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Original Article A comparative evaluation of natural and artificial

scaffolds in regenerative endodontics: A clinical
study

Shreya Sharma, Neelam Mittal

Department of Conservative Dentistry and Endodontics, Faculty of Dental Sciences, Institute of Medical
Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India

Key words:
Open apex, revascularization, scaffold
Address for correspondence:
Prof. Neelam Mittal,
Faculty of Dental Sciences, Institute of
Medical Sciences, Banaras Hindu
University, Varanasi,
Uttar Pradesh, India.
E‑mail: neelammittal@hotmail.com
ABSTRACT
Aim: To evaluate and compare the regenerative potential of natural
autologous scaffolds (blood clot and platelet rich fibrin [PRF]) with artificial
scaffolds  (commercially available collagen and poly‑lactic‑co‑glycolic
acid  [PLGA] polymer) in inducing apexogenesis in necrotic immature
permanent teeth. Materials and Methods: Necrotic immature permanent
maxillary incisors with or without radiographic evidence of periapical lesion
were included. Access opening was done under rubber dam isolation. Canal
disinfection was done using minimal instrumentation, copious irrigation, and
triple antibiotic paste as interappointment medicament for 4 weeks. After
4 weeks, asymptomatic teeth were divided into four groups on the basis
of scaffolds used for revascularization procedure: Group  I  (blood clot);
Group  II  (PRF); Group  III  (collagen); Group  IV  (PLGA). The clinical and
radiographic evaluations of teeth were done at 6 and 12 months after the
procedure and compared with baseline records. Result: Clinically, patients
were completely asymptomatic throughout the study period. Radiographically,
all cases showed improvement in terms of periapical healing, apical closure,
root lengthening, and dentinal wall thickening. PRF and collagen gave better
results than blood clot and PLGA in terms of periapical healing, apical closure,
and dentinal wall thickening. Conclusion: Revascularization procedure
is more effective and conservative over apexification in the management
of necrotic immature permanent teeth. This study has shown that PRF
and collagen are better scaffolds than blood clot and PLGA for inducing
apexogenesis in immature necrotic permanent teeth.

INTRODUCTION procedure with calcium hydroxide[3,4] or MTA.[4,5]

This, however, will not lead to root development.

N ecrotic immature teeth that have open and

divergent apices are not suitable for cleaning
and obturation with traditional techniques and
materials.[1] Because of their thin dentinal walls,
these teeth are susceptible to subsequent fracture
even after treatment. [2] Traditionally, teeth with
open apex have been treated using apexification
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DOI:
10.4103/1658-5984.171995
Thus, the ideal outcome for a tooth with an
immature root and necrotic pulp would be the
regeneration of pulp tissue into a canal capable
of promoting the continuation of normal root
development.[6]
Extrapolating the results of human avulsion
case series[7] and controlled animal studies,[8,9] it
was hypothesized that disinfection of a necrotic
infected immature permanent tooth with apical
periodontitis may render it to the same starting
point as a necrotic uninfected avulsed immature
permanent tooth. Revascularization should be
possible for the disinfected canals, just as it is for

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Sharma and Mittal: Natural and artificial scaffolds in regenerative endodontics
the uninfected canals in the avulsion scenario.[7,9] The
advantage of regenerative endodontic procedures over
apexification procedures is that it allows root thickening
and lengthening to continue by the generated vital
tissue.[10]
Hargreaves et  al.[11] have identified three components
contributing to the success of this procedure. They
include stem cells that are capable of hard tissue
formation, signaling molecules for cellular stimulation,
proliferation, and differentiation, and finally, a
three‑dimensional physical scaffold that can support
cell growth and differentiation.
An empty canal space will not support in‑growth of
new tissue from the periapical area on its own.[12] A
scaffold provides the framework for cell growth and
differentiation at a local site. Ideally, a scaffold should
be porous, biocompatible with the host tissues, the
correct shape and form to allow for replacement of
the lost tissues, and biodegradable.[13] Various natural
and artificial scaffolds have been used to regenerate
dentin or dentin‑pulp complexes in combination
with dental pulp cells.[14] Natural scaffolds offer good
biocompatibility and bioactivity, whereas synthetic
scaffolds offer more control over the degradation rate
and mechanical properties.[13]
In nearly all revascularization case reports, immature
permanent human teeth with a clinical diagnosis
of pulpal necrosis are disinfected, and bleeding is
evoked. Platelet rich fibrin  (PRF) is a second generation
platelet concentrate, which has a very significant
slow sustained release of key growth factors for at
least 1‑week [15,16] and up to 28 days. [17] PRF could
stimulate its environment for a significant time during
wound healing.[18] This lead to the idea of using PRF
membrane for pulp regeneration.
Although blood clot and PRF are natural autologous
scaffolds for pulp regeneration, intentional periapical
filing to induce the blood clot formation can cause
discomfort for the patient. Venous blood drawn from
the patients to make PRF can add to their discomfort
and can make children less cooperative during the
treatment. Hence, commercially available scaffolds
like collagen, and polymers such as poly glycolic
acid  (PGA), polylactic acid  (PLA), poly‑lactic‑co‑glycolic
acid  (PLGA), polycaprolactone  (PCL), etc., can be
used.[13]
10
As a scaffold, collagen allows for easy placement
of cells and growth factors and allows for
replacement with natural tissues after undergoing
degradation.[13] Dental pulp–like structures have been
successfully generated in mice by transplantation of
dental pulp stem cells onto a collagen scaffold. [13]
Several synthetic polymers, such as PLA, PGA, PLGA,
have been suggested as potential scaffolds for pulp
regeneration. These are nontoxic, biodegradable and
allow precise manipulation of the physicochemical
properties, such as mechanical stiffness, degradation
rate, porosity, and microstructure. [19] Huang et  al. [20]
used PLGA scaffolds seeded with stem cells
from apical papilla and dental pulp stem cells in
a tooth slice implantation model wherein dentin
like tissue and pulp like tissue was regenerated after
3–4 months of subcutaneous implantation of teeth in
immunocompromised mice.
The purpose of this clinical study was to evaluate and
compare the regenerative potential of blood clot, PRF,
collagen and PLGA scaffolds in immature necrotic
permanent teeth.
MATERIALS AND METHODS
Regenerative endodontic procedure was done in 16  cases
of immature necrotic permanent teeth using blood clot,
PRF, collagen, and PLGA as four different scaffolds
after approval from the ethical committee of the
university. Patients, both male and female, belonged
to the age group of 10–25  years. Necrotic immature
permanent maxillary incisors, due to trauma, with or
without radiographic evidence of periapical lesion were
selected. Medically compromised patients with systemic
conditions that compromise the healing response or
cause bleeding tendencies were excluded. Out of the
16 selected cases, 13 had periapical pathology while
3  cases had widening of periodontal ligament space
without periapical apthology. Clinically, 9  cases had
a history of spontaneous pain, 7  cases had tooth
discoloration, 2 had intraoral sinus and 2 were tender
on percussion. The detailed treatment protocol was
explained to the patient (or parents if the patient was
below 14  years of age) and written consent was obtained.
Under rubber dam isolation, access opening was
done in teeth with #2 round diamond bur  (Endo
Access Bur, DENTSPLY Maillefer). Further axial
wall extensions were done with safe tip fissure
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Sharma and Mittal: Natural and artificial scaffolds in regenerative endodontics
carbide bur  (Endo‑Z Bur, DENTSPLY Maillefer).
Minimal canal instrumentation was done with K–files
to remove the necrotic tissue, and the canals were
copiously irrigated with 2.5% sodium hypochlorite
solution  (Nimai Dento India) using a syringe and side
vented needle. The triple antibiotic paste was used as
the interappointment medicament for 4  weeks, and
the access cavity was sealed with temporary restorative
material Cavitemp  (AMMDENT, Mohali, India).
After 4  weeks, teeth were re‑accessed under rubber dam
isolation, and the triple antibiotic paste was washed out
of the canal using copious amount of 2.5% sodium
hypochlorite solution. Canals were dried, and further
revascularization procedure was carried out only if the
tooth was asymptomatic with no drainage from the
canal.
16 cases of immature necrotic permanent maxillary
incisors, selected for the study, were randomly divided
into four groups with each group containing four cases.
Group  I: Blood clot
Under local anesthesia without adrenaline, a sterile
23 gauge needle was passed beyond the confines of
the working length and bleeding was induced in the
canal. When frank bleeding was evident from the canal,
a tight cotton pellet was inserted in the coronal portion
of canal and pulp chamber for 7–10 min to induce clot
formation in the apical two third of the canal. Access
cavity was sealed with glass ionomer cement  [Figure  1].
Group  II: Platelet‑rich fibrin
Platelet‑rich fibrin was prepared by drawing 5  mL of
venous blood from the patient in dried glass test tube
and immediately centrifuging it at 3000  rpm for 10  min.
After centrifugation, three layers were formed in the
test tube–base layer of RBCs, top layer of acelluler
plasma, and a PRF clot in the middle. This clot was
a b c a
Figure 1: Radiographs of teeth number 11.21 showing preoperative
status (a), status after 6 months (b) and after 12 months (c) of using
blood clot as scaffold
Saudi Endodontic Journal • Jan-Apr 2016 • Vol 6 • Issue 1
then pressed between two gauge pieces to form a
membrane. The tooth was re‑accessed in the same
manner as described for Group  I. PRF was introduced
into the canal and carried to the apical part of root
canal using endodontic pluggers. Access cavity was
sealed with glass ionomer cement  [Figure  2].
Group  III: Collagen
The teeth in this group were re‑accessed as
mentioned for Group  I. Blood clot was induced in
the root canal as done in Group  I. Sterile collagen
sponge  (Cologenesis Healthcare Pvt. Ltd., India) was
then inserted into the root canal and pushed with the
help of endodontic pluggers. Access cavity was sealed
with glass ionomer cement  [Figure  3].
Group  IV: Poly‑lactic‑co‑glycolic acid
The teeth in this group were re‑accessed as mentioned
for Group  I. Blood clot was induced in the root
canal as done in Group  I. Sterile PLGA crystals
(Sigma Aldrich, USA) were introduced into the canal
with the help of tweezer and pushed inside with
endodontic plugger. Access cavity was sealed with glass
ionomer cement  [Figure  4].
Preoperative intra oral periapical radiograph was taken
as base line record. The clinical and radiographic
evaluations of teeth were done at 6 and 12  months
after the procedure and compared with base line
records. The clinical and radiographic evaluation was
done by two independent observers who were blinded
from the groups.
The scoring criteria used for radiographic healing was
as follows: No healing/improvement form baseline was
denoted by 0, Fair healing/improvement from baseline
by 1, Good healing/improvement from baseline by
2 and Excellent healing/improvement from baseline by
3 respectively.
b c
Figure 2: Radiographs of teeth number 11.21 showing preoperative
status (a), status after 6 months (b) and after 12 months (c) of using
platelet-rich fibrin as scaffold
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Sharma and Mittal: Natural and artificial scaffolds in regenerative endodontics
a b c
Figure 3: Radiographs of tooth number 21 showing preoperative
status (a), status after 6 months (b) and after 12 months (c) of using
collagen as scaffold
The data were analyzed by one‑way ANOVA test of
significance and Z‑test for proportions and P <  0.05
was considered statistically significant.
RESULTS
Clinical and radiographic evaluation after 12  months
follow-up showed that all the 16 cases showed
improvement as compared to the baseline levels.
Clinically, all the groups showed excellent results.
Patients were completely asymptomatic throughout
the study period with no tenderness to palpation
and percussion. The swelling and sinus had resolved
completely and did not reappear.
Radiographically, all 16  cases showed improvement
in terms of periapical healing, apical closure, root
lengthening and dentinal wall thickening.
Periapical healing
Platelet‑rich fibrin gave best results with 75%
cases showing excellent periapical healing. This was
followed by Group  III  (collagen), which showed
excellent results in 25% cases. This was followed by
Group  I  (blood clot). Least periapical healing was seen
in Group  IV  (PLGA) with 75% cases showing only
fair amount of periapical healing  [Table  1]. One‑way
ANOVA showed statistically significant difference
between these groups  (P  =  0.026). According to
Z‑test for proportions, difference between Group  II
and IV  (P  =  0.028) and between Group  III and
IV  (P  =  0.028) was statistically significant. This implies
that Group  II  (PRF) and Group  III  (collagen) were
better than Group  IV  (PLGA).
Apical closure
Group  II  (PRF) and Group  III  (collagen) gave best
results, both with 50% cases showing excellent results.
12
a b
Figure 4: Radiographs of tooth number 21 showing preoperative
status (a) and after 12 months (b) of using poly-lactic-co-glycolic acid
as scaffold
Table 1: Comparative evaluation of periapical
healing
Groups Fair (%) Good (%) Excellent (%) P
I 25 50 25 0.026
II - 25 75
III - 75 25
IV 75 25 -
This was followed by Group  I  (blood clot) with 75%
cases showing good apical closure. PLGA group
was least effective in apical closure with only 50%
cases showing good results  [Table  2]. There was no
statistically significant difference between these groups
in terms of apical closure (P = 0.197).
Root lengthening
Group  I  (blood clot) gave best results with 75% cases
showing good root lengthening. Group  IV  (PLGA)
was next with 50% cases showing good results.
This was followed by Group  III  (collagen),
which showed only 25% cases with good results.
PRF  (Group  II) gave the least effective results with
all the cases showing only fair amount of root
lengthening  [Table  3]. There was no statistically
significant difference between these groups in terms
of root lengthening  (P = 0.168).
Dentinal wall thickening
Group  III  (collagen) showed best results with 25%
cases showing excellent result. PRF group was next
with 75% cases showing good wall thickening. This
was followed by Group  I  (blood clot) with 50% cases
showing good results. PLGA was the least effective
scaffold for this property as only 25% cases showed
good dentinal wall thickening  [Table  4]. There was no
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Sharma and Mittal: Natural and artificial scaffolds in regenerative endodontics

Table 2: Comparative evaluation of apical closure and released cytokines in a fibrin clot. Granules
Groups Fair (%) Good (%) Excellent (%) P present in platelet contain many proteins, which may
I 25 75 - 0.197 be platelet specific  (e.g.,  beta‑thromboglobulins) or
II - 50 50 nonplatelet specific  (fibronectin, thrombospondin,
III 25 25 50 fibrinogen, and other coagulation, growth promoters,
IV 50 50 -
fibrinolysis inhibitors, immunoglobulins, etc.).
Activation and degranulation is important to release
Table 3: Comparative evaluation of root lengthening the cytokines  (interleukin‑1  (IL‑1) beta, IL‑6, tumor
Groups Fair (%) Good (%) Excellent (%) P necrosis factor‑alpha) and tumor growth factors  (TGF
I 25 75 - 0.168 beta 1, platelet derived growth factor, vascular
II 100 - - endothelial growth factor, epidermal growth factor)
III 75 25 - that stimulates cell migration and proliferation within
IV 50 50 -
the fibrin matrix and thus begins the healing process.
Dohan et  al. showed that Choukroun’s PRF seemed
Table 4: Comparative evaluation of dentinal wall to stimulate simultaneously, in a dose‑dependent way,
thickening the proliferation of oral bone mesenchymal stem
Groups Fair (%) Good (%) Excellent (%) P cells and some kind of differentiation characterized
I 50 50 - 0.383 by a strong activity of alkaline phosphatase, and the
II 25 75 - formation of mineralization nodules.[25] In our study,
III 25 50 25 PRF gave best results for the tested parameters. All
IV 75 25 -
the cases  (100%) showed good or excellent periapical
healing and apical closure. 75% cases showed good
statistically significant difference between these groups dentinal wall thickening. The success of PRF as a
in terms of dentinal wall thickening  (P = 0.383). scaffold can be attributed to the fact that it a strong
but flexible membrane with rich quantities of growth
DISCUSSION factors required for cellular proliferation, differentiation
and angiogenesis[26] available for a long duration.[15,16]
Regenerative endodontic procedures can be defined However, in terms of root lengthening, blood clot was
as biologically based procedures designed to better than PRF with all the cases showing only fair
replace damaged structures, including dentin and amount of root lengthening. This finding could not be
root structures, as well as cells of the pulp‑dentin explained.
complex.[21]
A collagen scaffold was selected because of its ease
A proper scaffold material is an essential component of placement and similarity to the collagen component
in the revascularization procedure. It provide sites of normal human dental pulp. Yamauchi et  al. [10]
for stem cell adhesion, to support cell proliferation demonstrated that the use of a crosslinked collagen
and differentiation, and thus to promote tissue scaffold with bleeding induction significantly increased
regeneration. [22] In an in vitro study, Chandrahasa, formation of mineralized tissues in teeth with incomplete
showed that different chemical composition of scaffolds root development and periapical periodontitis. Dental
result in different rates of mature dental pulp cell pulp–like structures[13] and complete tooth morphology
proliferation.[23] with rootlike structures[27] have been obtained from the
collagen sponge scaffolds. In this study also, collagen
In this study, four different scaffolds were used‑blood scaffold gave very good results, almost equivalent to that
clot, PRF, collagen and PLGA. PRF and collagen of PRF. 100% cases showed good or excellent periapical
gave better results than blood clot and PLGA in healing, 75% cases showed good apical closure, 75%
terms of periapical healing, apical closure and dentinal cases showed good or excellent dentinal wall thickening
wall thickening, though these differences were not and 25% cases showed good root lengthening. This could
statistically significant. be due to the osteoinductive property of collagen.[28] Its
resemblance to the natural extracellular matrix also helps
Developed in France by Choukroun et  al. [24] PRF in stem cell adhesion, proliferation and differentiation on
production protocol attempts to accumulate platelets this scaffold.

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Sharma and Mittal: Natural and artificial scaffolds in regenerative endodontics
The induced bleeding and subsequent formation of
blood clot serves as a scaffold and also as a source
of stem cells from the granulation tissue, apical
papilla, PDL, and/or from the bone marrow and
peripheral blood. [10] Human dentin contains several
angiogenic growth factors[29] that can promote tissue
regeneration in the root canal space. Blood clot in the
disinfected empty root canal space along with growth
factors derived from dentinal walls plays the role of a
protein‑rich scaffold. An animal study has shown that
root canals that had a blood clot formed inside them
after disinfection had better radiographic treatment
outcomes regarding the thickening of root canal walls
and apical closure compared with those that did not
have a blood clot in the canal space.[30]
However, blood clot makes a weak fibrin mesh as
compared to PRF. It may also get disintegrated in
the root canal as a result of which there might be no
carrier for stem cells to proliferate. Therefore, collagen
along with bold clot gave better results than blood
clot alone. Blood clot is not a concentrated source of
growth factors as PRF. This can also be a reason for
PRF and collagen giving better results.
Poly‑lactic‑co‑glycolic acid is the first copolymer
mixture to gain approval from Food and Drug
Administration. PLGA has been used in engineering
bone, liver and cartilage. [31] Bertoldi tested a
50:50 PLGA copolymer and stated that it is free
of inflammation effects, seems to stimulate bone
growth, and decomposes after 6–8  months. [32] They
also showed a strong alkaline phosphatase expression,
indicating a probable promotion effect on bone cells.
El‑Backly et al.[33] showed that 50/50 PLGA has good
porosity for osteoconduction and that PLG scaffold
may act as a suitable matrix to support dental pulp
stem cells and their differentiation to form an organized
dentine/pulp‑like tissue[33] hence we used 50:50 PLGA
scaffold. Tooth like structures have been obtained by
seeding dental pulp stem cells on PLGA scaffolds.[20,34]
In our study, however, only 25% cases showed good
periapical healing and dentinal wall thickening. And 50%
cases showed good apical closure and root lengthening.
In this study, PLGA gave the least impressive results
when compared with the other three scaffolds used.
This can be attributed to the fact that all previously
done studies were animal studies. [33] The effect of
PLGA as a scaffold for regenerative endodontics has
never been studied in human subjects. Therefore, those
results cannot be directly extrapolated for humans.
14
Blood clot, PRF and collagen have constituents of
human extracellular matrix while PLGA does not. This
can also be a reason for its inferior results as compared
to the other three scaffolds.
Continued root development does not appear to be a
predictable outcome of immature permanent necrotic
teeth after revascularization procedures in humans.
A  retrospective evaluation of radiographic outcomes in
immature teeth with necrotic root canal systems treated
with regenerative endodontic procedures indicated that
only a certain percentage of cases showed increase
in root length.[35] In our study also, only 37.5% cases
showed good root lengthening. But, 75% cases showed
good apical closure confirming that regenerative
endodontics is a successful treatment modality.
CONCLUSION
The present study, combined with prior reports on
revascularization of the nonvital immature permanent
teeth, constitute a growing case series suggesting
that this biologically based treatment approach is
of particular value in restoring root development
and apical closure in these otherwise difficult cases.
This pilot study also shows that PRF and collagen
are better scaffolds than blood clot and PLGA for
revascularization procedure in immature necrotic
permanent teeth.
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How to cite this article: Sharma S, Mittal N. A comparative evaluation
of natural and artificial scaffolds in regenerative endodontics: A clinical
study. Saudi Endod J 2016;6:9-15.
Source of Support: Nil. Conflict of Interest: None declared.
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