Systematic Review
## Maxillary Sinus Augmentation Using Autologous Platelet

## Concentrates (Platelet-Rich Plasma, Platelet-Rich Fibrin,

## and Concentrated Growth Factor) Combined with Bone Graft:

## A Systematic Review

**Giuseppina Malcangi 1,† , Assunta Patano 1,† , Giulia Palmieri 1 , Chiara Di Pede 1, Giulia Latini 1,**
### Alessio Danilo Inchingolo 1 , Denisa Hazballa 1 , Elisabetta de Ruvo 1, Grazia Garofoli 1,
### Francesco Inchingolo 1,* , Gianna Dipalma 1,* , Elio Minetti 2 and Angelo Michele Inchingolo 1

Abstract: Background: The current review aims to provide an overview of the most recent research
on the potentials of concentrated growth factors used in the maxillary sinus lift technique. Materials
and methods: “PRP”, “PRF”, “L-PRF”, “CGF”, “oral surgery”, “sticky bone”, “sinus lift” were the
Citation: Malcangi, G.; Patano, A.;
search terms utilized in the databases Scopus, Web of Science, and Pubmed, with the Boolean operator
Palmieri, G.; Di Pede, C.; Latini, G.;
“AND” and “OR”. Results: Of these 1534 studies, 22 publications were included for this review.
Inchingolo, A.D.; Hazballa, D.; de
Discussion: The autologous growth factors released from platelet concentrates can help to promote
Ruvo, E.; Garofoli, G.; Inchingolo,
bone remodeling and cell proliferation, and the application of platelet concentrates appears to reduce
F.; et al. Maxillary Sinus
the amount of autologous bone required during regenerative surgery. Many authors agree that
Augmentation Using Autologous
growth factors considerably enhance early vascularization in bone grafts and have a signiﬁcantly
Platelet Concentrates (Platelet-Rich
Plasma, Platelet-Rich Fibrin, and
positive pro-angiogenic inﬂuence in vivo when combined with alloplastic and xenogeneic materials,
Concentrated Growth Factor)
reducing inﬂammation and postoperative pain and stimulating the regeneration of injured tissues and
Combined with Bone Graft: A
accelerating their healing. Conclusions: Even if further studies are still needed, the use of autologous
Systematic Review. Cells 2023, 12,
platelet concentrates can improve clinical results where a large elevation of the sinus is needed by
improving bone height, thickness and vascularization of surgical sites, and post-operative healing.

cells12131797

      Keywords: PRP; PRF; CGF; Sinus Lift (S.L.); oral surgery; growth factor

Received: 22 May 2023
Revised: 30 June 2023
Accepted: 4 July 2023
      ### 1. Introduction

  The balance of bone resorption and bone creation is critical for the preservation and
regeneration of alveolar bone and supporting structures surrounding teeth and dental
implants [1]. Tissue regeneration in the oral cavity is inﬂuenced by a variety of cell types,
signaling systems, and matrix interactions [1,2]. Severe bone defects in the areas where the
implant is to be placed might restrict the surgery; as a result, numerous bone regeneration
techniques have been designed [3]. Maxillary sinus ﬂoor elevation (MSFE) is one of these

distributed under the terms and
procedures meant to increase bone volume in the atrophic posterior maxilla [4,5]. MSFE
conditions of the Creative Commons
aims to increase bone height in the posterior maxilla by raising the Schneiderian membrane
and inserting graft material into the surgically generated gap in the maxillary sinus ﬂoor [1].

creativecommons.org/licenses/by/
Clinical trials of MSFE and other bone grafting methods, including biomaterial grafting,
4.0/).

have been conducted to enable more predictable and strategic implant-supported pros-
theses [6]. Because of their osteoinductive and osteoconductive qualities, as well as their
immunogenic compatibility, autogenous bone transplants have long been employed [3].
However, there are disadvantages to using autogenous bone transplants, such as donor
site morbidity, insufﬁcient quantity, and bone resorption in patients after a long healing
period [7]. Although they provide the most biocompatible option, the disadvantages of
autogenous grafts have driven the search for alternatives [8]. In current dentistry, the
use of platelet-rich products derived from the patient’s own blood appears to be a fa-
vored therapeutic option [9]. Platelets serve as reservoirs for growth factors and cytokines
that aid in bone and soft tissue regeneration during wound healing [10]. Platelets, when
activated, establish a network in the ﬁbrin matrix and release growth factors that drive
the tissue-healing mechanism and, as a result, regeneration [4]. Platelets contain secre-
tory granules that are rich in growth factors: vascular endothelial growth factor (VEGF),
transforming growth factor-b1 (TGF-b1), platelet-derived growth factor (PDGF), epider-
mal growth factor (EGF), hepatocyte growth factor (HGF), ﬁbroblast growth factor (FGF),
insulin-like growth factor (IGF), etc. [10,11]. The main generations of APCs are platelet-rich
plasma (PRP), platelet-rich ﬁbrin (PRF) and concentrated growth factor (CGF) [4]. PRP,
the ﬁrst generation of platelet concentrates (PCs), is a plasma concentrate high in platelets
that may be produced by centrifuging the patient’s venous blood and then using it as a
bone-grafting material [12,13]. Because of the limits of PRP due to its anticoagulant compo-
sition, additional research by Joseph Choukroun in the early 2000s focused on generating
a second-generation platelet concentrate free of anticoagulant factors [14]. The second
generation of platelet concentrates, platelet-rich ﬁbrin (PRF), has the same qualities as PRP
but with the added beneﬁt of osteogenicity [14]. The presence of additives in PRF is not
required because of the presence of ﬁbrinogen, which is converted to ﬁbrin under the effect
of physiologically accessible thrombin; this minimizes the risk of postoperative complica-
tions [9]. Concentrated growth factor (CGF), ﬁrst used by Sacco in 2006, is a new platelet
concentrate product that has demonstrated promising outcomes in soft tissue stimulation
and acceleration as well as bone healing and creation [15–18]. CGF concentrates CD34+
stem cells and several growth factors in a small quantity of plasma [19]. CGFs are produced
by centrifuging blood samples at alternate and regulated speeds in a specially designed
centrifuge (Medifuge, Silfradentsrl, Italy) [20]. Different centrifugation rates allow for the
separation of a ﬁbrin matrix that is rich in growth factors and is signiﬁcantly bigger and
denser than PRP or PRF [20]. Sticky bone is an evolution of the regenerative technique with
CGF. The sticky bone is obtained by mixing the centrifuged liquid of the test tube with a
white smooth-walled cap that gels after a few minutes with the bone particulate of various
kinds composed of mixed granulometry (calcium triphosphate, BiOss, dentin deriving
from toot transformer) [21]. A compact and plastic compound is obtained that is easy to
insert into the site to be regenerated. By then also combining the chopped ﬁbrin clot before
the gelling of the preparation, it is possible to obtain a compound richer in growth factors
and therefore with greater regenerative potential [22] (Figure 1). The current review aims
to provide an overview of the most recent research on the therapeutic and experimental
potentials of autologous platelet concentrates (PRP, PRF and CGF) combined with bone
grafts in maxillary sinus augmentation.

Figure 1. Sticky bone: A compact and plastic compound, evolution of the regenerative technique
with CGF.
### 2. Materials and Methods
2.1. Protocol and Registration

This review was conducted in accordance with the standards of the Preferred Report-
ing Items for Systematic Reviews and Meta-analysis (PRISMA) [23].

2.2. Search Processing

PRP, PRF, CGF, ORAL SURGERY, STICKY BONE, SINUS LIFT were the search terms
utilized in the databases (Scopus, Web of Science, and Pubmed) to select the papers under
evaluation, with the Boolean operator “AND”.
The search was restricted to only items released in English during the previous ten
years (2010–2023) (Table 1).

Table 1. Database search indicators.

    Article screening
    Strategy

2.3. Eligibility Criteria

The reviewers, who worked in pairs, chose works that satisﬁed the following criteria
for inclusion: (1) human subjects-only research; (2) clinical studies or case reports.
Exclusion criteria were (1) in vitro studies, (2) animal studies, (3) systematic reviews,
narrative reviews, and meta-analyses.
The review was conducted using the PICO criteria:
Population: adults, both male and female who needed maxillary sinus lift;
Intervention: growth factors used in the maxillary sinus lift technique;
Comparison: maxillary sinus lift technique without growth factors;
Outcome: effectiveness in bone regeneration.

2.4. Data Processing

The screening procedure, which was carried out by reading the article titles and
abstracts chosen in the earlier identiﬁcation step, allowed for the exclusion of any publi-
Database: Scopus, Web of Science and Pubmed
Keywords: A “PRP”; B “PRF”; C “L-PRF”; D “CGF”; E
“ORAL SURGERY”; F “STICKY BONE”; G “SINUS LIFT”
  Boolean variable: “AND” and “OR”
    Timespan: 2010–2023
    Language: English

cations that varied from the themes looked at. The complete text of publications that had
been determined to match the predetermined inclusion criteria was then read. Reviewer
disagreements on the choice of the article were discussed and settled.
### 3. Results

Keyword searches in the Web of Science (307), Scopus (362) and Pubmed (1333)
databases yielded a total of 2002 articles. The subsequent elimination of duplicates (468)
resulted in the inclusion of 1534 articles. Of these 1534 studies, 1512 were excluded because
they deviated from the previously deﬁned inclusion criteria. The screening phase ended
with selecting 22 publications for this work (Figure 2). The results of each study were
reported in Table 2.

Figure 2. PRISMA ﬂowchart.

      Table 2. Results table.

      In ﬁve consecutive
      patients who had
      bilateral sinus lift
Anitua et al.,
    Areport of ﬁve cases augmentation, the
2012 [24]
      prospective effects of
      (PRGF) technology were
      assessed.

      To describe histological
    Two cases reported
      sinus augmentation.

      To examine the clinical
      effects of (OSFE)
      combined with (CGF)
Chen et al.,
    Aretrospective study and simultaneous
2021 [26]
      implant implantation
      with or without bone
      grafting.

      Following an open sinus
      lift treatment with and
    Clinical trial
      of the posterior of the
      maxillary bone

      To evaluate indirect sinus
      lift with hydraulic
Choudhary et al.,
    Clinical study pressure and
2022 [28]
      simultaneous PRF
      implant implantation.

      The aim of the study was
      to evaluate the clinical
    Retrospective study
      collagen (MC) in guided
      bone regeneration (GBR).
-Five patients;
      PRGF may play a role in
-One side treated with bovine
      lowering tissue
bone and PRGF, and the
      inﬂammation during
other only with bovine bone;
      surgery, boosting the
-Lateral wall technique;
      production of new bone,
-Two stage implants;
      and encouraging the
-Five-month
      vascularization of bone
histomorphometrical
      tissues.
analysis.
-Two patients;
-Patient A—PRF as sole graft
material;
-Osteotom crestal technique;
      Patient A—implant fail.
-Simultaneous implant
      Histological analysis
placement;
      supported new bone
-Patient B—PRF as sole graft
      growth in both situations.
material;
-Lateral window technique’
-Two stage implant
placement.
-Forty-four patient;
-Sixty implants;
      OSFE with CGF
-Transalveolar technique
      approach is safe and
with CGF combined or not
      dependable, whether
combined with graft
      bone grafting is used or
material;
      not.
-Twenty-four-month
follow-up.
-Fourteen patients;
-Lateral wall osteotomy;
-Forty-one implant PRF may improve both
-One side used PRF. of bone resorption.
The other side without graft No implant fail.
material;
-Follow-up at 6 months.
      The average pretreatment
-Twenty-four patients;
      mean height signiﬁcantly
-Indirect sinus lift with
      increased after surgery.
hydraulic pressure;
      After six-months, there
-Simultaneous PRF implant
      was seen an increase in
implantation;
      the implant stability
-Evaluation at six months.
      quotient.
      New bone growth and
      postoperative pain were
-Fifteen patients treated with both positively impacted
CGF+MC (study group); by the use of CGF and
-Fourteen patients treated MC. This indicates that
with only MC (control the CGF-MC complex is a
      biomaterial for bone
      augmentation.

      Table 2. Cont.

      The aim of the study was

Ghasemirad et al., Randomized to examine the effect of

2023 [29] controlled trial CGF on the healing of a

      maxillary sinus lift.

      To offer a quick and

      straightforward solution
Huang et al.,
    Case report for Schneiderian
2016 [30]
      membrane perforation

      repair.

      To demonstrate the

      efﬁciency of PRP as a
Inchingolo et al.,
    Prospective study grafting material in bone
2012 [1]
      regeneration for dental

      implant.

      To assess the results of

      maxillary sinus lift using

      PRF as a ﬁlling material
    Prospective study
    with 48 months of
    follow-up
      concurrent implant

      placement in patients

      with sinus pathology.

      To determine if a liquid

      PRF-DBBM combination

    A Split-mouth, is successful at
Irdem et al.,
    histomorphometric stimulating the growth of
2020 [32]
      maxillary sinus

      augmentation.
      After 6 months, the

      proportion of newly

      produced bone in the

      CGF group was

      considerably higher than

Nine patients undergoing in the control (xenograft)

maxillary sinus lift. Bovine group, according to

xenograft was randomly alizarin red and

applied to one side and CGF hematoxylin-eosin

to the other side. staining procedures. The

      amount of leftover

      material in the control

      group compared to the

      intervention was

      noticeably higher.

-A 62-year-old man;

-lateral wall protocol;

-PRF to cover Schneiderian The Schneiderian

membrane perforation; membrane’s perforation

-Synthetic bone graft and could be repaired by PRF.

implant placement;

-Thirty-month control.

      The test group showed a

      statistically signiﬁcant
-Sixty-three patients (study
      enhancement in
group): PRP+ autogenous or
      osseointegration in terms
organic or anorganic bone;
      of primary stability and
-Sixty-four patients (control
      peri-implant bone quality
group): bone graft without
      evaluated in tomographic
PRP.
      sections with 3D

      software (Master 3D).

      The soft tissues around

      the implants in all

      patients showed no signs

Atotal of 175 implants were of tissue damage, the

placed after sinus lift using implants had optimal

PRF in combination with primary stability, and the

deproteinized bovine oss density of the bone

(Bio-OSS) and beta tricalcium around the implants had

phosphate (SINT-Oss). increased. There had

      been no unfavorable

      progression of the

      sinusitis.

-Seven patients;

-Two groups, grafted with

deproteinized bovine bone The combination of

mineral (DBBM) with liquid DBBM and liquid PRF

PRF or DBBM alone; helped to build new

-Lateral wall protocol; bone, although this effect

-Two-stage implants; was not statistically
histomorphometric

evaluation.

      Table 2. Cont.

      To compare bone growth
      in the elevated maxillary
      sinus using an implant as
Kaarthikeyan et al., A randomized
      a tent pole and PRF or
2019 [33] controlled trial
      blood clot alone as the
      only sinus-ﬁlling
      material.

      To compare the use of
    Radiological study
      (BIO-OSS) for sinus lift.

      To assess the outcomes of
      simultaneous implant
      insertion and to compare
Lv et al., A randomized
      outcomes between the
2021 [35] controlled trial
      PESS approach and
      lateral sinus ﬂoor
      elevation (LSFE).

      Analyzed the results of
      implants placed in the
Merli et al., Controlled Clinical maxillary sinuses using a
      technique and either
      (CGFs) or (DBBM).

      To evaluate the results of
      simultaneous
    Case series, single implantation and SFE
Molemans et al.,
    cohort prospective utilizing leukocyte- and
2019 [37]
      (L-PRF) as the sole graft
      material.

      Suitable techniques and
      materials that can
      increase bone thickness
Narang et al.,
    Case report by more than 10 mm
2015 [38]
      using the osteotomy
      procedure and grafting
      materials.
-Seven patients;
-Lateral bony window; As the only material to
-Implant used as a tent pole; ﬁll the sinuses, PRF
other side only blood; than a blood clot.
-Twelve-month follow-up.

      Compared to the use of
The sample size was
      PRP alone, radiological
constituted by 22
      results revealed an
interventions of sinus lift
      important rise in bone
with lateral window
      density and in bone
technique using Bio-oss
      height in the Bio-oss
(group 1) or PRF (group 2).
      group.
-Forty patients;
-PESS with PRF as the sole
grafting material
(transcrestal);
      PESS was more
-LSFE with deproteinized
      acceptable than LSFE and
bovine bone matrix (lateral
      was linked to lower
wall);
      postoperative morbidity.
-Simultaneous implant
insertion;
-Control 3, 6 and 18 months
post-surgery;
-Lateral wall technique; two groups.
-CGFs or DBBM as the sole Between the CGF and
grafting material; DBBM groups, there was
-Simultaneous implant no statistically signiﬁcant
- Twelve-month follow-up. bone loss (MBL) change.
-Twenty-six patients (28 SFE);
-Six lateral sinus lift;
-Twenty-two transalveolar L-PRF has proven to be a
-L-PRF as a sole graft affordable subsinus graft
-L-PRF to protect the natural bone growth
Schneiderian membrane; when used as the only
-Follow-up at the time of graft material.
implantation and after
6 months.

-A 67-year-old female During the OSFE
- Summer’s osteotomes implantation, using PRF
modiﬁed techniques; and bone graft material is
-PRF combined with bone a safe and efﬁcient

      Table 2. Cont.

      To assess how (L-PRF) in

    Randomized conjunction with (DBBM)
Nizam et al.,
    controlled clinical affects bone regeneration
2017 [39]
      augmentation.

      To investigate leukocyte-
Powell et al.,
    Case series and platelet-rich ﬁbrin
2022 [40]
      (L-PRF) in sinus lift.

      To compare the

      long-term clinical results

      of bone regeneration
    Retrospective study
      demineralized anorganic

      bovine bone combined

      with PRP.

      The lateral sinus lift

      procedure using only
Simonpieri et al., Case series with
      PRF clots and
2012 [9] 6-year follow-ups
      membranes with

      immediate implantation,

      In this work, DBBM was

      used as a xenograft in
    Prospective study
    with 6 months of
    follow-up
      the effect of PRF on bone

      regeneration.
-Thirteen patients;

-One group DBBM with

L-PRF, the other group L-PRF in DBBM did not
-Lateral window approach; regenerated bone.

-Two-stage implantation;

-Twelve-month follow-up.

      Dental implants were
In the ﬁrst case, L-PRF+
      successfully placed in
allograft was employed to
      every patient.
support a maxillary hybrid
      In the second case,
denture by bilateral sinus
      freeze-dried bone
augmentation.
      allograft was used to
In the second patient, only
      offer around 4 mm of
L-PRF was used in the
      extra vertical height for
elevation of the Schneiderian
      implant insertion. Six
membrane.
      months after sinus
In the third case, implant
      augmentation, histology
was placed after
      from the third case
L-PRF/xenograft+ sinus
      showed that there was
augmentation, and a
      fresh, viable bone in
histology was provided six
      contact with the
months later.
      xenograft.

-Fifty-seven patients

-Lateral wall protocol and

split bone technique.
      For both groups, this
-Two groups:
Group Algipore® (n = 29) study revealed

Group Bio-Oss® (n = 28); predictable outcomes

      over time.
-Two-stage implant

placement;

-Seven-year follow-ups.

-Twenty-three lateral sinus

elevations;

-Classical lateral sinus-lift,

Caldwell-Luc approach; The periimplant crestal

-The Schneiderian membrane bone height was

was covered with L-PRF consistent, and the level
-L-PRF clots to ﬁll the ﬂoor was always in
-Follow-up was conducted at implant apical end.

six months, a year, and then

every year after that for

6 years.

-Five maxillary sinus lifts After a six-month healing

treated with a mixture of period, this study did not

Bio-Oss and PRF (study show either a beneﬁt or a
-Five maxillary sinus lifts in conjunction with

treated only with Bio-Oss DBBM in maxillary sinus

### 4. Discussion
4.1. Different Platelet Derivates
Based on different centrifugation parameters, platelet concentrates are classiﬁed into
PRP, PRF and CGF [42,43].
PRP is a rich source of growth factors and platelets, and it is found in low-volume
plasma. PRP includes FGF, TGF-β, IGF, PDGF-like growth factors and cell adhesion
molecules such as vitronectin, ﬁbrin and ﬁbronectin. Because of this content, PRP acceler-
ates wound healing [44].
Venous blood is drawn, and an anticoagulant agent is mixed in to prevent the blood
from clotting. The mixture is centrifuged at 2400 rpm for 10 min. At the end of the ﬁrst
centrifugation, the blood in the tube is divided into two parts (upper part yellow plasma,
lower part erythrocytes accumulate). The whole mixture, using the cannulation technique,
is transferred to a second tube and subjected to a second centrifugation at 3600 rpm for
15 min to collect the platelet fraction at the bottom of the tube. What you get is PRP to be
used for the surgical procedure [44].
Because of the limitations of PRP arising from its anticoagulant content, further studies
by Joseph Choukroun in the early 2000s focused on the development of a second-generation
platelet concentrate without the use of anticoagulant factors [45].
In this way, it was observed for the ﬁrst time that in a single centrifugation cycle at
2700 rpm (750 g), a platelet concentration was collected that did not carry clotting factors to
the top of the centrifuge tubes. This formulation is called PRF [46,47].
PRF is a second-generation platelet product that enables the formation of growth
factors and platelet-rich membranes. PRF also contains leukocytes (WBCs) within the ﬁbrin
matrix (L-PRF) [46,48].
Peripheral venous blood is collected and centrifuged in glass-lined plastic tubes free of
anticoagulants at 2700 rpm for 12 min or 3000 rpm for 10 min. Since there is no anticoagulant
in PRF, coagulation begins when the blood is collected in the tube [8]. After centrifugation,
a layer of cell-free plasma is formed at the top, a layer at the base rich in erythrocytes, and
an intermediate layer of PRF clot. The PRF clot consists of a strong ﬁbrin matrix in which
platelets and leukocytes are concentrated [46,47].
PRF contains mainly platelets, ﬁbrin, platelet growth factors, cytokines, leukocytes,
circulating stem cells, monocytes, T and B lymphocytes, and neutrophil granulocytes [49].
CGF is a leukocyte- and platelet-rich ﬁbrin structure ﬁrst used by Sacco in 2006 [50].
As in PRF, CGF is obtained by a single centrifugation method. Plastic tubes without
anticoagulants lined with red-capped silica particles are required, and no exogenous
substances need to be added in this process [50].
The blood is centrifuged at low and controlled speeds for 12 min at 2400–2700 rpm.
The resulting clot is divided into three layers (the upper layer contains platelet-poor plasma;
the middle layer includes polymerized dense ﬁbrin blocks containing ﬁbrin and CGF; and
the lower layer contains erythrocytes). The upper and lower layers are discarded, and CGF
is collected in the buffy coat layer [51].
In 2006, Sacco ﬁrst developed CGFs [52]. CGFs have stiffer ﬁbrin structures than
PRP and PRF [53]. In addition, CGF is more effective in bone regeneration and breast
augmentation as it promotes osteogenesis [53,54].
CGF contains growth factors, such as PDGF, TGF-β, VEGF, insulin-like growth fac-
tors, epidermal growth factor, ﬁbroblast growth factor, bone morphogenic protein and
CD34+ cells [55]. CGF play an important role in vascular maintenance, angiogenesis and
neovascularization [56].
Astudy by Dai et al. evaluated the efﬁcacy of CGFs combined with MC in GBR [19].
Patients in whom CGF+MC was used and patients with MC alone were compared. It was
seen that all implants healed, and the CGF+MC group had less swelling and less pain.
The complex of CGF and MC seems to be appropriate and efﬁcient as a biomaterial for
bone augmentation [19].

The double-blind study by Ghasemirad et al. evaluated the effect of CGF on bone
healing in a maxillary sinus lift [29]. A bovine xenograft was applied on one side and
CGF on the other side. Staining with alizarin red and hematoxylin-eosin showed that
the percentage of bone formed in the CGF group was signiﬁcantly higher than in the
control group [29].
So, the percentage of newly formed bone in the CGF group was signiﬁcantly higher
than in the control group (xenograft) after 6 months [29].
Zhang et al. evaluate the inﬂuence of PRF on bone regeneration in a xenograft-
associated sinus lift (deproteinized bovine bone) [41]. On histological examination, no
statistically signiﬁcant differences were found between patients treated with PRF and
patients treated only with xenograft. In conclusion, the study showed no differences of
the application of PRF associated with deproteinized bovine bone in sinus augmentation
6 months after surgery [41].

The “gold standard” for bone tissue regeneration is an autograft taken from an adjacent
site in the same patient [57]. This procedure has negative effects such as a second surgical
procedure, unpredictable extent of resorption, and shortage of donor sites [58,59]. So, bone
substitutes can be applied to avoid these disadvantages.
The maxillary sinus has been augmented using a variety of graft materials, including
autograft, xenografts and allografts, each of which has advantages and disadvantages [60].
PRF has greater advantages than other graft materials since platelets are essential for the
development and repair of soft tissue and bone [61,62].
PRP is a plasma concentrate high in platelets produced by centrifuged peripheral
venous blood from the patient and used as a bone-grafting material. PDGF, TGF-β, and
VEGF are three growth factors that are particularly abundant in PRP, and they have
a potential range of cellular activities that includes cell differentiation, tissue healing,
angiogenesis and increasing collagen formation [61,62]. This approach had already been
applied in other ﬁelds of medicine such as in dermatology up until the late 1990s when
Marx et al. discovered that the use of PRP in conjunction with autologous bone might
result in a noticeably better outcome [63].
The following cellular processes are stimulated by PRP three days after grafting in the
recipient site: proliferation of osteoblasts and ﬁbroblast, neoangiogenesis, and stimulation
of the mineralization of the newly created bone matrix [1,64].
In implantology, GBR operations frequently employ PRP to repair edentulous regions
that need an increase in bone volume [61].
Astudy by Inchingolo et al. involved a cohort of 127 patients requiring a maxillary
sinus lift. Half of the patients received PRP in combination with anorganic, organic or
autogenous bone; the control group received only grafting material without PRP. In all
cases, authors obtained successful results, but the test group with PRP showed a statistically
signiﬁcant enhancement in osseointegration in terms of primary stability and peri-implant
bone quality evaluated in tomographic sections with a 3D software [1].
Another strategy is to insert the implants during the sinus lift to save time and prevent
a second surgery; Inchingolo et al. assessed the efﬁcacy of PRP with deproteinized bovine
oss (Bio-OSS) and beta-tricalcium phosphate (SINT-Oss) for a sinus lift and simultane-
ous implant placement in patients with sinus pathology [31]. The PRP prepared with
Choukroun’s technique was used in two different ways: a portion was blended with Bio-
Oss and Sint-Oss; the remaining was modelled as a resistant ﬁbrin membrane that could
be transferred to the Schneiderian membrane, and the other portion was transferred to
the material used before closing the lateral window created with the use of piezosurgery.
The soft tissues around the implants in all patients showed no signs of tissue damage; the
implants had optimal primary stability, and the density of the bone around the implants
had increased. There was no unfavorable progression of the sinusitis. The authors con-
cluded that the combination of PRF and Piezosurgery decreased the healing time, favored
4.2. Different Bone Graft Materials Used in Combination with Platelet Derivates

optimum bone regeneration, and allowed sinus membrane integrity to be preserved during
surgical treatments [31].
Instead, Kempraj et al. compared the use of Choukroun’s PRP as a single-graft
material to Xenograft (BIO-OSS) for a sinus lift [34]. The sample size was constituted by
22 interventions performed with the lateral window technique. Compared to the use of PRP
alone, radiological results revealed an important rise in bone density and in bone height in
the Bio-oss group. This could be caused by the sinus membrane’s collapse of the PRF plug
due to the absence of a structure that support it, as also reported by Lundgren et al. [65].
Promising results were shown by Powell et al., who experimented with L-PRF using
three different methods: in the ﬁrst case, L-PRF was employed to support a maxillary hybrid
denture by bilateral sinus augmentation. In the second patient, it emphasized the use of
L-PRF associated with an elevation of the Schneiderian membrane. In the third patient’s
implant placement after L-PRF/xenograft sinus augmentation, a histological examination
was provided six months later [40]. Dental implants were successfully placed in every
patient; in the second case, freeze-dried bone allograft offered around 4 mm of extra vertical
height for implant insertion. Six months after sinus augmentation, histology from the third
case showed that there was fresh, viable bone in contact with the xenograft [40].
Simonpieri et al. stated that literature ﬁndings regarding PRP’s efﬁcacy could have
been clearer because different PRPs were tried in several different combinations with varied
bone materials [9].
Despite being an excellent way to manage bone graft material during the incision in
the subsinus cavity, and despite having the potential to speed up bone healing, the degree
of proof for this technique was still just marginal because the surgical treatment already had
a very high success rate even without PRP [9]. Surgical methods and how PRP and bone
grafts were combined varied between research, so Simonpieri et al. asserted that because
of the many methodological variations, it could appear hard to draw broad conclusions
from the diverse research present in literature [9] (Figures 3 and 4).
Figure 3. Timing of the sinus lift using lateral window technique.

Figure 4. Section of a CBCT before (A) and after (B) the sinus lift.
Tatum, in 1976, modiﬁed the Caldwell–Luc technique and performed the ﬁrst maxillary
sinus lift procedure. Through the lateral window, the membrane of the sinus was dissected
and elevated (Figure 5); in this case, autogenous bone was used as a bone substitute in
the sinus, and the implant was placed after 6 months [66]. Boyne and James proposed the
Caldwell–Luc sinus revision and the lateral window sinus ﬂoor elevation, and implant
placement was performed in 3 months [66]. Since the ﬁrst sinus ﬂoor elevation, numerous
graft techniques and materials have been proposed.

Figure 5. (A) Using piezo surgery to open the window of Tatum and protect the arteries and the
Schneiderian membrane during the sinus lift graft (B) Views of the antral alveolar artery indicated by arrow.
4.3. Surgical Techniques for Sinus Augmentation Using Platelet Derivatives

      ## A

      ## B

In 1986, Tatum Jr. developed the transalveolar sinus ﬂoor elevation to minimize pain
and suffering after surgery [67]. Summers modiﬁed this approach in 1994 [68].
The Summer’s osteotomy, which used no grafting material even in thin residual bone
height, has been associated with developing the idea of limited grafting. The bone’s and
the sinus membrane’s osteogenic potential is well-protected and effective in a closed space
like an elevated sinus [69,70].
Simonpieri et al. applied a sinus lift with the lateral window technique in 24 patients,
and the follow-up time for these patients from the placement of the implants was 2–6 years
(Table 2). The patients had a subantral augmentation category 4 (SA4) sinus morphology
where the height of the crestal bone from the ﬂoor of the sinus is <5 mm. A PRF membrane
was used for the Schneiderian membrane protection, and the implant served as “tent
pegs” for the L-PRF-patched Schneiderian membranes. In this study, the height of the
peri-implant crestal bone was consistent, and the ﬂoor level of the reconstructed sinus was
always continuous with the apical edge of the implant [71] (Figure 6).

In fact, if the preservation of the Schneiderian membrane is achieved at the right height
with the help of immediate implantation, this technique has given successful results [72].
But this technique does not accept tears of the sinus membrane and presents difﬁculties
in ﬁlling the base of the sinus cavity with a blood clot [71]. Kaarthikeyan et al. concluded
that PRF is an effective biomaterial when used alone for ﬁlling the maxillary sinus with an
implant as a tentacle (Table 3), but perforation of the sinus membrane during the procedure
may lead to unsatisfactory results [33].
Other authors have shown that the lateral approach can be performed in a full sinus
lift only with whole blood and no other graft material [73,74]. Chitsazi et al. (Table 2) used
only PRF as bone graft material for raising the maxillary sinus with an open window on
one side and did not use graft material on the other side. Implants were placed in one
session. This study (Table 3) stated that PRF may improve both the quantity and quality of
bone resorption [27].
The ﬁbrin network found in PRF has the tendency to develop a three-dimensional
structure comparable to the place of insertion, promoting the healing process. A three-
dimensional scaffold is created by the accumulation of ﬁbrin monomers, creating a thin
Figure 6. Surgical approach techniques for sinus lift and timing for implants.

mesh of soft porous material that enables the quick cell colonization of the site and sur-
rounding tissues [9,75,76].
Molemans et al. also conducted a study using only L-PRF as ﬁller material in a
maxillary sinus lift. Only in cases when the crestal height was <5 was the lateral window
technique performed; in contrast, the preference was for the crestal technique (Table 2).
The results showed that this biomaterial can be used in lateral sinus surgery with success.
Implant failure was seen only in the crestal technique; it is possible that the membrane was
perforated during the procedure [37].
Choudhary et al.’s goal was to assess the effects of simultaneous implant insertion
with PRF and indirect sinus lift with hydraulic pressure when the average mean height
at the beginning was 5.573 ± 0.66 mm (Table 3). The average pretreatment mean height
signiﬁcantly increased after surgery (Table 2). A six-month postoperative period saw an
increase in the implant stability quotient [28]. These results were in line with earlier research
that showed a considerable rise in residual alveolar ridge height after indirect sinus lift and
concurrent PRF implant insertion [77,78].
During Summer’s osteotomy, the use of PRF membranes offered a good result as
ﬁlling material. PRF servs as a cushion shock absorber during osteotomy and supports
healing in case of a damaged Schneiderian membrane [79]. Huang et al. showed how the
PRF membrane can be used to repair the perforation of Schneider’s membrane caused by
the maxillary sinus lift procedure with the lateral window technique. The Schneiderian
membrane’s perforation could be repaired by a PRF membrane [30]. The PRF membrane’s
ﬁbrin and platelet contents may both play a role in this impact [65,80,81].
Independently of whether a procedure was 1-stage or 2-stage, Rosen et al., for the
osteotomy sinus ﬂoor elevation, found that the success of implant placement was better
when the ridge bone height was ≥5 mm [82]. Other authors had shown that when the
bone crest is less than 5 mm, the failure rate increases [83]. However, Li [84] asserts that
if primary stability has been attained, the osteotomy procedure can be applied even in
residual ridges with heights of 3–4 mm. Krasny et al., in 26 patients with a residual bone
height of 3–5 mm using the transalveolar sinus lift technique in two stages, successfully
reconstructed the maxillary sinus [85].
Aoki et al. presented the results of histopathological analyses performed in two case
reports wherein sinus elevation was conducted—in one case with a lateral window and
with only PRF as bone ﬁlling material and placement of implants in two stages, and in the
second case a crestal approach with PRF as a bone-ﬁlling material (Table 2). The residual
bone height in both cases was <2.7 mm. The histopathological results showed that the
presence of PRF in the sinus cavity induced the formation of new bone [25].
The Schneiderian membrane has a high potential for osteogenesis, which explains
why the majority of graft materials result in bone development [86–88]. Without the use of
graft material, a sinus ﬂoor elevation can still be performed with enough bone development
and implant longevity [72,89,90]. However, in an animal study, Kim et al. shown that bone
development is restricted when no material for grafts is used in sinus lift surgery [91]; also,
Sul et al. asserted that without graft material, bone formation may be constrained and that
the implant apex could get caught with the Schneiderian membrane [92]. But in the study
by Simonpieri et al., it was thought that the presence of the PRF membrane does not allow
the implant apex to be enmeshed with the sinus membrane [71].
Anitua et al. conducted a study of bilateral maxillary sinus elevation where one side
was treated with bovine bone and plasma rich growth factor (PRGF) and the other side as
a control group only with bovine bone (Table 2). The results showed that the side where
PRGF was used with bovine bone created new bone faster and was denser and more
compact than that of the control group; in addition, the side that was treated only with
bovine bone was more inﬂamed compared to the side where PRGF was used. Patients
indicated pain on the side where only bovine bone was placed [24].

Table 3. Results (from 6–12–18 months after surgery) of a comparison between platelet-derived and
different graft materials used for bone regeneration in the sinus lift technique. RBH, residual bone
height before surgery; MBL, marginal bone loss; TBH, total bone height.
    Group A, CGF with
    bone grafting; A—5.01 ± 0.64 A—0.11 ± 0.02
Chen et al., [88] Group B, CGF B—5.23 ± 0.49 B—0.10 ± 0.02
    without bone grafting
Group A, DBBM A—2.3 (0.8) A—0.04 (0.1) A—9.4 (1.1)
Merli et al., [36]
Group B, CGF B—3.0 (0.8) B—0.2 (0.2) B—9.7 (1.9)
Group A, PESS A—3.35 ± 0.79 A—0.60 ± 0.25 A—7.67 ± 1.29
Lv et al., [35] Group B, LSFE B—2.92 ± 0.63 B—0.69 ± 0.35 B—10.32 ± 1.26
      after six months
pressure using PRF.

  Platelet products have been found to inhibit monocyte cytokine release and restrict
inﬂammation [93]. Additionally, new ﬁndings imply that platelets initially block the release
of interleukin-1 (IL-1) from activated macrophages. Broad implications for the description
of a process by which platelet-rich products may operate as an anti-inﬂammatory agent
could result from the ﬁrst reduction of the inﬂammatory response [3].
  According to Lv et al., the ﬂapless endoscope-supported osteotome sinus ﬂoor el-
evation using sole (PRF) has a lower incidence of postoperative pain and edema than
sinus elevation with lateral windows ﬁlled with bovine bone and is more bearable for
patients (Table 2). But compared to the transcrestal approach with PRF alone (Table 3), the
lateral window technique with bovine bone seems to offer more peri-implant bone height
and density [35].
  Rapone et al. observed over a period of 7 years the results obtained from the elevation
of the maxillary sinus with the lateral window technique [3]. Patients were divided in
two groups, and as grafting material, the natural porous ﬂuorohydroxyapatite combined
with PRF was used in one group, and bovine bone with autogenous bone (50:50) combined
with PRP was used for the other group. For both groups, this study revealed predictable
outcomes over time (Table 2). Compared to implanting an ungrafted maxillary, this method
offers a better long-term prognosis and a greater survival rate [3,94].
  Irdem et al. stated that over a four-month period, the combination of bovine bone and
liquid PRF helped create new bone, although this effect was not statistically signiﬁcant
compared to bovine bone alone [32]. Nizam et al. (Table 2) also came to the conclusion that
under histological and histomorphometric examination, the addition of L-PRF to particle
DBBM did not increase the amount of regenerated bone or the degree to which the graft
was integrated into the newly created bone [39].
  Narang et al. [38], in a case report, used PRF with bone graft material to reach a height
>10 mm in the maxillary sinus area when the patient had residual ridge heights of 1.49 mm
and 1.47 mm. The technique followed was the modiﬁed Summer’s. The results showed that
this method is successful in raising the maxillary sinus and placing the implants (Table 2).
This procedure often only needs 3–4 months of recovery compared to other techniques,
which typically need at least 6–9 months. One explanation would be the smaller access
hole established in the sinus cavity. Blood ﬂow is rarely affected by this approach. The
Implant success rate
was 100% in the
two groups after
24 months

No implant failed for
the two groups after
12 months
No implant failed in
both groups after
6 months
PESS—96.15%
LSFE—100% after 3,
6, and 9 months

main beneﬁt of this technique, unlike the lateral window technique, is that the implant and
bone grafts obtain most of their blood supply from buccal [38] (Figure 7).
Figure 7. Summer’s technique using CGF graft for sinus lift.

Also according to Merli et al. (Table 2), lateral sinus ﬂoor elevation using CGFs as the
only grafting material resulted in implant success rates and slight changes in bone level
that were comparable to demineralized bovine bone grafting [36], Between the CGF and
the DBBM groups, there was no statistically signiﬁcant difference in marginal bone loss
(Table 3).
In fact, CGF is considered a new generation of platelet products that have dense ﬁbrin
networks and a high concentration of GF and are important in cell proliferation [95]. The
CD34+ cells have been discovered at both levels (CGF-RBC) and are entrapped in the
CGF matrix in large numbers. Due to its promotion of osteogenic cell differentiation and
proliferation, the CGF seems to have more promise for tissue regeneration. As a result, the
CGF greatly boosts alkaline phosphatase (ALP) activity [52,96].
According to Chen et al., in patients with a residual bone height of 4–6 mm before
surgery (Table 3), the osteotome sinus ﬂoor elevation with a CGF approach is safe and
dependable, whether bone grafting is used or not. Individuals who had bone grafting
experienced postoperative discomfort and pain compared to individuals who did not get
bone grafting. For the two groups, there was no big difference in marginal bone loss [26].
According to some studies, the survival rate of implants inserted in augmented sinuses
is not improved by autogenous bone alone [97–100]. The disappointing 82% implant
success rate once autogenous block graft is employed was also highlighted in two of
these reviews [98,99].
On the other hand, when xenograft was utilized instead of autogenous bone, two reviews
found that 96% of 10,000 studied implants survived after sinus augmentation [97,98].
In the study developed by Forabosco et al., in the group using only xenograft, a 96.1%
survival rate was recorded; in the group using a combination of CGF and xenograft, a 96.4%
survival rate was recorded [101].

Chen et al., reported a 100% implant success rate in the two groups, which had either
CGF with bone graft or CGF without bone graft [26]. Other studies that have used only
CGF as graft material in maxillary sinus elevation [54] state that the bone level obtained
and the success of the implants can be compared to that of a bovine bone graft [36].
### 5. Conclusions

In conclusion, there are different surgical methods for the treatment of peri- and pre-
implant defects, from the use of zygomatic implants to the use of biomaterials capable
of increasing and accelerating bone formation. Following tooth extraction, a process of
bone resorption occurs, making it necessary to increase bone, especially with a view to
implant-supported rehabilitation. MSFE has become a standard surgical procedure to
solve the reduced levels of bone, allowing the positioning of dental implants. Different
biomaterials have been proposed from synthetic products up to heterologous or autologous
grafts for the purpose of bone conservation and regeneration.
Histological analyses reveal an enhanced vascularization and the early formation of
new bone thanks to the use of growth factors. The signiﬁcant positive pro-angiogenic
inﬂuence of PRF combined with bone grafts favors regeneration processes, exploiting the
body’s natural ability to repair injured bony tissue with new bone cells. The improved
vascularization of the surgical site through neoangiogenesis promotes the healing of surgical
wounds, and this is particularly advantageous, especially in surgical areas with reduced
vascularization, such as in sinus lifts. Pre-treatment with PRP provides primary stability,
improving in a statistically signiﬁcant way implant–prosthetic rehabilitation. Comparing
other bone substitutes, the sinus ﬂoor elevation performed with the use of CGFs alone
showed implant survival and marginal bone level changes comparable to a demineralized
bovine bone matrix.
Even if further studies are still needed, the use of CGF, PRF and PRP seems to have
the ability to improve clinical results by improving the vascularization of surgical sites, and
they can improve the post-operative quality of life of patients.
Platelet derivatives will certainly see further developments in the near future, which
will above all improve costs, preparation time, and surgical efﬁciency, given that clinicians
often complain of having minimal clinical advantages in the face of an expensive and
complex procedure.
Furthermore, it will certainly be necessary to work towards making these procedures
less operator-dependent, given that nowadays the effectiveness of these surgical procedures
is very much linked to the surgical skills of the clinician, their knowledge of these materials
and their ability to use them in the right way.

Author Contributions: Conceptualization, A.M.I., A.P., G.L., G.P. and G.M.; methodology G.M., G.G.,
A.D.I., A.M.I., G.P. and A.P.; software, A.M.I., G.L., D.H., E.d.R. and A.P.; validation, G.M., F.I., G.L.
and A.M.I.; formal analysis, A.M.I., E.M., A.D.I., F.I. and A.P.; investigation, G.M., A.M.I. and A.P.;
resources, A.D.I., A.M.I., G.P., D.H., E.M. and A.P.; data curation, G.G., A.D.I., G.M., G.P., C.D.P. and
A.P.; writing—original draft preparation, A.M.I., G.M., A.D.I., G.D. and A.P.; writing—review and
editing, G.L., C.D.P., F.I., E.M. and A.P.; visualization, G.P., G.G., F.I. and G.L.; supervision, A.M.I.,
E.M., D.H. and F.I.; project administration, G.P., G.G., E.M. and A.P. All authors have read and agreed
to the published version of the manuscript.

Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conﬂicts of Interest: The authors declare no conﬂict of interest.

### Abbreviations

ALP alkaline phosphatase
BMP bone morphogenetic protein
DBBM deproteinized bovine bone mineral
EGF epidermal growth factor
FGF Fibroblast growth factor
GBR guided bone regeneration
HGF hepatocyte growth factor
IGF Insulin-like growth factor
L-PRF leukocyte-platelet-rich ﬁbrin
MBL marginal bone loss
MC mineralized collagen
MSFE Maxillary sinus ﬂoor elevation
PCs platelet concentrates
PDGF Platelet-derived growth factor
PRF Platelet-Rich Fibrin
PRP Platelet-Rich Plasma
RBH residual bone height before surgery
TBH total bone height.
TGF Transforming growth factor
VEGF Vascular endothelial growth factor