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FBR Tissue Eng


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.


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.

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


Chemokine            Common name                 Receptor                Target cells                  Produced by              References
CXCL-1             GROa, CINC-1,              CXCR2                  PMN                           EC, fibroblast,
                    KC                                                                               macrophage,
CXCL-2             GROb, CINC-2a,             CXCR2                  PMN                           EC, fibroblast,
                    MIP-2                                                                            macrophage,
CXCL-8             IL-8                       CXCR1,                 EC, PMN                       EC, fibroblast,
                                              CXCR2                                                  macrophage,
CCL-2              MCP-1, JE                  CCR2                   Basophil,                     EC, monocyte,
                                                                       macrophage, mast              osteoblastic
                                                                       cell                          cell, SMC
CCL-3              MIP-1a                     CCR1, CCR5             B cell, basophil,             Macrophage,
                                                                       eosinophil,                   mast cell,
                                                                       macrophage,                   natural killer cell,
                                                                       monocyte, T cell              platelets, T cell
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


Cytokine                       Function relative to the FBR                                    Produced by                           References
G-CSF                  Chemotactic for and activator of PMNs                         Fibroblast, macrophage,
                                                                                       monocyte, PMN,
                                                                                       T cell
GM-CSF                 Activates PMN, eosinophil, monocyte                           EC, fibroblast, monocyte,
                       Enhances phagocytosis in macrophage                             T cell
                         and PMN
IFNc                   Induces IL-1b, G-CSF, M-CSF production                        Natural killer cell,
                       Inhibits growth of various cell types                           T cell
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
IL-2                   T-cell proliferation, induces IFNc, IL-1, and                 T cell
                         TNFa production
                       Activates macrophages
IL-4                   MnGC formation                                                T cell
                       Inhibits IL-1 and TNFa production
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
IL-10                  Reduces IL-1b, IL-6, TNFa, CXCL-1, and                        Macrophage, Th2
                         MIP-1a production
                       Inhibits phagocytosis
IL-12                  Enhances phagocytosis, increases IFNc                         Macrophage, PMN
                         production by T cells
IL-13                  MnGC formation, inhibits IL-1b, IL-6,                         T cell
                         TNFa, CXCL-8, and CCL3 production
                         IL-1RA, CR3, and CR4 upregulation
M-CSF                  Survival, proliferation, and differentiation of               B cell, EC, fibroblast,
                         phagocytes                                                    monocyte, PMN,
                       Proangiogenic                                                   T cell
PDGF                   Vessel maturation and chemotactic for                         EC, fibroblast, macrophage,
                         fibroblasts and SMC                                            mast cell, platelet
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
TNFa                   Enhances phagocytosis and chemotaxis                          Fibroblast, keratinocyte,
                       Induces chemokine production                                    macrophage, mast
                                                                                       cell, monocyte, natural killer
                                                                                       cell, PMN, Th
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
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
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
MMP-3           Collagens (III, IV, V,           IL-1b, IGFBP-3,              Plasmin,               AG3340
                  XI), gelatin,                    fibrinogen,                   tryptase              CGS 27023A
                  fibronectin, laminin              plasminogen,
                                                   MMP-7, -8, -9, -13
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
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. Wettero, J., Askendal, A., Bengtsson, T., and Tengvall, P.
permeability via the use of porous implants150 since it has               On the binding of complement to solid artificial surfaces in
been shown that porous implants induce a loosely packed                   vitro. Biomaterials 23, 981, 2002.
and vascularized capsule.151 On the other hand, artificial             10. Jenney, C.R., and Anderson, J.M. Adsorbed IgG: a potent
encapsulation of pancreatic islet cells can be used to enable             adhesive substrate for human macrophages. J. Biomed.
                                                                          Mater. Res. 50, 281, 2000.
insulin diffusion and prevent immune recognition. Individual
                                                                      11. Szaba, F.M., and Smiley, S.T. Roles for thrombin and fi-
cells are encapsulated by a semi-permeable capsule, thereby
                                                                          brin(ogen) in cytokine/chemokine production and macro-
enabling an implant half-life of several months.152 If                    phage adhesion in vivo. Blood 99, 1053, 2002.
knowledge of the expression and function of soluble med-              12. Richardson, D.L., Pepper, D.S., and Kay, A.B. Chemotaxis
iators in and around implants would increase, control over                for human monocytes by fibrinogen-derived peptides. Br. J.
the encapsulation processes via modulation of these med-                  Haematol. 32, 507, 1976.
iators could be feasible. This would aid resolution of the            13. Smiley, S.T., King, J.A., and Hancock, W.W. Fibrinogen
FBR and improve the function of the implanted material.                   stimulates macrophage chemokine secretion through toll-
                                                                          like receptor 4. J. Immunol. 167, 2887, 2001.
                                                                      14. Li, J., Zhang, Y.P., and Kirsner, R.S. Angiogenesis in wound
                      CONCLUSION                                          repair: angiogenic growth factors and the extracellular ma-
                                                                          trix. Microsc. Res. Tech. 60, 107, 2003.
   In this review we gave an overview of the diverse roles of         15. Lishko, V.K., Podolnikova, N.P., Yakubenko, V.P., Ya-
soluble mediators in the onset, progression, and resolution of            kovlev, S., Medved, L., Yadav, S.P., and Ugarova, T.P.
                                                                          Multiple binding sites in fibrinogen for integrin alphaMbeta2
the FBR. We think that since the onset is instantaneous and
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largely implant independent, the progression phase is the
                                                                      16. Hu, W.J., Eaton, J.W., Ugarova, T.P., and Tang, L. Mole-
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