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REVIEW ARTICLE OPEN

The role of dendritic cells in the immunomodulation to

implanted biomaterials
1✉
Siyuan Wang1, Yanqi Chen1, Zhaoting Ling 1
, Jia Li1, Jun Hu1, Fuming He and Qianming Chen1

Considering the substantial role played by dendritic cells (DCs) in the immune system to bridge innate and adaptive immunity,
studies on DC-mediated immunity toward biomaterials principally center on their adjuvant effects in facilitating the adaptive
immunity of codelivered antigens. However, the effect of the intrinsic properties of biomaterials on dendritic cells has not been
clarified. Recently, researchers have begun to investigate and found that biomaterials that are nonadjuvant could also regulate the
immune function of DCs and thus affect subsequent tissue regeneration. In the case of proteins adsorbed onto biomaterial surfaces,
their intrinsic properties can direct their orientation and conformation, forming “biomaterial-associated molecular patterns
(BAMPs)”. Thus, in this review, we focused on the intrinsic physiochemical properties of biomaterials in the absence of antigens that
affect DC immune function and summarized the underlying signaling pathways. Moreover, we preliminarily clarified the specific
composition of BAMPs and the interplay between some key molecules and DCs, such as heat shock proteins (HSPs) and high
mobility group box 1 (HMGB1). This review provides a new direction for future biomaterial design, through which modulation of
host immune responses is applicable to tissue engineering and immunotherapy.
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International Journal of Oral Science (2022)14:52 ; https://doi.org/10.1038/s41368-022-00203-2

INTRODUCTION foreign attacks.11 iDCs encountering self-antigens or in the absence

Biomaterials and biomedical devices implanted in a host trigger a of foreign signals differentiate into tolerogenic DCs (tolDCs), which
series of orchestrated immune reactions, including blood- promote immune tolerance.12 The double-edged role of DCs seems
biomaterial contact, the formation of adsorbed proteins, and to have been extensively studied for orchestrating immune
recruitment of immune cells (Fig. 1a, b).1 Successful integration of responses,1 of which plasticity is generated from their unique role
implanted biomaterials requires complete removal of inflammation as sentinels, consecutively signaling their peripheral cues and
and tissue regeneration, which is highly related to complex exerting context-dependent properties.13,14 Considering this, recent
immunity. In this context, ongoing efforts have been devoted to studies have revealed that modifying the physiochemical properties
excavating the interplay of biomaterials and host immune systems, of implanted biomaterials would generate exceptionally different
the involved signaling molecules, and the underlying mechanisms.2 immune milieus and elicit varied DC-mediated host responses,15
Biologically distinct subsets of DCs originate from hematopoietic thus leading to immune responses or tolerance.16–18 For instance,
stem cells (HSCs) in the bone marrow and regulate the function of genetically modified19–21 or pharmacologically conditioned22–24
T cells in different ways,3 including myeloid/conventional DCs, maturation-resistant DCs have been introduced to promote allograft
plasmatic DCs, and follicular DCs.4–6 As the most efficient antigen- survival, tissue regeneration, vaccine delivery,25 autoimmune disease
presenting cells (APCs), they serve as a jointing band between treatment26, and tumor immunotherapies. Therefore, a comprehen-
innate and adaptive immunity and maintain a core position in the sive elucidation of the interplay between biomaterial physiochem-
process of injury and healing. Recent knockout studies have ical properties and DC phenotypes is truly important.27 Based on
identified the critical role of DCs in immune responses.7 For this, future efforts might be attributed to inducing tolerogenic,
instance, conditional and constitutive ablation of DCs in mice might ‘alternatively activated’, and effective mDCs via biomaterial surface
lead to spontaneous development of autoimmune disease.8 modifications in an attempt to disseminate the profound application
Under steady state, DCs surveying in the periphery signal foreign of biomaterials.28,29 Nevertheless, within the limit of our knowledge,
antigens through pathogen-associated molecular patterns (PAMPs) approaches to modulate the function of DCs have historically
or damage-associated molecular patterns (DAMPs), thus generating focused on inducing the bioinertness of the materials but overlook
a battery of immune reactions.9,10 During the process, pattern- their intrinsic bioactivity, which is critical for tissue regeneration.30
recognizing receptors (PRRs) are adopted by immature tissue- Moreover, the underlying mechanisms involved in DC-biomaterial
resident DCs (iDCs) to capture antigens, including Toll-like receptors interactions have not been well established yet. In particular, the
(TLRs), C-type lectin receptors (CLRs) and nucleotide-binding definition and connotation of BAMP has been hardly expounded
oligomerization domain (NOD)-like receptors (NLRs).10 Initiated by upon, much less the idiographic chemical composition and
foreign signals, iDCs are transferred into mature DCs (mDCs), which structures. Herein, we provide an in-depth look at the current
are capable of launching T-cell mediated immune responses against knowledge on the multifaceted effects of the physiochemical

1
Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Clinical Research Center for Oral Disease of Zhejiang Province, Key Laboratory of Oral
Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310006, China
Correspondence: Fuming He ([email protected])

Received: 20 June 2022 Revised: 26 September 2022 Accepted: 29 September 2022

 The role of dendritic cells in the immunomodulation to implanted. . .
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2
a Type and amount of cells recruited to the implant sites
Relative
amount
Innate immune stage Adaptive immune stage
of
infiltrated
cells

Monocyte and
macrophage

Neutrophil T and B cells

Dendritic cell

minutes to hours 1-3 days 1-2 weeks

b Two mutually exclusive fates of DCs conferred by biomaterials

Anti-inflammatory cytokines
IL-10, TGF-b, ...
Monocyte IL-1, TNF-a, IFN-γ, ...
M2 Macrophage tol DC

DAMP

Tissue TLRs
Macrophage debris
Neutrophil
IL-4, IL10, IL-13, ... M1 Macrophage Dendritic cell
Inflammatory cytokines
IL-1, IL-6, TNF-a, IFN-γ, ... mature DC
BAMP Adsorbed
BAMP proteins
Implanted Biomaterials

c Morphology, phenotype, and biofunction of DCs in two states

Immunogenic state Immunotolerant state

Treg

Teff iDC iDC

tolDC T cell
T cell mDC
Anti-nflammatory cytokines
T helper 2
Inflammatory cytokines in the absence of DAMPs,
DAMPs, PAMPs, BAMPs... PAMPs, BAMPs... Anti-flammatory cytokines
Inflammatory cytokines
IL-10 TGF-β, ...
IFN, TNF-a, ... CD4+ T cell CD4+ T cell
CD28
CTLA-4 CTLA-4 MHC II
CD28
Changes in DC phenotype indicated
by: Changes in DC phenotype indicated
- More T cell co-stimulators like TCR Co-stimulatory PD1 by:
molecules
CD40, CD80, CD86 CD40, CD80, TCR Co-stimulatory - Less T cell co-stimulators like
- Succeed to process and present CD86, ... molecules
CD40, CD80,
CD40, CD80, CD86
MHC II CD86, ... - Fail to process and present MHC II
- Cytokines induction including IL-6, MHC II - Cytokines induction including
mDC PDL1/PDL2 tolDC
IL-12 IL-10, TGF-β

Fig. 1 Important immune events involved in host response towards implanted biomaterials. a Host proteins majorly adhere to the surface of
biomaterials within 4 h, which are followed by a series of subsequential chain responses like the infiltration of immune cells consecutively (see
Supplementary Fig. S1 for detailed illustration). b DCs surveying in the periphery signal foreign biomaterials through BAMP. Meanwhile, driven
by cytokines and chemokines released from the surrounding lymphocytes, DCs undergo the transformation towards mDCs or tolDCs.
c Specifically, having recognized the biomaterial through BAMP, iDCs experience the shift towards antigen-capturing mDCs with a ‘stellate’
morphology and upregulated expression of stimulatory and co-stimulatory molecules such as MHC-II, CD80, and CD86, which further initiated
T cell-mediated adaptive immune response. On the contrary, iDCs encountering self-antigens or in the absence of foreign signals would
differentiate into tolDCs, which downregulate the expression of co-stimulatory molecules, enhance the expression of inhibitory molecules,
and promote anti-inflammatory cytokines TGF-β and IL-10. *The arrows with solid lines in two different colors both indicate a progressive
meaning, with the red arrow involved in inflammation and the blue one in immunomodulation. In addition, the double-ended arrow in the
right part of Fig. 1(c) indicates that productions from T cell could also induce tolDCs differentiation (e.g., TGF-β, IL-10)

properties of biomaterials on DC biofunction and explicate DC HOST RESPONSE TO IMPLANTED BIOMATERIALS

behaviors toward implanted biomaterials, with a specific emphasis Biomedical devices or materials implanted in a host universally
on the underlying mechanisms. We believe that understanding this trigger a highly orchestrated chain of events, including inflamma-
complex scenario will assist in the innovative design and clinical tion, and the balance of the immune system breaks down when
application of biomaterials with desired immune effects in tumor inflammation is excessive or becomes chronic.31,32 When implanted
therapy, vaccine delivery, and tissue engineering. into the host, biomaterial comes into contact with blood or humoral

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 The role of dendritic cells in the immunomodulation to implanted. . .
Wang et al.
3
fluids, and proteins will instantly adsorb to the surface of the To date, many studies have focused on specific material proper-
material.1 Generally, host proteins primarily adhere to the surface ties, including chemical composition, surface chemistry, hydro-
within 4 h, which is followed by a series of subsequent chain philicity, topography and roughness, spatial structures, surface
responses occurring on the surface of the biomaterial, including charge, and incorporated bioactive inorganic ions, which are
complement activation, the coagulation cascade, and immune cell comprehensively characterized and discussed separately in this
adhesion.1 Early infiltration of the neutrophil population was section and are summarized in Table S1 and Fig. 2.
observed in minutes to hours according to Leifer,32 which lasted
until 24–48 h after implantation and was followed by monocyte Surface chemistrypatibility and tissue regeneration
accumulation on biomaterials as well as differentiation into Biomaterial-induced immune responses are directly determined
macrophages by 72 h postimplantation.33–35 by the surface chemistry, such as conjugated peptides or
With a relatively limited proportion of approximately chemical moieties, as well as elemental concentrations of
0.5%–1.5% of the total mononuclear cells in peripheral blood, carbon, oxygen, and nitrogen.60 Organic biomaterials, including
as well as short lifetimes of days to weeks,34,36,37 DCs serve as the agarose, alginate, chitosan, hyaluronic acid (HA), and 75:25
center of the immune system, providing a vital link between PLGA, are commonly applied in tissue engineering61 and display
innate and adaptive immune responses.10,38,39 In contact with immunologic roles in the microenvironment.62 Yoshida et al.
biomaterials, iDCs experience a shift toward antigen-capturing explored the effects of agarose and 75:25 PLGA MPs and films
mDCs (Fig. 1c), which are characterized by a ‘stellate’ morphol- on human monocyte-derived DCs63 and murine bone marrow-
ogy composed of actin.40 Apart from this, many coordinated derived DCs.44 They reported that under treatment with PLGA
events are involved in DC maturation, including the upregulated and agarose MPs or films, DCs, regardless of cell origin, showed
expression of peptide-major histocompatibility (MHC)-I and -II an upregulation in expression of MHC II and costimulatory
complexes permitting effective antigen presentation, enhanced molecules, such as CD80 and CD86, in contrast to iDCs but to a
expression of adhesion molecules and chemokine receptors, and lesser extent than that of lipopolysaccharide (LPS)-induced DCs.
prominent allo-stimulatory capacity and pro-inflammatory cyto- Babensee generated biofilms of five materials (agarose, alginate,
kine secretion profiles, including IL-1β, IL-6, and IL-12p70.10,41–43 chitosan, HA, PLGA) by casting techniques and examined their
As evidenced by Yoshida, markedly increased presentation of influences on iDCs derived from human peripheral blood
costimulatory molecules, including CD80, CD83, and CD86, was monocytes.62 They found that chitosan and PLGA (and agarose
observed at early time points (6 h, 24 h) on DCs treated with to a lower level) films could promote DC costimulatory capacity
75:25 poly(lactic-co-glycolic acid) (PLGA) films and MPs.44 As a equivalent to LPS-induced DCs, whereas alginate or HA films
result of the development of a repertoire of chemokine inhibited the costimulatory expression of DCs. Similarly, Park
receptors, including CCR7,45,46 mDCs spontaneously migrate to et al. found that cultivating DCs with alginate and HA did not
local lymph nodes.11 Subsequently, T-helper cells were spotted stimulate DCs, while DCs seeded on PLGA or chitosan films
as early as the third day locally at the implantation sites and in presented upregulated surface maturation molecules, including
the contralateral bone marrow according to a mouse model, CD80, CD86, CD83, and human leukocyte antigen-DQ (HLA-DQ),
signaling the arousal of adaptive immune responses, which accompanied by enhanced proinflammatory cytokine secretion,
lasted over seven days.47 DC-mediated T-cell activation depends such as tumor necrosis factor-α (TNF-α) and allo-stimulatory T-
on three major signals: (i) the first signal refers to the cell proliferation, as confirmed via mixed lymphocyte reactions
combination of MHC-peptide complexes with antigen-specific (MLR).61 Concludingly, diverse biomaterial chemistries might
TCRs; (ii) recognition and involvement of costimulatory mole- contribute to the development of distinct BAMPs in terms of
cules exhibited on DCs, including CD80 and CD86, by their proteins and carbohydrates.
receptors on the surface of T cells (e.g., CD28, CD40, CTLA-4), Compounding this, DC morphology and release of cytokines
which constitutes the second signal; (iii) other soluble or such as IL-12p40 and IL-10, are modulated via adhesive
membrane-bound signals, such as IL-12 and type I interferon substrates-associated signaling.64 Furthermore, Archaya et al.
(IFN-I), consisting of a “polarizing” signal.48 confirmed the substrate-dependent differences in the stimula-
In contrast, iDCs encountering certain biomaterial signals, tory and costimulatory capacities of DCs derived from nonobese
which have not been fully elaborated, differentiate into tolDCs.12 diabetic mice.65 Among adhesive substrates, including fibronec-
TolDCs preserve the ability of antigen presentation to antigen- tin, fibrinogen (Fg), collagen, vitronectin, laminin, albumin and
specific T cells while downregulating the expression of costimu- serum, DCs cultivated on vitronectin induced the highest
latory molecules (e.g., CD80, CD86, CD40) or proinflammatory immunogenicity, collagen elicited the highest IL-10 secretion in
cytokines, including IL-12, and enhancing the expression of DCs, and the fibronectin-coated surface gave rise to the highest
coinhibitory molecules (e.g., IgG-like transcript 3, PDL1) and anti- level of maturation in T cells.66 However, the expression of MHC-
inflammatory cytokines, such as transforming growth factor-β II and CD40, cytokine secretion profiles, and capability of
(TGF-β) and interleukin-10 (IL-10)49–54 (Fig. 1c). Immunological inducing allogeneic T-cell proliferation of DCs were independent
tolerance was maintained by inducing T-cell apoptosis, unre- of pre-adsorbed adhesive proteins.67 The seemingly contrasting
sponsive T-cell responses, Treg cell production and inhibition of outcomes might result from the solid substrates (Bioflex plates),
T-cell responses.8,9,27,55–57 which were different in nature from the TCPs used in prior
studies as indicated by the authors.
In terms of biomaterial surface modification, incorporation with
BIOMATERIALS PROPERTIES MODULATING DC RESPONSE bioactive inorganic ions is universally viewed as a convenient,
Modulating the immune-inflammatory axis via biomaterials can effective, and long-lasting tool to promote desired effects.68 For
significantly ameliorate the efficacy of tissue engineering.58 instance, zinc has displayed superior antibacterial and osteogenic
Recently, an increasing number of studies have incorporated properties in previous investigations, and its role is irreplaceable in
biomedical polymers with immunogenic or immunomodulatory immune responses.69–71 Specifically, the exogenous addition of
molecules in an effort to regulate host responses to implanted Zn2+ induced a tolerogenic phenotype of bone marrow-derived
biomaterials. Nevertheless, the influence of the intrinsic physio- DCs, with suppressed expression of MHC II and elevated
chemical properties of implanted biomaterials on DC phenotype expression of PD-L1 and PD-L2, skewing the balance of Treg/
and function has been overlooked. A better understanding of this Th17 cells in favor of FoxP3+ Tregs in a model of Histoplasma
complex interplay will help to modify the particular immune capsulatum fungal infection.72 Meanwhile, Chan et al. reported
function while eliminating unexpected immune reactions.59 that in comparison with alginate polymer-treated DCs, those

International Journal of Oral Science (2022)14:52

 The role of dendritic cells in the immunomodulation to implanted. . .
Wang et al.
4
Physiochemical properties

Biomaterial Surface topography

Surface
Surface chemistry and spatial Surface roughness Surface charge
properties hydropholicity
structures

Agarose +
chitosan,
PLGA

Boost DC Bronectin SLA substrate

maturation Collagen-chitosan
Vitronectin
scaffold
Cu2+ DOTAP/DOPC
pHEMA and PDMS
Zn2+ Hydrophobic PLA liposome
Incorporated scaffold
2+
Ba bioactive ions
PT substrate

-
Alginate
HA
2D cell culture
Promote DC plate
tolerance GQD particle
Collagen
2+
Cu ModSLA
Amphiphilic PELA
substrate
2+
Ca2+
Zn Incorporated 3D collagen
bioactive ions scaffold

Fig. 2 Biomaterials properties modulating DC response. Effects of physiochemical properties of biomaterials that potentially influence DC
phenotype and function are summarized in five columns: surface chemistry, hydrophilicity, topography and spatial structures, roughness, and
surface charge. Conjugated peptides, chemical moieties, and elemental concentration can surely determine DCs behavior, and DCs seeded on
agarose, chitosan or PLGA would boost DC maturation, whereas those treated with alginate or HA were associated with immune-tolerance.
Furthermore, PLA with higher hydrophobicity than PELA could promoted effective antigen uptake and induced a higher level of DC
maturation. However, DCs seeded on 3D scaffolds can either mature increasingly (e.g., collagen-chitosan scaffolds, pHEMA, and PDMS) or
decreasingly (e.g., 3D collagen microenvironment) in comparison with those cultured on 2D culture plates. DCs seeded on titanium substrates
with similar surface roughness (SLA, modSLA) presented different maturation. DOTAP/DOPC liposome, with a relatively cationic charge,
potently promoted DC maturation, while negatively charged GQD could significantly impair DC-mediated immune reactions. Notably, the
paired arrows with two directions in the figure indicated that contrasting outcomes were reported in terms of their effects on DC activation,
and no definitive judgment could thus far be drawn. Specifically, these material properties may interact synergistically with each other
to yield a microenvironment harmful to or favorable for tissue repair and regeneration. *Abbreviations: PLA poly(D,L-lactic acid), PELA
poly(monomethoxypolyethylene glycol-co-D,L-lactide), pHEMA poly(2-hydroxyethyl methacrylate), PDMS poly(dimethylsiloxane), GQD
graphene quantum dot

encapsulated in Ca2+-crosslinked alginate presented higher levels Surface hydrophilicity and hydrophobicity
of CD86 and MHC II while producing more inflammatory cytokine Hydrophobicity or the hydrophobic portion of biomaterials is
IL-1β, indicative of higher maturation levels, while Ba2+-cross- their inherent immunogenicity, which serves as a universal
linked alginate had no such effect. Additionally, significantly language of injury and repair.76 In contrast, hydrophilic surfaces
upregulated IL-1β secretion was observed from calcium alginate similar to those present in natural tissue may be able to stimulate
gel-surrounded tissue in mice.73 Moreover, Schuhladen and immune cells to switch activation, thus preventing a chronic
coworkers incorporated bioactive glasses (BGs) with biologically immune response.77 Specifically, the wettability of the biomater-
active ions, Cu2+, Zn2+, and Cu-Zn2+, on DCs and reported that ial surface determines the proteins adsorbed to it and the
the presence of copper modulated the phenotypic performance of subsequent formation of blood clots and fibrin networks.78
tolDCs in favor of T-cell polarization into an anti-inflammatory However, protein adsorption on a hydrophobic surface alters its
Treg milieu.74 In contrast, Li et al. proposed that γ-AlOOH conformation through hydrophobic interactions, exposing the
mesostrands incorporated with hierarchical Cu- and Zn-buds intrinsic domain and promoting the recruitment of host immune
(Cu- and Zn-AMSs) promoted BMDC maturation and proinflam- cells.79,80 Yang et al. fabricated a novel superamphiphilic material
matory cytokine release, which further facilitated T-cell prolifera- polycaprolactone (PCL) with an interconnected hierarchical pore
tion in mice.75 Heterogeneities within bioactive ion concentrations structure and ascendant wettability, as confirmed by a water
among different types of biomaterial carriers might be plausible contact angle of 45.3°. The hydrophilic PCL displayed a
for the different outcomes of DC behaviors. In this context, facilitating effect on DC adhesion and proliferation when
increasing research efforts should focus on incorporating available compared with hydrophobic surfaces. However, the authors did
biomaterials with biological ions in an effort to improve the not further investigate the phenotype and function of DCs.81
effectiveness and security of their profound applications. Meanwhile, Liu et al. confirmed that poly(D,L-lactic acid) (PLA)

International Journal of Oral Science (2022)14:52

 The role of dendritic cells in the immunomodulation to implanted. . .
Wang et al.
5
spherical microparticles19 possessed similar size, charge, and hydrophilicity and surface chemistry of the biomaterials adopted.
morphology but higher hydrophobicity than PLGA or poly(- Altogether, spatial structures may in this manner interact
monomethoxypolyethylene glycol-co-D,L-lactide) (PELA), which synergistically with other properties to yield a microenvironment
promoted effective antigen uptake and induced a higher level of favorable for tissue repair and regeneration.
DC maturation. In addition, adhesion force measurements further
validated the strong interaction between highly hydrophobic Surface roughness
PLA MPs and cell membranes, favoring MP internalization and Roughness is another critical parameter determining immune
the subsequent elicitation of immunity.82 Chaudhary et al. also responses, particularly for metallic implant materials. Nevertheless,
underscored that hydrophilic surfaces preferentially modulate it has been reported that among the multiplex properties that
biological functions, including protein adsorption, cell attach- influence DC behavior, surface roughness might not be the critical
ment, and proliferation, thereby enhancing bioactivity and determinant. Titanium substrates have been fabricated with
regulating biological functions.83 By immobilizing the adsorbed typical microtopography as well as surface energy by Kou and
proteins, it is therefore promising to develop a biointerface via coworkers:16 PT discs were chemically polished to be finely
improvement in hydrophilicity that can promote biocompat- smooth, SLA substrates displayed a hierarchical structure of
ibility and tissue regeneration.58 cavities with 10–50 µm indentations completely superposed by
1–2 µm pores,92 and modSLA surfaces displayed similar roughness
Surface topography, and spatial structures as SLA while maintaining its high surface energy. PT- and SLA-
Surface attributes such as porosity, roughness, three-dimensional treated DCs both displayed indistinguishably high dendritic
structures, and the presence and type of micro- and nano- morphology and expressed higher levels of CD86 than those
structures (NS) have profound influence on the phenotype and cultured on TCPs. ModSLA surfaces, on the other hand, rendered
function of immune cells.42 Micro- and nano-structures have been DCs cultivated on them to maintain a CD86 expression level
shown to significantly affect DC behaviors.58,78 Compounding this, similar to iDCs and process-free immature morphology.16–18
DCs seeded on poly(2-hydroxyethyl methacrylate) (pHEMA) and Enhanced expression of proinflammatory IL-6, IL-12, and IL-18
poly(dimethylsiloxane) (PDMS) scaffolds matured increasingly with was detected in DCs cultured on PT or SLA surfaces, while IL-1ra,
decreasing pore size, with those cultivated on 20-μm pore IL- 4, IL-10, and TNF-α were reduced, and the outcome was the
scaffolds matured most remarkably.84 In this context, topochip, opposite in terms of modSLA surfaces.18 The characteristics of
which was fabricated with polylactic acid (PLLA) or polyethylene biomaterial surfaces were confirmed by assessment of surface
oxide/polybutyl terephthalate (PEO/PBT), has been introduced roughness, contact angle, and surface chemistry via XPS analysis,
into biomedical immunity, thereby enabling the screening of DC as listed in Table 1.16–18,77,93–97 Collectively, different behaviors of
response to certain important biomaterial properties in a high- DCs might be interpreted as the outcome of a higher oxygen
throughput manner.85 For instance, Unadkat et al. developed percentage and hydrophilicity, whereas current studies have
chips of PLGA with 2176 different, nonbiased, random surface concluded that surface roughness was not decisive in DC-
patterns based on mathematical algorithms.86 Using this topochip, biomaterial interactions.17 Nevertheless, explicit effects of surface
Kou et al. reported that a human DC-like cell line (KG-1 cells) roughness on DC phenotype and function are not fully elaborated,
adhered discordantly toward different topoUnits.87 Collectively, and this prospective should be generalized in future efforts.
these findings highlighted that the surface topographic char-
acteristics of biomaterials are of great significance to DC Surface charge
phenotype and functions and that it is beneficial to interfere According to Gammon, the surface charge on the biomaterial
with cell-biomaterial interactions by modifying surface topogra- surface is critical in modulating the migration and differentiation
phy in an effort to manipulate the tissue repair responses. of immune cells and is generalizable across different biomater-
With most of the current studies ongoing relative to the ials.59 According to Andorko et al., neutral to positive zeta
biomaterial-surrounding milieu, the three-dimensional (3D) spatial potentials would induce conspicuous DC activation.98 For
structure, however, might better depict the microenvironment instance, Ma et al. evaluated DOTAP/DOPC liposome-regulated
where DCs function.88 In fact, good cytocompatibility of 3D immune responses and reported that liposomes with a relatively
hydrogels at various concentrations was shown in terms of DC cationic charge potently promoted DC maturation and antigen
extension and surface marker expression.89 Koen van den Dries uptake, whereas low-charge liposomes failed to facilitate DC-
et al. reported that 3D micropatterned surfaces inhibit PGE2- mediated immunity even at high concentrations.99 Meanwhile,
mediated RhoA activation, which resulted in impaired podosome with their negative surface charge, graphene quantum dot (GQD)
dissolution and higher MHC-II expression of DCs, suggesting the particles (large GQD: (−9.0 ± 1.5) mV; small GQD: (−9.4 ± 0.8) mV)
important role of three-dimensional geometry cues in regulating significantly impaired DC-mediated allogeneic T-cell proliferation
DC adhesive and immunomodulatory properties.90 Additionally, and Th1/Th17 polarization, which was in accordance with the
Daneshmandi et al. developed collagen-chitosan scaffolds to modified secretion of IL-12p70 and altered expression of CD40,
mimic the 3D microenvironment for DCs, where higher levels of CD83, and CD86.100,101 Nevertheless, cationic materials might, on
maturation and cytokine production, including IL-6, IL-12, and the other hand, lead to diminished activation of DCs with
TNF-α, were observed in comparison with those cultured on 2D suppressed antigen uptake.98,102,103 In fact, investigations on the
culture plates. Furthermore, the induced secretion of IFN-γ and IL- role of surface charge in DC-biomaterial interactions are ongoing,
4, together with the downregulated release of TGF-β, was and the aforementioned attempts primarily suggest that the
detected during DC-T-lymphocyte cocultures in a 3D system.88 surface charge of biomaterials is critical in DC activation and is
Consistently, Chen et al. reported that after exposure to pHEMA highly manageable, which might be a future direction in
and PDMS scaffolds, the secretion of MIP-1α, IL-6 and TNF-α, along bioengineering and vaccine delivery.104–106
with CD86 expression on DCs, significantly increased when Biomedical strategies targeting DCs for modulating the
compared to those grown on NTCPs, indicating promotion of balance between immunomodulation and immune reactions
mDC-induced inflammation.84 Nevertheless, Sapudom et al. can significantly improve the efficacy of tissue engineering.
showed that predifferentiated mDCs presented higher levels of Harnessing the surface properties (surface chemistry, hydrophi-
CCR7, MHC II, CD80, and CD86 when seeded on 2D tissue culture licity, topography and spatial structures, roughness, and surface
plastic, which were attenuated by a 3D collagen microenviron- charge) of biomaterials are promising to modify immune
ment.91 The deviations in DC maturation and function might be reactions while eliminating unexpected adverse reactions. Never-
attributed to different cell lines as well as the intrinsic theless, materials properties are generally intricate and interlace

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6
Table 1. Physiochemical properties of Titanium surface

Physiochemical PT SLA modSLA Ref.

properties
77
Roughness (Ra)/μm 0.59 ± 0.019 3.58 ± 0.042 3.64 ± 0.029
17
0.38 ± 0.02 1.78 ± 0.02 1.78 ± 0.04
96
~1.8 250–500 ~0.5
77
Air-water contact angle 93.6° 120.9° 0°
96
~90° ~130° ~0°
92
(91.31 ± 7.30)° (139.88 ± 8.69)° 0°
93
Not mentioned. (138.3 ± 4.2)° 0°
78
Not mentioned. (125.9 ± 6.8)° 0°
77
Surface O/% 48 48 60
Chemistry 47.6 ± 1.2 45.7 ± 1.12 50.58 ± 2.03 17

94
Not mentioned. 50.2 ± 2.6 60.1 ± 0.7
96
Not mentioned. 53.21 36.77
95
46.8 ± 1.9 50.2 ± 2.6 60.1 ± 0.7
92
Not mentioned. 49.2 ± 2.1 61.1 ± 0.9
93
Not mentioned. 44.2 ± 1.9 55.0 ± 2.0
Ti/% 18 15 22
13.48 ± 0.49 13.75 ± 1.84 15.17 ± 0.56
17.9 ± 1.0 14.3 ± 1.4 23.0 ± 1.1
Not mentioned. 19.33 11.23
Not mentioned. 14.3 ± 1.4 23.0 ± 1.1
18.4 ± 1.6 14.3 ± 1.3 22.5 ± 0.9
Not mentioned. 18.4 ± 1.6 26.5 ± 0.9
N/% 1.78 ± 0.14 1.37 ± 0.13 1.51 ± 0.14
1.2 ± 0.4 1.3 ± 0.3 0.7 ± 0.2
Not mentioned. 1.12 0.76
Not mentioned. 1.3 ± 0.3 0.7 ± 0.2
0.6 ± 0.2 1.3 ± 0.4 0.7 ± 0.3
C/% 31 35 17
40.86 ± 1.47 39.19 ± 1.95 32.74 ± 1.60
29.2 ± 1.5 34.2 ± 2.0 14.9 ± 0.9
Not mentioned. 26.35 26.20
Not mentioned. 34.2 ± 2.0 14.9 ± 0.9
30.9 ± 2.1 35.2 ± 2.2 14.2 ± 1.2
Not mentioned. 37.3 ± 3.4 18.4 ± 2.7
77
Topography Micron and submicron Micron structures Micron and nanostructures
structures
78
Not mentioned. Macro and microstructure Characteristic NS with needle-like shape of the
without characteristic NS. crystallites with dimensions of about 10 nm in width
and 30 nm in length.
78
Protein adsorption Not mentioned. Fg: 525.2 ± 135.2 Fn: 331.9 ± 134.8 Fg: 4 969.9 ± 1 619.5 Fn: 3 835.8 ± 795.6
The previously characterized surface properties of the Titanium discs were summarized in Table 1 for mean-peak-to-valley roughness (Ra), air-water contact
angle, surface chemistry, topography, and protein adsorption

with each other, rendering what and how biomaterial properties inherent chemical compositions, such as carbohydrate units
that potentially govern DC-mediated immune responses contained in mannuronic acids and guluronic acids, might
unknown. For instance, interpretation of the varied behaviors of possibly determine the resultant phenotype of DCs upon
DCs in response towards the five commonly adopted biomater- biomaterial exposure. In addition, carbon dioxide and hydro-
ials (agarose, alginate, chitosan, HA, and PLGA) triggered big carbon contaminants introduced from the environment during
confusions. Park indicated that hydrophobic PLGA and chitosan film formation, and rearrangement of hydrophobic sites of
with highly cationic glucosamine displayed higher levels of biomaterial molecules during biomaterial processing procedures
maturation. Nevertheless, alginate, absent in hydrophobicity or might, to some degree, account for the modified DC behaviors.61
negative charges, also induced higher levels of maturation within To cope with the limitations in delineate the interplay between
DCs in terms of TNF-α and IL-6 release.107 It is thereby reasonable single material property and DC performance, Kou et al.
to preliminarily postulate that apart from hydrophobicity and performed principal component analysis (PCA), and demon-
cationic charges associated with the biomaterial surface, the strated that titanium surface hydrophilicity and concentration of

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Implanted biomaterials

HSPs
DNAs

RNAs HMGB1
carbohydrate

Adsorbed proteins Conserved structures 'Danger signals'

and macromolecules characteristic of biomaterials

Inflammation Immunomodulation

- fibrotic encapsulation - improved bone healing

- scaffold failure - scaffold integration

Fig. 3 A brief illustration of Biomaterial-associated molecular patterns. When implanted in the host, biomaterials are capable of adsorbing or
desorbing contacting proteins and form a layer of adsorbed protein. Biomaterial surface properties determine the adsorbed proteomic
profiles and the subsequential cellular interactions. These recognizable motifs are referred to as ‘biomaterial associated molecule patterns’,
and the connotation of which could be could be summarized as three main parts: adsorbed proteins which can be allogenic (derived from
materials or contamination) or autologous (ECM existed in blood or body fluids); soluble ‘danger signals’ (e.g., DNA, RNA, HMGB1, HSOs); and
characteristics of the material itself

oxygen were associated with anti-inflammatory immature elaborate on the connotation of BAMPs based on related studies
phenotype of DCs. Considering that these biomaterials of and enumerate several BAMPs that are critical in DC-biomaterial
different forms have been ubiquitously adopted as scaffolds or interactions (Fig. 3).
cell carriers for tissue engineering,108–110 persistent efforts should
be distributed here to delineate a comprehensive map with Adsorbed proteins and other macromolecules
regard to material property-DC phenotype interactions. Fortu- A battery of studies has confirmed activation of DCs under
nately, the application of immune-mediated tissue engineering exposure towards HA, up-regulated adherence to fibronectin, and
has witnessed immense growth in recent decades with the induced mature phenotype treated with type 1 collagen and
development of high-throughput strategies (e.g., PCA and partial fibronectin.118 In addition, adhesion-limiting proteins (albumin,
least squares regression (PLSR)). vitronectin, and fibronectin) have higher affinity to hydrophilic
surfaces, whereas adhesion-promoting proteins (fibrinogen and
IgG2) adhere easily to hydrophobic surfaces.1 Acharya et al.
BIOMATERIAL-ASSOCIATED MOLECULE PATTERNS proposed that DC morphology and inflammatory cytokine
When implanted in the host, biomaterials are capable of expression (IL-12p40 and IL-10), instead of adhesion or expression
adsorbing or desorbing contacting proteins and form a dynamic of costimulatory molecules are adhesive substrate-dependent.64
layer of adsorbed protein, thus encouraging DCs binding and Nevertheless, Lewis reported that neither surface expression of
tissue repair.111,112 This layer of adhesion protein can be stimulatory molecules or cytokine secretion profiles were modu-
allogenic (derived from materials or contamination) or auto- lated via adhesive proteins, regardless of laminin, collagen, or
logous (extra-cellular matrix (ECM) existed in blood or body fibrinogen.67 These seemingly contrasted results may be attrib-
fluids), and modulate host responses, such as coagulation, uted to the different time points the two experiments undertake
complement activation, and innate immunity.29,113 A recent (24 h, 1 h).28 Compounding this, osteopontin (OPN),119 vitronec-
research uncovered that biomaterial surface properties deter- tin,120 and fibronectin121 adsorbed to foreign biomaterials may be
mined the adsorbed proteomic profiles and the subsequential recognized by DCs and resulted in foreign body reactions (FBR).
cellular interactions.114 These recognizable motifs are referred to Furthermore, Escalante and Swartzlander122,123 clarified the
as ‘biomaterial associated molecule patterns’ (BAMP), which are protein adsorption profiles on the surface of PEG hydrogels via
similar with DAMP/PAMP. As first put forward by Babensee, liquid chromatography-tandem mass spectrometry. According to
BAMP could be interpreted as either cognate binding ligands them, both regulators of wound healing, such as alpha-2
relevant to adsorbed proteins, soluble ‘danger signals’ such as macroglobulin and apolipoprotein A-I, together with inflammation
DNA, RNA, HSPs, and HMGB1, as well as intrinsic structures stimulators, including vitamin D binding protein and complement
characteristic of biomaterials, in particular carbohydrates.115–117 component 3 (C3), were identified at the interface. Proteins
However, the absolute conformational structures and chemical containing the bioactive motif Arg-Gly-Asp (RGD) serve as the
composition of BAMP have not been fully clarified. Herein, we primary cell attachment sites for a battery of adhesive ECM

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 The role of dendritic cells in the immunomodulation to implanted. . .
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8
proteins.124,125 Identified on fibronectin,126,127 the RGD sequence Babensee concluded that HSPs can probably link biomaterial-
has been initially recognized in numerous ECM proteins, including mediated cell stress or necrosis and the induction of innate
fibrinogen, vitronectin, laminin, and collagen.128–131 Specifically, immunity at implant sites.115 Having confirmed the presence of
Acharya et al. investigated the expression levels of DC maturation HSP60 within the substrates, McKiel also observed increased NF-
markers and cytokine production was enhanced in response to κB/AP-1-dependent SEAP activity on poly(methyl methacrylate)
increased RGD peptide density, with IL-12p40 being the most (PMMA) and polydimethylsiloxane (PDMS) with 10% FBS, which
sensitive marker.66,132 To better comprehend the effect of RGD in induced the expression of proinflammatory cytokines as com-
modulating the FBR, Swartzlander et al. investigated the immune pared to those preadsorbed with serum only. They speculated that
response toward polyethylene glycol (PEG), PEG-RGD and PEG- inflammatory cellular function and immunogenic responses rely
RDG hydrogels, a bioincompatible peptide with similar chemistry highly on the biomaterial-directed protein adsorption.
as RGD. An equivalent profile and quantity of adsorbed proteins
among these three hydrogels was observed. Conversely, inflam- Conserved structures characteristic of the material itself
matory cells can recognize the adhesion peptide RGD, and Intrinsic structures characteristic of biomaterials (e.g., surface
significantly reduced fibrous capsule density and thickness in chemistry, hydrophilicity) determined inflammatory cellular
comparison with PEG or PEG-RDG. Their studies further verified interactions, in particular DCs, and the subsequential immune
that RGD might influence the immunogenic cellular phenotype reactions. For instance, when an implanted hydrophobic bioma-
and function without modifying the composition of the adsorbed terial interact with blood, proteins may instantaneously adsorb,
protein layer. A possible attribution could be the retention of the generally through hydrophobic interactions.142 In contrast,
intrinsic structure of proteins on PEG-RGD, which might otherwise hydrophilic biomaterials indirectly generate an interfacial free
unfold without RGD.123 energy of low value with biological fluids.143 Hasek uncovered
multiple-layer protein adsorption profiles on the surfaces of PEG
Soluble danger signals released from residual cell components hydrogels in vivo, as a consequence of hydrophobic interactions
DAMPs, such as HMGB1 and HSPs, not in high abundance within polyacrylate chains144 or through hydrogen bonding amid
though, were also identified.123 According to Babensee, a PEG and amide groups contained in the polypeptide mainstay of
complicated mixture of DAMPs (such as heat shock proteins the proteins.145
(HSP60), HSP70, HMGB1, and heparin sulfate), either as a Carbohydrates at the DC-biomaterial interface, as a key
consequence of injuries or an outcome of conserved material component of the adsorbed protein or an intrinsic material
properties, was observed in the tissue adjacent to subcuta- structures, are prominent in balancing the biocompatibility and
neously implanted PLGA scaffolds.115 It is, therefore, speculated biodegradability of biomaterials.146 Considering the evidenced
that by binding DAMPs adsorbing to the surface of implanted linkage between altered glycosylation and disease progres-
biomaterial, DCs surface TLRs or CLRs might initiate biomaterial- sion,147 it is speculated that biomaterials may display analogous
mediated inflammation.133 In addition, Farshid et al. believed segments to migrating DCs if the adsorbed proteins are
that the conformation of biomaterial-determined adsorbed conformationally altered and present a modified carbohydrate
proteins might lead to the emergence of various BAMPs, which profile.148 To confirm the existence of analogous BAMPs in the
was similar to an exogenous DAMP (including HSPs and HMGB1) immunogenic cellular-biomaterial interface, Shankar and cow-
and generate DC-mediated immune responses through integrins orkers conducted enzyme-linked lectin assays (ELLA) to probe for
and PRRs.134 However, this interpretation should be viewed with carbohydrate ligands of CLRs on self-assembled monolayers
caution and substantiated experimentally. (SAMs) delivering -OH, -CH3, -COOH or -NH2. They observed
higher α-galactose on COOH SAMs and higher mannose on NH2
High mobility group box 1 (HMGB1). The axis high mobility group SAMs, indicating that unique presentation of associated carbo-
box 1 (HMGB1) and the Receptor for Advanced Glycation End hydrates at the biomaterial interface mediates the interactions of
Products (RAGE) are related to inflammatory and healing events, the innate immune response.149,150
with HMGB1 being the prototypical and well-characterized To our knowledge, however, efforts to systematically char-
DAMP.135 Considering this, molecular dynamics computer acterize the molecular composition of BAMPs have just set off,
simulations have been introduced to explore the content and and the mechanisms by which DCs recognize and react to
conformation of HMGB1 induced at the surface of titanium.136 biomaterials have not yet been fully elucidated. To better identify
Biguetti reported that the inhibition of HMGB1 or RAGE the adsorbed protein profiles and involved posttranslational
promoted inflammatory cell infiltration, impaired osseointegra- modifications, including carbohydrates and lipids, sophisticated
tion, and affected organic and mineralized bone matrix tools (mass spectrometry (MS),151 SDS-PAGE and immunoblot
dynamics.137 Nevertheless, questions remain as to whether the analysis152) and statistical modeling (PCA,16,153,154 PLSR,155 high-
enhanced HMGB1 detected in the implantation site is a throughput nanoimmunoassay chip,156 single-cell analysis157)
consequence of injuries that prime the immune system, or an have been introduced. Hopefully, extensive interpretation of the
outcome of biomaterial intrinsic properties. To further elucidate immune events involved in the formation of adsorbed proteins
the specific constitution, Bennewitz performed immunoblotting and biomaterial recognition might provide insights for the
analysis on the tissue exudates surrounding implanted PLGA development of next generation of biomaterials.158
scaffolds and injected PLGA MPs.138 In addition to the intragroup
heterogeneity arising from tissue damage which increased the
concentration of DAMPs, higher levels of HMGB1 were detected MECHANISMS UNDERLYING DENDRITIC CELLS RESPONSE TO
around PLGA materials, signaling the potential role of HMGB1 in BIOMATERIALS
DC-biomaterial interactions. Integrins
Integrins refer to heterodimeric type I transmembrane proteins
Heat shock proteins (HSPs). HSPs are a family of conserved consisting of α and β subunits, which also constitute one of the
chaperone molecules that prevent aggregation and misfolding of major intracellular receptors that modulate cellular survival,
nascent polypeptides while expediting protein folding, thereby proliferation, and differentiation.1,159,160 Random permutation of
maintaining cellular functions.139 HSPs (e.g., HSP 70A, 70B, 9,0 and subfamilies of α and β subunits contributes to the formation of 24
47) expressions were modulated by the hydrophilicity of the distinct types of integrins, and the partnering of different subunit
biomaterial,140 which have been involved in the host immune chains confers variable function to the receptor.1 Among them,
response via regulating the expression of TLR2 and TLR4.141 leukocytes uniquely express the β2 subfamily of integrins,

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9

Cytosol Nlrp3 multiprotein

NLRP3 complex regulates the
production of
inflammatory cytokines.

Cellular Caspase-1 IL-1β IL-18

adhesion
Inflammatory
Nucleus genes
NF-κB
Biomaterial-associated molecular patterns

TNF-α IL-6
β2 Integrins
NF-kB activation
potentiates multiple Immunoregulatory
inflammatory events genes
Biomaterial surface

TGF-β IL-10
TLR2/6
MyD88 TRAF6 Co-
stimulatory
molecules
CD80 CD86
P IRF3

Type I
TRIF interferons
TLR4 IFN-α IFN-β
P IRF7
Co-
inhibitory
Target gene
molecules
transcription
ILT3 PDL1
CD205
Autophage-
mTOR ULK1 related genes
ATF4 FOXO3
DC-SIGN

Fig. 4 Mechanisms underlying dendritic cells response to biomaterials. a The mechanism of integrins. β2 integrins are virtually the first
receptors adhering to the ECM proteins, thus initiating NF-kB signaling pathways, which potentiates multiple inflammatory events. b The
mechanism of TLRs, especially of TLR 2/4/6. TLR 2/4/6 signals through MyD88 or TRIF respectively, which terminated at two events: (i) activates
the NF-kB-mediated regulation of inflammatory (like TNF-α or IL-6) and immunoregulatory genes (like TGF-β or IL-10); (ii) phosphorylates IRF3
and IRF7, leading to the consequential expression of co-stimulatory molecules such as CD80 and CD86 and production of type I interferons
(e.g., IFN-α and IFN-β). c The mechanism of CLRs. DC-SIGN and CD205 are among the most efficient CLRs that enhance antigen uptake and
presentation by DCs. d The mechanism of inflammasomes, especially of NLRP3. In the presence of NF-kB, cytosolic NLRP3 can also be
stimulated via biomaterial-derived signals and forms an intracellular multiprotein complex that catalyzes the conversion of caspase-1, thus
regulating the production of highly inflammatory cytokines such as IL-1β and IL-18. e The mechanism of autophagy. DCs in the presence of
certain biomaterials express high levels of ILT3 and PDL1, as characteristic co-inhibitory molecules of tolDC, while upregulate transcriptional
profile of ATGs such as ATF4 and FOXO3

including αLβ2 (CD11a), αMβ2 (CD11b), αXβ2 (CD11c), and αDβ2 Jak/STAT signaling pathways,166 the former of which is considered
(CD11d). Moreover, a battery of immune events are regulated via a critical mediator of DC maturation molecules, including CD80
β2 integrins: recruitment to sites of inflammation,161 intracellular and CD86.167 However, the intracellular bonding between integrin
contact162 and signaling.163 Rogers et al. observed that β2 engagement and DC maturation is controversial. DCs treated with
integrins in DC adhesive podosomes are at the biomaterial PLGA films after 24 h did not necessarily reveal enhanced
interface and in direct contact with TCPs and PLGA films, and DCs expression of translational NF-κB.168 Considering this, one possible
treated with anti-β2 integrin antibody expressed lower levels of explanation indicated by Rogers was that adhesion alone was
CD86. In this regard, their study demonstrated that a basal level of insufficient for DC activation, which merely allowed for the
β2 signaling is a prerequisite to manipulate DC adhesion and localization of other coreceptors for engagement.164 It is reason-
maintain maturation in response to biomaterials.164 Similarly, able, in this context, to assume coreceptors other than integrins,
Farshid et al. postulated that DC adhesion to the biomaterial via such as TLRs and CLRs, to be effective targets associated with DC-
integrins correlated highly with DC maturation, which in turn biomaterial interactions, the role of which will be elaborated
determined the immune responses.1 Having reviewed published below (Fig. 4).
work concerning the role of DC integrin in biomaterials, Franz
speculated that integrin signaling might serve as an alternative Toll-like receptors
mechanism of DC activation to PRR engagement.165 TLRs with leucine-rich repeats in their ectodomains169,170 are PRRs
Integrins are the initial adhering receptors for ECM proteins, that bind PAMPs derived from pathogens and DAMPs from dying or
thus enabling the nuclear transcription factor-kappa B (NF-κB) and injured cells,171 the implication of which has been extended to

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BAMPs.115 Thirteen subtypes of TLRs have been reported, and Located on the surface of DCs, CLRs ligate to the carbohydrate
among them, a retro-viral insertion has inactivated TLR10 in mice,172 structures of pathogens, self-antigens and biomaterials.115,197
whereas TLR11, −12, and −13 do not occur in humans.173 TLR1, −2, DC-specific intracellular adhesion molecule-3 grabbing noninte-
−4, −5, −6, and −10 are presented at the cell membrane, which grin (DC-SIGN) recognizes mannose-containing structures as
mainly recognize microbial components, including lipids, proteins, well as Lewis antigens (Le(a), Le(b), Le(x), and Le(y)).198 By
and lipoproteins, while TLR3, −7, −8, −9, −11, −12, and −13 are exploiting DC-SIGN ligand multivalency, internalization, lysoso-
expressed in the endosome.174,175 All TLRs signal through myeloid mal trafficking, antigen presentation and cytokine release could
differentiation primary-response protein 88 (MyD88), a crucial be optimized with glycopeptide polymers Le(b)-conjugated
adaptor molecule recruited upon binding of TLRs, DAMPs and poly(amido amine) (PAMAM).199 Additionally, the notable
BAMPs,176 except for TLR3, which confers to the TIR domain feature of CD205 to facilitate DC antigen uptake and presenta-
containing adapter-inducing interferon-beta (TRIF), and TLR4 tion in an exceptionally efficient and specific manner has
through both MyD88 and TRIF.177 The network map of TLRs has rendered it one of the research focuses. Specifically, CD205
been delineated substantially owing to everlasting efforts, which could be a bilateral mediator, either immunogenic or immuno-
terminated at two events: (1) potentiates the transcription factor NF- tolerant, depending on the maturation level and the expression
κB178,179 which are involved in the regulation of many proinflam- of stimulatory signals.200,201
matory and immunoregulatory genes;180,181 (2) phosphorylates IFN CLR recognition is influenced by the glycosylation of the
regulatory factor 3 (IRF3) as well as IRF7,1 resulting in the carbohydrate recognition domain (CRD) region in dendritic cell
consequential costimulatory molecules expression and type I immunoreceptor (DCIR) via its immunoreceptor tyrosine-based
interferon secretions, such as IFN-α and IFN-β.175,182 inhibitory motif (ITIM). Currently, researchers have been devoted
Apart from the large body of work exploring macrophage- to clarifying the role of CLRs in DC-biomaterial interactions and
induced immune responses toward orthopedic metallic in this manner shed novel light on engineering cellular function
implants,177 biomedical polymers,183–186 nanoparticles, and micro- and modulating immunity. Hotaling et al. showed that as the
particles,187 the involvement of TLR signaling is progressively cationization level of conjugates or glycan density increased and
implicated in DC-biomaterial interactions. TLR4 serves as one of so did nonspecific lectin binding. Once blocked with EDTA or
the most potent PRRs188 and is considered the core receptor in specific antibodies for DC-SIGN or Dectin-1, antigen internaliza-
the recognition of ligands, including LPS,189 HSP60 and 70,141 tion and maturation of DCs was inhibited.158,202,203 Interestingly,
HMGB1,190 hyaluronan,191 and fibrinogen.192 A previous investiga- the interplay of CLRs and TLRs in DCs could possibly result either
tion by Rogers and colleagues revealed that once implanted in the onset of inflammatory reactions or in tolerance
intraperitoneally in TLR4-knockout mice for 16 h, PET discs maintenance by the defense system.204,205 Nevertheless, studies
triggered an altered infiltration of leukocytes, which shifted from concerning the collaborative role of CLRs and TLRs are rare and
equivalently neutrophils and monocytes/macrophages to predo- call for future efforts.
minantly neutrophils, suggesting the critical role of TLR4 in the
primary recognition of biomaterials.171 Nevertheless, no differ- Inflammasomes
ences could be discerned in regard to the thickness of fibrous Inflammasomes refer to a family of cytosolic multiprotein
encapsulation encompassing the PET discs at 14 days, indicating complexes206 and play a critical role in pathogen clearance,
that the impact of TLR4 was confined to the acute phase in adjuvant activity, and overall immunity.207 Upon binding with
response to the implanted biomaterial. In contrast, another study NOD-like receptors (NLRs),206,208 inflammasomes function through
in C57BL6-TLR4-/- mice reported less inflammatory cell infiltration activation of caspase-1, 4, 5, or 11 and cleavage of cytokines,
and angiogenesis around the silicone prosthesis and a 1.96-fold including IL-1β and IL-18, followed by pyroptosis.206 Among the
thicker capsule around the implant in the absence of TLR4 at Day well-understood inflammasomes, NLRP3 is effective in antitumor
14, pointing out the drastic effect of TLR4 in the host response to immunity and vaccination responses induced by DCs.209–211
silicone implants.193 Between the two opposite findings, the However, abnormal inflammasome activation has been associated
preadsorbed fibrinogen might account for the different extent to with numerous autoimmune diseases.212 Therefore, some
which immune reactions are exacerbated, and it coincides with researchers have attempted to tune inflammasome-mediated
and broadens our previous postulation that the adsorbed protein immunomodulation by harnessing the properties of implanted
layer might mediate fibrous encapsulation and the subsequent biomaterials in an attempt to facilitate future applications in
temporal immune response via TLR4.186 By MyD88-deficient DCs, immunotherapies. Li et al. found that NLRP3 played a substantial
Shokouhi et al. clarified that complicated TLR/MyD88- signaling role in mesoporous silica microrod (MSR) scaffold-induced BMDC
(particularly TLR2, TLR4, and TLR6) was involved in DC-biomaterial IL-1β secretion in vitro as well as immune cell trafficking in vivo.213
interactions, leading to the activation and maturation of DCs and Most DCs recruited to scaffolds in NLRP3−/− mice exhibited an
conferring on them the ability to switch on antigen-specific immature phenotype when compared to WT mice.213 Sharp et al.
T cells.31 To further clarify the influence of TLR4/MyD88 signaling demonstrated that uptake of PLG microparticles by DCs drama-
in DC-mediated biomaterial recognition, Uto et al. incubated tically accelerated IL-1β secretion and caspase-1 activation, which
murine BMDCs with biodegradable nanoparticles (NPs) supple- depended on the NLRP3 inflammasome, yet the production of
mented with poly(g-glutamic acid) (g-PGA). Significant enhance- antigen-specific antibodies was not influenced.214 Similarly,
ment regarding costimulatory marker expression (e.g., CD40, another study also observed that the immunogenicity of peptide
CD80, and CD86) and cytokine release (e.g., TNF-α, IL-6, and IL-12) nanofibers was not necessarily accompanied by the production of
was detected, which were probably mediated through phos- IL-1β or caspase-1/11. Their findings confirmed that activation of
phorylated forms of p38, SAPK/JNK, and ERK. Nevertheless, the NLRP3 inflammasome might not be a decisive factor involved
consistent trends were not observed in MyD88−/− or TLR4−/− in T-cell-mediated immune responses against these materials.215
mice.194 Collectively, their work elucidated that biomaterial- To elucidate the underlying mechanism, previous studies
triggered DCs that functioned predominantly via TLR4-MyD88- reported that uptake of microparticles could induce lysosomal
MAPK signaling pathways. damage,214 and DAMPs generated during this process were
recognized by NLRP3.216 Upon activation, NLRP3 forms an
C-type lectin receptors intracellular multiprotein complex that manipulates cytokine
CLRs strongly participate in the immune response and bioma- release (e.g., IL-1β and IL-18), leading to the infiltration of
terial recognition,195 representing a family of receptors, such as inflammatory cells for cleavage of the local particulates.213,216 Li
collectins, selectins, lymphocyte lectins, and proteoglycans.196 et al. also considered that a similar pathway might function in

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 The role of dendritic cells in the immunomodulation to implanted. . .
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11
terms of host immunity toward MSR scaffolds,213 and lysosomal therapy, while dampening immune responses by surface property
perturbation might be a fundamental regulator of NLRP3 modifications will assist in autoimmunity and tissue engineering.
inflammasome activation.216,217 As Saikat et al. indicated, lysoso- One major obstacle here in elucidating the immunogenic effects
mal rupture is an initial step in inflammasome activation, which of material properties lies in its multifactorial features. To cope
then precedes other pathways.217 with this, persistent efforts should be distributed here to
delineate a comprehensive map with regard to material
mTOR-NF-kB mechanism involved in autophagy property-DC performance interactions. Fortunately, the applica-
Autophagy refers to a lysosomal pathway for cellular homeostasis tion of immune-mediated tissue engineering has witnessed
control, which is presently known to be the signal light of immune immense growth in recent decades with the development of
cells, orchestrating their proliferation, cytokine secretion, and high-throughput strategies (e.g., PCA and PLSR). Furthermore,
survival. Reactive oxygen species (ROS) serve as crucial regulators BAMP serve as the key immunogenic cue associated with DC-
of oxidative stress and redox signaling in immune cells,218 the biomaterial interactions. To our knowledge, however, efforts to
inhibition of which is involved in the tolerogenic phenotype and systematically characterize the molecular composition of BAMPs
allo-stimulatory capacity of DCs.101 Nevertheless, the involvement have just set off, and the mechanisms by which DCs recognize
of ROS in the manipulation of DC-mediated immunity remains to and react to biomaterials have not yet been fully elucidated. To
be explicitly examined, considering some opposite findings.219 In extensively identify the adsorbed protein profiles and involved
addition, mammalian target of rapamycin (mTOR) is a decisive posttranslational modifications, including carbohydrates and
mediator of cellular metabolism, NF-κB translocation, phenotypic lipids, sophisticated tools and statistical modeling have been
conversion, antigen presentation, and T-cell activation of introduced, which might provide insights for the development of
DCs.220–222 Autophagy is thus mediated by mTOR inhibition- next generation of biomaterials. In addition, spatiotemporal
induced activation of Atg1/Unc-51-like autophagy activating activation of dendritic cells and their precise modulation
kinase 1 (ULK1) and subsequent posttranslational modifications mechanism can provide insights for future development of novel
of autophagy-related genes (ATGs).223 biomaterials, and such approaches have not been well explored
The role of autophagy in immunogenic function and cytokine in the tissue engineering community. It is postulated that
production upon exposure to biomaterials was explored in multiple receptors might be associated with DC-biomaterial
monocytes and macrophages.224–226 A recent study revealed that interactions collaboratively. Better understanding towards the
DCs in contact with GQD presented upregulated ILT3 as well as underlying mechanisms could pave the way for the rational
PDL1, characteristic coinhibitory molecules of tolDCs, and were design and clinical application of material-based strategies with
capable of potentiating allogeneic CD4+CD25hiFoxP3+ Treg cells. desired immune effects. Notably, the immunologic microenviron-
Autophagic turnover (flux) was enhanced in GQD-treated DCs, as ment is rather complex and rapidly changeable, while the
evidenced by the upregulated transition from microtubule-related majority of the work in this field relying on in vitro studies is
LC3-I to autophagosome-associated LC3-II and the upregulated less convincing. Compounding this, the remarkable advances in
transcriptional profile of ATGs, such as ATF4, FOXO1, and FOXO3. cell biology and biomaterials science and engineering also add to
Most notably, genetic suppression of autophagy via RNA the uncertainty and complexity. Therefore, much work still needs
interference (RNAi) techniques undermined the protolerogenic to be done to unveil the behavior and biofunction of DCs toward
effects of GQD on DCs.101 Consistently, the delivery of the novel implanted biomaterials in vivo.
autophagy inhibitor chloroquine enhanced p62 and LC3-II
expression and reduced IL-12p70 release in human monocyte-
derived DCs in a p38-dependent manner, thereby promoting ACKNOWLEDGEMENTS
Th17-mediated persistent inflammation.227 This study was supported by the Key Research and Development Program of Science
and Technology Department of Zhejiang Province (No. 2019C03081).

CONCLUSIONS AND FUTURE PERSPECTIVES

Novel understanding of immune responses towards implanted AUTHOR CONTRIBUTIONS
biomaterials can excitingly help tackle the challenges of F.H., S.W., and Y.C. conceived of the presented idea. S.W., Y.C., Z.L., and J.L discussed
the review contents. S.W., Y.C., Z.L., and J.L wrote the manuscript, J.H, Q.C. and F.H.
protracted inflammation or immune-mediated rejection, by
edited the manuscript. S.W. and Z.L. designed the figures.
harnessing the specificity of immune cells-biomaterial interac-
tions. During the process, immunocytes are often recruited
consecutively in an organized manner in the context of foreign ADDITIONAL INFORMATION
biomaterials, with DCs playing an orchestrating role. Within the Supplementary information The online version contains supplementary material
last decade, DC-mediated immune responses toward implanted available at https://doi.org/10.1038/s41368-022-00203-2.
biomaterials have been demonstrated to be diverse according to
their physiochemical properties, the comprehensive interpreta- Competing interests: The authors declare no competing interests.
tion of which may benefit future vaccination, cancer therapy, and
the design and manufacture of novel biomedical materials.
However, challenges remain. First, the new paradigm in REFERENCES
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