giant cells with heterogeneously distributed nuclei (black arrows) within the implantation site of a bone replacement material (*) on day 15. (b) Foreign body giant cells with heterogeneously distributed nuclei (black arrows) within the implantation site of silk fibroin (*) on day 60. (c) Foreign body giant cells with heterogeneously distributed nuclei (black arrows) within the implantation bed of expanded polytetrafluoroethylene (*) on day 60. (d) Langerhans’-like giant cells with peripherally oriented nuclei in a circle (black arrow) within the implantation site of a bone replacement material (*) on day 10. (e) Langerhans’-like giant cells with peripherally oriented nuclei (black arrow) within the implantation bed of silk fibroin (*) on day 15. (f) Langerhans’-like MNGCs with peripherally oriented nuclei in a circle (black arrow) within the implantation bed of expanded polytetrafluoroethylene (*) on day 30. All histological stains are hematoxylin and eosin with 400× magnification. Reed–Sternberg cells are found in malignant tumors, such as Hodgkin’s lymphoma, and have two nuclei. In addition, giant cell bone tumors have evenly distributed nuclei within the cytoplasm. The figure is adapted under creative common license from reference [6].

Figure 2

Actin cytoskeleton architecture of a migrating cell. Cell migration is associated with the protrusions emerging at the leading edge of the cell called lamellipodia, filopodia, and podosome/invadopodia. However, first, nascent adhesions (blue spheres) are formed in the lamellipodia of motile cells. While the formed diffraction-limited nascent can either disassemble (white spheres), if the biomaterial surface does not support cell adhesion, or elongated at the lamellipodia–lamella interface, if the biomaterial surface support cell adhesion. Nascent adhesions elongation is associated with the actin filament bundles, stabilizing the adhesion formation through actomyosin-induced contractility, and increasing the adhesion size which in turn lead to the adhesion maturation to the focal complex (green spheres), located at the transition zone, and focal adhesion (brown spheres), located at the leading edge of the lamella.

Figure 3

Organization of molecular connections mediating linkages between actin cytoskeleton and transmembrane adhesion receptors, integrins, at the cell–ECM adhesion sites.

Figure 4

Schematic of force induction through Myosin II and adhesion maturation. Actomyosin, which consist of actin filaments and myosin, exerts myosin II-related tension on actin filaments giving rise to backward flow of actin filaments. Then, talin molecules and, subsequently, integrins are stretched, providing binding sites for vinculin. Vinculin binding to both integrin and talin strengthens the linkage between integrin and talin and acts as an anchor for the actin cytoskeleton to the adhesion sites. Additionally, filamin and α-actinin are actively involved in actin-bundling and cross-linking. Meanwhile, new actin monomers are incorporated at the end of pre-existing actin filaments to continue VASP-dependent polymerization of the actin filaments. In the weak adhesions, exerted forces along with actin polymerization lead to the rapid retrograde flow without leading-edge protrusion and transmitting traction force on the ECM. While in the strong adhesion, the generated forces are transmitted to the ECM resulting in leading-edge protrusion and, subsequently, cell mobility. Paxillin, which is co-localized with talin head, is phosphorylated during high traction forces. Ca²⁺ channel is actively involved in creating fusion pore.