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TISSUE ENGINEERING Volume 12, Number 7, 2006 # Mary Ann Liebert, Inc. Cellular and Molecular Dynamics in the Foreign Body Reaction ¨ DANIEL T. LUTTIKHUIZEN, M.Sc., MARTIN C. HARMSEN, Ph.D., and MARJA J.A. VAN LUYN, Ph.D. ABSTRACT Intracorporally implanted materials, such as medical devices, will provoke the body to initiate an in- ﬂammatory reaction. This inﬂammatory reaction to implanted materials is known as the foreign body reaction (FBR) and is characterized by 3 distinct phases: onset, progression, and resolution. The FBR proceeds in the creation of a dynamic microenvironment that is spatially well organized. The progression of the FBR is regulated by soluble mediators, such as cytokines, chemokines, and matrix metallopro- teinases (MMPs), which are produced locally by tissue cells and inﬁltrated inﬂammatory cells. These soluble mediators orchestrate the cascade of cellular processes in the microenvironment that accom- panies the FBR, consisting of cellular activation, angiogenesis, extravasation, migration, phagocytosis, and, ﬁnally, ﬁbrosis. The nature of the FBR requires that the soluble mediators act in a spatial and temporally regulated manner as well. This regulation is well known for several inﬂammatory processes, but scarce knowledge exists about the intricate relationship between the FBR and the expression of soluble mediators. This review discusses the key processes during the initiation, progression, and re- solution phase, with emphasis on the role of soluble mediators. Besides other sites of implantation, we focus on the subcutaneous implantation model. THE ONSET OF THE FBR diators such as vascular endothelial growth factor (VEGF), C-X-C chemokine ligand (CXCL)-8/interleukin (IL)-8, and Wound healing transforming growth factor (TGF)-b. In response to these chemotactic factors and others, neutrophils (polymorpho- T HE FOREIGN BODY REACTION (FBR) is the primary reac- tion of the nonspeciﬁc immune system that is evoked by the implantation of foreign materials. These implanted nuclear neutrophils [PMNs]) and, at a later stage, macro- phages migrate toward the site of injury and facilitate the materials can be degradable or nondegradable. Materials wound healing process. At the same time, angiogenic factors can be implanted throughout the body; however, most of that were released by platelets and secreted by attracted this review concerns studies on the subcutaneous im- leukocytes stimulate local vascularization. In case of degrad- plantation of materials. The onset of the FBR shares several able materials, the FBR will in general become chronic, until aspects of wound healing. The wound healing process starts ﬁnal degradation. For nondegradable materials, on the other after the tissue is damaged by some kind of injury. hand, the reaction continues until a capsule is formed around As a result of tissue injury, blood vessel permeability to the implant, shielding it from the nonspeciﬁc immune sys- cells and macromolecules increases. This damage also cau- tem. Capsule shrinkage and damage to the implant may ses coagulation, enabling platelets to disintegrate and shed occur due to mechanical stress, resulting in revival of the their contents, among which are several inﬂammatory me- FBR and implant failure. Department of Pathology and Laboratory Medicine, Medical Biology Division, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 1955 1956 LUTTIKHUIZEN ET AL. Protein adsorption Fibrinogen Upon implantation of a material, the initial reaction is si- The implantation procedure causes coagulation around milar to wound healing, but the nature of the material changes the implant. Fibrinogen is hydrolyzed to ﬁbrin by thrombin, the progression of this inﬂammatory reaction. Although the leading to a dense ﬁbrin network. This hydrolysis generates materials that are used clinically are nonimmunogenic, non- small peptides that, just as with thrombin,11 are detected by toxic, and chemically inert, they trigger acute, potentially resident tissue macrophages and PMNs.12,13 In addition, chronic, inﬂammatory responses. Because of these properties, ﬁbrin promotes leukocyte adhesion11,13 and acts as a tran- it is unlikely that these materials generate this response di- sient matrix for leukocyte extravasation.14,15 Furthermore, rectly. Rather, the response is induced indirectly by pro- ﬁbrinogen can adsorb directly to the implanted material and teins that adsorb to the material (reviewed by Wilson et al.1). change its conformation, leading to exposure of the P1 frag- The surface chemistry and hydrophobicity strongly inﬂuence ment of ﬁbrinogen. Fibrinogen adsorption is most abundant the composition of this adsorbed layer.2,3 Furthermore, the on hydrophobic surfaces, where it progressively denatures charge of the implanted material inﬂuences PMN and mac- over time.16 Exposure of the P1 fragment enables binding rophage adhesion.4,5 Consequently, the FBR varies depend- to the phagocyte integrin complement receptor 3 (CR3), ing on the type of surface chemistry that was used, and the thereby activating tissue phagocytes.15,17 Upon activation, intrinsic material characteristics affect the course of the FBR. these phagocytes release cytokines and chemokines, such The onset of the FBR is a multicomponent process in as IL-1, TNFa, VEGF, C-C chemokine ligand (CCL)-2/ which, among others, ﬁbrinogen, complement, and anti- monocyte chemoattractant protein (MCP)-1, and CXCL-8/ bodies play a prominent role because they adsorb to the IL-8, that activate the proximal vasculature and attract material immediately (Fig. 1).6–10 The FBR comprises leukocytes and ﬁbroblasts. This will be further discussed in material-dependent and material-independent processes, the the next section. latter also occurring in wound healing. FIG. 1. Induction of the foreign body reaction. The implantation procedure induces platelet aggregation and activates the surrounding tissue, leading to cytokine release (a and b). Fibrinogen is converted to ﬁbrin during coagulation. The splice products are recognized by leukocytes (c). Fibrinogen can also adsorb to the implant, thereby exposing the P1 fragment that is recognized by leukocytes. Furthermore, ﬁbrinogen acts as a provisional matrix for leukocyte extravasation (d). Apart from this, antibodies can adsorb to the material (e). These antibodies are then recognized by leukocytes and the complement system (f and g). Finally, complement factor C3b can bind to the material, thereby inducing the complement system (h). This leads to the generation of C5a, which is a chemoattractant for leukocytes. CELLULAR COMMUNICATION DURING THE FBR 1957 Complement and antibodies endothelial cells.24 In addition, angiogenesis is stimulated by histamine, which is locally released by activated mast Besides ﬁbrin, complement protein C3b can sponta- cells.25 Histamine provokes VEGF release by these cells neously adsorb to implanted materials, leading to the acti- and increases the vascular permeability, thereby enhancing vation of the alternative complement pathway.18,19 It is leukocyte extravasation. Leukocytes express the chemo- suggested that especially hydroxyl and amine groups, which kines CXCL-1, -2, and -8, which, after binding to the C- are present in proteins that are adsorbed to the material, X-C chemokine receptor (CXCR)-2,26 promotes VEGF contribute to complement activation actuated by implanted expression by PMNs.27 Furthermore, PMNs and platelets materials.9,18 The C3b that is adsorbed to the implant is that are activated by injury release VEGF and ﬁbroblast recognized by inﬁltration phagocytes through binding to the growth factor, both of which are strong mitogens for en- CR1 receptor. Complement factor Bb can also bind to C3b, dothelial cells and thereby initiators of angiogenesis (Fig. resulting in the formation of C3 convertase C3bBb. Subse- 2b).28–30 After this ﬁrst angiogenic pulse, this signal is quently, C3bBb can splice many C3 molecules to C3a and maintained by recruited macrophages and ﬁbroblasts that C3b convertase, which is the initiation of the opsonization move beyond the range of oxygen diffusion. Anoxia then process. This opsonization then leads to the release of the triggers the release of VEGF, placenta growth factor (a potent leukocyte chemotactant C5a20,21 and the release of homologue of VEGF), platelet-derived growth factor oxidative metabolites. Since C5a is quickly hydrolyzed, it (PDGF), and other proangiogenic factors by these cells (Fig. contributes to leukocyte inﬁltration only during the acute 2e).31,32 In the angiogenic process multiple growth factors phase of inﬂammation.22 Both C3a and C5a also increase the are necessary for the generation of functional blood vessels. permeability of the capillary bed and induce the release of The released PDGF is the major maturation factor for newly histamine from mast cells,21,23 which augments the in- formed vessels because it attracts smooth muscle cells and ﬂammatory response and consequently the FBR. ﬁbroblasts that constitute the newly formed vasculature.33 Implantation of a foreign material may also lead to acti- Capillaries that are stimulated with growth factors start to vation of the classical complement pathway. This reaction form a dense vascular network. Currently, biodegradable starts with aspeciﬁc binding of antibodies to the implant. scaffolds are developed that stimulate angiogenesis and give Antibodies are present in serum at a concentration of ap- support for cells in order to regenerate the tissue.34 The proximately 15 mg/mL and thus are the second most abun- materials are porous or ﬂexible and, in some studies, contain dant serum protein fraction. Therefore, aspeciﬁc coating of growth factors such as VEGF, in order to enhance angio- biomaterial surface with antibodies is likely.10,17 The Fc genesis into these materials after implantation35 or to pro- domain of these antibodies is recognized by complement mote angiogenesis during tissue regeneration.36 In recent factor C1q. This causes deposition and activation of C3b on years it has become apparent that the combination of 2 or the foreign material, resulting in a similar response as seen more growth factors, each with distinct temporal delivery, is with spontaneously adsorbed C3b. necessary for successful regeneration of the vasculature.37 Thus, the onset of the FBR against implanted materials This is because too much VEGF alone leads to immature, partly depends on the physicochemical characteristics of leaky vessels.38 This pitfall was overcome by the generation the material. The adsorption of ﬁbrin, complement, and of a VEGF analog that was bound to ﬁbrin. The VEGF was antibodies further activates the inﬂammatory process that is gradually released from the ﬁbrin by MMPs, resulting in initiated by tissue damage. slow and local release of VEGF, hence creating mature vasculature.39 In another approach by Richardson, Peters, et al.,37 VEGF was combined with PDGF. In this construct, PROGRESSION OF THE FBR the release PDGF incorporated in microspheres succeeded the release of VEGF that was incorporated in the material, Angiogenesis leading to mature vasculature. Currently, scaffold materials At the end of the onset of the FBR, the inﬁltration of are seeded with endothelial progenitor cells (EPCs) in an leukocytes toward the implanted material depends on the attempt to create blood vessels from autologous tissue.40,41 generation of an efﬁcient delivery system (i.e., a network of blood vessels). Angiogenesis is the formation of new blood vessels from preexisting vessels via sprouting. During the Leukocyte extravasation FBR, angiogenesis is initiated by the coagulation cascade The release of proinﬂammatory cytokines such as IL-1b and by hypoxia. As discussed previously, the implantation and TNFa by activated leukocytes and mast cells stimulates procedure causes vascular damage and thus the formation vascular cell adhesion molecule (VCAM)-1, intercellular of a ﬁbrin network. Fibrin is a potent vasodilatory and adhesion molecule (ICAM)-1, and E-selectin expression on proangiogenic factor. Fibrin degradation product fragment vascular endothelial cells. These adhesion molecules facil- E is formed during coagulation (Fig. 2a). Fibrin fragment E itate extravasation of leukocytes from the bloodstream (Fig. promotes proliferation, migration, and differentiation of 2c and d). First, the glycoprotein E-selectin ligand-1 that is 1958 LUTTIKHUIZEN ET AL. FIG. 2. Activation of the vasculature and extravasation of leukocytes. Because of the implantation procedure, surrounding tissue is damaged, thereby inducing cytokine production (a). Furthermore, platelets and mast cells release vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and histamine. Together, this activates the endothelial cells, leading to angiogenesis (b) and upregulation of cell adhesion molecules (c). Meanwhile, leukocytes that sense chemokines upregulate their cell adhesion molecules. Together, this enables extravasation (d). Leukocytes migrate into the biomaterial and enter a hypoxic environment. This induces VEGF production by these cells (e), thereby activating the vasculature. ICAM: intercellular adhesion molecule; IL: interleukin; PMN: polymorphonuclear neutrophil; TNF: tumor necrosis factor; VCAM: vascular cell adhesion molecule. expressed on activated leukocytes binds to E-selectin that is inﬂammation (as shown in Fig. 3). Most chemokines can expressed on the activated endothelial cells. The leukocytes bind to the heparin or heparan sulfate domain of glycosa- start rolling over the endothelium and, in the continuous minoglycans (GAGs), which are expressed on the surface presence of chemokines, start expressing activated integrins. of many cell types and are also present in the extracellular The leukocytes can then bind ﬁrmly to ICAM-1 and VCAM- matrix (ECM). Leukocytes are guided through concentra- 1, resulting in arrest of these cells. This ﬁrm adhesion to tion gradients of chemokines that are bound to these GAGs. endothelial cells makes the migration of leukocytes through This gradient is sensed by chemokine receptors on the the endothelial layer toward the implant possible.42,43 migrating leukocytes. Although little is known about the expression and func- tion of chemokines during the FBR, studies in related Chemokine-induced leukocyte migration models of inﬂammation, such as wound healing, give insight toward the foreign material into the role these mediators might fulﬁll. Chemokines are Chemokines are cytokines with chemoattractive proper- sequentially and differentially expressed and sequestered ties. The superfamily of chemokines consists of the CXC, during the inﬁltration of leukocyte subsets in human wound CC, C, and CX3C family, based on a shared cysteine motif. healing.46–48 Chemokines orchestrate immune responses, enable che- An interdependent network has been suggested in which motaxis and activation of leukocytes, and play a role in 1 chemokine inﬂuences the expression of multiple other development and angiogenesis (Table 1).32,44,45 Chemo- chemokines.49,50 In this context it has been shown that kines are released by activated inﬂammatory cells and ac- CCL2 depletion inﬂuences the expression of multiple other tivated endothelial cells, and guide leukocytes to sites of cytokines and chemokines in wound healing.51 Since cells CELLULAR COMMUNICATION DURING THE FBR 1959 Table 1. CHEMOKINES THAT MIGHT PLAY A KEY ROLE IN THE FOREIGN BODY REACTION Chemokine Common name Receptor Target cells Produced by References 46,47,56 CXCL-1 GROa, CINC-1, CXCR2 PMN EC, ﬁbroblast, KC macrophage, PMN 47,56,153 CXCL-2 GROb, CINC-2a, CXCR2 PMN EC, ﬁbroblast, MIP-2 macrophage, PMN 46,56 CXCL-8 IL-8 CXCR1, EC, PMN EC, ﬁbroblast, CXCR2 macrophage, PMN 46,67,72,154 CCL-2 MCP-1, JE CCR2 Basophil, EC, monocyte, macrophage, mast osteoblastic cell cell, SMC 66,155 CCL-3 MIP-1a CCR1, CCR5 B cell, basophil, Macrophage, eosinophil, mast cell, macrophage, natural killer cell, monocyte, T cell platelets, T cell 156 CCL-5 RANTES CCR1, CCR5 Basophil, EC, epithelial eosinophil, cell, ﬁbroblast, macrophage, mast macrophage, T cell, platelet, cell SMC, T cell Abbreviations: CCL: C-C chemokine ligand; CCR: C-C chemokine receptor; CINC: cytokine-induced neutrophil chemoattractant; CXCL: C-X-C chemokine ligand; CXCR: C-X-C chemokine receptor; EC: endothelial cell; GRO: growth-related oncogene protein; IL: interleukin; MCP: monocyte chemoattractant protein; MIP: macrophage inﬂammatory protein; PMN: polymorphonuclear neutrophil; RANTES: regulated upon activation, normal T-cell expressed, and presumably secreted; SMC: smooth muscle cell. determine their role in inﬂammation upon the mixture of rophages, and endothelial cells. Both CXCL-1 and CXCL-2 inﬂammatory signals they receive, multiple subsets of bind to CXCR-2, expressed on leukocytes. CXCR-2 is es- leukocytes with distinct tasks are generated. The chemo- sential for PMN recruitment, since PMN recruitment is kine system shows redundancy, since there are multiple abrogated throughout wound healing both in CXCR2À/À chemokines for most receptors and most chemokines can mice and in mice treated with CXCR-2 antagonist.56,57 bind multiple receptors. This results in a very ﬂexible During the onset of inﬂammation, the levels of CXCL-1 system with a consistent output.52 On top of this, pleio- and CXCL-2 rise signiﬁcantly. This causes CXCR-2 sa- tropism, the property that cytokines act on multiple different turation, resulting in desensitization and downregulation of cell types, occurs frequently. Together, these complex in- this receptor.58 However, the inﬂux of PMNs can continue teractions make therapeutic control over this chemokine by mounting a secondary response via CXCR-1, using network difﬁcult, but certainly not impossible. CXCL-8 and, to a lower extent, CXCL-1.22,59 Thus, After leukocytes have extravasated, migration toward the CXCR-1 can adopt the role of CXCR-2 once the latter is implanted material is guided by chemokines. Upon activa- desensitized, exemplifying the robustness of this system. In tion, PMNs degranulate and release proinﬂammatory this context, it has been shown that high levels of CXCL-8 mediators that further enhance the recruitment of additional correlate with aseptic loosening of hip replacements.60 inﬂammatory cells. Furthermore, degranulation of recruited During the onset of the FBR, coagulating platelets re- mast cells stimulates recruitment, since histamine release is lease TGFb. During the progression, TGFb is produced by essential for leukocyte homing (Fig. 2).53 Besides, interac- macrophages.61 TGFb is a potent chemoattractant and ac- tion of inﬁltrated macrophages with other cell types in vitro tivator of monocytes, ﬁbroblasts, and, especially, PMNs.61 can enhance the chemokine expression on macrophages in Furthermore, TGFb inhibits TNFa production and promotes response to biomaterials.54 the production and secretion of ECM components, thus Polymorphonuclear neutrophils are mainly attracted by showing both pro- and anti-inﬂammatory functions. During CXCL-1, CXCL-2, and CXCL-8, whereas macrophages are the resolution phase, TGFb is a central mediator in the recruited via CCL2, CCL3, and CCL5 gradients. CXCL-8 encapsulation of the implanted materials and ﬁbrosis, as (IL-8) is the major PMN chemoattractant in humans, will be discussed in the next section. whereas CXCL-1 (keratinocyte-derived chemokine [KC]) The chemokines CCL2 (MCP-1), CCL5 (regulated upon and CXCL-2 (MIP-2) perform this task in rodents.47,55 activation, normal T-cell expressed, and presumably se- These chemokines are released by platelets, PMNs, mac- creted [RANTES]) and CCL3 (macrophage inﬂammatory 1960 LUTTIKHUIZEN ET AL. FIG. 3. Hypothetical scheme of the progression of the foreign body reaction. Leukocytes migrate over a chemokine gradient toward the biomaterial (a). The leukocytes express proinﬂammatory cytokines that further enhance their activation (b) and the vasculature (c). The proinﬂammatory signals are counteracted by anti-inﬂammatory cytokines that are also expressed by these leukocytes. Macrophages also express transforming growth factor (TGF)-b (d), which induces extracellular matrix (ECM) production by ﬁbroblasts (e). Giant cell formation is stimulated by activated T cells and macrophages (f). CCL: C-C chemokine ligand; CXCL: C-X-C chemokine ligand; IL: interleukin; PMN: polymorphonuclear neutrophil; TNF: tumor necrosis factor. protein [MIP]-1a) are the most potent macrophage che- moattractants.62–66 The chemokine CCL2 is associated with Cytokine-mediated communication during the FBR monocyte chemotaxis in several inﬂammatory models,67,68 Knowledge of cytokine expression in the course of the while other groups could not show this effect.69,70 Fur- FBR is limited and fragmentary. Since the FBR is basically thermore, the MCP receptor CCR2 was shown to be critical a sterile inﬂammatory reaction against an implanted ma- for macrophage migration.71 However, Kyriakides et al. terial, information can be gathered from wound healing showed that monocyte recruitment was not altered in the studies. An overview of cytokines important for the FBR is CCL2À/À mice.72 This difference in CCL2 responsiveness given in Table 2. In vitro studies on the interaction between can be explained by the existence of different macrophage implanted material and leukocytes also help elucidate the subpopulations.73 Monocytes maturate into different sub- complex communication patterns during the FBR in vivo. populations, depending on the signals they receive during Cytokines are secreted protein hormones that activate maturation. Each subpopulation has a different amount of leukocytes and modify the immune response. The cytokine CCR2 on its surface, and thus responds to a different extent superfamily encompasses the interleukins, colony-stimulating to CCL2 during the FBR.74,75 CCL2 was also shown to factors, and interferons, but also includes growth factor fa- be involved in foreign body giant cell formation45,72 and milies such as VEGF, TGF, and PDGF. Cells respond to the neovascularization.76,77 Therefore, CCL2 might have an combination of cytokine signals it receives. Even though important role in local regulation of the FBR. different cytokines generally do not share the same receptor, In wound healing, T cells are mainly attracted by CCL2, overlapping actions do occur as a result of shared receptor CXCL-9, CXCL-10, and CCL22.46 In addition, CCL5 and components or signaling pathways.83 Apart from this, pleio- CCL3 are potent T-cell chemoattractants and activators, as tropism and redundancy are fundamental to the cytokine shown in other models of inﬂammation.78,79 Recruited T network. cells express interferon (IFN)-c, IL-4, and IL-13. These During inﬂammation, activated leukocytes produce cytokines activate monocytes and actuate giant cell for- TNFa, IL-1, and IL-6. In addition, surrounding endothelial mation.80–82 cells and smooth muscle cells upregulate their IL-1b and CELLULAR COMMUNICATION DURING THE FBR 1961 Table 2. CYTOKINES INVOLVED IN WOUND HEALING AND THE FOREIGN BODY REACTION Cytokine Function relative to the FBR Produced by References 157 G-CSF Chemotactic for and activator of PMNs Fibroblast, macrophage, monocyte, PMN, T cell 157 GM-CSF Activates PMN, eosinophil, monocyte EC, ﬁbroblast, monocyte, Enhances phagocytosis in macrophage T cell and PMN 84,158 IFNc Induces IL-1b, G-CSF, M-CSF production Natural killer cell, Inhibits growth of various cell types T cell 159 IL-1 Acute-phase protein production, induces Fibroblast, edema, fever, and cytokine and adhesion keratinocyte, molecule production macrophage, Fibroblast chemotaxis and proliferation monocyte, PMN, T cell 160 IL-2 T-cell proliferation, induces IFNc, IL-1, and T cell TNFa production Activates macrophages 114 IL-4 MnGC formation T cell Inhibits IL-1 and TNFa production 97,99 IL-6 Acute-phase protein production, enhanced Many cell types IL-1Ra and soluble TNFaR production Lowers TNFa, CXCL-2, GM-CSF, and IFNc levels 102,105,107,161 IL-10 Reduces IL-1b, IL-6, TNFa, CXCL-1, and Macrophage, Th2 MIP-1a production Inhibits phagocytosis 162 IL-12 Enhances phagocytosis, increases IFNc Macrophage, PMN production by T cells 81 IL-13 MnGC formation, inhibits IL-1b, IL-6, T cell TNFa, CXCL-8, and CCL3 production IL-1RA, CR3, and CR4 upregulation 163 M-CSF Survival, proliferation, and differentiation of B cell, EC, ﬁbroblast, phagocytes monocyte, PMN, Proangiogenic T cell 33 PDGF Vessel maturation and chemotactic for EC, ﬁbroblast, macrophage, ﬁbroblasts and SMC mast cell, platelet 164 TGFb Increases ECM production EC, ﬁbroblast, keratinocyte, Macrophage, ﬁbroblast, and PMN macrophage, mast chemoattractant cell, platelet, PMN PMN and macrophage activator Induces TGFb production in macrophages 165 TNFa Enhances phagocytosis and chemotaxis Fibroblast, keratinocyte, Induces chemokine production macrophage, mast cell, monocyte, natural killer cell, PMN, Th 30 VEGF Angiogenic, mitogen for EC EC, ﬁbroblast, Induces vascular permeability and keratinocyte, vasodilatation macrophage, mast cell, platelet, PMN Abbreviations: CCL: C-C chemokine ligand; CXCL: C-X-C chemokine ligand; EC: endothelial cell; ECM: extracellular matrix; FBR: foreign body reaction; G-CSF: granulocyte colony-stimulating factor; GM-CSF: granulocyte-macrophage colony-stimulating factor; IFN: interferon; IL: interleukin; MIP: macrophage inﬂammatory protein; MnGc: multinucleated giant cell; PDGF: platelet-derived growth factor; PMN: polymorphonuclear neutrophil; SMC: smooth muscle cell; TGF: transforming growth factor; TNF: tumor necrosis factor; VEGF: vascular endothelial growth factor. 1962 LUTTIKHUIZEN ET AL. TNFa expression upon tissue damage. TNFa promotes IL-1 the production of IL-10, IL-1Ra, and soluble TNFa re- and chemokine expression in a cell type– and tissue-speciﬁc ceptor.98,99 In contrast, IL-6 binds to the soluble IL-6 re- manner. It also enhances phagocytosis by PMNs and en- ceptor that is released from PMNs stimulated with CXCL-1 hances cell adhesion molecule expression on endothelial cells. or CXCL-8.100 This complex can bind to and activate cells IL-1 activates leukocytes, T cells, endothelial cells, and mast via binding to the receptor glycoprotein 130 that is ubi- cells, leading to increased IL-6, IFNc, granulocyte colony- quitously present on cells.101 It reduces CXC chemokine, stimulating factor (G-CSF) and granulocyte-macrophage but stimulated CC chemokine expression, thereby directing colony-stimulating factor (GM-CSF) production by these the switch from PMN attraction to macrophage attraction, cells. guiding the inﬂammatory response toward the progression IFNc is produced by T cells, natural killer cells and, to a phase.100 Taken together, IL-6 shows both pro- and anti- lesser extent, activates monocytes and macrophages. It sti- inﬂammatory behavior. mulates effector functions of mononuclear phagocytes and Binding of IL-10 to its receptor and subsequent down- stimulates the production of IL-1b, G-CSF, and GM-CSF.84 stream signaling decreases the messenger RNA stability of Inhibition of IFNc with blocking antibodies delayed cellular proinﬂammatory cytokines such as TNFa, IL-1, and IL-6 in ingrowth into the implanted material and reduced major activated macrophages.102,103 The chemotaxis of PMNs is histocompatibility complex class II expression and giant cell also inhibited because IL-10 downregulates the production formation in rats.85 In mice, however, local addition of IFNc and secretion of CXCL-1 and CCL3 by macrophages.104,105 did not show enhanced phagocytosis and did not inﬂuence In a proinﬂammatory setting, IL-10 induces the expression the FBR.86 of functional decoy chemokine receptors on monocytes.106 In vitro, the release of cytokines by macrophages is These nonsignaling receptors bind chemokines, rendering greatly inﬂuenced by the biophysical nature of the material these chemokines unavailable for other receptors. These with which the cell interacts.74 The production of IL-10 by decoy receptors thereby functioning as chemokine sca- macrophages increased and that of CXCL-8 decreased on vengers. It has also been shown that IL-10 lowers the hydrophilic and anionic surfaces, while IL-10 and IL-1Ra phagocytotic capacity of macrophages.107 The immunosup- decreased on cationic surfaces. However, the expression pressive role of IL-10 has been further demonstrated in a levels of IL-1a and IL-6 remained constant in this in vitro wide variety of disease models in which it decreased T-cell study.87 The production of TGFb by ﬁbroblasts also depends proliferation and responsiveness.108–110 on surface chemistry, since differently cross-linked col- To improve our knowledge of the role of these soluble lagens showed a difference in TGFb expression by these mediators in the FBR, in vivo gene and protein expression cells.88 On the other hand, TNFa expression by macrophages proﬁles of these mediators must be studied in more detail. was shown to be independent of surface chemistry.89,90 Implanted materials can promote the production of TNFa and IL-1 by macrophages91 and CCL2 release by ﬁbroblasts Macrophages, giant cells, and phagocytosis in vitro.92 The in vitro response of monocytes to biomater- During the onset of the FBR, proteins such as antibodies ials differs between humans.93 Monocytes from some heal- may adsorb aspeciﬁc to implanted materials. The adsorbed thy volunteers expressed high levels of TNFa and IL-6 in antibodies, complement factors, and ﬁbrin can promote response to foreign materials, yet others did not initiate cy- phagocytosis of the implanted material by phagocytes that tokine expression. Thus, the variation in the response be- express receptors for these proteins. The most important tween humans is large.93 In most studies, the expression of phagocytotic receptors on phagocytes are the Fc receptors IL-1b and TNFa requires additional stimulation with lipo- (FcRs), the complement receptors, and the scavenger re- polysaccharide,89,94–96 suggesting that the in vitro introduct- ceptors. The FccRI, FccRII, and FccRIII detect particles that ion of a material by itself is not sufﬁcient to mount an are opsonized with IgG. Binding of IgG to the FcRs activates inﬂammatory response. In vivo, on the other hand, surface these receptors and stimulates phagocytes to release proin- chemistry did inﬂuence the cytokine expression in mice ﬂammatory mediators such as IL-1, IL-6, and TNFa. These exudate.48 In particular, the expression of IL-6 and CXCL-8 cytokines help to maintain the progression of the FBR. The by adhering cells differs depending on charge and hydro- complement receptors CR1, CR3, and CR4 are expressed on phobicity of polyethylene terephthalate (PET) implants macrophages. CR1 recognizes complement factors C3b, in vivo.48 This exempliﬁes that protein adhesion to implants C4b, and CR3bi and thus is involved in particle binding. might be essential for the induction of the FBR. CR3 and CR4 bind to C3bi and facilitate phagocytosis. The The action of proinﬂammatory cytokines such as IL-1 scavenger receptor family consists of receptors that bind and TNFa is counterbalanced by anti-inﬂammatory med- silica, dextran-sulfate, and titanium dioxide, among oth- iators, of which IL-6 and IL-10 are the most determining. In ers.111,112 Therefore, it is probable that this family of re- humans, IL-6 behaves as an anti-inﬂammatory cytokine ceptors also recognizes certain implanted materials. via downregulation of proinﬂammatory cytokines such as Phagocytosis of implanted materials is enhanced by MMPs TNFa, CXCL-2, GM-CSF, and IFNc97 and enhancement of that can predegrade the implanted material, provided that it CELLULAR COMMUNICATION DURING THE FBR 1963 is biodegradable. If the particles are too large for phago- inﬂammatory cells and hence in the progression of an in- cytosis by macrophages, these cells fuse to form multi- ﬂammatory reaction as a whole, several chemical inhibitors nucleated giant cells.113 Two types of morphologically have been generated for therapeutic purposes. Lack of distinct giant cells can be appreciated during the FBR: the bioavailability and clinical efﬁcacy, together with serious Langhans type, which has a round shape with up to ap- side effects, have hampered progression.124 The third gen- proximately 20 nuclei in a circular peripheral arrangement, eration of inhibitors is showing moderate effects in arthritis and the foreign body type (FBGC), which has an irregular and cancer studies125 and might therefore also facilitate shape and usually more than 20 nuclei that are randomly therapeutic modulation of implant degradation. dispersed. The Langhans cells are found in granulomatous During the progression phase of the FBR, the ECM inﬂammation tissue and can be formed around indigestible changes from a steady state to an activated form with dy- particles of organisms, such as certain types of collagen namically changing ECM components and ECM bound bundles.80 Formation of these giant cells is stimulated by mediators such as cytokines and chemokines. Marinucci IFNc, whereas FBGC formation is stimulated by IL-4 or et al. showed that cell adhesion, ECM, and collagen pro- IL-13.81,114,115 Beside these cytokines, receptors on mac- duction in ﬁbroblasts are dependent on surface chemistry of rophages such as P2X7, CD98, SiRPaD44, dendritic cell- the implanted materials in vitro.88 speciﬁc transmembrane protein (DC-STAMP), and integrins However, MMPs are involved in modulation of in- have also been reported to be essential for this fusion ﬂammation not only by enabling migration and ECM re- process.116–120 Cell fusion may be a result of cell-to-cell modeling but also by modulating signaling during the FBR. adhesion mediated by these receptors, since inhibition of The ECM serves as a reservoir for chemokines and cytokines these plasma membrane receptors blocks giant cell for- that can bind heparin and GAGs on proteoglycans. There- mation. Apart from this, the chemokine CCL2 is also in- fore, remodeling of the ECM leads to the release of cyto- volved in FBGC formation.72 When the foreign body is kines and chemokines that can activate phagocytes. Apart degraded, giant cells disappear, indicating that large parti- from ECM remodeling, multiple MMPs can process CCL2, cles are a signal for giant cell formation.113 leading to a CC receptor antagonist with anti-inﬂammatory properties.126 Furthermore, MMP-1, -2, -3, and -9 cleave pro-IL-1b to active IL-1b in a caspase-1–independent man- Extracellular matrix remodeling during the FBR ner.127 MMP-3, -7, -9, and -12 can cleave plasminogen to During the onset of the FBR, a transient ﬁbrin-based form angiostatin, a potent inhibitor of angiogenesis and matrix is formed around the implanted material, which is leukocyte recruitment.128–131 Taken together, this shows primarily caused by coagulation. To reach the site of in- that MMPs have a profound role in modulation of the in- ﬂammation, leukocytes must migrate through this extra- ﬂammatory process. Therefore, it is not surprising that ex- cellular matrix. This matrix functions as a structural scaffold pression of MMPs is tightly regulated by cytokines. IL- to maintain tissue integrity and to support cell adhesion. The 1bNF and TNFa promote the expression of MMPs, whereas matrix mainly consists of a ﬂexible and dynamic macro- TGFb inhibits its MMP expression but enhances expression molecular network, comprising macromolecules such as of tissue inhibitors of MMPs.122,132,133 ﬁbronectin, collagens, laminins, GAGs, elastins, and pro- Many degradable natural materials, such as collagens, can teoglycans. This matrix needs to be remodeled to enable be directly degraded by these MMPs. Biodegradable scaf- migration. This is done by the family of MMPs, which fold materials function as a temporary artiﬁcial ECM and collectively can degrade almost every extracellular matrix show signiﬁcant similarities with it. The FBR can therefore component. The MMP family consists of just under 30 be used to replace this synthetic matrix with the physiologic members, of which the collagenases and gelatinases are the ECM. In this process, adequate remodeling by MMPs is best known groups (see Table 3). The MMPs are zinc- essential. Therefore, insight into cytokine and chemokine dependent extracellular endopeptidases. Most MMPs are signaling leading to MMP production and activation is es- produced in an inactive pro-form that needs to be activated sential for proper tissue engineering. Apart from natural by other MMP family members or by other activators such as materials that can be degraded by MMPs, polymers that take plasmin, urokinase-type plasminogen activator, and tissue- advantage of these cell-secreted MMPs have been devel- type plasminogen activator.121 The activation of MMPs is an oped.134,135 In these smart materials, degradation of the important point of control that maintains the balance be- scaffold coincides with the development of newly formed tween matrix remodeling and matrix destruction. In addi- tissue. Lutolf et al. moreover developed a hydrogel with tion, ﬁbroblasts that are present in the implanted material MMP-sensitive linkage between polyethylene glycol and the will secrete novel ECM components. Activated leukocytes entrapped bone morphogenic protein.136 The latter was re- express high levels of MMPs to enable migration through the leased during the proteolytic invasion of the hydrogel, sti- ECM.122,123 The proteolytic activity of MMPs is regulated mulating rapid bone regeneration. by tissue inhibitors of MMPs, a family of physiologic in- The MMPs reform the ECM, process cytokines and hibitors. Since MMPs play a pivotal role in the migration of chemokines, and are essential for the degradation of many 1964 LUTTIKHUIZEN ET AL. Table 3. MEMBERS OF THE MATRIX METALLOPROTEINASE FAMILY MMP ECM targets Non-ECM targets Activated by MMP inhibitor References 121,123,125,166,167 MMP-1 Collagens (I, II, III, VII, IL-1b, pro-TNF, MMP-3, -10, CGS 27023A VIII, X), gelatin IGFBP-3, MMP-2, plasmin -9, FGF 121,123,125,167,168 MMP-2 Collagens (I, IV, V, VII, IL-1b, MMP-1, -9, MMP-1, -7, AG3340 X, XI, XIV), gelatin, -13 -13, -14, -15, BMS-275291 elastin, ﬁbronectin, -16, -17, -24, CGS 27023A laminin 1 and 5 -25 Col-3 SB3-CT 121–123,125,167 MMP-3 Collagens (III, IV, V, IL-1b, IGFBP-3, Plasmin, AG3340 XI), gelatin, ﬁbrinogen, tryptase CGS 27023A ﬁbronectin, laminin plasminogen, MMP1 superactivation, MMP-7, -8, -9, -13 121,123,126,167,168 MMP-9 Collagens (IV, V, VII, IL-1b, plasminogen, MMP-2, -3, AG3340 X, XIV), gelatin, CCL2 -13, plasmin BMS-275291 elastin, ﬁbronectin CGS 27023A Col-3 SB3-CT 121,125,167 MMP-13 Collagens (I, II, III, IV, MMP-9, MMP-2, -3, AG3340 IX, X, XIV), gelatin, plasminogen -10, -14, -15, ﬁbronectin activator-2 plasmin Abbreviations: CCL: C-C chemokine ligand; ECM: extracellular matrix; FGF: ﬁbroblast growth factor; IGFBP: insulin-like growth factor binding protein; IL: interleukin; MMP: matrix metalloproteinase; TNF: tumor necrosis factor. biodegradable implant materials. Therefore, these MMPs tensive production of collagen I, and III, ﬁbronectin, and are promising targets for the modulation of the implant proteoglycans around the implant by (myo-) ﬁbroblasts.141–143 degradation process. These collagen bundles are increasingly cross-linked both intra- and intermolecularly as wound healing progresses and are gradually replaced by collagen I.144 At the same time, the RESOLUTION production of matrix-degrading proteases is decreased, and protease inhibitors are upregulated by TGFb.132 Also, col- Resolution of the FBR lagen messenger RNA expression and stability are increased During the progression phase of the FBR, macrophages and tissue inhibitors of MMPs are upregulated, while MMP contribute to maintenance of the inﬂammatory process by production is decreased by TGFb.145 producing low levels of TNFa-1b. TNFa stimulates col- Under the inﬂuence of TGFb, ﬁbroblast-like cells differ- lagenase production by ﬁbroblasts133,137 and reduces type I entiate to myoﬁbroblasts. At the same time, release of PDGF collagen production,138 leading to ECM degradation. At the from macrophages promotes myoﬁbroblast proliferation.146 same time, the expression of TGFb, the most potent inducer These myoﬁbroblasts are critical to wound healing but also of ECM production, is increased. During the resolution actuate the formation of ﬁbrotic tissue and capsule shrinking phase, TGFb plays an anti-inﬂammatory role139 because it around the implant.17 inhibits the production and secretion of the chemoattractants TGFb is predominantly expressed by macrophages. Rest- CCL2 and CCL3 by macrophages. The decreased secretion ing monocytes stimulated by TGFb increase their TGFb of CCL2 and CCL3 reduces and eventually halts the inﬂux production and secretion. Activated macrophages, however, of phagocytic cells. If the material is completely degraded, show a reduced responsiveness to TGFb.147 The induction of the inﬂammatory stimulus will resolve. This leads to the ﬁbrosis mediated by TGFb also takes place during per- abandonment of leukocytes. Most macrophages do not die sistent, chronic inﬂammation, where progressive capsule locally but migrate toward the draining lymph nodes.140 formation can lead to capsule shrinkage, resulting in, for instance, breast implant dysfunction. It has been shown that TGFb expression is increased around these implants148 and Fibrosis that inhibition of TGFb reduces capsule formation.149 The Fibrosis is 1 of the major concerns in tissue engineering. It is encapsulation process also prevents the diffusion of mole- mainly caused by abundant TGFb production, leading to ex- cules to biosensors and from implanted pumps, respectively. CELLULAR COMMUNICATION DURING THE FBR 1965 Efforts will be made to reduce capsule stiffness and improve 9. 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