Journal of Conservative Dentistry
Home About us Editorial Board Instructions Submission Subscribe Advertise Contact e-Alerts Login 
Users Online: 140
Print this page  Email this page Bookmark this page Small font sizeDefault font sizeIncrease font size
 


 
Table of Contents   
REVIEW ARTICLE  
Year : 2015  |  Volume : 18  |  Issue : 1  |  Page : 1-6
Current overview on challenges in regenerative endodontics


1 Department of Conservative Dentistry and Endodontics, Institute of Dental Sciences, Sehora, Jammu and Kashmir, India
2 Department of Physiology, Government Medical College, Patiala, India
3 Department of Conservative Dentistry and Endodontics, Dasmesh Institute of Research and Dental Sciences, Faridkot, Punjab, India

Click here for correspondence address and email

Date of Submission30-Jul-2014
Date of Decision29-Sep-2014
Date of Acceptance23-Oct-2014
Date of Web Publication8-Jan-2015
 

   Abstract 

Introduction: Regenerative endodontics provides hope of converting the non-vital tooth into vital once again. It focuses on substituting traumatized and pathological pulp with functional pulp tissue. Current regenerative procedures successfully produce root development but still fail to re-establish real pulp tissue and give unpredictable results. There are several drawbacks that need to be addressed to improve the quality and efficiency of the treatment.
Aim: The aim of this review article is to discuss major priorities that ought to be dealt before applications of regenerative endodontics flourish the clinical practice.
Materials and Methods: A web-based research on MEDLINE was done using filter terms Review, published in the last 10 years and Dental journals. Keywords used for research were "regenerative endodontics," "dental stem cells," "growth factor regeneration," "scaffolds," and "challenges in regeneration." This review article screened about 150 articles and then the relevant information was compiled.
Results: Inspite of the impressive growth in regenerative endodontic field, there are certain loopholes in the existing treatment protocols that might sometimes result in undesired and unpredictable outcomes.
Conclusion: Considerable research and development efforts are required to improve and update existing regenerative endodontic strategies to make it an effective, safe, and biological mode to save teeth.

Keywords: Endodontics; regeneration; stem cells; tissue engineering

How to cite this article:
Bansal R, Jain A, Mittal S. Current overview on challenges in regenerative endodontics. J Conserv Dent 2015;18:1-6

How to cite this URL:
Bansal R, Jain A, Mittal S. Current overview on challenges in regenerative endodontics. J Conserv Dent [serial online] 2015 [cited 2020 Jul 6];18:1-6. Available from: http://www.jcd.org.in/text.asp?2015/18/1/1/148861

   Introduction Top


The advancement of science and technology has huge positive impacts on the present day world. It has contributed immensely to every aspect of our lives, including the medical and dental care. The treatment concepts that were once perceived to be imaginative are today considered achievable. One of such achievement is regenerative therapy. Regenerative therapy promises numerous clinical dental benefits, including biological strategies to repair teeth and re-grow lost teeth. Present concepts of regeneration of dental tissues can revolutionize the dental health provision. Research on large scale is being conducted worldwide to explore different aspects and feasibility of the regenerative therapy. Wei et al. successfully regenerated a functional bio-root structure for artificial crown restoration by using allogeneic dental stem cells and Vc-induced cell sheet. [1] Researchers have reported successfully functioning tooth in a mouse achieved through the transplantation of bio-engineered tooth germ into the alveolar bone. [2] The ability of stem cells in the mouth of American alligators to regenerate teeth in humans is also being studied. [3]

Regenerative therapy is the future of dentistry and endodontists can be on the leading edge of this new concept. Regenerative endodontics provides the hope of converting the non-vital tooth into vital once again. It focuses on substituting traumatized and pathological pulp with functional pulp tissue. The American Association of Endodontists' Glossary of Endodontic Terms (2012) defines regenerative endodontics as "biologically based procedures designed to physiologically replace damaged tooth structures, including dentin and root structures, as well as cells of the pulp-dentin complex."

This review article focuses on major priorities that ought to be dealt before applications of regenerative endodontics flourish the clinical practice.


   Materials and Methods Top


A web-based research on MEDLINE (www.pubmed.gov) was done. To limit our research to relevant articles, the search was filtered using terms Review, published in the last 10 years and Dental journals. Keywords used for research were "regenerative endodontics" (found 36 articles), "dental stem cells" (found 111 articles), "growth factor regeneration" (found 184 articles), "scaffolds" (found 30 articles), and "challenges in regeneration" (found 24 articles). Relevant articles were chosen to get the desired knowledge update. This review article screened about 150 articles and then the relevant information was compiled.


   A Look Into History Top


The foundation of tooth regeneration was laid when stomatologist G. L. Feldman (1932) proposed that through biological-aseptic principle of tooth therapy, regeneration of pulp might be achieved and used dentine fillings for stimulating pulp regeneration. [4] In 1957, Gavrilov demonstrated regeneration of dentin and cementum of tooth root in dogs. [4] Regeneration of pulp that was key to regenerative endodontic procedures was conceptualized by Ostby in 1961. [5] Subsequent researchers' i.e., Rule and Winter (1966) [6] Nygaard-Ostby and Hjortdal (1971), [7] Ham et al. (1972) [8] further worked in this regard. In 2001, Iwaya et al. described a procedure termed revascularization that resulted in thickening of the root canal walls and continued root development. [9] In 2004, Banchs and Trope proposed a clinical protocol for revascularization of infected immature teeth. [10] These two can be credited for sparking interest in regenerative endodontics.


   Present Scenario of Regenerative Endodontics Top


Various regenerative approaches used in endodontics are root canal revascularization, postnatal stem cell therapy, scaffold implantation, injectable scaffold delivery, pulp implantation, 3D cell printing, and gene therapy. [11] Out of all these, only pulp revascularization approach is presently a clinically feasible while rest other exist in research fields.

The 2011-2012 American Dental Association (ADA) Current Dental Terminology recognized pulp regeneration as an endodontic procedure and gave it code (D3354).

ADA codes for pulpal regeneration procedures

  1. First Phase of Treatment (D3351): Consists of debridement and antibacterial medication
  2. Interim Phase (D3352): Consist of interim medication replacement
  3. Final Phase (D3354): Completion of regenerative treatment in an immature permanent tooth with a necrotic pulp. It does not include final restoration



   Challenges Regenerative Endodontics Is Facing Top


Inspite of the impressive growth in regenerative endodontic field, numerous challenges remain unaddressed as discussed below:

To obtain a sufficient number of autogenous cells for scaffold seeding

To date, five kinds of human dental stem cells are isolated and characterized. These are dental pulp stem cells (DPSCs), stem cells from exfoliated deciduous teeth (SHED), stem cells from apical papilla (SCAP), periodontal ligament stem cells (PDLSCs), and tooth germ progenitor cell (TGPCs). [12]

Although human dental stem cells have promising regenerative therapeutic applications but from a practical prospect, retrieval of autologous dental stem cells is challenging and the prospect of obtaining a sub population of stem cells is even more difficult. Although stem cells are present in all teeth but only limited number of teeth fulfill the criteria of eligibility for stem cell extraction. Deciduous incisors and canines with no pathology and at least one-third of root left are candidates of SHED but most clinical cases possess more than one carious tooth, and also if the teeth take longer time to exfoliate, it may result in more than required resorption of root that contains no pulp, and thus, no stem cells. The DPSCs in adult humans are limited to the availability of the third molars and are not replenished after extraction like the bone marrow. [13] The cells isolated from adult tissues are often difficult to expand in vitro and generally do not maintain their phenotype. [14]

To overcome these issues, other stem cell sources have to be explored. Recent reports describe the presence of mesenchymal stem/progenitor cells with regenerative capabilities in human inflamed pulps [15] and inflamed periapical tissue [16] present intriguing possibilities yet to be explored. RS et al. investigated the possibility of using somatic mesenchymal stem cells (MSCs) from other sources using a bio-mimetic dental pulp extracellular matrix (ECM) incorporated scaffold and found that the dental pulp stem derived ECM scaffold stimulated odontogenic differentiation of PDLSCs and HMSCs without the need for exogenous addition of growth and differentiation factors. Epithelial rests of Malassez (ERMs) are also shown to be capable of undergoing epithelial-mesenchymal transition. [17] Non-dental stem cells for dental application. Cai et al. reported a method for growing teeth from stem cells obtained in urine. [18] In their study, pluripotent stem cells (iPSCs) derived from human urine were induced to generate tooth-like structures in a group of mice in the laboratory. Success rates up to 30% were reported. The generated teeth had physical properties similar to that of normal human teeth except hardness, which was about one-third the hardness of human teeth. The reported advantages to such an approach were being non-invasive technique, low cost, and use of somatic cells (instead of embryonic) that are flushed down the toilet daily. Also urine-derived stem cells do not form tumors when transplanted in the body unlike other stem cells. And sourcing cells from the patient's own body reduces the likelihood of rejection.

Scaffolds

Scaffolds act as carriers for specific cell types and they guide and support tissue regeneration. Scaffolds that have been commonly used for regenerative procedures are natural scaffolds such as collagen, chitosan, silk, fibrin, and synthetic scaffolds such as polyglycolide, polyglycerol sebacate etc. Blood clot, platelet-rich plasma [19] as well as platelet rich fibrin [20] have been recently tried as scaffolds in regenerative endodontics. Many other materials that include natural nanotoliths [21] nanofibers with the microalga Spirulina [22] bacterial cellulose nanocomposite [23] nanofiber scaffold [24] and various fibrin gels [25] have been investigated as potential scaffolds.

Various problems that must be addressed are: Requirement of an appropriate vascularized scaffold to promote formation of large tissue constructs. The size of most tissue engineered constructs is small (1-2mm) due to limited diffusion of nutrients and metabolites in non-vascularized scaffolds. As a consequence, studies using scaffold-based approaches often rely upon in vivo maturation of a small scaffold [26] followed by implantation into the jaw to develop a tooth-like structure. In vitro approaches overcome the problem of limited diffusion by relying upon perfusion [27] or flow-based bio-reactors [28] that facilitate a deeper exchange of molecules within the scaffold.

Microscale technologies that support vascularization and enhance diffusion might help in development of large tissue constructs. Microfabrication has been used to fabricate tissue-engineered scaffolds with micro-engineered capillary beds. [29] Micro- and nano-channels provide passage for diffusion of oxygen and nutrients to support cells in tissue-engineered constructs. Photolithography is one technique in which vascular networks in scaffolds are created by selectively exposing a light-sensitive solution to light by means of a photomask. The exposed solution polymerizes, whereas the unpolymerized masked solution gets washed away resulting in production of micro-channels. [30]

Distribution of cells in scaffold

The association of bio-electrospraying with scaffold production techniques can produce bio-materials with cells homogeneously distributed in the entire structure. [31]

Three-dimensional cell printing technique can be used to precisely position cells and create tissue constructs that mimic the natural tooth pulp tissue structure.

Scaffold-based approaches have the potential for rapid formation of a functional tooth of the correct shape and in the desired location but it has to overcome challenges associated with attachment to the jaw, infection, repetitive movement, and ability to withstand load during maturation. [32] Scaffold-free stem-cell sheet-derived pellet have greater odontogenic potential but require precise control over tooth shape and orientation. Sijia et al. proposed that SCAP-CSDPs with a mount of endogenous ECM can be used in the fabrication of bio-engineered dental roots. [33]

Growth factors

Growth factors act as signals to induce cellular proliferation and/or differentiation. Examples of key growth factors in regenerative dentistry include bone morphogenetic protein, transforming growth factor-beta, fibroblastic growth factor, platelet-derived growth factor (PDGF), and insulin-like growth factor (IGF). Growth factors found dentin [34] are also being investigated for their potential applications.

The major drawback in growth factors is that a different set of growth factors is required to induce stem cells from different sources to achieve specific differentiation. Along with this safety, quantity and time of delivery of the growth factors pose a significant challenge. This problem can be overcome by use of the bio-mimetic ECM embedded scaffold that can be produced in large quantities and are patient specific without complications of immune response and do not require any exogenous growth factor delivery. [35]

Another drawback is application of higher loading levels of growth factors to compensate their physiologic solubility [36] can result in unwanted side effects and limited spatial control. Microencapsulation [37] or binding of these factors to the scaffold [38] can relieve these problems. Also microparticles containing growth factors can be used control the activity of cells. [39]

Advances in disinfection techniques

Disinfection of the root canal spaces of immature teeth is quite challenging, and more effective antimicrobial regimens are required to create a conducive environment. Although triple antibiotic paste (TAP) is established antibiotic paste but it has its own drawbacks. TAP is radiolucent, [40] the vehicle of TAP (propylene glycol) may be difficult to remove from the dentin surface, an additional appointment is required to remove TAP and again opening the tooth to remove TAP introduces risk of recontamination. To overcome these problems better resorbable single or multiple antibiotics, compatible vehicles for delivery and radio-opaque material is necessary for achieving efficient and easy disinfection that could easily be monitored. Antibiotic containing scaffolds can answer such problems.

An electrospun nanofibrous polymeric scaffold with antibiotic incorporated into it, can serve in vitro drug delivery device, for canal disinfection. Its use can improve drug delivery due to its high surface area of the fibers arranged in an interconnecting structure that allows controlled drug release [41] and improve drug adaptation to the canal wall in the regeneration procedure. As the scaffold degrades over time [42] it does not required to be removed, thus reduces appointments and subsequent risk of bacterial contamination. Also, the drug release can be manipulated i.e., made rapid, intermediate, or delayed depending on the polymer used. [43] The effectiveness of an electrospun scaffold as a biologically safe antimicrobial drug delivery system for regenerative endodontics is reported in the literature. [44] Synthetic electrospun polymeric nanofibers are under investigation as drug delivery modes.

Can intracanal antibiotics be substituted for achieving disinfection?

The sole purpose behind intracanal antibiotic medicament is to eliminate microbes. If this motive is achieved by some other means then antibiotics can be avoided. The EndoVac apical negative-pressure system of irrigation can answer. EndoVac delivers irrigating agents safely to the full extent of the root-canal terminus, thereby removing of organic tissue and microbial contaminants effectively. [45] Also, it is the only method capable of cleaning the isthmus area. [46] Thus, creating optimum conditions for regenerative endodontic procedures without the use of antibiotics. Studies have also shown that apical negative pressure with sodium hypochlorite irrigation resulted in similar bacterial reductions as with use of apical positive pressure irrigation and a triple antibiotic in immature teeth [47] and equivalent mineralized tissue formation and the repair process resulted. [48] Additionally, using negative apical pressure and sodium hypochlorite also avoids the risk of drug resistance, tooth discoloration [48] and allergic reactions.

Discoloration

TAP is associated with severe discoloration due to the presence of minocycline in it [49] that binds with the calcium of dentin forming insoluble complexes. To avoid staining while using TAP, the pulp chamber should be sealed with dentine bonding agent and ensure that TAP remains below the cementoenamel junction (CEJ). The clinician should remove residual paste from the pulp chamber and wipe clean it with cotton pellets soaked in absolute alcohol. [50]

Modified TAP in which minocycline is substituted with non-discoloring medicaments like clarithromycin [51] or fosfomycin [51] or cefuroxime [52] or Arestin [53] or cefaclor [54] have shown to be effective in eliminating endodontic pathogens and were able to avoid the permanent staining effect of the crown. Calcium hydroxide can also be used alternatively or EndoVac apical negative-pressure irrigating system along with sodium hypochlorite irrigation can be used to avoid antibiotics completely as described in the disinfection section.

In addition, presence of gray mineral trioxide aggregate (MTA) and white MTA might be another source for discoloration [55] which can be prevented by using alternative tooth-colored bio-active materials like calcium enriched mixture (CEM) cement over the blood clot. [56]

Unpredictable outcome

Guidelines given by ADA for follow-up evaluation of pulp regeneration procedures include clinically asymptomatic and functional tooth. Radiographic evaluation at 6-12 months should show resolution of periapical radiolucency. Increased dentinal wall thickness might also be seen. At 12-24 months, radiograph should show increased dentinal wall thickness along with increased root length.

Based on these guidelines, many success stories have been reported in literature. [57],[58] Recently, Torabinejad and Faras [59] presented clinical, radiographic, and histologic findings showing "pulp-like vital connective tissue" from a tooth after regenerative endodontic treatment done using platelet-rich plasma (PRP) as a scaffold. Similar histological report was presented by Shimizu et al. from a tooth extracted after the completion of regenerative endodontic treatment in which more than one half of the canal was found filled with pulp-like loose connective tissue. [60] Positive response to cold and/or electric pulp tests occurs in some cases. [61] These findings indicate the success of regenerative endodontic procedures.

In contrast to this, literature also reports some cases in which despite following proper protocol, pulp regeneration and root development failed. Lenzi and Trope [62] found empty root canal space after treatment of an immature maxillary central incisor with a necrotic pulp. Nosrat et al.[55] showed the absence of vital tissue inside the root canal space of treated immature maxillary incisors with necrotic pulps after 6 years. Nosrat et al.[63] presented a case where root maturation occurred in a maxillary central incisor, even though a regenerative endodontic procedure resulted in an empty root canal space. Even after using tissue engineering strategies, cementum-like hard tissue was deposited on root canal walls, and bony islands were found throughout the root canals. [64] Formation of a hard-tissue barrier inside the canal between the coronal MTA plug and the root apex [65] is another reported unfavorable outcome.

These findings might not be considered as "clinical failures" but show that the outcome of the current protocol for pulp regeneration might be unpredictable. [66]


   Future Prospective Top


Regenerative endodontic strategies are continuously being updated and improved to benefit dentistry in every possible way. American Association of Endodontists Foundation has recently awarded a grant of $1.7 million [67] to evaluate the effectiveness of two regenerative approaches (REGENDO and REVASC) compared with the conventional MTA apexification. The trial will be carried out in collaboration with Loma Linda University, University of Texas Health Science Center at San Antonio and the University of Maryland School Of Dentistry and is estimated to complete in December 2019. Iohara et al. [68] aims to use pulp stem cells with granulocyte-colony stimulating factor (G-CSF) for pulp/dentin regeneration to fully restore the tooth instead of filling, capping or extracting it. Misako Nakashima (Japan) said that a clinical trial of pulp regeneration has already been initiated with the permission of the Japanese Ministry of Health, Labor and Welfare. Recently, PRF box has been announced [69] to produce homogenously thickened hydrated exudate rich in platelets, vitronectin, leukocytes, and fibronectin expressed from the fibrin clots that have improved the issues regarding the handling of the platelet-rich fibrin (PRF) clot. It is likely that the next advance in regenerative dentistry is the availability of regenerative dental kits, which will enable the dentists the ability to deliver regenerative therapies locally as part of routine dental practice.


   Conclusion Top


Regenerative endodontic strategies have tremendous potential to be an effective, safe, and biological mode to save teeth which have compromised structural integrity provided the above discussed problems are dealt with. Considerable research and development efforts are required to advance the regenerative therapeutics to next level. With new discoveries, innovative ideas, and high-quality research, in the future, the scope of regenerative endodontics might increase to include the replacement of periapical tissues, gingiva, and even whole teeth.

 
   References Top

1.
Wei F, Song T, Ding G, Xu J, Liu Y, Liu D, et al. Functional tooth restoration by allogeneic mesenchymal stem cell-based bio-root regeneration in swine. Stem Cells Dev 2013;22:1752-62.  Back to cited text no. 1
    
2.
Ikeda E, Morita R, Nakao K, Ishida K, Nakamura T, Takano-Yamamoto T, et al. Fully functional bioengineered tooth replacement as an organ replacement therapy. Proc Natl Acad Sci U S A 2009;106: 13475-80.  Back to cited text no. 2
    
3.
Wu P, Wu X, Jiang TX, Elsey RM, Temple BL, Divers SJ, et al. Specialized stem cell niche enables repetitive renewal of alligator teeth. Proc Natl Acad Sci U S A 2013;110:E2009-18.  Back to cited text no. 3
    
4.
Polezhaev LV. Restoration of lost regenerative capacity of dental tissues. Loss and Restoration of Regenerative Capacity in Tissues and Organs of Animals. O. Weiss, Editor. Volume 1. 1 st ed. Jerusalem: Keterpress; 1972. p. 141-52.  Back to cited text no. 4
    
5.
Ostby BN. The role of the blood clot in endodontic therapy. An experimental histologic study. Acta Odontol Scand 1961;19:324-53.  Back to cited text no. 5
[PUBMED]    
6.
Rule DC, Winter GB. Root growth and apical repair subsequent to pulpal necrosis in children. Br Dent J 1966;120:586-90.  Back to cited text no. 6
[PUBMED]    
7.
Nygaard-Østby B, Hjortdal O. Tissue formation in the root canal following pulp removal. Scand J Dent Res 1971;79:333-49.  Back to cited text no. 7
    
8.
Ham JW, Patterson SS, Mitchell DF. Induced apical closure of immature pulpless teeth in monkeys. Oral Surg Oral Med Oral Pathol 1972;33:438-49.  Back to cited text no. 8
[PUBMED]    
9.
Iwaya SI, Ikawa M, Kubota M. Revascularization of an immature permanent tooth with apical periodontitis and sinus tract. Dent Traumatol 2001;17:185-7.  Back to cited text no. 9
    
10.
Banchs F, Trope M. Revascularization of immature permanent teeth with apical periodontitis: New treatment protocol? J Endod 2004;30:196-200.  Back to cited text no. 10
    
11.
Murray PE, Garcia-Godoy F, Hargreaves KM. Regenerative endodontics: A review of current status and a call for action. J Endod 2007;33:377-90.  Back to cited text no. 11
    
12.
Ikeda E, Tsuji T. Growing bioengineered teeth from single cells: Potential for dental regenerative medicine. Expert Opin Biol Ther 2008;8:735-44.  Back to cited text no. 12
    
13.
Ravindran S, Huang CC, George A. Extracellular matrix of dental pulp stem cells: Applications in pulp tissue engineering using somatic MSCs. Front Physiol 2014;4:395.  Back to cited text no. 13
    
14.
Avital I, Feraresso C, Aoki T, Hui T, Rozga J, Demetriou A, et al. Bone marrow-derived liver stem cell and mature hepatocyte engraftment in livers undergoing rejection. Surgery 2002;132:384-90.  Back to cited text no. 14
    
15.
Alongi DJ, Yamaza T, Song Y, Fouad AF, Romberg EE, Shi S, et al. Stem/progenitor cells from inflamed human dental pulp retain tissue regeneration potential. Regen Med 2010;5:617-31.  Back to cited text no. 15
    
16.
Liao J, Al Shahrani M, Al-Habib M, Tanaka T, Huang GT. Cells isolated from inflamed periapical tissue express mesenchymal stem cell markers and are highly osteogenic. J Endod 2011;37:1217-24.  Back to cited text no. 16
    
17.
Xiong J, Gronthos S, Bartold PM. Role of the epithelial cell rests of Malassez in the development, maintenance and regeneration of periodontal ligament tissues. Periodontol 2000 2013;63:217-33.  Back to cited text no. 17
    
18.
Jia B, Chen S, Zhao Z, Liu P, Cai J, Qin D, et al. Generation of tooth-like structures from integration-free human urine induced pluripotent stem cells. Cell Regen 2013;2:6.  Back to cited text no. 18
    
19.
Torabinejad M, Turman M. Revitalization of tooth with necrotic pulp and open apex by using platelet-rich plasma: A case report. J Endod 2011;37:265-8.  Back to cited text no. 19
    
20.
Hotwani K, Sharma K. Platelet rich fibrin-a novel acumen into regenerative endodontic therapy. Restor Dent Endod 2014;39:1-6.  Back to cited text no. 20
    
21.
Olyveira GM, Acasigua GA, Costa LM, Scher CR, Xavier Filho L, Pranke PH, et al. Human dental pulp stem cell behavior using natural nanotolith/bacterial cellulose scaffolds for regenerative medicine. J Biomed Nanotechnol 2013;9:1370-7.  Back to cited text no. 21
    
22.
Steffens D, Lersch M, Rosa A, Scher C, Crestani T, Morais MG, et al. A new biomaterial of nanofibers with the microalga Spirulina as scaffolds to cultivate with stem cells for use in tissue engineering. J Biomed Nanotechnol 2013;9:710-8.  Back to cited text no. 22
    
23.
Xavier Acasigua GA, de Olyveira GM, Manzine Costa LM, Braghirolli DI, Medeiros Fossati AC, Guastaldi AC, et al. Novel chemically modified bacterial cellulose nanocomposite as potential biomaterial for stem cell therapy applications. Curr Stem Cell Res Ther 2014;9:117-23.  Back to cited text no. 23
[PUBMED]    
24.
Mitsiadis TA, Woloszyk A, Jiménez-Rojo L. Nanodentistry: Combining nanostructured materials and stem cells for dental tissue regeneration. Nanomedicine 2012;7:1743-53.  Back to cited text no. 24
    
25.
Galler KM, Hartgerink JD, Cavender AC, Schmalz G, D′Souza RN. A customized self-assembling peptide hydrogel for dental pulp tissue engineering. Tissue Eng Part A 2012;18:176-84.  Back to cited text no. 25
    
26.
Ohazama A, Modino SA, Miletich I, Sharpe PT. Stem-cell-based tissue engineering of murine teeth. J Dent Res 2004;83:518-22.  Back to cited text no. 26
    
27.
Timmins NE, Scherberich A, Fruh JA, Heberer M, Martin I, Jakob M. Three-dimensional cell culture and tissue engineering in a T-CUP (tissue culture under perfusion). Tissue Eng 2007;13:2021-8.  Back to cited text no. 27
    
28.
Jaasma MJ, Plunkett NA, O′Brien FJ. Design and validation of a dynamic flow perfusion bioreactor for use with compliant tissue engineering scaffolds. J Biotechnol 2008;133:490-6.  Back to cited text no. 28
    
29.
Borenstein JT, Weinberg EJ, Orrick BK, Sundback C, Kaazempur-Mofrad MR, Vacanti JP. Microfabrication of three-dimensional engineered scaffolds. Tissue Eng 2007;13:1837-44.  Back to cited text no. 29
    
30.
Wong AP, Perez-Castillejos R, Love JC, Whitesides GM. Partitioning microfluidic channels with hydrogel to construct tunable 3-D cellular microenvironments. Biomaterials 2008;29:1853-61.  Back to cited text no. 30
    
31.
Braghirolli DI, Zamboni F, Chagastelles PC, Moura DJ, Saffi J, Henriques JA, et al. Bio-electrospraying of human mesenchymal stem cells: An alternative for tissue engineering. Biomicrofluidics 2013;7:44130.  Back to cited text no. 31
    
32.
Hacking SA, Khademhosseini A. Applications of microscale technologies for regenerative dentistry. J Dent Res 2009;88:409-21.  Back to cited text no. 32
    
33.
Na S, Zhang H, Huang F, Wang W, Ding Y, Li D, et al. Regeneration of dental pulp/dentine complex with a three-dimensional and scaffold-free stem-cell sheet-derived pellet. J Tissue Eng Regen Med 2013.  Back to cited text no. 33
    
34.
Smith AJ, Scheven BA, Takahashi Y, Ferracane JL, Shelton RM, Cooper PR. Dentine as a bioactive extracellular matrix. Arch Oral Biol 2012;57:109-21.  Back to cited text no. 34
    
35.
Ravindran S, Zhang Y, Huang CC, George A. Odontogenic induction of dental stem cells by extracellular matrix-inspired three-dimensional scaffold. Tissue Eng Part A 2014;20:92-102.  Back to cited text no. 35
    
36.
McKay B, Sandhu HS. Use of recombinant human bone morphogenetic protein-2 in spinal fusion applications. Spine (Phila Pa 1976) 2002;27:S66-85.  Back to cited text no. 36
    
37.
Carrasquillo KG, Ricker JA, Rigas IK, Miller JW, Gragoudas ES, Adamis AP. Controlled delivery of the anti-VEGF aptamer EYE001 with poly (lactic-co-glycolic) acid microspheres. Invest Ophthalmol Vis Sci 2003;44:290-9.  Back to cited text no. 37
    
38.
Lin H, Zhao Y, Sun W, Chen B, Zhang J, Zhao W, et al. The effect of crosslinking heparin to demineralized bone matrix on mechanical strength and specific binding to human bone morphogenetic protein-2. Biomaterials 2008;29:1189-97.  Back to cited text no. 38
    
39.
Cheng J, Teply BA, Jeong SY, Yim CH, Ho D, Sherifi I, et al. Magnetically responsive polymeric microparticles for oral delivery of protein drugs. Pharm Res 2006;23:557-64.  Back to cited text no. 39
    
40.
Hoshino E, Kurihara-Ando N, Sato I, Uematsu, H, Sato M, Kota K et al. In-vitro antibacterial susceptibility of bacteria taken from infected root dentine to a mixture of ciprofloxacin, metronidazole and minocycline. Int Endod J 1996;29:125-30.  Back to cited text no. 40
    
41.
Cui W, Zhou Y, Chang J. Electrospun nanofibrous materials for tissue engineering and drug delivery. Sci Technol Adv Mater 2010;11:014108.  Back to cited text no. 41
    
42.
Moioli EK, Clark PA, Xin X, Lal S, Mao JJ. Matrices and scaffolds for drug delivery in dental, oral and craniofacial tissue engineering. Adv Drug Deliv Rev 2007;59:308-24.  Back to cited text no. 42
    
43.
Kim K, Luu YK, Chang C, Fang D, Hsiao BS, Chu B, et al. Incorporation and controlled release of a hydrophilic antibiotic using poly (lactide-co-glycolide)-based electrospun nanofibrous scaffolds. J Control Release 2004;98:47-56.  Back to cited text no. 43
    
44.
Bottino MC, Kamocki K, Yassen GH, Platt JA, Vail MM, Ehrlich Y, et al. Bioactive nanofibrous scaffolds for regenerative endodontics. J Dent Res 2013;92:963-9.  Back to cited text no. 44
    
45.
Glassman G. Endodontic irrigants and irrigant delivery systems. Roots 2013;1:30-7  Back to cited text no. 45
    
46.
Susin L, Liu Y, Yoon JC, Parente JM, Loushine RJ, Ricucci D, et al. Canal and isthmus debridement efficacies of two irrigant agitation techniques in a closed system. Int Endod J 2010;43:1077-90.  Back to cited text no. 46
    
47.
Cohenca N, Heilborn C, Johnson JD, Flores DS, Ito IY, da Silva LA. Apical negative pressure irrigation versus conventional irrigation plus triantibiotic intracanal dressing on root canal disinfection in dog teeth. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;109:42-6.  Back to cited text no. 47
    
48.
da Silva LA, Nelson-Filho P, da Silva RA, Flores DS, Heilborn C, Johnson JD, et al. Revascularization and periapical repair after endodontic treatment using apical negative pressure irrigation versus conventional irrigation plus triantibiotic intracanal dressing in dogs′ teeth with apical periodontitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;109:779-87.  Back to cited text no. 48
    
49.
Kim JH, Kim Y, Shin SJ, Park JW, Jung IY. Tooth discoloration of immature permanent incisor associated with triple antibiotic therapy: A case report. J Endod 2010;36:1086-91.  Back to cited text no. 49
    
50.
Ahmed HM, Abbott PV. Discolouration potential of endodontic procedures and materials: A review. Int Endod J 2012;45:883-97.  Back to cited text no. 50
    
51.
Mandras N, Roana J, Allizond V, Pasqualini D, Crosasso P, Burlando M, et al. Antibacterial efficacy and drug-induced tooth discolouration of antibiotic combinations for endodontic regenerative procedures. Int J Immunopathol Pharmacol 2013;26:557-63.  Back to cited text no. 51
    
52.
Lenherr P, Allgayer N, Weiger R, Filippi A, Attin T, Krastl G. Tooth discoloration induced by endodontic materials: A laboratory study. Int Endod J 2012;45:942-9.  Back to cited text no. 52
    
53.
Krastl G, Allgayer N, Lenherr P, Filippi A, Taneja P, Weiger R. Tooth discoloration induced by endodontic materials: A literature review. Dent Traumatol 2013;29:2-7.  Back to cited text no. 53
    
54.
Thibodeau B, Trope M. Pulp revascularization of a necrotic infected immature permanent tooth: Case report and review of the literature. Pediatr Dent 2007;29:47-50.  Back to cited text no. 54
    
55.
Nosrat A, Homayounfar N, Oloomi K. Drawbacks and unfavorable outcomes of regenerative endodontic treatments of necrotic immature teeth: A literature review and report of a case. J Endod 2012;38:1428-34.  Back to cited text no. 55
    
56.
Nosrat A, Seifi A, Asgary S. Regenerative endodontic treatment (revascularization) for necrotic immature permanent molars: A review and report of two cases with a new biomaterial. J Endod 2011;37:562-7.  Back to cited text no. 56
    
57.
Thibodeau B. Case report: Pulp revascularization of a necrotic, infected, immature, permanent tooth. Pediatr Dent 2009;31:145-8.  Back to cited text no. 57
    
58.
Thomson A, Kahler B. Regenerative endodontics-biologically-based treatment for immature permanent teeth: A case report and review of the literature. Aust Dent J 2010;55:446-52.  Back to cited text no. 58
    
59.
Torabinejad M, Faras H. A clinical and histological report of a tooth with an open apex treated with regenerative endodontics using platelet-rich plasma. J Endod 2012;38:864-8.  Back to cited text no. 59
    
60.
Shimizu E, Jong G, Partridge N, Rosenberg PA, Lin LM. Histologic observation of a human immature permanent tooth with irreversible pulpitis after revascularization/regeneration procedure. J Endod 2012;38:1293-7.  Back to cited text no. 60
    
61.
Law AS. Considerations for regeneration procedures. J Endod 2013;39:S44-56.  Back to cited text no. 61
    
62.
Lenzi R, Trope M. Revitalization procedures in two traumatized incisors with different biological outcomes. J Endod 2012;38:411-4.  Back to cited text no. 62
    
63.
Nosrat A, Li KL, Vir K, Hicks ML, Fouad AF. Is pulp regeneration necessary for root maturation? J Endod 2013;39:1291-5.  Back to cited text no. 63
    
64.
Yamauchi N, Nagaoka H, Yamauchi S, Teixeira FB, Miguez P, Yamauchi M. Immunohistological characterization of newly formed tissues after regenerative procedure in immature dog teeth. J Endod 2011;37:1636-41.  Back to cited text no. 64
    
65.
Chen MY, Chen KL, Chen CA, Tayebaty F, Rosenberg PA, Lin LM. Responses of immature permanent teeth with infected necrotic pulp tissue and apical periodontitis/abscess to revascularization procedures. Int Endod J 2012;45:294-305.  Back to cited text no. 65
    
66.
Nosrat A, Ryul Kim J, Verma P, S Chand P. Tissue engineering considerations in dental pulp regeneration. Iran Endod J 2014;9:30-9.  Back to cited text no. 66
    
67.
Dental Tribune International jan 29, 2014. New regenerative endodontics study receives almost $2 million.  Back to cited text no. 67
    
68.
Iohara K, Murakami M, Takeuchi N, Osako Y, Ito M, Ishizaka R, et al. A novel combinatorial therapy with pulp stem cells and granulocyte colony-stimulating factor for total pulp regeneration. Stem Cells Transl Med 2013;2:521-33.  Back to cited text no. 68
    
69.
Khiste SV, Tari RN. Platelet-rich fibrin as a biofuel for tissue regeneration. ISRN Biomaterials 2013. Available from: http://dx.doi.org/10.5402/2013/627367 .  Back to cited text no. 69
    

Top
Correspondence Address:
Dr. Aditya Jain
Department of Physiology, Government Medical College, Patiala - 147 001, Punjab
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-0707.148861

Rights and Permissions




 

Top
 
 
 
  Search
 
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Email Alert *
    Add to My List *
* Registration required (free)  
 


    Abstract
   Introduction
    Materials and Me...
   A Look Into History
    Present Scenario...
    Challenges Regen...
   Future Prospective
   Conclusion
    References

 Article Access Statistics
    Viewed7006    
    Printed123    
    Emailed0    
    PDF Downloaded1042    
    Comments [Add]    

Recommend this journal