Case Report/Clinical Techniques

Histologic Outcomes of Uninfected Human Immature Teeth

Treated with Regenerative Endodontics: 2 Case Reports
Ali Nosrat, DDS, MS,* Alireza Kolahdouzan, DDS, MS,†‡ Farzaneh Hosseini, DDS, MS,‡
Ehsan A. Mehrizi, DDS, MS,§ Prashant Verma, DDS, MS,k
and Mahmoud Torabinejad, DMD, MSD, PhD¶

Abstract
A growing body of evidence exists showing the possi-
bility of growing vital tissues in the root canal spaces
of teeth with necrotic pulps and open apices. How-
P ulpal necrosis in immature teeth often results in incomplete root development.
ever, there is very limited histologic information
regarding characteristics of tissues formed in the
root canal space of human teeth after regenerative
endodontics. The aim of this study was to examine
clinically and histologically the outcomes of human
immature teeth treated with regenerative endodon-
tics. Two healthy birooted human maxillary first pre-
molar teeth scheduled for extraction were included.
Preoperative radiographs confirmed that these teeth
had immature apices. Vitality tests showed the pres-
ence of vital pulps in these teeth. After receiving con-
sent forms, the teeth were isolated with a rubber dam,
and the pulps were completely removed. After the for-
mation of blood clots in the canals, the teeth were
covered with mineral trioxide aggregate. Four months
later, the teeth were clinically and radiographically
evaluated, extracted, and examined histologically.
Both patients remained asymptomatic after treatment.
Radiographic examination of the teeth showed signs
of root development after treatment. Histologic exam-
ination of tissues growing into the root canal space of
these teeth shows the presence of connective tissue,
bone and cementum formation, and thickening of
roots. Based on our findings, it appears that when
canals of teeth with open apices are treated with
regenerative endodontics, tissues of the periodontium
grow into the root canals of these teeth. (J Endod
2015;41:1725–1729)
Key Words
Immature tooth, pulp regeneration, regenerative
endodontics, stem cell
These teeth often have thin root canal walls that are susceptible to fracture after treat-
ment (1). Complete cleaning and shaping as well as obturation of these teeth are diffi-
cult or sometimes impossible. Apexification using a mineral trioxide aggregate (MTA)
apical plug has been shown to produce successful outcomes (2). The main short-
coming of this procedure is the fact that is does not promote continuation of root devel-
opment throughout the whole root, and these teeth remain susceptible to coronal root
fracture. An ideal treatment outcome for these teeth is true pulpal regeneration and re-
establishment of the pulp-dentin complex. The benefit of regenerative endodontics is
not only revitalization of the tooth but also continued root development and, potentially,
increasing fracture resistance. Regenerative endodontics has 3 critical steps: adequate
disinfection of the root canal system, induction of bleeding to create a scaffold for stem
cells, and coronal sealing of the blood clot with a biocompatible material (3, 4). Several
case reports and case series have shown clinically successful outcomes and further root
development after regenerative endodontic treatment (5, 6). Recent case reports and
clinical studies have shown that root development as a possible indicator of pulp
regeneration is not a predictable outcome (7–9). Among all aspects of root
development (ie, increase in length, increase in root wall thickness, and apical
closure), apical closure has been shown to be the most frequent finding (7), which
could be unrelated to pulp regeneration (9). Hence, histologic analysis of tissues
formed inside the root canal after regenerative treatment is important, especially
regarding the differentiation of stem cells into odontoblasts. Histologic data on treat-
ment outcomes in human teeth are limited to a few case reports. The available data
show formation of mainly loose connective tissue in the root canal space and
cementum/bonelike tissue deposited on the dentinal walls (1, 10–12) after the use
of a blood clot or platelet-rich plasma (PRP) as a scaffold. The aim of this study was
to examine clinically and histologically the outcomes of 2 noninfected human teeth
treated with regenerative endodontics.
Materials and Methods
Two birooted fully erupted immature maxillary first premolar teeth scheduled for
extraction as a part of orthodontic treatment from 2 patients aged 9 (a female) and 10
(a male) were included in this investigation. The study protocol was peer reviewed and
approved by the Institutional Review Board at the Ghazvin University of Medical Sci-
ences, Ghazvin, Iran (IRB# 28/20/9591; date of approval: June/02/2014). Written con-
sent was obtained from the parents. Preoperative radiographs were taken to confirm the

From the *Iranian Center for Endodontic Research, Dental Research Center, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran;
Departments of †Endodontics and §Orthodontics, School of Dentistry, Ghazvin University of Medical Sciences, Ghazvin, Iran; ‡Department of Endodontics, Shahed Dental
School, Tehran, Iran; kPrivate Practice in Endodontics, Columbia, Maryland; and ¶Advanced Specialty Education Program in Endodontics, School of Dentistry, Loma Linda
University, Loma Linda, California.
Address requests for reprints to Dr Mahmoud Torabinejad, Department of Endodontics, School of Dentistry, Loma Linda University, Loma Linda, CA 92350. E-mail
address: mtorabinejad@llu.edu
0099-2399/$ - see front matter
Copyright ª 2015 American Association of Endodontists.
http://dx.doi.org/10.1016/j.joen.2015.05.004

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Case Report/Clinical Techniques
presence of open apices and the absence of caries and restorations
(Fig. 1A1 and B1). Both teeth were treated by 1 clinician according
to the following protocol:
After pulp testing using Endo Ice (Hygenic, Akron, OH) and an
electrical pulp tester (Analytic Technology, Redmond, WA), local anes-
thesia was administered using 1.7 mL 3% Carbocaine without epineph-
rine (Novocol Pharmaceutical, Cambridge, Ontario, Canada). Each
tooth was isolated with a rubber dam, and an access cavity was prepared
using a high-speed bur and water spray. After establishing the working
length radiographically 1 mm short of the open apex, the coronal thirds
of the canals were enlarged using Gates Glidden drills (Dentsply Mail-
lefer, Ballaigues, Switzerland). All canals were instrumented using hand
files (Dentsply Maillefer) to completely remove the pulp tissue. The ca-
nals in the 9-year-old patient were taken to a size 90 master file and
those in the 10-year-old patient were taken to a size 60 master file. Be-
tween each instrument, the canals were gently irrigated with 1.25% so-
dium hypochlorite (NaOCl) at 1 mm short of the working length. After
completion of instrumentation, all canals were irrigated with 5 mL 17%
EDTA and dried with sterile paper points. Bleeding was induced by over-
extension of a size 30 hand file 2–3 mm beyond the working length. A
blood clot was allowed to form for 10 minutes. MTA powder and liquid
(ProRoot, Dentsply Tulsa Dental, OK) were mixed to a putty consistency,
placed over the blood clot, and gently adapted to the dentinal walls. The
access cavity of each tooth was filled with resin-modified glass ionomer
cement (Fig. 1A2 and B2).
The teeth were scheduled for extraction 4 months after treatment.
Before extraction, a periapical radiograph was taken to evaluate the
continuation of root development (Fig. 1A3 and B3). Cold and electrical
pulp vitality tests were performed, and results were recorded. After ob-
taining local anesthesia, the teeth were extracted. The teeth were imme-
diately placed in 10% formaldehyde for fixation. Both teeth were
decalcified in 7% formic acid. Complete decalcification of the speci-
mens was confirmed radiographically. After decalcification, the speci-
mens were rinsed with running tap water for 2 hours, dehydrated
with ascending concentrations of alcohol (70%, 90%, and 100%),
and embedded in paraffin. The glass ionomer restorations were
removed gently before embedding. Five-micrometer-thick labiolingual
Figure 1. (A) Case #1. (B) Case #2. From left to right: (1) preoperative radiograph, (2) immediate postoperative radiograph, and (3) recall radiograph after 4
months before extraction. Root development is evident in both teeth.
1726 Nosrat et al.
sections were prepared serially, and specimens were stained with
hematoxylin-eosin. Samples were evaluated microscopically (Zeiss,
Goettingen, Germany) by 2 independent oral pathologists to determine
the histologic features of tissues formed within the root canal spaces of
teeth after regenerative endodontics.
Results
Clinical examinations of patients after 4 months showed that they
were asymptomatic after regenerative endodontics. The 4-month
follow-up radiographs showed progression of root development and
maturation of the roots in both patients (Fig. 1A and B). Both teeth
did not respond to cold and electrical pulp tests before extraction.
The sections from the first premolar in the 9-year-old female re-
vealed the presence of soft and hard tissues within the 2 roots. The roots
showed a well-developed dentin layer surrounded by a periodontal lig-
ament (PDL) on the outer root margins. Foreign body material (MTA)
was noted in the coronal portions of this tooth. A thick layer of hard tis-
sue was observed beneath this material (Fig. 2A). There was a fibrotic
collagenous soft tissue with hypercellular and hypervascualr connective
tissue supporting hard tissue (Fig. 2B) consistent with osteocementum.
The hard tissues within the root canals have numerous resting lines
(Fig. 2C and D). Additionally, the osteodentin showed osteoblastic
rimming in places (Fig. 2C). Several epithelial rests are also observed
within the cellular fibrotic pulp chamber (Fig. 2E). No inflammatory
cells were found within the canal spaces. The tissues within the roots
of this tooth displayed features mimicking odontogenic fibroma–
PDL–type histology.
The sections from the first premolar in the 10-year-old male re-
vealed portions of roots showing well-developed dentin surrounded
by PDL on the outer root margins. A well-preserved primary dentin layer
was identified surrounding the canal spaces (Fig. 3A). The dentin layer
in this tooth was much thicker than in the other specimen. Foreign body
material (MTA) was also observed in the coronal portions of this tooth
(Fig. 3B). The hard tissue juxtaposed to the foreign body material
(MTA) was not as thick as that observed in the other specimen. There
was a fibrotic connective tissue within the canal spaces and occasional
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 Case Report/Clinical Techniques

Figure 2. Histology images from the first maxillary premolar of the 9-year-old patient. (A) Low magnification (10) of the coronal third of the root showing the
MTA layer (M) and the thick layer of mineralized tissue formed underneath the MTA. (B) The fibrotic collagenous soft tissue with hypercellular and hypervascualr
connective tissue supporting osteocementum. (C) The bonelike material formed in the root canal space with osteoblastic rimming. (D) A view of the apical third (d,
dentinal wall) showing ingrowth of bone (b). (E) A view of the apex showing the presence of epithelial rests of Malassez.

globular and malformed cementum and dystrophic calcification
(Fig. 3A and B). The root canal walls were covered with a well-
formed symmetric layer of reparative cementum admixed with osteoid
tissue (Fig. 3C–E). No epithelial rests or inflammatory cells were
observed within the soft tissue of this specimen. The tissues within
the roots displayed features of periodontium structures.
Discussion
The present case reports examined, clinically and histologically,
the outcomes of regenerative endodontics in noninfected pulpless
human teeth with immature apices. Clinically, the patients were
asymptomatic, and, radiographically, the root development occurred
in both teeth after regenerative endodontics. The radiographic root
development has been considered a sign for success after regenera-
tive endodontic treatment. However, histologic reports of human
immature teeth with radiographic root development show that the tis-
sue formed within the root canal is not a true pulp tissue (10–12).
The soft tissue in these case reports resembles periodontal tissue,
and the hard tissues deposited on the dentinal walls appear to be
bonelike or cementumlike tissues (10–12). The histologic findings
in our specimens were similar to those reported in the previous

Figure 3. Histology images from the first upper premolar of the 10-year-old patient. (A) Midroot section of the tooth showing the presence of a thick layer of
primary dentin (d) surrounding the root canal space. A newly formed tissue has filled the root canal space. (B) The coronal section of the tooth showing that the
newly formed tissue has reached the MTA layer (M). A layer of mineralized tissue is formed underneath the MTA. Particles of MTA are seen in the tissue formed
underneath (arrowhead). The root canal walls are covered with a layer of reparative cementum (c). (C) Higher (40) magnification of the midroot showing the
presence of connective tissue within the root canal space and reparative cementum on the dentinal walls. (D) A view of the apex showing the ingrowth of the
cementum on the dentinal walls. (E) A higher (100) magnification of the outlined area seen in D showing the tubular structure of the dentin (d) versus the
amorphous/cellular structure of the cementum (c) and the calicotraumatic line between the 2 structures.

JOE — Volume 41, Number 10, October 2015 Uninfected Human Immature Teeth 1727
Case Report/Clinical Techniques
human (10–12) and animal (13, 14) investigations. These findings
collectively show that when disinfected canals of teeth with open
apices are treated with regenerative endodontics, tissues of the
periodontium (consisting of fibrotic periodontal ligament, collagen
fibers, blood vessels, and cementum- and bonelike tissues) grow
into the root canals of these teeth.
It is generally recognized that tissue regeneration requires an
interaction between stem cells and growth factors in a bioactive scaffold,
referred to as the tissue engineering triad (15). In regenerative end-
odontics, the apical papilla is the likely source for stem cells. It is shown
that these stem cells differentiate into odontoblasts that are responsible
for forming new dentin to continue physiological root development in
immature teeth (16). Lovelace et al (17) in a clinical study showed that
the concentration of mesenchymal stem cell markers in the blood clot
formed inside the root canal space is significantly higher than that in the
peripheral blood (17). The present study shows that the stem cells in
the blood clot might not differentiate into odontoblasts. Inducing
bleeding from periapical tissues by extending instruments past the
root apex can mobilize and deliver stem cells from other sources
(including bone marrow) into the root canal space. Mesenchymal
stem cells from bone marrow have the potential to differentiate into
osteoblasts.
An ideal scaffold selectively binds and localizes cells, contains
growth factors, and undergoes biodegradation over time (18). The
blood clot has been used as a physical scaffold in many cases (4, 5).
One animal study showed that root canals that had a blood clot
formation inside them had a better radiographic outcome compared
with those without a blood clot (19). The lack of a blood clot was asso-
ciated with poor root development in clinical cases (5, 8). In the
present study, bleeding was induced in all roots, and the blood clot
was used as the scaffold. The presence of vital tissue filling the entire
root canal space in all roots shows that the blood clot served as a
stable physical scaffold in these cases.
The blood clot is a protein-rich scaffold that contains growth fac-
tors derived from platelets that can act as signaling molecules (18).
Also, the use of EDTA releases several angiogenic and growth factors
from dentinal walls into the blood clot, including transforming growth
factor beta-1 (20, 21), vascular endothelial growth factor, platelet-
derived growth factor, and fibroblast growth factor (22). These
signaling molecules and growth factors will promote the proliferation
and differentiation of stem cells. Signaling molecules, scaffold, and
root canal dentinal walls create a microenvironment that plays an
important role in the fate of stem cells. The absence of odontoblastlike
cells in the tissues generated inside the root canal spaces in our spec-
imens indicate that this microenvironment does not have the required
properties for differentiation of stem cells into odontoblasts.
Clinically, regenerative endodontic treatment is performed in
teeth with necrotic pulps and immature apices. To promote pulp
regeneration in previously infected root canals, a higher level of
disinfection is required compared with conventional endodontic
treatments (23–25). Moreover, in the teeth of young patients,
bacterial cells penetrate through more dentinal tubules and to
greater depths compared with adults (26). A review of regenerative
endodontic treatment in 18 immature teeth revealed that a history of
symptoms (related to pulp necrosis) longer than 6 months is corre-
lated with poor root development after treatment (8). This finding
might be because of a more established endodontic infection in these
teeth. The present study included vital immature teeth with no caries
or restorations. Nevertheless, regeneration of the dentin-pulp com-
plex was not observed in any of the roots. The use of this noninfected
model is suggested to examine the efficacy of future protocols for
dental pulp regeneration.
1728 Nosrat et al.
Disinfection protocols for regenerative procedures include NaOCl
irrigation followed by antibiotic or calcium hydroxide dressings (3).
NaOCl is toxic to stem cells from apical papilla (SCAP) and prevents repo-
pulation of SCAP in root canals (27). Irrigation with NaOCl was related to a
lower amount of cell adherence to dentinal walls (28). Triple/double anti-
biotic pastes at commonly used clinical concentrations have been shown
to be highly toxic for SCAP (29), and they also alter the dentin, resulting in
reduced SCAP survival (30). A lack of vital tissues in the root canals after
regenerative endodontic treatments has been reported (8, 9), and toxicity
of the antibiotics used for disinfection was assumed to be a culprit (9). The
present study was conducted in noninfected pulpless teeth. Therefore, all
microbial challenges to pulp regeneration were eliminated.
In the present investigation, 1.25% NaOCl was used as an irrigant
during instrumentation and 17% EDTA as a final irrigant before
inducing bleeding. Previous studies have shown that NaOCl has detri-
mental effects on the survival and differentiation of SCAP (31). However,
this negative effect can be prevented by using a low concentration of
NaOCl (1.5% or less) followed by 17% EDTA irrigation (31). EDTA
can release bioactive growth factors that are sequestered into the dentin
matrix (20, 21). The use of EDTA as a final irrigant during regenerative
endodontic procedures can promote stem cell survival (27). Condition-
ing of the root canal dentin with EDTA also enhances stem cell attach-
ment and differentiation into odontoblasts (32).
As in many previous studies, MTA was used as the coronal barrier
on the blood clot (9, 33). MTA is a bioactive material that produces
hydroxyapatite crystals when it is in contact with body fluids (34).
MTA is biocompatible, promotes cell differentiation, and induces
hard tissue production without adverse tissue reactions (35). The seal-
ing ability of MTA makes it a suitable biomaterial for sealing of the blood
clot and preventing bacterial leakage over time (35). As shown in the
present study, there is a hard tissue barrier formed underneath MTA
in all roots (with no inflammation).
Animal models have been used to evaluate the histologic outcomes
of regenerative endodontic treatments. Dogs (19) and ferrets (13, 36)
are 2 models that have been studied. Different tissue engineering
strategies have been used to regenerate the pulp-dentin complex in
these studies. The effect of different combinations of dental pulp stem
cells, collagen scaffolds, PRP, and growth factors have been examined
in dog model studies (14, 37, 38). Although use of these strategies
resulted in increased formation of hard tissue, none of the studies
showed true regeneration of the pulp-dentin complex. The use of condi-
tioned medium from murine preameloblasts was investigated in dogs’
teeth and resulted in the formation of pulplike tissue and a higher de-
gree of hard tissue formation (39). Nevertheless, the histologic findings
show that the newly formed hard tissue is atubular and cellular, resem-
bling cementum (39). The addition of PRP to regenerative endodontic
procedures in noninfected immature ferret teeth resulted in the forma-
tion of bone inside the root canal space (13). The histologic findings in
our specimens were similar to those reported in animal studies.
Based on our findings, it appears that when canals of teeth with
open apices are treated with regenerative endodontics, tissues of the pe-
riodontium grow into the root canals of these teeth. Future investiga-
tions should focus on tissue engineering strategies to isolate and
stimulate dental pulp stem cells for the regeneration of true pulp tissue
(40, 41).
Acknowledgments
The authors thank Dr Nasser Said Al Naief from the Depart-
ment of Oral Pathology at Loma Linda University for histologic
evaluations of our cases.
The authors deny any conflict of interest related to this study.
JOE — Volume 41, Number 10, October 2015

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