Clinical Oral Investigations

https://doi.org/10.1007/s00784-020-03240-5

REVIEW

Efficacy of growth factors for the treatment of peri-implant diseases:

a systematic review and meta-analysis
Ismael Khouly 1,2 & Simon Pardiñas-López 1,3,4 & Ryan Richard Ruff 5,6 & Franz-Josef Strauss 7,8,9

Received: 20 September 2019 / Accepted: 11 February 2020

# Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract
Objectives The aim of this study was to conduct a systematic review and meta-analysis on the efficacy of growth factors (GF) on
clinical outcomes after treatment (surgical/non-surgical) of peri-implant diseases (peri-implant mucositis and peri-implantitis).
Materials and methods A protocol was developed to answer the following focused question: Is there any difference for the use of GF
for treatment of peri-implant diseases versus comparative GF treatment or without GF? Electronic database and manual searches were
independently conducted to identify randomized controlled trials (RCTs). Publications were selected based on eligibility criteria and
then assessed for risk-of-bias using the Cochrane Handbook. The primary outcome was probing depth (PD) and bleeding on probing
(BOP) reduction along with changes in vertical defect depth (VDD). Changes in clinical attachment level, gingival recession, and
plaque index, among others, were studied as secondary outcomes. Based on primary outcomes, random-effects meta-analysis was
conducted.
Results A total of five RCTs were included. GF enhance the reduction of PD (standardized mean difference (SMD) = − 1.28;
95% confidence interval (CI) − 1.75, − 0.79; p = < 0.0001) and BOP (SMD = − 1.23; 95% CI − 1.70, − 0.76; p = < 0.0001) in the
management of peri-implant mucositis. For the treatment of peri-implantitis, the use of GF yielded to significantly greater
improvement in VDD (SMD = 0.68; 95% CI 0.22, 1.14; p = 0.004); however, there were no significant differences in terms of
PD (SMD = 0.08; 95% CI − 1.08, 1.26; p = 0.887) and BOP (SMD = 0.211; 95% CI − 0.20, 0.63; p = 0.317). The overall risk of
bias of the included studies was low to unclear.
Conclusion The results of the present systematic review suggest that the addition of GF might enhance the outcomes in the treatment
of peri-implant mucositis. However, there is a lack of evidence for supporting additional benefit of GF managing peri-implantitis.
Clinical relevance Within the limitations of the current systematic review and based on the meta-analyses, (1) the addition of GF
for the treatment peri-implant mucositis might be associated with better outcomes in terms of PD and BOP, and (2) an additional
benefit of GF for the treatment peri-implantitis could not be determined on the basis of the selected evidence.

Keywords Growth factors . Peri-implant diseases . Peri-implantitis . Peri-implant mucositis

Background surrounding dental implants. They are categorized into 2

Long-term success using dental implants is the ultimate goal
in implant dentistry; however, biological complications may
occur, and peri-implant diseases are among the most frequent
and challenging ones [1–3]. Peri-implant diseases are plaque-
associated pathological conditions that affect the tissues
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00784-020-03240-5) contains supplementary
material, which is available to authorized users.
* Ismael Khouly
dr.ismaelkhouly@gmail.com
Extended author information available on the last page of the article
types, peri-implant mucositis and peri-implantitis. Peri-
implant mucositis is assumed to precede peri-implantitis, and
it shows clinical signs of bleeding on probing and inflamma-
tion, whereas peri-implantitis is characterized by inflamma-
tion in the peri-implant mucosa and subsequent progressive
loss of supporting bone, which could finally lead to implant
failure [4]. The increasing placement of dental implants has
led to an inevitable increase in the prevalence of peri-implant
diseases. In a recent large-scale cross-sectional study, 32% of
subjects had peri-implant mucositis and 45% had peri-
implantitis [1]. This is of particular importance since the most
reliable and predictable treatment of peri-implant diseases has
not yet been described. As a consequence, their management
is challenging, particularly for peri-implantitis.

Both non-surgical and surgical treatments and regenerative
procedures have been used to control peri-implant diseases,
however, with inconsistent results [2]. While non-surgical
therapy has been performed for the treatment of both peri-
implant mucositis and peri-implantitis, surgical therapy is of-
ten used to treat peri-implantitis. Non-surgical therapy is con-
sidered less effective than surgical approaches in peri-
implantitis [5]; nevertheless, the mechanism by which one
therapy outperforms the other has not yet been established.
Hence, there is a clear demand to refine current treatment
protocols to arrest and prevent the progression of these le-
sions. In this sense, the main goal in the treatment of peri-
implant diseases is the decontamination of the implant surface
and resolution of the inflammatory process thereby arresting
the progression of loss of supporting bone [6]. However, a
decrease in bacterial load to a level that allows healing to
occur is rather difficult using only mechanical methods since
the results also depend on the access and the biofilm removal
[7]. As a result, adjunctive treatments including growth factors
have been suggested to improve clinical outcomes [8–14]
(Fig. 1).
Fig. 1 Drawing illustrating, step by step, the development and treatment
of peri-implantitis. a: healthy implant with intact peri-implant tissues; b:
peri-implantitis showing tissue inflammation, bone loss around the
implant and bacterial accumulation in the implant surface; c: bacteria
accumulation on the implant surface; d: close-up view of the processes
that occur due to peri-implantitis, including presence of bacteria, soft
Clin Oral Invest
Growth factors used in regenerative dentistry to enhance
clinical outcomes include enamel matrix derivative (EMD)
and platelet derivative factors such as platelet-rich fibrin
(PRF) and plasma rich in growth factors (PRGF), among
others [15, 16]. They contain and stimulate a variety of bioac-
tive molecules such as vascular endothelial growth factor
(VEGF), platelet-derived growth factor (PDGF), transforming
growth factor beta (TGF-β), and bone morphogenic protein
(BMP). The delivery of these growth factors is intended to
transiently stimulate cells locally, promoting proliferation
and differentiation and, consequently, regeneration [16–18].
For example, growth factors have been widely used to treat
periodontal intrabony and suprabony defects and to promote
bone regeneration and bone augmentation [19–27]. Moreover,
some studies indicate that these growth factors have antibac-
terial properties [28, 29], which may provide an additional
benefit due to the bacterial origin of peri-implant diseases.
Furthermore, the use of growth factors may improve
implant-related outcomes such as implant stability and alveo-
lar ridge preservation [30]. However, the additional effect of
tissue inflammation, bleeding and osteclastic activity that leads to bone
loss; e: mechanical decontamination of the implant surface; f: treatment of
peri-implantitis; g: healing of the peri-implant tissues after treatment; h:
close-up view of the processes that occur during healing of the peri-
implant tissues
Clin Oral Invest
using growth factors in the treatment of peri-implant diseases
still remains unclear.
Therefore, the aim of this study is to conduct a systematic
review and meta-analysis of randomized controlled trials on
the efficacy of growth factors for the treatment of peri-implant
diseases.
Materials and methods
Standardized criteria and type of study
This systematic review study was developed and de-
signed according to the established criteria by the
Cochrane collaboration [31] as well as the Preferred
Reporting Items for Systematic Review and Meta-
Analysis (PRISMA) criteria [32].
Registry protocol
A review protocol was registered by the International pro-
spective register of systematic reviews (PROSPERO) data
base under the number CRD42018116547 (available at:
https://www.crd.york.ac.uk/PROSPERO/display_record.
php?RecordID=116547).
Criteria for considering studies for this review
The study question included the following PICO-T criteria:
Population (P), Intervention (I), Comparison (C), Outcome
(O), and Time (T).
The PICO-T criteria were the following:
& Population: adult human subject, undergoing treatment for
peri-implant diseases
& Intervention: growth factors in combination with surgical/
non-surgical treatment
& Comparison: comparative growth factor treatment OR no
growth factor
& Outcomes: inflammation resolution in terms of re-
duction of bleeding on probing, probing depth, and
bone level (primary outcomes), and related parame-
ters (e.g. gingival recession, plaque index, complica-
tions, etc.) (secondary outcomes)
& Time: at least 3 months after treatment
The PICO question
Is there any difference for the use of growth factors for
surgical or non-surgical treatment of peri-implant dis-
eases, in terms of changes on bleeding on probing,
pocket depth and bone level, evaluated before and after
treatment, versus comparative growth factor treatment or
no growth factors, in human subjects?
Eligibility criteria
Inclusion criteria
Requirements for inclusion in this study meet the following
criteria:
1. Randomized controlled trials (RCT)
2. Human adult subjects (≥ 18 years) undergoing treatments
for peri-implant diseases using growth factors in at least
one study group
3. Presence of comparative growth factors treatment group
or no growth factors control
4. Clearly defined clinical and radiological parameters ac-
cording to which peri-implant disease (peri-implant mu-
cositis and peri-implantitis) diagnosis is made
5. Specification of probing depth, bleeding on probing, and/
or marginal bone levels at least 3 months after treatment
Exclusion criteria
Requirement for exclusion in this study meet the following
criteria:
1. Prospective cohort studies, non-randomized controlled
clinical trials, retrospective cohort studies, case-control
studies, case reports, systematic reviews, animal trials,
letter to editors, in vivo and in vitro studies
2. Less than 10 subjects per group
Type of outcome measures
Primary outcomes
The primary outcomes were probing depth (PD) reduction (in
mm), bleeding on probing (BOP) reduction (in per cent), and
changes in vertical defect depth (VDD) (in mm).
Secondary outcomes
Secondary outcomes included the following:
& Changes in clinical attachment levels (in mm)
& Change in gingival recession (in mm)
& Changes in plaque index
& Changes in gingival index
& Changes in keratinized tissue

& Post-operative infection
& Complications (e.g., wound dehiscence)
& Patient reported outcome measures (e.g., pain, patient sat-
isfaction and/or quality of life)
& Implant failures
& Prosthetic failure
& Adverse events related to the use of growth factors
Search methods for identification of studies
Electronics searches
The literature search strategy was performed in the PubMed,
CINAHL, Embase, and Dentistry & and Oral Sciences Source
(DOSS) electronic databases. Electronic databases including
articles published up to December 15th, 2019.
Concepts and subject headings were combined for each of
the database searches as detailed in Appendix I, with the help
of a medical and dental librarian (RM). The search was not
limited by any restrictions on language or date of publication
but limited to “clinical trials.” Primary and secondary con-
cepts were developed and searched for all databases.
Searching other resources
Hand searching
The electronic search was complemented by manual searches
of reference lists of selected articles and related review arti-
cles. In addition, hand searching of key related journals from
January 2000 up to December 15th, 2019 were performed:
Clinical Implant Dentistry and Related Research, Clinical
Oral Implant Research, Journal of Clinical Periodontology,
Journal of Dental Research, Journal of Periodontal Research,
Journal of Periodontology.
Unpublished studies
Online databases providing information about clinical trials in
progress were checked (clinicaltrials.gov, centerwatch.com/
clinicaltrials, clinicalconnection.com). We also searched for
unpublished studies in OpenGrey open access database.
Data collection and analysis
Selection of studies
Eligibility assessment was achieved through title and abstract
search followed by full-text review. Titles and abstracts for
studies, found through the electronic database search as well
as hand search and unpublished databases, were reviewed
Clin Oral Invest
independently by two reviewers (SPL, IK) for inclusion
conforming to the eligibility criteria.
After initial review, the full texts were read in detail also by
two reviewers, to determine if articles were in accordance with
all inclusion criteria. If the title and abstract did not provide
sufficient information regarding the inclusion criteria, then the
full-text papers were also reviewed. The exclusion criteria
justification of the excluded studies was documented. Any
disagreement was resolved by discussion and consensus and
moderated by a third party (FJS).
Data extraction and management
Data were extracted by one review author (SPL) using a data
form that was specifically designed for the present meta-
analysis and modified for a second review process as required
for presentation of additional general characteristics and pri-
mary and secondary outcomes. All data and data forms were
reviewed by a second review author (IK). Consensus meetings
for the selection of each paper, data collection and examina-
tion of the data entry were hold until completion of this re-
view. The reviewers worked together to consolidate the data
analysis of this review. Appendix II delineates the study char-
acteristics recorded in the data extraction form. Corresponding
authors of the included studies were contacted via email for
clarification of any missing information and/or clarification of
methodology and results.
Assessment of risks of bias in included studies
The methodological quality of all included randomized clini-
cal trials was assessed independently by two reviewers (SPL,
IK) according to the Cochrane Handbook for Systematic
Reviews of Interventions, Chapter 8 [31]. Corresponding au-
thors of the included studies were contacted via email for
detailed information on study methodology, when key do-
mains were assessed as unclear risk of bias by the two re-
viewers. Any disagreement between the reviewers was re-
solved after discussion and consensus.
Statistical analysis
For each included study, extracted data were entered into a
spreadsheet and the standardized mean differences (SMD) and
errors were calculated (Hedge’s g for bias-corrected SMDs).
Means and standard deviations for studies reporting medians,
minimums, and maximums and those reporting medians and
interquartile ranges were computed using the method of Wan
et al. [33] and Hozo et al. [34].
Estimates for PD and BOP were calculated by pooling
study-specific estimates using random-effects meta-analyses
to account for between-study heterogeneity. Analysis used the
inverse variance method and tau2 estimates for the variance of
Table 1 Detailed data of included studies

Study characteristics Treatment group characteristics

Clin Oral Invest

Author and COI/Source Study Location (country, Study Number patients/ Mean age ± Sex Disease definition History periodontal disease,
year of Funding Period number, groups number implants SD F/M smoking, diabetes etc.
type of center) and/or range excluded?

Peri-implantitis
Independent variable: surgical treatment
Autogenous Growth Factors (AGF)
Isler et al. 2018 COI: None 2015 to Department of 2 Groups 52/52 (60/60 at onset) NR 25F/27M Peri-implantitis: PD ≥5 mm Excluded history of systemic ATB
Funding: NR 2017 Periodontology, (1) BS + CGF 26/26 57.96 ± 9.07 10F/16M combined with BoP, during past 3 months,
Gazi University, Ankara, p = 0.646 and/or placement and prosthetic
Turkey (2) BS + CM 26/26 56.15 ± 9.23 15F/11M SoP, ≥2 mm peri-implant loading less than 1 year,
p = 0.646 marginal bone loss serious systemic diseases that
contraindicates surgery
Hamzacebi COI: None; Funding: NR Department of Oral and 2 Groups 19/38 60.98 ± 11.90 8F/11M Peri-implantitis: PD ≥5 mm Excluded history of allergy to
et al. 2015 Baskent University Maxillofacial Surgery (1) OFD 19/19 NR combined with BOP, metronidazole, general
Research Fund, and (2) OFD + PRF 19/19 NR and/or contraindications for
Ankara, Turkey Periodontology, Baskent SOP, ≥2 mm periodontal flap
University, Ankara, peri-implant surgery
Turkey marginal bone loss
EMD vs no EMD
Isehed COI: None; for Drs. Isehed, NR Gävle County Hospital, 2 Groups 25/25 (29/29 NR NR Peri-implantitis: PD ≥ 5 mm Excluded uncontrolled
et al. 2016 Holmlund, Johansson, Sweden at onset) combined with BOP, diabetes, intake
Svenson and Lundberg; (1) EMD 12/12 (15/15 at onset) 70(61–81) and/or of ATB or anti-inflammatory
Dr. Renvert reported grant p = 0.112 SOP in at least 1 implant medication during
from the (2) No EMD 13/ 13 (14/14 at 73.5 (67–83) with ≥3 mm angular the past 3 months
ITI Foundation, onset) p = 0.112 peri-implant bone loss or using drugs with gingival
Switzerland, during the measured on x-ray hyperplasia side effect
conduct of the study
Funding: self-funded by
the authors and their
institution
Peri-implant mucositis
Independent variable: non-surgical treatment
EMD vs no EMD
Kashefimehr COI: None; Funding: 2013 Tabriz University of Medical 2 Groups 41/41 (46/46 at onset) NR 20F/21M Peri-implant mucositis: Excluded uncontrolled systemic
et al. 2017 supported by the Sciences, Faculty of (1) EMD 20/20 49.95 ± 2.92 BOP, diseases, need for ATB
Dental and Periodontal Dentistry, Iran (2) No EMD 21/21 45.61 ± 2.93 PD ≥4 mm, no recession prophylaxis, if PD ≥6 mm
Research Center, Tabriz of soft tissue, bone at baseline, use of
University of Medical loss ≤ 2 mm systemic ATB during the past
Sciences, Tabriz, Iran 3 months, if they had any
intervention for PIT during the
past 3 months
Faramarzi COI: None; Funding: NR 2013–2014 Tabriz University of Medical 3 Groups 64 /64 (69/69 at NR 31F/33M Peri-implant mucositis and Excluded use of systemic ATB or
et al. 2015 Sciences, Faculty of onset) /or mild regular intake of
Dentistry, Iran (1) EMD 20/20 (23/23 at onset) 49.9 ± 2.9 peri-implantitis defined anti-inflammatories
(2) No EMD 21/21 (23/21 at onset) 45.6 ± 2.9 as BOP without soft in the past 3 months,
(3) MSM 23/23 48.4 ± 2.9 tissue any peri-implant
recession with or without treatment in the past
minimal rx bone loss 3 months, poor
(≤ 2 mm), PD ≥ 4 mm in oral hygiene, smoking, pregnancy
Table 1 (continued)
at least one site of the
implant.
and lactation, severe periodontal
disease, uncontrolled diabetes or
systemic disease, allergy to
tetracycline class drugs. History
of periodontal disease 31 patients

Study Surgical or non-surgical

characteristics protocols/additional treatment

Author and Surgical or non- Implant surface Pretreatment Maintenance Who carried One or Use of Implant Brand Implant
year surgical protocol decontamination out procedures two bone (surfaces, type of Loading Time
stage graft and platform)
implants? type

Peri-implantitis
Independent variable: surgical treatment
Autogenous Growth Factors (AGF)
Isler et al. 2018 Surgical: open flap mechanical Saline soaked Non-surgical OHI Radiographic NR ABBM Zimmer (TSV. NR
debridement cotton gauze pretherapy: Amoxicillin 500 evaluation: Resorbable blast
using ultrasonic mechanical mg + metronidazole 1 examiner with media and blasted
cleaner with debridement in 500 mg TID no access to info with HA)
special tip and teeth 7 days +0.12% about procedures Straumman (SLA
titanium curettes and implants chlorhexidine twice Clinical and SLActive)
a day 2 weeks measurements: Astra Tech (TiO2
Flurbinofren 100 mg examiners with blas + fluoride
3 days. 90% coefficients hydrofluoric acid surface)
At 3, 6, and agreement Dentsply (Xive
9 months Surgery: 1 S plus, Friadent
supragingival periodontist plus surface)
mechanical Nobel Biocare
debridement (Replace Select,
TiUnite)
Adin (Alumina Oxide
Blasted/Acid-Etched
surface)
MIS (Sandblasted/
acid-etched surface)
Hamzacebi Surgical: open flap mechanical 4% pH 1 citric acid Phase I full mouth OHI NR NR No Astra Tech (OsseoSpeed, NR
et al. 2015 debridement with titanium 3 min + sterile periodontal Metronidazole tapered screw,
brushes saline or treatment 500 mg TID fluoride-modified surface)
tetracycline 7 days + 0.12% chlorhexidine Biohorizons (tapered
hydrochloride twice a day internal, cylindric screw,
1 g in 20 mL 1 week resorbable blast-textured
sterile surface)
saline + sterile Straumann (standard,
saline cylindric screw,
sandblasted
and acid-etched SLactive
surface)
EMD vs no EMD
Isehed Surgical: open flap mechanical Sodium chloride Initial hygiene and Rinse twice daily for Specialist in NR No Nobel Biocare turned (1 NR
et al. 2016 debridement solution non-surgical 6 weeks with 10 ml Periodontology EMD,
using ultrasonic treatment chlorhexidine 2 mg/ml, all surgeries. 1 No EMD), Nobel
Clin Oral Invest
Table 1 (continued)
cleaner with special tip (9 mg/ml. 2 x 20 and not chew on Dental hygienist or Biocare TiUnite
and titanium curettes ml) the treated area patient’s (5 No EMD),
for 2 weeks own dentist Astra (8 EMD,
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Supportive care measures 5 No EMD),

at 6 weeks and every at 3–5 years Straumann SLA
third month until follow-up (5 EMD, 3 No
12 months EMD), Biomet 3i (1 EMD)
Peri-implant mucositis
Independent variable: non-surgical treatment
EMD vs no EMD
Kashefimehr Non-surgical: subgingival 24% EDTA for NR 0.12% chlorhexidine Calibrated examiner SLA NR
et al. 2017 debridement 2 min, rinsed with mouthrinse prior to blinded did the 3 one stage/ No 23.69 ± 2.14
with ultrasonic saline treatment, followed by clinical 17 two months
device with plastic tip 2 weeks. Enrolled measurements. stage
and glycine-based powder in a maintenance Another clinician 4 one stage/ No 26.49 ± 2.05
air polishing program every did the 17 two months
3 months treatment stage
procedures
Faramarzi Non-surgical: subgingival None Patient’s instructed to Avoid brushing NR Dentis, daegu, Korea. NR
et al. 2015 debridement use an effective and flossing on the 3 one stage/ No (resorbable
with ultrasonic home care treated areas for 17 two blasted media
scaler instruments and program for oral 7 days. After 1 week stage surface treatment)
glycine-based powder air hygiene brushing the areas 4 one stage/ No
polishing with a toothbrush 17 two
soaked in 0.12% stage
chlorhexidine twice 8 one stage/ No
a day 15 two
stage

ABBM, anorganic bovine bone matrix; ATB, antibiotics; BOP, bleeding on probing; BS, bone substitute; CM, collagen membrane; CGF, concentrated growth factor; COI conflict of interest; EDTA,
Ethylenediaminetetraacetic acid; EMD, enamel matrix derivative; GBR, guided bone regeneration; MSM, sustained-release micro-spherical minocycline; NR, no reported; OFD, open flap debridement;
OHI, oral hygiene instruction; PRF, platelet-rich fibrin; PD, probing depth; SLA, sandblasted and acid-etched; SOP, suppuration on probing; TID, three times a day
Table 2 Detailed primary outcome data of included studies

Study Treatment group characteristics Outcomes Outcomes Evaluation Period Primary Outcomes
characteristics measured & (m)
post-op eval/follow- VDD (vertical defect depth) Bleeding on
up probing (in per
cent)

Author and Study Patients (n)/implant Baseline/ Post-treatment (mm) Change within Intergroup Baseline/ Post-
year groups (n) group (mm) difference treatment (%)
(SS or not SS)
(p value)

Peri-implantitis
Independent variable: surgical
AGF vs No AGF
Isler et al. 2018 2 Groups 52 / 52 (60/60 at onset) PI, BOP, PD, MR, 12 Mean ± SD Median (min-max) NR B: No SS Mean ± SD
(1) BS+CGF 26 / 26 CAL, GI, at 4 B: 4.15 ± 1.44 B: 4.20 (1.90-7.15) (p=0.081) B: 97.12 ± 10.79
sites/implant, VDD 12m: 2.51 ± 12m: 2.14 (0.5-5.5) 12m: SS (p= 6m: 20.19 ± 23.47
Measurements at 1.45 0.015) 12m: 35.58 ± 30.14
(2) BS+CM 26 / 26 baseline, 6 and 12 B: 3.66 ± 1.02 B: 3.38 (1.95-6.32) B: 97.12 ± 8.15
months 12m: 1.67 ± 12m: 1.03 (0.42-3.11) 6m: 17.31 ± 16.98
0.76 12m: 29.81 ± 30.02
PRF vs no PRF
Hamzacebi et al. 2015 2 Groups 19 / 38 PD, CAL, KM, MR, 6 NR NR NR Mean ± SD
(1) OFD 19 / 19 PL, and BOP at four B: 65.47 ± 36.08
sites at each 3m: 23.76 ± 16.91
implant. 6m: 21.43 ± 16.57
(2) OFD+ 19 / 19 Measurements at B: 79.31 ± 31.7
PRF baseline,3 and 6 3m: 29.30 ± 22.11
months 6m: 25.29 ± 14.51
EMD vs no EMD
Isehed et al. 2016 2 Groups 25 / 25 (29/29 at onset) BOP, SOP and PI were 12 Median (min-max) Median (25-75 12m: No SS % of implants with
recorded at 4 percentile) (p=0.295) BOP
sites/implant Mean ± SD
(1) EMD 12 / 12 (15/15 at onset) Bone level was B: 5.6 (3.4-10.5) Between B and 12m: B: 93.3
analyzed 12m: 4.5 (3.3-7.9) 0.9 (0-1.3) 12m: 66.7
radiographically 0.7 ± 1.08
(2) No EMD 13/ 13 (14/14 at onset) Measurements B: 4.2 (2.5-9.2) Between B and 12m: B: 85.7
baseline, 3, 6 and 12 12m: 3.5 (1.8-7.5) -0.1 (-0.7-1.2) 12m: 69.2
months 0.24 ± 1.12
Peri-implant mucositis
Independent variable: non –surgical
EMD vs no EMD
Kashefimehr et al. 2 Groups 41/41 (46/46 at onset) PD, BOP, SOP at 6 3 NR NR NR Median
2017 sites per implant, (interquartile
POP, PI. range)
(1) EMD 20/20 Bone level was B: 75 (75-100)
analyzed 3m: 25 ± NR (0-50)
(2) No EMD 21/21 radiographically
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Table 2 (continued)
Peri-implant crevicular B: 75 ± NR
fluid collected. (75-100)
Measurements at 3m: 75 ± NR
Clin Oral Invest

baseline and 3 (50-100)

months
Faramarzi et al. 2015 3 Groups 64 / 64 (69/69 at onset) P.Gingivalis counts. 3 NR NR NR Median
PD, BOP, at (interquartile
baseline, 2 weeks range)
and 3 months
(1) EMD 20/ 20 (23/23 at onset) B: 75 (75-100)
2w: 75 (50-93.7)
3m: 25 (0-50)
(2) No EMD 21/ 21 (23/23 at onset)
B: 75 (75-100)
2w: 75 (50-100)
3m: 75 (50-100)
(3) MSM 23/23 (23/23 at onset)
B: 75 (75-100)
2w: 0 (0-25)
3m: 0 (0-25)

Study characteristics Primary Outcomes Conclusions

Bleeding on probing (in per cent) Probing Depth (in mm)

Author and Baseline/ Post- Change within Intergroup difference Baseline/ Posttreatment (mm) Change within Intergroup difference
year treatment (%) group (%) (SS or not SS) (p value) group (mm) (SS or not SS) (p value)

Peri-implantitis
Independent variable: surgical
AGF vs No AGF
Isler et al. 2018 Median NR B: No SS (p=0.681) Mean ± SD Median (min-max) NR B: No SS (p=0.072) Both regenerative
(min-max) 6m: No SS (p=0.866) 6m: No SS (p=0.186) procedures
B: 100 (50-100) 12m: No SS (p=0.503) B: 5.92 ± 1.26 B: 5.88 (3.75-8.75) 12m: SS (p=0.001) comparable
6m: 12.5 (0-75) 6m: 2.94 ± 0.82 6m: 2.75 (1.25-4.75) results at 6
12m: 25 (0-100) 12m: 3.71 ± 1.09 12m: 3.5 (2-6) months follow
up
B: 100 (75-100) B: 5.41 ± 1.16 B: 5.25 (3.75-8.25) CM group showed
6m: 25 (0-50) 6m: 2.60 ± 0.70 6m: 2.5 (1.5-5) better clinical
12m: 25 (0-100) 12m: 2.70 ± 0.80 12m: 2.5 (1.5-5.25) and radiographic
results at 12
months
Age, history of
periodontitis,
implant
location, and
implant
function time
may be factors
Table 2 (continued)
that influence
the outcomes of
peri-implantitis
treatment
PRF vs no PRF
Hamzacebi et al. 2015 Mean ± SD Mean ± SD NR Mean ± SD Mean ± SD 3m: SS (p<0.001) PRF provided
B: 65.47 ± 36.08 3m: 41.71 ± 40.14 B: 5.78 ± 0.71 3m: 1.65 ± 1.02 6m: SS (p<0.001) better clinical
3m: 23.76 ± 6m: 44.05 ± 36.17 3m: 4.11 ± 0.69 6m: 2.05 ± 0.77 results than
16.91 6m: 3.71 ± 0.42 conventional
6m: 21.43 ± 16.57 OFD
B: 79.31 ± 31.7 3m: 50.01 ± 33.31 B: 6.13 ± 1.05 3m: 2.41 ± 1.06
3m: 29.30 ± 22.11 6m: 54.02 ± 32.32 3m: 3.71 ± 0.67 6m: 2.82 ± 1.03
6m: 25.29 ± 14.51 6m: 3.30 ± 0.49
EMD vs no EMD
Isehed et al. 2016 % of implants NR NR Median (min-max) Median (25-75 percentile) 12m: No SS (p=0.270) EMD showed no
with BOP Mean ± SD additional
B: 93.3 Between B and 12m: 2.8 (0.4 to 3.9) effect on
12m: 66.7 B: 6.5 (5.3-8.8) 2.5 ± 2.03 clinical
12m: 4.5 (1.5-6.75) outcomes,
B: 85.7 Between B and 12m: 3.0 (1.9 to 7.0) although a
12m: 69.2 B: 7.6 (4-11) 4 ± 2.87 repressive
12m: 3.75 (1.25-8.0) effect on
Gram-/
anaerobic
peri-implant
microbiota and
a potential bone
regenerative
effect were
observed
Peri-implant mucositis
Independent variable: non –surgical
EMD vs no EMD
Kashefimehr et al. Median NR B: No SS (p=0.602) Median (interquartile range) NR B: No SS (p=0.209) Completely
2017 (interquartile 3m: SS (p<0.0001) 3m: SS (p<0.0001) recovery was
range) not obtained
B: 75 (75-100) B: 4.5 (4-5) with either
3m: 25 ± NR 3m: 3 (2-4.37) treatment
(0-50) group.
B: 75 ± NR B: 5 (4-5) Non-surgical
(75-100) 3m: 5 (4.5-6) MD alone has
3m: 75 ± NR limited effects
(50-100) in the treatment
of peri-implant
mucositis,
while EMD +
MD obtained
better clinical
outcomes
Clin Oral Invest
Table 2 (continued)
Faramarzi et al. 2015 Median NR No EMD vs MSM Median (interquartile range) NR No EMD vs MSM The use of MSM
(interquartile B: No SS (p=0.179) B: No SS (p=0.20) and EMD
range) 2w: SS (p=0.000) 2w: SS (p=0.000) can be
Clin Oral Invest

3m: SS (p=0.000) B: 4.5 (4-5) 3m: SS (p=0.000) considered as

B: 75 (75-100) No EMD vs EMD 2w: 4 (3.5-5) No EMD vs EMD an adjunctive
2w: 75 (50-93.7) B: No SS (p=0.602) 3m: 3 (2-4.37) B: No SS (p=0.209) therapy for the
3m: 25 (0-50) 2w: No SS (p=0.234) 2w: SS (p<0.001) MD in the
3m: SS (p<0.001) B: 4 (5-6) 3m: SS (p<0.001) non-surgical
B: 75 (75-100) 2w: 5 (5-6) management
2w: 75 (50-100) 3m: 4 (5-6) of peri-implant
3m: 75 (50-100) mucositis.
B: 4 (5-5) Improvement in
B: 75 (75-100) 2w: 2 (2-2) clinical
2w: 0 (0-25) 3m: 2 (2-3) parameters at 3
3m: 0 (0-25) months and
decrease in P.
Gingivalis
count

B, baseline; BOP, bleeding on probing; BS, bone substitute; CAL, clinical attachment level; CM, collagen membrane; CGF, concentrated growth factor; EMD, enamel matrix derivative; MSM, sustained-
release micro-spherical minocycline; MR, mucosal recession; NR, no reported; KM, keratonized mucosa; OFD, open flap debridement; PRF, platelet-rich fibrin; PD, probing depth; PI, plaque index; PL,
plaque along the mucosal margin; POP, pain on probing; SOP, suppuration on probing; SS, statistically significant; VDD, vertical defect depth
 Table 3 Detailed secondary outcome data of included studies

Treatment group characteristics Secondary Outcomes

Author Study Patients Evaluation Plaque index Gingival index Clinical attachment Level
and year groups (n)/ Period
implant (mo) Baseline/ Change Intergroup Baseline/ Change Intergroup Baseline/posttreatment (mm)
(n) posttreatment within difference (SS or posttreatment within difference (SS or
group not SS) (p value) group not SS) (p value)

Peri-implantitis
Independent variable: surgical
AGF vs No AGF
Isler et al., 2 Groups 52/52 12 Mean ± SD (Löe and Median NR B: No SS (p = 0.214) Mean (Silness Median NR Mean ± SD Median (min-max)
2018 (60/60 - Silness PI / 0–-3) (min-max) 6 m: No SS (p = 0.848) and Löe GI / 0-3) (min--
at onset) 12 m: No SS (p = 0.051) max)
(1) BS + CGF 26/26 B: 0.96 ± 0.58 B: 1 (0–2) B: 1.12 ± 0.59 B: 1 (0–2) B: No SS (p = 0.214) B: 5.95 ± 1.18 B: 5.88 (3.75–8.25)
6 m: 0.49 ± 0.42 6 m: 0.5 (0–1) 6 m: 0.07 ± 0.21 6 m: 0 (0–1) 6 m: No SS (p = 0.848) 6 m: 3.17 ± 1.01 6 m: 3.13 (1.26–5.5)
12 m: 0.67 ± 0.35 12 m: 0.75 (0–1) 12 m: 0.36 ± 0.45 12 m: 0 (0–1) 12 m: No SS (p = 0.051) 12 m: 3.98 ± 1.22 12 m: 3.63 (2–6)
(2) BS + CM: 26/26 B: 1.12 ± 0.59 B: 1 (0.5–2) B: 1.08 ± 0.27 B: 1 (1–2) B: 5.47 ± 1.31 B: 5.25 (3.75–8.25)
6 m: 0.47 ± 0.43 6 m: 0.5 (0–1) 6 m: 0.05 ± 0.14 6 m: 0 (0–0.5) 6 m: 2.82 ± 0.87 6 m: 2.5 (1.5–5)
12 m: 0.45 ± 0.44 12 m: 0.25 (0–1) 12 m: 0.13 ± 0.29 12 m: 0 (0–1) 12 m: 2.92 ± 1 12 m: 2.5 (1.5–5.25)
PRF vs No PRF
Hamzacebi 2 Groups 19/38 6 Mean ± SD Mean ± SD NR NR NR NR Mean ± SD
et al. (% of plaque around implants)
2015 (1) OFD 19/19 B: 40.48 ± 41.71 3 m: 23.83 ± 4-1.74 B: 6.59 ± 1
3 m: 16.64 ± 13.04 6 m 20.31 ± 3-8.80 3 m: 5.16 ± 1.21
6 m: 20.17 ± 11.57 6 m: 4.75 ± 1.07
(2) OFD + PRF 19/19 B: 47.70 ± 44.03 3 m: 27.08 ± 4-2.40 B: 6.74 ± 1.03
3 m: 20.62 ± 20.16 6 m: 14.56 ± 3-3.09 3 m: 3.86 ± 0.68
6 m: 33.14 ± 21.64 6 m: 3.44 ± 0.57
EMD vs no EMD
Isehed et al. 2 Groups 25/25 NR Median (min–max) for FMPS FMPS FMPS NR NR NR NR
2016 (29/29 & % for PII v12m: 3.0 12m: No SS (p = 0.297)
at onset) (3.3–19.8)
(1) EMD 12/12 FMPS, B: 16.0 (8–44) FMPS
(15/15 PII, B: 40 12m: 0.0
at onset) (–11.0–8.3)
(2) No EMD 13/ 13 FMPS, B:15.0 (0–62)
(14/14 PII, B: 35.7
at onset)
Peri-implant mucositis

Independent variable: non-surgical

EMD vs no EMD
Kashefimehr 2 Groups 41/41 3 Median (interquartile range) (O’Leary PI) NR B: No SS (p = 0.376) NR NR NR NR
et al. (46/46 3 m: SS (p = 0.033)
2017 at onset)
(1) EMD 20/20 B: 75 (75–100)
3 m: 50 (50–50)
(2) No EMD 21/21 B: 75 (50–100)
3 m: 50 (25–50)
Faramarzi 3 Groups 64 /64 3 NR NR NR NR NR NR NR
et al. (69/69
(2015) at onset)
(1) EMD 20/20
(23/23
at onset)
(2) No EMD 21/ 21(23/23
at onset)
(3) MSM 23/23
Clin Oral Invest
Treatment Secondary Outcomes
group
characteristics
Clin Oral Invest

Author and Clinical attachment Level Mucosal recession Keratinized mucosa Implant Post- Complications Post-
year failures operative operative
Change Intergroup Baseline/posttreatment (mm) Change Intergroup Baseline/ Change within Intergroup infection pain or
within group difference within difference posttreatment group (mm difference swelling
(SS or not group (SS or not (mm) (SS or not
SS) (p SS) (p SS) (p
value) value) value)

Peri-implantitis
Independent variable: surgical
AGF vs No AGF
Isler et al., 2018 NR Mean ± SD Median (min-max) NR B: No SS NR NR NR NR
B: no SS B: 0.04 ± 0.20 B: 0 (0–1) (p = 1) 1 removed 1 implant 0
(p = 0.076) 6 m: 0.25 ± 0.53 6 m: 0 (0–2) 6 m: No SS after suppura-
6 m: No SS 12 m: 0.25 ± 0.39 12 m: 0 (0–1) (p = 0.382) 12 mo- tion
(p = 0.338) 12 m: No SS nths
12 m: SS B: 0.06 ± 0.20 B: 0 (0–0.75) (p= 0.925) 0 0 11.5% membrane
(p = 0.001) 6 m: 0.26 ± 0.42 6 m: 0 (0–1.5) exposure
12 m: 0.27 ± 0.44 12 m: 0 (0–1.5)
PRF vs No PRF
Hamzacebi et al. Mean ± SD 6 m: SS Mean ± SD Mean ± SD B: No SS Mean ± SD Mean ± SD 6 m: SS 0/39 NR NR NR
2015 3 m: 1.43 ± 1.08 (p = 0.007) B: 0.83 ± 0.65 3 m: −0.21 ± 0.35 (p > 0.05) B: 1.45± 0.84 6 m: 0.05 ± 0.15 (p < 0.001)
6 m: 1.84 ± 0.81 3 m: 1.05 ± 0.68 6 m: −0.20 ± 0.32 3 m: SS 6 m: .40 ± 0.87
6 m: 1.04 ± 0.62 (p < 0.01)
3 m: 2.89 ± 1.01 B: 0.62 ± 0.49 3 m: 0.47 ± 0.45 6 m: SS B: 1.75 ± 1.05 6 m: −0.62 ± 0.58
6 m: 3.31 ± 1.08 3 m: 0.15 ± 0.29 6 m: 0.49 ± 0.51 (p < 0.01) 6 m: 2.37 ± 0.78
6 m: 0.14 ± 0.28

EMD vs no EMD
Isehed et al. 2016 NR NR NR NR NR NR NR NR 1 2 No No severe pain
0 2 implants at post--
3 months surgery in
post-surgery any of the
1 0 cases
Peri-implant mucositis

Independent variable: non-surgical

EMD vs no EMD
Kashefimehr et al. NR NR NR NR NR NR NR NR 0 NR NR NR
2017 0
0
Faramarzi et al. NR NR NR NR NR NR NR NR NR NR NR NR
(2015)

B, baseline; BOP, bleeding on probing; BS, bone substitute; CAL, clinical attachment level; CM, collagen membrane; CGF, concentrated growth factor; EMD, enamel matrix derivative; FMBS, full mouth
bleeding score; MSM, sustained-release micro-spherical minocycline; MR, mucosal recession; NR, no reported; KM, keratonized mucosa; OFD, open flap debridement; PRF, platelet-rich fibrin; PD,
probing depth; PI, plaque index; PPI: plaque around implants; SD, standard deviation; SOP, suppuration on probing; SS, statistically significant

the distribution of true effect sizes were estimated using the
DerSimonian-Laird estimator. VDD showed no evidence of
heterogeneity and was analyzed using fixed effects meta-anal-
ysis. Subgroup analyses by condition (peri-implantitis or peri-
implant mucositis) were analyzed using mixed effects models
with random effects within subgroups and fixed effects be-
tween. When included studies reported multiple endpoints,
the last endpoint was used. Between-study heterogeneity
was assessed using the Q statistic and I2, reflecting the total
proportion of variability in estimates attributed to heterogene-
ity. Significant Q statistics or an I2 value greater than 75% was
considered to be evidence of heterogeneity. For each meta-
analysis, forest plots were generated.
Statistical analyses and graphics were conducted in R
v3.5.2. (R Foundation for Statistical Computing, Vienna,
Austria). Statistical tests were two-sided, and significance
was based off a threshold of p < 0.05.
Results
The electronic search yielded a total of 4193 results and when
duplicates were removed the total results were 2284 articles.
The hand search yield to one additional relevant article. Two
reviewers (SPL, IK) independently screened 2285 abstracts,
ultimately excluding 2269 articles. Sixteen full-text articles
were reviewed. Eleven of the sixteen articles were excluded
as they did not meet eligibility criteria (Table 1 in the
Appendix) [35–45]. The remaining five studies were included
in the present systematic review group [14, 46–49] (Appendix
Fig. 1).
Description of included studies
General characteristics of included studies
A total of five trials met the aforementioned eligibility
criteria and were included in this systematic review. The
included studies consisted in 201 patients receiving treat-
ment in 220 implants. The included trials were carried out
in academic clinical settings across the world. Average age
and gender distributions were comparable across the stud-
ies. Study characteristics including study design, treatment
groups, study site, and surgical protocol are shown in
Table 1.
Three trials examined the effect of using GF during sur-
gical treatment of peri-implantitis, while two trials exam-
ined the effect of GF during non-surgical treatment of peri-
implant mucositis. Autogenous Growth Factors were used
in two trials for the treatment of peri-implantitis, and EMD
in three trials (one for treatment of peri-implantitis and two
for peri-implant mucositis).
Clin Oral Invest
Surgical treatment of peri-implantitis consisted mainly in
mechanical debridement with titanium instruments, while im-
plant surface decontamination methods were different in these
three trials. Pre-treatment was reported in four trials.
Definitions of peri-implant diseases were slightly different
across the trials. Isler et al. [14] and Hamzacebi et al. [49] used
the same definition for peri-implantitis, while Isehed et al. [48]
slightly different. Faramarzi et al. and Kashefimehr et al. used
the same definition for peri-implant mucositis and mild peri-
implantitis [46, 47].
Effects of interventions
Tables 2 and 3 summarize the primary and secondary out-
comes for included studies respectively.
Individual study outcomes
Results of primary outcomes
Peri-implant mucositis
EMD in non-surgical therapy Two studies examined the addi-
tion of EMD for the non-surgical treatment of peri-implant
mucositis. One trial reported statistically significant improve-
ments in terms of PD and BOP when EMD was added to non-
surgical treatment at 3 months [46]. However, the treatment
had a limited effect. Similarly, in another trial the addition of
EMD significantly improved the results of the non-surgical
therapy in terms of PD and BOP at 3 months follow-up [47].
Peri-implantitis
EMD in surgical therapy In one study, the addition of EMD to
open flap debridement failed to show additional benefits in
terms of PD, BOP, and VDD at 12-month follow-up [48].
The same cohort was followed up for 3 and 5 years but still
without significant differences for the aforementioned clinical
parameters [50].
Concentrated growth factor (CGF) and platelet-rich fibrin
(PRF) in surgical therapy One RCT examined the clinical ben-
efits of GF membranes versus a regular collagen membrane in
peri-implantitis defects [14]. The use of growth factor mem-
branes in conjunction with DBBM improved PD, VDD and
BOP at 12 months but rendered significantly inferior results as
compared to DBBM plus collagen membrane. In another
study, the addition of PRF to open flap debridement rendered
more favorable results when compared to open flap debride-
ment alone in terms of PD [49].
Clin Oral Invest
Fig. 2 Forest Plot for PD outcome in peri-implant mucositis
Results of secondary outcomes
Peri-implant mucositis
EMD in non-surgical therapy One trial exhibited statistically
significant improvements in the levels of local plaque index
but not in the whole-plaque index when EMD added to non-
surgical treatment at 3 months [46].
Peri-implantitis
EMD in surgical therapy The addition of EMD to open flap
debridement did not significantly improve the results in terms
of plaque levels, presence of pus (infection), and implant fail-
ures as compared to the control group at 1-, 3-, and 5-year
follow-ups [48, 50].
Concentrated growth factor (CGF) and platelet-rich fibrin
(PRF) in surgical therapy The use of growth factor membranes
in conjunction with DBBM improved CAL but rendered signif-
icantly inferior results as compared with DBBM plus collagen
membrane. However, both treatments improved plaque index,
gingival index and mucosal recession at 12 months follow-up
[14] without significant differences between both approaches.
The addition of PRF to open flap debridement rendered more
favorable results compared with open flap debridement alone in
terms of CAL at 3 and 6 months [49]. Furthermore, PRF signif-
icantly increased the keratinized mucosa and significantly re-
duced the recessions after treatment at 6 months [49].
Pooled data
Meta-analysis was attempted for primary and all secondary
study outcomes. Results from the meta-analysis revealed that
GF enhance the reduction of PD (SMD = − 1.28; 95% CI −
1.75,-0.8; p < 0.0001) (Fig. 2) and BOP (SMD = − 1.23; 95%
Fig. 3 Forest Plot for BOP outcome in peri-implant mucositis
CI − 1 .71, − 0.76; p < 0.0001) (Fig. 3) in the treatment of peri-
implant mucositis. For the treatment of peri-implantitis, the
meta-analysis reported a significantly greater improvement
in VDD (SMD = 0.68; 95% CI 0.22, 1.14; p = 0.004)
(Fig. 4) by the use of GF, however there were no significant
differences in terms of PD (SMD = 0.08; 95% CI − 1.09, 1.26;
p = 0.887) (Fig. 5) and BOP (SMD = 0.21; 95% CI − 0.20,
0.63; p = 0.317) (Fig. 6). Furthermore, there were no signifi-
cant differences in terms of PD (SMD = −0.46; 95% CI −
1.41, 0.49; p = 0.34) (Fig. 7) and BOP (SMD = − 0.49; 95%
CI − 1.31, 0.32; p = 0.23) (Fig. 8) combining treatment of
peri-implant mucositis and peri-implantitis. Analysis of
pooled data could not be conducted for any secondary out-
comes as, to our knowledge, no other trials examining com-
parative study groups and reporting on comparable outcomes
have been published.
Risk of bias of included studies
All included studies were designed as RCTs. The overall risk of
bias of the included studies was low to unclear (Fig. 9a). The risk
of bias assessed for seven key domains was unclear from one to
three key domains in three trials (Fig. 9b) [46, 47, 49]. Two
studies showed low risk of bias in all domains [14, 48].
Discussion
Summary of key findings
This systematic review was focused on evaluating the thera-
peutic value of growth factors in conjunction with non-
surgical and surgical modalities for the treatment for peri-
implant-related diseases. Regarding peri-implant mucositis,
our meta-analysis showed that the addition of EMD rendered
superior results relative to the control groups in terms of BOP

Fig. 4 Forest Plot for VDD outcome in peri-implantitis
(SMD = − 1.23; 95% CI − 1.71, − 0.76; p < 0.0001).
Furthermore, EMD reduced the PD to a higher extent in
peri-implant mucositis (SMD = − 1.28; 95% CI − 1.76,− 0.8;
p < 0.0001).
The present meta-analysis, however, indicated that GF
failed to produce an additional benefit in terms of PD
(SMD = 0.08; 95% CI − 1.09, 1.26; p = 0.887) and BOP
(SMD = 0.21; 95% CI − 0.20, 0.63; p = 0.317) in the treatment
of peri-implantitis. Nevertheless, the current analysis found
that the addition of GF improved the outcomes in terms of
VDD in subjects affected by peri-implantitis (SMD = 0.68;
95% CI 0.22, 1.14; p = 0.0040).
Quality of the evidence
The overall risk of bias of the included studies was low
to unclear. Two studies showed low risk of bias in all
domains whereas other two studies only the allocation
concealment was unclear. Only one study did not pro-
vide a detailed report of three key domains. Altogether,
these observations suggest a plausible bias that raises
some doubt about the results. Therefore, the information
presented in this systematic review should be interpreted
with caution.
Potential bias in the review process
The case definition for peri-implant diseases is highly variable
for peri-implant mucositis or peri-implantitis and, until recent-
ly, there was no single uniform definition of peri-implantitis.
The recent world workshop of periodontal and peri-implant
diseases and conditions has provided a definition for peri-
implant mucositis and peri-implantitis [51]. However, none
of the included studies used the proposed definition.
Fig. 5 Forest Plot for PD outcome in peri-implantitis
Clin Oral Invest
Concerning peri-implantitis, two [14, 49] out of three studies
defined it as follows: PD ≥ 5 mm + ≥ 2 mm of peri-implant
bone loss combined with BOP. Conversely, Isehed et al.
[48] defined peri-implantitis as if the patient had at least one
implant with PD ≥ 5 mm + ≥ 3 mm of peri-implant bone loss.
This difference in case definition may have an impact on the
outcomes and in the extrapolation of the data, especially when
the definition of peri-implantitis has been questioned [52].
According to some authors [52], peri-implantitis should
be redefined, implying a change of paradigm. As such,
peri-implantitis would be associated to a foreign body
reaction that is not counterbalanced by the host-immune
response [53]. Consequently, mucositis and bone loss
around implants may represent normal conditions and
not necessarily a state of diseases [52]. Hence, the ques-
tion arises whether the patients included in the present
review really suffered from a disease and not just an im-
mune response.
Agreements and disagreements with other previously
published articles
To date, there are few studies evaluating the effect of GF in the
treatment of peri-implant diseases. Consequently, the compar-
ison with other reviews in terms of disease resolution out-
comes is limited.
In general, the additional effect of GF in terms of BOP and
PD reduction are considerably better as compared with previ-
ous systematic reviews for peri-implant mucositis treatment.
Outcomes from one systematic review showed that the ad-
junctive or alternative use of glycine powder air polishing
failed to provide an additional improvement in BOP in the
treatment of peri-implant mucositis [54]. Similarly, findings
from another systematic review indicated that adjunctive
Clin Oral Invest
Fig. 6 Forest Plot for BOP outcome in peri-implantitis
antiseptics/antibiotics (local and systemic) does not improve
BOP and PD significantly [55], and outcomes of a more recent
systematic review suggest that non-surgical treatment is effec-
tive for peri-implant mucositis independent of adjunctive ther-
apy (e.g., local antiseptics, systemic antibiotics, air abrasive
device) [56]. This differs from the results obtained by the
current review since reduction of BOP and PD in peri-
implant mucositis was not achieved without the addition of
GF. Indeed, a 3-month RCT indicates that non-surgical de-
bridement yields a complete resolution of BOP in only 38% of
the implants diagnosed with peri-implant mucositis [57].
With respect to peri-implantitis, the current data synthesis
revealed that the addition of GF failed to provide an additional
effect in BOP and PD. This lack of difference might be ex-
plained due to methodological discrepancies between the se-
lected studies. For example, Isler et al. [48, 50] used GF in
conjunction with bone grafts, while the other studies [48–50]
did not include bone grafting procedures. This may have in-
fluenced the potential benefit of GF. Furthermore, one of the
included studies was underpowered for the chosen design,
thereby impeding the detection of an effect [48, 50].
However, the results of the present meta-analysis are in line
with recent systematic reviews focused on different therapies
for the management of peri-implantitis. For instance, findings
from a systematic review revealed that there was insufficient
evidence for supporting additional benefit of reconstructive
therapy to other treatment modalities of peri-implantitis man-
agement [58]. Results from another systematic review, which
evaluated adjunctive measures to conventional treatment of
peri-implantitis, failed to show any significant differences in
terms of BOP and PD [55]. These observations were further
confirmed in a more recent systematic review [59] where the
surgical treatment in peri-implantitis did not provide signifi-
cant differences in terms of PD or BOP [59].
Fig. 7 Forest Plot for PD outcome in both peri-implant mucositis and peri-implantitis
Interestingly, the present meta-analysis found that the ad-
dition of GF improved the outcomes in terms of VDD in
subjects affected by peri-implantitis (SMD = 0.68; 95% CI
0.22, 1.14; p = 0.0040). These positive observations match
those reported in a case series study where the combination
of EMD and PDGF in combination with bone grafts increased
bone fill [60]. Our results are also consistent with a recent
systematic review where a surgical procedure with
implantoplasty improved radiographic outcomes [61].
However, unlike our meta-analysis, the authors also reported
a significant difference in BOP and PD. Those significant
differences could be attributed to the implantoplasty itself
and not to the use GF. In fact, the selected studies in the
present review did not include implantoplasty or any modifi-
cation of the titanium surface.
Limitations and confounding variables
The present review has some limitations. First, there was a
small number of RCTs using growth factors in the treat-
ment of peri-implant diseases. Moreover, most of the stud-
ies included small sample sizes and were underpowered,
thereby reducing the possibility of detecting clinically rel-
evant effects. Second, the clinical outcomes following sur-
gical treatment of peri-implantitis may depend on the de-
fect morphology. The included studies provided limited
information on the morphology of treated defects. Third,
there were inconsistencies in methodology, specifically
various treatment modalities with different implant sys-
tems along with different follow-up periods. Hence, there
is a clear demand for randomized controlled studies with
proper designs and larger sample sizes, comparing the sur-
gical or non-surgical treatment of peri-implant diseases

Fig. 8 Forest Plot for BOP outcome in both peri-implant mucositis and peri-implantitis
with or without growth factors, to provide stronger evi-
dence about their possible additional benefit.
The selected studies included different implants sys-
tems, with different surfaces either cemented or screw-
retained, thereby affecting not only the quality of the
decontamination but also the flap design. Concerning pe-
ri-implantitis, there is some evidence indicating that non-
modified surfaces yield better results following surgical
treatment [62, 63] likely due to a different bacterial ad-
hesion [64]. For example, the use of antibiotics may
have a stronger effect in non-modified surface compared
with modified ones [63]. To overcome this issue, the
removal of the modified surface has been recommended,
a procedure termed implantoplasty [65]. None of the se-
lected studies included implantoplasty, although multiple
surfaces were included and in two out of five studies
antibiotics were given. This may stand as one of the
reasons why we failed to find significant difference in
terms of BOP and PD in peri-implantitis. It should be
mentioned, however, that the use of PD as a parameter
for disease resolution has been questioned [66, 67].
Following treatment of peri-implantitis the resolution of
the disease may arrest progressive bone loss, reduce BOP
and/or suppuration but maintaining deep PD due to
Fig. 9 Review of authors’ judgements about each risk of bias item presented as a percentage in a graph (a) and summary for each included study (b)
Clin Oral Invest
previous marginal loss [68]. In this sense, a precise phys-
iological PD at implant sites is difficult to establish [66].
Prosthetic design also plays a pivotal role as the prosthetic
design affects oral hygiene [6], however, two out of the five
included studies did not provide enough information about the
restoration which may have influenced the outcomes.
The centrifugation force and time lead to different PRF-
based matrices with biological differences [ 69].
Consequently, the use of different protocols inevitably com-
plicates the comparison between the included studies. In ad-
dition, the number of clots or membranes utilized during the
procedure might influence the clinical outcomes [30, 70]. Isler
et al. [14] reported the use of 2 membranes; Hamzacebi et al.
[49] did not report it.
The position of the implants seems to be a predisposing
factor to develop peri-implant mucositis and peri-implantitis
due to the difficulty for oral hygiene [66], nevertheless the
type of restoration that was performed in each study is unclear.
Another controversial aspect is the amount of keratinized tis-
sue which may affect the development and the long-term out-
comes [71–73]. Not every study reported on the amount of
keratinized tissue. Recent studies, however, have failed to
show any significant advantage of the amount of keratinized
tissue [74].
Clin Oral Invest
The cost-effectiveness of GF for the non-surgical and sur-
gical peri-implant diseases treatments may add another per-
spective beside the clinical outcomes. However, it was not
assessed as part of this review, as none of the included studies
reported any cost-effectiveness analysis. Therefore, the cost-
effectiveness of using GF for the treatment of peri-implant
mucositis and peri-implantitis must be further investigated.
Conclusions
Implications for clinical practice
Within the limitations of the current systematic review and
based on the meta-analyses, (1) the addition of growth factors
for the treatment of peri-implant mucositis might be associated
with better outcomes in terms of PD and BOP, and (2) an
additional benefit of GF for the treatment peri-implantitis
could not be determined on the basis of the selected evidence,
although GF may improve the outcomes in terms of VDD in
subjects affected by peri-implantitis. Hence, no definite con-
clusion may be drawn on the use of growth factors for the
treatment of peri-implant diseases.
Future research
There is a need for further properly designed and con-
ducted randomized clinical trials aimed at evaluating the
effect of different growth factors for the treatment of
peri-implant diseases. These clinical trials should incor-
porate the same definition of peri-implant diseases with
reproductible outcome assessment methods. Additionally,
these studies should be conducted to assess (1) the effi-
cacy of growth factors compared with another growth
factor or no growth factors (or placebo); (2) the efficacy
of combining various growth factors during the treatment
of peri-implant diseases; (3) the effect of local and sys-
temic factors on outcomes of interest such as implant
surface, anatomical morphology, soft tissue characteris-
tics, etc.; and (4) its cost-benefit ratio must be further
investigated.
Acknowledgments The authors are grateful to Mr. Richard McGowan
(NYU Health Sciences Library Liaison and NYU College of Dentistry)
for his assistance with the electronic database search process.
Author’s contribution I. Khouly and Pardiñas-López contributed to re-
view design, data acquisition, analysis and interpretation, and drafting
and revision of the manuscript; F.J. Strauss contributed to data interpre-
tation and drafting and revision of the manuscript; R.R. Ruff contributed
to data analysis and interpretation, and drafting and revision of the man-
uscript. All authors gave final approval and agree to be accountable for all
aspects of the work.
Compliance with ethical standards
Conflict of interest and source of funding statement Drs. Pardiñas-
López and Strauss declare that they have no conflict of interest. Dr.
Ruff reports grants from NIH, and Dr. Khouly from OsteoScience
Foundation, Sweden and Martina SpA and Dentsply Sirona, during the
conduct of the review. The review was self-funded by the authors.
Ethical approval This article does not contain any studies with human
participants or animals performed by any of the authors; ethical approval
is not required.
Informed consent For this type of study, formal consent is not required.
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Affiliations
Ismael Khouly 1,2 & Simon Pardiñas-López 1,3,4 & Ryan Richard Ruff 5,6 & Franz-Josef Strauss 7,8,9
1 5
Bluestone Center for Clinical Research, New York University
College of Dentistry, 421 First Avenue – BCCR 2W, New
York, NY 10010, USA
2
Department of Oral and Maxillofacial Surgery, New York University
College of Dentistry, New York, NY, USA
3
Cell Therapy and Regenerative Medicine Group, Centre for
Advanced Scientific Research (CICA), A Coruña, Spain
4
Biomedical Research Institute of A Coruña (INIBIC) strategic group,
Galician Health Service (SERGAS), Universidade da Coruña
(UDC), University Hospital Complex of A Coruña (CHUAC), A
Coruña, Spain
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Publisher’s note Springer Nature remains neutral with regard to jurisdic-
tional claims in published maps and institutional affiliations.
Department of Epidemiology & Health Promotion, New York
University College of Dentistry, New York, NY, USA
6
New York University College of Global Public Health, New
York, NY, USA
7
Department of Oral Biology, School of Dentistry, Medical
University of Vienna, Vienna, Austria
8
Department of Conservative Dentistry, School of Dentistry,
University of Chile, Santiago, Chile
9
Clinic of Reconstructive Dentistry, Center of Dental Medicine,
University of Zurich, Zurich, Switzerland