Biotechnology & Biotechnological Equipment

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Endodontic and surgical treatment of chronic

apical periodontitis: a randomized clinical study

Janet Kirilova, Dimitar Kirov, Dimitar Yovchev, Snezhanka Topalova-Pirinska

& Elitsa Deliverska

To cite this article: Janet Kirilova, Dimitar Kirov, Dimitar Yovchev, Snezhanka Topalova-Pirinska
& Elitsa Deliverska (2022) Endodontic and surgical treatment of chronic apical periodontitis: a
randomized clinical study, Biotechnology & Biotechnological Equipment, 36:1, 737-744, DOI:
10.1080/13102818.2022.2108338

To link to this article: https://doi.org/10.1080/13102818.2022.2108338

© 2022 The Author(s). Published by Informa

UK Limited, trading as Taylor & Francis
Group.

Published online: 08 Sep 2022.

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Biotechnology & Biotechnological Equipment
2022, VOL. 36, NO. 1, 737–744
https://doi.org/10.1080/13102818.2022.2108338

Endodontic and surgical treatment of chronic apical periodontitis:

a randomized clinical study
Janet Kirilovaa, Dimitar Kirovb, Dimitar Yovchevc, Snezhanka Topalova-Pirinskaa and Elitsa
Deliverskad
a
Department of Conservative Dentistry, Faculty of Dental Medicine, Medical University of Sofia, Sofia, Bulgaria; bDepartment of Prosthetic
Dental Medicine, Faculty of Dental Medicine, Medical University of Sofia, Sofia, Bulgaria; cDepartment of Imaging and Oral Diagnostic,
Faculty of Dental Medicine, Medical University of Sofia, Sofia, Bulgaria; dDepartment of Maxillofacial Surgery, Faculty of Dental Medicine,
Medical University of Sofia, Sofia, Bulgaria

ABSTRACT ARTICLE HISTORY

The development of regenerative endodontic therapy offers new opportunities for faster tooth Received 21 March 2022
recovery in chronic apical periodontitis. This study aimed to use three different surgical protocols Accepted 27 July 2022
to compare the results (filling the apical lesion with bone tissue over 6 months) of treatment in
patients with chronic apical periodontitis. This study included 23 patients and 30 teeth with KEYWORDS
chronic apical periodontitis. The patients were divided into three groups: (1) Endodontic treatment Chronic apical
and apical osteotomy without filling; (2) Endodontic treatment and apical osteotomy with the periodontitis;
placement of blood concentrate according to the advanced platelet-rich fibrin A-PRF + protocol; regenerative endodontic
(3) Endodontic treatment and apical osteotomy with the placement of blood concentrate therapy; platelet-rich
according to the ‘sticky bone’ and A-PRF + protocols with allograft. The results were reported fibrin; cone-beam
computed tomography;
after 6 months using cone-beam computed tomography. The results showed a statistically
apical surgery; treatment
significant difference (Mann–Whitney U test) in the filling of the bone defect in the healing outcomes
process between the first group (average rank 31.490) and the second group (average rank
96.015), as well as between the first group (average rank 31.490) and the third group (average
rank 91.765). No significant difference was found in the filling of the bone defects between the
second and third groups. We show that placement of A-PRF + blood concentrate alone or
combined with alloplastic graft after classical apical osteotomy of teeth with chronic apical
periodontitis leads to a size reduction of the bone defect with 95.25% for group 2 and 90.80%
for group 3 after 6 months.

Introduction possibilities for the endodontic treatment of affected

Endodontics has evolved with the introduction of
regenerative endodontic therapy (RET). This therapy
replaces damaged tissues, including dentin, root struc-
tures and cells in the pulp-dentin complex via biolog-
ically activated products [1]. In the apical periodontium,
the affected tissues are replaced with vital and viable
tissues by stimulating the healing process or by intro-
ducing biologically active substances [2, 3]. A biolog-
ically active product is the blood plasma-containing
growth factor within platelets. Blood plasma can be
used alone or in combination with other biologically
active products such as graft materials [4]. The proto-
cols for obtaining concentrate from blood are con-
stantly being improved [5]. This expands the
periapical tissues by shortening the time for complete
regeneration [5].
In chronic apical periodontitis (CAP) with granu-
loma, the dental pulp is irreversibly damaged, but the
recovery of periapical tissues is essential. The unfavor-
able outcome of this type of disease is associated with
the loss of teeth. Concurrently, treatment is compli-
cated and involves a lot of time and visits, with uncer-
tain results. Radical removal of the altered periapical
tissues is possible through surgery. The use of biolog-
ically active products in the combined endodontic
surgical treatment of CAP increases the possibility of
complete recovery of the affected apical tissues. Rapid
bone healing periapically is expected [6]. Data analysis
of the literature shows that previous studies described

CONTACT Janet Kirilova janetkirilova@gmail.com Department of Conservative Dentistry, Faculty of Dental Medicine, Medical University of Sofia,
Sofia, Bulgaria.
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unre-
stricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
738 J. KIRILOVA ET AL.
clinical cases with successful use of different blood
plasma- containing growth fac tors in the
endodontic-surgical treatment of CAP [7].
In RET, plasma therapy and graft materials are
applied in tissue engineering to treat CAP. It is import-
ant to understand what happens in periapical tissues
after introducing platelet-rich fibrin (PRF) after surgery.
Most authors have noted that the time for regenera-
tion of the affected bone is shortened [7]. However,
the difference between performing apical osteotomy
via the classical method without filling and after filling
with the last generation blood plasma (A-PRF+) with
or without a bone graft to restore bone tissue in the
affected area is unclear. Therefore, additional clinical
trials are warranted.
This study aimed to compare the results of end-
odontic surgical treatment of patients with CAP using
three different surgical protocols by monitoring the
filling of the apical lesion with bone tissue for 6 months.
The null hypothesis is no differences between the
studied treatment approaches.
Subjects and methods
Ethics statement
The Scientific Ethical Committee at the Medical
University in Sofia, Bulgaria, approved the study pro-
tocol before the initiation of the study (KENIMUS- No.
BK-459/17.03.2020 and No. 12/14.5.2020). In accor-
dance with the Helsinki Declaration II, all subjects
provided informed written consent for participation in
this study.
Teeth and subjects
The research included 30 teeth with CAP, diagnosed
preoperatively via clinical examination, electro-pulp
test, intraoral radiography, and cone-beam computed
tomography (CBCT ). Twenty-three patients aged
25–45 years were selected, without other diseases
and without established allergies to anesthetics,
medications and dental materials. These patients did
not undergo surgery in the areas of interest. The
exclusion criteria were a history of trauma in the
same place, congenital diseases, other causes leading
to changes in bone structure, and artifacts from
metal objects that interfere with the visualization of
periapical lesions that may degrade X-ray images.
Cases in which it was established that it was impos-
sible to treat the root canals to the apex or other
metal objects from the previous treatment were
excluded.
Endodontic treatment
Endodontic treatment included measuring the length
of the root canals radiologically and with an apex
locator (Raypex-6-VDW GmbH, Germany); treatment of
the root canal system with nickel-titanium files from
the Wave One Gold system (Maillefer Instruments,
Switzerland) with reciprocal movement; irrigation pro-
tocol: 1.5% sodium hypochlorite, chelator 17% eth-
ylenediaminetetraacetic acid (EDTA) and 2%
chlorhexidine solution (PPH CERKAMED, Poland); saline
solution was used for intermediate irrigation; and
obturation of root canals with epoxy sealer AH Plus
Jet (Dentsplay, Sirona, Germany) and obturators
Thermafil (Dentsplay, Maillefer).
After obturation of the root canals and placement
of glass ionomer cement for restoration (GC Fuji LC II,
GC Corporation Tokyo, Japan), the patient was pre-
pared for apical osteotomy according to the surgeon's
availability, but no later than 4 weeks after completion
of endodontic treatment.
After completing the endodontic treatment in
preparation for surgical treatment, each patient under-
went diagnostic CBCT to evaluate the apical lesion
volume and control CBCT 6 months after surgery. The
initial apical changes in the patients were assessed
using the Estrela index scale [8], CBST PAI 3–5 (from
2 to >8 mm).
Surgical treatment
All patients underwent apical osteotomy according to
the classical method. The root-end with granuloma
was resected (where it is possible). Periapical granu-
lation tissue was removed, and the surgical wound
wa s s u t u re d (G l yco l o n 5 / 0 D S 1 8 - R E S O R B A
Medical GmbH).
The patients were randomly divided into three
groups. In the different groups, the bone wounds were
treated as follows:
Group 1. Ten treated teeth and 11 roots with CAP
(seven patients). No additional treatment was admin-
istered for the bone wound.
Group 2. Ten treated teeth and 10 roots with CAP
(seven patients). Bone wound filling: Following veni-
puncture, 18 mL of blood was centrifuged according
to the Choukroun protocol for A-PRF+ (Low relative
centrifugal forces—208 g; centrifugation proto-
col—1300 rpm for 14 minutes; Duo centrifuge/Process
for PRF, Nica, France). Two fibrin membranes were
prepared from the A-PRF + blood concentrate. The
bone wound was filled with pieces of the prepared
membrane, and the bone defect was covered with the
whole membrane and sutured.

Group 3. Ten treated teeth and 14 roots with CAP (nine
patients). Bone wound filling: Following venipuncture,
18 mL of blood was centrifuged according to the
Choukroun protocol for A-PRF+ (Low relative centrifugal
forces—208 g; centrifugation protocol—1300 rpm for
14 min; Duo centrifuge/Process for PRF, Nica, France).
One red tube and one green tube were used. Sticky
bone and membranes were made from the obtained
blood plasma. The bone cavity was filled with the pre-
pared ‘sticky bone’ (liquid plasma from the green tube
with pieces of membrane and allograft). An allograft
(Allodyn-Bioregeneration, Biobank) was used as the
graft material. The bone defect was covered with a
membrane, and the surgical wound was sutured.
Patients were followed-up clinically on days 1 and
7. The control CBCT was taken after 6 months.
CBCT study
CBCT tests were performed using a Planmeca ProMax 3 D
conical beam computed tomography apparatus (Planmeca,
Helsinki, Finland), according to the manufacturer's recom-
mended protocol. The scans were performed with similar
parameters for all patients and with a voxel size of
0.20 mm to obtain a high spatial resolution. Subsequently,
the data were exported in DICOM file format.
The following processing methodology was used to
report the imaging study results [9, 10]. Two indepen-
dent observers (an endodontist and a radiologist) eval-
uated the periapical lesion images. To examine
pathological periapical lesions and postoperative peri-
apical defects, the observers used Digital Imaging and
Communications in Medicine files and Planmeca
Romexis Viewer (v. 6.1.0.997) visualization software. The
outlines of each periapical lesion and each periapical
defect were marked manually as polygons in each axial
section (axial Z) using the ‘Free region grow tool’ avail-
able in Planmeca Romexis Viewer (v. 6.1.0.997). After
completing the marking, each researcher evaluated
whether all the lesion outlines or postoperative defects
were marked. The polygon in each axial section pre-
cisely covers the entire lesion border (coronal and sag-
ittal). If necessary, corrections of the marked contours
are created so that the entire lesion or defect includes
manual markings. The "Create Region" option automat-
ically calculates the defect volume in cubic centimeters.
Two researchers independently performed segmenta-
tion and volume calculations for each CBCT scan. The
obtained data were subjected to statistical analyses.
Statistical methods
The statistical processing of the results is consistent
with the nature of the data and monitored variables.
Biotechnology & Biotechnological Equipment 739
Most indicators do not have a normal distribution,
which requires the use of non-parametric analysis
methods. Descriptive methods were used to process
categorical and quantitative variables (mean, median,
mode, standard deviation, minimum and maximum),
cross-tabulation, and hypothesis testing methods
(Kolmogorov–Smirnov, Mann–Whitney, Kruskal–
Wallis). Data processing was performed using IBM
SPSS Statistics version 20 (Ar monk , NY,
10504-1722, USA).
Results
Classical apical osteotomy without additional treatment
of the bone wound (Group 1) in the sixth month of
the study presented an average degree of filling of
39.0677 ± 19.973%. Classical apical osteotomy and fill-
ing of the operative cavity with A-PRF+ ‘blood con-
centrate’ rich in growth factors (group 2) in the sixth
month of the study presented an average filling vol-
ume of 95.23 ± 4.114% in the group. Classical apical
osteotomy and filling of the operative cavity with
‘sticky bone’ (group 3), in the sixth month of the study,
presented an average filling volume of 90.801 ± 7.041%
(Table 1, Figures 1, 2, 3).
To test the hypothesis that the bone tree filling for
the three studied groups was identical, the Kruskal–
Wallis test was applied (Table 2).
The Kruskal–Wallis test for bone defect filling in the
three studied groups showed a statistically significant
difference between them, χ2 (2) = 21.475, p < 0.00002.
The Mann–Whitney U test was applied to the thesis
that the degree of filling of the defect between the
first and second, first and third, and second and third
groups did not differ significantly (Table 3).
The results of the Mann–Whitney U test showed a
statistically significant difference between the filling
of the bone defect in the healing process between
the first group (average rank 31.490) and the second
group (average rank 96.015), U = 0.00, p = 0.0012,
z = 3.837, as well as between the first group (average
rank 31.490) and the third group (average rank 91.765),
U = 5.00, p = 0.0001, z = 3.914. No significant difference
was found in the filling of the bone defect between
the second (mean rank 96.015) and third groups (mean
rank 91.765), U = 46.00, p = 0.159, z = 1.405.
Table 1. Descriptive statistics of the study groups.
Before After degree of filling
Group n Mean + SD Mean + SD Mean + SD
1 11 0.3365 ± 0.1036 0.2279 ± 0.1285 39.0677 ± 19.973
2 10 0.7988 ± 0.4197 0.0386 ± 0.0387 95.23 ± 4.114
3 14 0.4346 ± 0.3071 0.0491 ± 0.0610 90.801 ± 7.041
740 J. KIRILOVA ET AL.

Figure 1. Patient from group 1 (endodontic treatment and classical apical osteotomy without additional treatment of the bone
wound); six months after the operative intervention, the postoperative defect can be observed on the CBCT image. Unrecovered
spongiosis and compact bone are visible. The results show significantly less recovery than group 2 and group 3 six months
after surgery. In patients of the first group with classical apical osteotomy, without additional treatment of the bone wound
after six months marked residual volume of the lesion was 39.0677 ± 19.973%. There is an improvement, but it is far less than
the recovery of bone tissue in the second and third groups.

Based on the results obtained for group 2 and
group 3, six months after surgery, we can accept that
treating teeth with chronic apical periodontitis can be
successful.
Discussion
To perform tissue engineering in tissue management
and augmentation, three factors are required: scaffolds,
growth factors and stem cells. These factors were pres-
ent in study groups 2 and 3.
Growth factors exist in all tissues, but the blood,
where they are located in platelets, is the main reser-
voir [11, 12]. Platelets showed significant metabolic
activity. Their life cycle includes inactive growth factors
that respond to clotting. Increasing the concentration
of platelets in blood products stimulates and acceler-
ates healing by releasing biologically active growth
factors and cytokines [13]. Growth factors are removed
from platelets during centrifugation, and promote
angiogenesis, lymphomagenesis and tissue regenera-
tion. Important growth factors include vascular endo-
thelial growth factor (VEGF), platelet-derived growth
factor (PDGF), transforming growth factor-beta (TGF-β),
epidermal growth factor (EGF) and insulin-like growth
factor (IGF-1). They cause new vascularization; normal-
ize hemodynamics, tissue respiration and metabolism;
stimulate extracellular matrix formation; and support
tissue maturation and remodeling. Cytokine release
stimulates cell migration and proliferation within the
fibrin matrix. This study confirms the findings of other
authors that significant results can be achieved in soft
tissue and bone augmentation management under the
influence of growth factors [14].
In 2001, Choukroun and Ghanaati developed a
second-generation protocol, resulting in an autoge-
nous concentrate rich in platelet mass containing
platelets, leukocytes and growth factors in a healthy
fibrin matrix [15]. The PRF has the following variants:
A-PRF and A-PRF + modern PRF matrix; injectable PRF
(i-PRF) and i-PRF+; and S-PRF, a product that allows
making "sticky bone" consistency of the used graft
material [15]. It is important to understand how pro-
posed protocols differ from the original protocol. The
classical centrifugation protocol requires a relatively
high centrifugation force of 1000–708 g [14, 15]. Thus,
a fibrin network with a dense structure and minimal
interfibrous spaces is obtained [15]. The fibrin scaffold
includes platelets, leukocytes, lymphocytes, macro-
phages and stem cells, but the cell distribution is
uneven. They are clustered near the erythrocytes, while
their density decreases drastically at the free end of
the tube (this part of the plasma is used for further
procedures). In addition, the plasma obtained contains
only platelets in a minimal quantity, and anticoagu-
lants, some of which are of animal origin, are added
to the tubes to slow the clotting process, triggering
an antigen–antibody allergic reaction.
In some protocols, the centrifugation force is low
and decreases to 60 g [16]. Another difference is that
 Biotechnology & Biotechnological Equipment 741

Figure 2. Patient from group 2 (endodontic treatment and apical osteotomy with the placement of blood concentrate according
to the advanced platelet-rich fibrin A-PRF + protocol). The GR (a) CBCT showed a substantial lesion volume before treatment
0.345 cm3. In the patient of the second group, the proximity of the maxillary sinus was visible, and intraoperatively a tiny area
with a visible Schneiderian membrane was observed. The GR (b) CBCT showed a healing process in which the bone structure
was restored after 6 months 0.004 cm3. Significant recovery of the spongiosa and partial recovery of the compacta bone was
found. For group 2, the bone repair was effective - 95.23 ± 4.114%. These results show success in bone repair after six months.

tubes without anticoagulants are used, eliminating the
possibility of an antigen–antibody reaction. The result-
ing fibrin matrix has a more porous structure and more
extensive interfibrous spaces (facilitating cell migra-
tion), and the distribution of platelets is uniform, sig-
nificantly increasing their number, and the plasma
contains leukocyte cells. The presence of leukocytes
has been shown to be a factor that attracts stem cells
to the wound surface. Ponte et al. [17] found that leu-
kocytes secrete signaling factors that stimulate tissue
regeneration and mesenchymal stem cell recruitment.
Therefore, the presence of leukocytes in the plasma
after Choukroun centrifugation is significant. This is a
fundamental factor in tissue engineering [11]. Clinical
studies have confirmed the importance of cell distri-
bution in vascularization and tissue regeneration [15,
16]. A significant increase in the growth factors TGF-β1,
VEGF, PDGF-AA and PDGF-AB, and PDGF-BB was
observed in the centrifuged plasma. With prolonged
centrifugation time (A-PRF + regimen), the growth fac-
tors TGF-β1, VEGF, EGF and IGF-1 were significantly
increased [15, 16]. Both Choukroun protocols (A-PRF
at 1300 rpm for 8 min and A-PRF + at 1300 rpm for
14 min) showed excellent biocompatibility and cellular
activity in an in vitro study [15]. We observed a 300%
increase in type 1 collagen synthesis. This is a key
742 J. KIRILOVA ET AL.

Figure 3. Patient from group 3 (endodontic treatment and apical osteotomy with the placement of blood concentrate according
to the "sticky bone" - A-PRF + protocols with allograft). The (a) CBCT image shows the volume of the lesion before treatment
0.016 cm3 for distal root and 0.013 cm3 for mesial root. The (b) CBCT image shows a healing process in which the bone structure
is restored after 6 months—0 for mesial root and 0.004 cm3 for distal root. In this group, most of the patients have significant
recovery of cortical bone. For group 3, the healing of bone tissue was significant – 90.801 ± 7.041%. These results show signif-
icant improvement in bone recovery after six months.

Table 2. Kruskal–Wallis analysis for mean of various groups. Table 3. Comparison between all tested groups of treat-
Group n Sum of ranks χ2 p Ɛ2 ment using Mann–Whitney test.
1 11 6.45 21.4757 <0.001* 0.632 Group 1 Group 2 Group 3
2 10 25.90 p value p value p value
3 14 21.43
Group 1 – <0.0001* <0.0001*
Group 2 – – 0.159
Group 3 – – –
factor in wound healing and remodeling. The *
The test is significant at the Bonferroni correction of α = 0.01667.
A-PRF + centrifugation regimen facilitated plasma sep-
aration from red blood cells. A-PRF + is a ‘blood con-
centrate’, not a ‘platelet concentrate’. The A-PRF and with the long-term release of autologous bone mor-
A-PRF + protocols aim to achieve a better composition phogenetic proteins [14, 15].
for the healing cascade: slow-release cytokines, natural Placement of blood concentrate with growth factors
fibrin, monocytes, granulocytes and plasma proteins, in the surgical wound stimulates healing. The results

of bone wound repair in patients from groups 2 and
3 can be explained by the degranulation of platelets
and the release of growth factors from them, with the
presence of leukocytes in the blood plasma and its
ability to attract stem cells from the blood [17].
It is important to note that augmentation uses a
membrane that acts as a guardian in the area imme-
diately below it and prevents the separation of blood
coagulation from the walls of the defect. The mem-
brane serves as a scaffold in the process of bone for-
mation; the barrier protects active tissue proliferation
and promotes bone growth. As such, a membrane for
the A-PRF + blood plasma protocol from the patient's
blood is used. This has been reported in several pre-
vious studies [15, 18, 19]. In addition to the membrane
obtained by the A-PRF + method in group 3, allograft
material was also used as a scaffold, that is, two matri-
ces were introduced into the bone wound. The graft
material used is alloplastic, which is advantageous
because it avoids the use of genetically different mate-
rials, such as xenografts and synthetic grafts. Allograft
materials were considered complete. Hip endoprosthe-
sis surgery and femoral head removal are usually per-
formed using living donors. Block grafts with low
mechanical strength and osteoconductive potential
(missing mineral components) were also obtained.
Simultaneously, this makes bone morphogenetic pro-
teins more accessible, which determines a higher oste-
oinductive potential [20]. The results achieved in
patients from groups 2 and 3 were due to the biolog-
ically active products. There was no statistically signif-
icant difference in the degree of bone defect filling
between groups 2 and 3 in the sixth month of the
study. This raises the possibility of placing the graft
material in the bone wound, as it is the second scaf-
fold in the surgical protocol. It is impossible to provide
such an answer within the framework of this study
and its methods.
Some authors described cases of endodontic surgi-
cal treatment of chronic apical periodontitis and
reported that after one-year recovery of the bone
lesion by 89–92.5% [21]. The difference with our study
is that the authors use another type of blood
plasma-containing growth factor (first-generation), and
the reported results are after one year.
Certain procedures of the endodontic treatment
protocol, such as irrigation solutions with specific con-
centrations, are essential for the regenerative recovery
of periapical tissues.
A sodium hypochlorite solution is recommended at
a concentration of no more than 1.5% for RET [22].
EDTA at a concentration of 17% has been shown to
increase and maintain viable apical papillary stem cells,
Biotechnology & Biotechnological Equipment 743
chlorhexidine solution, and antibiotics [23]. It is crucial
to not react with other wash solutions, which is
achieved by applying intermediate irrigation with ster-
ile saline [24].
This study demonstrated a statistically significant
recovery of the affected bone tissues with bioengi-
neering technology (A-PRF + blood concentrate alone
or combined with an alloplastic graft). The time of
regenerative healing of bone tissue is significantly
shortened. This confirms the findings of other studies
that plasma therapy and bone graft placement are
essential parts of modern regenerative therapy [11,
15, 24].
Conclusions
In this study, there was no difference in the endodon-
tic surgical treatment of the three studied groups with
CAP. It was demonstrated that placement of
A-PRF + blood concentrate rich in growth factors alone
or combined with alloplastic graft after classical apical
osteotomy of teeth with CAP leads to a size reduction
of the bone defect with 95.25% for group 2 and
90.80% for group 3 after 6 months. The results were
statistically significant compared to those in the group
of patients in whom apical osteotomy of teeth with
CAP was performed without additional filling of the
bone defect.
Disclosure statement
The authors deny any conflicts of interest related to
this study.
Funding
Data availability statement
The data that support the findings of this study are available
from the corresponding author, GK, upon reasonable request.
Funding
The present study was supported by grant № D-116/24.6.2020
from The Council of Medical Science at the Medical University
in Sofia, Bulgaria.
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