Al‑Maawi et al.

International Journal of
International Journal of Implant Dentistry (2021) 7:117
https://doi.org/10.1186/s40729-021-00393-0 Implant Dentistry

REVIEW Open Access

Efficacy of platelet‑rich fibrin in promoting

the healing of extraction sockets: a systematic
review
Sarah Al‑Maawi1, Kathrin Becker2, Frank Schwarz3, Robert Sader1 and Shahram Ghanaati1*

Abstract
Purpose: To address the focused question: in patients with freshly extracted teeth, what is the efficacy of platelet-rich
fibrin (PRF) in the prevention of pain and the regeneration of soft tissue and bone compared to the respective control
without PRF treatment?
Methods: After an electronic data search in PubMed database, the Web of Knowledge of Thomson Reuters and hand
search in the relevant journals, a total of 20 randomized and/or controlled studies were included.
Results: 66.6% of the studies showed that PRF significantly reduced the postoperative pain, especially in the first
1–3 days after tooth extraction. Soft tissue healing was significantly improved in the group of PRF compared to the
spontaneous wound healing after 1 week (75% of the evaluated studies). Dimensional bone loss was significantly
lower in the PRF group compared to the spontaneous wound healing after 8–15 weeks but not after 6 months.
Socket fill was in 85% of the studies significantly higher in the PRF group compared to the spontaneous wound
healing.
Conclusions: Based on the analyzed studies, PRF is most effective in the early healing period of 2–3 months after
tooth extraction. A longer healing period may not provide any benefits. The currently available data do not allow any
statement regarding the long-term implant success in sockets treated with PRF or its combination with biomaterials.
Due to the heterogeneity of the evaluated data no meta-analysis was performed.
Keywords: PRF, Platelet-rich fibrin, Socket preservation, Ridge preservation, Socket healing, Pain management, Soft
tissue healing

Introduction tissue are needed to support osseointegration. Therefore,

Dental implants have become an integral part of the oral a thorough understanding of the mechanisms of socket
and maxillofacial surgery. They provide the most com- healing became a central research topic in the last dec-
fortable and favorable method to replace lost teeth and ades [5, 6]. After tooth loss, the alveolar bone undergoes
reconstruct the esthetic and function for the patients [1, a remodeling process resulting in loss of bone quantity
2]. To achieve long-term success of dental implants many and changes of bone quality [7]. These processes finally
clinical, biomechanical and biological requirements are lead to alveolar bone atrophy. The process of atrophy was
needed [3, 4]. Especially, healthy and active bone and soft described as a rapid and continuous process. In this con-
text, 50–60% of the alveolar bone atrophies in the first
three months after tooth extraction [6, 8]. These findings
*Correspondence: [email protected]
1
FORM, Frankfurt Oral Regenerative Medicine, Clinic for Maxillofacial
highlight the importance of the initial period after tooth
and Plastic Surgery, Goethe University, Theodor‑Stern‑Kai 7, extraction as critical for the further healing and chang-
60596 Frankfurt/ Main, Germany ing of the alveolar bone. Accordingly, different protocols
Full list of author information is available at the end of the article

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Al‑Maawi et al. International Journal of Implant Dentistry (2021) 7:117 Page 2 of 27

were established to avoid bone atrophy and achieve den- mainly because it contains more leukocytes compared to
tal implantation. the first-generation blood concentrates PRP.
Socket preservation is a prophylactic intervention PRF matrices have been used in different indications
that includes applying bone substitute materials (BSMs) in oral and maxillofacial surgery and implant dentistry
into the extraction socket to preserve the alveolar bone [31]. Some clinical studies reported on the benefits and
dimension [9, 10]. Similarly ridge preservation is applied drawbacks of the different blood concentrate systems
when tooth extraction results in a larger defect. A wide [32]. Recently, different systematic reviews aimed to sum-
range of BSMs including synthetic and naturally derived marize the available evidence on the use of PRF [31, 33,
biomaterials is available for clinical application [11, 12]. 34]. However, they were not focused on socket preserva-
After BSMs application, a healing period of 3–6 months tion, but extended their investigation to a wider range of
is recommended according to the defect morphology indications and included different evidence levels. There-
and the applied BSM [13–15]. During the healing period fore, the present systematic review aimed to focus on the
of 3–6 months, the processes of natural alveolar healing role of PRF in ridge preservation to addressed the follow-
interferes with the BSM-based new bone formation and ing focused questions: in patients with freshly extracted
leads to the regeneration of a sufficient implant bed, that teeth, what is the efficacy of PRF in the prevention of pain
allows the delayed insertion of dental implant [16]. This and the regeneration of soft tissue and bone compared to
two-stage implantation concept is based on the prepara- the respective control without PRF treatment?
tion of the alveolar bone prior to implant insertion. Many
clinical studies reported about socket and ridge preserva-
Methods
tion using different types of BSMs [17]. However, there
This systematic review was designed and performed fol-
is still no clear evidence about the most suitable time of
lowing the preferred reporting items of the PRISMA
implant placement [18] Immediate implant placement
statement [35, 36].
after tooth extraction has been considered an alternative
option to limit alveolar bone resorption [18, 19]. How-
ever, this approach is limited to specific socket morphol- Focused question
ogies and indications, when a sufficient bone volume is This systematic review followed the structure of the
available and the buccal bone is preserved. This method focused questions (PICO) for the literature search [37]:
can be also applied in combination with BSMs to fill the
socket when needed [20]. – Population (P): patients with freshly extracted teeth.
In addition to BSMs, blood concentrate systems gained – Intervention (I): socket or ridge preservation using
increasing importance in different fields of regenerative platelet-rich fibrin (PRF) with or without biomateri-
medicine in the last decade [21]. Blood concentrates als.
are obtained from patients own peripheral blood [22]. – Comparison (C): spontaneous healing, biomaterials
Thereby, the blood components such as leukocytes, plate- without PRF.
lets, plasma proteins and growth factors are concentrated – Outcomes (O): measurements of at least one of the
by centrifugation and prepared using different protocols following parameters: postoperative inflammation
[23–25]. Platelet-rich plasma (PRP) is the first genera- and pain, soft tissue healing, dimensional bone vol-
tion of blood concentrates. PRP includes mainly platelets, ume changes, bone quality.
whereas leukocytes are removed during the preparation
process [25, 26]. For its preparation, the patients’ blood is
centrifuged in two centrifugation steps [27]. In addition, Search strategy
plasma rich in growth factors (PRGF) is a further concept An electronic search was conducted through PubMed
that utilizes the advantages of blood-derived growth fac- and Web of Science, followed by a hand search for rel-
tors [28]. Both systems apply a rather high relative cen- evant articles published between 1990 up to June 2021.
trifugal force (RCF) during their preparation [25]. By A commercially available software program (Microsoft
contrast, the second generation of blood concentrates, Excel) was used for data management. Two authors (S.A.
i.e., platelet-rich fibrin (PRF), is prepared by a one-step and S.G.) independently screened the identified articles.
centrifugation without the application of any anticoagu- In case of disagreement regarding inclusion, detailed
lants [29]. PRF consists of platelets, leukocytes and their review of the defined criteria was performed and the dis-
subgroups embedded in a fibrin matrix with plasma pro- agreements were resolved upon discussion.
teins [21]. The first protocol of PRF applies a compara- The combination of following keywords:
bly lower, but still high RCF (≈710×g) [30]. This protocol “PRF”, “platelet rich fibrin”, “socket preservation”, “ridge
was called leukocytes-rich platelet-rich fibrin (L-PRF), preservation”, “molar”, “premolar”.
Al‑Maawi et al. International Journal of Implant Dentistry (2021) 7:117 Page 3 of 27

Keywords combination: – Immediate implantation;

("platelet rich fibrin"[MeSH Terms] OR ("platelet- – Inadequate methods or reporting of the study design
rich"[All Fields] AND "fibrin"[All Fields]) OR "plate- and/or patients’ data.
let-rich fibrin"[All Fields] OR "PRF"[All Fields] OR
("platelet"[All Fields] AND "rich"[All Fields] AND *reasonable controls were considered as control groups
"fibrin"[All Fields]) OR "platelet rich fibrin"[All Fields]) in which all applied procedures were equivalent to the
AND ("socket" or "ridge" or "molar" or "premolar"[All test group except for PRF. Therefore, in case of the sole
Fields]). use of PRF in the test group, the reasonable control was
A manual search was additionally performed in the fol- considered as the spontaneous healing. In the case of the
lowing journals: use of biomaterials in combination with PRF in the test
group, the reasonable control was considered to be the
• International Journal of Oral and Maxillofacial application of the exact same biomaterial without PRF.
Implants;
• Clinical Implant Dentistry and Related Research; Quality evaluation of included studies
• Clinical Oral Implants Research; The quality of selected RCTs was reviewed to assess the
• Journal of Clinical Oral Investigations bias risk. Evaluation was performed according to the
• Journal of Implantology; Cochrane Handbook for Systematic Reviews of Inter-
• Journal of Oral and Maxillofacial Surgery; ventions version 6.2 (updated February 2021), (low, high,
• International journal of oral and maxillofacial sur- unclear). CCTs were evaluated according to Newcastle–
gery. Ottawa Quality Assessment Scale for non-randomized
studies. The following categories were analyzed: random
sequence generation, allocation concealment, blinding of
participants and personnel, blinding of outcome assess-
Inclusion criteria ment, and incomplete outcome data [38]. The assessment
was conducted by two independent reviewers (SA, SG)
– English language based on the published full text article. Disagreements
– Patient age 15–99 years were resolved upon discussion.
– Prospective controlled (CCTs) and/or randomized
clinical studies (RCTs) in humans with either a split- Data extraction
mouth or parallel design with reasonable controls* Data extraction was organized in a data-sheet including,
– Treatment of fresh sockets/ridge study design, number of treated subjects, case definition,
– Treatment using either PRF (with or without bioma- population, surgical extraction protocol, socket specifica-
terials, i.e., bone substitute materials, collagen mem- tions, PRF-preparation protocol, treated groups compari-
branes as well as any other membrane of different son. For data analysis following parameters were defined:
origin) or spontaneous healing
– Treatment without any additional chemical or physi- – Primary outcomes: radiological and clinical evalu-
cal agents in/on the alveolus after extraction except ation of bone regeneration, dimensional bone-level
suture materials change and histological assessment of bone regenera-
– Subject with and without anticoagulation intake. tion.
– Secondary outcomes: healing period, pain manage-
ment outcome and soft tissue regeneration.

Exclusion criteria
Results
– Preclinical in vitro or animal studies; Study inclusion
– Third molar extraction; The PubMed and Web of Science search resulted in 312
– Combination with biomaterials without reasonable and 215, respectively. The manual search in the relevant
controls; journals did not result in additional titles. One article
– Prospective randomized and/or controlled clinical was retrieved from other sources (published reviews).
studies (RCTs) in humans with either a split-mouth After removal of 215 duplicated articles, 312 titles and
or parallel design without reasonable controls; abstracts were reviewed from which 292 studies were
– Case reports, case series, cohort and retrospective excluded according to the exclusion criteria. Thirty-
studies; three full-text articles were reviewed, of which 20 were
Al‑Maawi et al. International Journal of Implant Dentistry (2021) 7:117 Page 4 of 27

Fig. 1 Flowchart describing the research strategy and study selection (modified according to the PRISMA 2020 statement: an updated guideline for
reporting systematic reviews [36])

included in the qualitative analysis. Due to parameter treatment of PRF alone in comparison to the spontane-
variation and data limitation, no meta-analysis could be ous wound healing and second the combination of PRF
conducted (Fig. 1). with a bone substitute material in comparison to the
bone substitute material alone [39]. Two further studies
Study designs compared Bone substitute materials in combination with
Twenty studies were analyzed in this review. Nine of PRF to Bone substitute materials without PRF.
the included studies were designed as parallel RCTs The case definition differed in the respective studies.
and seven were designed as split mouth RCT. Fur- Mainly patients in need of tooth extraction with or with-
ther two CCTs (one split mouth and one parallel study) out dental implantation were studied. Additionally, some
were included in this review. One study was not further studies focused on single rooted teeth or premolars only.
defined by the authors and one further study included Most of the studies did not report or specify the mor-
both split mouth and parallel design according to the phology of the treated sockets/ridge. When reported, the
teeth needed to extract in each patient. Seventeen stud- studies included sockets with presence of 50% or more
ies compared only the treatment of PRF as a test group to of the lingual/buccal socket walls. Most of the studies
the spontaneous healing without any further treatment. reported atraumatic tooth extraction without flap mobili-
One study included four groups and evaluated first the zation or intention of primary healing (Table 1).
Al‑Maawi et al. International Journal of Implant Dentistry (2021) 7:117 Page 5 of 27

Evaluation of bias risk resorption in the PRF group compared to the control
The reviewer judgment on the bias risk of RCTs showed group especially in the 1–3 mm below the alveolar crest
that the highest bias risk was assessed in the categories and the buccal wall. However, no difference was shown,
blinding of participant and personnel as well as blinding when evaluating the horizontal bone loss. Additionally,
of outcome assessment (Table 2, Fig. 2). The highest bias the total volume of new bone formation was statisti-
risk of the two included CCTs was referred to case selec- cally significantly higher in the PRF group compared to
tion and comparability (Table 3). the control group. Similarly, Srinivas et al. [48] showed
statistically significantly higher bone density in the PRF
PRF preparation protocol group after 3 months by CBCT analysis. However, no
Most of the included studies evaluated the L-PRF pro- differences were found in the bone height change. A fur-
tocol. Additionally, Giudice et al. [40] and Castro et al. ther study by Zhang et al. [49] performed CBCT analysis
[41] evaluated A-PRF + in comparison to L-PRF, Clark to assess bone resorption after 3 months. They showed
et al. [39] evaluated A-PRF and Ustaoglu et al. [42] ana- markedly lower resorption in all dimensions in the PRF
lyzed T-PRF in comparison to L-PRF. Most of the studies group compared to the control group. However, they did
reported solely the used rounds per minutes (rpm) and not report statistical significant differences. Moreover,
centrifugation time without referring to the centrifuge Temmerman et al. [50] analyzed the bone changes using
design or the applied relative centrifugal force (Table 4). CBCT and showed significantly lower vertical resorption
in the PRF group compared to the control group, espe-
Primary outcomes cially in the buccal wall. Similarly, a significantly lower
The results of the primary outcomes are described below. horizontal bone resorption was shown in the 1–5 mm
below the alveolar crest in the PRF group compared to
Bone regeneration the control group. The percent socket fill was significantly
Fifteen of 20 studies evaluated the dimensional bone- higher in the PRF group compared to the control group.
level changes and bone regeneration using different Castro et al. [41] also demonstrated a significantly higher
methods (Table 5). socket fill after 3 months using CBCT measurement in
Clinical evaluation. Kumar et al. [43] applied a clinical the PRF treated group compared to the untreated control
measurement method using metal capillaries to assess (Table 5).
the width and height bone loss after 6 months. In both Clark et al. [39] also analyzed the dimensional ridge
cases, no statistical significant differences were found reduction after treatment using a bone substitute mate-
between the PRF and the control group (spontaneous rial in combination with PRF compared the treatment
wound healing). Additionally, Clark et al. [39] evaluated using the biomaterial alone. No statistical significant dif-
the bone dimension change after an average of 15 weeks ferences were shown in the clinical evaluation. Two fur-
(3.75 months) using alginate impression and periodontal ther studies analyzed the socket augmentation using PRF
probe. The results showed that the A-PRF group under- in combination with bone substitute materials compared
went significantly lower ridge height reduction compared to the augmentation using native bone substitute mate-
to the control group. However, no statistical significant rial without PRF. Thakkar et al. [52] showed that the addi-
differences were found when assessing the alveolar bone tion of PRF significantly reduce the ridge width reduction
width. Alzahrani et al. [44] analyzed the alveolar ridge after 6 months. However, no significant difference was
with reduction after 1, 4 and 8 weeks using cast analy- found when evaluating the ridge height reduction. Yewale
sis. The results showed statistically significantly lower et al. [51] showed significantly higher alveolar width pres-
reduction in the PRF group after 4 and 8 weeks (1 and ervation in the group of A-PRF + only when measured at
2 months) compared to the control group. Moreover, 3 mm below the alveolar crest (Table 5).
Suttapreyasri et al. [45] did not show any statistical sig- Two-dimensional X-ray evaluation. Conventional
nificant difference in the alveolar bone width and buc- radiologic analysis performed by Ahmed et al. [53]
cal and lingual contour changes using cast analysis after showed significantly lower resorption in the PRF group
8 weeks. Hauser et al. [46] reported on statistically sig- after 4 months compared to the control group. Kumar
nificantly lower percent of alveolar crest width resorption et al. [43] showed no statistical significant differences
in the PRF group compared to the control group after between the groups when considering the percent of
8 weeks (Table 5). socket fill after 6 months. By contrast Alzahrani et al.
Cone beam computer tomography. (CBCT) CBCT [44] used similar evaluation method and showed signifi-
measurements of the dimensional bone alteration after cantly higher percent of bone fill in the PRF group after
3 months were performed by Canellas et al. [47] the 2 months compared to the control group. Suttapreyasri
results showed statistically significantly lower bone et al. [45] analyzed the resorption of marginal bone at the
Table 1 Study design
Study Design Number of Test (n) Control (n) Manage Case definition Socket Surgical Region/tooth Healing
patients definition procedure time until
implantation

Castro et al. [41] Split mouth RCT​ 21 (15 females, 6 21 21 Not reported Patients in need Not reported Tooth extrac‑ Premaxilla 3 months
males) of at least three tions were
tooth extractions performed
in the aesthetic under local
zone were anesthesia and
sterile conditions
with a flapless
approach
Sharma et al. Split mouth RCT​ 30 (16 females 30 30 23.90 Patients requir‑ Not reported Extraction of the Not reported Not reported
[54] and 14 males) ing extraction tooth on both
of bilateral case and control
mandibular side was done
Al‑Maawi et al. International Journal of Implant Dentistry

molars except as atraumatic as

third molars possible in the
same appoint‑
ment
Mourao et al. Parallel RCT​ 32 (19 females 16 16 37 Patients requir‑ Not reported All teeth were Molars and Not reported
[56] and 13 males) ing posterior extracted using premolars
(2021) 7:117

tooth extraction a minimally

(third molar traumatic
exception) in procedure. No
the mandible or vertical releasing
maxilla region incisions were
were included performed. To
avoid root and
bony fractures,
the molar teeth
were sec‑
tioned using a
multilaminated
drill. Luxation of
the teeth was
performed using
a periotome
followed by
removal using
forceps
Page 6 of 27
Table 1 (continued)
Study Design Number of Test (n) Control (n) Manage Case definition Socket Surgical Region/tooth Healing
patients definition procedure time until
implantation

Canellas et al. Parallel RCT​ 48 (27 females, 24 24 44.8 Patients in good Presence of buc‑ Teeth were Incisors, canines 3 months
[47] 21 males) general health cal and palatal/ extracted using and premolars
requiring a sin‑ lingual bone small levers
gle, non-molar walls without any
tooth extraction osteotomy or
mucoperiosteal
flap, to minimize
trauma
Srinivas et al. [48] CCT split moth 30 (not further Not reported Not reported Not reported Healthy subjects Not reported Extraction Maxilla and Not reported
specified) with chronic of teeth was mandible
periodontal performed
conditions and with emphasis
Al‑Maawi et al. International Journal of Implant Dentistry

who had teeth on atraumatic

indicated for extraction
extractions methods. A
periosteal eleva‑
tor was used
to reflect the
(2021) 7:117

gingival tissues
surrounding the
tooth. Tooth was
luxated from
its socket using
periotomes
and/or luxators.
Appropriate for‑
ceps were used
depending on
the availability of
tooth structure
to complete
the extraction
process in the
maxilla or the
mandible
Ahmed et al. [53] Parallel RCT​ 54 (22 females, Test 1:18, test 18 Not reported Patients requir‑ Not reported Not reported Not reported Not reported
32 males) 2: 18 ing extractions of
maxillary or man‑
dibular teeth
and who desire
replacement of
teeth by dental
implants
Page 7 of 27
Table 1 (continued)
Study Design Number of Test (n) Control (n) Manage Case definition Socket Surgical Region/tooth Healing
patients definition procedure time until
implantation

Areewong et al. Parallel RCT​ 36 (21 females 18 18 50.67 Healthy vol‑ Intact surround‑ A minimally Single rooted 2 months
[55] and 15 males) unteers above ing alveolar bone traumatic extrac‑ premolars and/
20 year of age, (remaining bone tion technique or maxillary
no systemic at least two-third was performed. anterior teeth
pathoses, that of root length) The periodontal
could disturb ligaments were
implant place‑ gently cut with a
ment; Single Piezotome. The
rooted premolars tooth was care‑
and/or maxil‑ fully mobilized
lary anterior using forceps
teeth with an without flap
Al‑Maawi et al. International Journal of Implant Dentistry

indication to reflection
extract and to be
replaced with a
dental implant
Ustaoglu et al. Parallel RCT​ 57 (29 females Test1:19 19 Female: 35.9 Patients in need Persistence of The tooth Single-rooted Not reported
[42] and 28 males) Test2: 19 Male:37.91 of single-rooted 50% or more of was extracted tooth
(2021) 7:117

tooth extrac‑ bone support using a flapless

tion with the technique with
persistence of as little trauma
50% or more of to the bone and
bone support soft tissue
(anterior or
premolar teeth);
demanded a
single implant-
supported pros‑
thetic restoration
in a premolar or
anterior site
Page 8 of 27
Table 1 (continued)
Study Design Number of Test (n) Control (n) Manage Case definition Socket Surgical Region/tooth Healing
patients definition procedure time until
implantation

Giudice et al. Split mouth RCT​ 40 (12 females 40 40 60.9 Patient taking Not specified Teeth extractions All regions Not reported
[40] and 28 males) long-term oral were performed
antiplatelets and as atraumati‑
requiring at least cally as possible
four extractions attempting to
of non-adjacent preserve the
teeth alveolar bone.
Molars were sec‑
tioned with drills
in two or three
parts. Extrac‑
tion sockets
Al‑Maawi et al. International Journal of Implant Dentistry

were carefully
cleaned from
any remains
of granulation
tissue. Flapless
extractions were
(2021) 7:117

attempted, but
if necessary flaps
were elevated
at the discretion
of the
Operator
Zhang et al. [49] Parallel CCT​ 28 (14 females 14 14 34.6 Patients with Not reported All patients were Molars 3 months
and 14 males) upper and treated with
lower man‑ the non‑flap
dibular molars minimally inva‑
diagnosed as sive extraction
fractured tooth technology
or could not
be retained for
other reasons
Kumar et al. [43] RCT Parallel/Split 48 (not further Not reported Not reported 44.4 Patients requir‑ Not reported All teeth were All regions Not reported
specified) ing tooth extrac‑ extracted atrau‑
tion matically using
periotomes and
luxators without
raising muco‑
periosteal flap
Asmael et al. [58] RCT split mouth 20 males 20 20 44.2 Smoker patient Not reported Extraction in All regions Not reported
with multiple atraumatic
teeth extraction manner
Page 9 of 27
Table 1 (continued)
Study Design Number of Test (n) Control (n) Manage Case definition Socket Surgical Region/tooth Healing
patients definition procedure time until
implantation

Clark et al. [39] Parallel RCT​ 45 enrolled 40 Test 1:10 Control1:10 58 Patients with Teeth were Non-traumatic Not reported 3.75 months
analyzed (22 Test2:10 Control2:10 single-rooted excluded if tooth extraction
females and 18 tooth requiring they demon‑ was completed
males) extraction and strated a buccal without the
replacement dehiscence of elevation of a
with a dental more than 25% mucoperiosteal
implant sup‑ of the length flap
ported restora‑ of the tooth
tion or presence of
acute infection
of endodontic
origin
Al‑Maawi et al. International Journal of Implant Dentistry

Alzahrani et al. Parallel RCT​ 24 (15 females 12 12 37.8 Subjects with Not reported The teeth were Not reported Not reported
[44] and 9 males) at least one site extracted with
bordered by minimal trauma
minimum of one and without
tooth, nonsmok‑ flap elevation,
ers, teeth with using periot‑
(2021) 7:117

root fracture, omes by single

patients having experienced
teeth with hope‑ periodontist
less periodontal
prognosis, teeth
with failed endo‑
dontic therapy
or advanced
carious
lesion
Temmerman Split moth RCT​ 22 (15 females 22 22 54 Symmetrical Not specified A flapless Incisors, canines Not reported
et al. [50] and 7 males) bilateral (e.g., approach, as and premolars
premolar versus atraumatically as
premolar, incisor possible using
versus incisor) periotomes,
tooth extractions was used. Sites
in the maxilla or with loss of the
mandible buccal or palatal
bone plate
(< 50% of the ini‑
tial height) were
not excluded.
Sockets were
carefully cleaned
using curettes
Page 10 of 27
Table 1 (continued)
Study Design Number of Test (n) Control (n) Manage Case definition Socket Surgical Region/tooth Healing
patients definition procedure time until
implantation

Marenzi et al. Split mouth RCT​ 26 (17 females 53 Patients who All extraction The teeth were Canines, premo‑ Not reported
[57] and 9 males) needed bilateral sites were simple extracted in a lars and molars
paired dental with alveolar nontraumatic
extractions walls preserved manner without
elevation of full-
thickness flaps
and preserving
the buccal and
lingual walls of
the sockets
Suttapreyasri Split mouth RCT​ 8 (5 women and 8 8 20.3 Patients who Not reported The tooth was Premolars Not reported
et al. [45] 3 men) are physically gently luxated
Al‑Maawi et al. International Journal of Implant Dentistry

healthy, with no with an elevator

underlying sys‑ and carefully
temic disease, as extracted with
determined by extraction for‑
medical history ceps, attempting
records. Need for to minimize the
(2021) 7:117

symmetrical pre‑ trauma to the

molars extraction bone circum‑
scribing the
alveolus
Page 11 of 27
Table 1 (continued)
Study Design Number of Test (n) Control (n) Manage Case definition Socket Surgical Region/tooth Healing
patients definition procedure time until
implantation

Hauser et al. [46] Parallel RCT​ 23 (9 females Test 1: 19 8 47.43 Patients, who Presence of A scalpel for the Premolars 2 months
and 14 males) Test 2: 6 required the the buccal and syndesmotomy;
extraction of an palatal/lingual a buccal and
upper or lower bony walls evalu‑ palatal/lin‑
premolar before ated clinically by gual mucosal
its replacement measuring the flap without
by a dental thickness of the discharge for
implant alveolar ridge the PRF-flap
and radiologi‑ group; use of
cally by a periapi‑ dental elevators,
cal radiograph, extraction with
and residual forceps, curet‑
Al‑Maawi et al. International Journal of Implant Dentistry

periodontal tage, and socket

attachment of at filling with PRF
least 6 mm membranes for
PRF and PRF-flap
groups; place‑
ment of the PRF
(2021) 7:117

membranes
over the alveolar
crest for the
PRF-flap group;
hemostasis by
compression;
and suture with
a point cross
Thakkar et al. RCT (not further 36 sites (Number Not reported Not reported Not reported Patients between Not described Periotomes and Single rooted Not reported
[52] defined) of patients not the age group of forceps were teeth
defined) 20 and 55 years, used with great
requiring extrac‑ care taken to
tion of at least maintain the
one maxillary buccal bone and
or mandibular the surrounding
nonrestorable soft and hard
single‑rooted tissues
tooth
Page 12 of 27
Table 1 (continued)
Study Design Number of Test (n) Control (n) Manage Case definition Socket Surgical Region/tooth Healing
patients definition procedure time until
implantation
Yewale et al. [51] Parallel RCT​ 20 (9 females Not reported Not 35 Sites in maxilla Intactness of Extraction was Single rooted Not reported
and 11 males) were selected buccal corti‑ carried out teeth
which where, cal plate was atraumatically.
single non examined and Subsequent
restorable teeth assessed to atraumatic
and indicated for extraction,
extraction height of buccal
and palatal bone
plate was clini‑
cally inspected
at mid buccal
Al‑Maawi et al. International Journal of Implant Dentistry

and mid lingual

region with aid
of periodontal
probe. With #15
blade, intrasulcu‑
lar incision was
(2021) 7:117

made elevating
marginal gingiva
and adjacent
interdental
papilla. Flap
reflection
was done by
Periosteal eleva‑
tor resulting
in exposure
of crestal
bone around
socket. This
aided in direct
visualization
and measure‑
ment of crestal
bone level. Bone
curette was
used to debride
extraction socket
if granulation tis‑
sue is present
Page 13 of 27
Al‑Maawi et al. International Journal of Implant Dentistry (2021) 7:117 Page 14 of 27

Table 2 Risk bias assessment according to according to the Cochrane collaborations tool
Study Random sequence Allocation Blinding of participants Blinding of outcome Incomplete
generation concealment and personnel assessment outcome
data

Castro et al. [41] + n.a − + +

Sharma et al. [54] + n.a − − +
Mourao et al. [56] + n.a − − +
Canellas et al. [47] + n.a + + +
Ahmed et al. [53] − n.a − − +
Areewong et al. [55] + n.a − − +
Ustaoglu et al. [42] + n.a Participant - + +
Personnel +
Giudice et al. [40] + n.a – + +
Kumar et al. [43] − n.a ? − +
Asmael et al. [58] − n.a − − −
Clark et al. [39] + n.a ? + +
Alzahrani et al. [44] − n.a − − +
Temmerman al. [50] + n.a − − +
Marenzi et al. [57] + n.a ? ? +
Suttapreyasri et al. [45] − n.a − − +
Hauser et al. [46] ? n.a − ? +
Thakkar et al. [52] + n.a − − +
Yewale et al. [51] + n.a − + +
+ low ristk, −high risk, ? unclear risk, n.a., not applicable

show statistical significant differences, when analyzing

the bone density by means of gray scale after 16 weeks of
healing (Table 5).
Histologic evaluation. Four of the 20 evaluated stud-
ies analyzed bone core biopsies by histology. Focus was
placed on the evaluation of the percent of new bone for-
mation by histomorphometry. Canellas et al. [47]; Zhang
et al. [49] and Castro et al. [41] showed significantly
higher percent of new bone formation in the PRF group
Fig. 2 Bias risk assessment of RCTs according to the Cochrane after 3 months compared to the control group. Aree-
collaborations tool
wong et al. [55] (healing time: 8 weeks) and Clark et al.
[39] (healing time 15 weeks) did not show statistical sig-
nificant differences in the ratio of new bone formation
Table 3 Risk bias assessment according to Newcastle–Ottawa
(Table 5).
Quality Assessment Scale case–control studies
Micro-computer tomography (micro-CT) Clark et al.
Selection Comparability Exposure [39] and Hauser et al. [46] analyzed core biopsies
Srinivas et al. [48] using micro-CT. Bone volume to tissue volume analy-
sis after 8 weeks did not show any differences between
Zhang et al. [49] the PRF and control group. Similarly, the bone density
measurement after 15 weeks did not show statistically
significant differences. Castro et al. [41] showed a sta-
tistically significantly higher percent of bone volume/
mesial and distal sites after 2 months and did not show tissue volume when comparing the group of A-PRF + to
statistically significant differences. Whereas Hauser et al. the untreated control. However, no statistical signifi-
[46] performed similar measurements after 2 months cant differences were documented for the L-PRF group
and showed statistically significant differences, especially (Table 5).
in the mesial site. Moreover, Sharma et al. [54] did not
Al‑Maawi et al. International Journal of Implant Dentistry (2021) 7:117 Page 15 of 27

Table 4 Centrifugation protocols used in each study

Study PRF-type Tube RPM (RCF [×g]) Centrifugation Centrifuge
time (min)

Castro et al. [41] L-PRF 9­ml silica-­coated plastic tubes 2700 rpm ­(RCFclot: 408 g) 12 Intra-­Spin, Intra-­Lock
without anticoagulant (BVBCTP-
­2, Intra-­Spin, Intra-­Lock)
A-PRF + 10-ml glass tubes without anti‑ 1300 rpm ­(RCFclot: 145 g) 8 DUO Process
coagulant (DUO) for A-­PRF +
Sharma et al. [54] PRF 6 ml intravenous blood was 3000 rpm 10 LabTech AVI-532-BL centrifugation
collected in a 10-ml sterile tube machine
without anticoagulant
10-ml red tubes (IntraSpin™, IntraSpin™, Biohorizons®, Birming‑
Biohorizons®)
Mourao et al. [56] L-PRF 2700 rpm (708×g) 12
ham, Alabama, USA
Canellas et al. [47] L-PRF sterile, glass-coated plastic tubes 2700 (708×g) 12 Intra-Lock, Boca Raton, Florida,
USA
Srinivas et al. [48] L-PRF 10 ml test tubes which were kept 3000 rpm 10 Not reported
without an anticoagulant
Ahmed et al. [53] L-PRF Not reported 3000 rpm 10 Not reported
Areewong et al. [55] L-PRF Glass tube 2700 rpm 12 IntraSpin, Intra-Lock, Nice, France
Ustaoglu et al. [42] L-PRF 9 mL tubes 2700 rpm 12 Intra-Spin System, L-PRF kit, Intra-
Lock, Boca-Raton, FL, USA
T-PRF Grade IV sterile titanium tubes 2800 rpm 12 Not reported
Giudice et al. [40] A-PRF + A-PRF + tubes 1300 rpm 8 DUO centrifuge (Process for PRF,
Nice, France);
L-PRF Red tubes 2700 rpm 18 (Intra-Lock International, Boca
Raton, Florida, USA
Zhang et al. [49] L-PRF test tubes without any antico‑ 400×g 10 Hettich® Universal 320 (Andreas
agulant Hettich GmbH & Co.KG, Tuttlingen,
Germany)
Kumar et al. [43] PRF Not reported 3000 rpm 10 Not reported
Asmael et al. [58] PRF Five or ten milliliters of intrave‑ 3000 rpm 10 Centrifuge machine (Xiangtian,
nous blood was drawn in 10 mL Jiangsu China)
glass vacuumed tube without
anticoagulants
Clark et al. [39] A-PRF 01 mL sterile glass vacuum tube 1300 rpm 8 Not reported
Alzahrani et al. [44] PRF Not reported 3000 (400×g) 10 Compact centrifuge (Hermle
labortechnik, Germany)
Temmerman et al. [50] L-PRF Plastic 10-mL tubes without 2700 rpm 12 (IntraSpin™, IntraLock, Boca Raton,
anticoagulant Florida, USA)
Marenzi et al. [57] L-PRF 9-mL tubes 2700 rpm 12 Intra-Lock, Boca-Raton, FL, USA
Suttapreyasri et al. [45] L-PRF 10-mL glass tube 3000 rpm 10 Hettich Zentrifugen centrifuge
EBA 20 (Andreas Hettich GmbH&
Co, KG,
Tuttlingen, Germany
Hauser et al. [46] PRF 8-mL tubes without anticoagu‑ 2700 rpm 8 Not reported
lant
Thakkar et al. [52] PRF 10 ml syringe 3000 rpm 10 Not reported
Yewale et al. [51] A-PRF + 10-mL tubes without antico‑ 1300 rpm (208×g) 8 Not reported
agulants

Secondary outcomes Pain assessment

The results of the secondary outcomes are described Six studies evaluated the patients pain reports using the
below. visual analogue scale (VAS) by comparing socket treat-
ment by means of PRF to spontaneous healing. 66.6% of
the studies showed statistically significantly lower pain
in the PRF group compared to the spontaneous wound
Table 5 Dimensional bone alteration and bone regeneration outcomes in the evaluated studies
Study n Test Control Method Results test Results control Statistical significance

Castro et al. [41] 20 L-PRF Spontaneous healing CBCT (thickness buccal 1.1 ± 0.3 mm 1.1 ± 0.4 mm No
A-PRF+ bone 1 mm below the 0.9 ± 0.3 mm No
crest) after 3 months
CBCT (horizontal resorp‑ Buccal: 1.6 ± 0.8 mm Buccal: 1,7 ± 1.0 mm No
tion 1 mm below the Palatal: 0.6 ± 0.7 mm Palatal: 0.5 ± 0.7 mm
alveolar crest) after 3 Buccal: 1.6 ± 0.7 mm No
months Palatal: 0.7 ± 0.8 mm
CBCT (horizontal resorp‑ Buccal: 1.5 ± 0.8 mm Buccal: 1.4 ± 0.8 mm No
tion 3 mm below the Palatal: 0.4 ± 0.4 mm Palatal: 0.3 ± 0.4 mm
alveolar crest) after 3 Buccal: 1.2 ± 0.6 mm No
months Palatal: 0.4 ± 0.7 mm
CBCT (horizontal resorp‑ Buccal: 1.0 ± 0.7 mm Buccal: 1.0 ± 0.6 mm No
tion 5 mm below the Palatal: 0.2 ± 0.4 mm Palatal: 0.1 ± 0.6 mm
alveolar crest) after 3 No
Al‑Maawi et al. International Journal of Implant Dentistry

Buccal: 0.8 ± 0.6 mm

months Palatal: 0.3 ± 0.6 mm
CBCT (socket fill) after 3 85.2 ± 22.9% 67.9 ± 19.2% Yes: p = 0.005
months 83.8 ± 18.4% Yes: p = 0.01
Histomorphometry 47.7 ± 7.9% 34.7 ± 6.9% Yes: p < 0.05
Yes: p < 0.05
(2021) 7:117

(percent of bone volume/ 54.5 ± 5.6%

tissue volume)
Micro-CT (percent of 43.4 ± 8.7% 35.0 ± 8.2% No: p = 0.09
bone volume/ tissue 50.7 ± 4.5% Yes: p < 0.001
volume)
Sharma et al. [54] 30 PRF Spontaneous healing Digital panoramic radio‑ 91.980 88.689 No: 0.668
graphs (grayscale value)
after 16 weeks
Canellas et al. [47] 45 L-PRF Spontaneous healing CBCT (bone loss 1 mm 0.93 ± 0.9 mm 2.27 ± 1.2 mm Yes
below the alveolar crest) P < 0.0001
after 3 months
CBCT (bone loss 3 mm 0.85 ± 0.8 mm 1.67 ± 1.1 mm Yes
below the alveolar crest) p < 0.005
after 3 months
CBCT (bone loss at the 0.70 ± 0.7 mm 1.39 ± 1.2 mm Yes
buccal bone wall) after 3 P < 0.02
months
CBCT (horizontal bone 0.67 ± 0.5 mm 1.08 ± 1.0 mm No
loss at 5 mm below the P = 0.094
crest) after 3 months
CBCT (vertical bone loss 0.67 ± 0.9 mm 1.24 ± 1.15 mm No
at the palatal/ lingual P = 0.064
wall) after 3 months
Page 16 of 27
Table 5 (continued)
Study n Test Control Method Results test Results control Statistical significance

CBCT (new bone forma‑ 190.90 ± 169.90 ­mm3 44.87 ± 200.20 ­mm3 Yes
tion) after 3 months P = 0.009
Histomorphometry 55.96 ± 11.97% 39.69 ± 11.13% Yes
(percentage of new bone p = 0.00001
formation after 3 months)
Srinivas et al. [48] 30 PRF Spontaneous healing CBCT (bone density) 24 h: 319.79 ± 95.472 24 h: 194.82 ± 78.986 24 h: Yes
3 months: 564.76 ± 94.856 3 months: 295.87 ± 87.217 P < 0.001
3 moths: Yes
P < 0.001
CBCT (Bone hight) 24 h: 13.93 ± 3.56 mm 24 h: 14.68 ± 4.32 mm 24 h: No
3 months: 3 months: P = 0.466
12.28 ± 3.84 mm 12.78 ± 3.82 mm 3 moths: No
P = 0.615
Al‑Maawi et al. International Journal of Implant Dentistry

Ahmed et al. [53] 54 PRF Spontaneous healing Radiographic analysis 0.17 ± 0.44 mm 2.12 ± 0.69 mm Yes
(bone hight reduction, p < 0.001
crest to tip of the root
taking adjoining tooth as
a guide) after 16 weeks
Radiographic analysis Yes
(2021) 7:117

0.47 ± 0.36 mm 1.71 ± 0.49 mm

(bone width reduction) p < 0.001
after 16 weeks
Radiographic analysis 0.44 ± 1.21 1.45 ± 0.51 Yes
(bone density change P = 0.006
using gray scale histo‑
gram) after 16 weeks
Areewong et al. [55] 38 PRF Spontaneous healing Histomorphometric: new 31.33 ± 18% 26.33 ± 19.63% No
bone formation ratio after P = 0.431
8 weeks
Zhang et al. [49] 28 PRF Spontaneous healing CBCT after 3 months 1.6000 ± 1.46416 mm 2.8000 ± 1.81487 mm No
(reduction of the buccal
alveolar)
CBCT after 3 months 1.0000 ± 0.70711 mm 2.0500 ± 1.29180 mm No
(reduction of the height
of the lingual/palatal
alveolar crest)
CBCT after 3 months 1.0500 ± 0.77862 mm 2.0760 ± 1.67149 mm No
(reduction of the width of
the alveolar crest)
Histomorphometric 9.7624 ± 4.0121% 2.8056 ± 1.2094% Yes
analysis after 3 months P < 0.01
(osteoid) area/tissue area)
Page 17 of 27
Table 5 (continued)
Study n Test Control Method Results test Results control Statistical significance

Kumar et al. [43] 48 PRF Spontaneous healing Clinical measurement 3 ± 0.8 mm 3.3 ± 0.61 mm No
using measured using
metal callipers (average
loss of alveolar width)
after 6 months
Clinical measurement 3 ± 0.64 mm 3 ± 0.83 mm No
using measured using
metal callipers (average
loss of alveolar height)
after 6 months
Radiological measure‑ 73.76 ± 0.14% 74.3 ± 0.13% No
ment (degree of alveolar
fill) after 6 months
Al‑Maawi et al. International Journal of Implant Dentistry

Clark et al. [39] 45 Test 1: A-PRF Control1: spontaneous Clinical measurement Test 1: A-PRF: Control 1: 3.8 ± 2.0 mm Test 1 vs. control 1: Yes
Test 2: A-PRF + FDBA healing using alginate impression 1.8 ± 2.1 mm Control 2: 2.2 ± 1.8 mm P < 0.05
Control 2: FDBA and a periodontal probe Test 2: A-PRF + FDBA: Test 2 vs. control 2: No
(loss ridge height reduc‑ 1.0 ± 2.3 mm
tion) after 15 weeks
Clinical measurement Test 1: A-PRF: Test 1 vs. control 1: No
(2021) 7:117

Control 1: 2.9 ± 1.7 mm

using alginate impression 2.8 ± 1.2 mm Control 2: 2.5 ± 1.1 mm Test 2 vs. control 2: No
and a metal callipers (Loss Test 2: A-PRF + FDBA:
of ridge width (coronal)) 1.9 ± 1.1 mm
after 15 weeks
Clinical measurement Test 1: A-PRF: Control 1: 1.8 ± 1.3 mm Test 1 vs. control 1: No
using alginate impression 1.8 ± 1.8 mm Control 2: 1.5 ± 1.2 mm Test 2 vs. control 2: No
and a metal callipers (Loss Test 2: A-PRF + FDBA:
of ridge width (middle)) 1.7 ± 1.2 mm
after 15 weeks
Clinical measurement Test 1: A-PRF: Control 1: 1.5 ± 1.6 mm Test 1 vs. control 1: No
using alginate impression 1.8 ± 1.5 mm Control 2: 1.2 ± 1.3 mm Test 2 vs. control 2: No
and a metal callipers (Loss Test 2: A-PRF + FDBA:
of ridge width (apical)) 1.6 ± 1.5 mm
after 15 weeks
Micro-CT analysis of bone Test 1: A-PRF: Control 1:487 ± 64 mg/ Test 1 vs. control 1: No
cores (bone mineral den‑ 493 ± 70 mg/cm3 cm3 Test 2 vs. control 2: No
sity) after 15 weeks Test 2: A-PRF + FDBA: Control 2: 551 ± 58 mg/
521 ± 58 mg/cm3 cm3
Histomorphometric analy‑ Test 1: A-PRF:46% ± 18% Not reported Test 1 vs. control 1: No
sis (percentage of vital Test 2: A-PRF + FDBA: Test 2 vs. control 2: No
bone) after 15 weeks 29% ± 14%
Page 18 of 27
Table 5 (continued)
Study n Test Control Method Results test Results control Statistical significance

Alzahrani et al. [44] 24 PRF Spontaneous healing Clinical Cast analysis Week 1: 2.09 ± 0.84 mm Week 1: 3.26 ± 2.21 mm Week 1:No
(reduction of alveolar Week 4: 5.22 ± 0.80 mm Week 4: 9.79 ± 6.02 mm P = 0.141
ridge width) Week 8: 8.58 ± 1.73 mm Week 8: 13.54 ± 6.57 mm Week 4:Yes
P = 0.012
Week 8:Yes
P = 0.036
Radiolographic analysis Week 1: 74.05 ± 1.66% Week 1: 68.82 ± 1.07% Week 1: Yes
(mean radiographic bone Week 4: 81.54 ± 3.33% Week 4: 74.03 ± 1.22% P = 0.012
fill) Week 8: 88.81 ± 1.53% Week 8: 80.35 ± 2.61% Week 4:Yes
P = 0.00
Week 8: Yes
P = 0.017
Temmerman et al. [50] 22 PRF Spontaneous healing CBCT after 3 months (Ver‑ 0.4 ± 1.1 mm 0.7 ± 0.8 mm No
tical resorption, lingual)
Al‑Maawi et al. International Journal of Implant Dentistry

CBCT 3 months (Vertical 0.5 ± 2.3 mm 1.5 ± 1.3 mm Yes

resorption, buccal) P = 0.0002)
CBCT 3 months (Horizon‑ 22.84 ± 24.28% 51.92 ± 40.31% Yes
tal width reduction 1 mm P = 0.0004
below the crest)
(2021) 7:117

CBCT 3 months (Horizon‑ 6.16 ± 6.16% 14.51 ± 19.6% Yes

tal width reduction 3 mm p = 0.007
below the crest)
CBCT 3 months (Horizon‑ 2.91 ± 4.54% 4.4 ± 4.89% Yes
tal width reduction 5 mm P = 0.02
below the crest)
CBCT 3 months (socket 8.1 ± 3.1 mm 6.2 ± 3.9 mm Yes, P = 0.005
fill) 94.7 ± 26.9% 63.3 ± 31.9% Yes, P = 0.0004
Suttapreyasri et al. [45] 8 PRF Spontaneous healing Clinical socket dimen‑ M-D: 1.76 ± 1.36 mm M-D 2.17 ± 1.65 mm M-D: no
sion measurements after B-L: 3.31 ± 0.09 mm B-L: 3.92 ± 0.64 mm B-L: no
8 weeks (mesial-distal
[M-D] and buccal-lingual
[B-L]) were measured
from the inner socket ori‑
fice at the midpoint of the
extraction site, a UNC-15
periodontal probe (Hu-
Friedy, Chicago, IL)
Cast analysis buccal con‑ Upper part: Upper part: 2.59 ± 0.7 mm Upper part: no
tour change after 8 weeks 1.96 ± 1.10 mm Middle part: Middle part: no
Middle part: 1.61 ± 0.43 mm Lower Lower part: no
1.79 ± 0.90 mm part: 0.56 ± 0.38 mm
Lower part: 0.5 ± 0.72 mm
Page 19 of 27
Table 5 (continued)
Study n Test Control Method Results test Results control Statistical significance

Cast analysis lingual con‑ Upper part: Upper part: Upper part: no
tour change after 8 weeks 1.59 ± 0.64 mm 1.03 ± 0.57 mm Middle part: no
Middle part: Middle part: Lower part: no
0.42 ± 0.39 mm 1.78 ± 0.47 mm
Lower part: Lower part:
1.78 ± 0.57 mm 0.39 ± 0.35 mm
Radiographic Resorption 2.22 ± 0.51 mm 2.86 ± 0.65 mm No
of Marginal Bone Levels
at Mesial of the Extraction
Site after 8 weeks
Radiographic Resorption 2.08 ± 0.09 mm 2.10 ± 0.50 mm No
of Marginal Bone Levels
at distal of the Extraction
Al‑Maawi et al. International Journal of Implant Dentistry

Site after 8 weeks

Hauser et al. [46] 23 PRF Spontaneous healing Clinical measurements of 0.48% 3.68% Yes
the alveolar crest P < 0.05
Width loss after 8 weeks
Radiographical analysis of Mesial: 1.21 ± 0.4 mm Mesial: 0.77 ± 0.17 mm Mesial: yes
the vertical linear Meas‑ Distal: no
(2021) 7:117

Distal: 0.76 ± 0.25 mm Distal: 2.07 ± 0.81 mm

urements on Superimpos‑
able Radiographs after
8 weeks
Micro CT (bone volume/ 0.281 ± 0.037 0.249 ± 0.037 No
Tissue Volume) after
8 weeks
Thakkar et al. [52] 36 sites demineralized Demineralized calibrated radiographs 0.75 ± 0.49 mm 1.3611 ± 0.70 mm Yes (p = 0.005)
freeze‑dried bone allo‑ freeze‑dried bone allo‑ (Ridge width reduction
graft (DFDBA) mixed with graft (DFDBA), covered by from baseline to 180 days)
PRF, covered by a collagen a collagen membrane
membrane
Ridge height reduc‑ 1.38 ± 0.50 mm 1.08 ± 0.428 mm No
tion (from baseline to
180 days)
Yewale et al. [51] Sybograf plus (70% HA Sybograf plus (70% HA CBCT after 6 months: hori‑ 2.123 ± 0.76 mm 1.83 ± 0.8 mm No
and 30% βTCP) mixed and 30% βTCP), covered zontal width at 1 mm
with A-PRF + , covered by by a Collagen sponge
a Collagen sponge (Col‑ (Collasponge ™)
lasponge ™)
CBCT after 6 months: hori‑ 1.689 ± 0.84 mm 0.596 ± 1.08 mm Yes (p = 0.041)
zontal width at 3 mm
CBCT after 6 months: hori‑ 0.97 ± 1.28 mm 0.59 ± 1.59 mm No
zontal width at 5 mm
Page 20 of 27
Al‑Maawi et al. International Journal of Implant Dentistry (2021) 7:117 Page 21 of 27

healing [42, 50, 56, 57]. Ustaoglu et al. [42] showed that [59]. Two studies showed no statistically significant dif-
both L-PRF and T-PRF significantly reduced patients’ ferences between the L-PRF, A-PRF + groups compared
pain on day 1 compared to the control group of sponta- to the spontaneous wound healing after one week [40,
neous wound healing. However, on day 2 the pain was 42]. Six studies (75% of the evaluated studies) reported
reduced in both groups without statistical significant remarkable improvement of the soft tissue healing in the
differences. Maurao et al. [56] showed that L-PRF sig- L-PRF and T-PRF groups compared to the spontaneous
nificantly reduced patients pain on day 7 compared to wound healing, especially in the early healing time point
the spontaneous healing without PRF. Kumar et al. [43] of one week [48, 53, 54, 56, 57]. Additionally, Ustaoglu
reported that 18% of the patients of the control group et al. [42] evaluated the percent of epithelialization and
(spontaneous healing) reported on pain, whereas 0% of showed statistically significantly faster epithelization
the PRF group had pain on day 1. Asmael et al. [58] did in the L-PRF and T-PRF groups compared to the spon-
not show any statistical significant difference between taneous wound healing on both time points week 1 and
the PRF treated side and the control side in their 2, whereas Asmael et al. [58] did not record any statis-
split mouth RCT. Tammerman et al. [50] evaluated tical significant difference between the evaluated groups
patients pain on day 3 and showed that L-PRF signifi- (Table 7).
cantly reduced the pain in comparison to the sponta-
neous wound healing. Additionally, Marenzi et al. [57] Discussion
showed significant differences in the pain reduction of Blood concentrates and especially PRF gained increas-
the L-PRF group compared to the spontaneous wound ing interest in the oral and regenerative medicine in the
healing on early time point. However, the differences last decade [31]. PRF is applied for different indications
subsided on day 4, (Table 6). to support wound healing and regeneration of both bone
One study by Yewale et al. [51] evaluated pain assess- and soft tissue. Recently, several systematic reviews eval-
ment after bone augmentation using bone substitute uated the existing clinical evidence of PRF in different
materials in combination with PRF versus bone substi- fields including oral and maxillofacial surgery [33, 60, 61]
tute material alone (n = 10 per group). The results were and orthopedics [62]. However, most of recent reviews
not statistically significant. analyzed more than one indication and used a broad set
of inclusion criteria, which hardly allow drawing concise
Soft tissue regeneration conclusions for specific indications of PRF [33, 60, 61].
Soft tissue regeneration was evaluated in 8 studies, Additionally, focus was frequently placed on the general
mainly using the soft tissue healing index by Landry et al. bone regeneration only, as an important parameter for

Table 6 Pain assessment outcomes in the evaluated studies

Study n Test Control Results test Results control Statistics

Mourao et al. [56] 32 L-PRF Spontaneous healing 7 days: 4 ± 1.15 7 days: 5.12 ± 1.08 Yes (p = 0.0128)
Ustaoglu et al. [42] 57 L-PRF Spontaneous healing Day 1: 3.30 ± 2.07 Day 1:5.11 ± 1.60 Day 1: yes (P = 0.047)
Day 2: 0.48 ± 0.92 Day 2 Day 2: No
T-PRF Spontaneous healing Day 1: 3.29 ± 1.85 Day 1: yes (P = 0.047)
Day 2: 0.47 ± 0.62 Day 2: No
T-PRF vs. L-PRF
No
Kumar et al. [43] 48 PRF Spontaneous healing Day 1: 0% of the Day: 1 18.1% of the Not reported
patients patients
Asmael et al. [58] 20 PRF Spontaneous healing 48 h After Extraction: 48 h After Extraction: No
0.65 1.8
Temmerman et al. [50] 22 L-PRF Spontaneous healing Day 3: 2,81 Day 3: 3,52 Yes
P = 0.03
Marenzi et al. [57] 26 L-PRF Spontaneous healing 3.2 ± 0.3 4.5 ± 0.7 Yes
P < 0.0001
Yewale et al. [51] 20 Sybograf plus (70% HA Sybograf plus (70% Pain frequency after Pain frequency after No
and 30% βTCP) mixed HA and 30% βTCP), 10 days: 10 days:
with A-PRF + , covered covered by a Collagen Mild:2 Mild:3

(Collasponge ™) ™
by a Collagen sponge sponge (Collasponge Moderate:8 Moderate: 7
)
Al‑Maawi et al. International Journal of Implant Dentistry (2021) 7:117 Page 22 of 27

Table 7 Soft tissue healing outcomes in the evaluated studies

Study n Test Control Method Results test Results control Statistics

Sharma et al. [54] 30 PRF Spontaneous healing The Landry wound Day 3: 3.43 ± 0.504 Day 3: 3.17 ± 0.379 Day 3: yes
healing index Day 7: 3.93 ± 0.254 Day 7: 3.73 ± 0.082 p = 0.025
(mean ± SD) Day 14: 4.83 ± 0.379 Day 14: 4.3 ± 0.46 Day 7: yes
P = 0.039
Day 14: yes
p = 0.00
Mourao et al. [56] 32 L-PRF Spontaneous healing Wound healing index Week 1: 3.81 ± 0.65 Week 1: 3.18 ± 0.54 Week 1: Yes
(mean ± SD) Week 2: 4.75 ± 0.44 Week 2: 4.5 ± 0.51 p = 0.0138
Week 2: No
Srinivas et al. [48] 30 PRF Spontaneous healing Wound healing index 3.8 ± 0.40 3.0 ± 0.53 Yes
after 7 days P < 0.001
Ahmed et al. [53] Spontaneous healing Wound healing index Very good 94.1% Very good in 86.7% Not reported
Ustaoglu et al. [42] 57 L-PRF Spontaneous healing The Landry wound Week 1: 3.58 ± 0.63 Week 1: 3.21 ± 0.66 Week 1: no
healing index Week 2: 4.59 ± 0.51 Week 2: 4.38 ± 0.49 Week 2: no
(mean ± SD)
Spontaneous healing Complete wound Week 1: 54.9 Week 1: 10.1 Week 1: yes
epithelization (%) Week 2: 100 Week 2: 40.7 P = 0.047
Week 2: yes
P = 0.041
T-PRF Spontaneous healing The Landry wound Week 1: 3.69 ± 0.51 Week 1: 3.21 ± 0.66 Week 1: no
healing index Week 2: 4.71 ± 0.50 Week 2: 4.38 ± 0.49 Week 2: no
(mean ± SD)
Spontaneous healing Complete wound Week 1: 70.1 Week 1: 10.1 Week 1: yes
epithelization (%) Week 2: 100 Week 2: 40.7 P = 0.047
Week 2: yes
P = 0.041
Giudice et al. [40] 40 A-PRF + Spontaneous healing Wound healing index Week 1: 1 Week 1: 1.05 No
(mean) Week 2: 0.25 Week 2: 0.33
L-PRF Spontaneous healing Wound healing index Week 1: 0.95 Week 1: 1.05 No
(mean) Week 2: 0.15 Week 2: 0.33
Asmael et al. [58] 20 PRF Spontaneous healing Percentage of epitheli‑ 52.7% 51.3% No
zation after 1 week
The Landry wound 3.45 4.2 Yes
healing index (mean) P = 0.0035
after 1 week
15 L-PRF Spontaneous healing Wound healing index Day 3: 4.8 ± 0.6 Day 3: 5.1 ± 0.9 Day 3: No p = 0.197
Marenzi et al. [57] (mean ± SD) Day 7: 4.5 ± 0.5 Day 7: 4.9 ± 0.3 Day 7: yes p = 0.05
Day 14: 4.2 ± 0.2 Day 14: 4.3 ± 0.3 Day 14: yes p = 0.01
Day 21: 4.1 ± 0.1 Day 21: 4.2 ± 0.2 Day 21: yes p = 0.0002

implantology, whereas little is known about the influence of conventional biomaterials [21, 23]. Therefore, it is not
of PRF on specific parameters of wound healing includ- comparable to other biomaterials such as bone substitute
ing soft tissue regeneration and pain. Interestingly, these materials or collagen-based membranes. Accordingly, a
factors were shown to contribute to patients satisfaction precise control group is needed to evaluate the efficacy
and the long-term success of dental implants. Addition- of PRF in the regeneration process. Hence, in this sys-
ally, many studies did not use “reasonable” control groups tematic review the native blood clot as a process of the
thus involving several additional cofactors [61, 63]. For spontaneous wound healing was considered as the most
example several studies were conducted to compare PRF suitable and reasonable control group to assess the regen-
in the test group with a collagen-based biomaterials [64, erative potential and efficacy of PRF. If biomaterials were
65] or mineralized bone substitute materials [64, 66] as utilized in combination with PRF, they had to be identi-
a control group. In this context, it has to be noted that cal in the test and control groups. This restriction to
PRF is an autologous bioactive blood concentrate system reasonable control groups additionally aimed to exclude
based on the blood components including platelets and bias from additional cofactors potentially influencing the
leukocytes, that are embedded in a fibrin network [21]. regeneration process. Based on this hypothesis, the pre-
It does not exhibit the physicochemical characteristics sent review addressed the following focused question: in
Al‑Maawi et al. International Journal of Implant Dentistry (2021) 7:117 Page 23 of 27

patients with freshly extracted teeth, what is the efficacy the centrifuge in most types and is usually adjustable; (b)
of PRF in in the prevention of pain and the regeneration the applied centrifugal force (RCF), a parameter that is
of soft tissue and bone compared to the respective con- mostly not visible on the centrifuge but can be calculated
trol without PRF treatment? according to the centrifuge radius and (c) the centrifuga-
The literature research revealed only 20 studies eligible tion time. Moreover, the used tube surface also influences
for the evaluation. In total 17 studies (RCTs and CCTs) the quality and bioactivity of the resulted PRF [78].
analyzed the effect of PRF compared to the spontaneous Most of the studies evaluated in the present review
wound healing. One study included four groups and eval- reported only the applied rpm, without any information
uated the treatment of PRF alone in the first test group about the radius of the used centrifuge or the resulted
compared to the spontaneous wound healing and in the RCF. Fourteen of the studies referred to the first intro-
second group the combination of PRF with a bone sub- duced protocol referred to “L-PRF” or “Choukrouns
stitute material in the second test group compared to PRF” and used a relatively high rpm of 2700–3000 for
the bone substitute material alone in the second control 10 to 12 min. Only three studies compared different PRF
group. Only 2 studies evaluated the combination of PRF protocols including advanced PRF, that implements a
with bone substitute materials in comparison to bone medium RCF (1300 rpm, 208×g) or T-PRF, that imple-
substitute material without PRF. ments specific titanium-based blood tubes. At this point,
A relatively high bias risk was assessed for most of the it has to be emphasized that the use of different prepa-
studies, especially concerning blinding of patients and ration protocols results in different PRF-qualities that
outcome assessment. Another limitation is the report on may manipulate the clinical outcome. Thereby, scientific
the morphology of the treated defects, i.e., the anatomy reporting on PRF should include the above-mentioned
of the socket after tooth extraction in terms of the pres- parameters. Accordingly, the authors recommend a
ence, quality and dimension of the buccal wall as well as recently published guideline to report on the preparation
the status of bone resorption at the time point of tooth of blood concentrates to be able to reproduce and evalu-
extraction. Recent studies showed that among others ate the scientific data [78, 79].
these parameters are highly important for the progress Within the limitations of the acquired data, 66% of the
of the regeneration process after tooth extraction and evaluated studies showed that the application of PRF
may predefine the risk of bone atrophy [5, 6]. These limi- significantly reduced the postoperative pain, especially
tations in the data acquisition point to the necessity to in early time points 1–3 days after surgery (Table 4).
improve the quality of reporting in future studies. This observation may be explained by the autologous
Additionally, when evaluating PRF it is important to and bioactive character of PRF and the release of differ-
analyze the preparation protocol. PRF is not a ready-to- ent growth factors and cytokines involved in pain con-
use product, but a freshly prepared blood derivate for trol. The application of PRF provides the wound with
each individual patient. Recently, many different centrif- all needed components to immediately start the healing
ugation protocols were reported in the literature [21, 29, process without the need for recruiting the immune cells
67, 68]. Additionally, there was a confusion in the litera- to the injury area.
ture concerning the reported parameters and the prepa- Additionally, 75% of the studies, that evaluated the
ration methods [69, 70]. Recent studies explored the role influence of PRF on the soft tissue healing, showed that
of the centrifugation process in the preparation of PRF PRF promoted a significantly faster wound healing com-
[67, 71–77]. These studies have shown that the applied pared to the control group (Table 7). In this context,
RCF has a crucial influence on the components and the according to the wound healing index by Landry et al.
bioactivity of PRF, thus influencing its therapeutic effi- [59], wound closure parameters were significantly better
cacy [67, 71–77]. Thereby, the application of a high RCF in the PRF group especially after 1 week of application.
during the centrifugation of PRF results in a significantly This finding reflects that PRF may be considered as an
lower number of platelets, leukocytes and growth factor autologous wound healing booster to accelerate wound
concentrations compared to PRF-matrices that are pre- healing. Various studies have shown that PRF releases
pared using a low RCF [67, 71–77]. This phenomenon important growth factors such as epidermal growth fac-
was proved in many studies and defined as the low-speed tor (EGF), that promotes epithelialization, transforming
centrifugation concept (LSCC), which explained for the growth factor beta (TGF-β), which is highly needed for
first time the role of the applied RCF in the preparation of fibroblasts proliferation and migration as well as vascular
blood concentrates [67]. In this context, three parameters endothelial growth factor (VEGF), which is a key signal
are mainly important when reporting on the preparation for neovascularization [67, 71–77].
of blood concentrates (a) the programmed revolutions The here reported clinical observations are in accord-
per minutes (rpm), which is a parameter that appears on ance with different preclinical studies showing the role
Al‑Maawi et al. International Journal of Implant Dentistry (2021) 7:117 Page 24 of 27

of PRF in wound healing. In vitro studies used soft tis- conventional biomaterials such as collagen matrices or
sue regeneration model by combining fibroblasts and bone substitute materials ranged from 3 months to years
endothelial cells previously provided explanation on the according to the biomaterial specific characterization
possible mechanisms of PRF in promoting wound heal- [16]. Therefore, when working with PRF, it is important
ing [74]. It was shown that in addition to the fibrin net- to understand its characteristics as a fibrin-based scaffold
work, which provides a favorable scaffold for residual and not as classical biomaterials.
cells such as endothelial cells and fibroblasts, PRF serves Thereby, the present systematic review suggests consid-
as a drug delivery system by gradually releasing growth ering PRF as a further group of regenerative biomaterials
factors and promote the building of a well-defined vascu- called blood-concentrates in addition to the xenogeneic,
lar network as well as enhancing fibroblasts proliferation allogeneic and synthetic biomaterials. This specific group
and migration [74, 77, 80]. Interestingly, the evaluated of blood concentrates provided completely different
clinical studies reported mostly no significant difference benefits and requirements and may be considered as an
in soft tissue healing after 2 weeks. This observation is adjuvant therapy [82]. Accordingly, different treatment
logic, as the wound healing process under physiological protocols apply for blood concentrates and they should
conditions normally finalize after 2 weeks so that no dif- not be treated likewise to the classical biomaterials in
ferences between the evaluated groups are observed after terms of guided bone regeneration (GBR) and guided
this time period [81]. tissue regeneration (GTR). Classical GBR/GTR bioma-
The analysis of the collected data concerning the effi- terials are inactive acellular materials, that require suf-
cacy of PRF in bone regeneration showed different out- ficient time until integrating into the implantation bed
comes according to the evaluation time point and applied and allowing for cell migration and therefore initiation of
method. Eleven studies reported on bone regeneration the regeneration process [83, 84]. Therefore, more time is
outcomes. Most of them evaluated bone regeneration needed in this case until the socket is ready for implan-
after 8 to 15 weeks. Three of four studies reporting on tation. However, PRF is as a bioactive scaffold including
clinical measurements showed significantly lower bone crucial blood cells that are necessary for the regeneration
resorption in the PRF group compared to the control process and can accelerate the phases of wound healing
group, especially when considering the buccal wall and and starts the regeneration process earlier.
the ridge height. Similarly, CBCT evaluation of bone The physiological atrophy process after tooth extrac-
resorption, bone density and socket fill showed sig- tion was described as a rapid and continuous process.
nificantly lower resorption in the PRF group compared About 50% of the alveolar bone atrophies in the first 3
to the control group after 8–15 weeks. Especially, the months after tooth extraction [7, 85]. Especially, in the
1–3 mm below the alveolar crest were well preserved first 3 months after tooth extraction the efficacy of PRF in
in the PRF group compared to the control group. Inter- delaying bone resorption was evidenced in the here eval-
estingly, one study reported on bone regeneration after uated studies. Consequently, after a period of 6 months
6 months using clinical measurements and did not show the effect of PRF subsided and bone atrophy as described
any differences between the PRF and control group. earlier. Only two studies were found, that evaluated the
Within the limitations of these data, a very important combination of bone substitute materials with PRF in
finding may be highlighted by this analysis concerning comparison to the native bone substitute material with-
the most suitable time point for implant insertion after out PRF. Based on the small number of patients and the
socket preservation using PRF. Based on the present limited data, it is not possible to draw a conclusion con-
results, it seems that PRF promotes accelerated soft tis- cerning the efficacy of PRF when combined with bioma-
sue and bone regeneration within the early healing phase. terials. Therefore, further well-designed RCTs are needed
Apparently, PRF is effective in delaying bone resorption, to answer this question.
but it cannot prevent it on the long run. Thereafter, the None of the here evaluated studies reported on the effi-
effect of PRF subsided, so that no difference could be cacy of PRF to reduce scar formation during soft tissue
observed after 6 months. These findings appear to be healing. Although liquid PRF is applied in esthetic treat-
plausible when looking at the properties of PRF, which is ment for skin rejuvenation and scar treatment [86, 87].
an autologous, bioactive, fibrin-based scaffold, and differ- Additionally, a recent study reported on the efficacy of
ent from ready-to-use biomaterials with stable scaffolds PRF in promoting wound healing in large defects after
such as collagen-based biomaterials or bone substitute three-dimensional augmentations in terms of the open
materials [67, 71–77]. An in vivo study has shown that healing concept as an alternative to flap mobilization
PRF degrades after 2–3 weeks, which is a sufficient time and to avoid flap dehiscence [3]. Moreover, no data were
period to expand its effect on the early wound heal- found about the implant survival rate of implants placed
ing [23]. By contrast, the degradation time periods of in sockets treated with PRF compared to the spontaneous
Al‑Maawi et al. International Journal of Implant Dentistry (2021) 7:117 Page 25 of 27

wound healing. Eventually, none of the evaluated studies Availability of data and materials
Not applicable.
reported on any adverse or server reactions related to the
application of PRF.
Altogether, the analysis of the available evidence of 20 Declarations
prospective, controlled studies highlighter the efficacy of Ethical approval and consent to participate
PRF in supporting socket healing after tooth extraction. Not applicable.
PRF was demonstrated to promote soft tissue regen- Consent for publication
eration, to reduce the postoperative pain and prevent- Not applicable.
ing bone dimensional bone loss in the early period of
Competing interests
2–3 months. This evidence refers to PRF protocols using The authors declare that they have no conflict of interests.
a high RCF during the preparation. It has to be stated
that the number of available studies in this field is very Author details
1
FORM, Frankfurt Oral Regenerative Medicine, Clinic for Maxillofacial and Plas‑
limited, and that the risk of bias was high. Future stud- tic Surgery, Goethe University, Theodor‑Stern‑Kai 7, 60596 Frankfurt/ Main,
ies are needed to evaluate further PRF protocols using a Germany. 2 Department of Oral Surgery and Implantology, Carolinum, Goethe
lower RCF protocols to further investigate the potential University, Frankfurt, Germany. 3 Department of Orthodontics, University
of Düsseldorf, 40225 Düsseldorf, Germany.
benefit of different preparation protocols as an indica-
tion-specific approach. Received: 12 August 2021 Accepted: 4 November 2021

Conclusion
The present reviews aimed to provide clinical evidence
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