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Review
Department of Dermatology, Venerology and Allergology, University Leipzig, 04103 Leipzig, Germany
Department of Trauma and Reconstructive Surgery, Dresden University Hospital Carl Gustav Carus, 01307 Dresden, Germany
c
Max Bergmann Center for Biomaterials, University of Technology Dresden, 01069 Dresden, Germany
d
Collaborative Research Center (SFB-TR67), Matrixengineering, Department of Dermatology, Venereology and Allergology, Philipp-Rosenthal-Str. 23, 04103 Leipzig, Germany
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 March 2011
Accepted 26 May 2011
Available online 28 June 2011
A key for long-term survival and function of biomaterials is that they do not elicit a detrimental immune
response. As biomaterials can have profound impacts on the host immune response the concept emerged
to design biomaterials that are able to trigger desired immunological outcomes and thus support the
healing process. However, engineering such biomaterials requires an in-depth understanding of the host
inammatory and wound healing response to implanted materials.
One focus of this review is to outline the up-to-date knowledge on immune responses to biomaterials.
Understanding the complex interactions of host response and material implants reveals the need for and
also the potential of immunomodulating biomaterials. Based on this knowledge, we discuss strategies
of triggering appropriate immune responses by functional biomaterials and highlight recent approaches
of biomaterials that mimic the physiological extracellular matrix and modify cellular immune responses.
2011 Elsevier Ltd. All rights reserved.
Keywords:
Immune response to biomaterials
Immunomodulation
Extracellular matrix
Biomaterial integration
1. Introduction
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Fig. 1. Immune response toward biomaterials. A) Adsorption of blood proteins and activation of the coagulation cascade, complement and platelets result in the priming and
activation of PMNs, monocytes and resident macrophages. B) Danger signals (alarmins) released from damaged tissue additionally prime the immune cells for enhanced function
via PRR engagement. C) The acute inammatory response is dominated by the action of PMNs. PMNs secrete proteolytic enzymes and ROS, corroding the biomaterial surface. IL-8
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cells as well as injured cells (Fig. 1A,B). Mast cell degranulation and
associated histamine release have been shown to play a role in
directing PMNs and monocytes to implanted biomaterials in mice
and humans [50,51]. Reaching the implantation site, PMNs
encounter the protein-coated biomaterial surface and subsequent
engagement of integrins and PRRs on the PMN surface triggers
a phagocytic response and degranulation [52,53] (Fig. 1C). PMNs
usually secrete proteolytic enzymes and ROS to promote and foster
pathogen killing [49]. At the implant site, the destructive agents
may corrode material surfaces as described for polyurethane [54].
Furthermore, the cytotoxic components damage surrounding
tissue, prolonging the inammatory response. Another adverse
effect of biomaterial-induced PMN activation is the metabolic
exhaustion and depletion of the granulocytes oxidative resources.
Due to the continuous release of ROS the microbial killing capacity
of PMNs is dramatically reduced, which has been related to severe
biomaterial-centered infections [55].
PMNs also represent a signicant source of immunoregulatory
signals which they synthesize upon activation [56], interleukin-8
(IL-8) being among the most prominent chemokines. The primary
targets of IL-8 are PMNs themselves. Various studies have reported
granulocyte migration and prolonged presence of granulocytes
within chitosan materials [57,58] due to persistent autocrine PMN
attraction by IL-8 [59]. Activated PMNs also secrete MCP-1 and MIP1b [49]. Both chemokines are known as potent chemoattractants
and activation factors for monocytes, macrophages, immature DCs
and lymphocytes [60]. Increased release of these chemokines by
PMNs suppresses further PMN inltration in favor of mononuclear
cell inux [61]. Due to a lack of further activation signals PMN
undergo apoptosis after having done their job as phagocytes and
are engulfed by macrophages [61]. Within the rst two days after
biomaterial implantation PMN typically disappear from implantation sites [62].
2.2. Chronic inammation: dual role of macrophages as
inammatory mediators and wound healing regulators in the
foreign body reaction
Chronic inammation develops as inammatory stimuli persist
at the implant site with macrophages representing the driving force
in perpetuating immune responses [63]. Monocytes arriving at the
implantation site undergo a phenotypic change differentiating to
macrophages. Their activation leads to further dissemination of
chemoattractants. Macrophages attached to the biomaterial can
foster invasion of additional inammatory cells by secreting chemokines like IL-8, MCP-1, MIP-1b [64] (Fig. 1D).
Macrophages also play a critical role in wound healing and
tissue regeneration. Phagocytosis of wound debris, release of
enzymes important for tissue reorganization and of cytokines and
growth factors inducing migration and proliferation of broblasts
are mediated by macrophages and constitute the initial steps
toward effective tissue regeneration [65]. These different functions
are typically promoted by different macrophage subsets, originally
referred to as M1 (classically activated) and M2 (alternatively
activated) macrophages [66]. Based on fundamental macrophage
functions involved in maintaining homeostasis these subsets have
been reclassied into classically activated, regulatory, and woundhealing macrophages [67] (Fig. 2). The latter two arise from
released from PMNs enhances PMN inux and priming. In the transition from acute to chronic inammation, PMNs stop secreting IL-8 in favor of cytokines promoting immigration
and activation of monocytes and macrophages. D) Macrophages are the driving force of chronic inammation. Constant release of inammatory mediators like TNFa, IL-6, and MCP1 results in permanent activation of macrophages. Fusion-inducing stimuli like IL-4 and IL-13 promote the fusion of macrophages to FBGC, which form a highly degradative
environment on the biomaterial surface. Furthermore, FBGC promote ECM remodeling and broblast activation resulting in excessive brosis and biomaterial encapsulation. E)
Macrophage-derived cytokines and PRR engagement activate DCs on the biomaterial surface. Depending on the nature of the stimulus, DCs mature to either immunogenic or
tolerogenic subtypes, amplifying or suppressing the inammatory response.
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Fig. 2. Classication of macrophages. Macrophages represent a heterogeneous population of cells with different phenotypic proles performing distinct functions in host defense,
wound healing, and immune regulation. This plasticity enables macrophages to adapt their functions to environmental cues. Adapted from Refs. [67,68].
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IL-6 and IL-1b have been described to convert nave T cells into
CD4/CD25 TReg or IL-10 secreting CD4 T cells (Tr1) [117e119].
The tolerogenic activity of semi-mature DCs can be additionally
enhanced by their release of IL-10 [113,114]. Cytokines have been
shown to play the major part in the induction of tolerogenicity.
Besides IL-10 and TGF-b, two important immunosuppressive regulators, various cytokines and growth factors including IL-6 and TNFa
at low concentrations as well as IL-16, granulocyte colony stimulating factor and hepatocyte growth factor have been reported to
generate DCs with tolerogenic activity [114,120e125]. With respect
to biomaterial application induction of tolerogenic DCs at the
implant site would provide a powerful means to limit the immune
response and to promote wound healing and biomaterial
integration.
The role of DCs in biomaterial application has mostly been
addressed in the presence of an immunogenic biological component. Biomaterials were found to exert adjuvant effects since they
potentiated immune responses toward co-delivered antigens [126].
However, acting as an adjuvant requires the capability to prime DCs
that has been shown to necessitate direct cell-material contact
[127]. It is assumed that biomaterials activate DCs by triggering
receptors and signaling cascades of the pathogen recognition
system [44] (Fig. 1B and E). As described above, DCs may sense
materials using PRRs including toll-like receptors and C-type lectins. The receptor-activating ligands are danger signals constituted
by proteins and carbohydrate moieties in the adsorbed protein
layer. A recent study suggests a substrate-dependent DC activation.
Albumin or whole serum stimulated DCs to the release of IL-10 or to
prime IL-4 producing T cells as typical for Th2 type responses [128].
In contrast, DCs cultured on collagen and vitronectin generated
high levels of IL-12p40 that correlated with the release of IFNg by T
cells indicating a Th1 type response [128]. Because collagen and
vitronectin function both as danger signals and adhesion substrates
for integrins, integrin signaling cannot be ruled out as an alternative mechanism of DC activation to PRR engagement. Indeed, DC
integrin binding to ECM proteins and subsequent DC maturation
has been shown, and for bronectin a dependency of DC maturation on b1 integrin binding was demonstrated [129,130].
Various biomaterial polymers (alginate, agarose, chitosan, HA,
poly(lactic-co-glycolic acid)) have been shown to exert differential
effects on DC maturation and activation [44,131,132]. DCs activated
upon biomaterial contact develop an immunogenic phenotype
similar to LPS-activated DCs which is characterized by increased
expression of co-stimulatory molecules (CD80/CD86), major histocompatibility complex class II (MHC-II) molecules and the DC
maturation marker CD83 [44,127]. Biomaterial-matured DCs are
capable to promote T cell proliferation and secrete inammatory
cytokines (TNFa and IL-6) known to further amplify DC maturation by
autocrine stimulation [44,127]. Nevertheless, some of the synthetic
materials tested (e.g. alginate or HA) restrained DC maturation [131].
These cells develop a tolerogenic phenotype [125] that, upon
encountering and presenting antigens, induce T cell tolerance.
Depending on which PRR is engaged, DC maturation can be
promoted or inhibited leading to immunity or tolerance, respectively [133]. Whereas immunogenic DCs may prolong the immune
response to biomaterials and delay wound healing, tolerogenic DCs
are capable to down-regulate the immune cells and resolve
inammation. Thus, induction of tolerogenic DC by designing the
surface chemistry appears to be a promising strategy of modulating
immune responses to biomaterials to improve biocompatibility.
2.4. T lymphocyte responses to biomaterials
T lymphocytes have been shown to adhere to synthetic
biomaterials in vitro [62]. In co-culture with macrophages, they
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Fig. 3. Structure and function of the ECM. A) ECM composition. B) Cellematrix interaction: engagement of cell surface receptors with proteins and proteoglycans of the ECM triggers
intracellular signaling events. C) Cytokineematrix interaction: proteoglycans bind growth factors and cytokines. Interaction with the ECM protects the signaling molecules from
enzymatic cleavage, enriches their local concentration and enhances or reduces their action on cells.
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Fig. 4. Current strategies in the design of immunomodulating biomaterials. A) Alterations of physicochemical features of biomaterials like chemistry or topography. B) Functionalization of biomaterials by incorporation of bioactive molecules like integrin adhesion sites as well as growth factors and anti-inammatory mediators. C) Coating of
biomaterials with articial ECM e mimicking the biofunctions of the natural ECM as a tool for modulating immune cell behavior. Collagen provides natural binding sites for cell
adhesion receptors (e.g. integrins). Proteoglycans are capable to interact with endogenous cytokines and growth factors allowing for their specic presentation to target cells.
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Fig. 5. Use of aECM coatings for synthetic implants. A) General assembly of aECM coatings: collagen brils serve as protein substrate in which distinct glycosaminoglycans (GAGs)
are incorporated. B) Signicantly greater bone contact and increased new bone formation around titanium implants coated with type I collagen and chondroitin sulfate (Ti Coll CS)
as compared with uncoated titanium rods (Ti) in a rat tibia model [231] 7 days after implantation (Goldner Trichrome stain, original magnication 25). C) Signicantly increased
number of TRAP-positive osteoclasts (red) around the newly formed bone (B) at the surface of titanium implants coated with type I collagen and chondroitin sulfate (Ti Coll CS) as
a sign of increased bone remodeling 7 days after implantation [231]. Around the uncoated pins there is less bone contact and a brous interface (F) at the same time point
(enzymehistochemical stain against TRAP, original magnication 100). D) Increased new bone formation around Schanz screws coated with type I collagen and chondroitin sulfate
(Ti Coll CS) as compared to uncoated screws (Ti) in the medullary canal of sheep tibiae [237] 6 weeks after implantation (Goldner Trichrome stain, original
magnication 16).(For interpretation of the references to colour in this gure legend, the reader is referred to the web version of this article).
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the inammatory response which in turn has an important inuence on bone regeneration and wound healing (Fig. 4B). Natural
occurring GAGs have been identied to bind and modify inammatory factors such as interleukins and chemokines [243e245]. An
important immunoregulatory cytokine is IL-10, exhibiting both
suppressive and stimulatory effects on the immune system. IL-10
acts anti-inammatory on macrophages and DCs by reducing the
production of pro-inammatory cytokines and presenting antigens
to T cells. Sulfated GAGs have been reported to bind human IL-10
and to modulate its activity [244]. Interestingly, GAG-promoted
linkage of IL-10 to the surface of monocytes/macrophages resulted in enhanced activity of IL-10 on the immune cells [244]. The
binding capability of the sulfated GAG was determined by grade of
sulfation, position of the sulfate groups (C4 or C6) and linkage of the
sulfate group to the sugar chain (N- or O-sulfation) indicating that
subtle differences in the GAG structure and/or sequence might be
sensed by signaling molecules and thus guides their interaction
with the ECM. Differential binding to subsets of various sulfated
GAGs was also observed for chemokines such as IL-8 [245]. Given
that GAG structures vary among tissues and that chemokine
interaction with GAG mediates their presentation to leukocytes, it
is conceivable that GAGs participate in determining the specicity
of leukocyte recruitment in vivo. This might be an important aspect
for the design of aECM coatings to modulate the invasion of
immune cells to the implantation site.
However, GAGs not only modulate the activity of inammatory
mediators they are also capable to directly interact with immune
cells. In this respect, CS and HA are of special interest because they
are known to act immunosuppressive on various cells. CS, for
example, is used as a therapeutic agent in osteoarthritis since it
exerts strong anti-inammatory effects in the joint [246]. It was
Fig. 6. Immunomodulating effects of aECM coatings on dendritic cells. A) Composition of the tested aECM coatings. B, C) Articial ECM coatings attenuate DC maturation induced by
collagen and LPS-stimulation: immature DCs (iDCs) were generated by culture of human CD14 monocytes for 4 days in the presence of GM-CSF and IL-4. The iDCs were cultured
for 24 h on either aECM or collagen alone with and without co-stimulation with LPS at 10 ng/ml. Expression of DC maturation markers and release of IL-12, the main cytokine for
activation of T cell immunity were assessed by ow cytometry and ELISA, respectively. DC viability was assessed by staining with annexin V and propidium iodide. Viability of DC
after 24 h culture on aECM was the same as in controls (DC cultured on plastic) and in all experiments over 85% (data not shown). At least three independent experiments were
performed. ManneWhitney U test was used for statistical analysis (*p < 0.05; **p < 0.005). Error bars represent standard deviation.
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