Received: 22 July 2022 | Revised: 5 July 2023 | Accepted: 15 August 2023

DOI: 10.1111/prd.12526

REVIEW ARTICLE

Do autologous platelet concentrates (APCs) have a role in intra-­

oral bone regeneration? A critical review of clinical guidelines
on decision-­making process

Marc Quirynen | Sam Siawasch | Andy Temmerman | Simone Cortellini |

Rutger Dhondt | Wim Teughels | Anna B. Castro
Department of Oral Health Sciences, Periodontology, KU Leuven & Dentistry, University Hospitals Leuven, Leuven, Belgium

Correspondence
M. Quirynen, Department of Oral Health Sciences, Periodontology, KU Leuven, Kapucijnenvoer 7, blook a - bus 7001, 3000 Leuven, Belgium.
Email: marc.quirynen@uzleuven.be

1 | I NTRO D U C TI O N • Leukocyte-­ and PRF (L-­PRF) with leukocytes (the amount de-
pends on the protocol) and a high-­density fibrin network, or an in-
1.1 | What are autologous platelet concentrates jectable subcategory containing platelets, leucocytes, and fibrin.
(APCs)?

Autologous platelet concentrates (APCs) are biological products
(bioactive additives) derived from the patient's whole blood via
chair-­side centrifugation and consist of supraphysiologic concentra-
tions of platelets and growth factors (GFs). They are intended to en-
hance, accelerate, and promote tissue healing and regeneration (soft
and hard tissues) due to their potential to allow the gathering and
concentration of platelets and other therapeutic blood constituents
­(fibrinogen/fibrin, growth factors, leukocytes, and circulating cells)
in situ.1
Four variants of APCs have been introduced during the past
three decennia: two platelet-­rich plasma (PRP) types representing
liquid platelet suspensions that can be transformed into a fibrin gel
after activation, and two platelet-­rich fibrin (PRF) types that repre-
sent solid platelet and fibrin clots (due to a strongly polymerized 3-­D
fibrin network). Based on the leukocyte content and fibrin structure,
APCs have been classified into four main categories2–­5:
• Pure PRP (P-­PRP) without leukocytes and with a low-­density fi-
brin network,
• Leukocyte-­ and PRP (L-­PRP), with leukocytes (the amount de-
pends on the protocol) but with a low-­density fibrin network,
• Pure PRF (P-­PRF) without leukocytes and with a high-­density fi-
brin network,
1.2 | Differences between different APCs
1.2.1 | 1st generation APCs
Platelet-­rich plasma (PRP)
PRP is a gel with a high concentration of autologous platelets sus-
pended in a small amount of plasma after blood centrifugation.
The patient's anticoagulated blood is subjected to a first “soft”
spin to separate the plasma from the red blood cells (RBC; Figure 1).
The plasma fraction (top fraction) is further subjected to a second
“hard” spin to separate the platelets (PRP fraction = platelet-­rich
plasma) from the platelet-­poor plasma (PPP). The platelet pellet with
some leukocytes is suspended in a lower volume of PPP and activated
by thrombin, calcium chloride (CaCl2), or type I collagen (e.g., from the
soft tissue in the surgical site). Through this dual centrifugation pro-
cess, platelets are significantly enriched compared to whole blood.6
Over the past 25 years, numerous attempts have been made to
standardize/improve the PRP preparation protocol. Unfortunately,
there is still a wide variation among studies with respect to the ro-
tational velocity, centrifugation time, blood volume, anticoagulants,
and coagulation activators. As such, it is difficult to directly compare
the reported outcomes. Whitman et al. and Marx et al. were the first
to promote the use of PRP in oral and maxillofacial surgery.7,8

M. Quirynen and S. A. M. Siawasch contributed equally to this article.

[Correction added on December 26, 2023 after first online publication: Given names for all authors have been included.]

© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

254 | 
wileyonlinelibrary.com/journal/prd Periodontology 2000. 2023;93:254–269.

QUIRYNEN et al.
F I G U R E 1 Differences in preparation
of APCs, with 1st (PRP, PRGF) and 2nd
(L-­PRF) generation APC. L-­PRF, leukocyte-­
and platelet-­rich fibrin; P-­PGF, plasma
poor in growth factors; PPP, platelet poor
plasma; P-­RGF, plasma rich in growth
factors; PRP, platelet rich plasma; WBC,
white blood cells.
Plasma rich in growth factor (PRGF)
PRGF, a subcategory of PRP, is a plasma in a gelatinous form, en-
riched with platelets and growth factors.
PRGF was introduced by Anitua et al.9,10 Patient's blood is com-
bined with an anticoagulant (1 mL of 3.8% sodium citrate for 10 mL
blood) and centrifuged at 460 g for 8 min. After centrifugation
(Figure 1) three fractions are created: plasma at the top contain-
ing mostly platelets (with two subfractions, F1 (the upper 20% in
a tube) and F2 (the next 20%)), the “buffy coat” (white blood cell
layer) in the middle (very small layer), and at the bottom the RBC
(lower 60%). The plasma poor in growth factors fraction (PPGF, the
top part, the first fraction, F1), and the plasma rich in growth fac-
tors fraction (PRGF just above the “buffy coat”, F2) are transferred
separately into “individual” fractionation tubes. CaCl2 is added as an
activator to both tubes to achieve platelet degranulation for the re-
lease of growth factors. The F1 fraction (PPGF) can be transferred in
a glass receptacle and placed on top of a heating block for ±30 min
to produce autologous fibrin (a fragile fibrin membrane) that can be
used, for example, to seal the extraction site. The F2 fraction (PRGF)
will form in ±10 min a gelatinous substance that can be placed in the
surgical site. The F2 fraction sometimes is further divided into the
upper and lower half, with the lower half representing a qualitative
more interesting PRGF.
In summary: Giusto et al.11 examined, from pig blood, the concen-
tration of platelets in both PRP variants. Compared to whole blood a
3.4-­fold higher (range 3.2–­4.2) concentration was reached with PRP,
and a 2.8-­fold higher (range 2.9–­4.9) concentration for PRGF. Nishi-
yama et al.12 conducted a similar trial (with higher g-­forces for PRP),
|
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255
now with human blood (14 volunteers). They reported, compared to
whole blood, an 8.8 versus 2.8-­fold higher concentration of platelets
in PRP versus PRGF, and a 5.5 fold versus nearly no increase in WBC,
respectively. PRP and PRGF need the addition of a coagulation acti-
vator to be transformed into a gel. Their fibrin network is looser than
in the second-­generation APCs, which may influence their capacity
to work as a scaffold.
1.2.2 | 2nd generation APCs
Leukocyte-­and platelet-­rich fibrin (L-­PRF)
Platelet-­r ich fibrin (PRF), considered a “second generation plate-
let concentrate”, is achieved with a simplified preparation, and
without biochemical manipulation of the patient's blood (no anti-
coagulants, no coagulation activator). The pure platelet-­r ich fibrin
(P-­PRF) subcategory only exists in a strongly activated gel form
and cannot be injected or used as traditional fibrin glue. There
is only one commercial product in this family (Vivostat®), and its
use remains limited. The leukocyte-­and platelet-­r ich fibrin (L-­PRF)
subcategory, however, offers many more advantages and is exten-
sively used.
For the preparation of L-­PRF, a solid form of APCs, one does
not require anticoagulants or thrombin (or any other gelling agent).
This feature makes this product very easy to use, with a low risk
of mistakes during the preparation stage.13 The patient's blood is
collected in either special glass tubes or plastic tubes with a silica
coating on the inside (to start up the coagulation cascade), in other
 |
256
words, the choice of the right blood tubes is crucial. The patient's
blood is immediately (within 1 min after collection) centrifuged at a
g-­force of 408 (in the region where the L-­PRF clot is formed). During
centrifugation (≥12 min) the fibrinogen in the blood is converted into
a strong 3-­D fibrin matrix by the patient's thrombin. Blood platelets
and leukocytes become trapped in this 3-­D fibrin net. After centrifu-
gation, blood is separated into three fractions (Figure 1):
• A clear solution of blood plasma in the upper phase,
• The buffy coat, a strong, fibrin clot (with enmeshed leukocytes
and platelets) in the middle, and
• An RBC fraction at the bottom of the tube (RBCs have the highest
density).
The L-­PRF clot can be collected from the blood tube with tweezers.
After gentle removal of the remaining RBCs on the clot, it can be gently
compressed into membranes (±5 min). L-­PRF is thus a 100% autologous
biomaterial rich in fibrin, platelets, white blood cells, growth factors,
cytokines, and other components conducive to tissue repair.14–­17 L-­
PRF membranes are stable, resilient, strong, adhesive, and malleable.
Within the L-­PRF membrane, the platelets are tightly merged, and
18
the enmeshed leukocytes remain alive and functional. They possess
attractive biochemical properties including hemostatic, angiogenic,
osteogenic, anti-­inflammatory, anti-­microbial, pain-­inhibitory, and
wound-­healing characteristics rendering L-­PRF, at least desirable and
revolutionary.19–­22 The original protocol of leukocyte-­ and platelet-­
rich fibrin (L-­PRF), was introduced by Choukroun et al.23–­27 When the
original composition of the patient's whole blood is compared to the
composition of an L-­PRF membrane (taking into consideration that an
L-­PRF membrane weighs only 3% of the drawn blood), platelets and
WBC are increased 20–­25-­fold.28 Over the past decade small modi-
fications to this original protocol have been introduced (CGF, A-­PRF,
A-­PRF+, T-­PRF, H-­PRF), with modification in centrifugation time and/
or speed, tubes, angle of tubes within centrifuge), but in reality, they
all remain subtypes of L-­PRF, and as such the acronym L-­PRF applies
to all of them.
In summary: Because it is a solid material, the L-­PRF membrane is
considerably easier (user-­friendly) to handle and position in a defect in
comparison to a PRP gel. When the recommended procedure for the
preparation of L-­PRF is carefully followed, the content and architec-
ture of the resulting membrane are very consistent. L-­PRF can be used
as an autogenous grafting material/substitute because of its ability to
accelerate physiologic wound healing and new bone formation. The
only drawback of L-­PRF is related to the timing during preparation; the
time between blood collection and centrifugation should be no more
than 1 min, which requires a stepwise centrifuge loading.17
1.2.3 | Major differences between 1st and 2nd
generation APCs
Table 1 summarizes the most significant differences between PRP
and PRGF (as 1st generation) and L-­PRF (as 2nd generation) APCs.
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QUIRYNEN et al.
The 1st generation APCs are available in liquid solutions or an ac-
tivated gel, whereas L-­PRF allows the formation of strong matrixes
(membranes), allowing their use as a true barrier membrane (with a
degradation of ±4 weeks). During the preparation of PRP and PRGF
anticoagulants (at the start) and platelet activators (at the end) are
required. Some of these factors can potentially have an adverse
­effect on the coagulation process and/or lead to an immune re-
sponse.5 Moreover, anticoagulants have more recently been shown
to interfere with the angiogenic and regenerative response mediated
by platelets. 29 For L-­PRF, however, the end product remains 100%
autologous; the fibrin for example is formed via the physiologically
available thrombin.
Moreover, the preparation of PRP and to a lesser extent PRGF is
complex, but simple for L-­PRF. The number of platelets and leuko-
cytes is clearly higher in L-­PRF membranes compared to PRGF and
PRP gels. Also, the time of growth factor release differs significantly.
PRP releases most growth factors within 60 min, whereas L-­PRF
shows a more gradual release (up to 2 weeks) as reported by Ko-
bayashi et al.32 A PRGF scaffold shows quite similar release kinetics
as L-­PRF.33
One of the main differences between L-­PRF and PRP and espe-
cially PRGF is the presence of leukocytes in the L-­PRF. This is a key
factor for confronting infectious pathogens, and as such can reduce
the probability of infection. They also play a key role in regulating the
immune response and in integrating host tissue and biomaterial.34,35
1.3 | Differences between the original L-­PRF and
recent modifications
1.3.1 | The original L-­PRF protocol
The original L-­PRF protocol foresees a relative centrifugal force
(RCF) of 408 g (in the area where the clot is formed), and a centrifu-
gation time of 12 min (Table 2). 23–­27
1.3.2 | CGF
Sacco introduced in 2006 the “Concentrated Growth Factors”
(CGF) protocol, with a centrifugation time of 13 min, changing the
RPM overtime (Medifuge centrifuge, Silfradent), in an attempt to
isolate a much larger, denser, and richer in growth factors fibrin
matrix. 36,37
1.3.3 | A-­PRF and A-­PRF+
The advanced PRF (A-­PRF) and the advanced plus PRF (A-­PRF+) pro-
tocols were introduced to further increase the cellular content in the
L-­PRF clot and as such the release of growth factors.38,39 For A-­PRF
a relative centrifugal force of 194 g, and for A-­PRF+ of 145 g, with a
centrifugation time of 14 and 8 min, respectively, are used (Table 2).
 |

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QUIRYNEN et al. 257

TA B L E 1 Major differences between

Platelet concentrates PRP (1998) PRGF (2001) L-­PRF (2004)
the 1st generation (PRP, PRGF) and 2nd
generation (L-­PRF) APCs.13,18,30,31 Protocol Very complex Complex Easy
Speed rate Slow Very slow Fast
Reproducibility Possible bias Possible bias No bias
Use of anticoagulants Yes Yes No
100% autologous No No Yes
Amount obtainable Enough Poor Good
Fibrin morphology Tetramolecular Tetramolecular Trimolecular
Leukocytes amount 0–­50% 0% ≥65%
Immunomodulatory properties Poor No Yes
Neo-­angiogenic potential + ++ +++++
Osteoconductive potential Poor Poor High
(scaffolding)
Mechanical properties Enough Poor Good
(sol–­gel-­membrane)
Presence of MSCs Yes Yes Yes
Release in
TGF-­β1 ++ + +++
PDGF-­BB ++ + +++
VEGF ++ + +++
Duration of growth factor 70% in first 10 min, Primarily 1st week Up to
release ±all within 1 h 2 weeks
Costs of the protocol High Relatively high Low

TA B L E 2 Centrifuge settings for

IntraSpin® Duo Quattro® Medifuge®
the preparation of different L-­PRF
modifications for IntraSpin® (radius at L-­PRF variant RCF a
Time RPM b
RPM b
RPMb
area where clot is formed = 50 mm), Duo
Quatro® (77 mm), or Medifuge centrifuge Solid forms: clots/membranes
and of liquid forms, respectively. L-­PRF 408 g 12 min 2.700 2.180
A-­PRF 194 g 14 min 1.865 1.500
A-­PRF+ 145 g 8 min 1.610 1.300
CGF 453 g 2 min 2.700
358 g +4 min 2.400
453 g +4 min 2.700
560 g +3 min 3.000
Liquid forms of platelet concentratesc
Liquid fibrinogen 408 g 3 min 2.700 2.180
i-­PRF 60 g 3 min 820 700
C-­PRF 408 g 12 min 2.700 2.180

Note: Indicated are: the required RCF (=g-­force), the RPM (rotations/revolutions per minute), and
the time of centrifugation (in min).
a
Measured at the area where the L-­PRF clot will form.
b
IntraSpin, DuoQuattro, and Medifuge centriguge have a fixed angle rotor, the radius of centrifuge
in area where clot is formed is 50, 77, and 55.5 mm, respectively.
c
These liquid forms are prepared in inert blood tubes to delay the coagulation process.

Theoretically, less centrifugation time and/or lower centrifugation 1.3.4 | T-­PRF

speed would reduce pull-­down forces during centrifugation, which
would increase the total number of cells trapped within the clot/ Tunalı et al.39 introduced the T-­PRF (titanium-­prepared platelet rich-­
membrane. fibrin). The centrifugation protocol is identical to the original L-­PRF
 |
258
protocol, but with the only difference that titanium tubes are used
to centrifuge the blood, with the hypothesis that titanium would be
more effective in activating platelets. This would result in a stronger
fibrin network.
1.3.5 | H-­PRF
Miron et al.40 introduced the horizontal centrifugation protocol,
stating that, when compared to the normally used fixed-­angle cen-
trifuge, more platelets and leukocytes could be trapped within the
membrane with a better distribution over the entire membrane.
1.3.6 | Overall impact
So far, contradictory laboratory data have been reported on the ben-
eficial effect of the above-­mentioned centrifugation modifications
in terms of cellular content and/or release in growth factors.17,38,40,41
Moreover, also the “clinical” benefits of these so-­called “improved”
clots/membranes still need to be confirmed. RCTs comparing these
modifications directly to each other are indeed desirable.
1.4 | Differences between i-­PRF, liquid fibrinogen,
and C-­PRF?
The flowable 2nd generation APCs (Table 2), the fibrin glues, also
known as fibrin sealants, have been introduced to be used in com-
bination with a bone substitute or to have an injectable alternative
(e.g., for joints (including the TMJ), chronic wounds).
1.4.1 | i-­PRF
i-­PRF (injectable PRF) is a liquid formulation, also prepared without
additives (without anti-­coagulants), but using plastic hydrophobic
inert tubes to slow down spontaneous clotting. Blood is centrifuged
at 60 g, for 3 min only. The upper liquid fraction represents the i-­
PRF. This flowable platelet-­rich fibrin can be either utilized alone
or combined with various biomaterials. Compared to the patient's
whole blood, i-­PRF contains slightly more platelets and leukocytes
(±1.3 × higher).42 The “clinical” benefits of i-­PRF in oral surgery still
need to be confirmed.
1.4.2 | Liquid fibrinogen
Liquid fibrinogen is also flowable.43 It has the significant advantage that
it can be prepared with the same setting as for L-­PRF (thus within the
same centrifugation procedure, no need for a 2nd centrifugation/blood
collection). For liquid fibrinogen, the spinning time is only 3 min at 2.700
RPM with a relative centrifugal force of 408 g, again using plastic tubes
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QUIRYNEN et al.
with an inert inner surface. The upper yellow fraction represents the
liquid fibrinogen. It can be aspirated from the blood tube and has to be
used within 30 min, after which it will slowly start to coagulate sponta-
neously. This liquid is rich in fibrinogen, platelets, and leukocytes and
will form a 3-­D fibrin network.30 The latter is useful to trap a biomate-
rial to form a stronger block (sticky bone or L-­PRF bone block). The
“clinical” benefit of this approach has recently been demonstrated.43
1.4.3 | C-­PRF
Miron et al.44 introduced a novel harvesting technique called C-­PRF
(concentrated-­PRF) in an attempt to isolate the liquid buffy coat layer
(0.3 to 0.5 mL directly above the RBC layer) immediately after blood
centrifugation. This part indeed contains high concentrations of leuko-
cytes and platelets (±20 times higher than in the blood). This flowable
platelet-­rich fibrin can be used alone or in combination with bioma-
terials. The “clinical” relevance of C-­PRF still needs to be confirmed.
1.5 | How to reach the desired g-­force in a
centrifuge?
The separation (layer formation) in the blood tube during centrifugation
(which is based on blood cell's density) depends on several factors in-
cluding: the time of spinning, the speed (rotations/revolutions per min-
ute, RPM), and the g-­force (also called the relative centrifugal force, RCF).
The RCF can be calculated with the following formula:
RCF = 11.18 × radius × (RPM/1000)2. For this equation, the radius is
the distance in centimeters from the center of the rotor to the sam-
ple, and RPM is the rotor speed expressed as revolutions per minute.
It is especially important to realize the significance of these pa-
rameters. It clarifies, for instance, why not each centrifuge (each of
them with its own radius) will lead to the same separation, and in the
case of L-­PRF to the same clot or membrane.45,46 Moreover, the RCF
differs slightly within the tube. Table 2 summarizes the g-­force cal-
culated for the region in which the L-­PRF clot is formed for tree fre-
quently studied centrifuges (IntraSpin®, Duo Quattro®, Medifuge®).
1.6 | Is there an impact of age or gender on the
outcome of APCs and how much blood can we donate
without complications?
Our blood is a mixture of about 55% plasma and 45% blood cells.
It accounts for about 7% to 8% of the total body weight and rep-
resents approximately 5 L. A healthy adult can lose almost 20%
of blood volume (1 L) before the first symptoms appear (restless-
ness), and approximately 40% of volume (2 L) before a hypov-
olemic shock sets in.
The RBC accounts for about 40% to 45% of the blood volume,
the WBC as well as the platelets for less than 1%. Eventhough RBCs
are smaller than WBCs, they are pushed to the bottom of blood
 |

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QUIRYNEN et al. 259

tubes during centrifugation, because they are more dense (higher
specific mass/weight).
The relative proportion of RBC, measured via a hematocrit test,
differs between men and women. It is normally 40.7% to 50.3% for
men (4.7–­6.1 million cells), and 36.1% to 44.3% for women (4.2–­
5.4 million cells per μL). On an individual level, the hematocrit value
decreases in men in their sixth decade and in women in their seventh
decade, and the change becomes more prominent with advancing
age, especially in men.47,48 The lower hematocrit in women and el-
derly people explain the increased size of their L-­PRF membranes.49
Yajamanya et al.50 observed that the fibrin network of L-­PRF mem-
branes was less dense as patient age increased. Whether these ob-
servations have a clinical impact is still unclear.
1.7 | How do APCs work?
1.7.1 | Platelets
transforming growth factor-­β (TGF-­β), fibroblast growth factor
(FGF), insulin-­like growth factor (IGF-­I and IGF-­II), vascular endo-
thelial growth factor (VEGF). The dense bodies contain adenosine
diphosphate (ADP), adenosine triphosphate (ATP), ionized calcium,
histamine, serotonin, and adrenaline. These bioactive molecules
play important roles in different areas of regenerative medicine, in-
cluding bone remodeling, wound healing, hair regrowth, nerve re-
generation, aging facial skin, acne scarring, androgenic alopecia, and
diabetic wounds.31
Signaling molecules of importance during bone healing (Table 3)
can be categorized into three groups: (i) the pro-­inflammatory cy-
tokines [interleukin-­1, interleukin-­6 , and tumor necrosis factor-­α
(TNF-­α)], (ii) the TGF-­β superfamily (including bone morphoge-
netic proteins) and other growth factors (PDGF, FGF, and IGF),
and (iii) the angiogenic factors [VEGF, angiopoietins 1 and 2, and
matrix metalloproteinases, that degrade bone and cartilage and
enable vessel invasion].

During wound healing, platelets arrive among the first cells at a wound
site. Besides their procoagulant effects, platelets form a rich source
of important growth factors. They contain more than 300 biologically
active molecules that are released upon activation from platelet alpha
granules and dense bodies. Alpha granules and dense bodies (also
known as dense granules or delta granules) are specialized secretory
organelles. Activated platelet-­derived factors serve as messengers and
regulators that influence a variety of cell–­cell and cell-­extracellular ma-
trix (ECM) interactions and modify the pericellular microenvironment.
The alpha granules contain fibrinogen, fibronectin, factor V and
von Willebrand's factor, platelet-­derived growth factor (PDGF),
1.7.2 | Leukocytes
At first sight, the presence of leukocytes may be controversial, due
to a potential risk of stimulating an inflammatory process.10 On the
contrary, several research groups insisted on the need for some leu-
kocyte population, even in the injectable PRP, to increase the pro-
duction of growth factors, the release of anti-­pain mediators, and
a natural anti-­infectious activity.51–­53 Leukocytes can also regulate
cell proliferation and cell differentiation. In addition, they are the
basic cells responsible for wound healing and the first cells to start
neo-­angiogenesis.54–­59

TA B L E 3 Production and action of signaling molecules (adapted from Upadhayaya et al.).31

Factors Produced by Action

Cytokines
Matrix metalloproteinases
Transforming growth
factor-­β (TGF-­β)
Platelet-­derived growth
factor (PGDF)
Fibroblast growth factor
(FGF)
Insulin-­like growth factor
(IGF)
Vascular endothelial growth
factor (VEGF)
Macrophages & mesenchymal
cells
Macrophages, smooth muscle
cells & osteoblasts
Osteoblasts
Platelets, monocytes,
macrophages, endothelial
cells & osteoblasts
Monocytes, macrophages,
mesenchymal cells,
chondrocytes & osteoblast
Bone matrix, endothelial cells,
osteoblasts & chondrocytes
Macrophages, smooth muscle
cells & osteoblasts
Exert chemotactic activity on inflammatory cells, enhance cellular matrix
synthesis and stimulate angiogenesis
Degrade cartilage and bone; this allows angiogenic factors to regulate vessel
ingrowth by either the vascular endothelial growth factor-­dependent
pathway or the angiopoietin-­dependent pathway
Stimulates the expression of bone matrix proteins and suppresses the
degrading activity of matrix metalloproteinases and other enzymes;
also induces the differentiation or proliferation of osteoblastic cells
while inhibiting the formation of osteoclast precursors and, in greater
concentrations, may exert an inhibitory effect on mature osteoclasts
Potent mitogen for mesenchymal cells, powerful chemotactic agent for
inflammatory cells and a stimulus for osteoblasts and macrophages
Chondrogenesis and bone resorption
Bone matrix formation and in the later stages of endochondral bone
formation
Induces the migration and proliferation of endothelial cells using
transmembrane adhesion proteins (intergrins); also induces relaxation in
the cell-­to-­cell contact of endothelial cells, resulting in hyperpermeability
of blood vessels
 |
260
Neutrophils are recruited to the site of injury within minutes
following trauma and are the hallmark of acute inflammation. Their
primary role is to phagocytize debris, microbes, and necrotic tissue,
in order to clean the wound and prevent infection. They also pro-
duce inflammatory cytokines and growth factors.9 After completing
these functions during the early inflammatory phase of healing, the
neutrophils die by apoptosis.
Monocytes are the second type of leukocytes that are recruited
to the wound site and mature to become macrophages. When ap-
plying L-­PRF to a wound, before circulating monocytes can extrava-
sate the blood vessels, L-­PRF could already supply monocytes. Since
monocytes must attach to the extracellular matrix for differentiation,
entrapment of the monocytes in the L-­PRF fibrin clot would already
60
induce their maturation to macrophages. Thereby, perhaps the early
and supplemented macrophage levels from L-­PRF could shorten the
inflammatory phase and wound healing. Macrophages phagocytose
the dead neutrophils and further debride the wound, which is of
course critical for normal wound healing. Together with the neutro-
phils and platelets, macrophages also prevent infections by eliminating
microbes. They also play an essential role in bone repair. Macrophages
apparently direct osteogenic cell signals and promote bone mineral-
ization during in vitro studies. Inducing angiogenesis is a key role of
macrophages. New blood vessels are of course essential for delivering
nutrients, inflammatory cells, and oxygen. Moreover, macrophages
also participate in the formation of granulation tissue and the removal
of necrotic tissue. Macrophages secrete collagenase, which promotes
the cleaning of the wound. Other critical roles of macrophages include
the release of growth factors and cytokines, recruitment of other cell
types to the wound, and stimulation of angiogenesis.
Like platelets and macrophages, other leukocytes also secrete
many growth factors important in healing, including: TGF-­β1, PDGF,
VEGF, IGF, epidermal growth factor (EGF), TGF-­α , and basic fibro-
blast growth factor (bFGF).55,61
In addition to growth factors, leukocytes express many pro-
teinases, such as serine and matrix metalloproteinases, which
also have critical roles in wound healing. 56 Proteinases have an-
timicrobial activities and contribute to the migration of polymor-
phonuclear leukocytes and modulate inflammatory responses.
Proteinases control the inflammatory response by deactivated
inflammatory cells to limit injury to surrounding tissues during
wound healing. Another crucial role of proteinases is to control
the activity of growth factors, such as TGF-­β, PDGF, and bFGF.
Matrix metalloproteinases also have important roles in cartilage
and bone remodeling and angiogenesis.
L-­PRF membranes also have an antibacterial capacity, for exam-
ple against methicillin-­resistant Staphylococcus aureus and Esche-
richia coli, and against several periodontopathogens. 20,62 Leukocytes
increase the antibacterial impact and might reduce the probability of
infection up to 10 times.
Leukocytes also present anti-­nociceptive effects through dif-
ferent chemokines, anti-­inflammatory cytokines (IL-­4, IL-­10, and
IL-­13) and opioid peptides (b-­endorphin, metenkephalin, and dynor-
phin-­A), and can therefore promote a clinically relevant inhibition of
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QUIRYNEN et al.
pathological pain. During inflammation, these cytokines counteract
the effects of the pro-­inflammatory mediators naturally generated
in the early stages of inflammation. This might explain the signifi-
cant reduction in complications after 3rd molar extraction. Recent
data indicate that L-­PRF has anti-­inflammatory activity and shifts the
macrophage polarization from an M1 toward an M2 phenotype.63
1.7.3 | L-­PRF Fibrin matrix
Although leukocytes and platelets play a vital role in the L-­PRF healing
capacity, it has also been suggested that it is the fibrin matrix that sup-
ports the healing (including the gradual release of growth factors) and
is also responsible for the therapeutic potential. L-­PRF might serve as
a resorbable membrane for guided bone regeneration (GBR), prevent-
ing the migration of non-­desirable cells into the bone defect, provid-
ing a space that allows the immigration of osteogenic and angiogenic
cells, and permitting the underlying blood clot to mineralize.34,64
2 | D O A P C S PL AY A “ S I G N I FI C A NT ”
RO LE I N B O N E R EG E N E R ATI O N?
To evaluate the “adjunctive” benefit of APCs in bone regeneration
within the oral cavity, a narrative review of the literature has been
conducted on their impact during alveolar ridge preservation (APR),
sinus floor augmentation, and guided tissue regeneration (GTR).
Only papers, published before June 2022, where APCs were used
as “sole” substitutes (thus not in combination with bone substitutes,
statins, or enamel matrix derivatives) and in humans were consid-
ered. However, because of the low number of papers on PRP and
PRGF as the “sole” substitute in GTR, for this indication, a combina-
tion of APCs with a bovine bone substitute was also considered.
For alveolar ridge preservation and guided tissue regeneration,
only randomized controlled trials (RCTs) or controlled clinical trials
(CCTs) were considered. For sinus floor, augmentation case series
were also included.
There is considerable confusion in the literature when the term
PRF is employed, as it is often not specified whether the authors
refer to P-­PRF or L-­PRF. However, all the studies identified in this
review mentioned a protocol where leukocytes were present in the
platelet concentrates, thus representing L-­PRF or one of its modifi-
cations (CGF, A-­PRF, A-­PRF+, T-­PRF, H-­PRF).
2.1 | What is the impact of APCs as “sole” bone
substitutes during “alveolar ridge preservation (ARP)”?
After tooth extraction, the alveolar ridge undergoes a remodeling
in both horizontal and vertical directions. After 6 months, according
to Tan et al.,65 the vertical resorption ranges from 11% to 22% and
the horizontal resorption from 29% to 63%. However, the exten-
sion of alveolar bone resorption may vary depending on tooth type

QUIRYNEN et al.
as observed by Couso-­Queiruga et al.66 with more horizontal bone
resorption in molar versus non-­molar sites (3.6 vs. 2.5 mm). An ad-
ditional bone loss of 2.4 mm in width and 1.1 mm in height has been
67
reported in sites with a compromised buccal bone wall. This often
jeopardizes the placement of implants in an optimal position.
Many surgical techniques have been introduced to minimize this
68–­70
alveolar bone resorption. Different bone grafts/bone substi-
tutes have been used to fill extraction sockets, with or without the
addition of a soft tissue graft and/or a soft tissue substitute to seal
the alveolus. Biological additives, for instance, APCs, have also been
proposed as substitutes for bone regeneration. The absence of bone
substitute remnants after healing when only APCs are used has been
seen as an important advantage.71–­73
2.1.1 | PRP
74,75
Two RCTs evaluated the use of PRP for ridge preservation. Alissa
et al.74 reported less pain, better soft tissue healing, and a denser trabec-
ular bone pattern when PRP was compared to unassisted healing. How-
ever, there were insufficient data to support the use of PRP to prevent
bone resorption. Nisar et al.,75 on the contrary, observed favorable out-
comes in terms of preservation of the alveolar bone height but failed to
show any significant results in terms of alveolar bone width resorption.
2.1.2 | PRGF
Several RCTs have analyzed the effect of PRGF on hard and soft tis-
sues after tooth extraction. Despite some controversy data,76 PRGF
has been reported to provide the following potential advantages:
9,77,78
• Significantly faster socket closure/healing
79
• Less post-­extraction pain
79
• Significantly improved soft tissue healing
• Histologically greater percentage of newly formed bone77,80
The use of PRGF may be recommended when early healing is
needed, for instance, in hospitalized patients.
2.1.3 | L-­PRF
A large number of RCTs and CCTs have examined the potential
benefits of applying L-­PRF in the socket immediately after tooth
extraction. Several protocols have been introduced using either the
non-­condensed L-­PRF clots or the condensed membranes/plugs.
Moreover, the number of L-­PRF clots/plugs/membranes per socket
varied significantly between studies.
When using the “correct” protocol (including the use of “con-
densed” membranes/plugs, the application of sufficient numbers of
them, and sealing of the alveolus with L-­PRF membranes) highly sig-
nificant improvements have been reported including:
|
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261
• Significantly less alveolar ridge resorption,73,81–­84
• Histologically improved bone quality and higher radiographically
bone density,81–­83,85
• Faster soft tissue healing,84,86–­88
• Less post-­extraction pain and swelling,86,87
• Lower incidence of alveolitis.86,87
Another important advantage is that primary wound closure is not
required, and even not advised since the release of a mucoperiosteal
flap and the use of releasing incisions will reduce the local blood supply
and as such jeopardize the regeneration process.85 This offers the ad-
ditional advantage of not losing gingival width and vestibulum depth.
However, the results are often less favorable when the following mod-
ifications are made to the above-­mentioned protocol: incomplete socket
fill with, for example, only one L-­PRF clot/membrane/plug, no sealing of
extraction socket entrance with an L-­PRF membrane, use of clots instead
of membranes/plugs, improper condensation of L-­PRF in the extraction
socket, removal of the face part of the clot, multiple extractions next to
each other, extraction site covered by a removable denture.89–­92
2.1.4 | Explanation for the beneficial effects when
applying L-­PRF during alveolar ridge preservation
The included articles proposed the following potential explanations
for beneficial effects obtained with L-­PRF:
• The formation of a natural fibrin matrix that supports clot forma-
tion and covers the clot to prevent mechanical dislodgement, 23–­25
• The increased potential for bone regeneration by the released
growth factors, including a reduced healing time,30
• The enhancement of the neo-­angiogenesis and vasculogenesis,19
• The immune regulation node with inflammation retro-­control
abilities, 26
• The sealing effect of the L-­PRF (in order to delay/prevent the in-
growth of epithelium),
• The antibacterial activity of L-­PRF constructs, 20
• The hemostatic effect.
2.2 | What is the impact of APCs as “sole” bone
substitutes during sinus floor elevation?
It still remains an open question whether a bone substitute is really
necessary for a sinus floor elevation via a transcrestal or a 1-­stage
lateral window approach, applying the “tent pole technique” with the
implant(s) keeping up the elevated Schneiderian membrane. Several
clinical trials indeed reported a favorable outcome for a sinus aug-
mentation without grafting (blood only) including solicitude regarding
remaining graft particles, reduced rates of complications, and lower
costs.93–­100 However, such a graft-­free procedure still remains contro-
versial. A crucial aspect for such a procedure is the absence of a per-
foration of the sinus membrane, which unfortunately occurs relatively
 |
262
frequently. This is of course not a concern in the case of the use of for
example an APC membrane.
2.2.1 | Transcrestal approach, APCs only
PRP
For PRP no studies could be identified.
PRGF
PRGF has been explored in one clinical trial, reporting a vertical
bone gain of 3.7 mm after 1 year, and of 4.2 mm after 3 years.101
L-­PRF
Five prospective case series reported on transcrestal sinus floor el-
evation with L-­PRF as the sole substitute.64,102–­105 In general, a bone
gain of 3.2–­4.4 mm could be obtained. In three out of the five stud-
ies, the implant survival rate after 1 year of loading was >97%. In the
study of Molemans et al., with data from post-­graduate students, the
implant survival rate was 91%.104 Testori et al.105 reported a 5-­year
cumulative survival rate of 93.3%. Similar observations were made in
two retrospective studies applying CGF as the only substitute.106,107
Cho et al.108 compared the use of 5 mL of saline with 5 mL of
L-­PRF as filling material after hydraulic transcrestal sinus lifting and
observed significantly more bone gain in the L-­PRF group.
It was suggested that you would need 1 L-­PRF membrane per
mm sinus augmentation.
2.2.2 | 1-­stage Window approach, APCs only
PRP/PRGF
We were not able to find a paper on the use of PRP or PRGF as a
single substitute during a 1-­stage sinus floor elevation.
L-­PRF
However, six clinical studies explored the outcome of L-­PRF for
104,109–­113
this indication. L-­PRF clots or membranes have been
used in these studies. The overall mean bone augmentation
ranged from 5.3 to 10.4 mm and the implant survival rate was al-
ways 100%, even up to 6 years follow-­u p. Several authors sug-
gested using the bony window (folded inside) on top of the apices
of the implants as a new floor for the sinus. The simultaneously
inserted implants of course functioned as tent poles to keep the
sinus membrane up. It was again recommended to use 1 L-­PRF
membrane per mm sinus augmentation.
112
Dominiak et al. compared in an RCT the amount of bone gain
between either a xenograft alone (Cerabone) or L-­PRF alone for a 1-­
stage lateral window approach. The survival rate of implants in both
groups was 100%, with no implant mobility or pain. At the 36-­month
follow-­up visit, the xenograft group showed significantly more bone
height gain (4.5 mm vs. 3.4 mm for the A-­PRF group). Merli et al.113
compared in another RCT the use of CGF (to fill the sinus and to seal
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QUIRYNEN et al.
the window) with the use of a bone substitute (DBBM) and a col-
lagen membrane over the window, and reported similar outcomes.
2.3 | What is the impact of APCs as “sole” bone
substitute for bone regeneration in intra-­bony defects
during open flap debridement (OFD)?
Deep crater-­shaped defects because of severe periodontitis are
often treated via non-­surgical periodontal therapy followed by peri-
odontal regeneration. Ideally, new bone, cementum, and periodontal
ligament will be formed. Wound stability (for stable blood clot for-
mation), and space provision (for new tissue formation within the
defect) are mandatory to obtain periodontal regeneration.
The regenerative surgery can be accompanied by the use of dif-
ferent biomaterials, including APCs.114–­118 The rational for applying
APCs is twofold. Firstly, APCs can serve as a stable scaffold ensuring
space provision/wound stability, and at the same time be a source of
crucial cells for wound cleaning and healing/repair. APCs for exam-
ple promote the neo-­angiogenesis, cell migration, and bone forma-
tion. Secondly, APCs can be used as a barrier membrane to cover the
intra-­bony defects. An APC barrier will prevent the apical migration
of gingival epithelial and connective tissue cells. This will provide the
regenerative cells more time to restore the periodontal tissues.119,120
In total, 22 RCTs reported on the adjunctive benefits of using
APCs as a sole biomaterial in the treatment of intra-­bony defects
during OFD. It is, however, important to realize that different strat-
egies have been applied (Figure 2). In the included studies, PRP and
PRGF were only used as a scaffold (Figure 2C), whereas L-­PRF has
been tested for all three strategies (Figure 2B–­D).
2.3.1 | PRP
Only one RCT evaluated the adjunctive benefit of applying PRP in
3-­wall intra-­bony defects. In comparison to OFD alone, the addition
of PRP resulted in significantly more: probing pocket depth reduc-
tion (0.8 mm), intra-­bony defect reduction (2.6 mm), and intra-­bony
defect fill (55%).121
2.3.2 | PRGF
The beneficial effect of PRGF was explored in one RCT in which only
2-­wall defects were treated. This study could not reveal any statistically
significant difference, but it is unclear if smokers were excluded or not.122
2.3.3 | L-­PRF
As barrier membrane
The benefit of covering the intra-­bony defect with L-­PRF as a bar-
rier membrane during OFD was explored in three RCTs.123–­125 In all
 |

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QUIRYNEN et al. 263

studies a statistically significant benefit with L-­PRF was found for
probing pocket depth reduction (±1.1 mm), two studies reported sig-
nificantly more gain in attachment level (±1.0 mm), and one study
observed significantly more reduction of the intra-­bony defect
depth (±2.0 mm). It remains unclear if there is more benefit when
using multiple membrane layers versus a single layer.
As defect filler
Seven RCTs evaluated the added value of applying L-­PRF during the
126–­132
OFD procedure to fill the intra-­bony defects. L-­PRF was ap-
plied in a clot (four studies) or membrane (three studies) form. As far
as mentioned all studies included 2 or 3 wall defects. The follow-­up
period was 9–­12 months, and smokers were excluded. Statistically
significant adjunctive benefits were found in favor of L-­PRF in terms
of probing pocket depth reduction (0.9–­2.4 mm), gain in attachment
level (0.8–­3.3 mm), and bone fill (several parameters). A clear differ-
ence between membrane and clot could not be made.
As bony defect filler + barrier membrane
In 10 RCTs L-­PRF was used both as filler and as barrier membrane
during OFD of 2 or 3 wall defects.121,133–­141 Again, L-­PRF as ad-
junct resulted in statistically more probing pocket depth reduction
(0.8–­1.4 mm), gain in attachment level (1.0–­1.6 mm), and bone defect
fill (several parameters).
2.3.4 | PRP versus L-­PRF
Two studies compared the benefits of L-­PRF with those of PRP,
as filler of intra-­bony defects, either covered or not with a barrier
membrane during OFD, and reported slightly better outcomes in
favor of the L-­PRF, especially when the intra-­bony defects were also
covered.121,142
2.4 | What is the impact of APCs + “xenograft” for
bone regeneration in intra-­bony defects during open
flap debridement?
To prevent collapse and preserve the space for regeneration, a com-
bination of APCs and another (more stable) grafting material could
be another treatment option for intra-­bony defects around teeth.
In total seven RCTs explored the beneficial effects of combin-
ing APCs with a xenograft for treatment of intra-­bony defects in

F I G U R E 2 Different protocols for the using APCs only in intra-­bony defects during OFD: (A) open flap debridement as control versus:
(B) the coverage of the defect only with a APC membrane as barrier (yellow orange layer in drawing), (C) the filling of the bony crater only
(yellow orange in drawing), or (D) the application of an APC to both fill and cover the defect.

F I G U R E 3 Different protocols for

using a xenograft in combination with
APCs in intra-­bony defects during OFD:
(A) OFD + xenograft alone as defect filler
(blue stars) serving as control treatment,
versus: (B) OFD + xenograft mixed
with an APC to fill the defect, and (C)
OFD + xenograft mixed with an APC to
fill the defect plus an APC membrane to
cover the defect.
 |
264
comparison to a xenograft alone. Again different strategies have
been applied (Figure 3).
2.4.1 | PRP
Three RCTs made the comparison between xenograft mixed
with PRP versus xenograft alone for the treatment of intra-­bony
defects.143–­145 Two studies found statistically significant adjunctive
benefits when adding PRP concerning probing pocket depth reduc-
tion (≥1.0 mm) and gain in attachment level (≥0.9 mm). One of those
studies reported additionally significant bone fill with PRP. The third
study however could not find any statistical differences.145
2.4.2 | PRGF
For PRGF no studies could be identified.
2.4.3 | L-­PRF
Four RCTs evaluated the benefit of combining a xenograft with L-­
PRF.146–­149 They all reported significantly more gain in the attach-
ment (0.9–­1.2 mm) and intra-­bony defect depth reduction (11%)
when L-­PRF was mixed with the xenograft.
3 | DISCUSSION
APCs have a number of benefits including: the release of growth
factor, a fibrous structure suitable for cell-­attachment, an improved
angiogenesis, an antibacterial capacity, and a differentiation of stem
cells toward the osteoblast. These characteristics should facilitate
wound healing/repair, and support soft-­ and hard-­tissue regenera-
tion. In the past decade, a large number of papers have investigated
the adjunctive impact of APCs in periodontal surgery.
3.1 | Alveolar ridge preservation
The benefits of PRPs on alveolar ridge preservation are controver-
sial, probably because of different preparation protocols. Therefore,
its application has become very limited.74,75,150 PRGF has shown to
be effective,77,80 although some studies could not find any differ-
76
ence with unassisted healing.
A series of studies supported the use of L-­PRF for ARP, not only
accelerating soft tissue healing,84,86–­88 but also limiting alveolar
ridge resorption.73,81,83,151 One should however realize that an in-
adequate use of L-­PRF (insufficient membranes apply, instability of
the wound, etc.) might jeopardize a promising bone regeneration. L-­
PRF also significantly improved the PROMs including pain, swelling
as well as post-­op bleeding.
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QUIRYNEN et al.
3.2 | Sinus floor elevation
Several case series indicated that L-­PRF can be successfully used
as a single substitute for a transcrestal approach, with high-­implant
survival rates and acceptable vertical bone gain (3–­4 mm). It also
has the benefit of reducing post-­op pain, and the long-­term vertical
bone resorption is limited.106,107,152 As such it can be recommended
in clinical practice. For PRP and PRGF, there is nearly no data for its
application, probably because of their weak physical characteristics.
L-­PRF is also the only APC used as a single substitute during
a 1-­stage lateral window approach. Several case series reported
high-­implant survival rates and good vertical bone gain with this ap-
proach. The use of L-­PRF, of course, reduces the costs of the treat-
ment, has the advantage of being 100% autogenous, and results in
a well-­vascularized bone without remnants of bone substitutes. Un-
fortunately, so far only two RCTs compared the use of L-­PRF (as a
single substitute) with the application of standard bone substitutes.
However, both studies indicated similar implant survival rates, but a
slightly lower vertical bone gain when using L-­PRF only.112,113
3.3 | Bone regeneration in intra-­bony defects
A large number of papers evaluated the benefits of using APCs dur-
ing open flap debridement. The large variety of protocols (APC as
filler material/as barrier membrane/or a combi of both, with/without
additional bone substitute) makes it difficult to give clear recommen-
dations, on which strategy is most beneficial. However, one can con-
clude that most applications resulted in significant improvements
in probing pocket depth reduction, clinical attachment gain, and
intra-­bony defect fill when compared with OFD alone. The latter is
confirmed by several systematic reviews including meta-­analyses.120
Unfortunately, there are no RCTs comparing the regenerative capac-
ity of APCs to more standard biomaterials like enamel matrix deri-
vates, hyaluronic acid, or bone substitutes.
4 | CO N C LU S I O N
L-­PRF is easy to prepare, simple to manage, not expensive, and
100% autogenous. As indicated in this review it offers a number
of benefits in ARP, sinus floor elevation, and the regeneration of
infra-­b ony craters around teeth. RCTs comparing their impact with
the “standard” periodontal treatments are scares or lacking, but
the data presented in this paper are promising and justifies their
clinical use. An important question is whether their application
offers additional benefits in more demanding conditions (elderly
patients, smokers, and patients with compromised wound heal-
ing). The clinical reports on the benefits of APCs in the healing
of chronic non-­responding wounds (e.g., diabetic foot, venous leg
ulcer, pressure ulcers) seem to indicate that one can expect a bene-
fit in these unfavorable conditions. The data on the 1st generation
APCs for the above-­m entioned indications are non-­conclusive.
 |

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QUIRYNEN et al. 265

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How to cite this article: Quirynen M., Siawasch SAM,
Temmerman A., et al. Do autologous platelet concentrates
(APCs) have a role in intra-­oral bone regeneration? A critical
review of clinical guidelines on decision-­making process.
Periodontol 2000. 2023;93:254-269. doi:10.1111/prd.12526