3Mixtatin Compared to MTA in Primary Molars with Inflammatory Root Resorption

A Randomized Trial Using 3Mixtatin Compared to MTA in Primary

Molars with Inflammatory Root Resorption: A Novel Endodontic
Biomaterial
Aminabadi NA*/ Huang B**/ Samiei M***/Agheli S****/ Jamali Z*****/ Shirazi S******

Objectives: Novel methods for preserving primary teeth can help to maintain their developmental, esthetic,
and functional capabilities. The aim of this study was to assess the success of the repair of bony defects, caused
by pre-treatment perforations, with a mixture of three antibiotics combined with simvastatin (3Mixtatin)
compared to MTA in hopeless primary molars. Study design: In this randomized clinical trial, 80 teeth from
65 healthy children aged 3–6 years with interradicular or periapical root resorption and/or perforation in
primary molars were treated either with 3Mixtatin or MTA before conventional pulpectomy and restoration.
The subjects were followed up clinically and radiographically for 4, 6, 12 and 24 months after pulp treatment
to evaluate and compare the healing process. The data were compared using chi-square test at a significance
level of 0.05. Results: By the end of 24 months in 3Mixtatin group, 31 (96.8%) teeth revealed no clinical
signs or symptoms with arrested resorption progress in radiographs. In MTA group, clinical signs and
symptoms including pain, mobility and sinus tract were observed in 18 (48.6%) teeth with cessation of root/
interradicular radiolucency in 7 (18.9%) teeth without bone repair. Conclusions: Radiographic and clinical
healing occurred more successfully following 3Mixtatin treatment compared to treatment with MTA, it may
lead to a paradigm shift in the pulpal treatment of primary teeth in the future.

Key words: 3Mix, Primary teeth, Regenerative treatment, Root resorption

INTRODUCTION

P
rimary teeth are significantly different from permanent
*Naser Asl Aminabadi, Professor, Department of Pediatric Dentistry, Faculty
teeth with regards to the cellular content of undifferentiated
of Dentistry, Tabriz University of Medical Science, Tabriz, Iran.
**Boyen Huang, Professor, Department of Pediatric Dentistry, School of mesenchymal stem cells. They contain a rich supply of
Dentistry and Health Sciences, Charles Sturt University, Australia. stem cells in their dental pulp compared to the permanent teeth 1.
***Mohammad Samiei, Associate Professor, Department of Endodontic, Mesenchymal cells may give rise to odontoclastic cells in response
Faculty of Dentistry, Tabriz University of Medical Science, Tabriz, to either the caries process or the pulp-capping material, resulting in
Iran.
the exaggerated inflammatory response and consequently internal
****Sepide Agheli, Postgraduate Student, Department of Paediatric
Dentistry, Faculty of Dentistry, Tabriz University of Medical Science, resorption in primary teeth 2. Pathologic root resorption is the most
Tabriz, Iran. common cause of premature tooth loss in primary dentition, with
*****Zahra Jamali, Assistant Professor, Department of Oral Science, Faculty long-term harmful effects such as space problems in the dental arch,
of Dentistry, Tabriz University of Medical Science, Tabriz, Iran. problems in the eruption of the successor tooth and alterations in
******Sajjad Shirazi, Research Fellow, Dental and Periodontal Research
tongue posture 3.
Center, Faculty of Dentistry, Tabriz University of Medical Science,
Tabriz, Iran. Modern pediatric dentistry seeks novel methods for regeneration
of remaining dental tissues in order to preserve primary teeth and
Send all correspondence to: maintain their developmental, esthetic, and functional capabilities.
For this purpose, the biocompatible materials such as bone morpho-
Naser Asl Aminabadi genetic proteins (BMPs) 4, osteogenic protein–1 (OP-1) 5, demin-
Daneshgah St, Golgasht St, Department of Pediatric Dentistry, Faculty of
Dentistry, Tabriz University of Medical Science, Tabriz, Iran
eralized dentin 6, and mineral trioxide aggregate (MTA) 7,8 have
Phone: +989144157200 been studied previously. Statin components are emerging materials
Fax: +984133346977 in regenerative processes. Local application of simvastatin gel can
E-mail: [email protected] stimulate the regeneration of alveolar bone defects 9. Statins might
[email protected] also improve the function of odontoblasts, thus dentin formation 10.
In addition, statins have an anti-inflammatory effect by decreasing
the production of interleukin-6 and interleukin-8 11.

The Journal of Clinical Pediatric Dentistry Volume 40, Number 2/2016 95

3Mixtatin Compared to MTA in Primary Molars with Inflammatory Root Resorption

Bacterial microleakage as well as the remaining bacteria in the with MTA. The primary outcome of the pilot study was only used
root canal system may cause recurrent symptoms after previous to calculate the sample size and pilot cases were not included in the
endodontic treatment 12. Therefore, the use of antibiotics with the study, in which all procedures and follow-ups were performed by
primary objective of eliminating causative bacteria is quite reason- an experienced pediatric dentist. Considering α = 0.05 and power =
able. A combination of metronidazole, minocycline and ciproflox- 80%, the 15% outcome difference lead to a required sample size of
acin (3Mix) has been used as an endodontic material under the 32 for each group, which was increased to 40 to improve the validity
concept of lesion sterilization and tissue repair (LSTR) therapy. of the study and compensate for probable lost to follow-up. Other
LSTR using 3Mix has been shown to provide an excellent outcome variables including pain, mobility, and radiographic repair were
in treatment of infected canals in primary teeth with periradicular considered as secondary outcomes.
lesions and those with physiological root resorption 13,14. An in vivo Clinical failure parameters were presence of sinus tract,
study has shown that 3Mix penetrates previous root canal obtura- provoked or spontaneous pain, and pathologic tooth mobility.
tion and disinfects lesions 13. It has been also demonstrated that Radiographic failure parameter was expanding periapical or furca-
periradicular radiolucent lesions disappeared or reduced, thus the tion radiolucency. Clinical and radiographic re-examination was
lesions repaired 14. independently performed at 12 and 24-month follow-up by two
This previously unstudied combination was applied with the experienced dentists (not the operator) blinded to the technique.
aims of suppressing bacteria, preventing pulp inflammation, and In case of disagreement, the examination of a third examiner was
inducing hard tissue formation, all leading to preservation of the recorded as the treatment outcome. Tooth mobility and root/furca-
primary teeth that are otherwise indicated for extraction according to tion radiolucency with or without the succedaneous permanent tooth
current guidelines 15. Therefore, the purpose of this ZOE pulpectomy follicle involvement were considered as corresponding clinical and
study was to assess success of pre-treating perforations in hope- radiographic criteria to assess the inter-examiner reliability using
less primary molars with a mixture of three antibiotics combined Kappa agreement coefficient. Teeth were screened for 4 and 6 month
with simvastatin compared to MTA on the repair of bony defects intermediary follow-ups. The flow of participants and pulpectomies
resulting from pulpal infections. We propose the term “3Mixtatin”, were followed from allocation to the final data analysis after 24
an acronym of 3Mix and simvastatin, for the new combination. We months (Fig. 1).
expected to detect significantly superior main outcomes in 3Mixtatin Finally, 80 teeth in 65 children were randomly divided into two
treated teeth compared to that of MTA at 24-month follow-up. groups. Random allocation list was generated using randomization
software (RandList version 1.2; DatIng GmbH, Tübingen, Deutsch-
MATERIALS AND METHOD land; seed number: 1,901,365,632). In 15 children with two teeth
This randomized clinical trial was performed at the Department enrolled in the study, teeth were randomly assigned to one of the
of Pediatric Dentistry, Tabriz University of Medical Sciences, treatment groups using allocation blocks defined in the software.
between April 2012 and April 2013. During a one-month period, The operator was not blinded to the treatment because of different
475 children were screened during the routine examination of chil- manipulation techniques implemented for the studied groups. All
dren to match the inclusion criteria: other contributors to the study were blinded to generation and
• 3-6 year old children with complete physical health without implementation of the treatment assignment.
any confounding medical history including no history of MTA (ProRoot, Dentsply/Tulsa Dental, Tulsa, OK, USA) and
allergic reactions to local or systemic drugs. 3Mixtatin were used in two intervention arms. MTA is widely used
in permanent teeth to seal perforations because of its biocompati-
• Presence of at least one restorable primary molar with
bility and sealability16,17. Further, microscopic examinations of peri-
adequate bone support and no pathology of the succeda-
odontal tissues after perforations in the furcal area and subsequent
neous permanent tooth follicle, indicated for extraction
sealing with MTA has demonstrated repair of the periodontium, and
due to interradicular or periapical root resorption and/or
new cementum formation(cementogenesis) over the material17,18.
perforation in the coronal third of roots as a result of infec-
3Mixtatin was prepared by mixing three commercially available
tive or inflammatory conditions, based on radiographic
antibiotics with simvastatin powder. After removal of the capsules
examination.
or coating materials that enclosed the drug products, they were
• Child’s parents willing to participate in the study. pulverized to fine powders using porcelain mortars and pestles 13,19.
As such teeth are indicated for extraction, the study procedure 100 mg ciprofloxacin (Ruzdarou, Tehran, Iran), 100 mg metroni-
and its alternatives as well as probable risks and benefits of the dazole (Tehranshimi, Tehran, Iran), and 100 mg cefixime (Farabi,
pulpectomy treatment were explained to the parents and written Tehran, Iran) were mixed in a ratio of 1:1:1 13,19. Minocycline was
informed consents were taken. The study design which was in replaced by cefixime because of its contraindication in children.
accordance with the Helsinki Declaration of Human Rights was Pure simvastatin powder was provided by the Faculty of Pharmacy.
submitted to and approved by the Committee for Ethics in Research The measurements were done by an analytical balance with 0.1 mg
on Humans at Tabriz University of Medical Sciences (Trial Number: accuracy. The 3Mixtatin preparation process was trained and super-
IRCT2013071714031N1). vised by a consultant pharmacist. 2 mg of simvastatin were added to
According to the pilot study which was conducted by a the powdered drug mix, which was then stored in a tightly capped
post-graduate student on 14 teeth equally distributed in two groups porcelain container with a small amount of silica gel in a bag to
and followed up for three month, the success rates for sinus tract maintain low humidity. The powder and normal saline were mixed
healing as the primary outcome were 58% with 3Mixtatin and 28% to form a paste of 3Mixtatin upon its clinical application.

96 The Journal of Clinical Pediatric Dentistry Volume 40, Number 2/2016

 3Mixtatin Compared to MTA in Primary Molars with Inflammatory Root Resorption

Figure 1. Flow of participants and pulpectomized teeth.

After screening of 475 patients, 91 primary molars in 75

patients were according to inclusion criteria
11 primary teeth in 10
patients were excluded
because of declining to
80 primary molars in 65 patients were randomly participate
allocated to two groups

Allocation
3Mixtatin MTA
 received intervention (N=40)  received intervention (N=40)

Primary molar (N=37) Primary molar (N=39)

 repair of radiolucency (N=16)  No repair of radiolucency

4 month
 3 dropouts (1 migration to other  1 dropout (migration to other
places and 2 inaccessible patient) places)

Primary molar (N=36) Primary molar (N=38)

 repair of radiolucency (N=28)  No repair of radiolucency

6 month
 1 dropout (migration to other  1 dropout (inaccessible patient)
places)

Primary molar (N=33) Primary molar (N=38)

 repair of radiolucency and no  No repair of radiolucency and 18

clinical sign and symptom (N=32) 12 month clinical signs and symptoms

 3 dropouts (2 migration to other

places, and 1 subject did not attend)

Primary molar (N=32) Primary molar (N=37)

 repair of radiolucency and no  No repair of radiolucency and 18

clinical sign and symptom (N=32) 24 month clinical signs and symptoms

 1 dropout (subject did not attend)  1 dropout (subject did not attend)

Analyzing primary molars (N=32) Analyzing primary molars (N=37)

Analysis
69 pulpectomies in 54 patients were analyzed, excluded from analysis were 11 dropouts (5 migration to
other places, 3 inaccessible subjects, 3 subjects did not attend session)

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3Mixtatin Compared to MTA in Primary Molars with Inflammatory Root Resorption

One pediatric specialist with twelve years of experience (the between the examiners at baseline and 12- month follow-up were
operator) performed all pulpectomies. In both groups, following excellent (Baseline Kappa=0.91, P < 0.001 and 12-month follow-up
administration of local anesthesia and standard isolation using Kappa = 0.94, P < 0.001). There was a statistically significant
rubber dam, caries were removed using a no. 330 bur mounted in difference in the clinical (P = 0.034) and radiographical (P < 0.01)
a water-cooled high-speed handpiece. A round bur in a slow speed characteristics between the two groups in the 12-month follow-up.
handpiece was used to excavate caries. The roof of the pulp chamber At the end of 12 months, in 32 (96.9%) teeth within 3Mixtatin
was removed by joining the pulp horns with the high speed bur cuts. group, the clinical symptoms including gingival swelling and sinus
Remaining radicular pulp was removed using Hedstrom files #15-30 tract disappeared and the patients did not report any pain. Radio-
(Dentsply/Maillefer, Ballaigues, Switzerland). A light flow of sterile graphically, resorption progress arrested and bone healing was
0.9% normal saline solution was delivered by a syringe and needle detected in the same 32 (96.9%) teeth (Fig 2). After 12 months, one
to wash away remaining tissues. The resoption area was cleaned of the teeth in 3Mixtatin group remained symptomatic (Table 2).
with 2% chlorhexidine followed by another sterile saline rinse. Absolute risk reduction values were 0.76, 0.34, 0.34 and 0.96 for
Thereafter, 1% NaOCl was applied using cotton pellet and after pain, mobility, sinus tract and repair of radiolucency respectively.
achieving homeostasis the pulp chamber and canals were rinsed After 12 months in MTA group, clinical symptoms, seen in 18
with normal saline and dried using paper cones. If bleeding could (47.3%) teeth, included pain, mobility and sinus tract in 9 (23.6%),
not be controlled, a dry cotton pellet was placed in the pulp chamber 13 (34.2%) and 13 (34.2%) teeth respectively. All teeth with pain
and tooth was temporized with a temporary filling material (Cavit, and four teeth with mobility also showed sinus tract. In MTA group,
3MESPE DentalAG, Seefeld/Oberbay, Germany). The treatment bone and root/interradicular radiolucency were ceased in 8 (21.0%)
was continued in a second appointment. teeth but none of them were repaired (Table 2) (Fig 2).
3Mixtatin paste was delivered to the perforation or resorption 69 teeth in 54 subjects (23 males, 31 females; mean age = 5.72)
site using small endodontic amalgam carrier and plugger instrument. were re-evaluated at 24 month follow-up (Table 1). The agreement
MTA paste (MTA powder mixed with normal saline) was delivered between the examiners at baseline and 24- month follow-up was
to the perforation site or resorption region using an MTA carrier good (Baseline Kappa=0.91, P < 0.001 and final follow-up Kappa =
(Sybro Endo, Orange, CA, USA), and packed with a cotton pellet 0.86, P < 0.001). There was also a statistically significant difference
moistened with sterile distilled water. A layer of glass-ionomer in the clinical (P = 0.03) and radiographical (P = 0.01) characteris-
cement (Fuji IX, GC, Tokyo, Japan) was applied to seal 3Mixtatin tics between the two groups in the 24-month follow-up (Table 2).
or MTA taking care not to compromise the isolation, in order to At 24-month follow-up, one tooth in the MTA group had
prevent 3Mixtatin or MTA contamination. Conforming to the stan- extensive mobility because of early root resorption and was
dard technique for pulpectomy, a thick mix of zinc oxided-eugenol extracted. In 3Mixtatin group, although one tooth showed slight
(ZOE) was condensed into other areas including the canals using furcal rarefaction, it was not considered treatment failure (Table2)
a root canal plugger and then the pulp chamber using a condenser (Fig 2). Absolute risk reduction values in 3Mixtatin group for pain,
to reach an at least 2 mm thickness 20. Teeth were subsequently mobility, sinus tract and repair of radiolucency were 0.76, 0.34,
restored with a stainless steel crown (Unitek SS Crown-3M Co, 0.34 and 0.91 respectively. In two cases, composite resin resto-
Monrovia, USA), restorative glass ionomer (Dentsply, Weybridge, rations (one case in each group) were replaced with stainless steel
UK), glass-ionomer reinforced amalgam (Permite; SDI Limited, crowns due to the failure of restorations (Table 1).
Bayswater, Australia) or composite resin (Filtek Z250; 3M-ESPE In overall, considering the clinical and radiographical signs
GmbH, Neuss, Germany) restoration according to standard indica- and symptoms in the MTA group during all follow-up visits, 18
tion. A periapical radiograph was taken immediately after treatment. (48.6%) teeth were deemed to be endodontic treatment failures.
Data were described as numbers (%). The main statistical Of these, nine (24.3%) teeth were extracted due to pain and sinus
assessment addressing the research question was chi-square test or tract and one tooth because of premature root resorption. In the
Fisher’s Exact test to compare qualitative data. Data were analyzed remaining 9 teeth with only sinus tract, the parents did not consent
using SPSS software (version 16). P < 0.05 was considered statisti- to an extraction due to no pain. In 3Mixtatin group during the
cally significant. 24-month follow-up, 31 (96.8%) teeth revealed no clinical signs
or symptoms with arrested resorption progress in radiographs.
RESULTS However, one tooth in 3Mixtatin group remained symptomatic
Prior to treatment, pathologic-clinical and radiographical find- between the two follow-ups and was deemed as failure.
ings in 3Mixtatin group were recorded as pain, mobility and sinus
tract in 31 (93.9 %), 19 (57.5%) and 19 (57.5%) teeth respectively. DISCUSSION
Root resorption and perforation were detected radiographically in Structural and molecular differences are reflected by a higher
19 teeth (57.5%) and 21 teeth (63.6%) respectively. In MTA group, susceptibility to root resorption seen in primary teeth. Under-
findings were recorded again as pain, mobility and sinus tract in 29 standing of the mechanisms that protect, control and regulate
(76.3%), 27 (71.0%) and 27 (71.0%) teeth respectively. Radiograph- root resorption may help in maintaining a primary tooth as long
ically, 17 teeth (44.7%) had root resorption and 23 teeth (60.5%) as it is necessary. Thus, this study aimed to preserve the primary
showed perforations. The differences in baseline characteristics teeth with pathologic interradicular or periapical root resorption
were not statistically significant (P > 0.05). and/or perforation by targeting the undifferentiated mesenchymal
71 teeth (Table 1) in 56 subjects (23 males, 33 females; mean age cells leading to odontoblast and osteoblast differentiation and
= 5.36) were re-evaluated at 12-month follow-up. The agreement activation. Simultaneously, action needs to be taken to reduce or

98 The Journal of Clinical Pediatric Dentistry Volume 40, Number 2/2016

 3Mixtatin Compared to MTA in Primary Molars with Inflammatory Root Resorption

Table 1. Clinical characteristics of the study samples at 12 and 24-month follow-up

12-month follow-up 24-month follow-up

Overall MTA 3Mixtatin Overall MTA 3Mixtatin

Pulpectomy 71 38 33 69 37 32

Tooth type

First molar 30 16 14 30 16 14

Second molar 41 22 19 39 21 18

Dental arch

Maxilla 24 14 10 24 14 10

Mandible 47 24 23 45 23 22

Restoration method

Stainless Steel Crown 34 18 16 36 19 17

Composite Resin Restoration 11 5 6 9 4 5

Amalgam Restoration 15 9 6 15 9 6

Glass Ionomer Restoration 11 6 5 11 6 5

Table 2. Frequency (%) of clinical and radiographical signs and symptoms in the study groups

Study groups
Before treatment After 12-month After 24-month
Evaluation criteria
3Mixtatin MTA 3Mixtatin MTA P value 3Mixtatin MTA P value
(n=33) (n=38) (n=33) (n=38) (n=32) (n=37)

Pain 31(93.9) 29(76.3) 0 (0) 9(23.6) 0.003 0 (0) 8(21.6) 0.006

Mobility 19(57.5) 27(71.0) 0 (0) 13(34.2) 0.005 0 (0) 13(35.1) 0.005

Sinus tract 19(57.5) 27(71.0) 0 (0) 13(34.2) 0.005 0 (0) 12(32.4) 0.005

Radiolucency 33(100) 34(89.4)

Cessation of radiolucency progress 32(96.9) 8 (21) <0.001 31(96.8) 7(18.9) <0.001

Repair of
32(96.9) 0 (0) <0.001 31(96.8) 0(0) <0.001
radiolucency

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3Mixtatin Compared to MTA in Primary Molars with Inflammatory Root Resorption

Figure 2. Pulp treatment of a primary molar (A) with 3Mixtatin, immediately after treatment (B) at 12-month (C) and
24-month follow-up (D). Another case (E) treated with 3Mixtatin, immediately after treatment (F) at 12-month
(G) and 24-month follow-up (H). Pulp treatment of a primary molar (I) with MTA, immediately after treatment
(J) at 12-month (K) and 24-month follow-up (L).

eliminate bacterial contamination and inflammation as the main attained by using a mixture of three antibiotics. 3Mix has shown
cause of treatment failure in primary teeth. In 3Mistatin, simvas- to be capable of eliminating bacteria from infected dental tissues
tatin was used as an anti-inflammatory and bioinductive agent in both permanent and primary dentitions31. The bactericidal effi-
and 3Mix served as an antibacterial agent, in an effort to preserve cacy of antibiotics has been shown previously in carious lesions
hopeless primary teeth with root resorption or perforation. of primary teeth, indicating the sterilizing effect of their topical
The overall direction of the obtained results demonstrated an application13,14. The results from in situ experiments suggest that
advantage of 3Mixtatin in preservation of hopeless primary teeth mixed drugs penetrate into the lesions and sterilize them within
with pathologic root/interradicular resorption in the 24-month one day 32. Furthermore, triple antibiotic paste has been used
follow-up. Consistent with our hypothesis, a substantial number successfully in regenerative endodontic treatment and in healing
of teeth in 3Mixtatin group revealed marked healing in the root/ large periradicular lesions33. Current evidence indicates successful
interradicular resorption areas. This outstanding outcome could be outcomes of 3Mix in the treatment of periradicular lesions of
attributed to the bioinductive effects of simvastatin in inhibition of permanent34 and primary teeth21.
bone resorption and osteocyte apoptosis and promotion of osteo- MTA is a more recent material used for pulpotomies and
blast proliferation and differentiation 21. BMP is an inducer for partial pulpectomy showing a superior rate of success. Currently
osteoblastic differentiation from a population of undifferentiated available evidence suggests MTA compared with formocresol,
cells 22. Several studies have shown that statin drugs can specifi- ferric sulfate and calcium hydroxide as a pulpotomy medicament
cally stimulate high levels of BMP-2 expression in osteoblasts 23-26 in primary teeth which results in significantly higher clinical and
which in turn induces the transformation of mesenchymal stem radiographic successes in all time periods up to exfoliation16. MTA
cells into osteoblasts, and thereby, increases the formation of bone has been shown to stimulate the propagation of human osteo-
tissues23,24. It has been shown that statins promote mineralization blasts by offering a biologically active substrate for the cells22,
in non-mineralizing osteoblasts through induction of BMP-2, which may justify the cessation of bone resorption observed in
suppression of osteoclast function and osteocalcin27-29. In addi- the MTA group of this study. However, no repair was seen on the
tion, simvastatin is shown to increase cancellous bone volume, radiographic images of cases treated with MTA, while significant
bone formation rate, and cancellous bone compressive strength 9. improvement was observed radiographically in the cases treated
Moreover, statins stimulate angiogenesis which contributes to the with 3Mixtatin. The superior results of 3Mixtatin compared to
wound healing process 30. Therefore, it is reasonable to assume those of MTA in primary teeth are probably related to the anti-
that all of these pathways lead to the observed bone and root repair bacterial and sterilizing effects along with anti-inflammatory and
and the elimination of clinical symptoms including pain, sinus bio-inductive properties of 3Mixtatin.
tract and mobility the primary teeth treated by 3Mixtatin. Although studies show MTA without matrix provides an effec-
Elimination of the pathogenic microorganisms is an integral tive seal of root perforations and clinical healing of the surrounding
part of pulp treatment in primary teeth. In our study, this goal was periodontal tissue17,35, radiographic results in the MTA group of the

100 The Journal of Clinical Pediatric Dentistry Volume 40, Number 2/2016
 3Mixtatin Compared to MTA in Primary Molars with Inflammatory Root Resorption

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