A review of biomarkers in peri-miniscrew implant crevicular fluid (PMICF)
Kaur et al. Progress in Orthodontics
A review of biomarkers in peri-miniscrew implant crevicular fluid (PMICF)
Avinash Kaur 2
Om P. Kharbanda 0
Priyanka Kapoor 1
Dinesh Kalyanasundaram 2
0 Centre for Dental Education and Research, All India Institute of Medical Sciences , New Delhi , India
1 Department of Orthodontics, Faculty of Dentistry, Jamia Millia Islamia , New Delhi , India
2 Centre for Biomedical Engineering, Indian Institute of Technology Delhi , New Delhi , India
Background: The temporary anchorage devices (TADs) which include miniscrew implants (MSIs) have evolved as useful armamentarium in the management of severe malocclusions and assist in complex tooth movements. Although a multitude of factors is responsible for the primary and secondary stability of miniscrew implants, contemporary research highlights the importance of biological interface of MSI with bone and soft tissue in augmenting the success of implants. The inflammation and remodeling associated with MSI insertion or loading are reflected through biomarkers in periminiscrew implant crevicular fluid (PMICF) which is analogous to the gingival crevicular fluid. Analysis of biomarkers in PMICF provides indicators of inflammation at the implant site, osteoclast differentiation and activation, bone resorption activity and bone turnover. The PMICF for assessment of these biomarkers can be collected non-invasively via paper strips, periopaper or micro capillary pipettes and analysed by enzyme-linked immunosorbent assay (ELISA) or immunoassays. The markers and mediators of inflammation have been previously studied in relation to orthodontic tooth movement include interleukins (IL-1β, IL-2, IL-6 and IL-8), growth factors and other proteins like tumour necrosis factor (TNF-α), receptor activator of nuclear factor kappa-B ligand (RANKL), chondroitin sulphate (CS) and osteoprotegerin (OPG). Studies have indicated that successful and failed MSIs have different concentrations of biomarkers in PMICF. However, there is a lack of comprehensive information on this aspect of MSIs. Therefore, a detailed review was conducted on the subject. Results: A literature search revealed six relevant studies: two on IL-1β; one on IL-2, IL-6 and IL-8; one on TNF-α; one on CS; and one on RANKL/OPG ratio. One study showed an increase in IL-1β levels upon MSI loading, peak in 24 hours (h), followed by a decrease in 21 days to reach baseline in 300 days. A 6.87% decrease in IL-2 levels was seen before loading and a 5.97% increase post-loading. IL-8 showed a 6.31% increase after loading and IL-6 increased by 3. 08% before MSI loading and 15.06% after loading. RANKL/OPG ratio increased in loaded compared to unloaded MSIs. Conclusions: Cytokines (mainly ILs and TNF-α) and RANKL/OPG ratio showed alteration in PMICF levels upon loading of MSIs as direct or indirect anchorage.
Biomarker; Peri-miniscrew implant crevicular fluid (PMICF); Orthodontic tooth movement (OTM); IL-1β; IL-2; IL-6; IL-8; TNF-α; RANKL; OPG
Miniscrew implants (MSIs) also known as temporary
anchorage devices (TADs) are used for enhancing
anchorage and are now a well-accepted armamentarium
in clinical orthodontic practice. The gaining popularity
of MSIs in varied orthodontic settings is due to their
ease of placement and removal, multitude of
applications as direct or indirect anchorage, affordable cost as
well as minimal surgical procedures required in their
placement. The MSIs can have immediate or delayed
loading protocols [
]. The MSIs success reported to
have an average survival rate of 84% (range 57–95.3%)
which is largely dependent on factors governing
primary and secondary stability [
]. The primary stability
pertains to the mechanical holding of MSI in the bone
], while the secondary stability relates to biological
]. Broadly, the factors affecting the stability
can be grouped into a host, miniscrew implant and
technique-related factors (Fig. 1). Contemporary
research has focused on the biological seal between the
implant and host tissue, more so on its surrounding
peri-implant (PI) oral epithelium.
The peri-miniscrew implant crevicular fluid (PMICF),
an inflammatory exudate secreted in the crevice between
MSI and PI tissue, has been investigated to monitor the
levels of biomarkers at multiple observation times upon
MSI insertion as well as loading [
]. The composition of
PMICF is analogous to other body fluids as gingival
crevicular fluid (GCF) and includes inflammatory biomarkers.
These are interleukins (ILs) (IL-1β, IL-2, IL-6, IL-8),
growth factors and other proteins such as tumor necrosis
factor (TNF)-α, receptor activator of nuclear factor
kappaB ligand (RANKL), chondroitin sulphate (CS) and
osteoprotegerin (OPG). The contents of PMICF are
analogous to the ones released in orthodontic tooth movement
(OTM) in the GCF. The biomarkers of peri-implantitis
seen in PMICF are also similar to those released in GCF
during periodontitis and gingivitis [
Information on biomarkers in PMICF and their
association with the success of MSI, though available, remains
scattered. Hence, this review aims to study the
biomarkers in PMICF associated with insertion of MSI,
different loading practices and their impact on the stability
of MSIs in the bone to finally deduce the evidence
mechanism of success and failure related to
inflammatory biomarkers present in PMICF.
Host response to MSI insertion in the bone
An immediate host response to MSI insertion in the
bone begins with a clot formation where cellular
migration occurs comprising of osteoprogenitor cells,
angiogenesis and protein surge including osteopontin, bone
sialoproteins and glycosaminoglycans [
At a microscopic level, a hypothesis of micro-crack
propagation in the bone upon MSI insertion has been
proposed, probably due to elasticity difference between
the bone and MSI structure [
]. A study done on beagle
dogs quantified this damage as a fractional
microcracked area, fractional diffuse damage and the total
fractional injured area in adjacent (0–0.5 mm) and
distant (0.5–1 mm) region. The percentage of damage was
found to vary with the type of implants, self-drilling or
non-drilling and thickness of the bone [
The repair of these micro-cracks is believed to occur
by a micro-callus formation triggered by calcium
phosphate leading to the creation of mineralized bone.
However, in the case of any inflammation or microbial
invasion, if acidification occurs, this process may get
]. Additionally, bone necrosis has also been
suggested due to heat generation at a critical temperature of
47 °C for 1 min on frictional contact of bone with MSI
]. In temperatures above this, the secondary
stability of MSIs gets compromised due to denaturation of
proteins leading to cell death. Understanding the host
factors at PI bony interface is thus imperative to ensure
the secondary stability of implants, for which the
biomarkers released in PMICF play a very significant role.
Understanding MSI-soft tissue interface
Comprehension of the biological seal in the
transmucosal region of MSI soft tissue interface is integral to
understanding the unexplained variables governing the
success of miniscrew implants. The histology of PI tissue
comprises of keratinized stratified squamous oral
epithelium and non-keratinized sulcular epithelium with
cellular arrangement favourable for leakage of neutrophils
from sub-epithelial connective tissue and mediators,
in cases of peri-implantitis or inflammation. Hence,
the integrity of this region is precarious for
shortand long-term success of MSIs which may be
corroborated based on the biochemical milieu of PMICF
that shows a variation in levels of mediators in the
presence of peri-implant inflammation [
Biomarkers in PMICF: markers of MSI success
PMICF is an inflammatory exudate that surrounds the MSI
crevice with a composition similar to the GCF, comprising
of inflammatory biomarkers (such as IL-1β and IL-2,
IL-6, IL-8), growth factors and other proteins (TNF-α,
RANKL, CS and OPG) [
]. During inflammation, the
amount of peri-miniscrew crevicular fluid as well as the
concentration of biomarkers in the fluid increases. Hence,
to understand the underlying biological processes, it is
imperative to analyze the mediators of inflammation at
multiple observation times. The non-invasive collection
methods via paper strips, periopaper or micro-capillary
pipettes are the standard methods of PMICF collection [
A literature search has identified the following mediators of
interest in PMICF:
Cytokines are produced by various types of cells such
as macrophages, B lymphocyte, T lymphocyte, mast
cells, endothelial cells, fibroblast and stromal cells. The
cytokines are significant in the modulation of
inflammation through the process of cell signaling via autocrine,
paracrine and endocrine signaling. They regulate the cell
maturation, growth and responsiveness of specific cell
population and include chemokines, interferons, ILs,
lymphokines and TNFs.
ILs are a group of pro-inflammatory cytokines
produced by fibroblast, osteoclast and polymorphonuclear
leukocytes (PMNLs) and are responsible for bone
turnover and remodeling process [
]. They include several
markers such as IL-1β, IL-2, IL-6 and IL-8, that can be
detected in crevicular fluids of the oral cavity including
GCF and PMICF.
IL-1β is a cytokine which is produced by the IL1B
]. It is a member of the interleukin-1 family of
cytokines and an essential mediator of the inflammatory
response. It plays an important role in various types of
cellular activities, such as differentiation, cell
proliferation and apoptosis, with a potential role in bone
metabolism, bone resorption and inhibition of bone formation.
It works through a synergistic activity with TNFs in
osteoclast differentiation by RANK-RANKL binding on
the osteoblast surface [
IL-1β is produced in a biologically inactive form that
requires protease-mediated cleavage to govern its
proinflammatory functions. Inflammasome complex is formed
during caspase-1-mediated cleavage of IL-1β that is
responsible for secretion of bioactive IL-1β in many
disease models [
]. Its levels have been reported to be
very high in inflamed gingival tissues [
] and also in
the crevicular fluid of diseased implant sites when
compared to healthy implant sites [
A study by Sari et al [
] assessed levels of IL-1β in
PMICF surrounding 20 implants used as direct
anchorage in MSI group and compared it to levels of IL-1β in
GCF of treatment group (maxillary canines). PMICF in
this study was collected at 1 hour(h), 24 h, 48 h, 168 h,
14 days and 21 days after loading. The IL-1β levels were
higher in the treatment group at 24 h (37.8 ± 6.7 pg/μL)
than those in the implant (22.0 ± 2.5 pg/μL) and control
(19.6 ± 2.6 pg/μL) groups. No significant change was
observed between the control and implant groups for all
the above periods [
]. Thus, this study favored the use
of implants for absolute anchorage.
Another study by Monga et al. [
] evaluated levels of
IL-1β in PMICF of MSIs used as an indirect anchorage
in 11 patients with all first premolar extractions. The
MSIs were loaded after a delay of 3 weeks using 200-g
Nitinol closed coil springs of 9-mm length for en masse
retraction. PMICF was collected at nine different time
intervals and the levels were significantly higher at 1 h
after MSI placement (0.27 pg/μL) and 1 day after loading
(0.27 pg/μL) as compared to the baseline (0.13 pg/μL).
However, the levels decreased after 21 days (0.15 pg/μL)
and 72 h after loading (0.14 pg/μL). The decline in the
levels of IL-1β around miniscrew 21 days after loading
towards the baseline is suggestive of an adaptive bone
response to stimulus and consequent cessation of active
1.2 Interleukins 2, 6 and 8
Other proinflammatory cytokines, IL-2, IL-6 and IL-8,
are also proven markers for periodontal (pdl)
inflammation and alveolar bone resorption during OTM [
are thus potential biomarkers for inflammation in MSI
insertion and loading. Of these, IL-2 produced by T
helper 1 cells stimulates macrophages, natural killer cells
and T cell proliferation, which in turn activate cellular
immune response [
]. It also encourages osteoclast
activity during bone resorption and also plays a vital role
in the pathogenesis of the periodontal disease [
on the other hand, is involved in differentiation of CD4
T cells [
] and induction of osteoclastic bone
resorption by mediating osteoclastogenesis . The
presence of IL-6 in human gingival tissues and cells indicates
its involvement in molecular events associated with
inflammatory periodontal diseases [
]. There is ample
evidence of high levels of IL-1β and IL-6 in inflamed
gingival tissues when compared to uninflamed tissues in
young adults, thus potentiating its role in inflammation.
Apart from these, IL-8 is a chemokine produced by
macrophage, epithelial cells and endothelial cells and is
essential in early inflammatory response [
] with a role
in neutrophil recruitment and degranulation during
]. Evidence also supports high IL-8 levels
in periodontitis and at PI inflammation sites [
]. A study
by Tuncer et al. [
] revealed high levels of IL-8 at pdl
tension sites during canine retraction that served as a
triggering factor for bone remodeling.
Hamamci et al. [
] evaluated levels of IL-2, IL-6 and
IL-8 in GCF and PMICF of 16 patients undergoing en
masse retraction of anterior teeth using MSIs as direct
anchorage. Samples were collected from GCF of treatment
teeth (maxillary canines), control teeth (second premolars)
and PMICF surrounding MSIs in implant group. The
sample collection began at 2 weeks after MSI insertion
(baseline) followed by six observation time points. Results
showed levels of IL-2 (74.19 ± 30.36 pg/μL) and IL-8
(83.52 ± 14.34 pg/μL) were higher in implant group than
in control group at 24 h after loading, while IL-6 levels
remained unchanged at all observation time points in all
three groups. These observations suggest that the force
applied to miniscrews during orthodontic loading may
lead to cytokine secretion and cause screw loosening.
1.3 Tumour necrosis factor (TNF-α)
There is a proven role of TNF-α, a pro-inflammatory
cytokine, in regulating and amplifying the inflammatory
response in periodontal and peri-implant tissues [
]. It is
produced by monocytes, macrophages, and osteoblasts and
stimulates fibroblast cells to produce collagenase. Lowney
et al. [
] reported an increase in TNF-α in GCF upon
application of orthodontic force. Another study could not find
a significant increase in levels of TNF-α in GCF/PMICF
after 21 days of de novo plaque accumulation [
Kaya et al. [
] estimated TNF-α levels around MSIs
during canine distalisation by collecting GCF and
PMICF samples of treatment (maxillary canines),
miniscrew (implant) and control (maxillary second premolars)
group. The samples were collected before and after
loading at 1, 24, and 48 h, 7 and 21 days and 3 months. The
difference in TNF-α levels was insignificant in the
implant (32.00 ± 4.50 pg/μL) and control group
(31.91 ± 7.26 pg/μL) 24 h after loading but higher in
treatment group (34.75 ± 6.93 pg/μL), thus favoring
MSIs for absolute anchorage.
2. Other inflammatory markers
2.1 Receptor activator of nuclear factor kappa-B ligand
RANK/RANKL/OPG ratio is known to determine
osteoclast genesis by virtue of the inter-relationships in
their mechanisms of action. Of these, RANKL is a
member of TNF cytokine family [
] and produced in the
plasma membrane of osteoblasts and stromal cells. It is
a ligand of OPG/osteoclastogenesis inhibitory factor
(OCIF) and induces osteoclast differentiation and
stimulates bone resorption activity. OPG, on the other hand,
is a decoy receptor of RANKL produced by osteoblastic
cells, which causes osteoclast apoptosis [
biological impact of OPG on bone cells incorporates
inhibition of terminal phases of osteoclast differentiation,
suppression of activated matrix osteoclasts and
induction of apoptosis. Hence, bone remodeling is regulated
by a balance between RANK-RANKL binding and OPG
] which has also been assessed in PMICF.
A study by Enhos et al. [
] measured levels of RANKL
and OPG in PMICF pre-loading and at 1, 2, 7 and
30 days after loading. A variation in OPG levels among
loaded (72.74 pg/μL) and unloaded (81.06 pg/μL) groups
were observed at 24 h. On the other hand, RANKL level
at 24 h was higher in the loaded group (4631.25 pg/μL)
than in unloaded group (3935.42 pg/μL), thus
indicating more osteoclastic resorption in loaded than in
the unloaded group.
2.2 Chondroitin sulphate
CS is a sulphated glycosaminoglycan with a significant
role in bone and tissue destruction. It is a fundamental
part of connective tissue extracellular matrix including
the hyaline cartilage, contributing to its elasticity and
other functions [
]. The level of CS in human GCF has
been used to study alveolar bone remodeling as a result
of pdl disease and orthodontic tooth movement [
few investigations have observed CS in PI tissue to
access the stability of dental implants and found that the
levels of CS in PICF might be a successful strategy for
monitoring changes in bone metabolic activity [
Intachai et al. [
] evaluated CS during unloaded (1, 3,
5 and 7 days) and loaded (14, 21, 28 and 35 days)
periods from ten patients. During pre-loading, high levels
of CS were found at day 1 (758.03 pg/μL) while post
loading observations depicted higher levels, at 28 days
(1025.11 pg/μL), but these differences were not
statistically significant. Thus, implying orthodontic force on
MSI does not significantly affect CS levels in PMICF.
The current review has attempted to generate evidence
on biomarkers in PMICF in orthodontic patients
(Table 1). We located a total of six studies on
biomarkers present in PMICF. These included two on
IL1β, one on IL-2, IL-6 and IL-8, one on TNF-α, one on
CS and one on RANKL/OPG ratio [
5, 17, 27, 28, 34, 40
The maximum duration of the study conducted for
IL1β was 300 days; IL-2, IL-6, IL-8 and TNF-α were 90 days;
RANKL and OPG was 30 days; and CS was 35 days. The
PMICF samples in all studies were collected using paper
strips except that for IL-1β which was collected using
micro-capillary pipettes . Oral hygiene of patients was
maintained in all the studies. Chlorhexidine gluconate
(0.2%) was used as a mouthwash to reduce inflammation
for the patients under orthodontic treatment only by
Monga et al [
Direct loading was used in all studies [
17, 27, 28, 34,
] except in a study assessing IL-1β levels which used
indirect loading [
]. Levels of IL-2, IL-6 and IL-8, TNF-α,
RANKL and OPG were analysed by applying a force of
150 g [
27, 28, 34
], while 50 g of force was applied to
study the levels of CS [
]. IL-1β levels were evaluated
by application of different force levels with 200g force
used in a study by Monga et al. [
] and 120 g force
applied in study by Sari et al [
The most widely considered biomarkers in PMICF are
cytokines comprising IL-1β, IL-2, IL-6 and IL-8 and
TNF-α, which is similar to biomarkers studied in GCF
during OTM [
]. In the present review, a rise in IL-1β
levels is seen immediately at MSI placement and 24 h
after loading of MSIs, initially due to the trauma of
insertion and later upon application of orthodontic forces
]. A similar trend in levels of IL-1β at 24 h after
activation of the orthodontic appliance has also been noticed
in GCF of treatment teeth in multiple studies [
peak in GCF can be explained by the release of IL-1β in
the paracrine area within 1–2 h of the mechanical
stimulus, further triggering the release of histamine from
mast cells, and increased vascular permeability, finally
leading to a peak in IL-1β levels between 24 and 48 h
]. De novo synthesis of IL-1β along with IL-6 mRNA
on application of forces for OTM has also been
documented by Alhashimi et al. in the maxillary first molars
of 12 rats where the maximum expression was seen in
3 days [
].This further strengthens the role of
proinflammatory cytokines in remodeling of bone consequent
to orthodontic force application.
Monga et al. [
] reported IL-1β levels peak in PMICF
at 24 h on miniscrew insertion and 24 h after loading.
The levels then gradually decrease at 21 days to reach
baseline in 300 days. This may be due to inherent
feedback mechanisms by the synergistic or antagonistic
action of various cytokines leading to fall in levels and
cessation of inflammation and restoration of pdl
Another study by Sari et al. [
] however showed no
significant increase in IL-1β in PMICF upon loading
when compared to levels in GCF of control teeth. The
IL-1β levels were 92.8% higher in GCF of treatment
teeth when compared to levels in PMICF of implant
group as well as GCF of control teeth. Similar results
have also been observed in levels of TNF-α where a
significant increase was seen only in GCF of treatment teeth
(maxillary canines) at 24 h when compared to control
and implant groups. This implies insignificant bony
resorption around MSIs when used as a direct anchorage,
and hence, it supports TADs as absolute anchorage
The percentage change in levels of ILs broadly showed
an increase upon loading of MSIs. IL-2 in PMICF depicted
6.87% decrease in levels before MSI loading and 5.97%
increase after loading. While IL-8 was 6.31% higher after
loading, IL-6 was 3.08% more before MSI loading and
15.06% after loading. Nevertheless, the percentage
difference was not comparable enough (IL-2, IL-6, IL-8 and
IL-1β); hence, more studies need to be performed to
measure the levels of IL-2, IL-6, IL-8 and IL-1β.
Studies on other cytokines receptors, RANKL and its
decoy receptor OPG revealed that in PMICF of loaded
implant group, the concentration of RANKL was higher
than in the unloaded group while OPG/RANKL ratio
was significantly reduced. This finds support in
animal and in vitro studies on pdl cells where RANKL
upregulation have been documented in compressive
orthodontic force while OPG has been shown to
inhibit RANK/RANKL interaction and thus inhibit bone
Chondroitin sulphate is another biomarker that has
been investigated in bone remodeling consequent to
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OTM, pdl disease and in implant stability [
Interestingly, the results of a single study evaluating CS in
PMICF have shown increased levels of CS 14 days before
failure of two MSIs out of 20 MSIs placed in the subjects
.This indicates higher bone resorption associated
with a rise in levels of CS (WF6 isotope) and hence MSI
mobility and failure.
Scope of future research
There is a scope of future research at a biochemical level
to evaluate all mediators associated with inflammation
and bone resorption. Extracellular high mobility box
protein (HMGB1) would be interesting to study for its
role in the production of cytokines IL-1β, IL-6, IL-17
and RANKL. Other potent mediators would be matrix
metalloproteinases (MMPs) that are zinc-dependent
endopeptidases released consequent to extracellular matrix
degradation and tissue remodeling. Few MMPs, namely,
MMP1, 2, 3, 7, 8, 9, 12 and 13 and MMP9/NGAL, have
been studied in OTM and may prove to be potential
biomarkers for remodelling associated with MSI stability as
Besides these, circulating nucleic acids, T cells,
hematopoietic cells, pentraxin-3 and macrophage
colony-stimulating factor (M-CSF) play a role in
osteoclast differentiation. These are few of the mediators to
be explored as prognostic indicators for implant stability.
The biofilm around MSIs can also contribute to
inflammation and presence of inflammatory biomarkers in
PMICF. The concentration of these biomarkers in
PMICF, besides being influenced by MSI insertion and
loading, can also vary in pdl inflammation or
inflammation in soft tissue. These factors should be considered in
This review provides substantiation of bone and tissue
remodeling process around MSIs with or without loading.
The following conclusions are drawn:
Alteration in levels of IL-1β, IL-2, IL-6 and IL-8,
TNF-α, and CS, as well as RANKL/OPG ratio was
seen in PMICF on placement as well as on loading
IL-1β increased in PMICF upon MSI loading, reaching
a peak in 24 h, then decreased in 21 days.
Percentage change in levels of ILs in PMICF depicted
a 6.87% decrease in IL-2 levels before loading and a
5.97% increase post-loading. IL-8 showed a 6.31%
increase after loading, and IL-6 increased by 3.08%
before MSI loading and 15.06% after loading.
TNF-α and CS did not show a significant variation
in placement and loading of MSIs.
RANKL/OPG ratio was higher in loaded MSIs than unloaded.
Further studies need to be conducted with robust
study design to resolve heterogeneity in the current
literature. In future studies, besides evaluating other
biomarkers, the sample size too needs to be increased with
age and sex consideration. Also, adequate observation
intervals pre- and post-loading may prove to be more
specific in understanding the biological factors of
CS: Chondroitin sulphate; ELISA: Enzyme-linked immunosorbent assay;
GCF: Gingival crevicular fluid; HMGB1: High mobility box protein; IL-1β:
Interleukin1β; IL-2: Interleukin-2; IL-6: Interleukin-6; IL-8: Interleukin-8; M-CSF: Macrophage
colony-stimulating factor; MMPs: Matrix metalloproteinases; MSIs: Miniscrew
implants; OPG: Osteoprotegerin; OTM: Orthodontic tooth movement;
pdl: Periodontal; PI: Peri-implant; PMICF: Peri-miniscrew implant crevicular
fluid; PMNLs: Polymorphonuclear leukocytes; RANKL: Receptor activator of
nuclear factor kappa-B ligand; TADs: Temporary anchorage devices;
TNF-α: Tumour necrosis factor alpha
This is a self-funded study.
OPK is responsible for conceptualizing the idea, formulation of the search
strategy, quality assessment and dissemination of results by writing and
rechecking the manuscript. AK has done data extraction and tabulation,
compiling of the data and writing the draft. PK rechecked each step,
formulated the preparation of the manuscript and also gave valuable inputs.
DK helped in tabulating, compiling of the data and drafting of the
manuscript. The final manuscript has been seen and approved by all the
authors and that they have taken due care to ensure the integrity of the
Ethics approval and consent to participate
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