Aya Sharshar
5th year, OF-13THE OUTCOMES OF REGENERATIVE ENDODONTIC
TREATMENT: LITERATURE REVIEW
Master’s Thesis
Supervisor Doc. Indrė Graunaitė
Annex No. 3 LITHUANIAN UNIVERSITY OF HEALTH
SCIENCES MEDICAL ACADEMY FACULTY OF
ODONTOLOGY DENTAL AND ORAL
DISEASES CLINIC THE OUTCOMES OF REGENERATIVE ENDODONTIC TREATMENT: LITERATURE REVIEW Master’s Thesis
The thesis was done
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Annex No. 8
1. EVALUATION TABLE OF THE MASTER’S THESIS
OF THE TYPE OF SYSTEMIC REVIEW OF SCIENTIFIC LITERATURE Evaluation: ...
Reviewer: ...
(scientific degree. name and surname) Reviewing date: ...
No. MT parts MT evaluation aspects
Compliance with MT requirements and evaluation Yes Partially No 1 Summary (0.5 point)
Is summary informative and in compliance with the
thesis content and requirements? 0.3 0.1 0
2 Are keywords
essence?
in compliance with the thesis
0.2 0.1 0
3 Introduc- tion, aim and tasks (1 point)
Are the novelty, relevance and significance of the
work justified in the introduction of the thesis? 0.4 0.2 0
4 Are the problem, hypothesis, aim and tasks formed
clearly and properly? 0.4 0.2 0
5 Are the aim and tasks interrelated? 0.2 0.1 0
6 Selection criteria of the studies, search methods and strategy (3.4 points)
Is the protocol of systemic review present? 0.6 0.3 0
7
Were the eligibility criteria of articles for the selected protocol determined (e.g., year, language, publication condition, etc.)
0.4 0.2 0
8
Are all the information sources (databases with dates of coverage, contact with study authors to identify additional studies) described and is the last
search day indicated?
0.2 0.1 0
9
Is the electronic search strategy described in such a way that it could be repeated (year of search, the last search day; keywords and their combinations; number of found and selected articles according to
the combinations of keywords)?
0.4 0.1 0
10
Is the selection process of studies (screening, eligibility, included in systemic review or, if applicable, included in the meta-analysis)
described?
0.4 0.2 0
11
Is the data extraction method from the articles (types of investigations, participants, interventions, analysed factors, indexes) described?
0.4 0.2 0
12
Are all the variables (for which data were sought and any assumptions and simplifications made) listed and defined?
0.4 0.2 0
13
Are the methods, which were used to evaluate the
information is to be used in data synthesis, described?
14 Were the principal summary measures (risk ratio,
difference in means) stated? 0.4 0.2 0
15 Systemiza- tion and analysis of data (2.2 points)
Is the number of studies screened: included upon assessment for eligibility and excluded upon giving the reasons in each stage of exclusion presented?
0.6 0.3 0
16
Are the characteristics of studies presented in the included articles, according to which the data were extracted (e.g., study size, follow-up period, type of respondents) presented?
0.6 0.3 0
17
Are the evaluations of beneficial or harmful outcomes for each study presented? (a) simple summary data for each intervention group; b) effect
estimates and confidence intervals)
0.4 0.2 0
18
Are the extracted and systemized data from studies presented in the tables according to individual tasks?
0.6 0.3 0
19
Discussion (1.4 points)
Are the main findings summarized and is their
relevance indicated? 0.4 0.2 0
20 Are the limitations of the performed systemic
review discussed? 0.4 0.2 0
21 Does author present the interpretation of the
results? 0.4 0.2 0
22
Conclusions (0.5 points)
Do the conclusions reflect the topic, aim and tasks
of the Master’s thesis? 0.2 0.1 0
23 Are the conclusions based on the analysed material? 0.2 0.1 0
24 Are the conclusions clear and laconic? 0.1 0.1 0
25
References (1 point)
Is the references list formed according to the
requirements? 0.4 0.2 0
26
Are the links of the references to the text correct? Are the literature sources cited correctly and precisely?
0.2 0.1 0
27 Is the scientific level of references suitable for Master’s thesis? 0.2 0.1 0
28
Do the cited sources not older than 10 years old form at least 70% of sources, and the not older than 5 years – at least 40%?
0.2 0.1 0
Additional sections, which may increase the collected number of points
29 Annexes Do the presented annexes help to understand the
analysed topic? +0.2 +0.1 0
30
Practical recommen-
dations
Are the practical recommendations suggested and
are they related to the received results? +0.4 +0.2 0
31
Were additional methods of data analysis and their results used and described (sensitivity analyses, meta-regression)?
32
Was meta-analysis applied? Are the selected statistical methods indicated? Are the results of each meta-analysis presented?
+2 +1 0
General requirements, non-compliance with which reduce the number of points
33
General require- ments
Is the thesis volume sufficient (excluding annexes)?
15-20 pages (-2 points)
<15 pages (-5 points)
34 Is the thesis volume increased
artificially? -2 points -1 point
35 Does the thesis structure satisfy the requirements of Master’s thesis? -1 point -2 points
36 Is the thesis written in correct language,
scientifically, logically and laconically? -0.5 point -1 points
37 Are there any grammatical, style or
computer literacy-related mistakes? -2 points -1 points
38 Is text consistent, integral, and are the
volumes of its structural parts balanced? -0.2 point -0.5 points
39 Amount of plagiarism in the thesis. >20%
(not evaluated) 40
Is the content (names of sections and sub- sections and enumeration of pages) in compliance with the thesis structure and aims?
-0.2 point -0.5 points
41
Are the names of the thesis parts in compliance with the text? Are the titles of sections and sub-sections distinguished logically and correctly?
-0.2 point -0.5 points
42 Are there explanations of the key terms
and abbreviations (if needed)? -0.2 point -0.5 points
43
Is the quality of the thesis typography (quality of printing, visual aids, binding) good?
-0.2 point -0.5 points
*In total (maximum 10 points): *Remark: the amount of collected points may exceed 10 points. Reviewer’s comments:
2. Table of Contents
FIRST TITLE PAGE (ANNEX NO.2) ... SECOND TITLE PAGE (ANNEX NO. 3) ... EVALUATION TABLE OF SYSTEMIC REVIEW OF SCIENTIFIC LITERATURE (ANNEX NO. 8)
SUMMARY ...
1. INTRODUCTION ... 1
2. LITERATURE REVIEW ... 2
2.1. PRINCIPLE FEATURES OF REGENERATED PULP TISSUE: ... 3
2.2. RET: DEFINITION, AIM, AND PREDICTABLE OUTCOMES: ... 3
2.3. TERMINOLOGY:REVASCULARIZATION AND REVITALIZATION,REGENERATION AND REPAIR: ... 4
2.4. RET:CELL-FREE APPROACH: ... 4
2.5. ENDOGENOUS STEM/PROGENITOR CELL TYPES: ... 5
2.6. BLOOD-DERIVED SCAFFOLDS FOR CF-RET: ... 5
2.7. GROWTH FACTORS: ... 5
2.8. THE PRINCIPLE OF CLINICAL RET: ... 6
2.9. LIMITATIONS OF REGENERATIVE ENDODONTIC THERAPY: ... 7
3. RESEARCH METHODOLOGY AND METHODS. ... 8
THE OUTCOMES OF REGENERATIVE ENDODONTIC TREATMENT: LITERATURE REVIEW
SUMMARY
In this literature review the outcomes of regenerative endodontic treatment based on Cell-free approach will be discussed as a future alternative to the traditional treatments for immature necrotic permanent teeth.
Aim: analyze clinical and radiographical outcomes of regenerative endodontic treatment. Material and methods: the electronic databases PubMed and Science Direct were used
additionally to manual selection for relevant studies to the topic after applying specific inclusion and exclusion criteria. Studies that fulfilled both the inclusion and exclusion criteria were included in this systematic review after full text screening.
Results: there is an increasing in root length, dentin wall thickness and presence of apical closure
and resolution of periapical lesions with almost complete resolution of clinical symptoms in all studies using Cell-Free approach. Knowing that the highest score recorded was for PRP, PRF, Bio-Gide collagen membrane, and BC respectively.
Conclusion: Based upon the included studies we can state the following:
1. CF‐RET has been widely used in clinics to treat immature permanent teeth with necrotic pulps/apical periodontitis, since its easier to deal with in addition to the source of scaffolds and growth factors which are taken from the host’s blood.
2. For necrotic immature permanent teeth, revascularization/revitalization utilizing PRP/PRF is a highly successful method and showed excellent 12-months prognosis.
3. Longer follow up period might have been required for pulp sensibility test to display positive reaction.
Keywords: Regenerative endodontic, revascularization, revitalization, outcomes, necrosis
1
1. INTRODUCTION
The loss of pulp vitality either because of infection or trauma will increase fragility of the tooth due to its important role. Traditional clinical protocol employed in cases with infected/necrotic
immature permanent teeth was termed ‘apexification’ and involving placing either Calcium Hydroxide (Ca(OH)2) as an intra‐canal medicament or Mineral Trioxide Aggregate (MTA) as a synthetic barrier. For CA(OH)2, it eliminates the intra‐radicular infection then induce an apical barrier over time. [1]. Whereas MTA is applied as a synthetic barrier on which hard tissue barrier is formed. The advantage of MTA is sometimes completed in one or two appointments comparing to Ca(OH)2 that might need multiple visits. However, ‘apexification’ techniques with either placement of Ca(OH)2 or MTA generally are not allowing the continuation of root development, gaining vitality and functionality in addition to the greater risk of fracture as a consequence of thin dentinal walls that might lead to premature loss of the tooth eventually. [2].
Case studies have shown that healing of apical periodontitis, continuing development of the root apex and increased thickness of the root canal wall of immature teeth with pulpal necrosis can occur after regenerative endodontic treatment (RET). [3]. Since its biologically based treatment on replacing damaged structures as cells of pulp-dentin complex.
Furthermore, Cell-Free regenerative endodontic treatment (CF-RET) as one of RET approaches, does not deliver or use exogenous cells or any iatrogenic material in the host’s pulp system, since it supports certain processed scaffold materials, growth factors, drugs, or the mix of them to be used clinically to assist tissue regeneration. Host derived materials like blood clot, platelet-rich
plasma/fibrin are often used as a scaffold and source of the growth factors that used in CF-RET approach after being obtained from the host clinically [4].
Aim: analyze clinical and radiographical outcomes of regenerative endodontic treatment. Tasks:
1. to discuss and elaborate about the regenerative endodontic treatment.
2
2. Literature review
Caries is that the most typical reason behind pulp-periapical diseases. When the pulp tissue is involved in caries, it becomes irreversibly inflamed and then necrotic. So, the treatment option is root canal therapy because the infected necrotic pulp within the root canal system isn't accessible to the host’s innate and adaptive immune defense mechanisms and antimicrobial agents.. [5]
As permanent immature teeth with necrotic pulp and periapical diseases are a constant problem and area of keen interest for endodontists since its complicated case with few obstacles including the difficulty of achieving root canal disinfection in these teeth using endodontic files of standard protocol, another difficulty arises during root canal filling due to lack of apical barrier in open apex and its impingement on periodontal tissues. And even if these challenges are faced and sorted out, the roots of those teeth are very thin and in a high risk of fracture. Various treatment possibilities are described in literature to form hard tissue barrier at the apex for instance the apexification using either Ca(OH)2 or MTA). [6]
For apexification using Ca (OH)2, studies have reported to own a good outcome. However, there are certain limitations related to this system. The main disadvantage is that the long duration of about 6-8 months required for the formation of hard tissue apical barrier, and follow-up every 3 months to check the progression of barrier formation. Additionally, this technique also tends to decrease the fracture resistance of the root dentine. Thus, there is always a possibility of root fracture before hard tissue formation. On other hand, apexification with MTA has also gained popularity among clinicians since its less time-consuming but lack regenerative capability and long-term survival is additionally guarded due to reduced fracture resistance.
3 In this literature review, the author would like to introduce briefly the fundamental information needed to answer the subjective question about ‘the outcomes of RET that make it superior to the traditional treatment?’.
2.1.Principle features of regenerated pulp tissue:
As known, dental pulp consists of loosely connective tissue enclosed within rigid dentine walls. Moreover, the lining of pre-dentine within the dental pulp contains blood vessels, nerves, and odontoblasts , which could help supply nutrients, react to infection, and form reactionary dentin, thus maintaining pulp homeostasis. [7]. So, the connection of regenerated blood vessels around the tooth with periapical or bone marrow tissues should be established in order to receive a regular blood flow from circulation and provide nutrient to the other regenerated tissue and dentin. Additionally, the regenerated tissue has to be innervated, so the teeth are able to sense hot/cold stimulation and also pain during infection. [8]. Therefore, the main principles of regenerated tissues:
(i) Produce new dentin with a rate similar controlled as the normal pulp.
(ii) Should exhibit similar cell density and architecture to the natural pulp.
(iii) Regenerated tissue needs to be vascularized.
(iv) Regenerated tissue needs to be innervated. [9]
2.2.RET: definition, aim, and predictable outcomes:
The stated definition of RET according to [10] is “a biologically based procedures designed to physiologically replace damaged tooth structure, including dentin and root structures, as well as the pulp-dentin complex.”
4
2.3.Terminology: Revascularization and Revitalization, Regeneration and Repair:
The first case report which described an endodontic procedure to maintain or regenerate vitality stated this approach as ‘revascularization’ [11]. However, the precise definition of
‘Revascularization’ in the medical field is a surgical procedure to restore the blood supply of ischemic tissue due to blockage or severance of vessels. So, the immediate replantation of an avulsed tooth may lead to reconnection or anastomosis of some vessels and the blood supply may be re-established and thus revascularized. Whereas angiogenesis is defined as the growing and dividing of existing vessels to establish new vessels. [12]. So, revascularization is not an optimal term for regeneration process, and the term ‘Revitalization’ is more suitable to use just in case of neo-vascularization of the tissue within the canal after CF-RET strategy been performed. Generally, for ‘Regeneration’ term it’s used to describe the ability of an organism to recreate lost or damaged tissues or organs to their original form and function. Despite this, histological studies both in animals and extracted teeth from patients which had received regenerative endodontic procedures provide evidence that the tissue formed inside the root canal contains elements of pulp tissue (fibroblasts, connective tissue, blood vessels, collagen), but other cell types are missing
(odontoblasts), and nontargeted cell types or tissue could also be present within the root canal such as osteoblasts and cementum [13] [14] [15]. Therefore, tissues mostly found in those canals imply that, what takes place in some cases will not be regeneration but healing or ‘Repairing’, which is defined as tissue formation with a (partial) loss of the original tissue function.
2.4.RET: Cell-free approach:
5
2.5.Endogenous stem/progenitor cell types:
The source of cells may come either from a far-off site like bone marrow, where cells are low in number and unlikely to play a very important role in pulp regeneration. Or Local and adjacent site of stem cells located within the apical papilla or periapical tissues are a crucial cell source to migrate into the canal space. Regardless the location, endogenous stem can be introduced into the canal space by 1) induction of periapical bleeding via formation of blood clot (BC).
2) growth factors present within the blood after induction of periapical bleeding.
2.6.Blood-derived scaffolds for CF-RET:
A scaffold basically is a framework or structural element that holds cells or tissues together and provides a three-dimensional environment for tissue formation and might also work as a reservoir of growth factors [16]. A blood clot consists of platelets and a meshwork of fibrin, which is a scaffold for cell attachment, migration, and proliferation in RET.
PRP or PRF has been recommended as an alternative to the blood clot used in regenerative endodontics [17]. Since PRP or PRF is taken and prepared from the patient’s blood, is rich in growth factors, and have been introducing a beneficial effect in tissue wound healing. Studies of PRP and PRF employed in CF-RET of immature permanent teeth with necrotic pulps/apical
periodontitis have shown promising outcomes including resolution of apical periodontitis, increased in canal wall thickness, continuation of root development and apical root closure [18] [19] [20] [21] [22] [23]. However, no histological studies have confirmed yet that regeneration of the pulp–
dentine complex can occur in necrotic immature permanent teeth using PRP or PRF. [4].
2.7.Growth factors:
6
2.8.The principle of clinical RET:
If cell homing is applied in endodontic treatment, then there are principally three clinical procedure: (i) Disinfection and enlargement of apical foramen.
(ii) Transplantation of bioactive scaffold with signaling molecules additional to tooth restoration.
(iii) Follow-up regularly in order to check the viability (neovascularization and re-innervation) of the regenerated tooth pulp.
When pulp inflammation process is ongoing, various oral and food-borne microorganisms invade the pulp space, forming biofilm on canal walls, and infiltrating the dentinal tubules [24]. Therefore the regeneration needs the pulp space and dentinal walls to be sufficiently disinfected before the performance of pulp regeneration procedures, and also the desired degree should be more than in traditional endodontic therapy [25]. This recommendation through disinfection irrigants (solutions) and intracanal medicaments, which could be either temporary calcium hydroxide or double/triple antibiotic paste. The disinfection process in REP starts with the use of irrigants, primarily sodium hypochlorite but also it can include saline, hydrogen peroxide or chlorhexidine. Sodium
hypochlorite solution particularly has excellent potency and antibacterial properties (bactericidal) with an efficient concentration shown to be ideally 5.25% for non-surgical root canal treatments. Disinfection continues with the use of an intracanal medicament placed within the root canal and sealed with a restorative material to permit its function for a period of time. Ca(OH)2 is an
intracanal medicament used temporarily between appointments thanks to its antibacterial effect and its ability to decrease bacteria further significantly within root canals after a disinfection irrigant has been used previously.
7
2.9.Limitations of RET:
1. The treatment is very sensitive technique and requires substantial training; evoking bleeding and placement of the biomaterial over an unstable blood clot will be challenging. The procedure may be more time-effective than an MTA apexification for the clinician. Also, obturation of the apical third of an immature tooth can sometimes be very difficult and time-consuming than obturating the coronal third.
2. Tooth discoloration is very common either due to the minocycline with using TAP or the MTA barrier placed at the cemento-enamel junction (CEJ). Its considered to be the main issue for most patients during recall appointments. However, discoloration can be decreased through the use of DAP (i.e., metronidazole and ciprofloxacin), Ca(OH)2 as an intracanal medicament between appointment, or by using other biocompatible materials, such as Biodentin as a barrier.
3. In case of post & core placement is needed, RET do not provide adequate space as the MTA barrier is placed at the CEJ level. Therefore, to achieve the best of both worlds, first could consider RET in order to achieve further root development and apical closure, then followed by root canal treatment and post & core placement.
8
3. Research methodology and methods.
3.1.Search methods:
Electronic search using two of common databases are PubMed (done 20/07/2020, updated 14/02/2021) and Science Direct (done 11/02/2021, updated 28/02/2021) additionally to manual selection through different medical journals (done 10/04/2021). Studies with no free-access were accessed through the online library of the Lithuanian University of Health Science ‘s EZproxy.
3.2.Selection criteria:
Randomized controlled trials studies of RET intervention that aimed to analyse the outcomes of immature permanent necrotic teeth population were considered eligible after following inclusion criteria mentioned below:
1. Articles assisting tooth/teeth survival as a primary outcome in the terms of tooth vitality and function, clinical and radiographic resolution of periapical radiolucency.
2. Articles assisting root maturation as a secondary outcome in the terms of increasing root wall thickness and/or length and/or decreasing in apical diameter (apical closure).
3. Done on vivo/Human models. 4. Studies published in English.
Furthermore, studies were excluded if had any of following criteria: 1. Animal studies.
2. Other study designs than what is selected.
3. Studies assisting different population than immature necrotic permanent tooth/teeth.
4. studies have not performed quantitative assessment of root length and/or width and/or apical diameter changes.
5. Studies were done in vitro/in situ. 6. Studies were not published in English. 7. Studies were published before 2016.
3.3.Search strategy:
9 ▪ P: (population); patients have necrotic immature permanent teeth.
▪ I: (intervention); Regenerative/revascularization/revitalization endodontic treatment. ▪ C: (comparison); Stem-cell based Vs Molecular-cell based RET.
▪ O: (outcomes); in terms of periapical bone healing (PBH), root development (RD) and pulp vitality.
Note that PICOs Index (Table 1) has been used to include more keywords synonymous regenerated by the researcher in order to find more articles.
3.1.Table 1 PICOs Index
PICO item Keywords PubMed
11 Vital pulp 2,418 Root maturation 6,937 Root development 79,120 Total O (Combination with OR) 2,948,931 Combination of PICO items P (P1+ P2) +I +C +O (Combination with AND) 1,154 Final result after filtration Showing articles were published not before 2016. 384
While articles are found during the search on Science Direct database were using keywords and short sentences placed in the search box i.e., outcomes of regenerative endodontic treatment, immature non-vital permanent teeth, immature inflamed permanent teeth, pulp revascularization,.. will described with its corresponding results below in Table 2.
3.4.Table.2
Keywords Results
Outcomes of regenerative endodontic treatment 79 Immature non-vital permanent teeth 201 Immature inflamed permanent teeth 231
Pulp revascularization 64
Pulp revitalization 56
Final results before filtration 631 Final result after filtration; Showing articles
were published not before 2016.
296
3.5.Study selection:
Among the 1,793 articles selected using the keywords aforementioned in databases and medical journals, duplicated or unrelated records (N = 636) were excluded, and unduplicated or related records were (N=1157). Records (N=966) were excluded after title/abstract screening phase, whereas records (N=191) were retrieved to exclude additional records (N=13) then full text screening was done for the rest of the records (N=168) to include eventually records (N=7) as it shows at the flowchart diagram in Figure 1 that summarise the selection process of the studies included in this systematic review. Furthermore, the total records of 7 are found in Table 3 at which more info regarding each study is analysed primarily in the methodology table. Followed by the analysis of the results found in Table 4.a, Table 4.b, Table 4.c, and Table 4.d respectively regarding the follow-up periods of 3 months, 6 months, 9 months, and 12 months.
3.6. Quality assessment risk:
12
13 3.7.Methodology table 3. Article Samp le size Rand omiza tion Blindi ng Interventi on Comparat or Instru mentat ion Irrigation
ICM D Outcomes Measuring tool F-U
1st visit 2nd visit [31] 30 Yes Doubl e blind PRP PRF Was avoide d 2% NaOCl (20 mL/canal) + EDTA 17% (20 mL/canal) 20 mL sterile Saline + EDTA 17% (20 mL/canal) TAP 3 W a) increase root length and width. b) Sensibility test. C) increase in bone density measurements. d) decrease in apical diameter. a) Periapical x-ray using J image software version 1.44. b) Statistical analysis using SPSS version 19 c) Pulp vitality testers 3, 6, 9 and 12 Mons [32] 88 Yes No PRP PRF PP BC No 20 mL 1.25% NaOCl 2% chlorhexidin e +10 mL sterile saline + 1 mL 17% EDTA TAP 4 W a) increase in root length b) increase in root width c) pulp vitality a) Periapical x-ray using Image J and Turboreg
b) Pulp vitality testers
14 variance (ANOVA) [33] 46 Yes Blind Obser ver RET with Bio-Gide collagen membrane scaffolds RET without Bio-Gide collagen membrane No 1.25% NaOCl (20 mL, 5 Min) + saline (20 mL/canal, 5 Min). 20 mL 17% EDTA. Ca(OH)2 paste 2 w a) Resolution of the periapical lesion b) Absence of any clinical sign or symptom. c) Root length d) Dentin wall thickness e) Apical foramen a) Periapical radiograph in JPEG format were transferred to ImageJ software (version 1.41) and Turboreg. b) Electrical pulp test. c) Microsoft Excel (Microsoft, Redmond, WA) spreadsheet. d) SPSS software (Version 20). From 7 to 28 Mons [34] 60 Yes Triple blinde d PRP PRF BC minim ally 5.25% NaOCl --- TAP 3 W a)continuation of root development. b) increase in the dentin wall thickness and narrowing of canal space. c) apical closure. d) resolution of the periapical lesion. e) response to pulp sensibility testing and response to a) Periapical Index (PAI).
15 percussion and palpation tests. [35] 30 Yes A Split Mout h Doubl e-blinde d PRP BC No 2% NaOCl (20 mL/canal, 5 Min) + EDTA 17% (20 mL/canal, 5 Min) 10-mL sterile physiologic al saline + 17% EDTA (20 mL/canal, 5 Min) TAP 3 W a)Primary outcome measured clinically were pain, mobility, swelling, and sinus/fistula. b) Radiographic outcome included increased root length and increase in root thickness, increase in bone density measurements and a decrease in apical diameter. c) discoloration and sensibility test a)periapical radiograph Image J software. b) (SPSS statistical version 19) c) Wilcoxon signed-rank test d) The Mann– Whitney U test e) Student's t test f) pulp sensibility tests (thermal (cold/heat), and electric pulp tester)
16 [36] 118 Yes --- RET Apexi ---
20 mL 1.5% NaOCl solution + 0.9% physiologic al saline, + 20 mL 17% EDTA 0.9% saline (for RET) + 20 mL 17% EDTA TAP for RET & Ca(OH)2 for Apexi 3 W a)Clinical symptoms such as pain, swelling, sinus tract, mobility, tooth discoloration, and the occlusion relationship. b) disappearance of apical radiolucency. c)increase of root length d) decrease of the apical foramen a)Periapical radiographic b)CBCT c) SPSS Statistics 17.0 3, 6, 9, and 12 Mons [37] 30 Yes A Split-mouth Doubl e-blind PRF BC --- 2% NaOCl + EDTA 17% physiologic al saline + EDTA 17% TAP 3 W a)Primary outcomes measured were sinus/fistula formation, pain complaint, mobility grade, and swelling presence/absence . b) Radiographic: root length elongation and increase in root thickness. c) sensibility test and crown color.
17
3.8.Result table 4.a.
Article
Results of 3 Month follow-up Root length
(mm, %)
Apical closure (mm, %)
Root wall thickness (mm, %)
Apical lesion (PAI)
#Pulp vitality
(thermal &electrical tests)
#Clinical symptoms Resolution [31] PRP*=0.225± 0.19 (1.52%±1.43%) PRF**=0.155± 0.099 (1.02%±0.673%) PRP=0.25 ±0.167 (9.91%±6.03%) PRF=0.34 ±0.2 (15.7%±8.84%) PRP= 0.153± 0.128 (6.03%±5.03%) PRF=0.19494± 0.172 (7.9%±6.2%) --- PRP=Neg - PRF=Neg -
For both, resolution
of pain, swelling, mobility and sinus/fistula.
PRF may need longer follow-up than PRP. [22] # In (%) only PRP=4.74±0.91 PRF=6.00±1.57 PP=4.17±1.33 BC=7.15±1.39 #CMAC: in (%) 73.9% (n= 54) #OGAC: 4.1% (n= 3) #RAG: PP = (82.4%) BC = (76.2%) PRF = (70.6%) PRP = (66.7%) #NSRD: 21.9% (n=16) # in (%)only: PRP=19.01 ± 4.20 PRF=9.80 ± 3.03 PP=8.55 ± 3.55 BC=14.91± 3.38
--- 1 case of PRF and I case of BC
showed failure with spontaneous pain and extreme sensitivity to percussion at 13 and 14 months of follow-up.
The rest clinically and
radiographically asymptomatic.
[33] # Con=all 22 increased
but only 5 CD.
E= all 21 increased but
only 8 CD. # Con= 91% (20/22) E= ALL # in apical 3rd Con= 91% (20/22). E= 86% (18/21) In middle 3rd Con= 55% (12/22) E= ALL --- Posi + : Con= 18% (4/22) E= 33% (7/21)
All cases were asymptomatic with complete resolution of signs and symptoms by the end of the treatment. #CD: Con= 64% (14/22) E= 71% (15/21) #PC: Con= 55% (12/22) E= 48% (10/21) [34] --- --- --- --- --- ---
18 PRP= 0.225 ± 0.19 (1.52% ± 1.43%) BC= 0.133 ± 0.217 (0.967% ± 1.75%) PRP= 0.25 ± 0.167 (9.91%±6.03%) BC= 0.137 ± 0.063 (6.06% ± 3.7%) PRP= 0.153 ± 0.128 (6.03% ± 5.03%) BC= 0.133 ± 0.27 (5.45% ± 9.48%)
in primary clinical outcomes (resolution of pain, swelling, mobility, and sinus/fistula). Regarding secondary clinical outcomes, BC group showed a higher crown discoloration than PR group, with significant difference between the groups. [36] --- --- --- --- --- A total of 30 RET cases showed
discoloration, mainly occurring in the first 3 months after treatment, whereas diffused calcification was found in 26 RET cases, the majority of which occurred at the 6-month follow-up. [38] PRF= 0.155 ± 0.099 (1.02% ± 0.673%) BC= 0.104 ± 0.081 (0.668% ± 0.507%) PRF= 0.34 ± 0.2 (15.7% ± 8.84%) BC= 0.274 ± 0.163 (11.98% ± 6.8%) PRF= 0.19494 ± 0.172 (7.9% ± 6.2%) BC= 0.133 ± 0.127 (6.3% ± 7.6%)
19
3.9.Result table 4.b
Article
Results of 6 Month follow-up Root length
(mm, %)
Apical closure (mm, %)
20
3.10. Result table 4.c
Article
Results of 9 Month follow-up Root length
(mm, %)
Apical Diameter (mm, %)
21
3.11. Result table 4.d
Article
Results of 12 Month follow-up Root length
(mm, %)
Apical closure (mm, %)
Root wall thickness (mm, %)
Apical lesion (PAI)
Pulp vitality
(thermal &electrical tests)
Clinical symptoms resolution [31] PRP=1.48± 0.37 (9.88%±2.85%) PRF=1.24± 0.54 (8.19%±3.64%) PRP=2.49 ±3.93 (64.83%±18.5%) PRF=1.73 ±0.665 (76.75%±8.5%) PRP=0.97 ±0.75 (39.27%± 32.04%) PRF=1.003± 0.392 (42.37%±16.49%) --- --- --- [22] --- --- --- --- A total of 63 teeth (86%) = posi+ after an average follow-up time of 28.25 ± 1.2 months. --- [33] --- --- --- --- --- --- [34] Chi-square test**
Chen and Chen Index: T1= GrA;2, GrB;2, GrC;2. T2= GrA;2, GrB;3, GrC;2. T3= GrA;10, GrB;8, GrC;12. T4= GrA;1, GrB;0, GrC;0. T5= GrA;1, GrB;1, GrC;0. No change= GrA;4, GrB;1, GrC;3. Chi-square test** CH in (N) GrA= 15 GrB= 12 GrC= 19 INCH (N) GrA= 3 GrB= 3 PAI(4) failure for 2 in GrA (Posi +) GrA= 15% GrB=13.3% GrC= 15.8% (Neg -) GrA= 85% GrB= 86.7% GrC= 84.2% A total of 18 patients in Group A, 15 patients in Group B and 19 patients in Group C showed a successful clinical outcome.
Two patients in Group A showed a failure outcome as their PAI score was 4 even though they were clinically
asymptomatic G
r
22 A 30 35 35 A 30 40 30 B 26.7 60 13.3 B 20 73.3 6.7 C 26.3 47.4 26.3 C 26.3 57.9 15.8 [35] PRP= 1.48 ± 0.37 (9.88% ± 2.85%) BC= 0.68 ± 0.44 (4.68% ± 3.45%) PRP= 2.49 ± 3.93 (64.83% ± 18.5%) BC= 2.2 ± 3.97 (53.45% ± 19.4%) PRP= 0.97 ± 0.75 (39.27% ± 32.04%) BC= 0.68 ± 0.678 (25.56% ± 26.5%)
--- Negative for all teeth. ---
[36] RET= 1.64 ± 1.43mm Apex= 0.60 ± 1.06mm RET= 1.49 ± 0.96mm Apex= 1.85 ± 0.67mm RET= 0.24 ± 0.25mm Apex= 0.08 ± 0.21mm The periapical lesions disappeared in all cases (100%) --- At the 12-month follow-up, all the teeth survived (100% survival rate) and were asymptomatic (100%). [38] PRF= 1.24 ± 0.54 (8.19% ± 3.64%) BC= 0.608 ± 0.228 (3.93% ± 1.46%) PRF= 1.73 ± 0.665 (76.75% ± 8.5%) BC= 1.47 ± 0.63 (64.6% ± 11.6%) PRF= 0.903 ± 0.392 (39.37% ± 16.49%) BC= 0.74 ± 0.54 (39.07% ± 35.22%)
--- All treated teeth were negative to sensibility test.
Blood clot displayed greater crown discoloration in comparison to PRF group
** Results labeled above are evaluated to be G; good, S; satisfactory, or No; no change according to:
Strict criteria of success (absence of pain, inflammation or swelling and conventional radiograph showing complete healing and presence of a normal
periodontal ligament space).
Loose criteria of success {absence of pain, inflammation or swelling and conventional radiograph showing complete healing and presence of a normal
23
3.12. Result table 5
Articles Randomization process.
Deviation from intended interventions effect of assignment to intervention Deviation from intended interventions effect of adhering to intervention Missing outcome data. Measurement of the outcomes. Selection of the reported results. Overall bias.
[31] Low risk Some concerns Low risk Low risk Low risk Low risk Some
concerns
[32] High risk Some concerns Low risk Low risk Low risk Low risk High risk
[33] High risk High risk High risk Low risk Low risk Low risk High risk
[34] Low risk Low risk Low risk Low risk Low risk Low risk Low risk
[35] Low risk Low risk Low risk Low risk Low risk Low risk Low risk
[36] High risk Low risk High risk Low risk High risk High risk High risk
24
4. Discussion
This literature review was conducted to summarize and appraise all appreciated studies published within the period from 2016 up to date regarding the selected study design of RCTs to answer the subjective question of the research ‘What are the outcomes of RET that make it superior to the traditional treatment?’.
Starting with the mean age of the selected cases for RET as an important factor based on which we can assume the success possibility of the treatment. The mean age was recommended for pulp regeneration is 5-15 years old due to the greater healing capacity and the presence of more stem cells potential for regeneration [39] [40]. On other hand, regarding some case reports [41] [42] [43] [44] the recommended age range is 8-16 years old since regenerative endodontic treatment
procedure should not be performed on deciduous teeth, because of the possible risk of impairing the eruption pattern of permanent teeth. [43]. So the mean age range of cases including in this review was (8 to 14) years old in five records [31] [35] [38] [22] [33], And (6 to 28) years old for the remaining two records [36] [34].
Mentioning other, apex diameter. Since a tooth with an open apex allows the migration of
mesenchymal stem cells into the root canal space that could allow host cell homing to form a new tissue in the root canal space [45] [46]. An apical opening of 1.1 mm in diameter or larger is beneficial, with natural RET occurring in approximately 18% to 34% of teeth with immature roots. [47]. Regarding all the studies conducted in this review, this factor was considered as one of the eligibility criteria. According to the recommended protocol stated by the European Society of Endodontology consists of the provision of the procedure over two appointments, is briefly outlined into following: [48]:
o Phase 1
• Access to the non-vital pulp under local anesthesia and aseptic techniques • Minimal mechanical disturbance of any pulp tissue in the canal
• Disinfection by irrigants
• Disinfection by intracanal medicaments (TAP or Ca(OH)2) • Provide a coronal seal.
o Phase 2 – (2-4 weeks after phase 1)
25 o Confirmation of success of phase 1:
• Access to the pulp under local anesthesia (without any vasoconstrictor component to allow bleeding induction) and aseptic techniques.
• Irrigate with 17% EDTA solution (chelating agent).
• Induce bleeding, via instrumentation, through the apex to fill the root canal with blood. • Place a collagen matrix above the formed blood clot.
• Seal with MTA followed by the placement of a resin composite.
In this literature review, treatment success was demarcated as tooth survival as a primary outcome in the terms of clinical and radiographical resolution of periapical radiolucency, tooth vitality, and well-functioning. Also, root maturation as secondary outcome in the terms of increasing root wall thickness and/or length and/or decreasing in apical diameter (apical closure). Note that discoloration and root calcification were not considered failure as it is inevitable in pulp regeneration cases.
4.1.Primary Outcomes:
The overall management of infection in all seven studies resulted in survival of all teeth and elimination of all clinical signs of infection due to the standard disinfection was established by the combined use of a sodium hypochlorite irrigant (1.25-5.25%) with either a temporary Ca(OH)2 intracanal medicament in [36] with apexification group and in [33], or TAP as it’s used in the rest of included studies. One study [22] used 2% chlorhexidine gel together with the sodium
26 Negative results to pulp sensibility test could be either due to long-standing periapical disease in cases with periapical radiolucency which have retarded neural regeneration, coronally present MTA layer which act as insulator, or the need of >12 months for complete formation of blood vessels and nerve fibers within the root canal [50]. Only study showed 100% pulp vitality was [22] after an average follow-up time of 28.25 ± 1.2 months.
For teeth discoloration, the percentage of teeth found in BC group is greater and statistically not significant than in PRF group for all time points. The results were in line with [51] & [52]. Scaffold could play a role in discoloration by their interacting with MTA during setting. Blood by itself could lead to discoloration by the accretion of hemoglobin in dentin. Staining of MTA is usually visible when material sets in interaction with red blood cells (RBCs) [53]. It could be hypothesized that iron ions and development of calcium aluminoferrite may cause discoloration. Alternative method to prevention discoloration could be using scaffold without RBCs, such as PRF. Additionally, almost complete healing and resolution of periapical radiolucency resulted of
existence lesion in all included studies according to Periapical Index (PAI) [54] which assessing the periapical status based upon score number given.
4.2. Secondary Outcomes:
In all the included studies the continuation of root development, increasing of root dentin walls, and decreasing of apical diameter have been observed by periapical radiograph with almost no
27 Additionally, in other studies was shown that the concentration of platelet in PRP is more than 1 million/ml, which is five times as higher than that of normal platelet count [55].
It is a concentrated suspension of different growth factors like platelet derived growth factor, transforming growth factor b, insulin like growth factor, vascular endothelial growth factor, epidermal growth factor, and epithelial cell growth factor and has been mentioned as an ideal scaffold for regenerative endodontic procedures. [56]. On other hand, PRF is an ideal scaffolding material for regeneration because, it is easy to prepare, requires no biochemical handling of blood and hence it is purely autologous in nature unlike PRP which requires biochemical processing of blood after drawing 10-15 ml blood from the patient.
For Bio-Gide collagen membrane in [33], All patients showed clinical success with complete resolution of signs and symptoms. Radiographically, the thickness of the dentin wall at the middle third of the root was higher for the group used Bio-Gide than the group did not use it. Additionally, Bio-Gide helped in gaining pulp vitality in seven patients comparing to the control group. The convenience of operation and the assured positioning of the sealing material make the Bio-Gide collagen membrane suitable especially for wide canal.
5. Acknowledgment:
I would like to thank my supervisors Dr. Indrė Graunaitė for all her help and advice with this master’s thesis.
6. CONFLICT OF INTERESTS:
The author reports no conflicts of interest.
7. Conclusion
Based upon the included studies and their corresponding follow-up periods we can conclude: 1) CF‐RET has been widely used in clinics to treat immature permanent teeth with
necrotic pulps/apical periodontitis, since it’s easier to deal with in addition to the source of scaffolds and growth factors which are taken from the host’s blood.
2) For necrotic immature permanent teeth, regeneration/revitalization utilizing PRP/PRF is a highly successful method and showed excellent 12-months prognosis.
28
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32
Annex No. 3 EVALUATION OF THE FINAL MASTER’S THESIS
(identification No. of the thesis) Reviewer’s Examination Form
Length of the thesis: no. of pages: ; no. of sources in the list of literature: ; no. of table(s): ; no. of figure(s): ; no. of annex(-es): .
No. Fulfilment of the structural and methodological criteria for the thesis Evaluation Yes No 1. The thesis consists of at least 20 pages (excluding annexes)
2. The thesis contains all the necessary structural elements 3. Titles of chapters and sections are clearly seen
4. The thesis is well-written, logical and concise 5. There are no grammatical errors
6. The volume of the thesis has not been artificially increased 7. Literature references have been cited correctly
8. The bibliography has been produced properly
9. At least 70% of the cited references are less than 10 years old 10. Tables, figures and annexes are presented correctly
Evaluation criteria of the Final Master’s Thesis Evaluation (on a 1–10-point scale)
11. Literature analysis: the latest and most relevant literature sources are analysed; the key claims of the topic under investigation and research problems are presented.
12. Aim and objectives: relevance of a selected scientific problem is
explained, the raised hypotheses are described and explained properly, aim and objectives are formulated correctly.
13. Methodology: a detailed explanation of the research methodologies is provided, the research instruments are described, an appropriate data collection method is selected and suitable statistical methods for
addressing the set objectives are applied
14. Results: the presented results are relevant in respect of the research topic. Analysis of the results is presented properly
15.
33
16. Conclusions: The findings are relevant to and consistent with the thesis topic and objectives; conclusions are biased on the results obtained;
suggestions and practical recommendations are submitted Final evaluation (mean average of 11-16 point evaluation)
Reviewer’s comments and questions:
Strengths of the Final Master’s Thesis:
Weaknesses of the Final Master’s Thesis:
Evaluation of the Final Master’s Thesis:
Can be presented / can be presented after corrections
Can be presented for the defence; evaluation of (on a 5–10-point scale) Cannot be presented for the defence; evaluation of (on a 1–4-point scale)
34
Annex No. 4
EVALUATION OF THE FINAL MASTER’S THESIS Evaluation Form of the Evaluation Commission Member
Final Master’s Thesis title: by the postgraduate from Group of the Medical Study Programme
Evaluation Criteria of the Final Master’s Thesis Presentation
No. Statements of the final master’s thesis evaluation Evaluation (on 1–10-point scale)
1. The primary research problem of the final master’s thesis is formulated and the aim and objectives are stated
2. The work methodology is explained; the main research instruments and data collection methods are indicated
3. Statistical or other methods for the implementation of the set objectives are clearly specified
4. Research results are presented clearly
5. Any visual material displayed is clear and informative 6. Conclusions are based on the achieved results and are
associated with the set tasks and objectives
7. Practical recommendations are presented (where possible) 8. The presentation has a logical progression
9. The fundamental idea of the final master’s thesis corresponds to the nature of the Medical Study Programme
10. Ability to present the thesis
Final evaluation (mean evaluation on a 1–10-point scale)
Comments of FMT Evaluation Commission member:
35 Annex No. 5
--- Department
THE EVALUATION JOURNAL FOR THE MASTER’S THESIS OF THE MEDICAL INTEGRATED MASTER’S STUDY PROGRAMME
Date of the defence ... Evaluation Commission: 1. 2.
3. 4.
The thesis is evaluated by 3 members of the Evaluation Commission. If the thesis supervisor is included in the Evaluation Commission, he/she cannot participate in the evaluation.
Student name, surname Evaluation by the reviewer Evaluation by the member of the Evaluation Commission (1) Evaluation by the member of the Evaluation Commission (2) Evaluation by the member of the Evaluation Commission (3) Final evaluation Evaluation ... ... Surname Evaluation... ... Surname Evaluation... ... Surname Evaluation... ... Surname
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